Main Article Content
roflumilast, fibrotic sarcoidosis, acute events, prednisone
Background: Fibrotic sarcoidosis patients often have acute events of increased cough and sputum production. We evaluated the impact of roflumilast in fibrotic sarcoidosis patients with repeated episodes of increased cough and sputum.
Methods: Sarcoidosis patients with pulmonary fibrosis and at least two acute episodes in the previous year were randomized to receive either roflumilast (ROF) or placebo (PLA) in a double blind, placebo controlled multi-center trial. Subjects were assessed initially and every three months for 12 months. At each visit, spirometry and health related quality of life questionnaires were completed. For each subject, the best forced expiratory volume at 1 second (FEV-1) was noted.
Results: Of the 38 subjects who enrolled in the study, 28 subjects (14 in each group) received at least three months of treatment and 10 in each arm completing all 12 months of study. During the treatment, patients treated with ROF were less likely to have visits in which the FEV-1 was less than 90% of the best FEV-1 (Odds ratio=0.34 (0.16 to 0.76 95% confidence interval, p=0.0073). At the end of treatment with ROF, patients had a significant improvement in their KSQ LUNG (Initial visit: 45.3 + 6.89 (Mean + S.D.); Last visit: 52.6+ 7.91, p<0.05) with no change for PLA treated patients.
Conclusion: Patients treated with at least three months of roflumilast had fewer follow-up visits with an FEV-1 of less than 90% of best value. At the end of treatment, ROF treated patients had a better quality of life as assessed by KSQ LUNG.
(2) Scadding JG. Prognosis of intrathoracic sarcoidosis in England. Br Med J 1961; 4:1165-1172.
(3) Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager HJ, Bresnitz EA et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001; 164:1885-1889.
(4) Loddenkemper R, Kloppenborg A, Schoenfeld N, Grosser H, Costabel U. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis--results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft fur die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis 1998; 15(2):178-182.
(5) Gerke AK, Yang M, Tang F, Cavanaugh JE, Polgreen PM. Increased hospitalizations among sarcoidosis patients from 1998 to 2008: a population-based cohort study. BMC Pulm Med 2012; 12:19. doi: 10.1186/1471-2466-12-19.:19-12.
(6) Swigris JJ, Olson AL, Huie TJ, Fernandez-Perez ER, Solomon J, Sprunger D et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med 2011; 183(11):1524-1530.
(7) Walsh SL, Wells AU, Sverzellati N, Keir GJ, Calandriello L, Antoniou KM et al. An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study. Lancet Respir Med 2014; 2(2):123-130.
(8) Nardi A, Brillet PY, Letoumelin P, Girard F, Brauner M, Uzunhan Y et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J 2011; 38(6):1368-1373.
(9) Kirkil G, Lower EE, Baughman RP. Predictors of Mortality in Pulmonary Sarcoidosis. Chest 2018; 153(1):105-113.
(10) Panselinas E, Judson MA. Acute pulmonary exacerbations of sarcoidosis. Chest 2012; 142(4):827-836.
(11) Baughman RP, Lower EE. Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients. Respir Med 2013; 107:2009-2013.
(12) Alobaidi NY, Stockley JA, Stockley RA, Sapey E. An overview of exacerbations of chronic obstructive pulmonary disease: Can tests of small airways' function guide diagnosis and management? Ann Thorac Med 2020; 15(2):54-63.
(13) Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med 2016; 194(3):265-275.
(14) Zantah M, Dotan Y, Dass C, Zhao H, Marchetti N, Criner GJ. Acute exacerbations of COPD versus IPF in patients with combined pulmonary fibrosis and emphysema. Respir Res 2020; 21(1):164-01432.
(15) McKinzie BP, Bullington WM, Mazur JE, Judson MA. Efficacy of short-course, low-dose corticosteroid therapy for acute pulmonary sarcoidosis exacerbations. Am J Med Sci 2010; 339(1):1-4.
(16) Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015; 385(9971):857-866.
(17) Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374(9691):685-694.
(18) Mata M, Martinez I, Melero JA, Tenor H, Cortijo J. Roflumilast inhibits respiratory syncytial virus infection in human differentiated bronchial epithelial cells. PLoS ONE 2013; 8(7):e69670.
(19) Fan CK. Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol 2006; 533(1-3):110-117.
(20) Manning CD, Burman M, Christensen SB, Cieslinski LB, Essayan DM, Grous M et al. Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B. Br J Pharmacol 1999; 128(7):1393-1398.
(21) Park MK, Fontana JR, Babaali H, Gilbert-McClain LI, Joo J, Moss J et al. Steroid sparing effects of pentoxifylline in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2009; 26:121-131.
(22) Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997; 155:1665-1669.
(23) Baughman RP, Judson MA, Ingledue R, Craft NL, Lower EE. Efficacy and Safety of Apremilast in Chronic Cutaneous Sarcoidosis. Arch Dermatol 2012; 148:262-264.
