Highlights on the American College of Rheumatology Meeting 2006

Transcription

1 Highlights on the American College of Rheumatology Meeting 2006 The ACR 2006 meeting was held in Washington DC, the capital of United States between November 11 and November 15. The weather was fine and the scientific sessions were well organized. The number of attendees reached a record high of 13,000. In addition to review course, workshops, clinical, scientific and abstract sessions, there was a new clinicopathological conference co-chaired by experts of different medical disciplines. As in previous years, the Hong Kong Society of Rheumatology supported junior trainees to attend the ACR meeting for education and training purpose. The first day of the ACR meeting began with a review lecture on B cell development and regulation by Dr. Jennifer Anolik and a State-of-the-Art lecture entitled "Interferon regulatory factor family transcription factors in inflammation and immunity" by Dr. Taniguchi of Japan. An exciting concurrent abstract session in the morning ensued. Data on the novel cytokine interleukin-32 were presented by Dr. Joosten. IL-32 is a proinflammatory cytokine that is mainly produced by activated monocytes and macrophages. It is induced by IFNγ, and in turn induces stimulation of TNF and IL-8 production via the activation of NF-kB and p38 MAP kinase, and maturation of IL-1β through a caspase-1-dependent mechanism. IL- 32 is strongly expressed in the rheumatoid synovium and is a potent inducer of joint inflammation which is TNF dependent. The 3-year data on the outcome of early RA patients participated in the BEST study were also presented by the Dutch investigators. Remission with discontinuation of all DMARDs occurred in 27% of patients originally treated with methotrexate and infliximab, whereas 53% of patients had discontinued infliximab (DAS remained 2.4). The PROMPT study revealed that in patients with anti-ccp positive undifferentiated arthritis, the use of methotrexate (as opposed to placebo) could prevent radiological disease progression. The clinicopathological conference in the afternoon presented a young woman who suffered from recurrent and severe intra-abdominal hemorrhage because of rupture of multiple visceral vascular aneurysms. The final diagnosis was the rare type IV Ehler Danlos syndrome. A concurrent session on clinical aspects of SLE consisted of six oral abstract presentations. The results of the Lupus Atherosclerosis Prevention Study (LAPS), which was a randomized double-blind placebo-controlled study on the efficacy of lipitor (40 mg/day) in SLE, were presented by Dr. Petri. After a follow-up of 2 years, no significant differences between the treatment and placebo groups in terms of progression of intimal media thickness (IMT), coronary calcium scores and markers of atherosclerosis such as hscrp and homocysteine could be demonstrated. The negative result could be attributed to the relatively short duration of follow-up. A review lecture on the positive and negative T-cell co-stimulatory pathways was presented by Dr. Sayegh of Boston on the third day of the meeting. Dr. Daniel Wallace presented the 76-week phase II multi-center randomized controlled trial of belimumab (Lymphostat B) in patients with active SLE. The FDA-approved outcome of improvement of SELENA- SLEDAI by 4 or more points, absence of BILAG A or B scores, as well as no deterioration in physicians' global scores was significantly more frequent in the treatment than placebo group. No differences in efficacy could be demonstrated among different doses used (1, 4 or 10 mg/kg). Adverse events were no more common with belimumab treatment than placebo. Another symposium on the management of the primary antiphospholipid antibody syndrome was conducted by Drs. Khamashta, Brey, Crowther and Lockshin. It remained controversial regarding the use of high dose versus standard dose warfarin in the treatment of arterial thrombosis in this syndrome. On the last day of the meeting, an interesting session on hepatotoxicity related to the TNF antagonists was presented. Postmarketing surveys indicated that hepatic function impairment occurred more frequently with infliximab than the other two TNF inhibitors. For patients with chronic hepatitis C infection, a randomized controlled study has demonstrated that etanercept on top of interferon-α2b and ribavirin was more effective than placebo in inducing a negative HCV RNA and was associated with fewer adverse events. For patients with chronic hepatitis B infection who are planned to receive anti- TNF therapy, preemptive therapy with lamivudine should be given. Close monitoring of liver function and the HBV DNA level is warranted and lamivudine should be continued as long as anti-tnf therapy is ongoing. There is evidence that emergence of viral resistance is not more frequent in patients receiving immunosuppressive treatment than those who are not. Dr. Chi-Chiu Mok 81

