Rheumatoid Arthritis: Block JA

Manadan AM, Block JA. · Section of Rheumatology, John H. Stroger Hospital of Cook County, Chicago, IL, USA. · Am J Ther. · Pubmed #18223354 No free full text.

Abstract: Significant advances have been made in the treatment of rheumatoid arthritis (RA). For instance, novel biologic therapeutics capable of blocking tumor necrosis factor-alpha (TNF-alpha) have improved outcomes for RA patients. New therapeutic agents directed at antagonizing two previously untargeted pathways have recently been approved by the U.S. Food and Drug Administration for RA patients who have had inadequate responses to anti-TNF therapy or who have failed to maintain an adequate clinical response. We review the data supporting the use of these agents, rituximab and abatacept.

Manadan AM, James N, Block JA. · Hospital of Cook County and Rush University Medical Center, Chicago, Illinois, USA. · Curr Opin Rheumatol. · Pubmed #17414952 No free full text.

Abstract: PURPOSE OF REVIEW: Tumor necrosis factor alpha antagonists are effective for signs and symptoms of ankylosing spondylitis. Recent studies have evaluated the efficacy of these agents for structural disease modification. We critically review recent radiographic data suggesting that tumor necrosis factor alpha inhibition may have structure-modifying effects in ankylosing spondylitis, and may thereby alter the disease course. RECENT FINDINGS: Recent studies employing MRI suggest that therapy with tumor necrosis factor alpha antagonists significantly reduces spinal inflammation in active ankylosing spondylitis when compared to placebo; there was no comparable improvement in the severity of chronic stigmata, such as syndesmyophytes and vertebral bridging. These studies were of relatively short duration and small size. SUMMARY: Despite insufficient evidence to conclude definitively that tumor necrosis factor alpha-antagonist therapy provides durable and effective structure modification in ankylosing spondylitis, the data strongly suggest a benefit, at least in the short term. In the future, MRI data coupled with clinical outcomes in larger cohorts followed for longer durations may result in a paradigm shift for ankylosing spondylitis treatment similar to that undergone for rheumatoid arthritis, where patients with ankylosing spondylitis are offered therapy early in the disease course to arrest and prevent structural disease progression.

Furst DE, Saag K, Fleischmann MR, Sherrer Y, Block JA, Schnitzer T, Rutstein J, Baldassare A, Kaine J, Calabrese L, Dietz F, Sack M, Senter RG, Wiesenhutter C, Schiff M, Stein CM, Satoi Y, Matsumoto A, Caldwell J, Harris RE, Moreland LW, Hurd E, Yocum D, Stamler DA. · University of California at Los Angeles Medical School, CA 90024, USA. · Arthritis Rheum. · Pubmed #12209503 links to  free full text

Abstract: OBJECTIVE: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA). METHODS: This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes. RESULTS: ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups. CONCLUSION: Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.

Felson DT, LaValley MP, Baldassare AR, Block JA, Caldwell JR, Cannon GW, Deal C, Evans S, Fleischmann R, Gendreau RM, Harris ER, Matteson EL, Roth SH, Schumacher HR, Weisman MH, Furst DE. · Boston University School of Medicine, Massachusetts, USA. · Arthritis Rheum. · Pubmed #10524687 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of the Prosorba column as a treatment for rheumatoid arthritis (RA) in patients with active and treatment-resistant (refractory) disease. METHODS: A sham-controlled, randomized, double-blind, multicenter trial of Prosorba versus sham apheresis was performed in patients with RA who had failed to respond to treatment with methotrexate or at least 2 other second-line drugs. Patients received 12 weekly treatments with Prosorba or sham apheresis, with efficacy evaluated 7-8 weeks after treatment ended. Patients were characterized as responders if they experienced improvement according to the American College of Rheumatology (ACR) response criteria at the efficacy time point. A data safety monitoring board (DSMB) evaluated interim analyses for the possibility of early completion of the trial. RESULTS: Patients in the trial had RA for an average of 15.5 years (range 1.7-50.6) and had failed an average of 4.2 second-line drug treatments prior to entry. After the completion of treatment of 91 randomized patients, the DSMB stopped the trial early due to successful outcomes. Of the 47 patients in the Prosorba arm, 31.9% experienced ACR-defined improvement versus 11.4% of the 44 patients in the sham-treated arm (P = 0.019 after adjustment for interim analysis). When results from 8 additional patients, who had completed blinded treatments at the time of DSMB action, were added to the analysis (n = 99), results were unchanged. The most common adverse events were a short-term flare in joint pain and swelling following treatment, a side effect that occurred in most subjects at least once in both treatment arms. Other side effects, although common, occurred equally as frequently in both treatment groups. CONCLUSION: Apheresis with the Prosorba column is an efficacious treatment for RA in patients with active disease who have failed other treatments.

