Rheumatoid Arthritis: Mease PJ

Mease PJ. · University of Washington School of Medicine, Seattle, Washington, USA. · Bull NYU Hosp Jt Dis. · Pubmed #18937633 links to  free full text

Abstract: There has been a burgeoning interest in the spondyloarthritides (SpAs) due to a confluence of elements. Basic science research has provided new insight into the unique pathophysiology of synovium, enthesium, and bone, highlighting the important differences from rheumatoid arthritis (RA). Through collaborative research of international working groups, classification criteria for psoriatic arthritis (PsA) and ankylosing spondylitis (AS) have been developed or are being refined to aid characterization and diagnosis of SpAs and aid in research. These same working groups, under the umbrella of Outcome Measures in Rheumatology Clinical Trials (OMERACT), have developed domain core sets to be measured in clinical trials and registries, and which allow validation of reliable outcome measures. Both through clinical trials and observational data from national clinical registries, the relative effectiveness and safety of old and new therapies are being demonstrated. This has been particularly shown with long-term data on anti-TNF therapy. Newer anti-TNF therapies are being developed, as are treatments with different mechanisms of action in order to treat patients who do not have long-term effectiveness or develop side effects to older disease modifying therapy and anti-TNFs. International treatment recommendations have been or are being developed based on the evidence base from clinical trials.

Mease PJ. · Seattle Rheumatology Associates, Seattle, Washington 98104, USA. · J Rheumatol. · Pubmed #18609733 No free full text.

Abstract: B cells play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other autoimmune diseases. Recently, a number of biologic agents that target B cells have been tested as therapies for these conditions. These agents either deplete B cells, by targeting cell-surface antigens such as CD20, or block B cell function, for example by inhibiting the activity of B cell survival factors such as BLyS. Of this group of agents, the first in clinical use has been rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen. Initially introduced as a treatment for non-Hodgkin's lymphoma, rituximab is now approved for the treatment of RA. In this review we explore the rationale behind B cell-targeted therapy, highlight the results of clinical trials with rituximab in RA and other autoimmune diseases, and describe other emerging therapies directed at B cells.

Mease PJ. · Seattle Rheumatology Associates, Rheumatology Clinical Research, Swedish Medical Center, University of Washington School of Medicine, Seattle, WA, USA. · Semin Arthritis Rheum. · Pubmed #18304610 No free full text.

Abstract: OBJECTIVES: To identify and describe measures that can be used to assess the impact of psoriatic arthritis (PsA) on patient functioning and health-related quality of life (HRQOL). METHODS: A literature search of the PubMed database to identify papers describing assessment tools for quality of life and function in rheumatic diseases. RESULTS: Many tools have been developed that can be used to assess the impact of rheumatic disease on patient functioning and HRQOL. Although several disease-specific tools have been developed for rheumatoid arthritis, ankylosing spondylitis, and psoriasis, few have been developed specifically for PsA, a condition that affects both skin and joints. However, several have been adopted from their use in other conditions and used in clinical trials, such as the Health Assessment Questionnaire and Short Form 36 and have shown good performance characteristics. The Psoriatic Arthritis Quality of Life questionnaire, a recently developed disease-specific instrument, has good internal consistency, validity, and reliability. Initiatives are underway by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis to evaluate Psoriatic Arthritis Quality of Life responsiveness to treatment in clinical trials, in addition to other projects intended to improve the assessment of quality of life and function in PsA. These efforts are influenced by "lessons learned" from assessment tools in rheumatoid arthritis, ankylosing spondylitis, and psoriasis. CONCLUSIONS: Assessing the impact of PsA and its treatment on patient function and quality of life is critical to improving patient outcomes, and therefore, valid and reliable tools that can be easily used in both clinical trials and clinical practice are being developed and refined.

Davis JC, Mease PJ. · University of California San Francisco, San Francisco, CA, USA. · Semin Arthritis Rheum. · Pubmed #18166219 No free full text.

