{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:31:10Z","timestamp":1787160670560,"version":"build-2736575974"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/100016724","name":"PGIMER","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016724","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Rheumatol"],"published-print":{"date-parts":[[2025,10]]},"DOI":"10.1007\/s10067-025-07646-y","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T22:02:19Z","timestamp":1756504939000},"page":"3869-3879","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Split vs single-dose oral methotrexate in rheumatoid arthritis: a randomized controlled trial (SMART study)"],"prefix":"10.1007","volume":"44","author":[{"given":"Chandra Bhushan","family":"Prasad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3626-0694","authenticated-orcid":false,"given":"Varun","family":"Dhir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjan","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koshy Nithin","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phani Kumar","family":"Devarasetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkatesh Srinivasa","family":"Pai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avinash","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GSRSNK","family":"Naidu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Saini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bidyalaxmi","family":"Leishangthem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aastha","family":"Khullar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh","family":"Manthri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shefali Khanna","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aman","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amita","family":"Aggarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"7646_CR1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.3899\/jrheum.200367","volume":"48","author":"KB Almutairi","year":"2021","unstructured":"Almutairi KB, Nossent JC, Preen DB, Keen HI, Inderjeeth CA (2021) The prevalence of rheumatoid arthritis: a systematic review of population-based studies. J Rheumatol 48:669\u2013676","journal-title":"J Rheumatol"},{"key":"7646_CR2","first-page":"S71","volume":"21","author":"T Sokka","year":"2003","unstructured":"Sokka T (2003) Work disability in early rheumatoid arthritis. Clin Exp Rheumatol 21:S71\u2013S74","journal-title":"Clin Exp Rheumatol"},{"key":"7646_CR3","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1002\/acr.23512","volume":"70","author":"A Hresko","year":"2018","unstructured":"Hresko A, Lin TC, Solomon DH (2018) Medical care costs associated with rheumatoid arthritis in the US: a systematic literature review and meta-analysis. Arthritis Care Res (Hoboken) 70:1431\u20131438","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"7646_CR4","first-page":"S179","volume":"21","author":"T Pincus","year":"2003","unstructured":"Pincus T, Yazici Y, Sokka T, Aletaha D (2003) SMOLEN JS: Methotrexate as the \u201canchor drug\u201d for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol 21:S179\u2013S185","journal-title":"Clin Exp Rheumatol"},{"key":"7646_CR5","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1136\/ard-2022-223356","volume":"82","author":"JS Smolen","year":"2023","unstructured":"Smolen JS, Landew\u00e9 RBM, Bergstra SA et al (2023) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 82:3\u201318","journal-title":"Ann Rheum Dis"},{"key":"7646_CR6","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1002\/art.41752","volume":"73","author":"L Fraenkel","year":"2021","unstructured":"Fraenkel L, Bathon JM, England BR et al (2021) 2021 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 73:1108\u20131123","journal-title":"Arthritis Rheumatol"},{"key":"7646_CR7","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1136\/ard.2010.141234","volume":"70","author":"NB Klarenbeek","year":"2011","unstructured":"Klarenbeek NB, G\u00fcler-Y\u00fcksel M, Van Der Kooij SM et al (2011) The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann Rheum Dis 70:1039\u20131046","journal-title":"Ann Rheum Dis"},{"key":"7646_CR8","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1136\/annrheumdis-2021-220512","volume":"80","author":"S Jain","year":"2021","unstructured":"Jain S, Dhir V, Aggarwal A et al (2021) Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: a multicentre, parallel group, randomised controlled trial. Ann Rheum Dis 80:1376\u20131384","journal-title":"Ann Rheum Dis"},{"key":"7646_CR9","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1056\/NEJMoa1303006","volume":"369","author":"JR O'Dell","year":"2013","unstructured":"O\u2019Dell JR, Mikuls TR, Taylor TH et al (2013) Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 369:307\u201318","journal-title":"N Engl J Med"},{"key":"7646_CR10","first-page":"645","volume":"31","author":"M Hoekstra","year":"2004","unstructured":"Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, Van de Laar M (2004) Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol 31:645\u2013648","journal-title":"J Rheumatol"},{"key":"7646_CR11","first-page":"481","volume":"33","author":"M Hoekstra","year":"2006","unstructured":"Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, Van de Laar M (2006) Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis. J Rheumatol 33:481\u2013485","journal-title":"J Rheumatol"},{"key":"7646_CR12","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1002\/art.27584","volume":"62","author":"D Aletaha","year":"2010","unstructured":"Aletaha D, Neogi T, Silman AJ et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology\/European League against rheumatism collaborative initiative. Arthritis Rheum 62:2569\u20132581","journal-title":"Arthritis Rheum"},{"key":"7646_CR13","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1093\/rheumatology\/41.12.1457","volume":"41","author":"A Kumar","year":"2002","unstructured":"Kumar A, Malaviya AN, Pandhi A, Singh R (2002) Validation of an Indian version of the Health Assessment Questionnaire in patients with rheumatoid arthritis. Rheumatology 41:1457\u20131459","journal-title":"Rheumatology"},{"key":"7646_CR14","doi-asserted-by":"crossref","unstructured":"Vijaykumar D, Dhir V, Jain S, et al (2021) Assessing methotrexate intolerance and its prevalence in rheumatoid arthritis: development and validation of the MISA questionnaire. Int J Rheum Dis","DOI":"10.1111\/1756-185X.14207"},{"key":"7646_CR15","first-page":"S93","volume":"23","author":"J Fransen","year":"2005","unstructured":"Fransen J, Van Riel PL (2005) The disease activity score and the EULAR response criteria. Clin Exp Rheumatol 23:S93\u2013S99","journal-title":"Clin Exp Rheumatol"},{"key":"7646_CR16","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1002\/art.1780380602","volume":"38","author":"DT Felson","year":"1995","unstructured":"Felson DT, Anderson JJ, Boers M et al (1995) American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38:727\u201335","journal-title":"Arthritis Rheum"},{"key":"7646_CR17","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1093\/rheumatology\/keg072","volume":"42","author":"JS Smolen","year":"2003","unstructured":"Smolen JS, Breedveld FC, Schiff MH et al (2003) A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxf) 42:244\u2013257","journal-title":"Rheumatology (Oxf)"},{"key":"7646_CR18","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1373\/49.10.1632","volume":"49","author":"T Dervieux","year":"2003","unstructured":"Dervieux T, Orentas Lein D, Marcelletti J et al (2003) HPLC determination of erythrocyte methotrexate polyglutamates after low-dose methotrexate therapy in patients with rheumatoid arthritis. Clin Chem 49:1632\u20131641","journal-title":"Clin Chem"},{"key":"7646_CR19","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3758\/BF03193146","volume":"39","author":"F Faul","year":"2007","unstructured":"Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175\u2013191","journal-title":"Behav Res Methods"},{"key":"7646_CR20","unstructured":"Dean AG SK, Soe MM. OpenEpi: open source epidemiologic statistics for public health, version 3.01, www.Openepi.com, updated 2013\/04\/06, acessed 4\/1\/2023."