2 It's my great honor to be one of the attendees of this year's ACR/ARHP scientific meeting which was held in Washing DC, USA. Having a chance to attend the ACR review course and clinical symposium, I was enriched with a wide diversity of knowledge in rheumatology. The antiphospholipid antibody syndrome was one of the enlightened topics in the meeting. The Sapporo criteria were revised in early 2006 at a meeting in Sydney. Dr. Lockshin talked on the current recommendations of prevention of thrombosis in this syndrome. No treatment is required for asymptomatic antiphospholipid antibody positive patients. For those with venous and arterial thrombosis, the target INR for anticoagulation would be and 3.0 respectively. In the case of catastrophic antiphospholipid syndrome, anticoagulation, corticosteroid, intravenous immunoglobulin or plamapheresis might be necessary. Biologic therapy for rheumatic disease was also an important discussion topic in the meeting. The mechanisms of action and efficacy of the TNF-α inhibitors (infliximab, etanercept and adalimumab) were fully reviewed in the meeting. All showed promising results in the treatment of rheumatoid arthritis, with 50-60% patients achieving ACR 20, 30-40% achieving ACR50 and 15-20% achieving ACR70 responses, respectively. Novel non-tnf biologics have emerged, such as the CTLA4- Ig (abatacept) and anti-cd20 (Rituximab), for the treatment of different rheumatic diseases such as psoriasis, rheumatoid arthritis and SLE. The concern of biologic agents' related liver toxicity has been raised in a clinical symposium. The hepatotoxicity of the anti-tnf inhibitors was reviewed with data collected from the FDA drug safely database since Infliximab accounts for the largest proportion of patients having liver failure, when compared with etanercept and adalimumab, with the number of cases being 799, 402 and 72, respectively. Regarding the safety of the anti-tnfα agents in chronic hepatitis B carriers, there is an increasing incidence of viral reactivation in patients treated with anti-tnfα. Concerning preventive strategies, data are only available with lamivudine, either given as preemptive therapy or after HBV reactivation develops. Close monitoring of parenchymal liver enzymes (ALT) and HBV DNA levels with or without preemptive therapy with antiviral agents is the suggested approach in majority of cases. As for HCV infection, the effect of TNF blockade on chronic HCV infection is unknown and therefore there is still concern with the safety of the anti-tnfα in patients with chronic HCV infection. However, there is some evidence that etanercept may be beneficial in promoting viral RNA clearance in patients with chronic active hepatitis C who are also receiving interferon-α therapy and ribavirin. No consensuses have yet been made on the preventive strategies of reactivation of hepatitis C infection in users of the TNF antagonists. There was great debate concerning the effectiveness of glucosamine and chondroitin sulfate in osteoarthritis. Dr. Theodosakis pointed out that glucosamine is at least equally effective, but with better safety profile when compared with traditional NSAIDs. Chondroitin sulfate has been shown to reduce NSAID usage by 63-85% in patients with osteoarthritis. However, according to the GAIT trial, glucosamine and condroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis. Subgroup analysis of those patients with moderate to severe knee pain showed a benefit of combined glucosamine and chondroitin compared to placebo. As for interstitial lung disease in systemic sclerosis, there was evidence that patients with scleroderma lung disease treated with oral cyclophosphamide for 1 year, compared to placebo, showed improved dyspnoea, decrease in FVC (2.53%) and total lung capacity (4.09%), as well as significant improvement in the HAQ disability score, SF-36 vitality and health-transition domain, and skin thickness. Dr. Catherine Lai-Wa Kwok 82 Hong Kong Bulletin on Rheumatic Diseases

