Bahram Bodaghi

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.

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.

Efficacy of interferon alpha in the treatment of refractory and sight threatening uveitis: a retrospective monocentric study of 45 patients

Aim: Severe uveitis is potentially associated with visual impairment or blindness in young patients. Therapeutic strategies remain controversial. The efficacy of interferon alpha-2a (IFN-α2a) in severe uveitis, refractory to steroids and conventional immunosuppressive agents, was evaluated. Patients and methods: Patients were included after a major relapse of uveitis following corticosteroids and immunosuppressants. IFN-α2a (3 million units three times a week) was administered subcutaneously. Efficacy was assessed by improvement in visual acuity, decrease in vitreous haze, resolution of retinal vasculitis and macular oedema, assessed by fundus examination and fluorescein angiography, and decrease in oral prednisone threshold. Results: 45 patients were included. Median age was 32.3 years (range 8–58) and sex ratio (F/M) was 0.66. Uveitis was associated with Behçet’s disease in 23 cases (51.1%) and with other entities in 22 cases (48.9%). Median duration of uveitis before interferon therapy was 34.9 months (range 3.4–168.7) and an average of 3.26 relapses following corticosteroids and immunosuppressants was noted. Uveitis was controlled in 82.6% of patients with Behçet’s disease and 59% of patients with other types of uveitis (p = 0.07). During a mean follow-up of 29.6 months (range 14–55), median oral prednisone threshold decreased significantly from 23.6 mg/day (range 16–45) to 10 mg/d (range 4–14) (p<0.001). Interferon was discontinued in 10 patients (22.2%) with Behçet’s disease and in four patients without Behçet’s disease. Relapses occurred in four and one cases, respectively. Conclusions: Interferon therapy appears to be an efficient strategy in severe and relapsing forms of Behçet’s disease but also in other uveitic entities. However, it seems to act more to suspend rather than cure the disease. Therefore, IFN-α2a may be proposed as a secondline strategy after failure of conventional immunosuppressants.

Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease

BACKGROUND Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown etiology. OBJECTIVE To determine the nature of T cells driving inflammatory lesions in BD. METHODS T cell homeostasis and cytokines production were analyzed in peripheral blood and brain inflammatory lesions from 45 adult patients with BD (active and untreated BD [n = 25] and patients in remission [n = 20]) and 20 healthy donors, using Luminex, flow cytometry, immunohistochemistry, and immunofluorescence analysis. RESULTS We found a marked increase in T(H)17 cells and a decrease in the frequency of CD4(+) forkhead box P3(+) regulatory T cells (Tregs) in peripheral blood that were induced by IL-21 production and that correlate with BD activity. The addition of serum from patients with active BD in a sorted CD4(+) T cells culture of healthy donors induced a significant and dose-dependent production of IL-17A and a decrease in forkhead box P3 expression. We demonstrated the presence of IL-21- and IL-17A-producing T cells within the cerebrospinal fluid, brain parenchyma inflammatory infiltrates, and intracerebral blood vessels from patients with active BD and central nervous system involvement. The stimulation of CD4(+) T cells with IL-21 increased T(H)17 and T(H)1 differentiation and decreased the frequency of Treg cells. Conversely, IL-21 blockade with an IL-21R-Fc restored the T(H)17 and Treg homeostasis in patients with BD. CONCLUSION We provided here the first evidence of the critical role of IL-21 in driving inflammatory lesions in BD by promoting T(H)17 effectors and suppressing Treg cells. IL-21 represents a promising target for novel therapy in BD.

