Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

BACKGROUND: Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS: We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. CONCLUSION: With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.

Belimumab for the treatment of recalcitrant cutaneous lupus.

Background Belimumab is a monoclonal antibody that reduces B lymphocyte survival by blocking the binding of soluble human B lymphocyte stimulator (BLyS) to its B cell receptors. The utility of belimumab for management of resistant systemic lupus erythematosus (SLE) skin manifestations has not been reported. We present our experience of using this novel molecule for the successful management of cutaneous lupus at our center. Methods We studied five patients with significant SLE skin manifestations. All patients met 1997 American College of Rheumatology (ACR) SLE criteria and had failed multiple medications to control their skin disease. SLE disease activity indexes (SLEDAI), Cutaneous LE disease Area and Severity Index (CLASI) and patient's global assessment (PGA) were recorded before and 16 weeks after belimumab treatment. Belimumab was added to concomitant standard therapy. Results All five patients demonstrated marked clinical improvement subsequent to belimumab treatment. The average time to clinical improvement after treatment initiation was 8-12 weeks. SLEDAI scores (median, range) improved in all the patients ((2, 2-6) to (0, 0-4); p = 0.025). PGA scores (median, range) were better in all patients ((3, 2-3) to (1, 0-1); p = 0.039). CLASI activity scores (median, range) improved dramatically in all patients ((17, 9-31) to (3, 2-14); p = 0.043). There was no worsening of the CLASI damage scores. The mean daily prednisone dose decreased significantly from 31 mg (±18.8) at baseline to 3 mg (± 2.7) ( p = 0.042). Conclusion In this case series, the addition of belimumab to standard therapy improved the signs and symptoms of refractory cutaneous lupus. This is one of the first reports highlighting the potential utility of this medication for the treatment of severe skin involvement in SLE refractory to conventional therapies. Additional studies need to be performed to assess the use of belimumab in the treatment of cutaneous lupus.

Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation.

Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils. Recent studies suggest that NETs play an active role in driving autoimmunity and tissue injury in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to investigate if celastrol, a triterpenoid compound, can inhibit NET formation induced by inflammatory stimuli associated with RA and SLE. We found that celastrol can completely inhibit neutrophil oxidative burst and NET formation induced by tumor necrosis factor alpha (TNFα) with an IC50 of 0.34 µM and by ovalbumin:anti-ovalbumin immune complexes (Ova IC) with an IC50 of 1.53 µM. Celastrol also completely inhibited neutrophil oxidative burst and NET formation induced by immunoglobulin G (IgG) purified from RA and SLE patient sera. Further investigating into the mechanisms, we found that celastrol treatment downregulated the activation of spleen tyrosine kinase (SYK) and the concomitant phosphorylation of mitogen-activated protein kinase kinase (MAPKK/MEK), extracellular-signal-regulated kinase (ERK), and NFκB inhibitor alpha (IκBα), as well as citrullination of histones. Our data reveals that celastrol potently inhibits neutrophil oxidative burst and NET formation induced by different inflammatory stimuli, possibly through downregulating the SYK-MEK-ERK-NFκB signaling cascade. These results suggest that celastrol may have therapeutic potentials for the treatment of inflammatory and autoimmune diseases involving neutrophils and NETs.

Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial.

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.

Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-cyclic citrullinated peptide antibody.

OBJECTIVE: To examine the association of treatment response and disease duration with changes in rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody levels among patients with rheumatoid arthritis (RA). METHODS: The study sample included 66 RA patients who completed double-blind, randomized clinical protocols and for whom baseline and followup serum samples were available. Anti-CCP and RF levels were measured using commercially available assay kits. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to describe the association of response and disease duration with declines in antibody levels. RESULTS: Patients had a mean +/- SD age of 49.9 +/- 12.0 years and were predominantly female (n = 51; 77%). The mean +/- SD duration between the times at which the baseline and followup serum samples were obtained was 13.7 +/- 8.6 months. Among the 64 subjects with positive antibody at baseline, 33 (52%) experienced a > or =25% reduction in the anti-CCP antibody level during the course of treatment, and 35 patients (55%) had a > or =25% reduction in RF. After adjustment for the baseline anti-CCP antibody level, only a shorter disease duration (< or =12 months) was significantly associated with a decline in the level of anti-CCP antibody (OR 3.0, 95% CI 1.0-8.8), and no association with treatment response was observed. Conversely, treatment response was the only significant determinant of a decrease in RF levels (OR 3.6, 95% CI 1.2-10.4). CONCLUSION: Shorter disease duration predicts greater declines in anti-CCP antibody levels with treatment in RA. Although treatment response is a robust determinant of a decrease in RF, it does not appear to be associated with declines in the anti-CCP antibody level.

Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine.

OBJECTIVE: To compare the efficacy of minocycline with that of a conventional disease-modifying antirheumatic drug (DMARD), hydroxychloroquine, in patients with early seropositive rheumatoid arthritis (RA). METHODS: Sixty patients with seropositive RA of <1 year's duration who had not been previously treated with DMARDs were randomized to receive minocycline, 100 mg twice per day, or hydroxychloroquine, 200 mg twice per day, in a 2-year, double-blind protocol. All patients also received low-dose prednisone. The primary end points of the study were 1) the percentage of patients with an American College of Rheumatology (ACR) 50% improvement (ACR50) response at 2 years, and 2) the dosage of prednisone at 2 years. RESULTS: Minocycline-treated patients were more likely to achieve an ACR50 response at 2 years compared with hydroxychloroquine-treated patients (60% compared with 33%, respectively; P = 0.04). Minocycline-treated patients were also receiving less prednisone at 2 years compared with the hydroxychloroquine group (mean 0.81 mg/day compared with 3.21 mg/day, respectively; P < 0.01). In addition, patients treated with minocycline were more likely to have been completely tapered off prednisone (P = 0.03). Trends favoring the minocycline treatment group were seen when outcomes were assessed according to components of the ACR core criteria set, with the differences reaching statistical significance for patient's global assessment of disease activity (P = 0.004). CONCLUSION: Minocycline is an effective DMARD in patients with early seropositive RA. Patients treated with minocycline were more likely to achieve an ACR50 response and did so while receiving less prednisone. In addition, minocycline-treated patients were more likely to have discontinued treatment with prednisone at 2 years.

Treatment of relapse after autologous blood stem cell transplantation for severe rheumatoid arthritis.

There is little information about the clinical course of patients with rheumatoid arthritis (RA) who relapse after autologous blood stem cell transplantation (ASCT). We describe 6 patients with severe RA who received ASCT in 3 US centers. Duration of followup was between 24 and 42 months posttransplant. Five patients achieved major responses but relapsed 3-22 months posttransplant. Two patients with relapse improved remarkably after restarting disease modifying antirheumatic drugs (DMARD). Two patients developed a mild RA flare at 3 and 5 months posttransplant and improved spontaneously. All 4 patients who improved after an initial disease flare remained highly functional at 14-22 months posttransplant. All patients in this study were anti-tumor necrosis factor (TNF) drug naive; all received a TNF blocker as a second line posttransplant salvage therapy, but only 3 responded. Future ASCT strategies need to focus on improving the durability of the early posttransplant responses.

Evaluating severity and status in rheumatoid arthritis.

There is general agreement regarding the most appropriate examinations and methods to use to evaluate change in status in randomized controlled trials (RCT). However, no guidelines exist to aid in determining and evaluating actual status rather than change in status, particularly when applied to individual patients with rheumatoid arthritis (RA). In addition, methods appropriate for clinical trials may not be useful in evaluating individual patients because of time constraints. This report reviews current methods of evaluation and develops modified methods, based on data bank research that will be useful in clinical practice and in the evaluation of RCT and observational studies. Using data from longitudinal observational data banks, further reduction in the number of joints examined is evaluated to reconcile the time constraints of clinical practice with the need to maintain reliability and validity. Percentile methods to determine severity status are applied to the variables used in RCT and extended further to observational studies and routine clinical practice. Shortened joint counts, based on modifications of the Ritchie method, are identified that allow for examination of groups of 18 (clinical-18) and 16 (clinical-16) joints, the clinical-16 omitting the metatarsophalangeal joints. Using percentile charts, actual severity valuations are given to the variables evaluated in the clinic as well as in RCT. Disease activity status of clinic patients can be determined quantitatively thus allowing clinicians further insight into the status and prognosis of their patients. By quantifying disease activity severity, clinicians and 3rd party payers can better evaluate the appropriateness of and response to disease modifying antirheumatic drugs and biologic therapies. Further, RCT can be evaluated as to severity status of patients participating, and the generalizability of RCT can be better evaluated.

Combinations of conventional disease-modifying antirheumatic drugs.

During the last decade, numerous new treatments and treatment approaches have literally transformed current thinking about rheumatoid arthritis (RA) and, more importantly, about the way patients are treated. The nearly universal acceptance of the use of combinations of disease-modifying antirheumatic drugs (DMARDs) to more effectively treat a growing percentage of patients with RA has been a central theme. Importantly, controlled studies have now shown many combinations to be well tolerated and significantly more effective than mono-DMARD therapy.

How is it best to treat early rheumatoid arthritis patients?

