Robert Phillip Baughman

Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline

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Abstract

Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure.

Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability.

Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality.

Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.

Diagnostic Evaluation of Suspected Extrapulmonary Disease

Question 1: Should Lymph Node Sampling Be Performed in a Patient Presenting with Asymptomatic Bilateral Hilar Lymphadenopathy?

Question 2: Should Patients with Suspected Sarcoidosis and Mediastinal and/or Hilar Lymphadenopathy, for Whom It Has Been Determined That Tissue Sampling Is Necessary, Undergo EBUS-guided Lymph Node Sampling or Mediastinoscopy as the Initial Mediastinal and/or Hilar Lymph Node Sampling Procedure?

Question 3: Should Patients with Sarcoidosis Who Do Not Have Ocular Symptoms Undergo Screening for Ocular Sarcoidosis by Routine Eye Examination?

Question 4: Should Patients with Sarcoidosis Who Do Not Have Renal Symptoms Undergo Screening for Renal Sarcoidosis by Routine Serum Creatinine Testing?

Question 5: Should Patients with Sarcoidosis Who Do Not Have Hepatic Symptoms Undergo Screening for Hepatic Sarcoidosis by Routine Transaminase and Alkaline Phosphatase Testing?

Question 6: Should Patients with Sarcoidosis Who Do Not Have Symptoms or Signs of Hypercalcemia Undergo Screening for Abnormal Calcium Metabolism by Routine Serum Calcium and Vitamin D Testing?

Question 7: Should Patients with Sarcoidosis Undergo Screening for Hematological Abnormalities by Routine Complete Blood Cell Count Testing?

Question 8: Should Patients with Sarcoidosis Who Do Not Have Cardiac Symptoms or Signs Undergo Routine Screening for Cardiac Sarcoidosis using ECG, TTE, or 24-Hour Ambulatory ECG Monitoring?

Question 9: Should Patients Who Are Suspected of Having Cardiac Sarcoidosis Undergo Cardiac MRI, TTE, or PET as an Initial Imaging Test?

Question 10: Should Patients with Sarcoidosis Who Are Suspected of Having PH Undergo TTE?

In patients for whom there is a high clinical suspicion for sarcoidosis (e.g., Löfgren’s syndrome, lupus pernio, or Heerfordt’s syndrome), we suggest NOT sampling lymph nodes (conditional recommendation, very low-quality evidence). Remarks: Patients who do not undergo lymph node sampling require close clinical follow-up.

For patients presenting with asymptomatic, bilateral hilar lymphadenopathy, we make no recommendations for or against obtaining a lymph node sample. Remarks: If lymph node sampling is not obtained, close clinical follow-up is a reasonable alternative approach.

For patients with suspected sarcoidosis and mediastinal and/or hilar lymphadenopathy for whom it has been determined that tissue sampling is necessary, we suggest endobronchial ultrasound (EBUS)-guided lymph node sampling, rather than mediastinoscopy, as the initial mediastinal and/or hilar lymph node sampling procedure (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis who do not have ocular symptoms, we suggest a baseline eye examination to screen for ocular sarcoidosis (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis who have neither renal symptoms nor established renal sarcoidosis, we suggest baseline serum creatinine testing to screen for renal sarcoidosis (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis who have neither hepatic symptoms nor established hepatic sarcoidosis, we suggest baseline serum alkaline phosphatase testing to screen for hepatic sarcoidosis (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis who have neither hepatic symptoms nor established hepatic sarcoidosis, we make no recommendation for or against baseline serum transaminase testing.

For patients with sarcoidosis who do not have symptoms or signs of hypercalcemia, we recommend baseline serum calcium testing to screen for abnormal calcium metabolism (strong recommendation, very low-quality evidence).

If assessment of vitamin D metabolism is deemed necessary in a patient with sarcoidosis, such as to determine if vitamin D replacement is indicated, we suggest measuring both 25- and 1,25-OH vitamin D levels before vitamin D replacement (conditional recommendation, very low-quality evidence).

We suggest that patients with sarcoidosis undergo baseline complete blood cell count testing to screen for hematological abnormalities (conditional recommendation, very low-quality evidence).

For patients with extracardiac sarcoidosis who do not have cardiac symptoms or signs, we suggest performing baseline ECG to screen for possible cardiac involvement (conditional recommendation, very low-quality evidence).

For patients with extracardiac sarcoidosis who do not have cardiac symptoms or signs, we suggest NOT performing routine baseline transthoracic echocardiography (TTE) or 24-hour ambulatory ECG (Holter) monitoring to screen for possible cardiac involvement (conditional recommendation, very low-quality evidence). Remarks: The panel recognizes the low risks attendant to the use of TTE or Holter to screen for cardiac sarcoidosis. Thus, these tests should be considered on a case-by-case basis.

For patients with extracardiac sarcoidosis and suspected cardiac involvement, we suggest cardiac magnetic resonance imaging (MRI), rather than positron emission tomography (PET) or TTE, to obtain both diagnostic and prognostic information (conditional recommendation, very low-quality evidence).

For patients with extracardiac sarcoidosis and suspected cardiac involvement who are being managed in a setting in which cardiac MRI is not available, we suggest dedicated PET, rather than TTE, to obtain diagnostic and prognostic information (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis in whom pulmonary hypertension (PH) is suspected, we suggest initial testing with TTE (conditional recommendation, very low-quality evidence). Remarks: “PH is suspected” refers to clinical manifestations, including exertional chest pain and/or syncope, exam findings of a prominent P2 or S4, reduced 6-minute walk distance, desaturation with exercise, reduced D l _CO, increased pulmonary artery diameter relative to ascending aorta diameter (e.g., by computed tomography [CT] scan), elevated brain natriuretic factor, and/or fibrotic lung disease.

For patients with sarcoidosis in whom PH is suspected and a transthoracic echocardiogram is suggestive of PH, we suggest right heart catheterization to definitively confirm or exclude PH (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis in whom PH is suspected and a transthoracic echocardiogram is NOT suggestive of PH, the need for right heart catheterization should be determined on a case-by-case basis (best practice statement).

The purpose of this clinical practice guideline is to make recommendations that address uncertainties that are commonly confronted by clinicians relating to the diagnosis and detection of sarcoidosis. The target audience is pulmonary, rheumatology, or other clinicians who manage patients with suspected or confirmed pulmonary sarcoidosis. This guideline was developed by an ad hoc committee of experts from the American Thoracic Society with guidance from experienced methodologists to objectively identify and summarize the best available evidence. The quality of the evidence was poor in most cases, reflecting the need for additional high-quality research to guide clinical practice. As such, clinicians, patients, payers, and other stakeholders should not consider these recommendations as mandates. Moreover, no guideline or recommendation can consider all potential clinical circumstances. Thus, clinicians are encouraged to apply the recommendations within the clinical context of each individual patient, including the patient’s values and preferences, and on the basis of regional factors, such as the prevalence of alternative diagnoses or consideration of alternative diagnostic approaches when the preferred diagnostic modality is unavailable.

A multidisciplinary panel of experts in sarcoidosis was composed to construct clinically important questions related to diagnostic testing for sarcoidosis. Systematic reviews were then performed to inform recommendations that answered each question. The panel used the Grading of Recommendations, Assessment, Development, and Evaluation approach to formulate and grade the strength of the recommendations. The guideline included three patients who participated on the guideline panel and provided perspective on patient values and preferences. A detailed description of the methods, including the implications of the strengths of the recommendation (i.e., strong vs. conditional) and the meaning of best practice statements, are described in the online supplement. The guideline underwent anonymous peer review by four content experts and one methodologist. After multiple cycles of review and revision, the guideline was reviewed and approved by a multidisciplinary board of directors. The guideline will be reviewed by the American Thoracic Society 3 years after publication, and it will be determined if updating is necessary.

The diagnosis of sarcoidosis is not standardized, but is based on three major criteria: a compatible clinical presentation, the finding of nonnecrotizing granulomatous inflammation in one or more tissue samples (not always required, as discussed subsequently here), and the exclusion of alternative causes of granulomatous disease. Presently, there are no established objective measures to determine if each of these diagnostic criteria has been satisfied, and, therefore, the diagnosis of sarcoidosis is never fully secure. In this section of the article, these three diagnostic criteria will be discussed separately.

The clinical presentation of sarcoidosis exhibits a spectrum of manifestations ranging from the asymptomatic state to that of progressive and relapsing disease. Disease progression often leads to pulmonary impairment or, in some cases, death due to complications of progressive pulmonary fibrosis or from cardiac involvement, including sudden cardiac death (arrhythmias) or congestive heart failure (myocarditis). The global health implications of sarcoidosis remain unknown, but new evidence indicates that the disease is much more prevalent than previously estimated (1), and mortality among patients with sarcoidosis is much higher than previously reported in some patient populations (e.g., 2.4-times higher mortality in African American women with sarcoidosis compared with a matching cohort without sarcoidosis [2]). There is great variability in the number of organs clinically involved with sarcoidosis, which adds to diagnostic uncertainty based on highly variable clinical presentations. Whereas many sarcoidosis cases are a diagnostic dilemma, certain clinical features of sarcoidosis are considered so highly specific for the disease that they have been deemed diagnostic (3). These include Löfgren’s syndrome (4), lupus pernio (5), and Heerfordt’s syndrome (6). Other features have been strongly associated with sarcoidosis, such as bilateral hilar adenopathy in patients without B symptoms (fevers, night sweats, and weight loss) (7).

To standardize organ involvement in sarcoidosis, consensus criteria were originally established in 1999 (8) and updated in 2014 (9). These instruments assumed that the patient had known sarcoidosis, and assessed the probability of specific organ involvement. The 2014 document was sponsored by the World Association of Sarcoidosis and Other Granulomatous Disorders. In that document, the criteria for sarcoidosis involvement of each organ were established on the basis of consensus among sarcoidosis experts using a structured Delphi methodology, and the confidence of organ involvement was further qualified on a scale of highly probable, probable, or possible. Consensus for a specific criterion was considered achieved if more than 70% of the experts agreed. Some clinical features failed to reach a consensus. Two recent reports using similar methodology from groups of sarcoidosis experts have developed clinical criteria for the diagnosis of cardiac (10) and neurologic sarcoidosis (11).

Table 1 provides a summary of clinical features and related relative probabilities supporting a diagnosis of sarcoidosis based on history, physical examination, imaging, and laboratory testing. This table is not an exhaustive list of the clinical manifestations of sarcoidosis, but encompasses clinical features of sarcoidosis that are relatively common and specific enough to inform the clinical suspicion of the disease. In recognition of the central role of imaging during the initial assessment of interstitial lung diseases, as briefly summarized in Table 1, we refer the interested reader to a more comprehensive review of this topic (12). This table has also simplified certain criteria from the more detailed World Association of Sarcoidosis and Other Granulomatous Disorders document (8), such as by combining various forms of uveitis under one heading.

Table 1. Clinical Features Supportive of a Diagnosis of Sarcoidosis

Definition of abbreviations: ACE = angiotensin-converting enzyme; AV = atrioventricular; AVNB = atrioventricular node block; CM = cardiomyopathy; CNS = central nervous system; CT = computed tomography; CXR = chest X-ray; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PET = positron emission tomography; VT = ventricular tachycardia.

*Löfgren’s syndrome is defined as bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis.

† Abnormal vitamin D metabolism is defined as normal to low parathyroid hormone, normal to elevated 1,25-dihydroxyvitamin D, and normal to low 25-hydroxyvitamin D.

‡ ACE elevated above 50% of the upper limit of normal was considered abnormal.

Table 1 does not account for the presence of multiple clinical features for the diagnosis of sarcoidosis that may reinforce the diagnosis of sarcoidosis beyond that when only one feature is present. Nevertheless, we endorse the proposed list of clinical features to aid clinicians during the initial diagnostic evaluation of patients with suspected sarcoidosis.

Given that the clinical manifestations of sarcoidosis are often nonspecific, histological evaluation of tissue granulomas is often required to establish the diagnosis. Histological features that are typical of a sarcoidosis granuloma include the presence of well-formed, concentrically arranged layers of immune cells, most prominent being the central core of macrophage aggregates and multinucleated giant cells. An outer layer of loosely organized lymphocytes, mostly T cells, is often observed with a few interposed dendritic cells. In some cases, the granulomas are surrounded by isolated collections of B lymphocytes. Sarcoidosis granulomas are most often nonnecrotic; however, variants of sarcoidosis, particularly the nodular pulmonary sarcoidosis phenotype, can present with a mixture of necrotic and nonnecrotic granulomas (13).

The differential diagnosis of granulomatous diseases is broad, as noted in the next section. Table 2 and Figure 1 provide histopathological features that are useful for discriminating sarcoidosis from other causes, although histopathologic features alone cannot distinguish sarcoidosis from other granulomatous diseases. Certain granulomatous diseases may have similar histological features, such as berylliosis (chronic beryllium disease).

Table 2. Key Pathological Features of Sarcoidosis

Figure 1. Comparison of pulmonary sarcoidosis granuloma histology to other granulomatous lung diseases. (A) Typical sarcoidosis histology with well-formed granulomas comprised of macrophage aggregates (G) and featuring multinucleated giant cells (white arrows, inset), with minimal surrounding lymphocytic inflammation (L). (B) Hypersensitivity pneumonitis featuring smaller granulomas (G) with more extensive surrounding lymphocytic alveolitis (L). (C) A large acellular necrotizing granuloma (NG) caused by pulmonary Histoplasma capsulatum infection.

To ensure diagnostic accuracy of sarcoidosis, the differential diagnosis must be considered and alternative diagnoses reliably excluded during the initial diagnostic evaluation or in presumed established sarcoidosis cases with atypical clinical features, such as those refractory to immune suppression treatment. Although tissue histopathology may reveal an alternative diagnosis ( Figure 1 ), granulomas found in patients with sarcoidosis have no unique histologic features to differentiate them from all other granulomatous diseases. The diagnosis of sarcoidosis, therefore, requires a complete history and physical examination and, when indicated, additional testing to exclude other disorders, especially those that also produce granulomas (14). The differential diagnosis of sarcoidosis is typically categorized into granulomatous disorders of infectious and noninfectious causes (Table 3 provides representative examples of each). An alternative schema classifies these diagnoses according to the affected organ system(s) (Table 4).

Table 3. Key Infectious and Noninfectious Differential Diagnoses for Granulomatous Lesions within Commonly Biopsied Sites

Definition of abbreviations: ACE = angiotensin-converting enzyme; Ag = antigen; EIA = enzyme-linked immunoassays; ANCA = antineutrophil cytoplasmic antibody; CCP = cyclic citrullinated peptide; CVID = common variable immune deficiency; EBV = Epstein-Barr virus; EGPA = eosinophilic GPA; GI = gastrointestinal; GLILD = granulomatous–lymphocytic interstitial lung disease; GLUS = granulomatous lesions of unknown significance syndrome; GPA = granulomatosis with polyangiitis; LIP = lymphocytic interstitial pneumonia; MAC = Mycobacterium avium complex; M. kansasii = Mycobacterium kansasii; MPA = microscopic polyangiitis; MPO = myeloperoxidase; p-ANCA = perinuclear ANCA; PR3 = PR3-ANCA; PET = positron emission tomography; TNF = tumor necrosis factor.

*More commonly found alternative diagnoses for granulomatous disease in U.S. populations. The differential diagnosis should be prioritized on the basis of the individual’s clinical history and presentation.

Table 4. Key Differential Diagnoses for Sarcoidosis within Individual Organ Systems

Definition of abbreviations: ANCA = antineutrophil cytoplasmic antibody; CNS = central nervous system; NK = natural killer; NSAIDs = nonsteroidal antiinflammatory drugs.

Tuberculosis (TB) and atypical mycobacterial infections can mimic sarcoidosis. These infections can be screened for by staining biopsies for acid-fast bacilli and latent TB infection can be detected by performing IFN-γ release assay testing or delayed-type hypersensitivity skin testing to TB antigens, as was previously recommended as a standard approach in patients with suspected sarcoidosis (14). It should be noted that false-negative IFN-γ release or skin test results can occur in those with acutely active forms of TB or sarcoidosis due to concurrent T-cell anergy; thus, negative test results should be interpreted with caution (15). When possible, sputum smear and culture for acid-fast bacilli (16) and molecular testing (17) for mycobacterial species is encouraged for patients residing in areas endemic for TB. Fungal infections (e.g., histoplasmosis) should also be considered in those with suspected sarcoidosis, including staining biopsies for fungal infections. Tissue culture, culture of BAL fluid, antigen detection in urine and/or blood, and serologic tests for fungal-specific antibodies may be used to confirm the diagnosis (18).

Additional testing for other infectious and noninfectious etiologies is guided by clinical and/or radiologic findings (Tables 3 and 4). Hypersensitivity pneumonitis and chronic beryllium disease should be considered in patients with a history of occupational and/or environmental exposures associated with these disorders. The blood lymphocyte proliferation test is diagnostic for chronic beryllium disease (19). Although BAL fluid analysis is insufficient to establish a specific diagnosis of any interstitial lung disease, BAL can be useful for excluding infections or malignancy or to identify cellular patterns suggestive of eosinophilic or hypersensitivity pneumonitis (20).

Sarcoidosis-like granulomatous reactions have been described in numerous clinical conditions and in association with several medications, including immunotherapeutics, such as immune checkpoint inhibitors, anti–TNF-α (tumor necrosis factor-α), and other immune modulating drugs (21). Sarcoid-like reactions to tumor should be considered in patients with granulomatous adenopathy who are suspected of having malignancy or in those with a recent or concomitant history of neoplasm (22). Erdheim-Chester, a histiocytic disorder with clinical and radiologic features similar to sarcoidosis, may be differentiated from sarcoidosis on the basis of histopathologic staining for the CD68 marker (23). The small-vessel antineutrophil cytoplasmic antibody–associated vasculitides (especially granulomatosis with polyangiitis) may affect the upper and lower airways, similar to sarcoidosis. Most patients with these vascular inflammatory diseases, however, exhibit MPO and/or PR3 antineutrophil cytoplasmic antibodies.

Patients with common variable immune deficiency may develop noncaseating granulomas in lymphoid or solid organs, referred to as granulomatous–lymphocytic interstitial lung disease, which mimics multiorgan sarcoidosis. Granulomatous–lymphocytic interstitial lung disease due to common variable immune deficiency should be suspected in patients with apparent sarcoidosis who have hypogammaglobulinemia, a history of recurrent sinopulmonary infections, autoimmune disease, or splenomegaly. IgG4-related disease may resemble pulmonary sarcoidosis (bilateral hilar adenopathy and/or lung nodules on CT of the chest) and extrapulmonary, multiorgan sarcoidosis (24); pathology can usually differentiate IgG4-related disease from sarcoidosis (25). Elevated serum IgG4 levels (high IgG4:IgG ratio) is present in approximately 66% of patients with IgG4 disease (26), and elevated tissue plasma cell IgG4 may further differentiate this disorder from sarcoidosis.

Question 1: Should Lymph Node Sampling Be Performed in a Patient Presenting with Asymptomatic Bilateral Hilar Lymphadenopathy?

Isolated involvement of mediastinal and hilar lymph nodes is a common presentation of sarcoidosis, and is readily detected by a routine chest X-ray. Many such patients are asymptomatic, and sarcoidosis is only suspected on the basis of radiographic testing for an unrelated reason. Patients with sarcoidosis with asymptomatic lymph node involvement generally have self-limited disease, and do not require treatment. However, the finding of enlarged hilar and mediastinal lymph nodes during radiographic testing is often alarming to healthcare providers and patients alike, primarily out of concern for an alternative diagnosis, such as occult malignancy or latent infection. Previous studies have reported that asymptomatic bilateral hilar lymphadenopathy is almost always caused by sarcoidosis (27), and, given the benign nature of this phenotype, there is clinical equipoise for pursuing diagnostic sampling in such patients.

Our systematic review identified 2,106 potentially relevant articles; the full text of 75 was reviewed. One study reported enrolling patients with bilateral hilar lymphadenopathy, but included both symptomatic and asymptomatic patients (28), so the panel decided to separately consider 16 studies that enrolled patients with suspected radiographic stage 1 sarcoidosis (29–44). The study that enrolled patients with symptomatic and asymptomatic bilateral hilar lymphadenopathy confirmed sarcoidosis in 72% (95% confidence interval [CI], 61–81%), but found lymphoma in 10% (95% CI, 5.3–19%) and other diagnoses (i.e., nonlymphomatous malignancy, silicosis, fibrosis, and amyloidosis) in 7.7% (95% CI, 3.6–15.8%). The 16 studies that enrolled patients with suspected radiographic stage 1 sarcoidosis collectively included 556 patients who underwent at least 1 sampling procedure. Sarcoidosis was confirmed in 85% (95% CI, 82–88%) of patients, an alternative diagnosis was made in 1.9% (95% CI, 1–3.7%) of patients, and sampling was nondiagnostic in 11% (95% CI, 8–14%) of patients. Among the alternative diagnoses, 38% (95% CI, 14–69%) were TB and 25% (95% CI, 7.1–59%) were lymphoma. The only complication reported was a case of mediastinitis that occurred after an esophageal endoscopic ultrasound procedure.

The committee acknowledged that most patients with bilateral hilar lymphadenopathy will be confirmed to have sarcoidosis, especially among those presenting with Löfgren’s syndrome, lupus pernio, or Heerfordt’s syndrome. In asymptomatic bilateral hilar lymphadenopathy cases, sampling will be nondiagnostic in a substantial number of patients, and an alternative diagnosis (e.g., malignancy or infections) will be identified in a few cases, but those few cases may have important treatment implications. Factors to consider when weighing the risks and benefits of biopsy may include: regional prevalence of alternative infectious etiologies; patient-specific risk factors for malignancy, infection, or enhanced procedural risk; enlarging lymph nodes; likelihood of obtaining close follow-up; and patient preference. Finally, the availability of a maximally safe, efficacious, and cost-effective means of biopsy procedure is considered. Thus, the committee concluded that the decision to biopsy asymptomatic patients with bilateral hilar adenopathy should be made on a case-by-case basis.

In patients for whom there is a high clinical suspicion for sarcoidosis (e.g., Löfgren’s syndrome, lupus pernio, or Heerfordt’s syndrome), we suggest NOT sampling lymph nodes (conditional recommendation, very low-quality evidence). Remarks: Patients who do not undergo lymph node sampling require close clinical follow-up.

For patients presenting with asymptomatic bilateral hilar lymphadenopathy, we make no recommendations for or against obtaining a lymph node sample. Remarks: If lymph node sampling is not obtained, close clinical follow-up was considered a reasonable alternative approach.

All but one study selected for the systematic review enrolled patients with suspected sarcoidosis; therefore, the probability of finding sarcoidosis and alternative diagnoses in unselected patients with asymptomatic bilateral hilar adenopathy is uncertain and requires further investigation. Studies are needed to determine which clinical factors, including CT or chest radiographic manifestations, and/or biomarkers are the best determinants of pretest probability of sarcoidosis and which radiographic features are predictive of disease progression (45). Such predictive modeling might enable certain patients to be spared from biopsy, while heightening the need for early diagnosis in others. Studies are also needed to determine the true incidence of both minor and major complications of biopsy. Finally, studies that determine long-term outcomes, including treatment and disease course, are needed to determine the utility of early biopsy in asymptomatic patients.

Question 2: Should Patients with Suspected Sarcoidosis and Mediastinal and/or Hilar Lymphadenopathy, for Whom It Has Been Determined That Tissue Sampling Is Necessary, Undergo EBUS-guided Lymph Node Sampling or Mediastinoscopy as the Initial Mediastinal and/or Hilar Lymph Node Sampling Procedure?

Tissue sampling is often helpful in the diagnostic evaluation of suspected sarcoidosis. It begins with the least-risky and least-invasive method, such as sampling skin or peripheral lymph node (e.g., axillary lymph node) abnormalities suggestive of sarcoidosis. However, most new sarcoidosis cases lack skin and peripheral lymph node findings, and invasive testing is pursued from the start. Superiority of EBUS-guided lymph node sampling over transbronchial lung biopsy in pulmonary sarcoidosis has already been established (46–48). The committee asked whether EBUS-guided lymph node sampling or mediastinoscopy is preferable.

Our systematic review identified 703 potentially relevant articles; the full text of 64 was reviewed and 29 were selected. There were no studies comparing EBUS-guided sampling to mediastinoscopy; all studies were nonrandomized studies that reported the diagnostic yield and other outcomes of either EBUS-guided lymph node sampling (30, 31, 36, 39, 41, 43, 44, 49–60) or mediastinoscopy (37, 61–70) in patients with suspected sarcoidosis.

