{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:48:37Z","timestamp":1791474517046,"version":"4.3.4"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Lung Foundation, the Netherlands"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Pulm Med"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Treatment of pulmonary sarcoidosis is recommended in case of significant symptoms, impaired or deteriorating lung function. Evidence-based treatment recommendations are limited and largely based on expert opinion. Prednisone is currently the first-choice therapy and leads to short-term improvement of lung function. Unfortunately, prednisone often has side-effects and may be associated with impaired quality of life. Methotrexate is presently considered second-line therapy, and appears to have fewer side-effects.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Objective<\/jats:title>\n<jats:p>The primary objective of this trial is to investigate the effectiveness and tolerability of methotrexate as first-line therapy in patients with pulmonary sarcoidosis compared with prednisone. The primary endpoint of this study will be the change in hospital-measured Forced Vital Capacity (FVC) between baseline and 24\u2009weeks. Secondary objectives are to gain more insights in response to therapy in individual patients by home spirometry and patient-reported outcomes. Blood biomarkers will be examined to find predictors of response to therapy, disease progression and chronicity, and to improve our understanding of the underlying disease mechanism.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods\/design<\/jats:title>\n<jats:p>In this prospective, randomized, non-blinded, multi-center, non-inferiority trial, we plan to randomize 138 treatment-na\u00efve patients with pulmonary sarcoidosis who are about to start treatment. Patients will be randomized in a 1:1 ratio to receive either prednisone or methotrexate in a predefined schedule for 24\u2009weeks, after which they will be followed up in regular care for up to 2\u2009years. Regular hospital visits will include pulmonary function assessment, completion of patient-reported outcomes, and blood withdrawal. Additionally, patients will be asked to perform weekly home spirometry, and record symptoms and side-effects via a home monitoring application for 24\u2009weeks.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Discussion<\/jats:title>\n<jats:p>This study will be the first randomized controlled trial comparing first-line treatment of prednisone and methotrexate and provide valuable data on efficacy, safety, quality of life and biomarkers. If this study confirms the hypothesis that methotrexate is as effective as prednisone as first-line treatment for sarcoidosis but with fewer side-effects, this will lead to improvement in care and initiate a change in practice. Furthermore, insights into the immunological mechanisms underlying sarcoidosis pathology might reveal new therapeutic targets.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Trial registration<\/jats:title>\n<jats:p>The study was registered on the 19th of March 2020 in the International Clinical Trial Registry, www.clinicaltrials.gov; ID <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04314193\">NCT04314193<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12890-020-01290-9","type":"journal-article","created":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T12:06:16Z","timestamp":1603109176000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Design of a randomized controlled trial to evaluate effectiveness of methotrexate versus prednisone as first-line treatment for pulmonary sarcoidosis: the PREDMETH study"],"prefix":"10.1186","volume":"20","author":[{"given":"Vivienne","family":"Kahlmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montse","family":"Janssen Bon\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharina C.","family":"Moor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coline H. M.","family":"van Moorsel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Kool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raisa","family":"Kraaijvanger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan C.","family":"Grutters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayka","family":"Overgaauw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Veltkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4527-6962","authenticated-orcid":false,"given":"Marlies S.","family":"Wijsenbeek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Collaborating investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Koopman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. J. M.","family":"Geelhoed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Janssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.E.","family":"Jonkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Moonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. L. M.","family":"Mostard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. J.","family":"Nossent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. J.","family":"Overbeek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.H. N. A. J.","family":"van Rijswijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Wagenaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Walen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. L. M. L.","family":"Wielders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. W.","family":"Loth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. A. H. A.","family":"Bogaarts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"van