Abstract: OBJECTIVE: The spondyloarthritides are a set of chronic inflammatory diseases that consists of 5 interrelated subsets (ankylosing spondylitis [AS], psoriatic arthritis [PsA], reactive arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy). The aim of this review was to evaluate the classification, genetic susceptibility, pathology, and response to treatment of spondyloarthritis (SpA). METHODS: Searches were conducted of the PubMed database for articles focusing on the classification, pathology, and treatment of SpA. RESULTS: The 5 subsets of SpA share many clinical, immunohistochemical, and genetic features, including the common presence of human leukocyte antigen-B27 and the absence of rheumatoid factor. Evidence suggests that the pathology of SpA is mediated by immune cells. In particular, tumor necrosis factor-alpha appears to be an important driver of inflammation and damage in SpA. A number of different SpA classification criteria have been developed, including the Modified New York Criteria for AS, the European Spondyloarthropathy Study Group criteria, the Amor criteria, as well as criteria for PsA, notably the Moll and Wright criteria and the Classification of Psoriatic Arthritis criteria. Suboptimal efficacy and adverse effects often limit the use of conventional pharmacologic treatments for SpA, including nonsteroidal antiinflammatory drugs and disease-modifying antirheumatic drugs, such as methotrexate and sulfasalazine. Recent evidence has demonstrated that targeted biologic response modifiers, such as TNF-alpha antagonists, are well tolerated and efficacious treatments for SpA. CONCLUSIONS: Significant advances have occurred in our understanding of the pathophysiology, diagnosis, and classification of the spondyloarthritides and effective treatments are available.

Keeling SO, Landewe R, van der Heijde D, Bathon J, Boers M, Garnero P, Geusens P, El-Gabalawy H, Inman RD, Kraus VB, Kvien TK, Mease PJ, Ostergaard M, Ritchlin C, Syversen SW, Maksymowych WP. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. · J Rheumatol. · Pubmed #17343310 No free full text.

Abstract: OBJECTIVE: A list of 14 criteria for guiding the validation of a soluble biomarker as reflecting structural damage endpoints in rheumatoid arthritis (RA) clinical trials was drafted by an international working group after a Delphi consensus exercise. C-reactive protein (CRP), a soluble biomarker extensively studied in RA, was then used to test these criteria. Our objectives were: (1) To assess the strength of evidence in support of CRP as a soluble biomarker reflecting structural damage in RA according to the draft validation criteria. (2) To assess the strength of recommendation for inclusion of individual criteria in the draft set. METHODS: A systematic literature review was conducted to elicit evidence in support of each specific criterion composing the 14-criteria draft set. A summary of the key literature findings per criterion was presented to both the working group and to participants in a special interest soluble biomarker group at OMERACT 8. Participants at OMERACT 8 were asked to rate the strength of evidence and the strength of the recommendation in support of each individual criterion on a 0-10 numerical rating scale. Working group members not present at OMERACT voted by a Web-based survey. RESULTS: Minimal data were extracted from the literature pertaining to those criteria listed under the category of truth. Ratings for strength of evidence were moderate to low (< 7) for CRP as a biomarker reflecting structural damage in RA; this was true for all criteria except those listed under the category of feasibility and 2 listed under the category of discrimination pertaining to assay reproducibility and evidence regarding sources of variability. Ratings for strength of recommendation for inclusion of each of the 14 criteria in the draft set were high (> 7) except for those criteria listed under the category of truth. CONCLUSION: The draft criteria serve as a useful template in the evaluation of the strength of evidence in support of a particular soluble biomarker as reflecting structural damage in RA.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, Dougados M, Emery P, Keystone EC, Klareskog L, Mease PJ. · 1000 Veteran Avenue Rehabilitation Centre, Room 32-59, Los Angeles, CA 90024, USA. · Ann Rheum Dis. · Pubmed #16239380 links to  free full text

This publication has no abstract.

Mease PJ, Antoni CE. · Seattle Rheumatology Associates, 1101 Madison St, 10th floor, Seattle, WA 98104, USA. · Ann Rheum Dis. · Pubmed #15708944 links to  free full text