The committee weighed the observations that mediastinoscopy has a higher diagnostic yield than EBUS-guided lymph node biopsy (98% and 87%, respectively), but EBUS-guided lymph node biopsy is less invasive than mediastinoscopy. The committee recognized probable underestimation of the risk of mediastinoscopy given the bias toward reporting only severe complications, implying that less severe complications, like vocal cord damage and their associated costs and inconveniences, were not counted (71, 72). In lieu of rigorous data directly comparing complication rates of mediastinoscopy to EBUS specifically among patients with suspected sarcoidosis, the committee considered a recent systemic review of 9 studies (960 cases) comparing complications of mediastinoscopy and EBUS among patients undergoing mediastinal staging of lung cancer. The systemic review found a statistically higher complication rate for mediastinoscopy (73). The committee also agreed that costs are typically lower for procedures such as EBUS that are performed in an endoscopy room compared with an operating room for mediastinoscopy, and that EBUS is better tolerated than mediastinoscopy because general anesthesia may be avoided (74, 75), although the committee acknowledged that dissenting opinions exist (76, 77). Finally, the committee noted the ease of adding transbronchial biopsy when lymphadenopathy is accompanied by radiographic findings of parenchymal disease, or endobronchial biopsy when mucosal abnormalities are noted during endoscopy, which further increase the yield of bronchoscopy with EBUS (78). The committee concluded that the advantages of EBUS-guided lymph node sampling for the 87% of patients in whom it is diagnostic outweigh the additional risks and burdens to the 13% of patients who require an additional sampling procedure.

The role of conventional blind transbronchial needle aspiration (TBNA) was not specifically investigated. Prior studies directly comparing blind TBNA to EBUS-guided TBNA show the performance of the latter to be significantly better (79, 80) with much higher negative predictive value (80). Nonetheless, the committee believed that conventional TBNA is a low-risk procedure that is widely available and, therefore, is a reasonable alternative to EBUS when the latter is unavailable.

For patients with suspected sarcoidosis and mediastinal and/or hilar lymphadenopathy for whom it has been determined that tissue sampling is necessary, we suggest EBUS-guided lymph node sampling, rather than mediastinoscopy, as the initial mediastinal and/or hilar lymph node sampling procedure (conditional recommendation, very low-quality evidence).

The committee concluded that there is a need for research to determine whether the addition of CT or chest radiographic manifestations, or genomic or biochemical profiling, increases diagnostic yield beyond histologic assessment for tissue samples obtained via EBUS-guided sampling.

Question 3: Should Patients with Sarcoidosis Who Do Not Have Ocular Symptoms Undergo Screening for Ocular Sarcoidosis by Routine Eye Examination?

Sarcoidosis can involve almost every portion of the eye, including the orbit, anterior and posterior chambers, lacrimal gland, sclera, and conjunctiva. Uveitis and retinal involvement are the most concerning manifestations, because they can result in blindness and are not typically apparent on a routine physical examination. Some patients present with uveitis as their initial clinical manifestation. Prevalence of ocular involvement varies by sex and race, with higher rates noted in women and Japanese and persons of African descent. The diagnosis of ocular sarcoidosis is based on a combination of signs and tests (81), which are often not sought until symptoms develop. The committee asked whether patients with sarcoidosis without ocular symptoms should undergo ophthalmologic screening for ocular sarcoidosis.

Our systematic review identified 582 potentially relevant articles; the full text of 25 was reviewed and 18 were selected. None of the studies compared eye exams to no eye exams; all were nonrandomized studies that enrolled patients with extraocular sarcoidosis and reported the frequency of abnormal eye exams and other outcomes (82–99). Although the question is intended for patients with sarcoidosis without ocular symptoms, all studies included patients with and without ocular symptoms.

Eye exams identified abnormalities consistent with ocular sarcoidosis in 26% (95% CI, 23–29%) of patients with sarcoidosis. The most common abnormality was anterior uveitis, which was detected in 53% (95% CI, 41–64%) of patients. Ocular symptoms were present in 78% (95% CI, 64–91%) of patients with an eye exam abnormality. Ocular disease was judged severe enough to warrant topical or systemic corticosteroid treatment in 83% (95% CI, 74–93%) of patients.

The systematic review estimated the prevalence of ocular sarcoidosis to be 26%. The committee was concerned that this estimate is higher than the actual prevalence among the population of interest (patients with sarcoidosis without ocular symptoms), as most patients with ocular abnormalities had ocular symptoms. However, other studies have similarly estimated the prevalence of ocular sarcoidosis to be 20–40% (100), and one study indicated that some patients with uveitis are asymptomatic (101). Among Japanese patients, the prevalence may be >50% (102, 103).

Regardless of the exact prevalence, the committee concluded that: 1) eye exams are required for detection of ocular involvement and are neither harmful nor burdensome; 2) vision is very precious to patients; and 3) treatment may be beneficial in reducing harm (i.e., reduction of loss of vision). The impact of treatment is based on the committee’s clinical experience and the systematic review, which suggested that most treated patients had improvement or stabilization of their visual acuity. However, the systematic review did not target treatment, and, therefore, better evidence about treatment of ocular sarcoidosis may exist. The committee’s recommendations also factored in the ancillary benefits of routine eye exams, such as identification of abnormalities that may guide nonimmunosuppressive therapy (e.g., for glaucoma) or detection of sarcoidosis treatment–related toxicity (e.g., hydroxychloroquine-induced retinopathy) that could impair vision if not identified.

For patients with sarcoidosis who do not have ocular symptoms, we suggest a baseline eye examination to screen for ocular sarcoidosis (conditional recommendation, very low-quality evidence).

The identification of risk factors for ocular sarcoidosis, particularly the more devastating forms of the disease, could obviate the need for screening all patients with sarcoidosis with eye exams. A better understanding of the natural history of ocular sarcoidosis, the identification of predictors of which patients will develop new onset of eye involvement after baseline negative screening and among those with active disease at baseline who will experience persistent or recurrent disease, and new diagnostic modalities are all needed (104). In those who initially have no evidence of eye involvement, the committee recommends ophthalmology evaluation based on development of new symptoms (Table 5). However, additional research is needed to determine if there is a clinical benefit, such as earlier detection and more effective treatment, to routine eye exams compared with exams based on the development of symptoms. Finally, treatment trials that enroll patients with ocular sarcoidosis are needed, because most treatment trials have enrolled patients with uveitis of many causes, including sarcoidosis.

Table 5. Best Practice Recommendations for Detection of Delayed Onset of Extrapulmonary Sarcoidosis Manifestations after Negative Baseline Screening

Approximately 23% of patients with sarcoidosis will develop a new disease manifestation within 3 years of baseline evaluation. Annual testing is recommended for calcium, creatinine, and alkaline phosphatase, because these manifestations are often asymptomatic. In contrast, routine testing is not recommended for ocular or heart sarcoidosis, unless the patient presents with related symptoms, as above.

Question 4: Should Patients with Sarcoidosis Who Do Not Have Renal Symptoms Undergo Screening for Renal Sarcoidosis by Routine Serum Creatinine Testing?

Sarcoidosis can cause compromised kidney function in a subgroup of patients through two mechanisms: 1) parenchymal granulomatous inflammation or 2) consequent to altered calcium metabolism (e.g., nephrocalcinosis, nephrolithiasis). Timely treatment (e.g., immune suppression) can attenuate sarcoidosis-induced renal complications. The committee asked if routine creatinine screening is indicated in patients with sarcoidosis with no known kidney disease.

Our systematic review identified 469 potentially relevant articles; the full text of 12 was reviewed and 8 were selected. None of the studies compared renal function testing to no testing; all were nonrandomized studies that reported the frequency of abnormal renal function and other outcomes (88, 99, 105–110). Only two studies included serum creatinine testing as a renal function test; the other studies used 24-hour urine collection alone or in combination with other tests. Meta-analysis of the selected studies found that abnormal renal function was detected in 7% (95% CI, 3–11%) of patients. Six out of eight studies reported kidney biopsy among those with abnormal renal function. Granulomas and nephrocalcinosis were the findings reported in most studies, although the frequency of occurrence varied broadly, ranging from 1% to 63% for granulomas and 0–50% for nephrocalcinosis. The committee’s confidence in the estimated frequency of the pathological abnormalities was limited by the wide ranges and concern about selection bias due to nonconsecutive selection of patients for kidney biopsy.

The guideline committee recognized that the prevalence of renal dysfunction identified among patients with sarcoidosis was modest. However, the committee’s discussion led to the following conclusions: 1) renal sarcoidosis is often asymptomatic; 2) progressive or persistent renal dysfunction is associated with poor clinical outcomes; 3) renal function testing is not harmful; and 4) most patients respond to therapy. The last conclusion is based on both the committee’s clinical experience and the systematic review, which suggested that roughly 90% of patients treated with immune suppression to suppress granulomatous inflammation and related vitamin D–mediated hypercalcemia, together with intravenous fluids, and/or other therapies to further correct hypercalcemia (a cause of renal dysfunction in sarcoidosis) had improvement or correction of coexisting renal dysfunction (105, 108). However, the systematic review was not designed to assess treatment effects, and, therefore, better evidence about treatment of renal sarcoidosis may exist.

The combination of serum creatinine testing being safe and potentially detecting a condition with a poor prognosis that responds well to treatment if detected early prompted the guideline committee to conclude that the desirable consequences of renal function testing exceed the undesirable consequences. The committee acknowledged its uncertainty about whether serum creatinine is the best test to screen for renal sarcoidosis, because many studies used 24-hour urine collection. It decided that creatinine testing is easy and less costly and, therefore, favored its use.

Failure to respond to treatment within 1 month indicates either irreversible sarcoidosis-related renal manifestations, such as nephrocalcinosis or glomerular sclerosis, or an alternative diagnosis. Alternative renal disorders are common among patients with sarcoidosis according to studies of patients with sarcoidosis who presented with renal insufficiency and underwent a diagnostic renal biopsy. These include membranous glomerulonephritis, IgA nephropathy, and focal glomerular sclerosis (111, 112). Failure of renal dysfunction in a patient with sarcoidosis to respond to immune suppression treatment should prompt further diagnostic testing.

In patients with an established diagnosis of sarcoidosis-induced renal dysfunction caused by granulomatous interstitial nephritis or hypercalcemia, relapses are common after withdrawal of immune suppression (113). As such, the panel considers it standard practice to monitor the serum creatinine in all patients with established renal sarcoidosis, especially after de-escalation of immune suppression, and annually in those who have no prior history of renal involvement (Table 5).

For patients with sarcoidosis who have neither renal symptoms nor established renal sarcoidosis, we suggest baseline serum creatinine testing to screen for renal sarcoidosis (conditional recommendation, very low-quality evidence).

The clinical presentation of renal sarcoidosis is often insidious, and renal damage is progressive without treatment. Elevated creatinine or available imaging technologies are not specific for renal sarcoidosis. Renal biopsy is often necessary to reliably establish the diagnosis of renal sarcoidosis, but carries risks of bleeding, pain, and, rarely, arteriovenous fistula formation. Future studies should consider convenient, noninvasive biomarkers of renal sarcoidosis; examples include evaluation of 24-hour urine parameters and research focused on prognosis, response to therapy, and mechanisms of fibrosis (114).

Question 5: Should Patients with Sarcoidosis Who Do Not Have Hepatic Symptoms Undergo Screening for Hepatic Sarcoidosis by Routine Transaminase and Alkaline Phosphatase Testing?

The liver is commonly involved in sarcoidosis and is more common in African Americans than white individuals (88). Although liver fibrosis, cirrhosis, and portal hypertension can result and require transplantation, the prevalence of these outcomes and the long-term consequences of hepatic sarcoidosis are not established, and the indications for treating hepatic sarcoidosis are unclear. Thus, the benefits of routine screening for hepatic sarcoidosis, based on liver function tests, is unknown. The committee asked if patients with sarcoidosis presenting with no liver manifestations should undergo routine baseline screening with liver function tests.

Our systematic review identified 575 potentially relevant articles; the full text of 15 was reviewed and 8 were selected to inform the guideline committee. None of the studies compared liver function testing to no testing; all were nonrandomized studies that reported the frequency of abnormal liver function and other outcomes (83, 88, 99, 115–119). Only one study explicitly stated that the patients had no hepatic symptoms; the others only implied that most patients had minimal to no hepatic symptoms. Meta-analysis of the selected studies found that liver function testing was abnormal in 12% (95% CI, 6–19%) of patients. Among those who underwent subsequent liver biopsy, granulomas were identified in 96% (95% CI, 88–99%). The committee’s confidence in the generalizability of this result was limited by concern about selection bias due to nonconsecutive selection of patients for liver biopsy. The proportion of patients with abnormal liver function tests in whom systemic corticosteroids were initiated varied widely across studies, ranging from 25% to 95%.

The evidence suggests that liver laboratory abnormalities will be found in 12% of patients with sarcoidosis who undergo routine liver function testing, most of whom have hepatic granulomas. We did not identify a specific pattern of liver function abnormalities indicative of hepatic sarcoidosis, but some studies suggest that liver granulomas are more often associated with increases of alkaline phosphatase and less frequently with rises in transaminases (120).

The committee discussed reports that immune suppression and ursodeoxycholic acid reduce transaminitis and cholestasis in patients with related symptoms (pruritus) (121), suggesting that treatment is effective in reducing disease activity in patients with symptomatic hepatic sarcoidosis. However, according to both the committee’s clinical experience and the systematic review, it is uncertain whether these effects can be extrapolated to asymptomatic patients with hepatic sarcoidosis. The systematic review found no difference in resolution or improvement of abnormal liver function tests with treatment; however, it was not designed to estimate the effects of treatment of hepatic sarcoidosis, and, therefore, better evidence about treatment may exist. Treatment decisions should not be undertaken carelessly, because death due to cirrhosis or liver failure is uncommon (122), yet the risks of chronic treatment, especially immune suppression, are significant. The committee also noted that prednisone treatment may confound the assessment, as it can cause transaminitis. The committee agreed that the evidence is too scarce to conclude whether treatment affects progression to cirrhosis or reduces the need for liver transplantation.

Taken together, the evidence suggests that more than 1 out of every 10 patients with sarcoidosis who undergo liver function testing will be identified as having liver involvement, but the implication on treatment is unclear. The committee concluded that there is value in identifying patients with liver involvement at the time of initial diagnosis, and to screen for liver involvement annually even if the initial screen is negative (Table 5), if for no other reason than to avoid hepatotoxic treatments, and to follow such patients more carefully for the development of symptoms that warrant treatment.

For patients with sarcoidosis who have neither hepatic symptoms nor established hepatic sarcoidosis, we suggest baseline serum alkaline phosphatase testing to screen for hepatic sarcoidosis (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis who have neither hepatic symptoms nor established hepatic sarcoidosis, we make no recommendation for or against baseline serum transaminase testing.

Studies are needed to delineate the best screening test for hepatic sarcoidosis, such as alkaline phosphatase, serum transaminases, or others. In addition, little is known about the natural history of hepatic sarcoidosis. Case series demonstrate a broad range of disease outcomes, from spontaneous resolution to rapid progression to cirrhosis (123). Future studies should use long-term longitudinal follow-up to determine the natural history of hepatic sarcoidosis and consider the influence of genetic and environmental factors. Better tools are needed to: 1) detect progression from hepatitis to early fibrosis and cirrhosis, such as liver elastography ultrasound; 2) more accurately characterize disease phenotypes; and 3) identify patients who might need and respond best to therapy.

Question 6: Should Patients with Sarcoidosis Who Do Not Have Symptoms or Signs of Hypercalcemia Undergo Screening for Abnormal Calcium Metabolism by Routine Serum Calcium and Vitamin D Testing?

Abnormal calcium metabolism in sarcoidosis can lead to hypercalcemia, hypercalciuria, and their manifestations, including kidney stones and renal failure; it is the most common cause of sarcoidosis-related renal insufficiency. Dysfunctional calcium metabolism can also result in elevated bone resorption and increased renal and intestinal absorption of calcium. The mechanisms of abnormal calcium metabolism are likely multifactorial, including increased 1α‐hydroxylase production by granulomatous macrophages, which converts 25-(OH) vitamin D to 1,25-(OH)₂ vitamin D, increased expression of parathyroid hormone–related protein in sarcoidosis macrophages (124), and cytokine and other growth factor production (125, 126). Although hypercalcemia- or hypercalciuria-related symptoms may bring the problem to attention, the committee asked whether patients with sarcoidosis without symptoms should undergo screening for abnormal calcium metabolism by baseline serum calcium and vitamin D testing.

Our systematic review identified 1,531 potentially relevant articles; the full text of 14 was reviewed and 11 were selected to inform the guideline committee. None of the studies compared serum calcium or vitamin D testing to no testing; rather, all were nonrandomized studies that reported the frequency of abnormal calcium testing (88, 99, 105, 109, 127–133). One of the studies further reported the consequences of untreated and treated hypercalcemia, as well as the frequency of abnormal vitamin D testing among patients with sarcoidosis (127).

Hypercalcemia was detected in 6% (95% CI, 4–8%) of patients, with renal failure developing in 42% (95% CI, 33–52%) of untreated patients. In the one study that reported vitamin D testing, no patient had an elevated 25-(OH) vitamin D level, 84% (95% CI, 79–88%) had a low 25-(OH) vitamin D level, 11% (95% CI, 8–15%) had a high 1,25-(OH)₂ vitamin D level, and 0.4% (95% CI, 0.07–2%) had a low 1,25-(OH)₂ vitamin D level. There were no differences in the 25-(OH) vitamin D and 1,25-(OH)₂ vitamin D levels among patients with hypercalcemia and normal serum calcium levels. However, 1,25-(OH)₂ vitamin D levels were relatively higher than 25-(OH) vitamin D levels among patients with a history of hypercalcemia compared with patients who did not have a history of hypercalcemia.

Our systematic review suggests that serum hypercalcemia will be detected in 6% of patients with sarcoidosis who undergo routine serum calcium testing; nearly half will develop renal failure. Our systematic review did not target treatment of sarcoidosis-related hypercalcemia, and, therefore, better evidence about treatment may exist. However, according to the committee’s clinical experience and our systematic review, hypercalcemia improves or resolves in more than 90% of patients who are treated with immune suppression. In contrast, once hypercalcemia-induced renal failure is established, chronic renal impairment is common, despite immune suppression. The committee concluded that, despite the low prevalence of hypercalcemia, the accessibility of a nonburdensome test, coupled with the opportunity to intervene before the development of irreversible consequences, warrants baseline testing, and annual screening thereafter (Table 5). In addition, the committee determined that a strong recommendation for initial screening was indicated, despite the very low quality of evidence, because the importance of the potential benefits of early detection of hypercalcemia (i.e., the prevention of irreversible kidney disease) substantially outweighs the harms, burdens, and costs of testing.

The committee noted that data to support 1,25-(OH)₂ vitamin D testing for abnormal calcium metabolism was neither extensively studied nor supported by the systematic review, although it was recognized that there may be other reasons for 1,25-(OH)₂ vitamin D testing in patients with sarcoidosis. For example, it has been hypothesized that 1,25-(OH)₂ vitamin D may be a biomarker of granulomatous burden, with one study reporting an association between disease chronicity and 1,25-(OH)₂ vitamin D levels (134). A comprehensive discussion of alternative reasons for 1,25-(OH)₂ vitamin D testing is beyond the scope of this guideline, but is provided elsewhere (135). Testing of 25-(OH) vitamin D levels is often undertaken in the primary care setting, and may be useful in conjunction with 1,25-(OH)₂ vitamin D levels in a subset of patients with sarcoidosis, such as those with severe fatigue or exposed to chronic corticosteroids, for whom vitamin D repletion may be beneficial (136).

Patients who require calcium repletion are at risk for hypercalciuria and/or hypercalcemia, and need to be monitored closely, because the effects of calcium and vitamin D supplementation are complex. Studies have reported a small, but significant, increase in hypercalcemia with calcium and vitamin D supplementation (136–138), with another finding that withdrawal of calcium and vitamin D supplementation improved the hypercalcemia (127). Whereas hypercalcemia caused by vitamin D supplementation did not cause sustained renal damage, vitamin D supplementation was shown to be ineffective in terms of improved bone health or other benefits (123). The committee had no basis to recommend routine vitamin D screening but did recommend that both types of vitamin D testing (1,25-[OH]₂ and 25-[OH] vitamin D) be undertaken in patients who are being evaluated for possible vitamin D replacement.

For patients with sarcoidosis who do not have symptoms or signs of hypercalcemia, we recommend baseline serum calcium testing to screen for abnormal calcium metabolism (strong recommendation, very low-quality evidence).

If assessment of vitamin D metabolism is deemed necessary in a patient with sarcoidosis, such as to determine if vitamin D replacement is indicated, we suggest measuring both 25- and 1,25-OH vitamin D levels before vitamin D replacement (conditional recommendation, very low-quality evidence).

Although the cause of abnormal calcium metabolism, hypercalcemia, and hypercalciuria appears to be multifactorial, better delineation of the mechanisms, such as genetic variation, may help define better screening tests and/or ways to treat this manifestation of sarcoidosis. The question of whether 24-hour urine calcium or other biomarkers are better assessments of abnormal calcium metabolism than serum calcium or vitamin D testing needs to be evaluated. The potential benefits of calcium and vitamin D supplementation on bone health and/or the potential antiinflammatory effects of vitamin D supplementation need to be weighed against the risk of hypercalcemia and hypercalciuria, and the role of monitoring of vitamin D metabolism after vitamin D supplementation also needs to be further established. Finally, whether low 25-(OH) vitamin D or elevated 1,25-(OH)₂ vitamin D levels are biomarkers for disease severity and/or granulomatous burden needs to be determined.

Question 7: Should Patients with Sarcoidosis Undergo Screening for Hematological Abnormalities by Routine Complete Blood Cell Count Testing?

Hematologic abnormalities (i.e., leukopenia, lymphopenia, anemia, thrombocytopenia, and/or pancytopenia) are manifestations of sarcoidosis that raise the possibility of bone marrow involvement, although this is not the most common cause of such abnormalities. Splenomegaly with sequestration may be a more common cause of hematologic abnormalities. In the absence of splenomegaly, compartmentalization of white blood cells to the site of organ involvement is a common cause of leukopenia and lymphopenia (3, 130, 139–141). Additional causes of hematologic abnormalities are hepatic sarcoidosis, nonsarcoidosis medical problems, and treatment with immunosuppressive therapies, like methotrexate. Less-frequent hematologic abnormalities attributed to sarcoidosis include eosinophilia, hemolytic anemia, and idiopathic thrombocytopenia. Pancytopenia may be a presenting manifestation of sarcoidosis, but the cytopenia more often presents as a secondary finding in those with active disease. As a result, the committee asked whether patients with sarcoidosis should undergo a baseline complete blood cell count testing to screen for hematological abnormalities.

Our systematic review identified 2,767 potentially relevant articles; the full text of 13 was reviewed and 10 were selected. None of the studies compared complete blood cell testing to no testing; rather, all were nonrandomized studies that reported the frequency of anemia, leukopenia, or lymphopenia (88, 130–133, 141–145). Only four of the studies were published within the past 20 years; six were published more than 50 years ago.

The evidence suggests that hematological abnormalities are commonly detected in patients with sarcoidosis by a peripheral blood complete blood cell count and differential cell count. However, the abnormalities are often transient and, according to our systematic review, might be just as common among healthy control subjects. The committee noted that leukopenia and lymphopenia are common complications of sarcoidosis, and are related in almost all cases to inflammatory mechanisms, such as granulomatous bone marrow infiltration (142) and the systemic effects of inflammatory mediators, such as TNF-α (146). Thus, there is no compelling reason to sample the bone marrow for alternative diagnoses in cases of sarcoidosis accompanied by leukopenia. Anemia, however, was common and an important finding, because it can contribute to sarcoidosis symptoms and signs, such as fatigue and shortness of breath, which may impact a patient’s care. It can also be an indicator of other medical problems, and a complete blood cell count is usually needed when initiating cytotoxic immunosuppressive therapy. Taken together, the committee concluded that anemia, whether attributable to sarcoidosis or not, is clinically relevant, important to patients, and requires further evaluation.

We suggest that patients with sarcoidosis undergo baseline complete blood cell count testing to screen for hematological abnormalities (conditional recommendation, very low-quality evidence).

The literature addressing hematologic abnormalities in sarcoidosis is decades old, and it is unclear whether it is applicable today, given the different laboratory tests and thresholds that are currently used. Splenectomy was previously used to treat cytopenia due to hypersplenism; even though splenectomy is less common today, there are no definitive alternative approaches that have been evaluated as treatments for hematologic abnormalities due to sarcoidosis. Lymphopenia and CD4, CD8, and CD19 lymphocyte subsets have been proposed as markers of more severe sarcoidosis (147), and patients with lymphopenia with sarcoidosis may be particularly responsive to anti–TNF-α treatment (146), although additional study is needed.

