Rheumatoid Arthritis May Predict Articular Destruction 2 Years Later Clinical Activity After 12 Weeks of Treatment with Nonbiologics in Early

Objective. To investigate earlier prediction of future articular destruction in patients with early rheumatoid arthritis (RA). Methods.We randomly allocated patients with RA with disease duration < 2 years to different nonbiologic disease modifying antirheumatic drug (DMARD) therapies in a double-blind trial. Progression of articular destruction over the 96-week treatment period was assessed using the modified Sharp method. Results. Progression of articular destruction correlated more strongly with the American College of Rheumatology (ACR) core set measures after 12 weeks of treatment than with pretreatment values. Multiple regression analysis of data after 12 weeks yielded a correlation coefficient of 0.711. The sensitivity and specificity to predict articular destruction over the 75th percentile of the cohort were 78.6% and 84.6%, respectively. Patients who showed articular destruction over the 75th percentile of the cohort had low response to treatment at 12 weeks, and continued to have high clinical disease activity thereafter. Contrasting data were found in patients with slow progression of articular destruction. Conclusion. In patients with early RA, ACR core set measures after 12 weeks of nonbiologic DMARD treatment may predict articular destruction 2 years later. Low response to treatment at 12 weeks and continuing high disease activity thereafter were found in patients with rapid radiological progression. These data can be used to determine the appropriateness of treatment at 12 weeks and aid the decision to introduce biologic DMARD. (First Release March 1 2010; J Rheumatol 2010;37:723–9; doi:10.3899/jrheum.090776) Key Indexing Terms: RHEUMATOID ARTHRITIS PROGNOSIS DISEASE ACTIVITY DISEASE MODIFYING ANTIRHEUMATIC DRUGS JOINT EROSIONS From the Department of Rheumatic, Collagen and Allergic Diseases, St. Marianna University School of Medicine, Kawasaki; Institute of Rheumatology, Tokyo Woman’s Medical University, Tokyo; Department of Internal Medicine, Yokohama Municipal Citizen’s Hospital, Yokohama; Department of Internal Medicine, Kitazato University School of Medicine, Sagamihara; Department of Internal Medicine, Juntendo University School of Medicine, Tokyo; Department of Internal Medicine, Fujita Health University, Toyoake; Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki; Department of Internal Medicine, School of Medicine, Keio University, Tokyo; Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Kawagoe; Department of Internal Medicine, Konan Kakogawa Hospital, Kakogawa; Department of Internal Medicine, Kawasaki Municipal Hospital, Kawasaki; The Centre for Rheumatic Diseases, Matsuyama Red Cross Hospital, Matsuyama; Department of Orthopedics, Matsubara Mayflower Hospital, Kato; Department of Rheumatology, National Hospital Organization, Osaka Minami Medical Center, Osaka; and Department of Orthopedics, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan. Supported by a “Research for Establishment of Therapeutic Guidelines in Early Rheumatoid Arthritis” grant from the Japanese Ministry of Health, Labor and Welfare. Santen Pharmaceutical Co., Ltd. and Wyeth Co., Ltd. kindly supplied bucillamine and methotrexate, respectively, as well as the corresponding placebos. Y. Ichikawa, MD, Professor of Medicine, Department of Rheumatic, Collagen and Allergic Diseases, St. Marianna University School of Medicine; T. Saito, MD, Professor of Medicine; H. Yamanaka, MD, Professor of Medicine, Institute of Rheumatology, Tokyo Woman’s Medical University; M. Akizuki, MD, Department of Internal Medicine, Yokohama Municipal Citizen’s Hospital; H. Kondo, MD, Professor of Medicine, Department of Internal Medicine, Kitazato University School of Medicine; S. Kobayashi, MD, Assistant Professor, Department of Internal Medicine, Juntendo University School of Medicine; H. Oshima, MD, Professor of Medicine, Department of Internal Medicine, Fujita Health University; S. Kawai, MD, Professor of Medicine, Institute of Medical Science, St. Marianna University School of Medicine (current affiliation: Professor of Medicine, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University); N. Hama, MD, Assistant Professor; H. Yamada, MD, Associate Professor, Department of Rheumatic, Collagen and Allergic Diseases, St. Marianna University School of Medicine; T. Mimori, MD, Department of Internal Medicine, School of Medicine, Keio University (current affiliation: Professor of Medicine, Department of Clinical Immunology, University of Kyoto); K. Amano, MD, Associate Professor, Second Department of Internal Medicine, Saitama Medical Center; Y. Tanaka, MD, Department of Internal Medicine, Konan Kakogawa Hospital; Y. Matsuoka, MD, Department of Internal Medicine, Kawasaki Municipal Hospital; S. Yamamoto, MD, The Centre for Rheumatic Diseases, Matsuyama Red Rheumatology The Journal of