Petros P. Sfikakis

EULAR recommendations for the management of Behçet disease

Objectives: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion. Methods: The multidisciplinary expert committee, a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), consisted of nine rheumatologists (one who was also a clinical epidemiologist and one also a Rehabilitation Medicine doctor), three ophthalmologists, one internist, one dermatologist and one neurologist, representing six European countries plus Tunisia and Korea. A patient representative was also present. Problem areas and related keywords for systematic literature research were identified. Systematic literature research was performed using Medline and the Cochrane Library databases from 1966 through to December 2006. A total of 40 initial statements were generated based on the systematic literature research. These yielded the final recommendations developed from two blind Delphi rounds of voting. Results: Nine recommendations were developed for the management of different aspects of BD. The strength of each recommendation was determined by the level of evidence and the experts’ opinions. The level of agreement for each recommendation was determined using a visual analogue scale for the whole committee and for each individual aspect by the subgroups, who consider themselves experts in that field of BD. There was excellent concordance between the level of agreement of the whole group and the “experts in the field”. Conclusion: Recommendations related to the eye, skin–mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.

Effect of infliximab on sight-threatening panuveitis in Behçet's disease

Permanent loss of vision resulting from relapsing ocular inflammation occurs frequently in patients with Behçets disease, despite intensive, chronic immunosuppressive therapy. Since tumour necrosis factor (TNF) might have an important pathogenetic role in Behçets disease, we decided to give a single infusion of infliximab-a monoclonal antibody against TNF-to five patients with relapsing panuveitis, at the immediate onset of last relapse. Remission of ocular inflammation was evident within the first 24 h, and complete suppression was seen 7 days after treatment in all patients. No side-effects were noted. We suggest that infliximab is a rapid and effective new therapy for sight-threatening ocular inflammation in Behçets disease.

Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients.

OBJECTIVE Off-label use of anti-tumor necrosis factor (TNF) agents for Behçets disease (BD) is increasing. We evaluated published data on their efficacy and safety for patients with unmet medical needs due to severe disease manifestations, including ocular, gastrointestinal, and central nervous system involvement. METHODS Peer-reviewed articles on anti-TNF agents for BD appearing in Medline/PubMed through March 2010 were identified using the appropriate indexing terms. RESULTS We found 88, 12, and 13 primary articles from 20 countries on infliximab, etanercept, and adalimumab, reporting on 325, 37, and 28 patients, respectively. All patients were inadequately controlled with, or intolerant to, other immunosuppressive regimens, including interferon; 20 patients received more than 1 anti-TNF agent. In the only randomized placebo-controlled trial, 4-week administration of etanercept was effective in suppressing most of the mucocutaneous manifestations. In 16 open prospective studies evaluating the effect of repetitive infliximab injections (174 patients in total, men:women = 3:1, median follow-up = 16.2 months), sustained organ-specific, clinical responses were evident in 90%, 89%, 100%, and 91% of patients with resistant mucocutaneous, ocular, gastrointestinal, and central nervous system involvement, respectively. Combination of infliximab with azathioprine and/or cyclosporine-A appeared superior to monotherapy for sustained ocular remission. However, due to the fact that necessary data were lacking, formal estimation of anti-TNF treatment effect on the disease activity indexes for different organ involvement was not possible. CONCLUSIONS Although more controlled data are needed, there is enough published experience to suggest that TNF blockade represents an important therapeutic advancement for patients with severe and resistant, or intolerant, to standard immunosuppressive regimens BD.

The First Decade of Biologic TNF Antagonists in Clinical Practice: Lessons Learned, Unresolved Issues and Future Directions

Results from clinical trials of biologic anti-TNF drugs performed in the late 1990s confirmed the biological relevance of TNF function in the pathogenesis of chronic noninfectious inflammation of joints, skin and gut, which collectively affects 2-3% of the population. Up to April 2009, more than two million patients worldwide have received the first marketed drugs, namely the monoclonal anti-TNF antibodies infliximab and adalimumab and the soluble TNF receptor etanercept. All three are equally effective in rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, but, for not clearly defined reasons, only the monoclonal antibodies are effective in inflammatory bowel disease. About 60% of patients who do not benefit from standard nonbiologic treatments for these diseases respond to TNF antagonists. Less than half of responding patients achieve complete remission of disease. Importantly, some of those patients with rheumatoid arthritis in whom long-term anti-TNF therapy induced disease remission remain disease-free after discontinuation of any kind of treatment. There are not yet reliable predictors of which patients will or will not respond on anti-TNF therapy, whereas subsequent loss of an initial clinical response occurs frequently. The spectrum of efficacy anti-TNF therapies widens to include diseases such as systemic vasculitis and sight-threatening uveitis. While paradoxical new adverse effects are recognized, i.e. exacerbation or development of new onset psoriasis, reactivation of latent tuberculosis remains the most important safety issue of anti-TNF therapies. Clinical practice guidelines and consensus statements on the criteria of introduction, duration of treatment and cessation of TNF antagonists, including safety issues, are under constant revision as data from longer periods of patient exposure accumulate. It is hoped that more efficacious drugs that will ideally target the deleterious proinflammatory properties of TNF without compromising its protective role in host defense and (auto)immunity will be available in the near future.