Question 8: Should Patients with Sarcoidosis Who Do Not Have Cardiac Symptoms or Signs Undergo Routine Screening for Cardiac Sarcoidosis Using ECG, TTE, or 24-Hour Ambulatory ECG Monitoring?

Cardiac sarcoidosis is an underrecognized manifestation of sarcoidosis that can present with sudden cardiac death. These features make early detection and management of cardiac sarcoidosis desirable. Providers should ask specifically about symptoms of palpitations, lightheadedness, chest pain, and syncope, because these presenting signs and symptoms greatly increase the likelihood of cardiac sarcoidosis. ECG, TTE, and 24-hour ambulatory ECG (Holter) monitoring are noninvasive methods to potentially screen asymptomatic patients for cardiac sarcoidosis. However, the tests provide fundamentally different information. Although the ECG and Holter monitoring appraise conductivity within the heart, TTE assesses the mechanical function of the heart. The committee asked if any of these tests should be employed in screening asymptomatic patients with sarcoidosis for cardiac involvement.

Our systematic review identified 1,212 potentially relevant articles. For ECG, we reviewed the full text of 13 articles and selected 4 (148–151). For TTE, we reviewed the full text of 30 articles and selected 2 (148, 149). For Holter monitoring, we reviewed the full text of six articles and selected two (148, 152). None of the studies compared the diagnostic test(s) to no testing; all were nonrandomized studies that reported the results of one or more diagnostic tests. Most enrolled consecutive patients who were being followed in a sarcoidosis or pulmonary clinic. No study specifically enrolled patients with sarcoidosis without cardiac symptoms; the studies either enrolled both symptomatic and asymptomatic patients or did not report whether the patients had symptoms.

ECGs were abnormal in 7% (95% CI, 4–11%) of patients with sarcoidosis. The definition of abnormal varied among studies, but all included conduction abnormalities and ventricular ectopy. Results of the two ECG studies were too different to aggregate: one study reported a sensitivity and specificity of 9% (95% CI, 1–27%) and 97% (95% CI, 86–100%), respectively, whereas the other reported a sensitivity and specificity of 92% (95% CI, 65–99%) and 73% (95% CI, 54–86%), respectively, potentially reflecting the use of different reference standards. An abnormal ECG was associated with an increased risk of cardiac events, including atrioventricular block, ventricular tachycardia, and systolic dysfunction (hazard ratio [HR], 11.27; 95% CI, 3.29–38.64) and a trend toward increased all-cause mortality (44% vs. 36%; relative risk [RR], 1.40; 95% CI, 0.80–2.42) assessed over a median follow-up of 27 years.

TTEs were abnormal in 11% (95% CI, 5–17%) of patients with sarcoidosis, typically defined as a diminished ejection fraction and/or wall motion abnormalities inconsistent with coronary artery disease. An abnormal TTE identified cardiac sarcoidosis with a sensitivity and specificity of 25% (95% CI, 10–47%) and 97% (95% CI, 86–99%), respectively. It also predicted conduction system abnormalities (58% vs. 22%; RR, 2.6; 95% CI, 1.38–4.92).

Holter monitoring was abnormal in 5% (95% CI, 1–9%) of patients with sarcoidosis. An abnormal ambulatory ECG monitor was defined as frequent premature ventricular contractions in one study, and ventricular ectopy or conduction abnormalities in the other study. Abnormal ambulatory ECG monitoring identified cardiac sarcoidosis with a sensitivity and specificity of 56% (95% CI, 40–70%) and 95% (95% CI, 87–98%), respectively.

Only one of the selected studies evaluated all three modalities in a single population, finding that ECG, TTE, and ambulatory ECG monitoring have sensitivities of 9% (95% CI, 1–27%), 25% (95% CI, 10–47%), and 50% (95% CI, 29–71%), respectively, and specificities of 97% (95% CI, 86–100%), 95% (95% CI, 83–99%), and 97% (95% CI, 86–100%), respectively (148).

The committee recognized the hazards of comparing diagnostic tests across studies (i.e., it is uncertain whether differences are due to the test or the population) and, therefore, heavily weighted the only study in the systematic review that evaluated all three tests within a single population (148). Because the study found that each test alone is insensitive, the committee considered the possibility of using combinations of tests to screen for cardiac sarcoidosis with the plan to pursue advanced testing (cardiac magnetic resonance [CMR] and/or cardiac PET [cPET]) if any test is positive and to forego advanced testing if all three tests are negative. The committee began with ECG plus echocardiography, because both tests have attributes that are favorable in screening tests (i.e., they are inexpensive, noninvasive, reliable, and easily administered). If both tests are performed, their combined sensitivity (i.e., the likelihood that one of the tests will be abnormal in patients with cardiac sarcoidosis) is only 32%, providing minimal clinical utility. The committee next assessed TTE plus ambulatory ECG monitoring, because they are the two tests with the highest sensitivity. Their combined sensitivity is 63%, which was deemed insufficient for screening, particularly given that ambulatory ECG monitoring often requires more than one office visit. Finally, the committee considered ECG plus ambulatory ECG monitoring, but, again, the combined sensitivity was judged too low for routine screening.

These conclusions were supported by a more recent study that similarly assessed all three tests within a single population (153); this study was not included in the systematic review, because it couldn’t be determined if the study defined the tests as abnormal using the same criteria that were established a priori for the systematic review. Notably, in the first study that compared the three tests in a single population (148), all three diagnostic tests were specific. However, the more recent study (153) did not confirm the high specificity, and, therefore, the potential role was not pursued further.

Regardless of the tests’ inability to detect cardiac sarcoidosis, ECG identified patients at increased risk of cardiac events. Given that ECG is readily available in many institutions, noninvasive, harmless, and relatively inexpensive, the committee concluded that baseline ECG was recommended to identify patients who may warrant additional evaluation.

For patients with extracardiac sarcoidosis who do not have cardiac symptoms or signs, we suggest performing baseline ECG to screen for possible cardiac involvement (conditional recommendation, very low-quality evidence).

For patients with extracardiac sarcoidosis who do not have cardiac symptoms or signs, we suggest NOT performing routine baseline TTE or 24-hour continuous ambulatory ECG (Holter monitor) to screen for possible cardiac involvement (conditional recommendation, very low-quality evidence). Remarks: The panel recognizes the low risks attendant to the use of TTE or 24-hour continuous ambulatory ECG (Holter monitor) to screen for cardiac sarcoidosis. Thus, these tests should be considered on a case-by-case basis.

The committee concluded that large research studies that compare diagnostic tests within a single population are needed to identify the optimal screening test(s) for cardiac sarcoidosis in asymptomatic individuals with sarcoidosis. Research studies are also needed to determine whether screening with CMR is warranted. Alternative screening tests for cardiac sarcoidosis should be developed and investigated, to detect cardiac sarcoidosis before it causes symptoms, and significant morbidity and mortality.

Question 9: Should Patients Who Are Suspected of Having Cardiac Sarcoidosis Undergo Cardiac MRI, TTE, or PET as an Initial Imaging Test?

Given the risks and treatment implications for accurate detection of cardiac sarcoidosis, as previously discussed, definitive detection is a high clinical priority. Endomyocardial biopsy, even when aided with electroanatomic mapping guidance, is unreliable for the detection of cardiac sarcoidosis (e.g., ∼13% diagnostic yield), and requires specialized equipment and skills, is invasive, and has potentially serious complications (10, 154). Thus, imaging techniques are more commonly used for cardiac sarcoidosis detection. TTE is the most widely available imaging procedure, and is shown in small, isolated studies to detect clinically symptomatic cardiac sarcoidosis (148). CMR and fludeoxyglucose F 18 ( 18 F-FDG) cPET are both reported to be effective for the detection of cardiac sarcoidosis (155); however, uncertainty exists on the basis of inconclusive and conflicting reports as to which imaging modality is preferred, particularly among patients with established extracardiac sarcoidosis with suspected cardiac involvement. Figure 2 demonstrates typical ECG, CMR, and cPET manifestations of cardiac sarcoidosis.

Figure 2. Typical ECG and radiographic features of cardiac sarcoidosis. (A) ECG demonstrates first-degree A-V block (P-R interval, 200 ms) and right bundle branch block. (B) Cardiac magnetic resonance showing multifocal abnormal late gadolinium enhancement involving the mid- to epicardial lateral ventricular wall (arrowheads). (C) Cardiac positron emission tomography demonstrates intense hypermetabolic uptake of 18 F-fluorodeoxyglucose in the lateral left ventricular wall (arrow).

Our systematic review identified 2,152 potentially relevant articles. No study included all three modalities; therefore, we sought studies that separately evaluated CMR, cPET, and TTE. For CMR, we reviewed the full text of 45 articles and selected 11 (156–166). For cPET, we reviewed the full text of 34 articles and selected 6 (164–169). For TTE, we reviewed the full text of 30 articles and selected 2 (148, 149). Most studies specified that the patients had “suspected cardiac sarcoidosis,” defined as an abnormal ECG or cardiac symptoms, although asymptomatic patients frequently outnumbered symptomatic patients.

Cardiac MRIs were abnormal in 27% (95% CI, 23–31%). In all cases, CMR was considered abnormal if there was late gadolinium enhancement (LGE). An abnormal CMR was associated with increased overall mortality (9.9% vs. 4.7%; RR, 2.54; 95% CI, 0.38–17.16), cardiac mortality (13% vs. 1.5%; RR, 9.00; 95% CI, 1.93–41.97), aborted sudden cardiac death (28% vs. 0%), ventricular arrhythmias (38% vs. 3.6%; RR, 11.71; 95% CI, 2.59–52.92), diastolic heart failure (67% vs. 33%; RR, 2.0; 95% CI, 1.39–2.88), other heart failure (47% vs. 4%; RR, 11.88; 95% CI, 3.69–38.21), atrial arrhythmias (36% vs. 12%; RR, 3.01; 95% CI, 1.53–5.93), complete heart block (12% vs. 1.4%; RR, 9.5; 95% CI, 1.10–81.72), and PH (25% vs. 8%; RR, 3.17; 95% CI, 1.19–8.39). In addition, three studies reported a markedly increased risk of major cardiac events (i.e., ventricular arrhythmias, sudden cardiac death, implantable cardioverter–defibrillator shocks, etc.), but the estimates could not be pooled due to differential reporting across studies. Sensitivity and specificity were deemed biased estimates, because CMR is a component of the reference standard.

cPET scans were abnormal in 52% (95% CI, 43–60%) of patients with sarcoidosis, using a variety of definitions of “abnormal.” An abnormal cPET scan was associated with major adverse cardiac events, although the estimate could not be pooled due to differential reporting across studies and was associated with a trend toward increased overall mortality (HR, 1.33; 95% CI, 0.68–2.26). Sensitivity and specificity were deemed biased estimates, because cPET scanning is a component of the reference standard.

TTEs were abnormal in 11% (95% CI, 5–17%) of patients with sarcoidosis, typically defined as a diminished ejection fraction and wall motion abnormalities inconsistent with coronary artery disease. An abnormal TTE identified cardiac sarcoidosis with a sensitivity and specificity of 25% (95% CI, 10–47%) and 97% (95% CI, 86–99%), respectively. It also predicted conduction system abnormalities (58% vs. 22%; RR, 2.6; 95% CI, 1.38–4.92).

Three studies evaluated both CMR and cPET, thereby enabling comparison of the tests within a population (164–166). In one study, adverse cardiac events were better predicted by CMR (HR, 10.63; 95% CI, 1.4–80.78) than cPET (HR, 2.29; 95% CI, 0.72–7.33) (166). This was supported by another study, although the outcome measures were different for CMR (RR, 8.33; 95% CI, 1.18–58.51) and cPET (HR, 3.3; 95% CI, 1.1–10.0) (164). The third study compared sensitivity and specificity, which the panel deemed too biased to report (165).

The guideline panel recognized that comparing the diagnostic accuracy of CMR with LGE to cPET was difficult due to: 1) the lack of a reference standard that is independent of both tests; and 2) lack of studies that directly compared the tests in large cohorts of patients with suspected cardiac sarcoidosis. Regarding the former, the tests themselves are included in the reference standards used by most of the studies we reviewed (2006 Japanese Ministry of Health and Welfare diagnostic criteria include CMR as a minor diagnostic criterion [170] and the Heart Rhythm Society diagnostic criteria rely on either CMR or cPET for diagnosis of cardiac sarcoidosis [10]), which means that sensitivity and specificity are biased estimates. Nonetheless, the selected studies clearly demonstrate that TTE has a lower sensitivity for cardiac sarcoidosis detection.

The clinical importance of CMR-LGE abnormalities is supported by several observations: 1) CMR-LGE has direct histopathological correlation with CS (157); 2) the prevalence of CMR-LGE abnormalities among patients with sarcoidosis approaches the prevalence of CS reported by serial autopsies (157, 163, 171); 3) the absence of CMR-LGE findings predicts no serious cardiac events for at least 3 years to follow (172); and 4) the extent of LGE correlates with the risk of future adverse events (173). Likewise, 18 F-FDG PET uptake has been shown to predict future adverse cardiac events (174).

The body of evidence supporting the prognostic capability of CMR is larger than that supporting cPET. Moreover, CMR is less expensive, more widely available, and less prone to the false-positive results, such as those that can result from failure to convert cardiac myocyte metabolism fully away from carbohydrates. cPET may be less reproducible, despite identical patient preparation (175). On the basis of these considerations, CMR emerged as the preferred modality for imaging patients with suspected cardiac sarcoidosis, with the caveats that CMR with LGE is contraindicated in the setting of advanced kidney disease, and considering emerging evidence indicating that CMR and cPET are complementary for the detection of myocardial fibrosis and inflammation, respectively (176). It should be emphasized that these imaging technologies are continually advancing; thus, the capacity to detect clinically important cardiac sarcoidosis manifestations are expected to further improve in coming years.

The committee recognizes that subclinical cardiac involvement may develop over time in some patients with sarcoidosis based on advanced imaging modalities, such as CMR or cPET, but the committee does not recommend routine screening (e.g., ECG, TTE, CMR, and cPET) for cardiac sarcoidosis in those who are asymptomatic (Table 5). This recommendation is based on the current consensus that clinically silent cardiac sarcoidosis is associated with a benign prognosis (177).

For patients with extracardiac sarcoidosis and suspected cardiac involvement, we suggest cardiac MRI, rather than cPET or TTE, to obtain both diagnostic and prognostic information (conditional recommendation, very low-quality evidence).

For patients with extracardiac sarcoidosis and suspected cardiac involvement who are being managed in a setting in which cardiac MRI is not available, or when CMR results are inconclusive, we suggest dedicated cPET, rather than a TTE, to obtain diagnostic and prognostic information (conditional recommendation, very low-quality evidence).

Future studies are encouraged to develop disease-specific biomarkers of granulomatous inflammation that could further enhance the performance of existing imaging techniques. For example, combined use of CMR and cPET, or integration of CMR-LGE with T1 or T2 parameters, may improve the detection of acute and chronic disease manifestations (177). Newer applications of PET are being developed, such as imaging based on deoxy-3′-[18F]-fluorothymidine (178) or 4′[methyl- 11 C]-thiothymidine uptake (179), which have the advantage of not requiring dietary restriction, as per 18 F-FDG PET. Larger studies are needed to further validate these newer imaging modalities and combinations before strong recommendations can be offered on the basis of the rigorous Grading of Recommendations, Assessment, Development, and Evaluation approach upon which clinical practice guidelines are based. Research is also needed to develop readily available biomarkers (e.g., blood derived) to serve as convenient and less-expensive surrogates for advanced imaging modalities and to guide therapy.

Sarcoidosis-associated PH (SAPH) occurs in 5–20% of patients seen in sarcoidosis clinics (180–183). Nearly half of patients with sarcoidosis with persistent dyspnea have been found to have SAPH (184, 185), and SAPH is an independent risk factor for increased mortality in sarcoidosis (181, 186). Other clinical manifestations, including exertional chest pain and/or syncope, exam findings of a prominent P2 or S4, reduced 6-minute walk distance, desaturation with exercise, reduced D l _CO, increased pulmonary artery diameter relative to ascending aorta diameter (e.g., by CT scan), elevated brain natriuretic factor, and fibrotic lung disease, are proposed as methods to identify patients at risk for SAPH (182, 184, 187–189), but these clinical parameters are unreliable. TTE is the most commonly recommended method to initially screen for the presence of PH (189, 190). Thus, we investigated the utility of TTE in the evaluation of possible SAPH.

Our systematic review identified 137 potentially relevant articles; the full text of 13 was reviewed and 9 were selected. None of the studies compared TTE to no testing; rather, all were nonrandomized studies that selected patients with sarcoidosis (most enrolled patients who had persistent respiratory symptoms despite treatment of their sarcoidosis) and reported the frequency of abnormal TTE results (180, 184, 191–197). Some studies also reported the rate of confirmation by right heart catheterization. Of note, the definition of PH has evolved through the years, which may bias the populations included in our literature review.

TTE identified abnormalities suggestive of PH (i.e., high estimated systolic pulmonary arterial pressure) in 29% (95% CI, 20–39%) of patients. Among those with an abnormal TTE, 78% (95% CI, 67–86%) were subsequently confirmed to have PH by right heart catheterization, indicating that 78% of the abnormal TTEs were true positives and 22% were false positives. The proportion of patients with confirmed PH for whom treatment was initiated or changed was not reported in any of the studies.

An association between PH and lung disease severity was noted in the systemic review. Patients with PH had more severe lung disease than patients without PH, with a mean difference of the percent predicted FVC of −16.5% (95% CI, −22.4% to −10.6%). Although not selected during the systematic review, another series known to committee members found that impaired diffusing capacity is also correlated with PH, perhaps even more than diminished FVC, but the correlation between TTE and right heart catheterization pressures was most reliable (198).

The systematic review had several limitations. One was the criteria for identifying PH by TTE. The studies that we selected estimated right ventricular end systolic pressure (or pulmonary artery systolic pressure) based on tricuspid regurgitation (TR). However, up to one-third of patients do not have a sufficient TR jet to estimate pressure. TTE may identify right ventricular strain due to PH, but this alternative measure was not accounted for in the selected studies. Guidance on how to use evidence of right ventricular strain to detect pulmonary artery hypertension has been published elsewhere (190).

Another limitation was the inability of elevated pulmonary artery pressure identified by TTE to distinguish between precapillary PH and elevated pressure due to left ventricular dysfunction. These different types of PH have different causes and treatment (190), and different prognoses. In one study, patients with sarcoidosis with precapillary PH had worse survival than those with left ventricular dysfunction (185).

The evidence suggests that if TTE is performed on patients with sarcoidosis with suspected PH (i.e., persistent dyspnea despite treatment of their sarcoidosis), 29% will be abnormal, among which PH will be confirmed by right heart catheterization in roughly three-fourths and excluded in one-fourth. The committee concluded that TTE is a worthwhile screening test for suspected SAPH, because TTE abnormalities are prevalent and correlate directly with PH severity (185), but falsely abnormal TTE is too common to justify decision-making based on TTE alone. Right heart catheterization is necessary to confirm PH and to distinguish postcapillary PH (World Health Organization group II PH) from pre-capillary PH (World Health Organization group V PH), which are managed differently. Appropriate therapy has been shown to improve outcomes (183, 199–201), although the finding has not been universal (202).

For patients with sarcoidosis in whom PH is suspected, we suggest initial testing with TTE (conditional recommendation, very low-quality evidence). Remarks: “PH is suspected” refers to clinical manifestations, including exertional chest pain and/or syncope, exam findings of a prominent P2 or S4, reduced 6-minute walk distance, desaturation with exercise, reduced D l _CO, increased pulmonary artery diameter relative to ascending aorta diameter (e.g., by CT scan), elevated brain natriuretic factor, and fibrotic lung disease.

For patients with sarcoidosis in whom PH is suspected and a transthoracic echocardiogram is suggestive of PH, we suggest right heart catheterization to definitively confirm or exclude SAPH (conditional recommendation, very low-quality evidence).

For patients with sarcoidosis in whom PH is suspected and a transthoracic echocardiogram is NOT suggestive of PH, the need for right heart catheterization should be determined on a case-by-case basis.

Finally, routine screening for SAPH is unnecessary in those who are asymptomatic (Table 5).

The impact of underlying sarcoidosis on echocardiogram needs to be better defined. Sarcoidosis can directly affect the heart, including the right and left ventricle. In addition, parenchymal lung disease, especially pulmonary fibrosis, and hilar adenopathy impact the pulmonary artery architecture. Future studies are needed to better understand how such changes affect the accuracy of the echocardiogram. The estimated pulmonary artery pressure is based on TR, the severity of which may be influenced by right heart failure. The value of other radiographic features for predicting right ventricular failure is demonstrated in other forms of PH (190), and this needs to be considered in sarcoidosis; for example, CMR can visualize the right ventricle, and may provide a more reliable evaluation of right ventricular performance. Future studies are needed to evaluate the diagnostic and prognostic value of biomarkers, such as pro-BNP, to augment the detection and management of PH among patients with sarcoidosis (181, 203)

Committee members concur that there is a pressing need for higher-quality evidence to guide clinical practice relating to the diagnosis and detection of sarcoidosis, and to better define the natural history of disease progression in each organ system. A large body of related data has been published, but very few of these studies were properly designed to guide clinical practice. Nonetheless, this document establishes the current standards of care based on a rigorous and unbiased analysis of the available data, and provides direction for future investigations to further refine clinical practice to improve diagnosis and detection of sarcoidosis. Figure 3 provides an algorithm that incorporates the recommendations of these guidelines within the scope of clinical practice for the diagnosis and detection of sarcoidosis.

Figure 3. Schematic of recommended diagnostic algorithm. The figure outlines a general approach to the diagnosis of sarcoidosis and refers to tables presented with this article. PICO = problem, intervention, comparison, outcome question format.

This official clinical practice guideline was prepared by an ad hoc subcommittee of the ATS Assembly on Clinical Problems.

Members of the subcommittee are as follows:

E lliott D. C rouser , M.D. (Co-Chair) 1

R obert P. B aughman , M.D. (Co-Chair) 3

1 Division of Pulmonary, Critical Care, and Sleep Medicine and 23 Division of Cardiovascular Medicine, the Ohio State University, Columbus, Ohio; 2 Division of Environmental and Occupational Health and 16 Library and Knowledge Services, National Jewish Health, Denver, Colorado; 3 Department of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio; 4 Division of Pulmonary, Allergy, Sleep, and Critical Care Medicine, Boston University School of Medicine, Boston, Massachusetts; 5 Division of Pulmonary, Allergy, and Critical Care Medicine, Penn State University, Hershey, Pennsylvania; 6 Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; 7 Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia; 8 Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical School, Baltimore, Maryland; 9 Department of Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio; 10 Division of Infectious Diseases, Vanderbilt University, Nashville, Tennessee; 11 Interstitial Lung Disease Center of Excellence, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands; 12 Department of Toxicology and Pharmacology, Faculty of Health, Medicine and Life Sciences, University Maastricht, Maastricht, the Netherlands; 13 Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa, Iowa City, Iowa; 14 Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Medical University of South Carolina, Charleston, South Carolina; 15 Division of Pulmonary Medicine, Albany Medical College, Albany, New York; 17 Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, California; 18 Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; 19 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 20 Brighton and Sussex Medical School, Brighton, England; 21 Department of Diseases of the Thorax, Morgagni Hospital, Forlì, Italy; 22 Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 24 Kaiser Permanente Northern California, Oakland, California; and 25 Division of Pulmonary and Critical Care Medicine, Morehouse School of Medicine, Atlanta, Georgia

The committee acknowledges the American Thoracic Society (ATS) for supporting this project, including members of the ATS Documents Committee, and ATS staff, Kimberly Lawrence, John Harmon, and Judy Corn, for administrative assistance. It also appreciates the many peer reviewers and representatives of patients with sarcoidosis who took part in the face-to-face meetings. Special thanks also to Dr. Konstantin Shiloh for providing histopathology images for Figure 1 .

Robert Phillip Baughman

Dr. Baughman is Professor of Medicine at the University of Cincinnati. After completing undergraduate training at Yale University, he received his medical degree from Case Western Reserve School of Medicine. He joined the Internal Medicine staff at the University of Cincinnati after completing both an Internal Medicine residency and fellowship training in pulmonary diseases at the University of Cincinnati. His major research interests include two major clinic areas: the treatment of sarcoidosis and the diagnosis of pneumonia. Along with his long time collaborator Dr. Elyse Lower, he has developed several novel treatments for sarcoidosis, including methotrexate, thalidomide, leflunomide, and infliximab. Current studies include treatments for sarcoidosis associated fatigue and pulmonary hypertension due to sarcoidosis.