3 It is my pleasure to have a chance to attend the 70th ACR scientific meeting which was held in Washington DC from 11th to 15th November, In recent years, there has been growing interest in the contribution of B cells to immunopathogenesis of autoimmune disease especially rheumatoid arthritis and systemic lupus erythematosus. In the first immunology update session, B cells were discussed. Role of B cells in autoimmunity include the production of self-reactive antibodies, acting as an antigen presenting cell, secretion of inflammatory cytokines or chemokines, augmentation of T cell activation, inhibition of regulatory T cells and generation of ectopic lymphogenesis. Rituximab (a chimeric anti-cd20 monoclonal antibody), depletes selective subsets of B cells, resulting in decreased T cell activation and increase in regulatory T cells. B cell depletion therapy in systemic lupus erythematosus demonstrated that B cells are required for ongoing disease activity. The clinical response without a concomitant change in autoantibody titres supports an autoantibody-independent role of B cells. The variability in auto-antibody response and the kinetics of decrease in serologic responders suggest the existence of auto-reactive plasma cells of heterogeneous lifespan. Long term responses raise the possibility that tolerance can be reestablished, give rise to the postulation of B cell reconstitution. New criteria for the antiphospholipid syndrome were brought up. According to the Sydney revision of the Sapporo criteria for the antiphospholipid syndrome in 2006, the positivity of the antiphospholipid antibodies (including anticardiolipin IgG/M, anti-β2 glycoprotein 1 antibody and lupus anticoagulants) on 2 or more occasions has been changed to 12 weeks apart instead of 6 weeks. Concerning the treatment recommendation, there was no data supporting treatment use in asymptomatic bearers of antiphospholipid antibodies. Warfarin was recommended for both venous and arterial thrombosis. For recurrent thrombosis in antiphospholipid syndrome, long term warfarin is protective but the target INR is controversial. Latest discovered cytokine, IL-32, a new proinflammatory cytokine had been discussed. IL-32 is produced by several cell types (epithelial cells, NK cells, PBMC's). IL-1, IL-12, IL-18, IFN- and LPS are potent inducers of IL-32. IL-32 induces several pro-inflammatory cytokines, including TNF-α and IL-8. IL-32 is present in chronic inflammation and in inflammation in RA. It is highly expressed in rheumatoid arthritis synovial biopsies but not in osteoarthritis. IL-32 induces joint inflammation in mice and promotes cell influx. Its driven joint inflammation is TNF-α dependent, but induced cartilage is TNF-α independent. It acts in synergy with TLR / NOD ligands to induce joint inflammation and cartilage destructions. These data indicated that IL-32 may be a novel therapeutic target in autoimmune disease like rheumatoid arthritis. Two potential new therapies for gout are worth mentioning. Febuxostat, a selective xanthine oxidase inhibitor which is a non-purine analog, is administered orally and is metabolized in liver. A febuxostat 52-week phase III clinical trial (from NEJM 2005) comparing the efficacy of febuxostat (80 mg daily), febuxostat (120 mg daily) and allopurinol (300 mg daily) in the treatment of 762 patients with gouty arthritis. The proportions of patients with serum uric acid level lowered to <6 mg/dl were 75%, 80% and 38% respectively. This illustrated that febuxostat is a potential alternative to allopurinol. It reduced serum urate concentration, diminished flare frequency, reduced tophus size and its overall adverse events were similar to allopurinol. However, febuxostat did show a greater overall discontinuation rate mainly due to liver function abnormalities. Efficacy relative to allopurinol requires future clinical trials. The second new drug for gout is uricase. It is a urate oxidase which converts uric acid to a water soluable form (allantoin). Pegylated (PEG)-uricase, a purified recombinant porcine urate oxidase has undergone a phase II study. It led to substantial and sustained lowering of serum uric acid levels with greatest reduction was observed with the 8 mg every 2 week dose. Most common adverse event was gout flare which was around 5%. A 200-patient phase III multicenter randomized placebo-controlled trial of PEG-uricase is now underway. Dr. Catherine Ka-Yan Yuen 83

4 A plenary session of the ACR meeting ACR review course Dr. Mok presenting his oral abstract on the last day of the meeting 84 Hong Kong Bulletin on Rheumatic Diseases

5 Poster presentation Hong Kong delegates at the Washington DC conference center White House Washington DC 85