Rheumatoid Arthritis: Weisman M

Chiou CF, Sherbourne CD, Cornelio I, Lubeck DP, Paulus HE, Dylan M, Weisman M. · Cerner Health Insights, Beverly Hills, CA 90212, USA. · J Rheumatol. · Pubmed #16465655 No free full text.

Abstract: OBJECTIVE: To assess the psychometric characteristics of the original 33-item Cedars-Sinai Health-Related Quality of Life in Rheumatoid Arthritis Questionnaire (O-CSHQ-RA) and 11-item CSHQ-RA Short Form (SF) using a representative population of patients with rheumatoid arthritis (RA) from 55 sites across the United States. METHODS: Data were from a 24-week multicenter, open-label, single-arm study of 312 RA patients receiving anakinra. Cronbach's alpha coefficient was used to indicate the internal consistency. Test-retest reliability was assessed by establishing the intraclass correlation coefficient (ICC) for screening and baseline visit responses. Convergent validity was tested with the Pearson correlation coefficient. Analysis of variance was performed to determine discriminant validity. A Wilcoxon signed-rank test and analysis of covariance were used to assess the responsiveness. A discriminant function was generated to determine the clinically meaningful change. RESULTS: Test-retest reliability was demonstrated for both versions of the CSHQ-RA, with ICC ranging from 0.82 to 0.94. Cronbach's alpha coefficients were > or = 0.9, indicating good internal consistency. Pearson correlations between health-related quality of life instruments and CSHQ-RA measures ranged from -0.33 to -0.73 and 0.39 to 0.76, demonstrating good convergent validity. Scores on both versions of the CSHQ-RA differed significantly (p < 0.0001) for patients with different levels of physical disability as measured by the Stanford Health Assessment Questionnaire. Both instruments were responsive to differences in patient health as measured by the general health question (p < 0.0001). Clinically meaningful changes were calculated for all 5 domains of the O-CSHQ-RA (6.9-14.0) and the overall O-CSHQ-RA SF (12.7). CONCLUSION: These results support the validity and reliability of both the original CSHQ-RA and the 11-item CSHQ-RA SF when tested in a representative patient population.

Kremer J, Genovese M, Cannon GW, Caldwell J, Cush J, Furst DE, Luggen M, Keystone E, Bathon J, Kavanaugh A, Ruderman E, Coleman P, Curtis D, Kopp E, Kantor S, Weisman M, Waltuck J, Lindsley HB, Markenson J, Crawford B, Fernando I, Simpson K, Strand V. · Center for Rheumatology, Albany, New York 12206, USA. · J Rheumatol. · Pubmed #15290730 No free full text.

Abstract: OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, St Clair EW, Weisman M, Smolen J, Lipsky PE, Maini RN. · Department of Rheumatology, University of Leiden, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #14722203 links to  free full text

Abstract: OBJECTIVE: To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA). METHODS: Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group. RESULTS: The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet. CONCLUSIONS: Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.

Furst DE, Weisman M, Paulus HE, Bulpitt K, Weinblatt M, Polisson R, Zaug M, Kneer J, Van der Auwera P, Stevens RM. · Virginia Mason Research Center, Seattle, Washington, USA. · J Rheumatol. · Pubmed #14528504 No free full text.

Abstract: OBJECTIVE: To determine the optimal dose regimen of intravenous (IV) Ro 45-2081 (lenercept), a tumor necrosis factor receptor p55-Fc IgG1 fusion protein, in patients with active rheumatoid arthritis (RA) METHODS: In a double-blind, placebo-controlled, parallel-group, multicenter trial, adult patients with long-standing active RA stabilized on conventional therapy were randomly assigned to receive 3 IV infusions, one every 4 weeks, of one of the following: (a) placebo, (b) lenercept 0.01 mg/kg (maximum 1 mg), (c) lenercept 0.05 mg/kg (maximum 5 mg), (d) lenercept 0.2 mg/kg (maximum 20 mg), or (e) lenercept 0.5 mg/kg (maximum 50 mg). The material utilized in the study had a lower relative bioavailability [lower area under the time-concentration curve (AUC) per mg infused] than that used in a recent similar trial. Efficacy variables included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain. RESULTS: Patients treated with lenercept exhibited improvement as early as one day after the first IV infusion. The treatment benefit, however, was modest, maximized by 2 weeks and then diminished or vanished as non-neutralizing anti-lenercept antibody concentrations increased. The majority of adverse experiences were mild or moderate and not considered related to study drug. CONCLUSION: Our results showed that lenercept administered by IV infusion every 4 weeks is well tolerated, but only transiently effective in patients with long-standing RA, likely due to both the low relative bioavailability of the material used in the study and the formation of non-neutralizing anti-lenercept antibodies.