He is on the editorial board of multiple subspecialty journals, and his publications include over 150 original papers and over 70 review articles and/or book chapters. He is on the editorial board of several journals, including American Journal of Respiratory and Critical Care Medicine and Chest. In addition, Dr. Baughman is the recent editor of books on sarcoidosis, interstitial lung disease, and ventilator associated pneumonia.

Education

Bachelor’s Degree: Yale University New Haven, CT, 1973

Medical Degree: Case-Western Reserve Cleveland, OH, 1977

Internship & Residency: University of Cincinnati Cincinnati, OH, 1980

Fellowship: University of Cincinnati Cincinnati, OH, 1982 (Pulmonary)

Chief Resident: University of Cincinnati Cincinnati, OH, 1983 (Internal Medicine)

Certifications

American Board of Internal Medicine (Certification Date: 09-09-1980 )

American Board of Internal Medicine (Pulmonary Disease) (Certification Date: 11-09-1982 )

Clinical Interests

Research and Practice Interests

Caseswill also be followed to gain information on the natural history of thisdisease including risk factors for progression of disease. A steeringcommittee will develop a protocol and manual of operations which willaddress the most promising hypotheses to be pursued to identify thecauses of sarcoidosis. The protocol will include a comprehensiveclinical characterization of each participant and determination of markersof immune responsiveness. The contractor will participate in a system forbanking biological specimens. A clinical coordinating center will be established to collect, manage andanalyze the data from the clinical centers. It is estimated that thetotal study population will consist of 720 cases and 1,440 controls. Itis estimated that each clinical center will enroll, interview, and examine72 cases age 21 years or older with sarcoidosis and, enroll, interviewand collect a blood specimen from 144 matched control subjects over a fouryear period. Clinical centers will 1 test specific hypotheses involvingrisk factors, familial aggregation, and genetics of the etiology of thisdisease and 2 describe the natural history of sarcoidosis. A six yearschedule is envisioned as follows: Phase I 12 Months: A collaborativeprotocol and manual of operations will be developed; Phase II 48 Months: will involve the recruitment and follow-up of patients and recruitment andinterviewing of control subjects, and Phase III 12 Months: will involvedata analysis.

Positions and Work Experience

1983 -1990 Assistant Professor, University of Cincinnati, Cincinnati, OH

1990 -1997 Associate Professor, University of Cincinnati, Cincinnati, OH

1997 -To Present Professor of Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH

Research Support

Grant: #CHMC 333 / HL 072987 Investigators:Baughman, Robert 08-06-2003 -07-31-2007 National Heart, Lung and Blood Institute Mechanisms: IL-13 Induced Mucus Hypersecretion in Asthma Role:PI $242,095.00 Closed Level:Federal

Grant: #3-N01-HR-56069-06-A0-S1-E1 Investigators:Baughman, Robert 07-17-1995 -05-16-2002 National Heart, Lung and Blood Institute Clinical Centers for Etiology of Sarcoidosis: A Case Control Study Role:PI $587,685.00 Closed Level:Federal

Grant: #5-U01-HL-60263-05-A0-S0-E0 Investigators:Baughman, Robert 05-15-1999 -04-30-2004 National Heart, Lung and Blood Institute Sarcoidosis Genetic Linkage Consortium Role:PI $383,119.00 Closed Level:Federal

Grant: #VUMC 42525 / R01 HL117074 Investigators:Baughman, Robert; Shipley, Ralph 08-16-2013 -06-30-2018 National Heart, Lung and Blood Institute Microbial induction of sarcoidosis CD4+ T cell dysfunction Role:PI $100,866.00 Active Level:Federal

Grant: #Clin. Studies Network Investigators:Baughman, Robert 04-01-2015 -03-31-2017 Foundation for Sarcoidosis Research Defining Minimal Clinical Important Difference in Treatment Trials of Pulmonary Sarcoidosis Role:PI $30,000.00 Awarded Level:Private Non-Profit

Grant: #VUMV 42525 / R01 HL117074 Investigators:Baughman, Robert; Shipley, Ralph 07-01-2016 -06-30-2018 National Heart, Lung and Blood Institute Microbial induction of sarcoidosis CD4+ T cell dysfunction Role:PI $111,840.00 Active Level:Federal

Grant: #Clinical Trial Agreement – PAPLAND Investigators:Baughman, Robert; Lower, Elyse 11-26-2018 -11-25-2020 Foundation for Sarcoidosis Research Validation of a Sarcoidosis Diagnostic Score (SDS) Role:PI $80,000.00 Awarded Level:Private Non-Profit

Grant: #Check 3150 Investigators:Baughman, Robert 06-01-2019 -05-31-2021 Foundation for Sarcoidosis Research Foundation for Sarcoidosis Research addt’l network funding Role:PI $20,000.00 Awarded Level:Private Non-Profit

Publications

Peer Reviewed Publications

Levin, Benjamin; Baughman, Robert P; Sweiss, Nadera J (2021. ) Detection of early phenotype cardiac sarcoidosis by cardiovascular magnetic resonance. Current opinion in pulmonary medicine, , 27 (5 ) ,478-483 More Information

Chanson, Noémie; Ramos-Casals, Manuel; Pundole, Xerxes; Suijkerbuik, Karijn; José de Barros E Silva, Milton; Lidar, Merav; Benesova, Karolina; Leipe, Jan; Acar-Denizli, Nihan; Pradère, Pauline; Michot, Jean-Marie; Voisin, Anne-Laure; Suárez-Almazor, Maria E; Radstake, Timothy R D; Fernandes Moça Trevisani, Virginia; Schulze-Koops, Hendrik; Melin, Audrey; Robert, Caroline; Mariette, Xavier; Baughman, Robert P; Lambotte, Olivier (2021. ) Immune checkpoint inhibitor-associated sarcoidosis: A usually benign disease that does not require immunotherapy discontinuation. European journal of cancer (Oxford, England : 1990), , More Information

Zhou, Ying; Gerke, Alicia K; Lower, Elyse E; Vizel, Alexander; Talwar, Deepak; Strambu, Irina; Francesqui, Joel; Sellares, Jacobo; Sawahata, Michiru; Obi, Ogugua Ndili; Nagai, Sonoko; Tanizawa, Kiminobu; Judson, Marc A; Jeny, Florence; Valeyre, Dominique; Cunha Castro, Marina Dornfeld; Pereira, Carlos; Balter, Meyer; Baughman, Robert P (2021. ) The impact of demographic disparities in the presentation of sarcoidosis: A multicenter prospective study. Respiratory medicine, , 187 ,106564 More Information

Baughman, Robert P; Shlobin, Oksana A; Gupta, Rohit; Engel, Peter J; Stewart, Jeffrey I; Lower, Elyse E; Rahaghi, Franck F; Zeigler, Joyce; Nathan, Steven D (2021. ) Riociguat for Sarcoidosis-Associated Pulmonary Hypertension: Results of a 1-Year Double-Blind, Placebo-Controlled Trial. Chest, , More Information

Baughman, Robert P; Kotzin, Jacob; Lower, Elyse E (2021. ) The Value of a Patient Global Assessment in Management of Sarcoidosis. Lung, , 199 (4 ) ,357-362 More Information

Baughman, Robert P; Valeyre, Dominique; Korsten, Peter; Mathioudakis, Alexander G; Wuyts, Wim A; Wells, Athol; Rottoli, Paola; Nunes, Hiliaro; Lower, Elyse E; Judson, Marc A; Israel-Biet, Dominique; Grutters, Jan C; Drent, Marjolein; Culver, Daniel A; Bonella, Francesco; Antoniou, Katerina; Martone, Filippo; Quadder, Bernd; Spitzer, Ginger; Nagavci, Blin; Tonia, Thomy; Rigau, David; Ouellette, Daniel R (2021. ) ERS clinical practice guidelines on treatment of sarcoidosis. The European respiratory journal, , More Information

Saketkoo, Lesley Ann; Russell, Anne-Marie; Jensen, Kelly; Mandizha, Jessica; Tavee, Jinny; Newton, Jacqui; Rivera, Frank; Howie, Mike; Reese, Rodney; Goodman, Melanie; Hart, Patricia; Strookappe, Bert; De Vries, Jolanda; Rosenbach, Misha; Scholand, Mary Beth; Lammi, Mathew R; Elfferich, Marjon; Lower, Elyse; Baughman, Robert P; Sweiss, Nadera; Judson, Marc A; Drent, Marjolein (2021. ) Health-Related Quality of Life (HRQoL) in Sarcoidosis: Diagnosis, Management, and Health Outcomes. Diagnostics (Basel, Switzerland), , 11 (6 ) , More Information

Obi, Ogugua Ndili; Judson, Marc A; Birring, Surinder S; Maier, Lisa A; Wells, Athol U; Lower, Elyse E; Baughman, Robert P (2021. ) Assessment of dyspnea in sarcoidosis using the Baseline Dyspnea Index (BDI) and the Transition Dyspnea Index (TDI). Respiratory medicine, , 106436 More Information

Drake, Wonder P; Culver, Daniel A; Baughman, Robert P; Judson, Marc A; Crouser, Elliott D; James, W Ennis; Ayers, Gregory D; Ding, Tan; Abel, Kenny; Green, Abena; Kerrigan, Amy; Sesay, Ahmed; Bernard, Gordon R (2021. ) Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis. Chest, , 159 (5 ) ,1902-1912 More Information

Manansala, Michael; Baughman, Robert; Novak, Richard; Judson, Marc; Sweiss, Nadera (2021. ) Management of immunosuppressants in the era of coronavirus disease-2019. Current opinion in pulmonary medicine, , 27 (3 ) ,176-183 More Information

Manansala, Michael; Chopra, Amit; Baughman, Robert P; Novak, Richard; Lower, Elyse E; Culver, Daniel A; Korsten, Peter; Drake, Wonder P; Judson, Marc A; Sweiss, Nadera (2021. ) COVID-19 and Sarcoidosis, Readiness for Vaccination: Challenges and Opportunities. Frontiers in medicine, , 8 ,672028 More Information

Baughman, Robert P; Judson, Marc A; Beaumont, Jennifer L; Maier, Lisa A; Sweiss, Nadera J; Culver, Daniel A; Chen, Edward S; Singh, Noopur; Lower, Elyse E; Reeves, Rebecca; Hamzeh, Nabeel; Grutters, Jan C; Valeyre, Dominique; Birring, Surinder S (2021. ) Evaluating the Minimal Clinically Important Difference of the King’s Sarcoidosis Questionnaire in a Multicenter Prospective Study. Annals of the American Thoracic Society, , 18 (3 ) ,477-485 More Information

Sweiss, Nadera J; Korsten, Peter; Baughman, Robert P; Culver, Daniel A; Judson, Marc A (2021. ) Response. Chest, , 159 (3 ) ,1307-1308 More Information

Vagts, Christen; Ascoli, Christian; Fraidenburg, Dustin R; Baughman, Robert P; Huang, Yue; Edafetanure-Ibeh, Russell; Ahmed, Samreen; Levin, Benjamin; Lu, Yang; Perkins, David L; Finn, Patricia W; Sweiss, Nadera J (2021. ) Unsupervised Clustering Reveals Sarcoidosis Phenotypes Marked by a Reduction in Lymphocytes Relate to Increased Inflammatory Activity on 18FDG-PET/CT. Frontiers in medicine, , 8 ,595077 More Information

Obi, Ogugua Ndili; Lower, Elyse E; Baughman, Robert P (2021. ) Biologic and advanced immunomodulating therapeutic options for sarcoidosis: a clinical update. Expert review of clinical pharmacology, , 14 (2 ) ,179-210 More Information

Baughman, Robert P; Lower, Elyse E (2021. ) COVID-19 infections in sarcoidosis: a prospective single center study of 886 sarcoidosis patients. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 38 (2 ) ,e2021029 More Information

Singha, Arindam; Liao, Shu-Yi; Herman, Derrick D; Crouser, Elliott D; Maier, Lisa A; Baughman, Robert P; Ruminjo, Joseph K; Thomson, Carey C (2020. ) Summary for Clinicians: Clinical Practice Guideline for the Diagnosis and Detection of Sarcoidosis. Annals of the American Thoracic Society, , 17 (12 ) ,1510-1515 More Information

Lo, K H; Donohue, J; Judson, M A; Wu, Y; Barnathan, E S; Baughman, R P (2020. ) The St. George’s Respiratory Questionnaire in Pulmonary Sarcoidosis. Lung, , 198 (6 ) ,917-924 More Information

Patterson, Karen C; Bonham, Catherine A; Wilson, Kevin C; Crouser, Elliott D; Baughman, Robert P; Maier, Lisa A (2020. ) Reply to P. B. et al., to Fahim and Rosewarne, and to Reich. American journal of respiratory and critical care medicine, , 202 (9 ) ,1322-1324 More Information

Obi, Ogugua Ndili; Baughman, Robert P (2020. ) Mixed Obstructive and Restrictive Ventilatory Defect in Sarcoidosis: A New Phenotype? .Chest, , 158 (5 ) ,1816-1817 More Information

Trivieri, Maria Giovanna; Spagnolo, Paolo; Birnie, David; Liu, Peter; Drake, Wonder; Kovacic, Jason C; Baughman, Robert; Fayad, Zahi A; Judson, Marc A (2020. ) Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review. Journal of the American College of Cardiology, , 76 (16 ) ,1878-1901 More Information

Gupta, Rohit; Baughman, Robert P (2020. ) Advanced Pulmonary Sarcoidosis. Seminars in respiratory and critical care medicine, , 41 (5 ) ,700-715 More Information

Baughman, Robert P; Judson, Marc (2020. ) Sarcoidosis: Advances in Therapy. Seminars in respiratory and critical care medicine, , 41 (5 ) ,605-606 More Information

Sweiss, Nadera J; Korsten, Peter; Syed, Huzaefah J; Syed, Aamer; Baughman, Robert P; Yee, Arthur M F; Culver, Daniel A; Sosenko, Teresa; Azuma, Arata; Bonella, Francesco; Costabel, Ulrich; Drake, Wonder P; Drent, Marjolein; Lower, Elyse E; Israel-Biet, Dominique; Mostard, Remy L M; Nunes, Hilario; Rottoli, Paola; Spagnolo, Paolo; Wells, Athol U; Wuyts, Wim A; Judson, Marc A (2020. ) When the Game Changes: Guidance to Adjust Sarcoidosis Management During the Coronavirus Disease 2019 Pandemic. Chest, , 158 (3 ) ,892-895 More Information

Lower, Elyse E; Sturdivant, Madison; Grate, Lisa; Baughman, Robert P Use of third-line therapies in advanced sarcoidosis. Clinical and experimental rheumatology, , 38 (5 ) ,834-840

Sellarés, Jacobo; Francesqui, Joel; Llabres, Marta; Hernandez-Gonzalez, Fernanda; Baughman, Robert P (2020. ) Current treatment of sarcoidosis. Current opinion in pulmonary medicine, , 26 (5 ) ,591-597 More Information

Shlobin, Oksana A; Kouranos, Vasilis; Barnett, Scott D; Alhamad, Esam H; Culver, Daniel A; Barney, Joseph; Cordova, Francis C; Carmona, Eva M; Scholand, Mary Beth; Wijsenbeek, Marlies; Ganesh, Sivagini; Lower, Elyse E; Engel, Peter J; Wort, John; Price, Laura; Wells, Athol U; Nathan, Steven D; Baughman, Robert P (2020. ) Physiological predictors of survival in patients with sarcoidosis-associated pulmonary hypertension: results from an international registry. The European respiratory journal, , 55 (5 ) , More Information

Harper, Logan J; Gerke, Alicia K; Wang, Xiao-Feng; Ribeiro Neto, Manuel L; Baughman, Robert P; Beyer, Kelli; Drent, Marjolein; Judson, Marc A; Maier, Lisa A; Serchuck, Leslie; Singh, Noopur; Culver, Daniel A (2020. ) Income and Other Contributors to Poor Outcomes in U.S. Patients with Sarcoidosis. American journal of respiratory and critical care medicine, , 201 (8 ) ,955-964 More Information

Rahaghi, Franck F; Sweiss, Nadera J; Saketkoo, Lesley Ann; Scholand, Mary Beth; Barney, Joseph B; Gerke, Alicia K; Lower, Elyse E; Mirsaeidi, Mehdi; O’Hare, Lanier; Rumbak, Mark J; Samavati, Lobelia; Baughman, Robert P (2020. ) Management of repository corticotrophin injection therapy for pulmonary sarcoidosis: a Delphi study. European respiratory review : an official journal of the European Respiratory Society, , 29 (155 ) , More Information

Rahaghi, Franck F; Baughman, Robert P; Saketkoo, Lesley Ann; Sweiss, Nadera J; Barney, Joseph B; Birring, Surinder S; Costabel, Ulrich; Crouser, Elliott D; Drent, Marjolein; Gerke, Alicia K; Grutters, Jan C; Hamzeh, Nabeel Y; Huizar, Isham; Ennis James, W; Kalra, Sanjay; Kullberg, Susanna; Li, Huiping; Lower, Elyse E; Maier, Lisa A; Mirsaeidi, Mehdi; Müller-Quernheim, Joachim; Carmona Porquera, Eva M; Samavati, Lobelia; Valeyre, Dominique; Scholand, Mary Beth (2020. ) Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. European respiratory review : an official journal of the European Respiratory Society, , 29 (155 ) , More Information

Baughman, Robert P; Scholand, Mary Beth; Rahaghi, Franck F (2020. ) Clinical phenotyping: role in treatment decisions in sarcoidosis. European respiratory review : an official journal of the European Respiratory Society, , 29 (155 ) , More Information

Kirkil, Gamze; Lower, Elyse E; Baughman, Robert P Chest CT scan: The best predictor of mortality in advanced pulmonary sarcoidosis? .Respiratory medicine, , 170 ,106059 More Information

Baughman, Robert P; Lower, Elyse E; Buchanan, Mindy; Rottoli, Paola; Drent, Marjolein; Sellares, Jacobo; Terwiel, Michelle; Elfferich, Marjon; Francesqui, Joel; Barriuso Cabrerizo, María Rita; Sweiss, Nadera; Martone, Filippo; Al-Hakim, Tamara; Judson, Marc A (2020. ) Risk and outcome of COVID-19 infection in sarcoidosis patients: results of a self-reporting questionnaire. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 37 (4 ) ,e2020009 More Information

Baughman, Robert P; Cremers, Johanna P; Harmon, Martina; Lower, Elyse E; Drent, Marjolein (2020. ) Methotrexate in sarcoidosis: hematologic and hepatic toxicity encountered in a large cohort over a six year period. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 37 (3 ) ,e2020001 More Information

Syed, Huzaefah; Ascoli, Christian; Linssen, Catharina Fm; Vagts, Christen; Iden, Thomas; Syed, Aamer; Kron, Jordana; Polly, Kelly; Perkins, David; Finn, Patricia W; Novak, Richard; Drent, Marjolein; Baughman, Robert; Sweiss, Nadera J (2020. ) Infection prevention in sarcoidosis: proposal for vaccination and prophylactic therapy. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 37 (2 ) ,87-98 More Information

Brito-Zerón, Pilar; Kostov, Belchin; Superville, Daphne; Baughman, Robert P; Ramos-Casals, Manuel Geoepidemiological big data approach to sarcoidosis: geographical and ethnic determinants. Clinical and experimental rheumatology, , 37 (6 ) ,1052-1064

Martusewicz-Boros, Magdalena M; Boros, Piotr W; Wiatr, El?bieta; Zych, Jacek; Kempisty, Anna; Kram, Marek; Piotrowska-Kownacka, Dorota; Weso?owski, Stefan; Baughman, Robert P; Roszkowski-Sli?, Kazimierz (2019. ) Cardiac sarcoidosis: worse pulmonary function due to left ventricular ejection fraction?: A case-control study. Medicine, , 98 (47 ) ,e18037 More Information

Kampstra, Nynke A; van der Nat, Paul B; Dijksman, Lea M; van Beek, Frouke T; Culver, Daniel A; Baughman, Robert P; Renzoni, Elisabetta A; Wuyts, Wim; Kouranos, Vasilis; Zanen, Pieter; Wijsenbeek, Marlies S; Eijkemans, Marinus J C; Biesma, Douwe H; van der Wees, Philip J; Grutters, Jan C (2019. ) Results of the standard set for pulmonary sarcoidosis: feasibility and multicentre outcomes. ERJ open research, , 5 (4 ) , More Information

Baughman, Robert P; Wells, Athol (2019. ) Advanced sarcoidosis. Current opinion in pulmonary medicine, , 25 (5 ) ,497-504 More Information

Brito-Zerón, Pilar; Bari, Khurram; Baughman, Robert P; Ramos-Casals, Manuel (2019. ) Sarcoidosis Involving the Gastrointestinal Tract: Diagnostic and Therapeutic Management. The American journal of gastroenterology, , 114 (8 ) ,1238-1247 More Information

Ramos-Casals, Manuel; Kostov, Belchin; Brito-Zerón, Pilar; Sisó-Almirall, Antoni; Baughman, Robert P (2019. ) How the Frequency and Phenotype of Sarcoidosis is Driven by Environmental Determinants. Lung, , 197 (4 ) ,427-436 More Information

Voortman, Mareye; Drent, Marjolein; Baughman, Robert P (2019. ) Management of neurosarcoidosis: a clinical challenge. Current opinion in neurology, , 32 (3 ) ,475-483 More Information

Trisolini, Rocco; Baughman, Robert P; Spagnolo, Paolo; Culver, Daniel A (2019. ) Endobronchial ultrasound-guided transbronchial needle aspiration in sarcoidosis: Beyond the diagnostic yield. Respirology (Carlton, Vic.), , 24 (6 ) ,531-542 More Information

Kampstra, Nynke A; Grutters, Jan C; van Beek, Frouke T; Culver, Daniel A; Baughman, Robert P; Renzoni, Elisabetta A; Wuyts, Wim; Kouranos, Vaslis; Wijsenbeek, Marlies S; Biesma, Douwe H; van der Wees, Philip J; van der Nat, Paul B (2019. ) First patient-centred set of outcomes for pulmonary sarcoidosis: a multicentre initiative. BMJ open respiratory research, , 6 (1 ) ,e000394 More Information

Lower, Elyse E; Sturdivant, Madison; Baughman, Robert P (2019. ) Presence of onconeural antibodies in sarcoidosis patients with parasarcoidosis syndrome. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 36 (4 ) ,254-260 More Information

Baughman, Robert P; Tillinger, Michael; Qin, Yimin; Sweiss, Nadera; Lower, Elyse E (2019. ) A composite score to assess treatment response in pulmonary sarcoidosis: the Sarcoidosis Treatment Score (STS). Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 36 (1 ) ,86-88 More Information

Baughman, Robert P; Barriuso, Rita; Beyer, Kelli; Boyd, Jeanette; Hochreiter, Johann; Knoet, Chris; Martone, Filippo; Quadder, Bernd; Richardson, Jack; Spitzer, Ginger; Valeyre, Dominique; Ziosi, Gianluca (2018. ) Sarcoidosis: patient treatment priorities. ERJ open research, , 4 (4 ) , More Information

Stern, Barney J; Royal, Walter; Gelfand, Jeffrey M; Clifford, David B; Tavee, Jinny; Pawate, Siddharama; Berger, Joseph R; Aksamit, Allen J; Krumholz, Allan; Pardo, Carlos A; Moller, David R; Judson, Marc A; Drent, Marjolein; Baughman, Robert P (2018. ) Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group. JAMA neurology, , 75 (12 ) ,1546-1553 More Information

Bickett, Alexandra N; Lower, Elyse E; Baughman, Robert P (2018. ) Sarcoidosis Diagnostic Score: A Systematic Evaluation to Enhance the Diagnosis of Sarcoidosis. Chest, , 154 (5 ) ,1052-1060 More Information

Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D; Luo, Weifeng; Creecy, Amy; Abad, Andrew T; Chioma, Ozioma S; Lee, Grace; Hassell, Natalie E; Shaginurova, Guzel I; Wang, Yufen; Johnson, Joyce E; Kerrigan, Amy; Mason, Wendi R; Baughman, Robert P; Ayers, Gregory D; Bernard, Gordon R; Culver, Daniel A; Montgomery, Courtney G; Maher, Toby M; Molyneaux, Philip L; Noth, Imre; Mutsaers, Steven E; Prele, Cecilia M; Peebles, R S; Newcomb, Dawn C; Kaminski, Naftali; Blackwell, Timothy S; Van Kaer, Luc; Drake, Wonder P (2018. ) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Science translational medicine, , 10 (460 ) , More Information

