Optimal responses in disease activity scores to treatment in rheumatoid arthritis: Is a DAS28 reduction of >1.2 sufficient?

BACKGROUND: The overall benefit of intensive treatment strategies in rheumatoid arthritis (RA) remains uncertain. We explored how reductions in disability and improvements in quality of life scores are affected by alternative assessments of reductions in disease activity scores for 28 joints (DAS28) in two trials of intensive treatment strategies in active RA. METHODS: One trial (CARDERA) studied 467 patients with early active RA receiving 24 months of methotrexate monotherapy or steroid and disease-modifying anti-rheumatic drug (DMARD) combinations. The other trial (TACIT) studied 205 patients with established active RA; they received 12 months of treatment with DMARD combinations or biologic agents. We compared changes in the health assessment questionnaire (HAQ) and Euroqol-5D (EQ5D) at trial endpoints in European League Against Rheumatism (EULAR) good and moderate EULAR responders in patients in whom complete endpoint data were available. RESULTS: In the CARDERA trial 98 patients (26 %) were good EULAR responders and 160 (32 %) were EULAR moderate responders; comparable data in TACIT were 66 (35 %) and 86 (46 %) patients. The magnitude of change in the HAQ and EQ5D was greater in both trials in EULAR good responders than in EULAR moderate responders. HAQ scores had a difference in of -0.49 (95 % CI -0.66, -0.32) in the CARDERA and -0.31 (95 % CI -0.47, -0.13) in the TACIT trial. With the EQ5D comparable differences were 0.12 (95 % CI 0.04, 0.19) and 0.15 (95 % CI 0.05, 0.25). Both exceeded minimum clinically important differences in HAQ and EQ5D scores. CONCLUSIONS: We conclude that achieving a good EULAR response with DMARDs and biologic agents in active RA results in substantially improved mean HAQ and EQ5D scores. Patients who achieve such responses should continue on treatment. However, continuing such treatment strategies is more challenging when only a moderate EULAR response is achieved. In these patients evidence of additional clinically important benefits in measures such as the HAQ should also be sought.

Role of spleen tyrosine kinase inhibitors in the management of rheumatoid arthritis.

Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase involved in signalling in many of the cells that drive immune inflammation. The development of small molecules that inhibit Syk kinase may change the way we treat disorders such as rheumatoid arthritis (RA), as well as a range of other inflammatory diseases. Fostamatinib (R-788) is an orally bioavailable small molecule. It is the prodrug of R406, which is a potent Syk inhibitor. Fostamatinib was developed because it has more favourable physiochemical properties. It is rapidly converted to R406 by intestinal enterocytes. It has been evaluated in experimental models of RA, such as collagen-induced arthritis. In these models, fostamatinib suppressed clinical arthritis, bone erosions, pannus formation and synovitis. A phase II programme with fostamatinib has largely been completed. Three key trials have been published, lasting 12-26 weeks and each enrolling 189-457 patients (875 in total). All these trials involved placebo therapy and patients continued to receive methotrexate in addition to active treatment with fostamatinib. The first dose-ranging trial evaluated three treatment doses in RA patients who had not fully responded to methotrexate therapy. The second trial compared two treatment doses in patients who had not responded to methotrexate therapy. The third trial compared a single treatment dose with placebo in patients who had not responded to biological therapy. The primary outcome measure was the number of patients achieving American College of Rheumatology (ACR) 20% (ACR20) responses. Placebo ACR20 response rates in all three trials were similar (35-38%). All three trials involved one treatment arm receiving fostamatinib 100 mg twice daily; ACR20 responses with this active treatment ranged from 38% to 67%. A meta-analysis of ACR responses in these trials, using responses to the highest dose in each trial for comparisons with placebo therapy in a random effects model, showed a borderline benefit with ACR20 responses. There were more significant differences with ACR50 and ACR70 responses. The reason that this meta-analysis was not more strongly positive is that the third trial, which evaluated patients who had failed to respond to biological treatments, gave negative results. Individual ACR response components, such as changes in swollen joint counts, showed significant differences in the first two trials, but there were no definite treatment benefits in the third trial. Overall, the differences were significant in a meta-analysis of all three trials. The most important adverse reactions were diarrhoea, neutropenia and raised ALT levels, which all showed significant excesses with active treatment compared with placebo. Too few patients have been studied for a definitive safety profile to be known. Overall, the results of the phase II trials were sufficiently encouraging for a phase III programme to be initiated. It will be some years before their definitive results are available.

Cost-effectiveness of combination nonbiologic disease-modifying antirheumatic drug strategies in patients with early rheumatoid arthritis.

OBJECTIVE: To compare the costs and benefits of alternative combination strategies of disease-modifying antirheumatic drugs (DMARD) and DMARD monotherapy in patients with early, active rheumatoid arthritis (RA). METHODS: Data were drawn from randomized controlled trials that compared DMARD monotherapy or any DMARD combination strategy, with or without combined steroid therapy. Mixed treatment comparison methods were used to estimate the relative effectiveness of the different strategies. A mathematical model was developed to compare the longterm costs and benefits of the alternative strategies, combining data from a variety of sources. Costs were considered from a health sector viewpoint and benefits were expressed in terms of quality-adjusted life-years (QALY). RESULTS: If decision makers use a threshold of £20,000 (US$29,000) per QALY, then the strategies most likely to be cost-effective are either DMARD combination therapy with downward titration (probability of being optimal = 0.50) or intensive, triple DMARD combination therapy (probability of being optimal = 0.43). The intensive DMARD strategy generated an additional cost of £27,392 per additional QALY gained compared to the downward titration strategy. Other combination strategies were unlikely to be considered cost-effective compared to DMARD monotherapy. Results were robust to a range of scenario sensitivity analyses. CONCLUSION: Combination DMARD therapy is likely to be cost-effective compared to DMARD monotherapy where treatment entails rapid downward dose titration or intensive, triple DMARD therapy.

Rheumatoid arthritis.

Rheumatoid arthritis is characterised by persistent synovitis, systemic inflammation, and autoantibodies (particularly to rheumatoid factor and citrullinated peptide). 50% of the risk for development of rheumatoid arthritis is attributable to genetic factors. Smoking is the main environmental risk. In industrialised countries, rheumatoid arthritis affects 0·5-1·0% of adults, with 5-50 per 100 000 new cases annually. The disorder is most typical in women and elderly people. Uncontrolled active rheumatoid arthritis causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Disease-modifying antirheumatic drugs (DMARDs), the key therapeutic agents, reduce synovitis and systemic inflammation and improve function. The leading DMARD is methotrexate, which can be combined with other drugs of this type. Biological agents are used when arthritis is uncontrolled or toxic effects arise with DMARDs. Tumour necrosis factor inhibitors were the first biological agents, followed by abatacept, rituximab, and tocilizumab. Infections and high costs restrict prescription of biological agents. Long-term remission induced by intensive, short-term treatment selected by biomarker profiles is the ultimate goal.