der Maten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"issue":"Supplement_6","key":"1290_CR1","doi-asserted-by":"publisher","first-page":"S421","DOI":"10.1513\/AnnalsATS.201707-564OT","volume":"14","author":"AK Gerke","year":"2017","unstructured":"Gerke AK, Judson MA, Cozier YC, Culver DA, Koth LL. Disease Burden and Variability in Sarcoidosis. Ann Am Thorac Soc. 2017;14(Supplement_6):S421\u2013S8.","journal-title":"Ann Am Thorac Soc"},{"issue":"4","key":"1290_CR2","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.ccm.2015.08.013","volume":"36","author":"M Drent","year":"2015","unstructured":"Drent M, Strookappe B, Hoitsma E, De Vries J. Consequences of Sarcoidosis. Clin Chest Med. 2015;36(4):727\u201337.","journal-title":"Clin Chest Med"},{"issue":"4","key":"1290_CR3","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/j.ccm.2015.08.015","volume":"36","author":"MS Wijsenbeek","year":"2015","unstructured":"Wijsenbeek MS, Culver DA. Treatment of Sarcoidosis. Clin Chest Med. 2015;36(4):751\u201367.","journal-title":"Clin Chest Med"},{"key":"1290_CR4","doi-asserted-by":"publisher","unstructured":"Paramothayan NS, Lasserson TJ, Jones PW. Corticosteroids for pulmonary sarcoidosis. Cochrane Database Syst Rev. 2005;(2):Art. No.: CD001114. https:\/\/doi.org\/10.1002\/14651858.CD001114.pub2.","DOI":"10.1002\/14651858.CD001114.pub2"},{"issue":"4","key":"1290_CR5","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1034\/j.1399-3003.1999.14d02.x","volume":"14","author":"U Costabel","year":"1999","unstructured":"Costabel U, Hunninghake GW. ATS\/ERS\/WASOG statement on sarcoidosis. Sarcoidosis statement committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999;14(4):735\u20137.","journal-title":"Eur Respir J"},{"issue":"2","key":"1290_CR6","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1164\/ajrccm.160.2.ats4-99","volume":"160","author":"Statement on sarcoidosis","year":"1999","unstructured":"Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the world Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of directors and by the ERS executive committee, February 1999. Am J Respir Crit Care Med. 1999;160(2):736\u201355.","journal-title":"Am J Respir Crit Care Med"},{"issue":"155","key":"1290_CR7","doi-asserted-by":"publisher","first-page":"190146","DOI":"10.1183\/16000617.0146-2019","volume":"29","author":"FF Rahaghi","year":"2020","unstructured":"Rahaghi FF, Baughman RP, Saketkoo LA, Sweiss NJ, Barney JB, Birring SS, et al. Delphi consensus recommendations for a treatment algorithm in pulmonary sarcoidosis. Eur Respir Rev. 2020;29(155):190146.","journal-title":"Eur Respir Rev"},{"issue":"1","key":"1290_CR8","doi-asserted-by":"publisher","first-page":"1702089","DOI":"10.1183\/13993003.02089-2017","volume":"51","author":"CE Broos","year":"2018","unstructured":"Broos CE, Wapenaar M, Looman CWN, In\u2019t Veen J, van den Toorn LM, Overbeek MJ, et al. Daily home spirometry to detect early steroid treatment effects in newly treated pulmonary sarcoidosis. Eur Respir J. 2018;51(1):1702089.","journal-title":"Eur Respir J"},{"key":"1290_CR9","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.1016\/j.rmed.2017.10.022","volume":"138S","author":"CE Broos","year":"2018","unstructured":"Broos CE, Poell LHC, Looman CWN, In\u2019t Veen J, Grootenboers M, Heller R, et al. No evidence found for an association between prednisone dose and FVC change in newly-treated pulmonary sarcoidosis. Respir Med. 2018;138S:S31\u2013S7.","journal-title":"Respir Med"},{"key":"1290_CR10","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.rmed.2017.09.003","volume":"132","author":"NA Khan","year":"2017","unstructured":"Khan NA, Donatelli CV, Tonelli AR, Wiesen J, Ribeiro Neto ML, Sahoo D, et al. Toxicity risk from glucocorticoids in sarcoidosis patients. Respir Med. 2017;132:9\u201314.","journal-title":"Respir Med"},{"issue":"4","key":"1290_CR11","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.rmed.2015.01.019","volume":"109","author":"MA Judson","year":"2015","unstructured":"Judson MA, 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. Respir Med. 2015;109(4):526\u201331.","journal-title":"Respir Med"},{"issue":"5","key":"1290_CR12","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1097\/MCP.0b013e3283642a7a","volume":"19","author":"JP Cremers","year":"2013","unstructured":"Cremers JP, Drent M, Bast A, Shigemitsu H, Baughman RP, Valeyre D, et al. Multinational evidence-based world Association of Sarcoidosis and Other Granulomatous Disorders recommendations for the use of methotrexate in sarcoidosis: integrating systematic literature research and expert opinion of sarcoidologists worldwide. Curr Opin Pulm Med. 2013;19(5):545\u201361.","journal-title":"Curr Opin Pulm Med"},{"issue":"1","key":"1290_CR13","first-page":"60","volume":"17","author":"RP Baughman","year":"2000","unstructured":"Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17(1):60\u20136.","journal-title":"Sarcoidosis Vasc Diffuse Lung Dis"},{"issue":"3","key":"1290_CR14","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1378\/chest.12-1728","volume":"144","author":"ADM Vorselaars","year":"2013","unstructured":"Vorselaars ADM, Wuyts WA, Vorselaars VMM, Zanen P, Deneer VHM, Veltkamp M, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144(3):805\u201312.","journal-title":"Chest."