Spagnolo, Paolo; Rossi, Giulio; Trisolini, Rocco; Sverzellati, Nicola; Baughman, Robert P; Wells, Athol U (2018. ) Sarcoidosis: is cryobiopsy not cool enough? – Authors’ reply. The Lancet. Respiratory medicine, , 6 (9 ) ,e45 More Information

James, W Ennis; Baughman, Robert (2018. ) Treatment of sarcoidosis: grading the evidence. Expert review of clinical pharmacology, , 11 (7 ) ,677-687 More Information

Cooley, Joseph; Balestra, Rick; Aragaki-Nakahodo, Alejandro A; Caudell Stamper, Danielle N; Sriprasart, Thitiwat; Swank, Zulma; Baughman, Robert P; Benzaquen, Sadia (2018. ) Safety of performing transbronchial lung cryobiopsy on hospitalized patients with interstitial lung disease. Respiratory medicine, , 140 ,71-76 More Information

Baughman, Robert P; Lower, Elyse E; Kirkil, Gamze (2018. ) Response. Chest, , 153 (6 ) ,1507-1508 More Information

Baughman, Robert P; Shlobin, Oksana A; Wells, Athol U; Alhamad, Esam H; Culver, Daniel A; Barney, Joseph; Cordova, Francis C; Carmona, Eva M; Scholand, Mary Beth; Wijsenbeek, Marlies; Ganesh, Sivagini; Birring, Surinder S; Kouranos, Vasilis; O’Hare, Lanier; Baran, Joanne M; Cal, Joseph G; Lower, Elyse E; Engel, Peter J; Nathan, Steven D (2018. ) Clinical features of sarcoidosis associated pulmonary hypertension: Results of a multi-national registry. Respiratory medicine, , 139 ,72-78 More Information

Pirozzi, Cheryl S; Mendoza, Daniel L; Xu, Yizhe; Zhang, Yue; Scholand, Mary Beth; Baughman, Robert P (2018. ) Short-Term Particulate Air Pollution Exposure is Associated with Increased Severity of Respiratory and Quality of Life Symptoms in Patients with Fibrotic Sarcoidosis. International journal of environmental research and public health, , 15 (6 ) , More Information

Spagnolo, Paolo; Rossi, Giulio; Trisolini, Rocco; Sverzellati, Nicola; Baughman, Robert P; Wells, Athol U (2018. ) Pulmonary sarcoidosis. The Lancet. Respiratory medicine, , 6 (5 ) ,389-402 More Information

Baughman, Robert P; Lower, Elyse E (2018. ) Steroids for sarcoidosis: How much and for how long? .Respiratory medicine, , 138S ,S5-S6 More Information

Culver, Daniel A; Baughman, Robert P (2018. ) It’s time to evolve from Scadding: phenotyping sarcoidosis. The European respiratory journal, , 51 (1 ) , More Information

Irwin, Richard S; Manaker, Scott; Metersky, Mark L; Baughman, Robert P; Otulana, Tunde; Weinberger, Steven E; Sussman, Andrew J; McGrath, Norine A (2018. ) Higher Priced Older Pharmaceuticals: How Should We Respond? .Chest, , 153 (1 ) ,23-33 More Information

Kirkil, Gamze; Lower, Elyse E; Baughman, Robert P (2018. ) Predictors of Mortality in Pulmonary Sarcoidosis. Chest, , 153 (1 ) ,105-113 More Information

Kamata, Yoshinori; Sato, Hiroshi; Joh, Kensuke; Tsuchiya, Yoshinori; Kunugi, Shinobu; Shimizu, Akira; Konta, Tsuneo; Baughman, Robert P; Azuma, Arata (2018. ) Clinical characteristics of biopsy-proven renal sarcoidosis in Japan. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 35 (3 ) ,252-260 More Information

Mirsaeidi, Mehdi; Omar, Hesham R; Calzadilla, Andrew; Khatib, Ahmad El; Whitney, Philip; Sweiss, Nadera; Culver, Daniel; Campos, Michael; Baughman, Robert; Machado, Roberto (2018. ) Circulatory TGF-beta1 is significantly higher in early stage of pulmonary sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 35 (3 ) ,213-217 More Information

Sauer, William H; Stern, Barney J; Baughman, Robert P; Culver, Daniel A; Royal, Walter (2017. ) High-Risk Sarcoidosis. Current Concepts and Research Imperatives. Annals of the American Thoracic Society, , 14 (Supplement_6 ) ,S437-S444 More Information

Baughman, Robert P; Shlobin, Oksana A (2017. ) Treatment of sarcoidosis-associated pulmonary hypertension: so close, and yet so far. The European respiratory journal, , 50 (4 ) , More Information

Aragaki-Nakahodo, Alejandro Adolfo; Baughman, Robert P; Shipley, Ralph T; Benzaquen, Sadia (2017. ) The complimentary role of transbronchial lung cryobiopsy and endobronchial ultrasound fine needle aspiration in the diagnosis of sarcoidosis. Respiratory medicine, , 131 ,65-69 More Information

Baughman, Robert P; Veltkamp, Marcel (2017. ) Sarcoidosis update: approaching the disease from multiple directions. Current opinion in pulmonary medicine, , 23 (5 ) ,432 More Information

Baughman, Robert P; Papanikolaou, Ilias (2017. ) Current concepts regarding calcium metabolism and bone health in sarcoidosis. Current opinion in pulmonary medicine, , 23 (5 ) ,476-481 More Information

Lower, Elyse E; Khan, Shagufta; Kennedy, Diane; Baughman, Robert P (2017. ) Discordance of the estrogen receptor and HER-2/neu in breast cancer from primary lesion to first and second metastatic site. Breast cancer (Dove Medical Press), , 9 ,515-520 More Information

Zhou, Ying; Lower, Elyse E; Li, Huiping; Farhey, Yolanda; Baughman, Robert P (2017. ) Clinical characteristics of patients with bone sarcoidosis. Seminars in arthritis and rheumatism, , 47 (1 ) ,143-148 More Information

Shlobin, Oksana A; Baughman, Robert P (2017. ) Sarcoidosis-Associated Pulmonary Hypertension. Seminars in respiratory and critical care medicine, , 38 (4 ) ,450-462 More Information

Uzunhan, Yurdagül; Nunes, Hilario; Jeny, Florence; Lacroix, Maxime; Brun, Sophie; Brillet, Pierre-Yves; Martinod, Emmanuel; Carette, Marie-France; Bouvry, Diane; Charlier, Caroline; Lanternier, Fanny; Planès, Carole; Tazi, Abdellatif; Lortholary, Olivier; Baughman, Robert P; Valeyre, Dominique (2017. ) Chronic pulmonary aspergillosis complicating sarcoidosis. The European respiratory journal, , 49 (6 ) , More Information

Monast, C S; Li, K; Judson, M A; Baughman, R P; Wadman, E; Watt, R; Silkoff, P E; Barnathan, E S; Brodmerkel, C (2017. ) Sarcoidosis extent relates to molecular variability. Clinical and experimental immunology, , 188 (3 ) ,444-454 More Information

Baughman, Robert P; Sweiss, Nadera; Keijsers, Ruth; Birring, Surinder S; Shipley, Ralph; Saketkoo, Lesley Ann; Lower, Elyse E (2017. ) Repository corticotropin for Chronic Pulmonary Sarcoidosis. Lung, , 195 (3 ) ,313-322 More Information

Sriprasart, Thitiwat; Aragaki, Alejandro; Baughman, Robert; Wikenheiser-Brokamp, Kathryn; Khanna, Gaurav; Tanase, Daniel; Kirschner, Michelle; Benzaquen, Sadia (2017. ) A Single US Center Experience of Transbronchial Lung Cryobiopsy for Diagnosing Interstitial Lung Disease With a 2-Scope Technique. Journal of bronchology & interventional pulmonology, , 24 (2 ) ,131-135 More Information

Zhou, Ying; Lower, Elyse E; Li, Hui-Ping; Costea, Alexandru; Attari, Mehran; Baughman, Robert P (2017. ) Cardiac Sarcoidosis: The Impact of Age and Implanted Devices on Survival. Chest, , 151 (1 ) ,139-148 More Information

Baughman, R P; Lower, E E Measuring sarcoidosis around the world: Using the same ruler. Revista portuguesa de pneumologia, , 23 (5 ) ,247-248 More Information

Tandon, Rajive; Baughman, Robert P; Stanley, Janice; Khan, Ali A (2017. ) The link between chronic thromboembolic pulmonary hypertension and sarcoidosis: association or visual masquerade? .Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 34 (4 ) ,352-355 More Information

Baughman, Robert P; Judson, Marc A; Wells, Athol (2017. ) The indications for the treatment of sarcoidosis: Wells Law. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 34 (4 ) ,280-282 More Information

Berg, Sara A; Yeung, Howa; English, Joseph C; Keimig, Emily L; Kim, Ellen J; Micheletti, Robert G; Wanat, Karolyn A; Judson, Marc A; Baughman, Robert P; Rosenbach, Misha (2017. ) Inter-rater reliability of cutaneous sarcoidosis assessment tools via remote photographic assessment. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 34 (2 ) ,165-169 More Information

Brito-Zerón, Pilar; Pérez-Alvarez, Roberto; Pallarés, Lucio; Retamozo, Soledad; Baughman, Robert P; Ramos-Casals, Manuel (2016. ) Sarcoidosis: an update on current pharmacotherapy options and future directions. Expert opinion on pharmacotherapy, , 17 (18 ) ,2431-2448 More Information

Ford, H J; Baughman, R P; Aris, R; Engel, P; Donohue, J F (2016. ) Tadalafil therapy for sarcoidosis-associated pulmonary hypertension. Pulmonary circulation, , 6 (4 ) ,557-562 More Information

Al-Kofahi, Khalid; Korsten, Peter; Ascoli, Christian; Virupannavar, Shanti; Mirsaeidi, Mehdi; Chang, Ian; Qaqish, Naim; Saketkoo, Lesley A; Baughman, Robert P; Sweiss, Nadera J (2016. ) Management of extrapulmonary sarcoidosis: challenges and solutions. Therapeutics and clinical risk management, , 12 ,1623-1634 More Information

Baughman, Robert P; Field, Shelli; Costabel, Ulrich; Crystal, Ronald G; Culver, Daniel A; Drent, Marjolein; Judson, Marc A; Wolff, Gerhard (2016. ) Sarcoidosis in America. Analysis Based on Health Care Use. Annals of the American Thoracic Society, , 13 (8 ) ,1244-52 More Information

Saketkoo, Lesley Ann; Baughman, Robert P (2016. ) Biologic therapies in the treatment of sarcoidosis. Expert review of clinical immunology, , 12 (8 ) ,817-25 More Information

Korsten, Peter; Strohmayer, Katharina; Baughman, Robert P; Sweiss, Nadera J (2016. ) Refractory pulmonary sarcoidosis – proposal of a definition and recommendations for the diagnostic and therapeutic approach. Clinical pulmonary medicine, , 23 (2 ) ,67-75 More Information

Baughman, Robert P; Judson, Marc A; Lower, Elyse E; Drent, Marjolein; Costabel, Ulrich; Flavin, Susan; Lo, Kim Hung; Barnathan, Elliot S (2016. ) Infliximab for chronic cutaneous sarcoidosis: a subset analysis from a double-blind randomized clinical trial. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 32 (4 ) ,289-95

Zhou, Ying; Lower, Elyse E; Li, Huiping; Baughman, Robert P (2016. ) Clinical management of pulmonary sarcoidosis. Expert review of respiratory medicine, , 10 (5 ) ,577-91 More Information

Baughman, Robert P; Barney, Joseph B; O’Hare, Lanier; Lower, Elyse E (2016. ) A retrospective pilot study examining the use of Acthar gel in sarcoidosis patients. Respiratory medicine, , 110 ,66-72 More Information

Baughman, Robert P; Culver, Daniel A (2015. ) Sarcoidosis. Clinics in chest medicine, , 36 (4 ) ,xv More Information

Baughman, Robert P; Engel, Peter J; Nathan, Steven (2015. ) Pulmonary Hypertension in Sarcoidosis. Clinics in chest medicine, , 36 (4 ) ,703-14 More Information

Zhou, Ying; Lower, Elyse E; Li, Huiping; Baughman, Robert P (2016. ) Sarcoidosis patient with lupus pernio and infliximab-induced myositis: Response to Acthar gel. Respiratory medicine case reports, , 17 ,5-7 More Information

Baughman, Robert P; Grutters, Jan C (2015. ) New treatment strategies for pulmonary sarcoidosis: antimetabolites, biological drugs, and other treatment approaches. The Lancet. Respiratory medicine, , 3 (10 ) ,813-22 More Information

Zhou, Y; Wei, Y-R; Zhang, Y; Du, S-S; Baughman, R P; Li, H-P (2015. ) Real-time quantitative reverse transcription-polymerase chain reaction to detect propionibacterial ribosomal RNA in the lymph nodes of Chinese patients with sarcoidosis. Clinical and experimental immunology, , 181 (3 ) ,511-7 More Information

Baughman, Robert P; Lower, Elyse E; Saketkoo, Lesley Ann (2015. ) Clinical trials in pulmonary sarcoidosis. Current opinion in pulmonary medicine, , 21 (5 ) ,525-31 More Information

Baughman, Robert P; Lower, Elyse E (2015. ) Treatment of Sarcoidosis. Clinical reviews in allergy & immunology, , 49 (1 ) ,79-92 More Information

Baughman, Robert P; Culver, Daniel A; Jankovi, Vladimir; Fischkoff, Steven; Brockway, Giorgia; Lower, Elyse E (2015. ) Placenta-derived mesenchymal-like cells (PDA-001) as therapy for chronic pulmonary sarcoidosis: a phase 1 study. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 32 (2 ) ,106-14

Mirsaeidi, Mehdi; Machado, Roberto F; Schraufnagel, Dean; Sweiss, Nadera J; Baughman, Robert P (2015. ) Response. Chest, , 147 (2 ) ,e65-e66 More Information

Mirsaeidi, Mehdi; Machado, Roberto F; Schraufnagel, Dean; Sweiss, Nadera J; Baughman, Robert P (2015. ) Racial difference in sarcoidosis mortality in the United States. Chest, , 147 (2 ) ,438-449 More Information

Baughman, Robert P; Lower, Elyse E (2015. ) Features of sarcoidosis associated with chronic disease. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 31 (4 ) ,275-81

Lammi, Matthew R; Baughman, Robert P; Birring, Surinder S; Russell, Anne-Marie; Ryu, Jay H; Scholand, Marybeth; Distler, Oliver; LeSage, Daphne; Sarver, Catherine; Antoniou, Katerina; Highland, Kristin B; Kowal-Bielecka, Otylia; Lasky, Joseph A; Wells, Athol U; Saketkoo, Lesley Ann Outcome Measures for Clinical Trials in Interstitial Lung Diseases. Current respiratory medicine reviews, , 11 (2 ) ,163-174 More Information

Krupa, Agnieszka; Fol, Marek; Dziadek, Bozena R; Kepka, Ewa; Wojciechowska, Dominika; Brzostek, Anna; Torzewska, Agnieszka; Dziadek, Jaroslaw; Baughman, Robert P; Griffith, David; Kurdowska, Anna K (2015. ) Binding of CXCL8/IL-8 to Mycobacterium tuberculosis Modulates the Innate Immune Response. Mediators of inflammation, , 2015 ,124762 More Information

Judson, Marc A; Baughman, Robert P; Costabel, Ulrich; Drent, Marjolein; Gibson, Kevin F; Raghu, Ganesh; Shigemitsu, Hidenobu; Barney, Joseph B; Culver, Daniel A; Hamzeh, Nabeel Y; Wijsenbeek, Marlies S; Albera, Carlo; Huizar, Isham; Agarwal, Prasheen; Brodmerkel, Carrie; Watt, Rosemary; Barnathan, Elliot S (2014. ) Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. The European respiratory journal, , 44 (5 ) ,1296-307 More Information

Pereira, Carlos A C; Dornfeld, Marina C; Baughman, Robert; Judson, Marc A (2014. ) Clinical phenotypes in sarcoidosis. Current opinion in pulmonary medicine, , 20 (5 ) ,496-502 More Information

Judson, Marc A; Baughman, Robert P (2014. ) Worsening of pulmonary sarcoidosis. Current opinion in pulmonary medicine, , 20 (5 ) ,508-16 More Information

Baughman, Robert P; Lower, Elyse E (2014. ) Medical therapy of sarcoidosis. Seminars in respiratory and critical care medicine, , 35 (3 ) ,391-406 More Information

Carbone, Roberto G; Penna, Daniele; Baughman, Robert P; Lower, Elyse E (2014. ) Accuracy of Serial PET-CT Imaging in Systemic Sarcoidosis. Journal of clinical imaging science, , 4 ,21 More Information

Baughman, Robert P; Culver, Daniel A; Cordova, Francis C; Padilla, Maria; Gibson, Kevin F; Lower, Elyse E; Engel, Peter J (2014. ) Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest, , 145 (4 ) ,810-817 More Information

Baughman, Robert P; Judson, Marc A (2014. ) Relapses of sarcoidosis: what are they and can we predict who will get them? .The European respiratory journal, , 43 (2 ) ,337-9 More Information

Judson, Marc A; Baughman, Robert P; Costabel, Ulrich; Mack, Michael; Barnathan, Elliot S (2014. ) The potential additional benefit of infliximab in patients with chronic pulmonary sarcoidosis already receiving corticosteroids: a retrospective analysis from a randomized clinical trial. Respiratory medicine, , 108 (1 ) ,189-94 More Information

Lower, Elyse E; Malhotra, Atul; Sudurlescu, Victoria; Baughman, Robert P (2013. ) Sarcoidosis, fatigue, and sleep apnea. Chest, , 144 (6 ) ,1976-1977 More Information

Baughman, Robert P; Lower, Elyse E (2013. ) Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients. Respiratory medicine, , 107 (12 ) ,2009-13 More Information

Narula, Tathagat; Baughman, Robert P; Mehta, Atul C (2013. ) “Sarcoidosis Americana-route Europa”. Journal of bronchology & interventional pulmonology, , 20 (4 ) ,293-6 More Information

Baughman, R P; Janovcik, J; Ray, M; Sweiss, N; Lower, E E (2013. ) ??Calcium and vitamin D metabolism in sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 30 (2 ) ,113-20

Baughman, Robert P; Nunes, Hilario; Sweiss, Nadera J; Lower, Elyse E (2013. ) Established and experimental medical therapy of pulmonary sarcoidosis. The European respiratory journal, , 41 (6 ) ,1424-38 More Information

Baughman, R P (2013. ) Treatment of sarcoidosis. Panminerva medica, , 55 (2 ) ,175-89

Julian, Mark W; Shao, Guohong; Schlesinger, Larry S; Huang, Qin; Cosmar, David G; Bhatt, Nitin Y; Culver, Daniel A; Baughman, Robert P; Wood, Karen L; Crouser, Elliott D (2013. ) Nicotine treatment improves Toll-like receptor 2 and Toll-like receptor 9 responsiveness in active pulmonary sarcoidosis. Chest, , 143 (2 ) ,461-470 More Information

Lower, Elyse E; Malhotra, Atul; Surdulescu, Victoria; Baughman, Robert P (2013. ) Armodafinil for sarcoidosis-associated fatigue: a double-blind, placebo-controlled, crossover trial. Journal of pain and symptom management, , 45 (2 ) ,159-69 More Information

Baughman, Robert P; Meyer, Keith C; Nathanson, Ian; Angel, Luis; Bhorade, Sangeeta M; Chan, Kevin M; Culver, Daniel; Harrod, Christopher G; Hayney, Mary S; Highland, Kristen B; Limper, Andrew H; Patrick, Herbert; Strange, Charlie; Whelan, Timothy (2012. ) Monitoring of nonsteroidal immunosuppressive drugs in patients with lung disease and lung transplant recipients: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, , 142 (5 ) ,e1S-e111S More Information

Baughman, Robert P; Meyer, Keith C; Nathanson, Ian; Angel, Luis; Bhorade, Sangeeta M; Chan, Kevin M; Culver, Daniel; Harrod, Christopher G; Hayney, Mary S; Highland, Kristen B; Limper, Andrew H; Patrick, Herbert; Strange, Charlie; Whelan, Timothy (2012. ) Executive summary: monitoring of nonsteroidal immunosuppressive drugs in patients with lung disease and lung transplant recipients: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, , 142 (5 ) ,1284-1288 More Information

Baughman, R P; Drent, M; Culver, D A; Grutters, J C; Handa, T; Humbert, M; Judson, M A; Lower, E E; Mana, J; Pereira, C A; Prasse, A; Sulica, R; Valyere, D; Vucinic, V; Wells, A U (2012. ) Endpoints for clinical trials of sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 29 (2 ) ,90-8

Baughman, Robert P; Lower, Elyse E; Gibson, Kevin (2012. ) Pulmonary manifestations of sarcoidosis. Presse medicale (Paris, France : 1983), , 41 (6 Pt 2 ) ,e289-302 More Information

Baughman, Robert P; Weiss, Kenneth L; Golnik, Karl C (2012. ) Neuro-ophthalmic sarcoidosis. Eye and brain, , 4 ,13-25 More Information

Baughman, R P; Lower, E E; Ingledue, R; Kaufman, A H (2012. ) Management of ocular sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 29 (1 ) ,26-33

Lower, Elyse E; Baughman, Robert P; Kaufman, Adam H (2012. ) Rituximab for refractory granulomatous eye disease. Clinical ophthalmology (Auckland, N.Z.), , 6 ,1613-8 More Information

Baughman, Robert P; Nunes, Hilario (2012. ) Therapy for sarcoidosis: evidence-based recommendations. Expert review of clinical immunology, , 8 (1 ) ,95-103 More Information

Baughman, R P; Nagai, S; Balter, M; Costabel, U; Drent, M; du Bois, R; Grutters, J C; Judson, M A; Lambiri, I; Lower, E E; Muller-Quernheim, J; Prasse, A; Rizzato, G; Rottoli, P; Spagnolo, P; Teirstein, A (2011. ) Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 28 (1 ) ,56-64

Baughman, Robert P; Culver, Daniel A; Judson, Marc A (2011. ) A concise review of pulmonary sarcoidosis. American journal of respiratory and critical care medicine, , 183 (5 ) ,573-81 More Information

Baughman, Robert P; Engel, Peter J; Taylor, Lisa; Lower, Elyse E (2010. ) Survival in sarcoidosis-associated pulmonary hypertension: the importance of hemodynamic evaluation. Chest, , 138 (5 ) ,1078-85 More Information

Baughman, Robert P; Lower, Elyse E; Kaufman, Adam H (2010. ) Ocular sarcoidosis. Seminars in respiratory and critical care medicine, , 31 (4 ) ,452-62 More Information

Baughman, Robert P; Culver, Daniel A; Costabel, Ulrich (2010. ) Sarcoidosis. Seminars in respiratory and critical care medicine, , 31 (4 ) ,373-4 More Information

Baughman, Robert P; Lower, Elyse E; Tami, Thomas (2010. ) Upper airway. 4: Sarcoidosis of the upper respiratory tract (SURT). Thorax, , 65 (2 ) ,181-6 More Information

Engel, Peter J; Baughman, Robert P (2009. ) Treatment of right ventricular dysfunction in pulmonary arterial hypertension: theoretical considerations. Medical hypotheses, , 73 (3 ) ,448-52 More Information

Baughman, Robert P; Shipley, Ralph; Desai, Sujal; Drent, Marjolein; Judson, Marc A; Costabel, Ulrich; du Bois, Roland M; Kavuru, Mani; Schlenker-Herceg, Rozsa; Flavin, Susan; Lo, Kim Hung; Barnathan, Elliot S (2009. ) Changes in chest roentgenogram of sarcoidosis patients during a clinical trial of infliximab therapy: comparison of different methods of evaluation. Chest, , 136 (2 ) ,526-535 More Information

Baughman, Robert P The use of carbapenems in the treatment of serious infections. Journal of intensive care medicine, , 24 (4 ) ,230-41 More Information

Baughman, R P; Judson, M A; Lower, E E; Highland, K; Kwon, S; Craft, N; Engel, P J (2009. ) Inhaled iloprost for sarcoidosis associated pulmonary hypertension. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 26 (2 ) ,110-20

de Kleijn, W P E; Elfferich, M D P; De Vries, J; Jonker, G J; Lower, E E; Baughman, R P; King, T E; Drent, M (2009. ) Fatigue in sarcoidosis: American versus Dutch patients. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 26 (2 ) ,92-7