(24) Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois RM et al. ATS/ERS/WASOG Statement on sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16:149-173.
(25) Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42(2):377-381.
(26) Patel AS, Siegert RJ, Creamer D, Larkin G, Maher TM, Renzoni EA et al. The development and validation of the King's Sarcoidosis Questionnaire for the assessment of health status. Thorax 2013; 68(1):57-65.
(27) Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003; 58(4):339-343.
(28) de Vries J, Michielsen H, van Heck GL, Drent M. Measuring fatigue in sarcoidosis: the Fatigue Assessment Scale (FAS). Br J Health Psychol 2004; 9(Pt 3):279-291.
(29) Mahler DA, Ward J, Fierro-Carrion G, Waterman LA, Lentine TF, Mejia-Alfaro R et al. Development of self-administered versions of modified baseline and transition dyspnea indexes in COPD. COPD 2004; 1(2):165-172.
(30) Hopewell S, Clarke M, Moher D, Wager E, Middleton P, Altman DG et al. CONSORT for reporting randomized controlled trials in journal and conference abstracts: explanation and elaboration. PLoS Med 2008; 5(1):e20.
(31) Wedzicha JA, Singh R, Mackay AJ. Acute COPD exacerbations. Clin Chest Med 2014; 35(1):157-163.
(32) Burgel PR, Nesme-Meyer P, Chanez P, Caillaud D, Carre P, Perez T et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 2009; 135(4):975-982.
(33) Balter MS, La FJ, Low DE, Mandell L, Grossman RF. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can Respir J 2003; 10 Suppl B:3B-32B. doi: 10.1155/2003/486285.:3B-32B.
(34) Judson MA. Endpoints in sarcoidosis: More like IPF or asthma? Respir Med 2018; 138S:S3-S4. doi: 10.1016/j.rmed.2017.11.010. Epub@2017 Nov@20.:S3-S4.
(35) Pirozzi CS, Mendoza DL, Xu Y, Zhang Y, Scholand MB, Baughman RP. Short-Term Particulate Air Pollution Exposure is Associated with Increased Severity of Respiratory and Quality of Life Symptoms in Patients with Fibrotic Sarcoidosis. Int J Environ Res Public Health 2018; 15(6):ijerph15061077.
(36) Yuan L, Dai X, Yang M, Cai Q, Shao N. Potential treatment benefits and safety of roflumilast in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 2016; 11:1477-83. doi: 10.2147/COPD.S106370. eCollection;%2016.:1477-1483.
(37) Baughman RP, Judson MA, Beaumont JL, Maier LA, Sweiss NJ, Culver DA et al. Evaluating the Minimal Clinically Important Difference of the King's Sarcoidosis Questionnaire (KSQ) in a Multi-center, Prospective Study. Ann Am Thorac Soc 2020;10-607OC.
(38) Pornsuriyasak P, Thungtitigul P, Kawamatawong T, Birring SS, Pongmesa T. Minimal Clinically Important Differences (MCIDs) of the Thai Version of the Leicester Cough Questionnaire for Subacute and Chronic Cough. Value Health Reg Issues 2017; 12:57-62. doi: 10.1016/j.vhri.2017.03.009. Epub@2017 May 4.:57-62.
(39) Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2017; %19;9:CD002309. doi: 10.1002/14651858.CD002309.pub5.:CD002309.
(40) Tong Z, Dai H, Chen B, Abdoh Z, Guzman J, Costabel U. Inhibition of cytokine release from alveolar macrophages in pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone. Chest 2003; 124(4):1526-1532.
(41) Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U. Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. Am J Respir Crit Care Med 1999; 159(2):508-511.
(42) Baughman RP, Lower EE. The effect of corticosteroid or methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis. Am Rev Respir Dis 1990; 142:1268-1271.
(43) Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, Du BR et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006; 174(7):795-802.
(44) Vorselaars AD, Crommelin HA, Deneer VH, Meek B, Claessen AM, Keijsers RG et al. Effectiveness of infliximab in refractory FDG PET positive sarcoidosis. Eur Respir J 2015; 46:175-185.
(45) Baughman RP, Judson MA, Lower EE, Drent M, Costabel U, Flavin S et al. Infliximab for chronic cutaneous sarcoidosis: a subset analysis from a double-blind randomized clinical trial. Sarcoidosis Vasc Diffuse Lung Dis 2016; 32(4):289-295.
(46) Facius A, Marostica E, Gardiner P, Watz H, Lahu G. Pharmacokinetic and Pharmacodynamic Modelling to Characterize the Tolerability of Alternative Up-Titration Regimens of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease. Clin Pharmacokinet 2018; 57(8):1029-1038.
(47) Judson MA, Costabel U, Drent M, Wells A, Maier L, Koth L et al. The WASOG Sarcoidosis Organ Assessment Instrument: An update of a previous clinical tool. Sarcoidosis Vasc Diffuse Lung Dis 2014; 31(1):19-27.