Abstract: In recent years there has been a surge of interest in the treatment of chronic inflammatory disorders as a result of the development and application of targeted biological therapies. The elucidation of the overlapping cellular and cytokine immunopathology of such diverse conditions as rheumatoid arthritis (RA), Crohn's disease, and psoriasis points to specific targets for bioengineered proteins or small molecules.Similar to clinical trials in RA, trials in psoriatic arthritis (PsA) have shown excellent clinical results with the tumour necrosis factor (TNF) blockers, etanercept, infliximab, and adalimumab in a variety of domains including the joints, quality of life, function, and slowing of disease progress as evidenced radiologically. In addition, these agents have shown benefit in domains more unique to PsA, such as the skin lesions of psoriasis, enthesitis, and dactylitis, pointing out the similar pathogenesis of the disease in the skin, the tendons, and the synovial membrane. This therapy has been generally safe and well tolerated in clinical trials of PsA.Other logical candidates for targeted therapy in development include other anti-TNF agents, costimulatory blockade agents that affect T cell function, blockers of other cytokines such as interleukin (IL)-1, 6, 12, 15, or 18, and B cell modulatory medicines. Also, it will be useful to learn more about the effects of combining traditional disease modifying drugs and the newer biologicals.

Mease PJ, Antoni CE, Gladman DD, Taylor WJ. · Seattle Rheumatology Associates and Swedish Medical Center Rhematology Research Division, University of Washington School of Medicine, Seattle, WA 98104, USA. · Ann Rheum Dis. · Pubmed #15708937 links to  free full text

Abstract: In order to measure disease activity, progression, and change with therapy in psoriatic arthritis (PsA), it is important to use accurate, reliable, and feasible outcome measures that can ideally be employed in longitudinal cohorts, clinical trials, and clinical practice. Until recently, there has been little focus on this methodology in PsA. Clinical trials and long term clinical registries have used disparate outcome measures. With emerging therapies, the focus on the methodology of outcome assessment has increased to ensure that discriminant and responsive instruments are used. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), in conjunction with the society, Outcome Measures in Rheumatology (OMERACT), is focused on refining and developing outcome measures for a variety of disease domains reviewed in this report. Key domains to assess include joints, skin, enthesitis, dactylitis, spine, joint damage as assessed radiologically, quality of life, and function. These domains can be assessed by individual and composite measures. A number of measures have been "borrowed" from the fields of rheumatoid arthritis, ankylosing spondylitis, and psoriasis and adapted to PsA. Others are being developed specifically for PsA. Few are validated but most have been shown to perform well in distinguishing placebo from treatment response. This report reviews the current state of the art of assessment in PsA and points toward future directions of development of this field.

Mease PJ. · Seattle Rheumatology Associates, Seattle, Washington 98104, USA. · Curr Opin Rheumatol. · Pubmed #15201598 No free full text.

Abstract: PURPOSE OF REVIEW: The incidence of psoriatic arthritis is currently estimated at 7 to 42% of the population with active psoriasis, considered to affect 2 to 3% of the general population. Unmanaged psoriatic arthritis may result in progressive radiologic erosion, severe physical limitations, and disability. Newer trials in psoriatic arthritis therapy demonstrate ongoing ability to control disease symptoms and signs and the progression of the disease significantly. RECENT FINDINGS: Recognition of the immunopathogenesis of psoriatic arthritis, as with rheumatoid arthritis and psoriasis, prompts ongoing examination of the efficacy of several disease-modifying antirheumatic drugs. A new crop of biologics and pharmaceuticals with increased molecular specificity compared with traditional immunosuppressant disease-modifying antirheumatic drugs have been shown to be highly effective in inhibiting the symptoms and progression of psoriatic arthritis with less severe side effects. SUMMARY: Therapies either recently approved or pending approval by the Food and Drug Administration for psoriatic arthritis management are safe and effective in the treatment of symptoms, significantly improve quality of life, and prevent long-term progression of the disease.

Fleischmann RM, Cohen SB, Moreland LW, Schiff M, Mease PJ, Smith DB, Keenan G, Kremer JM, Anonymous00083. · Radiant Research--Dallas, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX 75235, USA. · Curr Med Res Opin. · Pubmed #16083527 No free full text.