Aggarwal R, Manadan AM, Poliyedath A, Sequeira W, Block JA. · Department of Rheumatology, Rush University Medical Center, Chicago, IL 60612, USA. · J Rheumatol. · Pubmed #19332623 No free full text.

Abstract: OBJECTIVE: The magnitude of the risk of reactivation of tuberculosis (TB) on use of etanercept, especially in patients with positive purified protein derivative (PPD) test, has not been assessed. We evaluated the risk of developing active TB among PPD-positive patients treated with etanercept. METHODS: All patients with a positive PPD test, as defined by American Thoracic Society guidelines, who received etanercept at Cook County Hospital from 2001 to 2008 were retrospectively reviewed. The primary endpoint was the development of active TB either while receiving or after completing etanercept therapy. RESULTS: Four hundred eighty-seven patients received etanercept, of whom 84 were PPD-positive and constituted the primary cohort. The cohort was composed largely of patients who were at high risk for development of active TB: born in endemic area (80%), ethnic/racial minorities (51 Hispanic, 16 African American, and 8 Asian), and low socioeconomic status (66, 78.57%). Overall etanercept exposure was a mean of 24.6 months (range 3 to 60 mo), with 196 patient-years of etanercept exposure in PPD-positive individuals. Indications for etanercept use included rheumatoid arthritis 58 (69%), ankylosing spondylitis 11 (13%), psoriatic arthritis 13 (15.5%), juvenile inflammatory arthritis 1 (1.2%), and vasculitis 1 (1.2%). Of the 80 subjects, 74 received treatment for latent TB infection (LTBI) prior to initiating etanercept. A comprehensive review of these patients' medical records failed to reveal any active TB infection. CONCLUSION: This systematic analysis suggests that the risk of reactivation of LTBI during etanercept therapy is low in appropriately treated individuals.

Chubinskaya S, Frank BS, Michalska M, Kumar B, Merrihew CA, Thonar EJ, Lenz ME, Otten L, Rueger DC, Block JA. · Department of Biochemistry, Rush University Medical Center, Chicago, Illinois, USA. · Arthritis Res Ther. · Pubmed #16646979 links to  free full text

Abstract: The measurement of body fluid levels of biochemical markers in joint tissues has begun to provide clinically useful information. Synovial fluid (SF) plays an important role in articular joint lubrication, nutrition, and metabolism of cartilage and other connective tissues within the joint. The purpose of our study was to identify and characterize osteogenic protein 1 (OP-1) in SF from patients with rheumatoid arthritis (RA) or with osteoarthritis (OA) and to correlate levels of OP-1 with those of hyaluronan (HA) and antigenic keratan sulfate (AgKS). SF was aspirated from the knees of patients with either RA or OA and from the knees of asymptomatic organ donors with no documented history of joint disease. The presence of detectable OP-1 in SF was demonstrated by western blots with specific anti-pro-OP-1 and anti-mature OP-1 antibodies. Measurement of levels of OP-1, HA and AgKS was performed using ELISAs. OP-1 was identified in human SF in two forms, pro-OP-1 and active (mature) OP-1--mature OP-1 being detected only in SF from OA patients and RA patients. Levels of OP-1 and HA were higher in RA patients than in OA patients and asymptomatic donors, while the level of AgKS was highest in SF from asymptomatic donors. Statistically significant differences were found between SF levels of OP-1 in RA and OA patients and between SF levels of AgKS among the three groups tested. The SF content of OP-1 tended to correlate positively with HA levels, but negatively with AgKS concentrations. In conclusion, the results of this study suggest that measurement of OP-1 in joint fluid may have value in the clinical evaluation of joint disease processes.

Mohan AK, Coté TR, Block JA, Manadan AM, Siegel JN, Braun MM. · Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, Rockville, Maryland, USA. · Clin Infect Dis. · Pubmed #15306993 No free full text.

