Rheumatoid Arthritis: Merkel PA

Merkel PA, Lo GH, Holbrook JT, Tibbs AK, Allen NB, Davis JC, Hoffman GS, McCune WJ, St Clair EW, Specks U, Spiera R, Petri M, Stone JH, Anonymous00025. · Boston University School of Medicine, Vasculitis Center, E-5, 715 Albany Street, Boston, MA 02118, USA. · Ann Intern Med. · Pubmed #15838068 links to  free full text

Abstract: BACKGROUND: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known. OBJECTIVE: To measure the incidence of VTEs in patients with Wegener granulomatosis. DESIGN: Prospective, observational cohort study. SETTING: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis. PATIENTS: 180 patients with Wegener granulomatosis enrolled during periods of active disease. MEASUREMENTS: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE. RESULTS: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4). LIMITATIONS: Although prospectively recorded, screening for VTEs did not occur. CONCLUSIONS: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.

Choi HK, Slot MC, Pan G, Weissbach CA, Niles JL, Merkel PA. · Massachusetts General Hospital, Boston, USA. · Arthritis Rheum. · Pubmed #11083272 links to  free full text

Abstract: OBJECTIVE: Case reports have suggested that minocycline, sulfasalazine, and penicillamine are associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. This study evaluated ANCA seroconversion due to these agents in serum samples prospectively collected in randomized, double-blind, controlled trials. METHODS: The sources of study sera were 3 clinical trials: 1) a 48-week trial of minocycline for early rheumatoid arthritis, with 64 patients receiving minocycline compared with 68 receiving placebo; 2) a 37-week trial of sulfasalazine for rheumatoid arthritis, with 51 receiving sulfasalazine compared with 38 receiving placebo; and 3) a 104-week trial of penicillamine for early systemic sclerosis, with 15 undergoing high-dose penicillamine treatment versus 12 receiving low-dose penicillamine. ANCA were measured in the baseline and study-end serum samples by indirect immunofluorescence (IIF) for perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA) patterns, and by antigen-specific enzyme-linked immunosorbent assay (ELISA) for antibodies to myeloperoxidase (anti-MPO) and proteinase 3 (anti-PR3). Laboratory personnel were blinded to the group identity of the samples. ANCA results were interpreted using an ANCA scoring system that combines the results of IIF and ELISA testing. RESULTS: No patient in any of the active study drug groups demonstrated ANCA seroconversion according to the final interpretation of the combined IIF and ELISA results. Twelve of the 248 patients (5%) were positive for anti-MPO with pANCA at baseline. No subject was positive for anti-PR3 with cANCA. There were no findings suggestive of vasculitis in any of these patients. CONCLUSION: From our study results, there was no suggestion of ANCA seroconversion induced by minocycline, sulfasalazine, or penicillamine. However, these findings do not rule out the possibility of rare, sporadic cases of either ANCA seroconversion or true drug-induced vasculitis with these drugs.

Merkel PA, Chang Y, Pierangeli SS, Harris EN, Polisson RP. · Medical Practice Evaluation Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · J Rheumatol. · Pubmed #10090168 No free full text.

Abstract: OBJECTIVE: Antiphospholipid (aPL) antibodies are present in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody syndrome (APS) and are associated with recurrent thromboses, thrombocytopenia, and pregnancy losses. The presence of aPL antibodies is routinely tested using a standardized ELISA that utilizes cardiolipin as antigen (aCL ELISA). This test, although sensitive, is frequently positive in patients with nonrelated autoimmune disorders and some infectious diseases, making the test less specific. Thus there is a need for more specific tests for aCL with equivalent sensitivity to the standard assay. We evaluated the diagnostic utility of a new aPL antibody test kit with a unique phospholipid mixture designed to be more specific than the standard anticardiolipin ELISA. METHODS: aPL antibodies (IgG, IgM) were measured by both a standard ELISA and a new ELISA kit (APhL ELISA Kit, Louisville APL Diagnostics, Inc., Louisville, KY, USA) in the baseline serum from patients enrolled in a 5 year inception cohort, prospective study of early rheumatoid diseases: rheumatoid arthritis (N = 70), SLE (70), scleroderma (45), inflammatory myositis (36), and early undifferentiated connective tissue disease (CTD) (165). Diagnosis was based on standardized criteria and determined at the last study visit. A nested group of patients with Sjogren's syndrome (44) was also defined. Serum from 200 blood donors (BD) served as controls. Patients with known APS (33) and antinuclear cytoplasmic antibody positive renal vasculitis (52) were also studied. Laboratory personnel were blinded to sample diagnostic group. RESULTS: The kit was 90.9% sensitive for detecting APS. Seven patients missed by the kit all had standard aCL values < 40 PL units. Assuming controls do not have APS, the kit was 99.5% specific vs 96.0% for the standard assay. For the patients with CTD, the kit never detected a patient that was not also detected by the standard aCL assay. CONCLUSION: The APhL ELISA Kit appears to be more specific than the standard aCL ELISA without adding potential false positive results. The new test may be useful for followup study for patients found to be aCL positive by standard assays to increase specificity for aCL screening.

Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, Anonymous00077. · CDC, Atlanta, Georgia 30341-3717, USA. · Arthritis Rheum. · Pubmed #18163481 links to  free full text

Abstract: OBJECTIVE: To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by arthritis overall, rheumatoid arthritis, juvenile arthritis, the spondylarthritides, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome. A companion article (part II) addresses additional conditions. METHODS: The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey (NHIS). For analysis of overall arthritis, we used the NHIS. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition. RESULTS: More than 21% of US adults (46.4 million persons) were found to have self-reported doctor-diagnosed arthritis. We estimated that rheumatoid arthritis affects 1.3 million adults (down from the estimate of 2.1 million for 1995), juvenile arthritis affects 294,000 children, spondylarthritides affect from 0.6 million to 2.4 million adults, systemic lupus erythematosus affects from 161,000 to 322,000 adults, systemic sclerosis affects 49,000 adults, and primary Sjögren's syndrome affects from 0.4 million to 3.1 million adults. CONCLUSION: Arthritis and other rheumatic conditions continue to be a large and growing public health problem. Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions, more studies generalizable to the US or addressing understudied populations are needed.

Gazi H, Pope JE, Clements P, Medsger TA, Martin RW, Merkel PA, Kahaleh B, Wollheim FA, Baron M, Csuka ME, Emery P, Belch JF, Hayat S, Lally EV, Korn JH, Czirjak L, Herrick A, Voskuyl AE, Bruehlmann P, Inanc M, Furst DE, Black C, Ellman MH, Moreland LW, Rothfield NF, Hsu V, Mayes M, McKown KM, Krieg T, Siebold JR. · Division of Rheumatology, Department of Medicine, The University of Western Ontario, London, Ontario, Canada. · J Rheumatol. · Pubmed #17299843 No free full text.

Abstract: OBJECTIVE: To obtain a consensus on the minimal clinically relevant treatment effect in various scleroderma disease outcome measures to be used in future clinical trials. METHODS: A Delphi consensus building exercise using a survey was sent out to members of the Scleroderma Clinical Trials Consortium (SCTC). The 65 SCTC members were divided into 2 groups. Group 1 was informed, in a cover letter, of the usual American College of Rheumatology 20% response results in randomized trials using effective biologic treatments for rheumatoid arthritis, while Group 2 was not. The first round of the exercise presented the scleroderma experts with a survey composed of 95 questions/clinical scenarios divided into 8 categories. These included situations where the treatment group improved, or worsened, or where some outcome measures improved, while others worsened. From the responses of this first round, a mean, mode, median, and range of responses for each of the 95 questions was obtained. This information was sent out, in the second round of the Delphi exercise, only to those respondents who answered the first round. The respondent's previous answer and the mean and range from the first round were provided for each question. It gave respondents the option to change any of their initial responses. The median of their responses in the second round was used to calculate the values for the minimal clinically relevant treatment effect. RESULTS: Thirty-two of the 65 SCTC members returned the first round of the Delphi exercise. Twenty-eight members returned the second round. Intraclass correlation coefficients between responses to round 1 and 2 were calculated for the questions. These varied from 0.99 (excellent agreement) to 0.02 (poor agreement). The p value was under 0.09 for 9 questions and under 0.19 for 20 questions. Standard deviations (SD) were calculated and were found to be lesser for each of the questions in round 2 when compared to the SD in responses from round 1, thus indicating a movement towards a consensus by the second round. An average of 33% of the responses were changed by the respondents in the second round of the Delphi exercise to a value closer to the median/average of the first round's responses. A range in required values for the minimal clinically relevant treatment effect for Modified Rodnan skin score is 3 to 7.5 units, Health Assessment Questionnaire Disability Index (HAQ-DI) 0.2 to 0.25 units, HAQ pain 0.2 to 0.3 units, MD global (100 mm visual analog scale) 8 to 13, patient global assessment 10 to 12, and diffusing capacity (percentage predicted) 9 to 10. The scenarios were especially weighted towards overall disease modification, thus organ-specific measures, such as 6 minute walk time (which has been used in many pulmonary artery hypertension trials), forced vital capacity, and a dyspnea rating (which may be important in scleroderma lung trials), were not included in the survey. CONCLUSION: Our study begins to address the current deficiency in our knowledge of appropriate values for the minimal clinically relevant treatment effect in various scleroderma disease outcome measures. A consensus could be achieved, or at least a range of minimal clinically relevant treatment effect values could be found for several outcome measurements. Of course, this consensus statement will be modified by evidence as it accrues in each consensus area.