},{"issue":"5","key":"1290_CR15","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1097\/00063198-200209000-00022","volume":"8","author":"VM Vucinic","year":"2002","unstructured":"Vucinic VM. What is the future of methotrexate in sarcoidosis? A study and review. Curr Opin Pulm Med. 2002;8(5):470\u20136.","journal-title":"Curr Opin Pulm Med"},{"issue":"8","key":"1290_CR16","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1001\/archinte.1995.00430080088011","volume":"155","author":"EE Lower","year":"1995","unstructured":"Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med. 1995;155(8):846\u201351.","journal-title":"Arch Intern Med"},{"issue":"1","key":"1290_CR17","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41572-019-0096-x","volume":"5","author":"J Grunewald","year":"2019","unstructured":"Grunewald J, Grutters JC, Arkema EV, Saketkoo LA, Moller DR, Muller-Quernheim J. Sarcoidosis. Nat Rev Dis Primers. 2019;5(1):45.","journal-title":"Nat Rev Dis Primers"},{"key":"1290_CR18","first-page":"219","volume-title":"Sarcoidosis A Clinician\u2019s Guide","author":"MCV Schimmelpennink","year":"2019","unstructured":"Schimmelpennink MCV, Vorselaars ADM, Grutters JC. Biomarkers in sarcoidosis. In: Baughman DV, editor. Sarcoidosis A Clinician\u2019s Guide; 2019. p. 219\u201338."},{"issue":"11","key":"1290_CR19","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1164\/rccm.201507-1499OC","volume":"193","author":"J Ramstein","year":"2016","unstructured":"Ramstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, et al. IFN-gamma-producing T-helper 17.1 cells are increased in Sarcoidosis and are more prevalent than T-helper type 1 cells. Am J Respir Crit Care Med. 2016;193(11):1281\u201391.","journal-title":"Am J Respir Crit Care Med"},{"issue":"4","key":"1290_CR20","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1183\/13993003.00709-2016","volume":"48","author":"D Hijdra","year":"2016","unstructured":"Hijdra D, Vorselaars AD, Crommelin HA, van Moorsel CH, Meek B, Claessen AM, et al. Can intermediate monocytes predict response to infliximab therapy in sarcoidosis? Eur Respir J. 2016;48(4):1242\u20135.","journal-title":"Eur Respir J"},{"issue":"2","key":"1290_CR21","doi-asserted-by":"publisher","first-page":"23","DOI":"10.3390\/jpm9020023","volume":"9","author":"CC Moor","year":"2019","unstructured":"Moor CC, Gur-Demirel Y, Wijsenbeek MS. Feasibility of a Comprehensive Home Monitoring Program for Sarcoidosis. J Pers Med. 2019;9(2):23.","journal-title":"J Pers Med"},{"issue":"8","key":"1290_CR22","doi-asserted-by":"publisher","first-page":"e26","DOI":"10.1164\/rccm.202002-0251ST","volume":"201","author":"ED Crouser","year":"2020","unstructured":"Crouser ED, Maier LA, Wilson KC, Bonham CA, Morgenthau AS, Patterson KC, et al. Diagnosis and detection of Sarcoidosis. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(8):e26\u201351.","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"1290_CR23","doi-asserted-by":"publisher","first-page":"00054","DOI":"10.1183\/23120541.00054-2020","volume":"6","author":"CC Moor","year":"2020","unstructured":"Moor CC, van den Berg CAL, Visser LS, Aerts J, Cottin V, Wijsenbeek MS. Diurnal variation in forced vital capacity in patients with fibrotic interstitial lung disease using home spirometry. ERJ Open Res. 2020;6(1):00054\u20132020.","journal-title":"ERJ Open Res"},{"key":"1290_CR24","unstructured":"NICE guideline. Rheumatoid arthritis in adults: management 2018 [updated 11-07-2018. Available from: https:\/\/www.nice.org.uk\/guidance\/ng100\/resources\/rheumatoid-arthritis-in-adults-management-pdf-66141531233989.."},{"issue":"7","key":"1290_CR25","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1136\/ard.2008.092668","volume":"68","author":"K Visser","year":"2009","unstructured":"Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68(7):1094\u20139.","journal-title":"Ann Rheum Dis"},{"issue":"2","key":"1290_CR26","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.rmed.2014.11.009","volume":"109","author":"AD Vorselaars","year":"2015","unstructured":"Vorselaars AD, van Moorsel CH, Zanen P, Ruven HJ, Claessen AM, van Velzen-Blad H, et al. ACE and sIL-2R correlate with lung function improvement in sarcoidosis during methotrexate therapy. Respir Med. 2015;109(2):279\u201385.","journal-title":"Respir Med"}],"container-title":["BMC Pulmonary Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12890-020-01290-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12890-020-01290-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12890-020-01290-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T23:59:18Z","timestamp":1634601558000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcpulmmed.biomedcentral.com\/articles\/10.1186\/s12890-020-01290-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,19]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1290"],"URL":"https:\/\/doi.org\/10.1186\/s12890-020-01290-9","relation":{},"ISSN":["1471-2466"],"issn-type":[{"value":"1471-2466","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,19]]},"assertion":[{"value":"9 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study will be performed according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act. The medical ethical committee of the Erasmus Medical Center has approved the trial with the protocol reference number MEC-2019-0730. Written informed consent will be obtained from all participants. The trial is registered on  (NCT04314193).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare they have no competing interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"271"}}