on July 18, 2015 Published by www.jrheum.org Downloaded from Cross Hospital; T. Matsubara, MD, Department of Orthopedics, Matsubara Mayflower Hospital; N. Murata, MD, Department of Rheumatology, National Hospital Organization, Osaka Minami Medical Center; T. Asai, MD, Department of Orthopedics, National Hospital Organization, Nagoya Medical Center; Y. Suzuki, MD, Department of Rheumatic, Collagen and Allergic Diseases, St. Marianna University School of Medicine (current affiliation, Professor of Medicine, Department of Rheumatic Diseases, Tokai University). Address correspondence to Dr. Y. Ichikawa, Department of Internal Medicine, St. Joseph’s Hospital, 28 Midorigaoka, City of Yokosuka, Kanagawa-ken, Japan 238-8502. E-mail: j-incho@aqua.ocn.ne.jp Accepted for publication November 25, 2009. The usefulness of biologic disease-modifying antirheumatic drug (DMARD) therapy is well known in the treatment of rheumatoid arthritis (RA), and in particular the effects in suppressing articular destruction are revolutionary1-3. These therapies are expensive, however, and sometimes cause severe adverse reactions. It is necessary to select those patients who will benefit most from the treatment. In general, treatment commences with nonbiologic DMARD, and biologic DMARD are introduced when disease activity cannot be fully controlled, progression of articular destruction is rapid, or prognosis is otherwise poor4,5. Conversely, patients with a rather benign disease course would prefer treatment without biologic DMARD in order to avoid the potential adverse reactions and added expense. It has been reported that rheumatoid factor (RF) positivity1,6-12, anticyclic citrullinated peptide (CCP) antibody positivity10-14, presence of HLA-DRB1 genes for shared epitope7,9,12,14,15, and female sex16 are poor prognostic factors for articular destructions in patients with early RA. Other prognostic factors include indicators of disease activity, such as swollen joint count12, serum C-reactive protein (CRP)13, and erythrocyte sedimentation rate (ESR)7,12. The averaged values of clinical activities over an observation period correlated significantly with the progression of articular destruction17,18. However, it is important to be able to anticipate bone destruction at an early stage, rather than depending on mean values over a longer period. We conducted a randomized double-blind controlled study evaluating prognostic factors, including pretreatment of clinical disease activity and treatment at 12-week intervals thereafter, with the aim of determining the measures that better and earlier predict the progression of articular destruction over 96 weeks of treatment. MATERIALS AND METHODS We conducted a double-blind controlled trial of the efficacy and safety of methotrexate (MTX) monotherapy 8 mg/week, bucillamine monotherapy 200 mg/day (BUC; with molecular structure similar to that of D-penicillamine19), and MTX and BUC combination therapy for 96 weeks20. At the same time, we investigated prognostic factors for the progression of articular destruction. Because the dosage of MTX, 8 mg per week at most, is set by official regulation in Japan, the initial dosage was determined accordingly. We enrolled 55 patients who fulfilled the American College of Rheumatology (ACR) 1987 revised criteria for the classification of RA21, with symptoms for < 2 years. The Institutional Review Board of St. Marianna Medical College approved the study protocol, and all participants provided informed consent at the time of enrollment. All patients had a tender joint count of at least 6 out of 48 joints and a swollen joint count of at least 3 of 46 joints, and either serum CRP ≥ 1.0 mg/dl or ESR ≥ 30 mm/h. All subjects had taken no DMARD previously, and were receiving a corticosteroid dosage ≤ 7.5 mg/day prednisolone equivalent. The study was conducted at 15 participating institutions, using a double-dummy double-blind method. The following factors were assessed at 12-week intervals: tender joint count, swollen joint count, patient’s pain estimation using a visual analog scale (VAS), patient’s global assessment of disease activity using a VAS, physician’s overall assessment of disease activity by VAS, the modified Health Assessment Questionnaire (MHAQ)22, ESR using the Westergren method, and serum CRP. HLA-DRB1 typing was done using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method (SRL Inc., Tokyo, Japan). Anti-CCP antibody was assayed by MBL Co., Ltd. (Nagoya, Japan). The initially allocated DMARD could be changed after 24 weeks if an ACR20 response was not achieved, and DMARD could be changed if adverse reactions did not permit continuation. Subsequent treatment was at the discretion of the treating physician, including the dose of MTX being increased more than 8 mg per week. Articular destruction was evaluated using Sharp’s method modified by van der Heijde23, scoring plain radiographs of both hands taken at commencement of treatment and after 96 w