Abstract: OBJECTIVE: Infliximab plus methotrexate (MTX) is approved for the treatment of rheumatoid arthritis (RA). Based on the benefit/risk profile of this combination therapy, lower doses of MTX would be preferable when infliximab efficacy can be maintained. We evaluated the ability of patients receiving infliximab plus MTX to achieve and maintain a clinical response while the dose of MTX was tapered. METHODS: Infliximab infusions were administered at a minimum dosage of 3 mg/kg at 8-week intervals (following three loading doses at weeks 0, 2, and 6) to patients who had an inadequate response to MTX. MTX tapering was initiated at week 22 or later when at least a 40% improvement in the combined tender and swollen joint count was achieved; dosages were reduced by 5 mg every 8 weeks to a protocol-specified minimum dosage of 5 mg per week. If the required dosage of MTX after a flare was greater than the baseline dosage, the patient was considered a treatment failure. RESULTS: Of the 210 patients enrolled, 159 (76%) achieved a 40% or better improvement in the combined tender and swollen joint count and had their MTX doses tapered. In these 159 responders, the median (mean) dose of MTX was reduced from 15 (16.5) mg per week at baseline to 5 (7.1) mg per week at week 54. From the time of initial response, 79% of these patients had a zero- or a one-vial increase in infliximab, corresponding to an approximate dose increase of 1 mg/kg, through week 54. CONCLUSION: Approximately 75% of the patients participating in this trial achieved at least a 40% reduction in the combined swollen and tender joint count (correlating with an American College of Rheumatology 20% [ACR20] response in 83% of patients) while reducing the mean MTX dose by 57%.

Mease PJ. · Seattle Rheumatology Associates, Division of Clinical Research, Washington, USA. · Skin Therapy Lett. · Pubmed #12728284 links to  free full text

Abstract: Etanercept (Enbrel, Amgen and Wyeth), a tumor necrosis factor (TNF) antagonist, was approved in January 2002, for the treatment of psoriatic arthritis (PsA). The anti-inflammatory effects of etanercept are due to its ability to bind to the pro-inflammatory cytokine TNF, preventing it from interacting with cell-surface receptors and rendering it biologically inactive. Etanercept was evaluated for the treatment of PsA and psoriasis in a preliminary study of 60 patients and in a confirmatory phase III study of 205 patients. In both studies, etanercept was shown to be significantly superior to placebo for the treatment of PsA, evaluated by Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) criteria. It also was superior to placebo in improving psoriatic skin lesions, evaluated by the Psoriasis Area and Severity Index (PASI) and target lesion scores. Side-effects were minimal; mild injection site reactions, which resolved during continued therapy, were experienced by approximately one-quarter of the patients. Overall, etanercept is highly effective and well tolerated by patients with PsA, with a safety profile similar to that seen in rheumatoid arthritis.

Husni ME, Maier AL, Mease PJ, Overman SS, Fraser P, Gravallese EM, Weinblatt ME. · Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Arthritis Rheum. · Pubmed #12115220 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety and efficacy of etanercept in the treatment of adult patients with Still's disease. METHODS: Twelve adult patients who met criteria for Still's disease and had active arthritis were enrolled in a 6-month open-label trial of etanercept given in biweekly doses of 25 mg. The mean disease duration at study entry was 10.7 years. All patients had been treated unsuccessfully with other disease-modifying antirheumatic drugs. Efficacy was evaluated according to American College of Rheumatology (ACR) improvement criteria, and adverse events were recorded. RESULTS: Ten patients successfully completed the study; 2 withdrew due to disease flare. In 4 patients, the dosage of etanercept was increased from 25 mg biweekly to 25 mg 3 times per week. Seven patients met ACR 20% response criteria. Of these 7 responders, 4 met ACR 50% response criteria and 2 met ACR 70% response criteria. Among the 3 patients with systemic features of Still's disease (fever and rash), improvement in these features was seen in 1; the arthritis did not improve in any of these 3 patients. Except in the 2 patients who withdrew due to disease flare (rash, fever, and arthritis), no other significant adverse events occurred. CONCLUSION: In this initial study of etanercept therapy for Still's disease in the adult, this treatment resulted in improvement in the arthritis and was well tolerated. Additional trials should be performed to elucidate the effects of tumor necrosis factor inhibitors in Still's disease.

Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. · Minor and James Medical, Seattle, WA 98104, USA. · Lancet. · Pubmed #10972371 No free full text.