Baughman, Robert P; Costabel, Ulrich; du Bois, Ronald M (2008. ) Treatment of sarcoidosis. Clinics in chest medicine, , 29 (3 ) ,533-48, ix-x More Information

Baughman, Robert P; Drent, Marjolein (2008. ) Preface. Sarcoidosis. Clinics in chest medicine, , 29 (3 ) ,xiii-xiv More Information

Lower, Elyse E; Harman, Stacy; Baughman, Robert P (2008. ) Double-blind, randomized trial of dexmethylphenidate hydrochloride for the treatment of sarcoidosis-associated fatigue. Chest, , 133 (5 ) ,1189-95 More Information

Baughman, Robert P; Judson, Marc A; Teirstein, Alvin; Lower, Elyse E; Lo, Kim; Schlenker-Herceg, Rozsa; Barnathan, Elliot S (2008. ) Chronic facial sarcoidosis including lupus pernio: clinical description and proposed scoring systems. American journal of clinical dermatology, , 9 (3 ) ,155-61 More Information

Baughman, Robert P (2007. ) Technical aspects of bronchoalveolar lavage: recommendations for a standard procedure. Seminars in respiratory and critical care medicine, , 28 (5 ) ,475-85 More Information

Baughman, Robert P; Lower, Elyse E (2007. ) Six-minute walk test in managing and monitoring sarcoidosis patients. Current opinion in pulmonary medicine, , 13 (5 ) ,439-44 More Information

Baughman, Robert P; Sparkman, Brian K; Lower, Elyse E (2007. ) Six-minute walk test and health status assessment in sarcoidosis. Chest, , 132 (1 ) ,207-13 More Information

Baughman, Robert P; Lower, Elyse E Evidence-based therapy for cutaneous sarcoidosis. Clinics in dermatology, , 25 (3 ) ,334-40 More Information

Baughman, Robert P Sarcoidosis. Clinics in dermatology, , 25 (3 ) ,231 More Information

Engel, Peter J; Baughman, Robert P; Menon, Santosh G; Kereiakes, Dean J; Taylor, Lisa; Scott, Mark (2007. ) Pulmonary hypertension in neurofibromatosis. The American journal of cardiology, , 99 (8 ) ,1177-8 More Information

Baughman, Robert P; Lower, Elyse E (2007. ) Novel therapies for sarcoidosis. Seminars in respiratory and critical care medicine, , 28 (1 ) ,128-33 More Information

Baughman, Robert P (2007. ) Pulmonary hypertension associated with sarcoidosis. Arthritis research & therapy, , 9 Suppl 2 ,S8 More Information

Baughman, Robert P; Drent, Marjolein; Kavuru, Mani; Judson, Marc A; Costabel, Ulrich; du Bois, Roland; Albera, Carlo; Brutsche, Martin; Davis, Gerald; Donohue, James F; Müller-Quernheim, Joachim; Schlenker-Herceg, Rozsa; Flavin, Susan; Lo, Kim Hung; Oemar, Barry; Barnathan, Elliot S (2006. ) Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. American journal of respiratory and critical care medicine, , 174 (7 ) ,795-802 More Information

Baughman, Robert P; Engel, Peter J; Meyer, Cris A; Barrett, Amanda B; Lower, Elyse E (2006. ) Pulmonary hypertension in sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 23 (2 ) ,108-16

Baughman, R P; Judson, M A; Teirstein, A; Yeager, H; Rossman, M; Knatterud, G L; Thompson, B (2006. ) Presenting characteristics as predictors of duration of treatment in sarcoidosis. QJM : monthly journal of the Association of Physicians, , 99 (5 ) ,307-15 More Information

Bradley, Deborah A; Lower, Elyse E; Baughman, Robert P (2006. ) Diagnosis and management of spinal cord sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 23 (1 ) ,58-65

Baughman, R P; Glauser, M P (2005. ) Managing serious infections in the hospital: a new model. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, , 11 Suppl 5 ,1-3 More Information

Baughman, Robert P; Lower, Elyse E; Bradley, Deborah A; Raymond, Lawrence A; Kaufman, Adam (2005. ) Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial. Chest, , 128 (2 ) ,1062-47 More Information

Baughman, R P; Lower, E E (2005. ) Fungal infections as a complication of therapy for sarcoidosis. QJM : monthly journal of the Association of Physicians, , 98 (6 ) ,451-6 More Information

Baughman, Robert P (2005. ) Microbiologic diagnosis of ventilator-associated pneumonia. Clinics in chest medicine, , 26 (1 ) ,81-6 More Information

Baughman, Robert P (2005. ) Diagnosis of ventilator-associated pneumonia. Microbes and infection, , 7 (2 ) ,262-7 More Information

Baughman, R P; Bradley, D A; Lower, E E (2005. ) Infliximab in chronic ocular inflammation. International journal of clinical pharmacology and therapeutics, , 43 (1 ) ,7-11 More Information

Baughman, Robert P (2005. ) Considerations in the choice and administration of agents for empiric antimicrobial therapy. Surgical infections, , 6 Suppl 2 ,S-71-82

Engel, Peter J; Baughman, Robert; Johnson, Heide; Kereikes, Dean J (2004. ) Reversible pulmonary hypertension in a patient treated with protacyclin. The Journal of invasive cardiology, , 16 (11 ) ,660-2

Baughman, Robert P (2004. ) Pulmonary sarcoidosis. Clinics in chest medicine, , 25 (3 ) ,521-30, vi More Information

Baughman, Robert P; Lower, Elyse E (2004. ) Leflunomide for chronic sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 21 (1 ) ,43-8 More Information

Baughman, Robert P; Lower, Elyse E (2004. ) Newer therapies for cutaneous sarcoidosis: the role of thalidomide and other agents. American journal of clinical dermatology, , 5 (6 ) ,385-94 More Information

Baughman, Robert P (2003. ) Diagnosis of ventilator-associated pneumonia. Current opinion in critical care, , 9 (5 ) ,397-402 More Information

Baughman, Robert P; Kerr, Marie A Ventilator-associated pneumonia patients who do not reduce bacteria from the lungs have a worse prognosis. Journal of intensive care medicine, , 18 (5 ) ,269-74 More Information

Baughman, Robert P (2003. ) Nonbronchoscopic evaluation of ventilator-associated pneumonia. Seminars in respiratory infections, , 18 (2 ) ,95-102

Baughman, Robert P; Lower, Elyse E; du Bois, Roland M (2003. ) Sarcoidosis. Lancet (London, England), , 361 (9363 ) ,1111-8 More Information

Baughman, Robert P; Koehler, Allison; Bejarano, Pablo A; Lower, Elyse E; Weber, Fredrick L (2003. ) Role of liver function tests in detecting methotrexate-induced liver damage in sarcoidosis. Archives of internal medicine, , 163 (5 ) ,615-20 More Information

Baughman, Robert P; Iannuzzi, Michael (2003. ) Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, , 17 (6 ) ,425-31 More Information

Baughman, R P; Lynch, J P (2003. ) Difficult treatment issues in sarcoidosis. Journal of internal medicine, , 253 (1 ) ,41-5 More Information

Baughman, Robert P; Lower, Elyse E (2002. ) Therapy for extrapulmonary sarcoidosis. Seminars in respiratory and critical care medicine, , 23 (6 ) ,589-96 More Information

Bradley, Deborah; Baughman, Robert P; Raymond, Lawrence; Kaufman, Adam H (2002. ) Ocular manifestations of sarcoidosis. Seminars in respiratory and critical care medicine, , 23 (6 ) ,543-8 More Information

Baughman, Robert P (2002. ) Extrapulmonary sarcoidosis. Seminars in respiratory and critical care medicine, , 23 (6 ) ,503 More Information

Baughman, Robert P (2002. ) Antibiotic resistance in the intensive care unit. Current opinion in critical care, , 8 (5 ) ,430-4 More Information

Baughman, Robert P; Iannuzzi, Michael C; Lower, Elyse E; Moller, David R; Balkissoon, Ronald C; Winget, Donna B; Judson, Marc A (2002. ) Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 19 (3 ) ,198-204

Baughman, Robert P; Lower, Elyse E (2002. ) Can persistent tumor necrosis factor release lead to refractory sarcoidosis? .Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 19 (3 ) ,164-6

Baughman, Robert P (2002. ) Therapeutic options for sarcoidosis: new and old. Current opinion in pulmonary medicine, , 8 (5 ) ,464-9 More Information

Baughman, Robert P; Judson, Marc A; Teirstein, Alvin S; Moller, David R; Lower, Elyse E (2002. ) Thalidomide for chronic sarcoidosis. Chest, , 122 (1 ) ,227-32 More Information

Baughman, Robert P; Henderson, Rogene F; Whitsett, Jeffrey; Gunther, Karen L; Keeton, Deborah A; Waide, James J; Zaccardelli, David S; Pattishall, Edward N; Rashkin, Mitchell C (2002. ) Surfactant replacement for ventilator-associated pneumonia: a preliminary report. Respiration; international review of thoracic diseases, , 69 (1 ) ,57-62 More Information

Baughman, R P; Teirstein, A S; Judson, M A; Rossman, M D; Yeager, H; Bresnitz, E A; DePalo, L; Hunninghake, G; Iannuzzi, M C; Johns, C J; McLennan, G; Moller, D R; Newman, L S; Rabin, D L; Rose, C; Rybicki, B; Weinberger, S E; Terrin, M L; Knatterud, G L; Cherniak, R (2001. ) Clinical characteristics of patients in a case control study of sarcoidosis. American journal of respiratory and critical care medicine, , 164 (10 Pt 1 ) ,1885-9 More Information

Lower, E E; Hawkins, H H; Baughman, R P (2001. ) Breast disease in sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 18 (3 ) ,301-6

Baughman, R P; Alabi, F O (2001. ) Nonsteroidal therapy for idiopathic pulmonary fibrosis. Current opinion in pulmonary medicine, , 7 (5 ) ,309-13 More Information

Amin, R S; Wert, S E; Baughman, R P; Tomashefski, J F; Nogee, L M; Brody, A S; Hull, W M; Whitsett, J A (2001. ) Surfactant protein deficiency in familial interstitial lung disease. The Journal of pediatrics, , 139 (1 ) ,85-92 More Information

Baughman, R P; Drent, M (2001. ) Role of bronchoalveolar lavage in interstitial lung disease. Clinics in chest medicine, , 22 (2 ) ,331-41 More Information

Baughman, R P; Ohmichi, M; Lower, E E (2001. ) Combination therapy for sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 18 (2 ) ,133-7

Baughman, R P; Lower, E E (2001. ) Infliximab for refractory sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 18 (1 ) ,70-4

Baughman, R P; Spencer, R E; Kleykamp, B O; Rashkin, M C; Douthit, M M (2000. ) Ventilator associated pneumonia: quality of nonbronchoscopic bronchoalveolar lavage sample affects diagnostic yield. The European respiratory journal, , 16 (6 ) ,1152-7 More Information

Dohn, M N; White, M L; Vigdorth, E M; Ralph Buncher, C; Hertzberg, V S; Baughman, R P; George Smulian, A; Walzer, P D (2000. ) Geographic clustering of Pneumocystis carinii pneumonia in patients with HIV infection. American journal of respiratory and critical care medicine, , 162 (5 ) ,1617-21 More Information

Zeitlin, J F; Tami, T A; Baughman, R; Winget, D Nasal and sinus manifestations of sarcoidosis. American journal of rhinology, , 14 (3 ) ,157-61 More Information

Baughman, R P (2000. ) Protected-specimen brush technique in the diagnosis of ventilator-associated pneumonia. Chest, , 117 (4 Suppl 2 ) ,203S-206S More Information

Baughman, R P; Winget, D B; Lower, E E (2000. ) Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 17 (1 ) ,60-6

Baughman, R P; Pina, E (2000. ) Infections in acute exacerbation of chronic bronchitis: what are they and how do we know? .Seminars in respiratory and critical care medicine, , 21 (2 ) ,87-96 More Information

Kaneshiro, E S; Amit, Z; Chandra, J; Baughman, R P; Contini, C; Lundgren, B (1999. ) Sterols of Pneumocystis carinii hominis organisms isolated from human lungs. Clinical and diagnostic laboratory immunology, , 6 (6 ) ,970-6 More Information

Chandra, J; Amit, Z; Baughman, R P; Kleykamp, B; Kaneshiro, E S Pneumocystis infection is correlated with a reduction of the total sterol content of human bronchoalveolar lavage fluid. The Journal of eukaryotic microbiology, , 46 (5 ) ,146S-148S

Baughman, R P; Lower, E E (1999. ) A clinical approach to the use of methotrexate for sarcoidosis. Thorax, , 54 (8 ) ,742-6 More Information

Baughman, R P; Pina, E M (1999. ) Role of bronchoscopy in lung cancer research. Clinics in chest medicine, , 20 (1 ) ,191-9 More Information

Baughman, R P; Lower, E E; Miller, M A; Bejarano, P A; Heffelfinger, S C (1999. ) Overexpression of transforming growth factor-alpha and epidermal growth factor-receptor in idiopathic pulmonary fibrosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 16 (1 ) ,57-61

Baughman, R P; Tapson, V; McIvor, A (1999. ) The diagnosis and treatment challenges in nosocomial pneumonia. Diagnostic microbiology and infectious disease, , 33 (2 ) ,131-9 More Information

Baughman, R P (1999. ) The lung in the immunocompromised patient. Infectious complications Part 1. Respiration; international review of thoracic diseases, , 66 (2 ) ,95-109 More Information

Harlamert, H A; Mira, J; Bejarano, P A; Baughman, R P; Miller, M A; Whitsett, J A; Yassin, R Thyroid transcription factor-1 and cytokeratins 7 and 20 in pulmonary and breast carcinoma. Acta cytologica, , 42 (6 ) ,1382-8 More Information

Baughman, R P (1998. ) Methotrexate for sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 15 (2 ) ,147-9

Baughman, R P; Sharma, O P; Lynch, J P (1998. ) Sarcoidosis: is therapy effective? .Seminars in respiratory infections, , 13 (3 ) ,255-73

Baughman, R P; Conrado, C E (1998. ) Diagnosis of lower respiratory tract infections: what we have and what would be nice. Chest, , 113 (3 Suppl ) ,219S-223S More Information

Baughman, R P; Gunther, K L; Buchsbaum, J A; Lower, E E Prevalence of digital clubbing in bronchogenic carcinoma by a new digital index. Clinical and experimental rheumatology, , 16 (1 ) ,21-6

Baughman, R P; Liming, J D (1998. ) Diagnostic strategies in Pneumocystis carinii pneumonia. Frontiers in bioscience : a journal and virtual library, , 3 ,e1-12 More Information

Baughman, R P; Lower, E E (1997. ) Steroid-sparing alternative treatments for sarcoidosis. Clinics in chest medicine, , 18 (4 ) ,853-64 More Information

Lower, E E; Broderick, J P; Brott, T G; Baughman, R P (1997. ) Diagnosis and management of neurological sarcoidosis. Archives of internal medicine, , 157 (16 ) ,1864-8

Baughman, R P; Winget, D B; Bowen, E H; Lower, E E (1997. ) Predicting respiratory failure in sarcoidosis patients. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 14 (2 ) ,154-8

Baughman, R P; Lower, E E (1997. ) Alternatives to corticosteroids in the treatment of sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 14 (2 ) ,121-30

Baughman, R P; Keeton, D A; Perez, C; Wilmott, R W (1997. ) Use of bronchoalveolar lavage semiquantitative cultures in cystic fibrosis. American journal of respiratory and critical care medicine, , 156 (1 ) ,286-91 More Information

Baughman, R P; Keely, S P; Dohn, M N; Stringer, J R (1997. ) The use of genetic markers to characterize transmission of Pneumocystis carinii. AIDS patient care and STDs, , 11 (3 ) ,131-8 More Information

Turner, G A; Lower, E E; Corser, B C; Gunther, K L; Baughman, R P (1997. ) Sleep apnea in sarcoidosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, , 14 (1 ) ,61-4

Baughman, R P; Fernandez, M (1996. ) Radionuclide imaging in interstitial lung disease. Current opinion in pulmonary medicine, , 2 (5 ) ,376-9 More Information

Keely, S P; Baughman, R P; Smulian, A G; Dohn, M N; Stringer, J R (1996. ) Source of Pneumocystis carinii in recurrent episodes of pneumonia in AIDS patients. AIDS (London, England), , 10 (8 ) ,881-8 More Information

Baughman, R P; Gunther, K L; Rashkin, M C; Keeton, D A; Pattishall, E N (1996. ) Changes in the inflammatory response of the lung during acute respiratory distress syndrome: prognostic indicators. American journal of respiratory and critical care medicine, , 154 (1 ) ,76-81 More Information

Bejarano, P A; Baughman, R P; Biddinger, P W; Miller, M A; Fenoglio-Preiser, C; al-Kafaji, B; Di Lauro, R; Whitsett, J A (1996. ) Surfactant proteins and thyroid transcription factor-1 in pulmonary and breast carcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, , 9 (4 ) ,445-52

Lemert, C M; Baughman, R P; Hayner, C E; Nestok, B R Relationship between cytomegalovirus cells and survival in acquired immunodeficiency syndrome patients. Acta cytologica, , 40 (2 ) ,205-10 More Information

Keely, S P; Stringer, J R; Baughman, R P; Linke, M J; Walzer, P D; Smulian, A G (1995. ) Genetic variation among Pneumocystis carinii hominis isolates in recurrent pneumocystosis. The Journal of infectious diseases, , 172 (2 ) ,595-8 More Information

Lower, E E; Baughman, R P (1995. ) Prolonged use of methotrexate for sarcoidosis. Archives of internal medicine, , 155 (8 ) ,846-51

Sternberg, R I; Whitsett, J A; Hull, W M; Baughman, R P (1995. ) Pneumocystis carinii alters surfactant protein A concentrations in bronchoalveolar lavage fluid. The Journal of laboratory and clinical medicine, , 125 (4 ) ,462-9

Hayner, C E; Baughman, R P; Linnemann, C C; Dohn, M N (1995. ) The relationship between cytomegalovirus retrieved by bronchoalveolar lavage and mortality in patients with HIV. Chest, , 107 (3 ) ,735-40 More Information

Baughman, R P; Dohn, M N; Frame, P T (1994. ) The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients. The American journal of medicine, , 97 (6 ) ,515-22 More Information

Smulian, A G; Linke, M J; Cushion, M T; Baughman, R P; Frame, P T; Dohn, M N; White, M L; Walzer, P D (1994. ) Analysis of Pneumocystis carinii organism burden, viability and antigens in bronchoalveolar lavage fluid in AIDS patients with pneumocystosis: correlation with disease severity. AIDS (London, England), , 8 (11 ) ,1555-62 More Information

Keely, S; Pai, H J; Baughman, R; Sidman, C; Sunkin, S M; Stringer, J R; Stringer, S L Pneumocystis species inferred from analysis of multiple genes. The Journal of eukaryotic microbiology, , 41 (5 ) ,94S

Connolly, M G; Baughman, R P; Dohn, M N; Linnemann, C C (1994. ) Recovery of viruses other than cytomegalovirus from bronchoalveolar lavage fluid. Chest, , 105 (6 ) ,1775-81 More Information

Baughman, R P; DeSante, K A; Lanier, T L; Conforti, P M; Sides, G D (1994. ) The penetration of dirithromycin into bronchoalveolar lavage fluid and alveolar macrophages. The Journal of antimicrobial chemotherapy, , 33 (5 ) ,1045-50 More Information

O’Brien, G M; Baughman, R P; Broderick, J P; Arnold, L; Lower, E E (1994. ) Paranoid psychosis due to neurosarcoidosis. Sarcoidosis, , 11 (1 ) ,34-6

Connolly, M G; Baughman, R P; Dohn, M N (1993. ) Mycobacterium kansasii presenting as an endobronchial lesion. The American review of respiratory disease, , 148 (5 ) ,1405-7 More Information

Stringer, J R; Stringer, S L; Zhang, J; Baughman, R; Smulian, A G; Cushion, M T Molecular genetic distinction of Pneumocystis carinii from rats and humans. The Journal of eukaryotic microbiology, , 40 (6 ) ,733-41 More Information

Sternberg, R I; Baughman, R P; Dohn, M N; First, M R (1993. ) Utility of bronchoalveolar lavage in assessing pneumonia in immunosuppressed renal transplant recipients. The American journal of medicine, , 95 (4 ) ,358-64 More Information

Baughman, R P; Lower, E E; Flessa, H C; Tollerud, D J (1993. ) Thrombocytopenia in the intensive care unit. Chest, , 104 (4 ) ,1243-7 More Information

Baughman, R P; Sternberg, R I; Hull, W; Buchsbaum, J A; Whitsett, J (1993. ) Decreased surfactant protein A in patients with bacterial pneumonia. The American review of respiratory disease, , 147 (3 ) ,653-7 More Information

Baughman, R P; Dohn, M N; Shipley, R; Buchsbaum, J A; Frame, P T (1993. ) Increased Pneumocystis carinii recovery from the upper lobes in Pneumocystis pneumonia. The effect of aerosol pentamidine prophylaxis. Chest, , 103 (2 ) ,426-32 More Information

Dohn, M N; Baughman, R P; Vigdorth, E M; Frame, D L (1992. ) Equal survival rates for first, second, and third episodes of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Archives of internal medicine, , 152 (12 ) ,2465-70 More Information

Baughman, R P; Lower, E E (1992. ) Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. Chest, , 102 (4 ) ,1090-4 More Information

Lower, E E; Baughman, R P (1992. ) Pulmonary lymphangitic metastasis from breast cancer. Lymphocytic alveolitis is associated with favorable prognosis. Chest, , 102 (4 ) ,1113-7 More Information

Baughman, R P; Rhodes, J C; Dohn, M N; Henderson, H; Frame, P T (1992. ) Detection of cryptococcal antigen in bronchoalveolar lavage fluid: a prospective study of diagnostic utility. The American review of respiratory disease, , 145 (5 ) ,1226-9 More Information

Dohn, M N; Frame, P T; Baughman, R P; Lafon, S W; Smulian, A G; Caldwell, P; Rogers, M D Open-label efficacy and safety trial of 42 days of 566C80 for Pneumocystis carinii pneumonia in AIDS patients. The Journal of protozoology, , 38 (6 ) ,220S-221S

Baughman, R P; Dohn, M N; Frame, P T Generalized immune response to Pneumocystis carinii infection in the lung. The Journal of protozoology, , 38 (6 ) ,187S-188S

Baughman, R P; Lower, E E (1991. ) An inhibitor of tumor necrosis factor found in pleural effusions. The Journal of laboratory and clinical medicine, , 118 (4 ) ,326-31

Baughman, R P; Shipley, R T; Loudon, R G; Lower, E E (1991. ) Crackles in interstitial lung disease. Comparison of sarcoidosis and fibrosing alveolitis. Chest, , 100 (1 ) ,96-101 More Information

Colangelo, G; Baughman, R P; Dohn, M N; Frame, P T (1991. ) Follow-up bronchoalveolar lavage in AIDS patients with Pneumocystis carinii pneumonia. Pneumocystis carinii burden predicts early relapse. The American review of respiratory disease, , 143 (5 Pt 1 ) ,1067-71 More Information

Baughman, R P; Dohn, M N; Loudon, R G; Frame, P T (1991. ) Bronchoscopy with bronchoalveolar lavage in tuberculosis and fungal infections. Chest, , 99 (1 ) ,92-7 More Information

Baughman, R P; Lower, E E (1990. ) The effect of corticosteroid or methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis. The American review of respiratory disease, , 142 (6 Pt 1 ) ,1268-71 More Information

Baughman, R P; Strohofer, S; Colangelo, G; Frame, P T (1990. ) Semiquantitative technique for estimating Pneumocystis carinii burden in the lung. Journal of clinical microbiology, , 28 (6 ) ,1425-7 More Information

Miles, P R; Baughman, R P; Linnemann, C C (1990. ) Cytomegalovirus in the bronchoalveolar lavage fluid of patients with AIDS. Chest, , 97 (5 ) ,1072-6 More Information

Lower, E E; Baughman, R P (1990. ) The use of low dose methotrexate in refractory sarcoidosis. The American journal of the medical sciences, , 299 (3 ) ,153-7 More Information

Lower, E E; Baughman, R P (1990. ) The effect of cancer and chemotherapy on monocyte function. Journal of clinical & laboratory immunology, , 31 (3 ) ,121-5