Behçet’s disease: a new target for anti-tumour necrosis factor treatment

Behçet’s disease is a multisystemic, chronic relapsing inflammatory disease classified among the vasculitides. Recurrent mucocutaneous lesions may be the only symptoms in mild cases, but articular, ocular, vascular, and/or gastrointestinal and central nervous system involvement may occur in most of the patients. Ocular disease is the most frequent cause of morbidity leading to blindness in 25% of those affected. The various non-specific immunosuppressive drugs, used either alone or in combinations, frequently fail to control inflammation or maintain remissions. The aetiology of Behçet’s disease is unknown, however it is currently thought that a central pathogenetic role of tumour necrosis factor (TNF) in the inflammatory process is possible. Until June 2002, and according to published and anecdotal data, more than 80 patients from 10 different countries have received anti-TNF treatment. The short-term effects of the anti-TNF monoclonal antibody infliximab have been reported in several case reports and small case series, whereas the effects of etanercept have been presented in recent conferences. Preliminary results strongly suggest that infliximab is remarkably effective in inducing short-term remission of almost all manifestations of the disease, including acute, sight threatening panuveitis. A double blind, placebo controlled, one month study on the efficacy of etanercept in suppressing the mucocutaneous manifestations of the disease showed beneficial results. To date, significant side effects have not been reported. It seems that TNF block is an effective new treatment for patients with Behçet’s disease. Whether such treatment is superior to the conventional therapeutic approaches in preventing relapses and progression of the disease remains to be determined by carefully controlled studies. At least three open, long term studies, including larger numbers of patients are currently being conducted.

The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine a reappraisal

PURPOSE To define the risk of hydroxychloroquine (HCQ)-related retinal toxicity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who are receiving recommended dosages of the drug (< or =6.5 mg/kg/day). DESIGN Prospective cohort study, from 1985 to 2000. PARTICIPANTS Greek patients with RA (n = 335) and SLE (n = 191) treated with HCQ, 400 of whom had completed at least 6 years of treatment. METHODS Ophthalmologic evaluation was performed every 6 months from 1985 to 1995, and yearly thereafter. This consisted of best-corrected visual acuity, color vision testing, static central visual field testing, fundoscopy, electroretinography, and fluorescein angiography, when indicated. MAIN OUTCOME MEASURES Fundus lesions attributed to HCQ. RESULTS No HCQ retinal toxicity was noted in any of the 526 patients during the first 6 years of treatment. Two (3.4%) of the first 58 long-term (>6 years) treated patients developed HCQ-related maculopathy at 8 and 6.5 years of treatment, despite regular ophthalmologic evaluation. On follow-up 7 and 9 years after cessation of HCQ treatment, both patients had stable eye disease. No HCQ retinal toxicity was observed in the subsequent 342 patients who were treated for >6 years. Overall, the incidence of HCQ-related retinopathy in 400 patients who were treated with recommended dosages of the drug for a mean of 8.7 years was reduced to 0.5%. CONCLUSIONS After a baseline ophthalmic examination to confirm the absence of preexisting fundus pathology, patients with normal renal function may receive HCQ at a maximal daily dosage of 6.5 mg/kg and continue safely for 6 years. However, annual screening is recommended in patients who have taken the drug, even in recommended doses, for >6 years.

Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future.