Kavanaugh A, Genovese M, Baughman J, Kivitz A, Bulpitt K, Olsen N, Weisman M, Matteson E, Furst D, van Vollenhoven R, Anderson J, Cohen S, Wei N, Meijerink J, Jacobs C, Mocci S. · Division of Rheumatology, Allergy and Immunology, University of California, San Diego, San Diego, CA 92037-0943, USA. · J Rheumatol. · Pubmed #12610799 No free full text.

Abstract: OBJECTIVE: Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant autoantigen in patients with rheumatoid arthritis (RA). Administration of major histocompatibility complex (MHC) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance. We evaluated the safety, pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263 is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13-mer peptide derived from HC gp-39 (also referred to as CDP263). METHODS: Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria. RESULTS: Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263. CONCLUSION: AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA.

Mason U, Aldrich J, Breedveld F, Davis CB, Elliott M, Jackson M, Jorgensen C, Keystone E, Levy R, Tesser J, Totoritis M, Truneh A, Weisman M, Wiesenhutter C, Yocum D, Zhu J. · GlaxoSmithKline Pharmaceuticals, Greenford, Middlesex, UK. · J Rheumatol. · Pubmed #11838838 No free full text.

Abstract: OBJECTIVE: Double blind studies were conducted with the anti-CD4 monoclonal antibody (Mab) keliximab in patients with active, stable rheumatoid arthritis (RA), to confirm preliminary evidence of efficacy and safety from open. uncontrolled studies. METHODS: We enrolled 136 and 186 patients into 2 consecutive, randomized, double blind trials, with similar populations [apart from inclusion of disease modifying antirheumatic drug (DMARD)-naïve patients in Study 2]. Patients received 4 weeks intravenous placebo or keliximab [40, 80, 120, or 140 mg twice weekly (bw), or 240 mg once weekly (ow)].The primary endpoint was the American College of Rheumatology (ACR) 20 response criteria, one week after the end of treatment. RESULTS: ACR 20 response rates in Study I were 19%, 42%, 51%*, and 69%* (*p < 0.05 compared to placebo), with placebo, 40, 80, or 140 mg keliximab bw, respectively. The response rates in Study 2 were 30%, 39%, 46% and 47% with placebo, 80 or 120 mg bw, or 240 mg keliximab ow, respectively. In the 2 studies, there was a dose dependent increase in peripheral blood CD4+ T cell coating with keliximab, but a different pattern of CD4 depletion was seen. While only 12% of keliximab treated patients in Study I had CD4 counts below 250 cells/mm3 at the end of the treatment period, 47% fell below this level in Study 2. Clinical response was not correlated with CD4 depletion, but was correlated with CD4+ T cell coating with keliximab. CONCLUSION: Coating of peripheral blood CD4+ T cells with keliximab, but not CD4 depletion, is a determinant of clinical response.

Moreland L, Gugliotti R, King K, Chase W, Weisman M, Greco T, Fife R, Korn J, Simms R, Tesser J, Hillson J, Caldwell J, Schnitzer T, Lyons D, Schwertschlag U. · Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Arthritis Res. · Pubmed #11438043 links to  free full text

Abstract: Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates the growth and development of hematopoietic stem cells and decreases the proinflammatory mediators of cytokine and nitric oxide production. In animal models of arthritis, treatment with recombinant human IL-11 (rhIL-11) reduces both the level of synovitis and the histologic lesion scores in the joints.The goal of this phase-I/II study in adults with rheumatoid arthritis (RA) was to evaluate the safety and clinical activity of different doses and schedules of rhIL-11 in patients with active RA for whom treatment with at least one disease-modifying antirheumatic drug had failed.This was a multicenter, randomized, placebo-controlled trial that evaluated the safety and tolerability of rhIL-11 in 91 patients with active RA. rhIL-11 was administered subcutaneously; patients were randomized into one of five treatment groups (ratio of rhIL-11 to placebo, 4:1). Patients were treated for 12 weeks with either 2.5 or 7.5 microg/kg of rhIL-11 or placebo twice per week or 5 or 15 microg/kg of rhIL-11 or placebo once per week. The status of each subject's disease activity in accordance with the American College of Rheumatology (ACR) criteria was assessed before, during, and after completion of administration of the study drug.Administration of rhIL-11 was well tolerated at all doses and schedules. The most frequent adverse event was a reaction at the injection site. The data suggest a statistically significant reduction in the number of tender joints (P < 0.008) at the 15 microg/kg once-weekly dose schedule but showed no overall significant benefit at the ACR criterion of a 20% response.The trial showed rhIL-11 to be safe and well tolerated at a variety of doses and schedules over a 12-week treatment period in patients with active RA. The only adverse event clearly associated with rhIL-11 administration was reaction at the injection site.

Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN, Anonymous00015. · University of Texas Southwestern Medical Center at Dallas, USA. · N Engl J Med. · Pubmed #11096166 links to  free full text

Abstract: BACKGROUND: Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. METHODS: We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. RESULTS: The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response. CONCLUSIONS: In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.

Moreland LW, McCabe DP, Caldwell JR, Sack M, Weisman M, Henry G, Seely JE, Martin SW, Yee CL, Bendele AM, Frazier JL, Kohno T, Cosenza ME, Lyons SA, Dayer JM, Cohen AM, Edwards CK. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 35294-7201, USA. · J Rheumatol. · Pubmed #10743796 No free full text.

Abstract: OBJECTIVE: To evaluate the safety, immunogenicity, pharmacokinetics, and efficacy of intravenous administration of tumor necrosis factor binding protein (TNFbp) dimer in patients with rheumatoid arthritis (RA). METHODS: This phase I/II study was a multicenter, randomized, double blind, placebo controlled, ascending dose study evaluating TNFbp dimer administered by i.v. infusion. Thirty-three patients with RA divided into 3 cohorts received TNFbp dimer (30, 100, 300 microg/kg) or placebo during a 5 min infusion at baseline and at 3 and 6 weeks; patients were followed at routine intervals after each infusion through 77 days postinfusion. Pharmacokinetics were analyzed using a log-linear regimen and comparisons were made between half-life after first, 2nd, and 3rd doses. Plasma TNFbp dimer concentrations and serum antibody levels were used in the measurement of pharmacokinetics. RESULTS: Administration of 30 microg/kg of TNFbp dimer was generally well tolerated; the maximum tolerated dose was 100 microg/kg. No serious adverse events were reported. A significant antibody response affected the half-life and clearance of TNFbp dimer at each dose group. Anti-TNFbp antibodies were noncytotoxic and nonagonistic. Clinical evaluations provided evidence of in vivo activity of TNFbp dimer in these patients. CONCLUSION: TNFbp dimer administered to patients with long standing RA resulted in significant antibody production to the study drug. This effect reduced the half-life and clearance of the TNFbp. This TNFbp will not be a viable option for treating patients with RA secondary to immunogenicity.

Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. · The Kennedy Institute of Rheumatology and The Imperial College School of Medicine at Charing Cross Hospital, London, UK. · Lancet. · Pubmed #10622295 No free full text.

Abstract: BACKGROUND: Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate. METHODS: In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. FINDINGS: At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group. INTERPRETATION: During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.

Furst DE, Lindsley H, Baethge B, Botstein GR, Caldwell J, Dietz F, Ettlinger R, Golden HE, McLaughlin GE, Moreland LW, Roberts WN, Rooney TW, Rothschild B, Sack M, Sebba AI, Weisman M, Welch KE, Yocum D. · Virginia Mason Research Center, Seattle, Washington 98101, USA. · Arthritis Rheum. · Pubmed #10025931 links to  free full text

Abstract: OBJECTIVE: To investigate the usefulness of hydroxychloroquine (HCQ) dose-loading to increase the percentage of responders or rate of response in treating rheumatoid arthritis (RA). METHODS: Two hundred twelve patients with early RA (mean duration 1.5 years) were enrolled in a 24-week trial. Patients were stabilized with 1,000 mg naproxen/day and then began a 6-week, double-blind trial comparing treatment with HCQ at 400 mg/day (n = 71), 800 mg/day (n = 71), and 1,200 mg/day (n = 66), followed by 18 weeks of open-label HCQ treatment at 400 mg/day. RESULTS: All patients had mild, active disease at the time of initiation of HCQ treatment (31-43% rheumatoid factor positive; no previous disease-modifying antirheumatic drugs; mean swollen joint count 8.6-10.4). Based on the Paulus criteria, response during the 6-week double-blind portion of the study was 47.97%, 57.7%, and 63.6% in the 400 mg/day, 800 mg/day, and 1,200 mg/day groups, respectively (P = 0.052). Discontinuations for adverse events were dose related (3 in the 400 mg/day group, 5 in the 800 mg/day group, 6 in the 1,200 mg/day group). Most involved the gastrointestinal (GI) system, with the background naproxen treatment possibly contributing. Ocular abnormalities occurred in 17 of 212 patients (8%) but were not dose related. CONCLUSION: Dose-loading with HCQ increased the degree of response at 6 weeks in this group of patients with early, predominantly seronegative RA. Adverse GI events were dose related, while adverse ocular events were not.

Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, Wolfe F, Lum RF, Massarotti E, Weisman M, Bombardier C, Karlson EW, Criswell LA, Vlietinck R, Gregersen PK. · Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. · Arthritis Rheum. · Pubmed #17530703 links to  free full text

Abstract: OBJECTIVE: Recently, Swedish members of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) provided evidence that smoking may trigger RA-specific immune reactions to citrullinated protein in carriers of HLA-DR shared epitope alleles. In an effort to confirm this interaction between smoking and shared epitope alleles, we performed a case-only analysis of 3 North American RA cohorts. METHODS: A total of 2,476 white patients with RA were studied, 1,105 from the North American Rheumatoid Arthritis Consortium (NARAC) family collection, 753 from the National Inception Cohort of Rheumatoid Arthritis Patients (Inception Cohort), and 618 from the Study of New Onset Rheumatoid Arthritis (SONORA). All patients were HLA-DRB1 typed, and tested for anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor. Information about smoking history was obtained by questionnaire. RESULTS: A significant association was found between smoking and the presence of anti-CCP in the NARAC and the Inception Cohort, but not in the SONORA. The shared epitope alleles consistently correlated with anti-CCP in all 3 populations. Using multiple logistic regression analyses, shared epitope alleles were still the most significant risk factor for anti-CCP positivity. Weak evidence of gene-environment interaction between smoking and shared epitope alleles for anti-CCP formation was found only in the NARAC. CONCLUSION: Unlike the EIRA data, we could not confirm a major gene-environment interaction for anti-CCP formation between shared epitope alleles and smoking in 3 North American RA cohorts. Our data indicate a need for further studies to address the full range of environmental factors other than smoking that may be associated with citrullination and RA.

Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, Weisman M, Wallace DJ, Crues J, Khanna D, Eckel G, Yeilding N, Callegari P, Visvanathan S, Rojas J, Hegedus R, George L, Mamun K, Gilmer K, Troum O. · Division of Rheumatology, Department of Medicine, University of California Los Angeles, CA 90095-1670, USA. · Ann Rheum Dis. · Pubmed #17412737 links to  free full text

Abstract: OBJECTIVE: To incorporate a new trial design to examine clinical response, cytokine expression and joint imaging in patients with rheumatoid arthritis (RA) switching from etanercept to infliximab treatment. METHODS: A randomised, open-label, clinical trial of 28 patients with an inadequate response to etanercept was conducted. Eligible patients received background methotrexate and were randomised 1:1 to discontinue etanercept and receive infliximab 3 mg/kg at weeks 0, 2, 6, 14 and 22, or to continue etanercept 25 mg twice weekly. Data were analysed for clinical response, serum biomarker levels, radiographic progression, MRI and adverse events. RESULTS: At week 16, 62% of infliximab-treated patients achieved American College of Rheumatology 20% criteria for improvement in RA (ACR20) responses compared with 29% of etanercept-treated patients. A 30.8% decrease from baseline in Disease Activity Score 28 was observed in patients receiving infliximab, compared with a 16.0% decrease in patients receiving etanercept. ACR20 and American College of Rheumatology 50% criteria for improvement in RA responses correlated at least minimally with intracellular adhesion molecule-1 and interleukin 8 in patients receiving infliximab. 38% of patients who were switched to infliximab showed reductions in Health Assessment Questionnaire scores (>0.4), compared with 0% of patients receiving etanercept. MRI analyses were inconclusive. Both drugs were well tolerated; 54% of infliximab-treated patients and 50% of etanercept-treated patients reported adverse events. CONCLUSIONS: In this exploratory, open-label trial (with single-blind evaluator), patients were randomised to continue with etanercept or switch to infliximab. The small sample size of this hypothesis-generating study was underpowered to show statistical differences between groups. There was a numerical trend favouring patients who switched to infliximab, therefore warranting further study with a more rigorous design.

