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Endpoints in sarcoidosis: More like IPF or asthma?

Open ArchivePublished:November 20, 2017DOI:https://doi.org/10.1016/j.rmed.2017.11.010

      Keywords

      Sarcoidosis remains an enigmatic disease. Its cause is unknown, the indications for treatment are often unclear, and its natural history is variable. An additional important enigmatic issue that has hampered clinical sarcoidosis research is the failure to develop reliable and universally accepted clinical endpoints.
      As pulmonary sarcoidosis is thought to be an interstitial lung disease, the traditional primary endpoint that has been selected for clinical trials is the forced vital capacity (FVC) [
      • Baughman R.P.
      • Drent M.
      • Kavuru M.
      • et al.
      Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.
      ,
      • Judson M.A.
      • Baughman R.P.
      • Costabel U.
      • et al.
      Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis.
      ], mirroring a common endpoint in clinical trials of idiopathic pulmonary fibrosis (IPF). Indeed, in a survey of sarcoidosis experts [
      • Baughman R.P.
      • Drent M.
      • Culver D.A.
      • et al.
      Endpoints for clinical trials of sarcoidosis.
      ], the FVC was the consensus recommendation as the premiere clinical endpoint for pulmonary sarcoidosis trials.
      There is strong clinical evidence supporting the FVC as a reliable clinical endpoint in IPF. Several studies of mixed groups of patients with IPF and fibrotic non-specific interstitial pneumonitis (NSIP) found that a serial decline in FVC over 6–12 months was associated with an increased mortality [
      • Wells A.U.
      • Behr J.
      • Silver R.
      Outcome measures in the lung.
      ,
      • Latsi P.I.
      • du Bois R.M.
      • Nicholson A.G.
      • et al.
      Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends.
      ,
      • Flaherty K.R.
      • Mumford J.A.
      • Murray S.
      • et al.
      Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia.
      ,
      • Jegal Y.
      • Kim D.S.
      • Shim T.S.
      • et al.
      Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia.
      ].
      However, there are many important differences between IPF and pulmonary sarcoidosis that may not justify extrapolating the FVC endpoint from the former disease to the latter. First, IPF is a relentlessly progressive restrictive disease with a high mortality. In IPF, the FVC almost uniformly declines over time. Pulmonary sarcoidosis, other the other hand, is not necessarily progressive. In fact, in terms of spirometry, there is a tendency for it to improve, if not normalize over time in the majority of patients [
      • Judson M.A.
      • Boan A.D.
      • Lackland D.T.
      The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States.
      ,
      • Judson M.A.
      • Baughman R.P.
      • Thompson B.W.
      • et al.
      Two year prognosis of sarcoidosis: the ACCESS experience.
      ]. Second, pulmonary sarcoidosis is rarely fatal. The estimated age adjusted sarcoidosis-related mortality rate in the United States has been estimated between 3 and 6 per 1,000,000 [
      • Swigris J.J.
      • Olson A.L.
      • Huie T.J.
      • et al.
      Sarcoidosis-related mortality in the United States from 1988 to 2007.
      ]. Certainly, the FVC cannot be used as a surrogate biomarker for death in sarcoidosis. Third, although sarcoidosis is often classified as an interstitial lung disease, the disease may predominantly affect the airways and cause significant airflow obstruction [
      • Kalkanis A.
      • Judson M.A.
      Distinguishing asthma from sarcoidosis: an approach to a problem that is not always solvable.
      ,
      • Polychronopoulos V.S.
      • Prakash U.B.
      Airway involvement in sarcoidosis.
      ]. Therefore, in a significant percentage of pulmonary sarcoidosis patients, the predominant symptoms and quality of life impairment are better reflected by physiologic measurements of airflow obstruction than by measurements of lung restriction such as the FVC. Fourth, unlike IPF which is an isolated pulmonary disease, sarcoidosis often has pulmonary and extrapulmonary manifestations. Therefore, the treatment of a pulmonary sarcoidosis patient is often directed at improving quality of life issues caused by associated a) extrathoracic sarcoidosis; b) parasarcoidosis syndromes [
      • Judson M.A.
      The three tiers of screening for sarcoidosis organ involvement.
      ] such as fatigue [
      • Drent M.
      • Lower E.E.
      • De Vries J.
      Sarcoidosis-associated fatigue.
      ] and small fiber neuropathy [
      • Tavee J.
      • Culver D.
      Sarcoidosis and small-fiber neuropathy.