Gerson, M C; Hurst, J M; Hertzberg, V S; Baughman, R; Rouan, G W; Ellis, K (1990. ) Prediction of cardiac and pulmonary complications related to elective abdominal and noncardiac thoracic surgery in geriatric patients. The American journal of medicine, , 88 (2 ) ,101-7 More Information

Guerra, L F; Baughman, R P (1990. ) Use of bronchoalveolar lavage to diagnose bacterial pneumonia in mechanically ventilated patients. Critical care medicine, , 18 (2 ) ,169-73 More Information

Baughman, R P; Strohofer, S A; Buchsbaum, J; Lower, E E (1990. ) Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. The Journal of laboratory and clinical medicine, , 115 (1 ) ,36-42

Baughman, R P; Doers, J; Lower, E E; Buchsbaum, J (1989. ) Isolation of functionally active pleural macrophages. Journal of clinical & laboratory immunology, , 30 (3 ) ,147-51

Fara, E F; Baughman, R P (1989. ) A study of capillary morphology in the digits of patients with acquired clubbing. The American review of respiratory disease, , 140 (4 ) ,1063-6 More Information

Baughman, R P; Strohofer, S S; Clinton, B A; Nickol, A D; Frame, P T (1989. ) The use of an indirect fluorescent antibody test for detecting Pneumocystis carinii. Archives of pathology & laboratory medicine, , 113 (9 ) ,1062-5

Wong, B; Baughman, R P; Brauer, K L (1989. ) Levels of the Candida metabolite D-arabinitol in sera of steroid-treated and untreated patients with sarcoidosis. Journal of clinical microbiology, , 27 (8 ) ,1859-62 More Information

Linnemann, C C; Baughman, R P; Frame, P T; Floyd, R (1989. ) Recovery of human immunodeficiency virus and detection of p24 antigen in bronchoalveolar lavage fluid from adult patients with AIDS. Chest, , 96 (1 ) ,64-7 More Information

Baughman, R P; Loudon, R G (1989. ) Stridor: differentiation from asthma or upper airway noise. The American review of respiratory disease, , 139 (6 ) ,1407-9 More Information

Tollerud, D J; Wesseler, T A; Kim, C K; Baughman, R P (1989. ) Use of a rapid differential stain for identifying Pneumocystis carinii in bronchoalveolar lavage fluid. Diagnostic efficacy in patients with AIDS. Chest, , 95 (3 ) ,494-7 More Information

Baughman, R P; Strohofer, S (1989. ) Lung derived surface active material (SAM) inhibits natural killer cell tumor cytotoxicity. Journal of clinical & laboratory immunology, , 28 (2 ) ,51-4

Baughman, R P (1988. ) Sarcoidosis. Usual and unusual manifestations. Chest, , 94 (1 ) ,165-70 More Information

Baughman, R P; Lower, E E; Pierson, G; Strohofer, S (1988. ) Spontaneous hydrogen peroxide release from alveolar macrophages of patients with active sarcoidosis: comparison with cigarette smokers. The Journal of laboratory and clinical medicine, , 111 (4 ) ,399-404

Lower, E E; Strohofer, S; Baughman, R P (1988. ) Bleomycin causes alveolar macrophages from cigarette smokers to release hydrogen peroxide. The American journal of the medical sciences, , 295 (3 ) ,193-7 More Information

Lower, E E; Smith, J T; Martelo, O J; Baughman, R P (1988. ) The anemia of sarcoidosis. Sarcoidosis, , 5 (1 ) ,51-5

Baughman, R P; Loudon, R G (1988. ) The utility of a long-acting sympathomimetic agent, procaterol, for nocturnal asthma. Chest, , 93 (2 ) ,285-8 More Information

Ploysongsang, Y; Baughman, R P; Loudon, R G; Rashkin, M C (1988. ) Factors influencing the production of wheezes during expiratory maneuvers in normal subjects. Respiration; international review of thoracic diseases, , 54 (1 ) ,50-60 More Information

Baughman, R P; Shipley, R; Eisentrout, C E (1987. ) Predictive value of gallium scan, angiotensin-converting enzyme level, and bronchoalveolar lavage in two-year follow-up of pulmonary sarcoidosis. Lung, , 165 (6 ) ,371-7 More Information

Honors and Awards

Alpha Omega Alpha – Case-Western Reserve

Richard W. Vilter Faculty Teaching Award 1986 and 1991

Keywords

Handbook,Immunity,Biomarker,Sarcoidosis,Case History,Human Subject,Clinical Trial,Data Collection,Family Genetics,Information System,Pathologic Process,Disease Proneness Risk,Patient Care Management,Longitudinal Human Study,Tissue Resource Registry

Contact Information

Academic – University of Cincinnat Medical Center- Homes, Room 1001
PO Box 670565
Cincinnati Ohio, 45267-0565
Phone: 513-584-5224
Fax: 513-584-5110
[email protected]

Real‐world treatment patterns, healthcare resource utilization, and cost among adults with pulmonary arterial hypertension in the United States

Copyright © 2022 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.

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Abstract

Treatment for pulmonary arterial hypertension (PAH) has evolved over the past decade, including approval of new medications and growing evidence to support earlier use of combination therapy. Despite these changes, few studies have assessed real‐world treatment patterns, healthcare resource utilization (HCRU), and costs among people with PAH using recent data. We conducted a retrospective cohort study using administrative claims from the HealthCore Integrated Research Database®. Adult members with claims for a PAH diagnosis, right heart catheterization, and who initiated PAH treatment (index date) between October 1, 2015 and November 30, 2020 were identified. Members had to be continuously enrolled in the health plan for 6 months before the index date (baseline) and ≥30 days after. Treatment patterns, HCRU, and costs were described. A total of 843 members with PAH (mean age 62.3 years, 64.2% female) were included. Only 21.0% of members received combination therapy as their first‐line treatment, while most members (54.6%) received combination therapy as second‐line treatment. All‐cause HCRU remained high after treatment initiation with 58.0% of members having ≥1 hospitalization and 41.3% with ≥1 emergency room visit. Total all‐cause costs declined from $15,117 per patient per month at baseline to $14,201 after treatment initiation, with decreased medical costs ($14,208 vs. $6,349) more than offsetting increased pharmacy costs ($909 vs. $7,852). In summary, despite growing evidence supporting combination therapy, most members with PAH initiated treatment with monotherapy. Total costs decreased following treatment, driven by a reduction in medical costs even with increases in pharmacy costs.

Keywords: healthcare costs, healthcare resource utilization, pulmonary arterial hypertension, treatment patterns

INTRODUCTION

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling resulting in a progressive increase in pulmonary vascular resistance, right heart failure, and premature mortality. The 6th World Symposium on Pulmonary Hypertension (PH) has defined five types of PH: PAH (Group 1); PH due to left heart disease (Group 2); PH due to chronic lung disease and/or hypoxia (Group 3); PH due to pulmonary artery obstruction including chronic thromboembolic PH (Group 4); and PH due to unclear or multifactorial mechanisms (Group 5). 1 PAH (PH Group 1) is characterized by mean pulmonary artery pressure greater than 20 mmHg, pulmonary arterial wedge pressure less than or equal to 15 mmHg, and pulmonary vascular resistance greater than or equal to three Wood Units measured by right heart catheterization (RHC) at rest and negative evaluation for other precapillary PH Groups 3–5. 1 Estimates of PAH incidence range between 2.0 and 7.6 cases per million adults per year. 2 , 3 , 4 In general, people with PAH have high comorbidity burden, high rates of premature mortality (approximately 21% after 3 years), low quality of life, and high healthcare resource utilization (HCRU) and costs. 2 , 5 , 6 , 7 , 8 , 9

Treatment of PAH includes medications that target three signaling pathways involved in disease pathogenesis: the nitric oxide, endothelin, and prostacyclin pathways. Phosphodiesterase 5 inhibitors (PDE5is), which include sildenafil and tadalafil, and soluble guanylate cyclase stimulators (sGCs), which include riociguat, target the nitric oxide pathway. Medications that target the endothelin pathway include three endothelin receptor antagonists (ERAs): bosentan, ambrisentan, and macitentan. Prostacyclin and IP receptor agonists target the prostacyclin pathway and are available parenterally through a continuous infusion either intravenously (epoprostenol and treprostinil) or subcutaneously (treprostinil), or via inhalation (iloprost and treprostinil) or orally (treprostinil and selexipag). 10 Various multiparametric risk assessment tools are used to predict survival in people with PAH and to guide treatment decisions with an aim for achieving a low risk status. 11 , 12

Because three signaling pathways can be targeted by the currently available medications, increasing attention has been placed on using combination therapy, the use of two or more classes of drugs simultaneously, for the treatment of PAH. 13 Before 2015, treatment guidelines for PAH recommended initial monotherapy followed by sequential combination therapy with clinical worsening. 2 , 14 In the AMBITION clinical trial, initial combination therapy with an ERA (ambrisentan) plus a PDE5i (tadalafil) in a treatment‐naïve population lowered the risk of clinical failure events (defined as the first occurrence of a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long‐term clinical response), which led the Food and Drug Administration (FDA) to approve the treatment combination in treatment‐naïve people. 15 Other clinical trials have also noted reductions in clinical worsening and long‐term morbidity among people on combination therapy. 16 , 17 , 18 In 2015, the European Society of Cardiology (ESC)/European Respiratory Society (ERS) issued updated treatment guidelines that noted the benefits of initial combination therapy for low‐ and intermediate‐risk persons which was further highlighted in the 6th World Symposium on PH. 19 , 20 Finally, given the complex routes of administration and the potential for severe side effects of parenteral prostacyclins, they are usually reserved for higher risk people with PAH. 21 The FDA approval of oral treprostinil in 2013 and selexipag in 2015 has allowed for earlier use of prostacyclins in combination therapy. 7 , 22 , 23

Few studies have examined treatment patterns among persons with PAH since release of the 2015 guidelines. To our knowledge, only one study has examined treatment patterns across all available PAH medications after the 2015 guidelines, which was limited to data through March 2017. 23 That study examined medication adherence and time to discontinuation of the index treatment regimen for newly diagnosed people. 23 A second study examined medication adherence, healthcare utilization, and cost using data through September 2017, however, the study was limited to people treated with oral prostacyclins. 24 The purpose of the current study is to examine treatment patterns, HCRU, and cost among health plan members with PAH beginning treatment since the 2015 update of the PAH treatment guidelines.

METHODS

Study design and data source

This retrospective study used the HealthCore Integrated Research Database (HIRD®), which includes medical and pharmacy administrative healthcare claims data from 14 geographically diverse commercial health plans with members across the United States. 25 Member enrollment data, inpatient and outpatient medical care, and outpatient prescription drug use are tracked longitudinally for each member. Researchers accessed data in the format of a limited data set for which data use agreements were in place with the covered entities in compliance with the Health Insurance Portability and Accountability Privacy Rule. Because this study was a secondary data analysis using a limited data set, Institutional Review Board approval was not required in accordance with HealthCore’s Federal Wide Assurance.

Study population

Health plan members with commercial insurance or Medicare Advantage/Supplemental Part D insurance with ≥1 claim for a PAH medication between October 1, 2015 and November 30, 2020 (member identification period) were selected for inclusion in the study. PAH medications included an ERA (ambrisentan, bosentan, or macitentan), PDE5i (sildenafil or tadalafil), prostacyclin and IP receptor agonists (epoprostenol, iloprost, selexipag, or treprostinil), or an sGC (riociguat). We sought to identify newly treated members, and the first PAH medication received during the identification period was set as the index date. Members with claims for a PAH medication at any point before the index date (variable time for each patient with a minimum of 6 months) were excluded. Members were required to be greater than 18 years old on the index date. Additionally, members were required to have at least one inpatient or two or more outpatient claims on two distinct dates with a diagnosis of PH or PAH (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD‐9‐CM] codes 416.0, 416.8, 416.9; International Classification of Diseases, Tenth Revision, Clinical Modification [ICD‐10‐CM] codes I27.0, I27.21, I27.2, I27.20, I27.29, I27.89, I27.9) and at least one claim for a RHC during the 6 months before and including the index date. Finally, members were required to have continuous pharmacy and medical benefit enrollment for at least 6 months before (baseline period) and at least 30 days after the index date. The postindex period ended on the earlier of health plan disenrollment or study end date (December 31, 2020, Figure ​ Figure1 1 ).

Study design. HCRU, healthcare resource utilization; PAH, pulmonary arterial hypertension; RHC, right heart catherization. 1 ≥1 claim for a PAH medication during the member selection period (October 1, 2015 and November 30, 2020). The first PAH medication is set as the index date. 2 Defined as member’s start of continuous enrollment (variable) in database. 3 ≥1 inpatient or ≥2 outpatient claims on two distinct dates for PAH. 4 ≥1 claim for RHC. 5 Earliest of disenrollment or end of the study period (December 31, 2020).

Study measures

Member demographics and clinical characteristics (age, sex, insurance type, prescriber specialty) were assessed on the index date, and the Quan‐Carlson comorbidity index 26 and other comorbidities were assessed between the health plan enrollment date and index date.

Treatment patterns were assessed during the variable post‐index period. The first line of treatment was determined by the number of different medication classes observed within the first 30 days after the index date, a definition used in prior administrative claims studies. 7 , 22 , 23 Those with only one medication class within the first 30 days were defined as initiating monotherapy, whereas those with two or more medication classes within the first 30 days post‐index were considered to initiate combination therapy. Oral prostacyclin/IP receptor agonists, inhaled prostacyclin, and parenteral prostacyclin were distinguished as three medication classes. The end of the first line of treatment was prompted by either a treatment interruption or modification of treatment. Treatment interruption was defined as a gap in treatment of at least 60 days after the run‐out of days’ supply of the last prescription filled. If members had a gap of more than 60 days after the run‐out of days’ supply and restarted the same medication after that gap, this would still prompt a new line of treatment. Modification of treatment included the sequential combination of a new medication class or switching medication classes without treatment interruption. The second treatment line started when the member received a new fill for a PAH medication after treatment interruption or at the time of modification of treatment. Treatment patterns were assessed for up to four lines of treatment. Within each line of treatment, medications (by class and drug) and treatment regimens (by class) (e.g., monotherapy ERA, combination ERA + PDE5i) were calculated. A Sankey diagram showing the treatment lines by class of medications for up to four lines of treatment was also created.

All‐cause and PAH‐related HCRU and healthcare costs were assessed during the 6‐month baseline and post‐index periods overall and by each line of treatment. PAH‐related medical visits were defined as claims with an ICD‐9‐CM or ICD‐10‐CM diagnosis of PAH in any position (ICD‐9‐CM codes 416.0, 416.8, 416.9; ICD‐10‐CM codes I27.0, I27.2, I27.20, I27.21, I27.29, I27.89, I27.9), and PAH‐related pharmacy claims were those that included a Healthcare Common Procedure Coding System or a Generic Product Identifier code for a PAH medication. All‐cause and PAH‐related HCRU were calculated as the number and percentage of members with at least one inpatient hospitalization, emergency room visit, outpatient visit, or medication claim (either under the medical or pharmacy benefit). All‐cause and PAH‐related costs were adjusted to 2020 US Dollars (USD) based on the most recent medical price index information provided by the Bureau of Labor Statistics and calculated as the combined health plan paid, member paid, and coordination of benefits costs (third party payer). 27

Statistical analysis

Demographic, clinical characteristics, treatment patterns, HCRU, and costs were presented using descriptive statistics. HCRU and costs in US dollars were presented as per patient per month (PPPM) and calculated by taking the sum number of medical and pharmacy claims and costs and dividing it by the total number of PAH patient‐months during the specified time of interest. Frequencies and percentages are provided for categorical variables and means with standard deviations are presented for continuous variables. All analyses were performed using Instant Health Data software (Panalgo).

RESULTS

Baseline demographic and clinical characteristics

The study population included 843 health plan members with PAH (Table ​ (Table1) 1 ) with a mean age of 62.3 years (standard deviation [SD] = 14.1 years) and 541 (64.2%) were female. Most (59.0%) had commercial insurance as opposed to Medicare Advantage/Supplement/Part D (41.0%), and most were prescribed the first PAH medication by a pulmonologist (43.4%) or cardiologist (25.1%). Members with PAH had a high comorbidity burden with an average Quan‐Charlson comorbidity (QCI) score of 4.6 (SD = 2.7). Common comorbidities included congestive heart failure (75.0%), chronic pulmonary disease (79.8%), and peripheral vascular disease (42.9%). Furthermore, 33.7% were diagnosed with anxiety and 28.2% had depression (Table ​ (Table2 2 ).

Table 1

Step	Criteria	Member counts	% from previous step
1	Members in the HIRD between October 1, 2015 to November 30, 2020	26,943,277	–
2	From step 1, members with ≥1 claim for a PAH medication a between October 1, 2015 to November 30, 2020; set first PAH medication administration or fill date as the index date	6,431	0.02%
3	From step 2, members ≥18 years old on index date	6,018	94%
4	From step 3, members with ≥1 inpatient or ≥2 outpatient claims on two distinct dates for PAH during 6‐month period before and including the index date	2,452	41%
5	From step 4, members with ≥1 claim for RHC within 6 months before and including the index date	1,127	46%
6	From step 5, exclude members with ≥1 claim for PAH medication before index date (start of continuous enrollment to day [index date ‐ 1])	965	86%
7	From step 6, members with ≥6 months of continuous pharmacy and medical benefit enrollment before index date	870	90%
8	From step 7, members with ≥30 days of continuous pharmacy and medical benefit enrollment after index date	843	97%

Note: Member Selection Period: October 1, 2015 to November 30, 2020. Abbreviations: HIRD, HealthCore Integrated Research Database; PAH, pulmonary arterial hypertension; RHC, right heart catherization.

a PAH medications include endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclins, and soluble guanylate cyclase stimulators.

Table 2

Baseline (6 months) characteristics of PAH study population

Members
Number of members, N	843
Pre‐index duration months, mean (SD)	68.4 (52.7)
Post‐index duration months, mean (SD)	18.5 (15.4)
Age at index (years), mean (SD)	62.3 (14.1)
Female, n (%)	541 (64.2%)
Insurance type, n (%)
Commercial	497 (59.0%)
Medicare advantage	200 (23.7%)
Medicare other	146 (17.3%)
Geographic region of member, n (%)
Midwest	274 (32.5%)
Northeast	123 (14.6%)
South	262 (31.1%)
West	184 (21.8%)
Year of index date, n (%)
2015 a	42 (5.0%)
2016	179 (21.2%)
2017	173 (20.5%)
2018	158 (18.7%)
2019	158 (18.7%)
2020	133 (15.8%)
Specialty of index prescriber, n (%)
Pulmonologist	366 (43.4%)
Cardiologist	212 (25.1%)
PCP	50 (5.9%)
Nonphysician clinician (e.g., PA/NP)	116 (13.8%)
Other/Unknown	99 (11.7%)
QCI, mean (SD)	4.6 (2.7)
Comorbidities
Congestive heart failure	632 (75.0%)
Peripheral vascular disease	362 (42.9%)
Chronic pulmonary disease	673 (79.8%)
Anxiety	284 (33.7%)
Depression	238 (28.2%)

Abbreviations: N, number; NP, nurse practitioner; PA, physician’s assistant; PAH, pulmonary arterial hypertension; PCP, primary care physician; QCI, Quan‐Charlson comorbidity score; SD, standard deviation.

Treatment patterns

On average, members with PAH were followed for 18.5 months (SD = 15.4) after the index date and had 1.7 (SD = 1.2) lines of treatment (Table ​ (Table3). 3 ). In total, 39.7% remained on the first line of treatment throughout the duration of their post‐index period, 29.7% experienced a treatment interruption of 60 days or more while on their first line of treatment, and 30.6% modified their first line of treatment. After the first line, 38.7%, 17.5%, and 9.6% of members began a second, third, and fourth line of treatment, respectively. Among those (n = 250) who experienced a treatment interruption of 60 days or more while on the first line, 27.2% eventually restarted treatment with either the same or different medications (Table ​ (Table3 3 ).

Table 3

Post‐index treatment patterns among members with PAH by treatment line. a

First line	Second line	Third line	Fourth line
Number of members initiating each line, N	843 (100.0%)	326 (38.7%)	148 (17.5%)	81 (9.6%)
Treatment patterns
Months in treatment line b , mean (SD)	7.8 (9.8)	7.4 (9.5)	6.8 (8.1)	6.4 (6.4)
Remain on treatment line through end of postindex c , n (%)	335 (39.7%)	139 (42.6%)	50 (33.8%)	35 (43.2%)
Treatment interruption d , n (%)	250 (29.7%)	56 (17.2%)	26 (17.6%)	≤10
Restart treatment after interruption e , n (%)	68 (27.2%)	17 (30.4%)	≤10	≤10
Do not restart treatment after interruption e , n (%)	182 (72.8%)	39 (69.6%)	17 (65.4%)	≤10
Members who modify f , n (%)	258 (30.6%)	131 (40.2%)	72 (48.6%)	36 (44.4%)
Medications in treatment line g
ERA, n (%)	238 (28.2%)	163 (50.0%)	80 (54.1%)	51 (63.0%)
Ambrisentan	123 (14.6%)	79 (24.2%)	43 (29.1%)	27 (33.3%)
Bosentan	≤10	0 (0.0%)	0 (0.0%)	0 (0.0%)
Macitentan	117 (13.9%)	85 (26.1%)	38 (25.7%)	24 (29.6%)
PDE5i, n (%)	588 (69.8%)	218 (66.9%)	92 (62.2%)	42 (51.9%)
Sildenafil	409 (48.5%)	121 (37.1%)	47 (31.8%)	25 (30.9%)
Tadalafil	201 (23.8%)	106 (32.5%)	47 (31.8%)	17 (21.0%)
Prostacyclin, n (%)	118 (14.0%)	100 (30.7%)	57 (38.5%)	44 (54.3%)
Oral	30 (3.6%)	45 (13.8%)	34 (23.0%)	24 (29.6%)
Oral trepostinil	≤10	13 (4.0%)	≤10	≤10
Selexipag	22 (2.6%)	33 (10.1%)	24 (16.2%)	18 (22.2%)
Inhaled	35 (4.2%)	29 (8.9%)	≤10	≤10
Iloprost	0 (0.0%)	≤10	0 (0.0%)	0 (0.0%)
Inhaled treprostinil	35 (4.2%)	28 (8.6%)	≤10	≤10
Parenteral	54 (6.4%)	28 (8.6%)	19 (12.8%)	11 (13.6%)
Treprostinil	26 (3.1%)	17 (5.2%)	14 (9.5%)	≤10
Epoprostenol	28 (3.3%)	11 (3.4%)	≤10	≤10
sGC stimulator (riociguat), n (%)	94 (11.2%)	40 (12.3%)	18 (12.2%)	14 (17.3%)
Treatment regimens h
Monotherapy, n (%)	664 (78.8%)	148 (45.4%)	67 (45.3%)	30 (37.0%)
ERA	99 (11.7%)	27 (8.3%)	21 (14.2%)	≤10
PDE5i	436 (51.7%)	89 (27.3%)	35 (23.6%)	13 (16.0%)
Oral prostacyclin	≤10	≤10	≤10	≤10
Inhaled prostacyclin	22 (2.6%)	≤10	≤10	≤10
Parenteral prostacyclin	30 (3.6%)	≤10	≤10	≤10
sGC	72 (8.5%)	13 (4.0%)	≤10	≤10
Combination therapy, n (%)	179 (21.2%)	178 (54.6%)	81 (54.7%)	51 (63.0%)
ERA + PDE5i	103 (12.2%)	72 (22.1%)	24 (16.2%)	≤10
Other combinations	76 (9.0%)	106 (32.5%)	57 (38.5%)	41 (50.6%)

Abbreviations: ERA, endothelin receptor antagonist; IQR, interquartile range; N, number; PAH, pulmonary arterial hypertension; PDE5i, phosphodiesterase 5 inhibitor; SD, standard deviation; sGC, soluble Guanylate Cyclase stimulator.

a Post‐index period is defined at index date to end of continuous enrollment or study period end (December 31, 2020), whichever comes first.

b Measured as the number of months from treatment initiation to treatment interruption or modification.

c The proportion of members who remain on continuous treatment from index date to the end of post‐index period allowing for a maximum fixed gap of 60 days. Gap refers to the time between the run‐out date of the previous fill, calculated as fill date plus days’ supply, and the date of the subsequent fill between index date and day 365.

d The proportion of members who have a gap of >60 days between fills. Gap refers to the time between the run‐out date of the previous fill, calculated as fill date plus days’ supply, and the date of the subsequent fill between index date and day 365.

e Among those who have treatment interruption. Member may restart the same treatment or a different treatment after the 60 days.

f Modification occurs when a member switches drug classes (without treatment interruption) or when members adds a sequential combination therapy.