Chiou CF, Suarez-Almazor ME, Sherbourne CD, Chang CH, Reyes C, Dylan M, Ofman J, Wallace DJ, Mizutani W, Weisman M. · Amgen, Inc., Thousand Oaks, California, USA. · J Rheumatol. · Pubmed #17080516 No free full text.

Abstract: OBJECTIVE: To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to report health states and estimate preference weights. METHODS: Survey materials were mailed to 748 patients. Factor analysis, an item response theory-based model, and an internal consistency test were used to identify attributes and evaluate items. Two multiattribute preference weight functions (MAPWF) were constructed. Construct validity of the new measures was then tested. RESULTS: Four hundred eighty-seven patients returned the survey; 24 items on 6 health attributes were selected to form the new outcomes measure. Two MAPWF were derived with preference weights measured with time tradeoff and visual analog scales as dependent variables. All validity test results were statistically significant. CONCLUSION: Our results reveal that the new measures are reliable and valid in assessing health states and associated preference weights of patients with RA.

Chiou CF, Weisman M, Sherbourne CD, Reyes C, Dylan M, Ofman J, Wallace DJ, Mizutani W, Suarez-Almazor ME. · Cerner Health Insights, Beverly Hills, California 90212, USA. · J Rheumatol. · Pubmed #16331757 No free full text.

Abstract: OBJECTIVE: To estimate weights for health states comprising American College of Rheumatology (ACR) response and different levels of adverse events associated with rheumatoid arthritis (RA) treatments. METHODS: A survey was mailed to 748 patients with RA from southern California. In addition to several questionnaires commonly used for patients with RA, patients were instructed to evaluate 10 hypothetical health states, in which they could have an ACR response and/or adverse events due to new treatments, with a visual analog scale (VAS). Patients also evaluated their current health with a VAS question and a time tradeoff (TTO) question. Linear extrapolation was used to derive 6 more health states. The Pearson correlation coefficient was used to validate VAS and TTO results. RESULTS: A total of 487 (65%) patients returned the survey. Among the 10 health states evaluated with VAS directly, the health state in which a patient has ACR70 with no adverse events had the highest VAS weight (0.84), followed by the one having an ACR50 response with no adverse events (0.80). Correlation coefficients ranged from 0.63 for the correlation between VAS and physical component summary to -0.18 between TTO and pain and tender joint count; the correlation coefficients were all statistically significant, indicating there was convergent validity of the VAS and that VAS functioned differently from TTO in how it measured weights. CONCLUSION: VAS weights for 16 ACR response health states of patients with RA were derived. These weights could be used for cost-utility analyses of interventions for patients with RA.

Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F, Lum RF, Massarotti E, Weisman M, Bombardier C, Remmers EF, Kastner DL, Seldin MF, Criswell LA, Gregersen PK. · North Shore-Long Island Jewish Institute for Medical Research, Manhasset, New York 11030, USA. · Arthritis Rheum. · Pubmed #16320316 links to  free full text

Abstract: OBJECTIVE: To examine the association between HLA-DRB1 alleles and the production of anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) autoantibodies in patients with rheumatoid arthritis (RA). METHODS: We studied 1,723 Caucasian RA patients enrolled in the North American Rheumatoid Arthritis Consortium (NARAC) family cohort and the Study of New Onset Rheumatoid Arthritis (SONORA) cohort. All patients were tested for anti-CCP antibodies (by enzyme-linked immunosorbent assay), RF (by nephelometry), and HLA-DR genotype (by polymerase chain reaction and sequence-specific oligonucleotide hybridization). RESULTS: When controlled for the presence of RF, anti-CCP positivity was strongly associated with the HLA-DRB1 shared epitope (SE). In RF+ patients, the presence of the SE was very significantly associated with anti-CCP positivity, with an odds ratio (OR) of 5.8 and a 95% confidence interval (95% CI) of 4.1-8.3. This relationship was also seen in RF- patients (OR 3.1 [95% CI 1.8-5.3]). In contrast, RF positivity was not significantly associated with presence of the SE independently of anti-CCP antibodies. Strikingly, HLA-DRB1*03 was strongly associated with reduced anti-CCP titers, even after controlling for the presence of the SE and restricting the analysis to anti-CCP+ patients. HLA-DR3 was also associated with anti-CCP- RA in our population. CONCLUSION: The HLA-DRB1 SE is strongly associated with the production of anti-CCP antibodies, but not RF. In contrast, HLA-DR3 alleles are associated with anti-CCP- disease and with lower levels of anti-CCP antibodies, even when controlling for the SE. These data emphasize the complexity of the genetic effects of the major histocompatibility complex on the RA phenotype.