      ]; and c) anti-sarcoidosis therapy, specifically corticosteroids [
      • Cox C.E.
      • Donohue J.F.
      • Brown C.D.
      • Kataria Y.P.
      • Judson M.A.
      Health-related quality of life of persons with sarcoidosis.
      ,
      • Judson M.A.
      • Chaudhry H.
      • Louis A.
      • Lee K.
      • Yucel R.
      The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis.
      ] that are not recommended for the treatment of IPF [
      • Raghu G.
      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      ]. The FVC does not accurately reflect these extrapulmonary manifestations of the disease.
      To summarize, the prototypical patient enrolled in an IPF trial is an individual with significant dyspnea and functional impairment with a restrictive lung disease that is expected to worsen clinically and physiologically with a significant chance of death within the following 5 years. The prototypical pulmonary sarcoidosis patient enrolled in a clinical trial is an individual with pulmonary restriction and/or obstruction who has active granulomatous inflammation in the lung that responds to corticosteroids and other anti-granulomatous therapy. The pulmonary sarcoidosis patient's pulmonary function waxes and wanes over time, depending upon the dosing of corticosteroids [
      • Judson M.A.
      • Baughman R.P.
      • Costabel U.
      • Mack M.
      • Barnathan E.S.
      The potential additional benefit of infliximab in patients with chronic pulmonary sarcoidosis already receiving corticosteroids: a retrospective analysis from a randomized clinical trial.
      ] and other anti-sarcoidosis therapy. The pulmonary function of some of these patients will decline if their granulomatous inflammation is undertreated, and they may develop permanent reductions in pulmonary function from worsening lung fibrosis. However, this fibrosis is usually not imminently life-threatening and rarely causes rapid declines in physiology, as evidenced by the fact that the placebo group in several recent sarcoidosis trials (the majority of whom were receiving a maintenance dose of corticosteroids) did not demonstrate a significant decrement in FVC over the trial period [
      • Baughman R.P.
      • Drent M.
      • Kavuru M.
      • et al.
      Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.
      ,
      • Judson M.A.
      • Baughman R.P.
      • Costabel U.
      • et al.
      Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis.
      ].
      This description of a pulmonary sarcoidosis trial participant displays many similarities to a patient with chronic asthma. Like sarcoidosis, chronic asthma is rarely fatal, with a mortality rate of less than 3/100,000 [
      • Kochanek K.D.
      • Murphy S.L.
      • Xu J.
      • Tejada-Vera B.
      Statistics DoV. Deaths: final data from 2014.
      ]. Although chronic asthma may result in acute exacerbations that dramatically reduce lung function, permanent lung damage usually does not develop acutely. Rather, progressive and permanent fixed airflow obstruction may develop over time in chronic asthma patients if the disease is undertreated (remodeled asthma). Although corticosteroids are very effective in asthma and are commonly used to treat acute asthma exacerbations, the side effects of corticosteroids make them unattractive for long-term use. Like the chronic sarcoidosis patient, the concerns in the chronic asthma patient are not primarily focused on the prevention of death but rather on quality of life impairment, the severity of symptoms, rate of exacerbations and the need for additional therapy. Because of these clinical asthma features, the forced expiratory volume in 1 s (FEV1) is not an ideal endpoint in asthma trials. More useful endpoints are the frequency of exacerbations, the need for rescue inhalers, corticosteroid dependence and dose, quality of life and asthma-related symptoms.
      We would encourage consideration of similar endpoints in pulmonary sarcoidosis trials as in asthma trials that we believe more closely reflect important health issues of pulmonary sarcoidosis patients than those that can be extrapolated from the FVC. Potential endpoints that come to mind include quality of life measures, symptoms of cough, dyspnea, and wheeze, the frequency of exacerbations of sarcoidosis (requiring corticosteroid bursts or additional anti-sarcoidosis therapy), and corticosteroid-sparing effects of interventions.

      Summary of conflict of interest of the authors

      MAJ is a consultant for Biogen. No other author has a conflict of interest to disclose.

      Acknowledgement

      The author wishes to acknowledge Dr. Johann Christian Virchow for his thoughtful editorial advice.

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