Abstract: BACKGROUND: Etanercept, a tumour-necrosis-factor inhibitor, has shown efficacy in the treatment of rheumatoid arthritis. Psoriatic arthritis and psoriasis are disease states in which tumour necrosis factor, a proinflammatory cytokine, is present in increased concentrations in joints and in the skin. Therefore, psoriatic arthritis and psoriasis may be appropriate therapeutic targets for etanercept. METHODS: This randomised, double-blind, placebo-controlled, 12 week study assessed the efficacy and safety of etanercept (25 mg twice-weekly subcutaneous injections) or placebo in 60 patients with psoriatic arthritis and psoriasis. Psoriatic arthritis endpoints included the proportion of patients who met the Psoriatic Arthritis Response Criteria (PsARC) and who met the American College of Rheumatology preliminary criteria for improvement (ACR20). Psoriasis endpoints included improvement in the psoriasis area and severity index (PASI) and improvement in prospectively-identified individual target lesions. FINDINGS: In this 12 week study, 26 (87%) of etanercept-treated patients met the PsARC, compared with seven (23%) of placebo-controlled patients. The ARC20 was achieved by 22 (73%) of etanercept-treated patients compared with four (13%) of placebo-treated patients. Of the 19 patients in each treatment group who could be assessed for psoriasis (> or = 3% body surface area), five (26%) of etanercept-treated patients achieved a 75% improvement in the PASI, compared with none of the placebo-treated patients (p=0.015). The median PASI improvement was 46% in etanercept-treated patients versus 9% in placebo-treated patients; similarly, median target lesion improvements were 50% and 0, respectively. Etanercept was well tolerated. INTERPRETATION: Etanercept offers patients with psoriatic arthritis and psoriasis a new therapeutic option for control of their disease.

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.

Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, Weisgerber GA, Hart J. · Department of Pathology, University of Chicago Medical Center, Chicago, IL 60637, USA. · N Engl J Med. · Pubmed #19587341 No free full text.

Abstract: We present a case of disseminated histoplasmosis, complicated by retroperitoneal bleeding and leading to death, in a patient who was receiving systemic immunosuppressive therapy for rheumatoid arthritis and who was enrolled in a gene-therapy trial. This trial was designed to evaluate intraarticular delivery of a tumor necrosis factor alpha (TNF-alpha) antagonist, through an adeno-associated virus (AAV) type 2 delivery system, for inflammatory arthritis. The patient's receipt of concurrent anti-TNF-alpha therapy and other immunosuppressive therapy while she was living in an area where histoplasmosis was endemic was thought to be the most likely explanation for the infection; the evidence presented suggests that this fatal infection was unlikely to have been related to exposure to the agent administered in the gene-therapy trial. This case reinforces the importance of considering infectious complications, such as those from endemic mycoses, in patients receiving treatment with a TNF-alpha antagonist and the importance of having a well-designed monitoring plan when subjects in a research study become ill. (ClinicalTrials.gov number, NCT00126724.)

Cohen SB, Cohen MD, Cush JJ, Fleischmann RM, Mease PJ, Schiff MH, Simon LS, Weaver AL. · The University of Texas Southwestern Medical Center, Office of Continuing Education, 5323 Harry Hines Blvd., Dallas, TX 75390-9059. · J Rheumatol Suppl. · Pubmed #19193621 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic, multisystem, inflammatory disorder of the joints that affects about 1% of the world population. The ultimate goals of therapy include remission of disease and prevention of joint damage. Reaching these goals has become a realistic outcome for an increasing number of patients as treatment options have expanded over the past 3 decades. In addition to older therapies, such as methotrexate (MTX), other disease modifying drugs (DMARD), and tumor necrosis factor (TNF) inhibitors, newer biologic treatments have become available. For the substantial number of patients who experience an inadequate response to standard medications, biologic response modifiers (BRM) provide an important therapeutic alternative. The availability of multiple treatment options in the absence of clear definitions or criteria for remission and inadequate response, however, makes clinical decisions about measuring outcomes, predicting response to treatment, and prescribing pharmacologic therapies challenging. In this program, distinguished rheumatologists weigh the evolving body of clinical evidence to draw sound conclusions and resolve key issues in managing inadequate response to treatment and in achieving optimal outcomes in RA.

Furfaro N, Mease PJ. · Seattle Rheumatology Associates, Seattle, Washington 98104, USA. · J Infus Nurs. · Pubmed #19018189 No free full text.