Lee AT, Li W, Liew A, Bombardier C, Weisman M, Massarotti EM, Kent J, Wolfe F, Begovich AB, Gregersen PK. · North Shore-LIJ Research Institute, Manhasset, NY 11030, USA. · Genes Immun. · Pubmed #15674368 No free full text.

Abstract: We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46-2.10, P=1.3 x 10(-9)). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92-1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35-8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.

Chiou CF, Sherbourne CD, Ofman J, Lee M, Lubeck DP, Paulus HE, Weisman M. · Zynx Health, Beverly Hills, California 90212, USA. · Arthritis Rheum. · Pubmed #15188319 links to  free full text

Abstract: OBJECTIVE: To develop an abridged version of the 33-item Cedars-Sinai Health-Related Quality of Life in Rheumatoid Arthritis instrument (CSHQ-RA) and test the validity and reliability of the abridged instrument. METHODS: Items from the original 33-item, 5-domain CSHQ-RA were assessed using psychometric and regression analyses of survey responses from 274 patients with rheumatoid arthritis. Items were retained in the final instrument based on statistical analysis and evaluation by an expert panel. Test-retest reliability, internal consistency, convergent and discriminant validity, and ceiling and floor effects were examined for the shortened CSHQ-RA. RESULTS: Statistical analysis and expert assessment yielded an 11-item instrument including questions in 4 domains. Test-retest reliability and internal consistency were high and the instrument showed good convergent and discriminant validity. CONCLUSION: The abridged CSHQ-RA short form is a valid and reliable instrument that can be used to examine the impact of RA on patients' health-related quality of life. Prospective validation in clinical trial settings is warranted.

Russak SM, Croft JD, Furst DE, Hohlbauch A, Liang MH, Moreland L, Ofman JJ, Paulus H, Simon LS, Weisman M, Tugwell P, Anonymous00333. · Zynx Health Incorporated, Beverly Hills, California, USA. · Arthritis Rheum. · Pubmed #12910566 links to  free full text

Abstract: OBJECTIVE: The utilization of health-related quality of life (HRQOL) patient questionnaires by clinical rheumatologists is limited. Yet, considerable literature exists defining the value of such data. In an effort to understand this apparent paradox, we performed a literature review and conducted a survey to describe what has been learned over the past 2 decades concerning the use of these measures in clinical care and explore the reasons for their underutilization. METHODS: A panel of rheumatologists with extensive clinical experience was convened to review the relevant literature pertaining to the use of HRQOL patient instruments in clinical practice. Additionally, a survey of all American College of Rheumatology practicing clinicians was conducted to assess the use of and beliefs about these measures. RESULTS: The literature provided evidence to support the use of HRQOL patient measures in clinical practice. Forty-seven percent of the responding rheumatologists stated that none of their patients complete HRQOL patient questionnaires. The majority of respondents (63%) reported that such information is "somewhat valuable." The most frequently reported reason for the underutilization was that such instruments "require too much staff time." CONCLUSIONS: The literature supports the potential value of HRQOL patient questionnaires in clinical practice. Few rheumatologists routinely gather such information as part of patient care. Reasons for this discrepancy between utility and use are given along with recommendations intended to help increase their utilization in clinical care.

Munster T, Gibbs JP, Shen D, Baethge BA, Botstein GR, Caldwell J, Dietz F, Ettlinger R, Golden HE, Lindsley H, McLaughlin GE, Moreland LW, Roberts WN, Rooney TW, Rothschild B, Sack M, Sebba AI, Weisman M, Welch KE, Yocum D, Furst DE. · University of Erlangen, Erlangen, Germany. · Arthritis Rheum. · Pubmed #12115175 links to  free full text

Abstract: OBJECTIVE: A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug. METHODS: Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis. RESULTS: The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3. CONCLUSION: There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.

van der Heijde D, Simon L, Smolen J, Strand V, Sharp J, Boers M, Breedveld F, Weisman M, Weinblatt M, Rau R, Lipsky P. · Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #11954017 No free full text.

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