Rheumatoid Arthritis: Ruderman EM

Ruderman EM, Pope RM. · Division of Rheumatology, Northwestern University Feinberg School of Medicine, 675 North St. Clair Street, Chicago, IL 60611, USA. · Nat Clin Pract Rheumatol. · Pubmed #17133250 No free full text.

Abstract: Although the development of tumor necrosis factor antagonists has improved the clinical outcome of many patients with rheumatoid arthritis (RA), some patients fail to respond to these drugs or have contraindications preventing their use. Other approaches for treating this disease are, therefore, keenly sought. As T cells promote numerous disease pathways in RA, these cells are a logical target for anti-inflammatory therapy. One of the approaches being investigated involves targeting the co-stimulatory signals that accompany antigen-derived signals involved in the activation of T cells. Abatacept is a recombinant fusion protein that interrupts the T-cell co-stimulatory signal mediated through the CD28-CD80/CD86 pathway. Several clinical trials have now confirmed the efficacy of this compound in the treatment of RA. This article discusses the proposed mechanism of action of abatacept and reviews the data from phase II and phase III clinical trials on the safety and efficacy of this drug in RA.

Gordon KB, Ruderman EM. · Division of Dermatology, Evanston Northwestern Healthcare, Skokie, Illinois 60077, USA. · J Am Acad Dermatol. · Pubmed #16488334 No free full text.

Abstract: Psoriatic arthritis is a common inflammatory arthritis associated with psoriasis, occurring in 5% to 40% of patients with cutaneous disease. Recently, there has been an increased appreciation of the need to use an integrated approach to these 2 diseases, considering both entities when determining therapeutic choices. In this review, the available therapeutic options for psoriatic arthritis are considered, along with the potential benefit that these medications may have for cutaneous psoriasis. Finally, a conceptual model for the therapy of psoriasis and psoriatic arthritis, the Four Quadrant Model, is presented as a simplified framework to use when considering treatment for psoriatic disease.

Ruderman EM. · Northwestern University Feinberg School of Medicine, 675 North St. Clair, Suite 14-100, Chicago, IL 60611, USA. · Curr Rheumatol Rep. · Pubmed #16045835 No free full text.

Abstract: Treatment of psoriatic arthritis, like the treatment of rheumatoid arthritis, now commonly includes the use of inhibitors of tumor necrosis factor in addition to traditional synthetic disease-modifying antirheumatic drugs. This paper examines the most recent data from therapeutic trials in psoriatic arthritis, with particular emphasis on the effectiveness of the tumor necrosis factor inhibitors. Recent data on potential future therapies is discussed as well, along with data on the mechanisms of current therapies that may have relevance for future treatment approaches.

Ruderman EM, Pope RM. · Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Arthritis Res Ther. · Pubmed #15833145 No free full text.

Abstract: Abatacept (CTLA4-Ig) is a novel fusion protein designed to modulate the T cell co-stimulatory signal mediated through the CD28-CD80/86 pathway. Clinical trials have provided preliminary evidence of the efficacy of this compound in the treatment of rheumatoid arthritis. This review describes the molecular and biologic bases for the use of abatacept in rheumatoid arthritis and summarizes the current clinical data on its safety and effectiveness in this disease.

Ruderman EM. · Northwestern University of Feinburg School of Medicine, USA. · Curr Pharm Des. · Pubmed #15720281 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, inflammatory arthritis with a population prevalence of approximately 1%. Pharmaceutical treatment includes both anti-inflammatory medications and disease modifying drugs (DMARDs) that impact the course of the damage associated with this disease. Traditional DMARD therapy includes immunomodulatory agents such as methotrexate, used both alone and in combination. Recently available biologic response modifiers are very effective at reducing both the clinical symptoms of disease and the radiographic damage that accompanies them. This manuscript describes the clinical assessments used to measure response to therapy in RA and reviews the results seen with the various treatment strategies in this disease. In addition, the clinical and structural outcomes seen in trials of newly available and pending biologic therapies are reviewed, along with the specific toxicity issues associated with these agents. Clinical trial data is reviewed for the TNF antagonists, which have become the standard of care in RA patients with an inadequate response to methotrexate. RA has been clearly shown to be a destructive and disabling disease. The widespread use of newer agents, however, along with more aggressive use of existing therapies, appears to limit disease progression very effectively, and should lead to better long-term outcomes for these patients.

Issa SN, Ruderman EM. · Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, USA. · Postgrad Med. · Pubmed #15580917 No free full text.

Abstract: Right from the onset, rheumatoid arthritis is an aggressive disease that can quickly alter joint structure and integrity. Such rapid pathogenesis requires that the diagnosis be established early and aggressive therapy initiated swiftly. In this article, Drs Issa and Ruderman describe what is known about the cause, progression, and outcomes of rheumatoid arthritis. They review the steps toward its diagnosis and urge that treatment be started promptly--to both contain disease and reduce joint destruction as soon as possible.