During the past decade, many important changes have occurred in the treatment of rheumatoid arthritis, perhaps the most important of which has been the realization that early diagnosis and early treatment are critical. This has challenged our health-care systems to make sure that patients with early arthritis have access to the appropriate physicians. Additionally, the last decade has also seen many new treatment options become available for patients with rheumatoid arthritis. These new options have included the use of old drugs more effectively; the use of combinations of two or more disease-modifying anti-rheumatic drugs; new evidence to support the use of steroids; the resurrection of tetracyclines; the introduction of leflunomide; and, finally, the tumour necrosis factor inhibitors etanercept and infliximab. The availability of all these new options is clearly excellent news for patients with RA and their physicians. It is hoped that we will, in the next few years, better understand how most effectively to utilize these treatment options for the optimal care of our patients.

Combination DMARD therapy with hydroxychloroquine, sulfasalazine, and methotrexate.

Triple combination therapy with hydroxychloroquine, sulfasalazine, and methotrexate (MTX) has been shown in double-blind, placebo-controlled studies to be significantly superior to MTX alone (Paulus 50% responses of 77% versus 33%). In long-term follow-up studies, this therapy has now been shown to be well-tolerated with continued efficacy in the majority of patients.

Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy.

The traditional "pyramid" or sequential approach to treatment of patients with rheumatoid arthritis involved use of a nonsteroidal anti-inflammatory drug for months to years while seeking to avoid use of second-line antirheumatic drugs until evidence of joint damage was seen. This approach led to short-term reduction of inflammation and a few remissions. However, long-term remissions were rare, and most patients experienced poor long-term outcomes, including joint destruction, severe functional declines, considerable economic losses, work disability, and premature mortality. At this time, a "preventive" strategy is evolving in which early aggressive treatment with disease-modifying antirheumatic drugs is used, seeking to minimize long-term joint damage. When residual inflammation remains after maximum doses of single agents, as is usually the case, combinations of disease-modifying antirheumatic drugs appear to be a reasonable consideration for many patients. Methotrexate is the most commonly used "anchor drug" in combination therapy. Evidence from randomized, controlled clinical trials and observational studies have indicated increased efficacy and acceptable (and often lower) toxicity for combinations of methotrexate plus cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, and infliximab. Further studies lasting 5 years or more are needed to determine the long-term effectiveness, toxicities, and optimal clinical use of disease-modifying antirheumatic drug combinations. At this time, such combinations are taken by at least some patients under care of almost all rheumatologists, and it appears likely that they will be used increasingly in the coming decades.

Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial.

OBJECTIVE: Rheumatoid arthritis (RA) causes substantial morbidity and mortality, and current treatments are suboptimal. Recent studies have demonstrated the short-term efficacy of minocycline in the treatment of patients with early RA. This study was undertaken to compare patients treated with conventional therapy in the early phase of their RA and those treated with minocycline, after 4 years of followup. METHODS: Forty-six patients with seropositive RA of <1 year's duration had been enrolled in a double-blind study of minocycline (100 mg twice daily) versus placebo. After the blinded portion of the study (3-6 months, depending upon response), all patients were treated with conventional therapy. This report compares those patients randomized to receive placebo for 3 months and then conventional therapy for the duration of 4 years versus those originally randomized to receive minocycline. RESULTS: Twenty of the 23 original minocycline-treated patients and 18 of the 23 original placebo-treated patients were available for followup (mean 4 years). At followup, RA was in remission (American College of Rheumatology criteria) without disease-modifying antirheumatic drug (DMARD) or steroid therapy in 8 of the patients originally treated with minocycline compared with 1 patient in the placebo group (P = 0.02). Ten patients in the minocycline group versus 16 in the original placebo group currently require DMARD therapy (P = 0.02). CONCLUSION: Among patients with seropositive RA, remissions are more frequent and the need for DMARD therapy is less in those treated early in the disease course with minocycline compared with those treated with conventional therapy delayed by an average of only 3 months. Minocycline appears to be an effective therapy for early RA; further investigation into its mechanism of action is needed.

Is there a role for antibiotics in the treatment of patients with rheumatoid arthritis?

Despite many advances in the understanding and treatment of rheumatoid arthritis, its pathophysiology remains incompletely understood. An infectious aetiology of rheumatoid arthritis has long been postulated but, even though many continue to believe that there is a 'triggering agent for rheumatoid arthritis', none has been identified. Currently, both sulfasalazine and minocycline have been shown to be effective treatments for rheumatoid arthritis and are being used increasingly. In the case of minocycline, it appears that its ability to inhibit metalloproteases is an important characteristic that may account for some or part of its action against rheumatoid arthritis. Whether the antibacterial effects of these drugs or others are important in the treatment of rheumatoid arthritis continues to be investigated.