Abstract: Therapeutic agents in use for years may receive Food and Drug Administration approval for new indications, challenging infusion nurses to keep in mind differences in therapy for more than 1 disease state. For example, many infusion nurses are familiar with using rituximab in an oncology setting; however, because it has been approved relatively recently (February 2006) for treatment of rheumatoid arthritis (RA), infusion specialists must improve their understanding of how dosing and administration differ in the RA setting. This article focuses on the specific pathophysiology of the RA disease state and patient characteristics that may affect infusion therapy, illustrated by a case study.

Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E, Furst DE, Anklesaria P, Heald AE. · Seattle Rheumatology Associates/Swedish Medical Center Research, Seattle, Washington, USA. · Ann Rheum Dis. · Pubmed #18678578 No free full text.

Abstract: OBJECTIVE: To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR:Fc, an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis. METHODS: In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumour necrosis factor alpha (TNFalpha) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR:Fc at 1 x 10(10) (n = 5) or 1 x 10(11) (n = 6) DNase resistant particles per ml joint volume or placebo (n = 4) into a knee (n = 14) or ankle (n = 1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a four-point scale, were evaluated. RESULTS: Intra-articular injections of rAAV2-TNFR:Fc were well tolerated with no major safety issues. One event, mild knee pruritis, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. At 12 weeks after injection, a two-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively. CONCLUSION: A single dose of intra-articular rAAV2-TNFR:Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.

Mease PJ. · Seattle Rheumatology Associates Seattle, WA, USA. · Ther Clin Risk Manag. · Pubmed #18360621 links to  free full text

Abstract: Tumor necrosis factor (TNF) has been implicated in a number of arthritic disease states, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Adalimumab is the first fully human, high-affinity, recombinant immunoglobulin G(1) (IgG(1)) anti-TNF monoclonal antibody. Adalimumab in combination with methotrexate or standard antirheumatic therapies, or as monotherapy, is effective in the treatment of adults with active rheumatoid arthritis who have had an inadequate response to disease-modifying antirheumatic drugs. Adalimumab is also effective in the treatment of patients with moderately to severely active psoriatic arthritis, improving both joint and skin manifestations of the disease as well as disability due to joint damage. In the Adalimumab Trial Evaluating Long-term Efficacy and Safety in Ankylosing Spondylitis (ATLAS), adalimumab significantly reduced the signs and symptoms of active ankylosing spondylitis and established a sustained clinical response in patients who had an inadequate response or intolerance to nonsteroidal antiinflammatory drug therapy. Overall, across these indications, adalimumab demonstrated a rapid onset of action, sustained efficacy with long-term treatment, and was well-tolerated, with few patients discontinuing treatment because of adverse events. The safety profile was similar to other TNF antagonists. Inhibition of TNF activity by adalimumab also significantly improved physical functioning and quality of life measures.

Mease PJ, Revicki DA, Szechinski J, Greenwald M, Kivitz A, Barile-Fabris L, Kalsi J, Eames J, Leirisalo-Repo M. · Seattle Rheumatology Associates, Seattle, WA 98104, USA. · J Rheumatol. · Pubmed #18050385 No free full text.

Abstract: OBJECTIVE: To evaluate the effect of rituximab treatment on health-related quality of life (HRQOL) in patients with active rheumatoid arthritis (RA), who have had an inadequate response to disease-modifying antirheumatic drugs, including biologic agents. METHODS: A randomized, multicenter, double-blind, placebo-controlled clinical trial involving 367 rheumatoid factor-positive patients was conducted. Patients received 2 infusions 2 weeks apart of placebo (n = 122), rituximab 500 mg (n = 123), or rituximab 1000 mg (n = 122), with or without glucocorticoids. All patients received stable doses of methotrexate (10 25 mg/wk). Measures included SF-36, assessed at baseline and at 24 weeks, as well as the HAQ and FACIT-Fatigue scale assessed at baseline and monthly for 24 weeks. Patients exceeding prespecified minimal clinically important differences (MCID) were examined. Clinical efficacy measurements (ACR20/50/70 and EULAR responses) were compared with HRQOL outcomes. RESULTS: At 24 weeks, the rituximab 500 mg and 1000 mg groups both reported statistically significantly greater improvements on the SF-36 physical component summary (4.37 and 4.89 points higher, respectively, vs placebo; p < 0.001). SF-36 physical function, bodily pain, vitality, social function, and role-physical subscale scores also statistically significantly improved vs placebo. At 24 weeks, 62.6% and 67.2% of the rituximab 500 mg and 1000 mg groups, respectively, exceeded the MCID of 0.22 in HAQ (p < 0.001). For FACIT-Fatigue, 55.3% and 65.6% of patients exceeded the MCID of 3.5 points compared with 35.2% of placebo over 24 weeks (p < 0.001). ACR20/50/70 and EULAR responders demonstrated greater improvements in mean baseline to 24 week changes in SF-36 and FACIT-Fatigue scores compared with nonresponders (p < 0.05). CONCLUSION: Both rituximab doses in combination with methotrexate were effective in improving all HRQOL outcomes in patients with active RA consistent with clinical efficacy.

