Rheumatoid Arthritis: Arkfeld DG

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.

Metyas SK, Tadros RM, Arkfeld DG. · Department of Medicine-Rheumatology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. · Rheumatol Int. · Pubmed #18762943 No free full text.

Abstract: Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration, primarily of the lungs and lymphatic system. While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed, the more widely used infliximab has demonstrated clear efficacy in this disease. The association between tumor necrosis factor (TNF)-inhibitors and noncaseating granulomas in the lung has been reported in literature. With the exception of one patient treated with adalimumab, who developed pulmonary granuloma, the remaining patients described in literature were treated with etanercept. The current case study is, to our knowledge, the first to describe adalimumab-induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although TNF-inhibitors are used in the treatment of granulomatous disorders, their use should be carefully monitored as, in rare cases, TNF-inhibitors may leave sufficient cytokine activation to support granuloma formation.

Arkfeld DG. · Division of Rheumatology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. · Rheumatol Int. · Pubmed #17957371 links to  free full text

Abstract: Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs-rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20-was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren's syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still's disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders.

Oliveira B, Arkfeld DG, Weitz IC, Shinada S, Ehresmann G. · Division of Rheumatology, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA. · J Clin Rheumatol. · Pubmed #17414538 No free full text.

Abstract: Acquired factor VIII deficiency due to antibody inhibition can result in life-threatening hemorrhage. Rarely such antibody inhibition of factor VIII can be associated with other autoimmune disorders including rheumatoid arthritis. We present the first case of a patient with active rheumatoid arthritis and refractory bleeding diatheses due to a factor VIII inhibitor who was successfully treated with rituximab. A 61-year-old Caucasian female with rheumatoid arthritis unresponsive to multiple therapies developed an acute hematoma while having a peripheral catheter placed. Her aPTT was prolonged at 61.4 with low factor VIII activity and an inhibitor level for factor VIII of 2.0 Bethesda Units. She received rituximab 375 mg/m in 4 weekly doses. Normalization of the aPTT and resolution of the bleeding occurred in 2 weeks. After 45 days, the levels of factor VIII inhibitor and factor VIII activity were <0.4 BU/mL and 130%, respectively. After 1 year, the aPTT remained normal and there was no further bleeding. An added benefit was the substantial improvement in her rheumatoid arthritis.Treatment of acquired factor VIII inhibitors in rheumatoid arthritis should be guided by the levels of the inhibitor. Patients with low levels of the inhibitor may respond to rituximab monotherapy, whereas higher levels may necessitate combination therapies. The dual benefit of RA disease control and resolution of bleeding makes rituximab therapy compelling in the rare patient who presents with these 2 disorders.

Oh J, Arkfeld DG, Horwitz DA. · Division of Rheumatology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90032, USA. · J Rheumatol. · Pubmed #15801037 No free full text.

Abstract: In addition to its well known proinflammatory effects, tumor necrosis factor-alpha (TNF-a) has complex effects on the growth, differentiation, and death of immune cells. TNF antagonists have had dramatic effects on the suppression of rheumatoid arthritis and other rheumatic inflammatory diseases. However, TNF inhibition of RA has led to an increased incidence of drug induced anti-dsDNA production, with cases of systemic lupus erythematosus as well as exacerbations of multiple sclerosis. While etanercept does not generally alter the course of Crohn's disease we describe a rare instance where this agent may have contributed to the development of clinically significant inflammatory bowel disease.

Tan SM, Xu D, Roschke V, Perry JW, Arkfeld DG, Ehresmann GR, Migone TS, Hilbert DM, Stohl W. · Los Angeles County + University of Southern California Medical Center, 90033, USA. · Arthritis Rheum. · Pubmed #12687540 links to  free full text

Abstract: OBJECTIVE: To determine whether synovial fluid (SF) levels and cell-surface expression of B lymphocyte stimulator (BLyS) protein and SF levels of APRIL are elevated in patients with inflammatory arthritis (IA). METHODS: Same-day blood and SF samples from 89 patients with 103 knee effusions (81 knees with IA and 22 with noninflammatory arthritis [NIA]) were evaluated for BLyS protein and APRIL levels by enzyme-linked immunosorbent assay. Blood and SF mononuclear cells were double-stained for surface BLyS protein and surface CD14 (monocyte marker) and were analyzed by flow cytometry. Complete blood cell counts and SF nucleated cell counts were performed by the clinical hematology laboratory. RESULTS: BLyS protein levels were higher in SF than in corresponding serum samples from both IA and NIA patients. SF BLyS protein levels, but not surface expression of BLyS protein, were disproportionately elevated in IA patients. APRIL levels were higher in SF than in corresponding serum samples from most IA patients but not NIA patients. SF BLyS protein and APRIL levels correlated with each other, and each correlated with SF monocyte, lymphocyte, neutrophil, and total nucleated cell counts. Although SF and serum BLyS protein levels correlated with each other, SF and serum APRIL levels did not, suggesting that SF BLyS protein levels are more dependent upon systemic factors than are SF APRIL levels. Moreover, in 8 patients who underwent sequential arthrocenteses, changes in SF BLyS protein levels did not immutably parallel changes in SF APRIL levels, indicating their differential regulation. CONCLUSION: BLyS protein and APRIL are locally produced in inflamed joints. Their respective SF levels are differentially regulated, suggesting that they serve different functions. Together, their local production may foster survival and/or expansion of B cells that produce pathogenic autoantibodies and/or promote local T cell activation and consequent joint destruction.

Arkfeld DG. · No affiliation provided · Ann Intern Med. · Pubmed #18316759 links to  free full text

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Metyas S, La D, Arkfeld DG. · No affiliation provided · Ann Rheum Dis. · Pubmed #17934084 No free full text.

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Rubenstein EJ, Arkfeld DG. · No affiliation provided · J Am Geriatr Soc. · Pubmed #15571562 No free full text.

This publication has no abstract.