{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:20:37Z","timestamp":1791181237373,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2006,1,30]],"date-time":"2006-01-30T00:00:00Z","timestamp":1138579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2006,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To compare the efficacy of doxycycline plus methotrexate (MTX) versus MTX alone in the treatment of early seropositive rheumatoid arthritis (RA), and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sixty\u2010six patients with seropositive RA of &lt;1 year's duration who had not been previously treated with disease\u2010modifying antirheumatic drugs were randomized to receive 100 mg of doxycycline twice daily with MTX (high\u2010dose doxycycline group), 20 mg of doxycycline twice daily with MTX (low\u2010dose doxycycline group), or placebo with MTX (placebo group), in a 2\u2010year double\u2010blind study. Treatment was started with an MTX dosage of 7.5 mg\/week, which was titrated every 3 months until remission was reached (maximum dosage of 17.5 mg\/week). The primary end point was an American College of Rheumatology 50% improvement (ACR50) response at 2 years.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ACR50 responses were observed in 41.6% of patients in the high\u2010dose doxycycline group, 38.9% of those in the low\u2010dose doxycycline group, and 12.5% of patients in the placebo group. Results of chi\u2010square analysis of the ACR50 response in the high\u2010dose doxycycline group versus that in the placebo group were significantly different (<jats:italic>P<\/jats:italic> = 0.02). Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups (<jats:italic>P<\/jats:italic> = 0.04 and <jats:italic>P<\/jats:italic> = 0.03, respectively). MTX doses at 2 years were not different among groups. Four patients in the high\u2010dose doxycycline group, 2 patients in the low\u2010dose doxycycline group, and 2 patients in the placebo group were withdrawn because of toxic reactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In patients with early seropositive RA, initial therapy with MTX plus doxycycline was superior (based on an ACR50 response) to treatment with MTX alone. The therapeutic responses to low\u2010dose and high\u2010dose doxycycline were similar, suggesting that the antimetalloproteinase effects were more important than the antibacterial effects. Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.21620","type":"journal-article","created":{"date-parts":[[2006,1,30]],"date-time":"2006-01-30T22:26:37Z","timestamp":1138659997000},"page":"621-627","source":"Crossref","is-referenced-by-count":105,"title":["Treatment of early seropositive rheumatoid arthritis: Doxycycline plus methotrexate versus methotrexate alone"],"prefix":"10.1002","volume":"54","author":[{"given":"James R.","family":"O'Dell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack A.","family":"Mallek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted R.","family":"Mikuls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Weaver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Glickstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent M.","family":"Blakely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Hausch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob D.","family":"Leff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,1,30]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)01300-7"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)08513-4"},{"key":"e_1_2_6_4_2","first-page":"699","article-title":"Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis","volume":"17","author":"Calguneri M","year":"1999","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200002)43:2<464::AID-ANR30>3.0.CO;2-U"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400510"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200110)44:10<2235::AID-ART385>3.0.CO;2-A"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380602"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780280603"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780370505"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-122-2-199501150-00001"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(199908)42:8<1691::AID-ANR18>3.0.CO;2-S"},{"key":"e_1_2_6_14_2","first-page":"1967","article-title":"Lack of effect of doxycycline on disease activity and joint damage in patients with rheumatoid arthritis: a double\u2010blind, placebo controlled trial","volume":"28","author":"Van der Laan W","year":"2001","journal-title":"J Rheumatol"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200105)44:5<1043::AID-ANR183>3.0.CO;2-C"},{"key":"e_1_2_6_16_2","first-page":"41","article-title":"Pilot clinical trial of intravenous doxycycline versus placebo for rheumatoid arthritis","volume":"30","author":"Pillemer S","year":"2003","journal-title":"J Rheumatol"},{"key":"e_1_2_6_17_2","first-page":"804","article-title":"Doxycycline in the treatment of rheumatoid arthritis: a pilot study","volume":"48","author":"Sreekanth VR","year":"2000","journal-title":"J Assoc Physicians India"},{"key":"e_1_2_6_18_2","first-page":"2112","article-title":"Should tetracycline treatment be used more extensively for rheumatoid arthritis? 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