While on the first line of treatment, 69.8% of cohort members received a PDE5i, 28.2% an ERA, 14.0% a prostacyclin, and 11.2% an sGC. Use of PDE5is decreased slightly by line of treatment from 69.8% among those who initiated a first line of treatment to 66.9%, 66.2%, and 51.9% among those initiating a second, third, and fourth line of treatment, respectively. While PDE5is declined with each line of treatment, the proportion who used ERAs, prostacyclins, and sGCs tended to increase with each subsequent line of treatment. Specifically, the prevalence of prostacyclin use among those initiating a first, second, third, and fourth line of treatments was 14.0%, 30.7%, 38.5%, and 54.3%, respectively. In general, use of parenteral prostacyclins was low with only 6.4%, 8.6%, 12.8%, and 13.6% using as a first, second, third, and fourth line of treatment, respectively (Table ​ (Table3 3 ).

For the first line of treatment, most members with PAH were on monotherapy (78.8%) with 51.7% receiving a PDE5i, 11.7% receiving an ERA, and 8.5% receiving an sGC. Only 21.2% of members initiated a combination therapy as the first line of treatment with the most common combination therapy being an ERA + PDE5i, received by 12.2% of members in the cohort. The proportion of the study population on combination therapy increased among those who initiated subsequent lines of treatment to 54.6%, 54.7%, and 63.0% in the second, third, and fourth lines, respectively (Table ​ (Table3). 3 ). An ERA + PDE5i combination remained the most prevalent combination through the second line of treatment. The flow of members across lines of treatment is presented in a Sankey diagram (Figure ​ (Figure2 2 ).

PAH medications by treatment line. 1 ERA, endothelin receptor antagonist; IP, inhaled prostacyclin; OP, oral prostacyclin; PAH, pulmonary arterial hypertension; PDE5I, phosphodiesterase 5 inhibitor; PP, parenteral prostacyclin; sGCs, soluble guanylate cyclase stimulators. 1 Sankey diagrams show treatments that comprise ≥1% of total line *n ≤ 10.

Healthcare resource utilization

HCRU was high in both the 6‐month baseline and post‐index period. While the percent of members with at least one all‐cause inpatient hospitalization increased slightly from the baseline to the post‐index period (from 56.0% to 58.0%), the number of inpatient hospitalizations PPPM decreased from 0.17 in the baseline to 0.09 in the post‐index period. All members (100.0%) had an all‐cause outpatient visit in the 6‐month baseline, and nearly all (98.8%) had an all‐cause outpatient visit in the post‐index period. All‐cause outpatient visits decreased slightly from 5.84 PPPM in the baseline period to 5.60 visits PPPM in the post‐index period. In total, 4.5% of members had a lung or lung and heart transplant after treatment initiation (Table ​ (Table4 4 ).

Table 4

Baseline (6 months) and post‐index healthcare resource utilization overall and by treatment line

Baseline a	Post‐index b	First line	Second line	Third line	Fourth line
Number of members, N	843	843	843	326	148	81
Number of months in time period, mean (SD)	6.0 (0.0)	18.5 (15.4)	7.8 (9.8)	7.4 (9.5)	6.8 (8.1)	6.4 (6.4)
≥1 claim, n (%)
All causes
Inpatient hospitalization	472 (56.0%)	489 (58.0%)	313 (37.1%)	114 (35.0%)	40 (27.0%)	27 (33.3%)
Lung or lung/heart transplant	45 (5.3%)	34 (4.0%)	≤10	≤10	0 (0%)
Emergency room visits	212 (25.1%)	348 (41.3%)	199 (23.6%)	63 (19.3%)	24 (16.2%)	18 (22.2%)
Outpatient visits	843 (100.0%)	833 (98.8%)	825 (97.9%)	317 (97.2%)	147 (99.3%)	76 (93.8%)
Pharmacy fills	827 (98.1%)	834 (98.9%)	833 (98.8%)	324 (99.4%)	148 (100%)	80 (98.8%)
PAH related c
Inpatient hospitalization	422 (50.1%)	419 (49.7%)	255 (30.2%)	102 (31.3%)	37 (25.0%)	26 (32.1%)
Emergency room visits	40 (4.7%)	124 (14.7%)	70 (8.3%)	23 (7.1%)	13 (8.8%)	≤10
Outpatient visits	725 (86%)	774 (91.8%)	723 (85.8%)	285 (87.4%)	121 (81.8%)	66 (81.5%)
PAH medication claims d
Medical administration	109 (12.9%)	72 (8.5%)	42 (12.9%)	25 (16.9%)	13 (16.0%)
Pharmacy fills	819 (97.2%)	806 (95.6%)	305 (93.6%)	135 (91.2%)	74 (91.4%)
PPPM e
All causes
Inpatient hospitalization	0.17	0.09	0.10	0.09	0.07	0.07
Emergency room visits	0.07	0.05	0.05	0.04	0.03	0.04
Outpatient visits	5.84	5.60	5.90	5.40	5.81	4.96
Pharmacy fills	2.95	3.86	4.08	4.47	4.24	4.16
PAH‐related d
Inpatient hospitalization	0.11	0.06	0.07	0.07	0.06	0.07
Emergency room visits	0.01	0.01	0.01	0.01	0.02	0.02
Outpatient visits	1.24	1.34	1.57	1.58	1.75	1.75
PAH medication claims
Medical administration	0.10	0.09	0.13	0.49	0.35
Pharmacy fills	0.85	1.08	1.35	1.27	1.38

Abbreviations: GPI, generic product identifier; HCPCS, Healthcare common procedure coding system; ICD‐10‐CM, International Classification of Diseases, Tenth Revision, Clinical Modification; ICD‐9‐CM, International Classification of Diseases, Ninth Revision, Clinical Modification; N, number; PAH, pulmonary arterial hypertension; PPPM, per patient per month; SD, standard deviation.

b Post‐index period is defined as index date to end of continuous enrollment or study period (whichever comes first).

c PAH medical utilization is based on medical claims with an ICD‐9‐CM or ICD‐10‐CM diagnosis code for PAH.

d Includes ERA, PDE5i, prostacyclin, and sGC medications dispensed under medical (identified via HCPCS codes) or pharmacy benefit (identified via GPI codes).

e PPPM is calculated by summing the total number of claims across members in the cohort during the specified time period and dividing by the sum of total months of enrollment across all members in the cohort during the specified time period.

Between the 6‐month baseline and post‐index periods, all‐cause medical costs decreased from $14,208 to $6,349 PPPM, and all‐cause pharmacy costs increased from $909 to $7,852. Even with increases in pharmacy costs, total all‐cause costs decreased from $15,117 to $14,201 PPPM driven by the overall decrease in medical costs. All‐cause total costs increased with each line of treatment. Costs were $15,352 PPPM while on the first line of treatment and subsequently increased to $20,021, $20,891, and $25,038 PPPM on the second, third, and fourth line of treatment, respectively (Table ​ (Table5 5 ).

Table 5

Baseline (6 months) and post‐index healthcare costs (in 2020 USD) overall and by treatment line

PPPM Healthcare costs a	Baseline b	Post‐index c	First line	Second line	Third line	Fourth line
Number of members, N	843	843	843	326	148	81
Number of months in time period, mean (SD)	6.0 (0.00)	18.5 (15.41)	7.8 (9.78)	7.4 (9.51)	6.8 (8.11)	6.4 (6.43)
All cause
Total costs	$15,117	$14,201	$15,352	$20,021	$20,891	$25,038
Medical costs	$14,208	$6,349	$7,480	$6,510	$7,028	$8,074
Pharmacy costs	$909	$7,852	$7,871	$13,510	$13,863	$16,964
PAH‐related d
Total costs	$10,868	$10,506	$11,365	$16,810	$18,420	$23,198
Medical costs	$10,868	$3,617	$4,460	$4,171	$5,604	$7,046
Pharmacy costs	$6,889	$6,905	$12,639	$12,816	$16,152

Abbreviations: COB, coordination of benefits; ERA, endothelin receptor antagonist; ICD‐10‐CM, International Classification of Diseases, Tenth Revision, Clinical Modification; ICD‐9‐CM, International Classification of Diseases, Ninth Revision, Clinical Modification; N, number; PAH, pulmonary arterial hypertension; PDE5i, Phosphodiesterase 5 inhibitor; PPPM, per patient per month; SD, standard deviation; sGC, soluble Guanylate Cyclase stimulator; USD, United States Dollar.

a Costs include plan paid, member paid, and COB (third party payer) and were adjusted to 2020 USD; PPPM is calculated by summing the total costs across members in the cohort during the specified time period and dividing by the sum of total months of enrollment across all members in the cohort during the specified time period.

c Post‐index period is defined as index date to end of continuous enrollment or study period (whichever comes first).

d PAH medical costs is based on medical claims with an ICD‐9‐CM or ICD‐10‐CM diagnosis code for PAH; PAH pharmacy costs are for ERA, PDE5i, prostacyclin, and sGC medications dispensed under pharmacy benefit.

DISCUSSION

This study examined real‐world treatment patterns, HCRU, and cost following publication of the 2015 ESC/ERS guidelines, which put forth evidence that physicians could treat people with low‐ and intermediate‐risk PAH with either upfront or sequential combination therapy. 19 In this study, 21.2% of members with PAH initiated treatment on combination therapy. The findings show a modest increase in use of first‐line combination therapy from previous studies using real‐world data in which between 4% and 10% of cohort members initiated treatment with combination therapy. 7 , 22 , 23 , 28 Importantly, these studies were largely conducted on administrative data before the 2015 guideline update. In the study by Studer et al., 13.0% of their cohort used combination therapy as a first‐line treatment in the period after guideline update (August 2015 to March 2017). 23

The 2015 guidelines did not recommend upfront combination therapy over sequential combination therapy in people with low‐ to intermediate‐risk PAH and instead provided evidence supporting either treatment strategy. 19 In our study, if sequential combination occurred more than 30 days after the index date, the first line of treatment would have been classified as monotherapy. A sequential combination therapy treatment strategy may, in part, explain lower than expected utilization of combination therapy as a first line of treatment in the present study. In 2019, the American College of Chest Physicians (CHEST) Guideline and Expert Panel Report on Pharmacotherapy recommended upfront combination therapy over monotherapy for treatment‐naïve people with a WHO functional class (FC) II or III provided the person is willing and able to tolerate it. 29 The recommendations noted that some people may be unwilling to use combination therapy as it has higher costs and can increase risk for adverse events. 29 Additionally, the 6th World Symposium on Pulmonary Hypertension published guidelines in 2019 indicating the treatment strategy should be guided by a risk stratification approach. 20 Specifically, for people with low‐ or intermediate‐risk PAH, combination therapy should be used with only a residual role for monotherapy in specific subsets of people with PAH in whom the efficacy or safety of initial combination therapy was not established. 20 Because this study included less than 2 years of data since publication of these guidelines, further research is needed to understand the impact of these more recent guidelines on real‐world treatment patterns.

The most common first‐line combination therapy in this study was an ERA + PDE5i with 57.5% of members in the cohort receiving this regimen. According to the 2015 ESC/ERS guidelines and more recent 2019 CHEST guidelines, the combination with the greatest evidence base for treatment of WHO FC II and III is ambrisentan (ERA) and tadalafil (PDE5i). 19 , 29 Although this study did not look at specific medications so it is unknown if members had this specific combination of drugs, the high prevalence of the ERA + PDE5i combination may be in part driven by these recommendations. For people on an established PAH therapy, there are several recommendations for sequential combination therapy in the 2015 ESC/ERS guidelines and upheld by the 6th World Symposium on Pulmonary Hypertension, which include macitentan (ERA) added to sildenafil (PDE5i), riociguat (sGC) added to bosentan (ERA), selexipag (oral prostacyclin) added to an ERA or PDE5i, and sildenafil (PDE5i) added to epoprostenol (parenteral prostacyclin). 19 , 20 Among members who initiated a second‐line combination therapy (n = 178) in the present study, the most prevalent treatment combination remained an ERA + PDE5i (40.5%). The high prevalence of ERA + PDE5i as the most prevalent first‐ and second‐line combination is also consistent with previous studies. 5 , 7 , 22

The prevalence of prostacyclin use among members in this cohort initiating a first or second line of treatment was 14.0% and 30.7%, respectively, which is higher than a previous study in which only 8.1% and 22.4% of the cohort used a prostacyclin as a first and second line of treatment, respectively. 7 The prior study used data predating the approval of selexipag in 2015, and the higher prevalence of prostacyclin use in our study appears to be driven by selexipag. This result aligns with the 2015 ESC/ERS guidelines, which recommended selexipag as monotherapy or added to an ERA and/or PDE5i as sequential therapy for WHO‐FC II or III. 19

Riociguat, an sGC, was approved to treat PAH by the FDA in 2013. In our cohort, 11.2% of members used riociguat as a first‐line treatment. This is markedly higher than prior studies in which between 0% and 5% of studied cohorts used an sGC as a first‐line treatment, although these prior studies spanned years that included time before 2013 when riociguat was approved. 7 , 22 , 23 In a systematic review of interventions for PAH, monotherapy riociguat and combination ERA + PDE5i ranked best at reducing clinical worsening followed by monotherapy PDE5i and monotherapy ERA. 30 Importantly, the estimate for riociguat was based on a single study, so this should be interpreted with caution. 30

Nearly 30% of members with PAH in the present study had a treatment interruption to their first line of treatment lasting at least 60 days. Although different definitions of treatment interruption have been used (e.g., 30‐ and 90‐day gaps), this result is a slight improvement compared with previous studies in which between 37% and 38% of people had a treatment interruption. 7 , 22 , 31 Factors driving high rates of interruption may include misdiagnosis, intolerable side effects, and high medication costs. 7

Hospitalization is an important measure of clinical worsening among people with PAH. 32 The Registry to Evaluate Early and Long‐Term PAH Disease Management (REVEAL) risk calculator (REVEAL 2.0) is used to help physicians make treatment decisions based on an individual’s risk profile. 11 All cause hospitalization within the previous 6 months was added to the calculation such that those with prior hospitalizations will have greater REVEAL 2.0 risk scores. 11 Future studies may consider examining the role of hospitalization in real‐world treatment intensification and decision making. Although the hospitalization rate decreased after treatment initiation, the proportion of members hospitalized remained high with 58.0% of members experiencing at least one hospitalization and 49.7% of members having a PAH‐related hospitalization. High rates of hospitalization were also found in the REVEAL Registry where 56.8% of people in the registry had at least one hospitalization over the 3‐year post‐index period and in a study by Studer et al. in which 66.4% of the cohort had a hospitalization in the post‐index period. 7 , 33 As hospitalization has been associated with increased mortality and is an important determinant of medical costs among people with PAH, 5 , 31 , 33 further understanding of the impact of different treatment patterns on hospitalization outcomes would help support and refine treatment guidelines.

Findings from the present study underscore the high healthcare cost associated with PAH. Total all‐cause and PAH‐related costs were $14,201 PPPM and $10,506 PPPM, respectively, with costs increasing with each subsequent line of treatment. Even with adjustments for inflation, all‐cause costs are higher in the present study compared to prior studies. 5 , 22 , 28 , 31 For example, Sikirica et al. found all‐cause costs to be $8,187 per month (2011 USD), Copher et al. found all‐cause costs to be $9,295 PPPM (2008 USD), Angalakuditi et al. found PAH all‐cause costs to be $3,236 PPPM (2008 USD), and Burger et al. found all‐cause costs to be $8,987 PPPM (2014 USD). 5 , 22 , 28 , 31 The higher costs in the present study may be due in part to member selection criteria (e.g., our study required a PAH medication and RHC for inclusion) but may also be related to increased utilization of high cost specialty medications such as riociguat and selexipag. All‐cause medical costs decreased after initiating treatment, a finding mirrored in studies by Burger et al. and Sikirica et al. 22 , 31 In addition, the offset resulted in a net decrease in total costs, a finding also seen by Sikirica et al. 31 This suggests that the high cost of PAH medications may be offset by reductions in medical costs associated with treating PAH such as decreasing hospitalizations, a hypothesis that requires further research to evaluate.

The findings should be interpreted with consideration of several limitations. First, administrative claims are collected for the purpose of payment and not for research and may not reflect true diagnoses and treatment as coding issues may occur and medications may not be taken as prescribed. Some of the ICD‐9‐CM and ICD‐10‐CM diagnosis codes used to identify members with PAH were for PH and not PAH specifically, so it is possible we inadvertently captured members with PH Groups 2–5 in our definition. We increased specificity of identifying members with PAH by also requiring medications for PAH and an RHC as inclusion criteria, 34 , 35 , 36 but riociguat is used to treat both PH group 1 (i.e., PAH) and PH group 4 disease. Second, important member demographics, clinical characteristics, and data on health‐related quality of life are not available in medical and pharmacy claims. For example, functional class, exercise capacity, and echocardiogram results are important measures used in risk assessments and to guide treatment decisions, but these data are unavailable in claims. 19 , 20 , 29 Third, it is possible that the definition of index treatment (i.e., evidence of two or more classes of PAH medications within the first 30 days after index date) was too rigorous and may not account for slower uptake of combination therapy. For example, providers may want to monitor tolerability of a medication before adding a second, or delays in prior authorization may delay uptake of combination therapy. Combination therapy was defined similarly to previous studies that have examined treatment patterns among people with PAH. 7 , 22 , 23 Fourth, follow‐up time for some members occurred during the COVID‐19 pandemic, which may have impacted treatment patterns and outcomes. Finally, study results may not be generalizable to the overall PAH population because people who have commercial and Medicare insurance may have different characteristics than those who are uninsured or on Medicaid.

This study provides a real‐world perspective on treatment patterns, HCRU, and cost following changing treatment guidelines and approval of new medications. Most people initiated treatment on monotherapy during our study period even with growing evidence to support initiating treatment with combination therapy. HCRU remained high following treatment initiation although the number of all‐cause inpatient stays, emergency room visits, and outpatient visits PPPM decreased from the baseline to the postindex period. Initiation of treatment reduced total all‐cause spending even with increases in pharmacy costs. These findings highlight the value of real‐world studies in examining treatment patterns and outcomes among people with PAH. Future studies should compare effectiveness of different treatment modalities (e.g., upfront monotherapy vs. combination therapy) on HCRU and cost.

AUTHOR CONTRIBUTIONS

Lia N. Pizzicato designed the study and prepared the first draft of the protocol. Vijay R. Nadipelli, Samuel Governor, Stephan Lanes, John Butler, Rebecca S. Pepe, Hemant Phatak, and Karim El‐Kersh contributed to and approved the final version of the protocol. Lia N. Pizzicato and Samuel Governor conducted all statistical analyses. Lia N. Pizzicato, Vijay R. Nadipelli, Samuel Governor, Jianbin Mao, Stephan Lanes, John Butler, Rebecca S. Pepe, Hemant Phatak, and Karim El‐Kersh reviewed and interpreted results. Lia N. Pizzicato drafted the first draft of the manuscript. Vijay R. Nadipelli, Samuel Governor, Jianbin Mao, Stephan Lanes, John Butler, Rebecca S. Pepe, Hemant Phatak, and Karim El‐Kersh contributed to and approved the final version of the manuscript.

CONFLICTS OF INTEREST

Authors Vijay R. Nadipelli, Jianbin Mao, John Butler, and Hemant Phatak are employees of Acceleron Pharma Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, which funded this study. Karim El‐Kersh provided consultative services to Acceleron Pharma Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, served on advisory boards for J&J Actelion, and United Therapeutics, received institutional research funding from J&J Actelion and United Therapeutics. Lia N. Pizzicato, Samuel Governor, Stephan Lanes, and Rebecca S. Pepe are employees of HealthCore Inc. (Wilmington, DE), which was contracted by Acceleron Pharma Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, to perform this study.

ETHICS STATEMENT

Researchers accessed data in the format of a limited data set for which data use agreements were in place with the covered entities in compliance with the Health Insurance Portability and Accountability Privacy Rule. Because this study was a secondary data analysis using a limited dataset, Intistutional Review Board approval was not required in accordance with HealthCore’s Federal Wide Assurance.

ACKNOWLEDGMENT

This research was funded by Acceleron Pharma Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Notes

Pizzicato LN, Nadipelli VR, Governor S, Mao J, Lanes S, Butler J, Pepe RS, Phatak H, El‐Kersh K. Real‐world treatment patterns, healthcare resource utilization, and cost among adults with pulmonary arterial hypertension in the United States . Pulmonary Circulation . 2022; 12 :e12090. 10.1002/pul2.12090 [CrossRef] [Google Scholar]

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Sildenafil citrate (Synonyms: UK-92480 citrate)

Sildenafil citrate is a potent phosphodiesterase type 5 (PDE5) inhibitor with IC₅₀ of 5.22 nM.

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Sildenafil citrate is a potent phosphodiesterase type 5 (PDE5) inhibitor with IC₅₀ of 5.22 nM.

Pretreatment with 1 μM Sildenafil citrate potentiates the phosphorylation of ERK1/ERK2, an increase in the percentage of cells in S phase and cell proliferation, compared with serotonin stimulation alone (P [2] .

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

In the dog model of erection, Sildenafil citrate significantly increases ICP and ICP/BP but shows no significant effect on BP compared with vehicle [1] . Sildenafil treatment significantly decreases the number of TL + -cells at 10 but not 0.5 mg/kg. At this time point, cells positive for the M1-like marker COX-2 + are found in the ischemic core in PBS-treated animals, whereas they are mostly observed in the penumbra in 10 mg/kg (but not 0.5 mg/kg) Sildenafil-treated animals. In contrast, 8 days after pMCAo the number of microglia/macrophages stained by Iba-1 are significantly reduced by Sildenafil treatment (0.5 and/or 10 mg/kg dose) [3] . Sildenafil citrate has been reported to decrease flap necrosis in preclinical animal models by increasing the secretion of growth factors (FGF and VEGF), and histologically is shown to be effective in rat cavernous nerve architecture [4] .

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Room temperature in continental US; may vary elsewhere.

* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

DMSO : 50 mg/mL (75.00 mM; Need ultrasonic)

H₂O : 2 mg/mL (3.00 mM; Need ultrasonic)

Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% saline

Solubility: ≥ 5 mg/mL (7.50 mM); Clear solution

Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in saline)

Solubility: ≥ 5 mg/mL (7.50 mM); Clear solution

Add each solvent one by one: 10% DMSO 90% corn oil

Solubility: ≥ 5 mg/mL (7.50 mM); Clear solution

Cells at approximately 90% confluence are harvested with 0.1% trypsin/0.01% ethylene diamine tetraacetic acid (EDTA) solution and seeded into a 96-well plate at a density of 2×10 4 cells/well and grown in RPMI-1640 containing 10% FBS for three days, followed by serum starvation for three days. Cells are then incubated for different time with various concentration of serotonin or 1 μM Sildenafil followed by serotonin with or without U0126, as indicated. Control cells are treated in the same way except sterile PBS replaced the drug. After treatment, medium is changed to fresh medium, and cells are incubated with 5 g/L of MTT for four hours. MTT is then dissolved with 150 μL of 10% DMSO for 20 minutes. The optical densities (OD) in the 96-well plates are determined using a microplate reader at 570 nm [2] .

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Mice [3]
Ischemia is induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or Sildenafil intraperitoneal (i.p.) injections. In the first set of experiments, animals are randomly divided into five groups and treated with either PBS or a single dose of Sildenafil citrate (0.5, 2.5, 10, and 15 mg/kg), given intraperitoneally (i.p.) 5 min after pMCAo. In the second set of experiments, animals are randomly divided into three groups and treated with either PBS or a single dose of Sildenafil citrate (0.5 and 10 mg/kg, i.p.) 5 min after pMCAo.
Rats [4]
Thirty male Sprague-Dawley rats weighing between 210 and 240 g are used. Rats from all groups are anesthetized with xylazine + ketamine and then a crush injury is created by using a one-minute long vascular clamp to the right sciatic nerve. One day before the procedure, rats from Group 1 are started on a 28-day treatment consisting of a daily dose of 20 mg/kg body weight Sildenafil given orally via nasogastric tube, while the rats from Group 2 are started on an every-other-day dose of 10 mg/kg body weight Sildenafil citrate. Rats from Group 3 did not receive any drugs. Subjects in all 3 groups are fed ad libitum with normal rat chow and tap water. Forty-two days after the nerve damage is created, the rats underwent a static sciatic index (SSI) test, sedation and motor coordination tests, and accelerated rotarod tests. Rats are sacrificed under anesthesia and their sciatic nerves are removed surgically. Histopathologic analyses of the nerves and bone densitometry evaluation of the extremities are then performed.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.