Ocular and central nervous system lymphoma: clinical features and diagnosis

PURPOSE: To evaluate the clinical, angiographic, and cytopathologic features of ocular and central nervous system (CNS) lymphoma. PATIENTS AND METHODS: Retrospective study of 44 patients over a 10-year period. RESULTS: A total of 36 women and six men, mean age 54 years (range: 36-90 years), were included. The mean time interval between onset of ocular symptoms and diagnosis was 40 months (range: 1-144 months). Ocular involvement was bilateral in 84% of the cases. Laser flare photometry readings averaged 9.6 photons/ms (2.9-78.3 photons/ms). Vitritis was constant. Funduscopy revealed RPE abnormalities in 60.49% of the cases and punctuate retinal infiltrates in 33.5%. The most common findings with fluorescein angiography were window defects and hypofluorescent round lesions. Patients had CNS involvement in 66% of the cases. Cytologic examination of the vitreous samples showed high-grade B lymphoma in 86% of the cases. Interleukin-10 dosage, when performed, showed elevated levels averaging 2352 pg/ml in all vitreous samples. Molecular biology based on PCR confirmed the diagnosis in 12 patients. Treatment included systemic chemotherapy alone or associated with radiotherapy in various regimens. Fourteen patients died during follow-up. Only 12 patients were in complete remission. CONCLUSION: The prognosis of the disease remains poor. However, the new diagnostic tools and therapeutic strategies may improve the diagnostic delay and the survival outcome.

Understanding uveitis: the impact of research on visual outcomes.

The term uveitis encompasses a very diverse group of inflammatory ocular diseases that cause a significant burden of legal and economic blindness. Indeed, the socioeconomic impact of uveitis is at least as significant as that of diabetic retinopathy and, in the majority of cases, those affected are young individuals of working age. Significant progress has been made in our understanding of the mechanisms underlying the inflammatory process through the use of animal models, but correlation with human disease has proved elusive and many scientific approaches which appear highly effective in animal models prove to be less effective in patients. Nevertheless, effective, targeted treatments are needed in uveitis as current treatment is based on corticosteroids and immunosuppressive drugs whose usefulness is limited by their many side-effects. The aims of this review are to summarize the state of clinical research in uveitis, to identify gaps in our knowledge, and to propose new opportunities and methodologies for future developments in all aspects of uveitis research, including epidemiology, economic impact analysis, diagnosis, therapeutics, and clinical study design. Optimal patient management and efficient drug development depend on validated structured tools, such as those that have helped to drive a rapid acceleration in the means and methods available to assess and treat patients with rheumatoid arthritis and cancer. Uveitis care should witness a similar boom as the issues discussed are resolved.

Efficacy of interferon alfa-2a in severe and refractory uveitis associated with Behçet's disease.

PURPOSE: To evaluate the efficacy of interferon alfa-2a (IFN alfa) in severe uveitis associated with Behçets disease, that is refractory to steroids and conventional immunosuppressive agents. PATIENTS AND METHODS: Patients with Behçets disease (according to the International Study Group criteria), who relapsed despite steroids and immunosuppressive agents, were included in this retrospective study. Ophthalmological examination, laser flare photometry, and fluorescein angiography associated with laboratory tests were performed at regular intervals. IFN alfa (3 millions units thrice a week) was injected subcutaneously. RESULTS: Eight patients (sex ratio: 1) were included between May 1995 and January 1999. The mean age was 29.1 years (14-54 years) and the disease was present between 11 and 167 months before the administration of IFN alfa. IFN alfa was efficient in all cases with a mean follow-up of 22 months (10-55 months). Steroids were tapered from a mean dosage of 47 mg/d to a mean dosage of 8.5 mg/d. Ocular inflammation was controlled and visual acuity improved in all cases. Treatment was generally well tolerated despite a constant but transient flu-like syndrome. IFN alfa was tapered in three patients and stopped in one case without any relapse after five months. CONCLUSIONS: Within the limitations of this retrospective study, low-dose IFN alfa seems to be well tolerated, promising in the management of refractory forms of uveitis due to Behçets disease, and effective in allowing a reduction of steroid dosage. A prospective controlled study is necessary to confirm these preliminary results.

Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis.