},{"key":"7646_CR21","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1111\/1756-185X.12910","volume":"21","author":"P Dhaon","year":"2018","unstructured":"Dhaon P, Das SK, Srivastava R, AgarwAL G, Asthana A (2018) Oral methotrexate in split dose weekly versus oral or parenteral methotrexate once weekly in rheumatoid arthritis: a short-term study. Int J Rheum Dis 21:1010\u20131017","journal-title":"Int J Rheum Dis"},{"key":"7646_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00296-002-0186-y","volume":"22","author":"S Pandya","year":"2002","unstructured":"Pandya S, Aggarwal A, Misra R (2002) Methotrexate twice weekly vs once weekly in rheumatoid arthritis: a pilot double-blind, controlled study. Rheumatol Int 22:1\u20134","journal-title":"Rheumatol Int"},{"key":"7646_CR23","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1111\/1756-185X.13931","volume":"23","author":"S Nagaoka","year":"2020","unstructured":"Nagaoka S, Katayama K, Kasama T et al (2020) Weekly split-dose regimen for oral methotrexate reduced polyglutamation in red blood cells in patients with rheumatoid arthritis compared with single-dose regimen: results from a multicentered randomized control trial. Int J Rheum Dis 23:1328\u20131336","journal-title":"Int J Rheum Dis"},{"key":"7646_CR24","doi-asserted-by":"crossref","unstructured":"Kremer JM. Use of methotrexate in the treatment of rheumatoid arthritis. In: JR OD, editor. UpToDate. UptoDate, Waltham, MA (Acessessed March 16, 2023).","DOI":"10.1097\/01.NPR.0000000000000072"},{"key":"7646_CR25","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/S0889-857X(05)70360-4","volume":"23","author":"JR O'Dell","year":"1997","unstructured":"O\u2019Dell JR (1997) Methotrexate use in rheumatoid arthritis. Rheum Dis Clin North Am 23:779\u201396","journal-title":"Rheum Dis Clin North Am"},{"key":"7646_CR26","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1136\/bmj.1.5801.654","volume":"1","author":"MG Dahl","year":"1972","unstructured":"Dahl MG, Gregory MM, Scheuer PJ (1972) Methotrexate hepatotoxicity in psoriasis\u2013comparison of different dose regimens. Br Med J 1:654\u2013656","journal-title":"Br Med J"},{"key":"7646_CR27","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1001\/archderm.1973.01620220007001","volume":"108","author":"HH Jr Roenigk","year":"1973","unstructured":"Jr Roenigk HH, Maibach HI, Weinstein GP (1973) Methotrexate therapy for psoriasis Guideline revisions. Arch Dermatol 108:35","journal-title":"Arch Dermatol"},{"key":"7646_CR28","doi-asserted-by":"publisher","first-page":"e0221823","DOI":"10.1371\/journal.pone.0221823","volume":"14","author":"AM Bujor","year":"2019","unstructured":"Bujor AM, Janjua S, Lavalley MP, Duran J, Braun J, Felson DT (2019) Comparison of oral versus parenteral methotrexate in the treatment of rheumatoid arthritis: a meta-analysis. PLoS ONE 14:e0221823","journal-title":"PLoS ONE"},{"key":"7646_CR29","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/art.23144","volume":"58","author":"J Braun","year":"2008","unstructured":"Braun J, Kastner P, Flaxenberg P et al (2008) Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum 58:73\u201381","journal-title":"Arthritis Rheum"}],"container-title":["Clinical Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10067-025-07646-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10067-025-07646-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10067-025-07646-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:26:05Z","timestamp":1760365565000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10067-025-07646-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":29,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["7646"],"URL":"https:\/\/doi.org\/10.1007\/s10067-025-07646-y","relation":{},"ISSN":["0770-3198","1434-9949"],"issn-type":[{"value":"0770-3198","type":"print"},{"value":"1434-9949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]},"assertion":[{"value":"9 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 August 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Institutional ethics committee of Post Graduate Institute of Medical Education and Research (IEC 03\/2021\u20131937); Institutional ethics committee of All India Institute of Medical Sciences, New Delhi (IEC-189); Institutional ethics committee of Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow (PGI\/BE\/1532\/2021); Institutional ethics committee of All India Institute of Medical Sciences, Rishikesh (AIIMS\/IEC\/21\/309); Institutional ethics committee of Nizams Institute of Medical Sciences (EC\/NIMS\/2800\/2021), Hyderabad; Institutional ethics committee of Sawai Man Singh Hospital, Jaipur (969 MMC\/EC\/2021).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"N\/A.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"None.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosures"}}]}}