Fransen J, Antoni C, Mease PJ, Uter W, Kavanaugh A, Kalden JR, Van Riel PL. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, PO Box 9101, NL-6500HB Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #16644783 No free full text.

Abstract: BACKGROUND: In recent clinical trials in patients with psoriatic arthritis (PsA), the response criteria and disease activity measures that have been used were those developed for rheumatoid arthritis. However, these have not yet been validated in PsA. OBJECTIVE: To compare the responsiveness and discriminative capacity of the psoriatic arthritis response criteria (PsARC), American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria and the Disease Activity Score (DAS) and core-set measures in patients with PsA and peripheral arthritis, using the data from two randomised placebo-controlled trials of tumour necrosis factor inhibitors. METHODS: In an infliximab trial, 104 patients with active PsA were randomised to receive placebo or infliximab for 16 weeks. In an etanercept trial, 60 patients with active PsA were randomised to receive placebo or etanercept for 12 weeks. Data from baseline and the end of the intervention phase were used from each study. Responsiveness was assessed using the standardised response mean and effect size. Capacity to discriminate between the active drug and placebo was assessed using t values or a chi2 test. Measures were ranked in order of their t value or chi2 value. RESULTS: The EULAR criteria performed better in discriminating the active drug from placebo than the ACR20 improvement criteria, which in turn performed better than the PsARC. It was also found that the pooled indices (DAS and DAS28) were generally more responsive, and performed better in discriminating active drug from placebo, than the single core-set measures. CONCLUSION: Response criteria and pooled indices developed for rheumatoid arthritis are useful for the assessment of arthritis in PsA clinical trials.

Johnsen AK, Schiff MH, Mease PJ, Moreland LW, Maier AL, Coblyn JS, Helfgott SM, Leff JA, Weinblatt ME. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · J Rheumatol. · Pubmed #16482646 No free full text.

Abstract: OBJECTIVE: To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha (TNF-alpha) blocker-naäve active rheumatoid arthritis (RA). METHODS: Seventy-seven patients with RA were randomized in an unequal allocation (2:1) in a blinded fashion to receive either 50 mg (51 patients) or 25 mg (26 patients) of etanercept twice a week for 24 weeks. RESULTS: The primary outcome measure, the ACR-N AUC at 24 weeks, showed no difference between the 2 dose groups. In addition, there was no difference in ACR 20, 50, and 70 responses or in EULAR response criteria by Week 24. There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event. The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg etanercept compared with those receiving 25 mg (26% vs 4%, p = 0.027). CONCLUSION: Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the standard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients.

Gladman DD, Mease PJ, Healy P, Helliwell PS, Fitzgerald O, Cauli A, Lubrano E, Krueger GG, van der Heijde D, Veale DJ, Kavanaugh A, Nash P, Ritchlin C, Taylor W, Strand V. · The University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #17477479 No free full text.

Abstract: Psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis usually seronegative for rheumatoid factor, has emerged as a more common and severe disease than previously appreciated. The disease is multifaceted. Thus the assessment of PsA requires attention to peripheral joint involvement, axial disease, dactylitis, and enthesitis, as well as the skin manifestations. In addition, the assessment of patient reported features such as patient assessment of disease activity, pain, fatigue, quality of life, and the new concept of participation are important. The assessment of damage and the assessment of tissue histology are also important outcome measures. This article summarizes these features of PsA as well as current knowledge on the instruments available for the assessment of these domains.