Purpose of reviewTo discuss the clinical effects and the immunologic consequences of transient B-cell depletion using the anti-CD20 monoclonal antibody rituximab in systemic lupus erythematosus. Recent findingsA total of 100 rituximab-treated patients with severe disease, refractory to major immunosuppressive treatment, have been reported so far. Within a median follow-up period of 12 months rituximab was well tolerated, which is compatible with the experience accumulated from its use in more than 500 000 lymphoma patients. About 80% of patients achieved marked and rapid reductions in global disease activity. Because of the clinical heterogeneity, dosing differences, and concomitant treatments, including cyclophosphamide in 35% of patients, a proper evaluation of the clinical efficacy or rituximab is difficult. Variable degrees of clinical benefit have been reported for all clinical systemic lupus erythematosus manifestations, including active proliferative nephritis. Whereas 4-weekly infusions of 375 mg/m2 of rituximab result in complete B-cell depletion lasting most often from 3 to 8 months, a prolonged depletion does not always correlate with a more favorable clinical response. Total immunoglobulin levels and protective antibodies are preserved, but anti-dsDNA antibody titers decrease, often independently of the clinical response. SummaryThe findings reviewed point to a growing optimism for targeting B cells in the treatment of systemic lupus erythematosus; therefore double-blind studies comparing rituximab with existing immunosuppressive therapies are needed. Moreover, careful assessments of the effects of transient B-cell depletion on distinct autoimmune pathogenetic processes will enable optimization of therapeutic single or combined therapeutic schemes.

Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease

Objectives: To present and analyse the literature sources regarding the management of Behçet disease (BD) identified during the systematic literature research, which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for the management of BD. Methods: Problem areas and related keywords regarding the management of BD were determined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A systematic literature research was performed using MedLine and Cochrane Library resources through to December 2006. Meta-analyses, systematic reviews, randomised controlled trials (RCTs), open studies, observational studies, case control studies and case series’ involving ⩾5 patients were included. For each intervention the effect size and number needed to treat were calculated for efficacy. Odds ratios and numbers needed to harm were calculated for safety issues of different treatment modalities where possible. Results: The literature research yielded 137 articles that met the inclusion criteria; 20 of these were RCTs. There was good evidence supporting the use of azathioprine and ciclosporin A in eye involvement and interferon (IFN)α in mucocutaneous involvement. There were no RCTs with IFNα or tumour necrosis factor (TNF)α antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking. Conclusion: Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.

Atherosclerosis in Rheumatoid Arthritis Versus Diabetes: A Comparative Study

Objective—The extent to which atherosclerosis is accelerated in chronic inflammatory diseases is not established. We compared preclinical atherosclerosis in rheumatoid arthritis with diabetes mellitus, a known coronary heart disease equivalent. Methods and Results—Endothelial function, arterial stiffness, carotid intima-media thickness, and analysis of atheromatous plaques were examined in 84 rheumatoid arthritis patients without cardiovascular disease versus healthy controls matched for age, sex, and traditional cardiovascular disease risk factors, as well as in 48 diabetes patients matched for age, sex, and disease duration with 48 rheumatoid arthritis patients. Rheumatoid arthritis duration associated with arterial stiffening, whereas disease activity associated with carotid plaque vulnerability. All markers of preclinical atherosclerosis were significantly worse in rheumatoid arthritis compared to controls, whereas they did not differ in comparison to diabetes despite a worse cardiovascular risk factor profile in diabetics. Both diseases were associated independently with increased intima-media thickness; rheumatoid arthritis, but not diabetes, was independently associated with endothelial dysfunction. Conclusions—Preclinical atherosclerosis appears to be of equal frequency and severity in rheumatoid arthritis and diabetes of similar duration with differential impact of traditional risk factors and systemic inflammation. Cardiovascular disease risk factors in rheumatoid arthritis may need to be targeted as aggressively as in diabetes.

Cutaneous side effects of anti–tumor necrosis factor biologic therapy: A clinical review

BACKGROUND Anti-tumor necrosis factor (anti-TNF) biologic agents have been associated with a number of adverse events. OBJECTIVE To review the cutaneous reactions that have been reported in patients receiving anti-TNF therapy. METHODS We performed a systematic MEDLINE search of relevant publications, including case reports and case series. RESULTS Reported cutaneous events included infusion and injection site reactions, psoriasiform eruptions, lupus-like disorders, vasculitis, granulomatous reactions, cutaneous infections, and cutaneous neoplasms. Infusion reactions and injection site reactions were definitely associated with anti-TNF administration, whereas all other events had a varying strength of association and severity, not necessarily requiring drug discontinuation. LIMITATIONS Most information was derived from spontaneous case reports, where ascertainment biases and frequency of reporting may impair detection methodology and causal relationships. CONCLUSIONS As anti-TNF biologic agents are progressively being used in clinical practice, cutaneous adverse events will be encountered more frequently. Until more data are accumulated with respect to their pathogenesis and potential association with anti-TNF therapy, dermatologists should become more familiar with the clinical presentation and management of such events.