Abstract: Infliximab, a tumor necrosis factor (TNF) antagonist, is associated with tuberculosis (TB), but it is unknown whether this phenomenon is true of all TNF antagonists. We reviewed 25 cases of TB due to another TNF antagonist, etanercept, that were reported to the US Food and Drug Administration (FDA) between November 1998 and March 2002. Such cases are sometimes incomplete and are subject to underreporting. Fifteen patients received other immunosuppressive medications. The median interval between the receipt of the first dose of etanercept and the diagnosis of TB was 11.5 months. Thirteen patients had extrapulmonary TB at the time of diagnosis. Diagnosis was made on the basis of culture results for 12 patients, biopsy findings for 9, and sputum staining for 4. There were 2 deaths, 1 of which was directly attributed to TB. The estimated number of TB cases reported to the FDA for each person-year of treatment with etanercept (i.e., the "reporting rate") among patients with rheumatoid arthritis (RA) was ~10 cases/100,000 patient-years of exposure. Clinicians considering etanercept for patients with RA should be alert to the possibility of the occurrence of TB, sometimes with an unusual extrapulmonary presentation. It is unclear whether etanercept therapy increases the risk of TB beyond the elevated TB rates already documented for patients with RA.

Shakoor N, Block JA, Shott S, Case JP. · Section of Reumatology, Rush Medical College, Chicago, Illinois 60612, USA. · Arthritis Rheum. · Pubmed #12483722 links to  free full text

Abstract: OBJECTIVE: Patients with unilateral hip or knee replacements for end-stage osteoarthritis (OA) are at high risk for future progression of OA in other joints of the lower extremities, often requiring additional joint replacements. Although the risks of future surgery in the contralateral cognate joints (i.e., contralateral hip replacement after an initial hip replacement) have been evaluated, the evolution of end-stage hip OA to OA involving the knee joints, and vice versa (i.e., noncognate progression) has not been investigated. Because characterization of OA progression in noncognate joints may shed light on the pathogenesis of multijoint OA, we investigated the pattern of evolution of end-stage lower extremity OA in a large, clinical cohort. METHODS: Total joint replacement (TJR) was selected as a marker of end-stage OA, and a database comprising all lower extremity TJRs performed at a large referral center between 1981 and 2001 was accessed. Of the 5,894 patients identified, 486 patients with idiopathic OA who underwent hip replacement and 414 who underwent initial knee replacement were analyzed to determine the relative likelihood of subsequent TJRs. Patients with the systemic inflammatory arthropathy, rheumatoid arthritis (RA), were evaluated as a control population because RA progression is not considered to be a primarily mechanically mediated process. RESULTS: The contralateral cognate joint was the most common second joint to undergo replacement in both the OA and the RA groups. However, in OA patients for whom the second TJR was in a noncognate joint, that joint was >2-fold more likely to be on the contralateral limb than on the ipsilateral limb (hip to knee P < 0.001; knee to hip P = 0.013). In contrast, among the RA cohort, the evolution was random and no laterality for noncognate TJR was observed at either the hip or the knee (P = 0.782). CONCLUSION: This characterization of end-stage lower extremity OA demonstrates that the disease evolves nonrandomly; after 1 joint is replaced, the contralateral limb is significantly more likely to show progression of OA than is the ipsilateral limb. Thus, OA in 1 weight-bearing joint appears to influence the evolution of OA in other joints. The absence of such laterality in RA suggests that OA progression may be mediated by extrinsic factors such as altered joint loading.

Manadan AM, Block JA, Sequeira W. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #12942713 No free full text.

This publication has no abstract.

Shakoor N, Michalska M, Harris CA, Block JA. · No affiliation provided · Lancet. · Pubmed #11867114 No free full text.

Abstract: Specific antagonists of tumour necrosis factor (TNF)-alpha have rapidly gained popularity for the treatment of rheumatoid arthritis. The monoclonal antibody against TNF-alpha, infliximab, has been associated with induction of systemic lupus erythematosus (SLE); however, there have been no published reports of drug-induced SLE associated with the soluble TNF-alpha receptor etanercept. We describe four female patients who developed signs and symptoms of SLE during treatment with etanercept; in two SLE was unambiguous. On diagnosis of SLE, etanercept was discontinued and the SLE-related symptoms promptly resolved. Etanercept should be considered in the list of agents associated with drug-induced SLE.