Aim: To describe the diagnostic and therapeutic management of cytomegalovirus (CMV) anterior uveitis unassociated with retinal necrosis in immunocompetent patients. Methods: Patients referred between 2001 and 2003 for management of unilateral, chronic, recurrent uveitis associated with secondary glaucoma underwent extensive investigation including laboratory tests for herpes virus infections. Specific antiviral treatment was initiated in all cases and the level of ocular inflammation was evaluated during the follow up. Results: Five patients, three men and two women, were included. Median age was 50 years old (range 30–80 years). Anterior unilateral uveitis without iris atrophy was observed in all cases. Uveitis was chronic in three cases and recurrent in two cases. Glaucoma was observed in all patients with a median intraocular pressure of 30 mm Hg (range 22–43 mm Hg). Five patients responded initially to specific anti-CMV therapy. Even though glaucoma surgery was necessary in two cases, both ocular inflammation and glaucoma were controlled in all cases. Relapses occurred in three cases after cessation of therapy, requiring prolonged maintenance therapy with valganciclovir. Conclusions: CMV infection and specific antiviral therapy should be considered in all cases of relapsing or chronic iridocyclitis and secondary glaucoma. Maintenance regimens of valganciclovir may be necessary to prevent further relapses.

Frequency of Distinguishing Clinical Features in Vogt-Koyanagi-Harada Disease

PURPOSE To determine the frequency of occurrence of limited clinical features which distinguish patients with Vogt-Koyanagi-Harada (VKH) disease from those with non-VKH uveitis. DESIGN Comparative case series. PARTICIPANTS We included 1147 patients. METHODS All patients with bilateral ocular inflammatory disease presenting to any of 10 uveitis centers in the 3-month period between January 1 and March 31, 2006 (inclusive), were asked to participate. The clinical and historical features of disease were obtained from the participants via direct interview and chart review. Patients were stratified based on whether they were diagnosed with VKH disease or non-VKH uveitis for statistical analysis. MAIN OUTCOME MEASURES Presence or absence of various clinical features in the 2 populations. RESULTS Of 1147 patients, 180 were diagnosed with VKH disease and 967 with non-VKH uveitis. Hispanics and Asians were more likely to be diagnosed with VKH than non-VKH disease compared with other ethnicities. In acute disease, the finding of exudative retinal detachment was most likely to be found in VKH disease with a positive predictive value (PPV) of 100 and negative predictive value (NPV) of 88.4, whereas in chronic disease, sunset glow fundus was most likely to be found, with a PPV of 94.5 and NPV of 89.2. CONCLUSIONS Numerous clinical findings have been described in the past as important in the diagnosis of VKH. The current study reveals that of these, 2 are highly specific to this entity in an ethnically and geographically diverse group of patients with nontraumatic bilateral uveitis. These clinical findings are exudative retinal detachment during acute disease and sunset glow fundus during the chronic phase of the disease.

Syphilitic uveitis in patients infected with human immunodeficiency virus

BackgroundThis work investigates the incidence and clinical features of syphilitic uveitis in patients infected with human immunodeficiency virus (HIV).Material and methodsWe retrospectively reviewed syphilitic uveitis in patients coinfected with HIV that presented at a referral center between July 2001 and November 2003.ResultsTwelve patients (20 eyes) were included. The ocular manifestations of syphilis led to the discovery of HIV-1 seropositivity in three patients. All patients were male and homosexual. One patient has been previously treated for syphilis with benzathine penicillin G. One patient presented with anterior uveitis and 11 patients had panuveitis or posterior uveitis. Necrotizing retinitis was noted in seven eyes (35%), posterior placoid chorioretinitis in six eyes (30%) and optic nerve involvement in five eyes (25%). Of nine patients with available cerebrospinal fluid (CSF) studies, seven (77.8%) had CSF abnormalities. Eleven patients were treated with intravenous penicillin G and one with intravenous ceftriaxone sodium. One patient required a second course of antibiotics to control uveitis. Ocular inflammation decreased and visual acuity improved in all nine patients for whom follow-up was available after treatment.ConclusionManifestations of syphilitic uveitis in HIV-infected patients are multiple, with high frequencies of posterior uveitis, posterior placoid chorioretinitis, necrotizing retinitis and optic nerve involvement. Syphilitic uveitis in HIV-infected patients seems to have a more severe course and may relapse despite high-dose intravenous penicillin therapy.