Ruderman EM. · Division of Rheumatology, Feinberg School of Medicine, Northwestern University, 300 East Chicago Avenue, Ward 3-315, Chicago, IL 60611, USA. · J Am Acad Dermatol. · Pubmed #12894136 No free full text.

Abstract: Clinicians often view psoriatic arthritis (PsA) as a rather minor arthritic disorder because many are unaware of the substantial damage, disability, and reduced quality of life that patients with this disease can suffer. Compared with better-studied arthritic conditions, such as rheumatoid arthritis (RA) with well-known consequences of disease progression, PsA does not elicit the same urgency to treat early and aggressively. This is largely owing to the lack of predictive epidemiologic data regarding disease progression in PsA. However, numerous studies indicate that PsA and RA are comparable in terms of overall severity of joint involvement and disability over equivalent disease duration. Many of the drugs traditionally used for PsA therapy are also used to treat RA, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, methotrexate (MTX), sulfasalazine, cyclosporine, etretinate, auranofin, intramuscular gold, and azathioprine. All of these drugs have significant risk of toxicity over long-term use, and all provide variable efficacy. This makes it difficult for clinicians to make sound risk-benefit assessments regarding treatment or nontreatment of PsA, because the risks of disease progression cannot be weighed against the risks of therapy. The newer biologic antirheumatic drugs appear to combine greater efficacy of treatment with significantly less toxicity by targeting specific mediators involved in the pathogenesis of PsA.

Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM. · The Center for Rheumatology, LLP, 1367 Washington Avenue, Suite 101, Albany, NY 12206, USA. · Ann Intern Med. · Pubmed #12416946 links to  free full text

Abstract: BACKGROUND: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. OBJECTIVE: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. DESIGN: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: 20 centers in the United States and Canada. PATIENTS: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. INTERVENTION: Leflunomide or matching placebo added to existing methotrexate therapy. MEASUREMENTS: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. RESULTS: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. CONCLUSIONS: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ, Ruderman EM, Horwitz DA, Arkfeld DG, Garrison L, Burge DJ, Blosch CM, Lange ML, McDonnell ND, Weinblatt ME. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 35294-7201, USA. · Ann Intern Med. · Pubmed #10075615 links to  free full text

Abstract: BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors. SETTING: 13 North American centers. PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

Weinblatt ME, Schiff MH, Ruderman EM, Bingham CO, Li J, Louie J, Furst DE. · Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #18576334 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of treatment with 50 mg of etanercept twice a week plus weekly methotrexate (MTX; > or =15 mg) in patients with rheumatoid arthritis (RA) who had a suboptimal response to 50 mg of etanercept once a week plus weekly MTX (> or =15 mg). METHODS: In this multicenter, randomized, double-blind, active drug-controlled study, suboptimal responders to treatment with MTX plus etanercept 50 mg once weekly were given MTX plus etanercept 50 mg twice weekly (n = 160) or MTX plus etanercept 50 mg once weekly plus a placebo (n = 40) for 12 weeks. In a subsequent 12-week open-label period, patients who responded to etanercept 50 mg twice weekly decreased their dosage to 50 mg once weekly, those who had a partial response to etanercept 50 mg once weekly increased their dosage to 50 mg twice weekly, and those who had no response to etanercept 50 mg twice weekly were discontinued. The primary end point was the proportion of patients with a response on the Disease Activity Score 28-joint assessment (DAS28) at week 12. RESULTS: A total of 201 patients were randomized; 187 completed 12 weeks, and 102 completed 24 weeks. At week 12 (double-blind period), the DAS28 response in the 50 mg twice weekly and the 50 mg once weekly groups was not significantly different (45.6% versus 35.0%; P = 0.285), and similar proportions of patients in the groups taking 100 mg and 50 mg experienced adverse events (34.4% versus 37.5%; P = 0.711). Serious adverse events occurred in 7 of 160 of the 50 mg twice weekly group and 0 of 40 of the 50 mg once weekly group (P = 0.387), and serious infectious events occurred in 3 of 160 patients in the 50 mg twice weekly group (P = 0.884). CONCLUSION: Etanercept 50 mg once weekly is an optimal dosage in most patients with RA. Increasing the dosage from 50 mg once weekly to 50 mg twice weekly in suboptimal responders did not significantly improve their DAS28 responses.

Tambar S, Ruderman EM. · Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. · Manag Care Interface. · Pubmed #17849729 No free full text.

Abstract: Rheumatoid arthritis (RA), the most common form of inflammatory arthritis, is a chronic, inflammatory, progressive disease. Most patients have moderate disease, with a variable disease course and symptomatic flares interspersed with periods of relatively lower disease activity. Over the last 2 decades, the treatment of RA has evolved dramatically, from use of disease-modifying antirheumatic drugs to newer biologics. None of these therapies represents a cure for RA; however, the availability and the efficacy of multiple treatments has made remission of the disease a realistic target.