Behçet's syndrome: a critical digest of the recent literature.

A similar disease severity among men and women in Brasil, a high frequency of gastrointestinal involvement in China, Japan and USA, a low frequency of pathergy positivity in Japan and USA underline the ethnic variations reported in recent studies. Polymorphisms pertaining both to innate and adaptive immunity in genome wide association studies, clusters in phenotype, and new mechanisms for emerging therapeutic implications have been reported. A Th17 dominance seems to be likely with the exception of gastrointestinal involvement. Infliximab, interferon-alpha and cyclosporine-A may be showing their beneficial effects also by affecting the Th17 cells. The clinical course and outcome of isolated pulmonary artery thrombosis is similar to pulmonary artery aneurysms. Parenchymal lesions (nodules, consolidations, cavities and ground glass lesions) are common in patients with pulmonary involvement. Pericarditis is a frequent cardiac manifestation in France. Treatment of BS became more intensive than before. Immunosuppressives and corticosteroids seem to prevent relapses of venous thrombosis. Studies are needed to understand the role of anticoagulants. Interferon alpha-2a appears to be effective at lower dosage, which brings the advantage of decreased cost and increased tolerability. Switching between anti-TNF agents, when needed, is possible. Interleukin-1 and interleukin-6 are new promising targets.

Frequent oral ulceration during early disease may predict a severe disease course in males with Behçet's syndrome.

OBJECTIVES: The numbers and recurrence rates of mucocutaneous manifestations can be highly variable among patients with Behçet's syndrome (BS) but it is not known whether these differences influence the disease course at the long-term. METHODS: We evaluated the outcome of 30 patients that made up the placebo arm of a 6 months controlled trial of thalidomide and looked at the relation between the frequencies of mucocutaneous manifestations during the trial and the development of major organ involvement necessitating immunosuppressives during the post-trial period. RESULTS: Fifteen (50%) patients had received immunosuppresives for major organ involvement during the post-trial period. Patients receiving immunosuppressive treatment were significantly younger at the onset of BS compared to those who did not (24.5±5 vs. 29.7±3.8 SD years; p=0.003). The mean number of oral ulcers recorded throughout the trial was significantly higher among patients using immunosuppressives compared to those who did not (2.09±0.96 vs. 1.43±0.8; p=0.029). This significance disappeared when adjusted for age of onset of BS (p=0.16). ROC curve analysis showed that having 10 or more ulcers during 6 months has a sensitivity of 86.7% and a specificity of 53% for the subsequent necessity of immunosuppressive use. The same association was not true for genital ulcers, follicular lesions and erythema nodosum. CONCLUSIONS: These findings on a limited number of patients suggest that frequent occurrence of oral ulceration during the initial years of the disease may predict the development of major organ involvement in men with BS.

Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. METHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. CONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis.

NRAMP1 gene has multiple pleiotropic effects on macrophage activation pathways. These pleiotropic effects may increase resistance to infections such as tuberculosis (TB), but may also lead to susceptibility of autoimmune diseases such as rheumatoid arthritis (RA). It has been hypothesized that allele 3 would be associated with autoimmune diseases, whereas allele 2 would be associated with infectious diseases, and genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA. We analysed four NRAMP1 gene polymorphisms including 5' promoter (GT)(n) (rs34448891), INT4 (469 + 14G/C) (rs3731865), 3'UTR (1729 + 55del4) (rs17235416) and D543N (codon 543, Asp to Asn) (rs17235409) in 112 patients with TB, 98 patients with RA, 80 healthy controls for TB and 122 healthy controls for RA using ARMS-PCR and PCR-RFLP. We found a significant association between INT4 and RA (P = 0.004, odds ratio: 2.06, 95% CI: 1.24-3.41), but no significant differences between 5' promoter, D543N, 3'UTR polymorphisms and RA. There were no associations between NRAMP1 gene polymorphisms and TB. Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB. INT4 polymorphism may be associated with RA in Turkish patients.

Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists.

OBJECTIVE: Recommendations and/or guidelines represent a popular way of integrating evidence-based medicine into clinical practice. The 3E Initiatives is a multi-national effort to develop recommendations for the management of rheumatic diseases, which involves a large number of experts combined with practising rheumatologists addressing specific questions relevant to clinical practice. METHODS: Ten countries participated in three rounds of discussions and votes concerning the management of AS. A set of nine questions was formulated in the domains of diagnosis, monitoring and treatment, after a Delphi procedure. A literature search in MedLine was conducted. Predefined outcome parameters for the domains of diagnosis, monitoring and treatment were assessed. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements by each national group, following which the final international recommendations were formulated. RESULTS: A total of 2699 papers were found and 467 were selected for analysis. Twelve key recommendations were developed: three in the domain of diagnosis addressing general diagnostic considerations, early AS diagnosis and general practitioners' referral recommendations; three concerning monitoring of AS disease activity, severity and prognosis; six concerning pharmacological treatment (except biologics): non-steroidal anti-inflammatory drugs/COX-II inhibitors, bisphosphonates and treatment of enthesitis. The compiled agreement among experts ranged from 72% to 93%. CONCLUSION: Recommendations for the management of AS were developed using an evidence-based approach followed by expert/physician consensus with high level of agreement. Involvement of a larger and more representative group of rheumatologists may improve their dissemination and implementation in daily clinical practice.

Thalidomide has both anti-inflammatory and regulatory effects in Behcet's disease.

Thalidomide is shown to be an effective treatment for mucocutaneous symptoms of Behcet's disease (BD). In this study, the effects of thalidomide on peripheral blood mononuclear cells were investigated ex vivo. In an open prospective study, ten patients were given 200 mg/day thalidomide for 12 weeks and cluster of differentiation 4 (CD4), CD8, CD11a, CD11b, CD16, CD18, CD28, CD44, CD45RO, CD45RA, CD56, CD120a and gammadelta+ T cells were analysed with flow cytometry at 0, 3, 7, 30 and 90 days. Two patients were excluded from the analysis for attacks of uveitis within the first 2 weeks. At day 7, tumour necrosis factor-alpha (TNF-alpha) receptor+ (CD120a; 12% vs 5%), CD8/CD11b+ (12% vs 6%) and CD16/CD56+ (16% vs 9%) cells decreased in BD patients compared to day 0. On the other hand, CD4+CD45RO+ T cells (24% vs 34%) at day 30 and gammadelta+ T cells (11% vs 21%) at day 90 increased after treatment. These results suggest that thalidomide tends to decrease TNF-alpha receptor levels, CD8/CD11b+ T cells and natural killer cells in early treatment and increases CD4+CD45RO+ memory T and gammadelta+ T cells later in BD.

Anti-Saccharomyces cerevisiae antibodies (ASCA) in Behçet's syndrome.

OBJECTIVES: Anti-Saccharomyces cerevisiae antibodies (ASCA) are found in 50-60% of patients with Crohn's disease. Increased as well as normal levels have been reported in Behçet's syndrome (BS). We reassessed the level of IgG and IgA ASCA antibodies in BS and in a group of diseased and healthy controls. METHODS: Eighty-five patients with BS were studied along with 20 patients with ankylosing spondylitis (AS), 24 with Crohn's disease (CD), 25 with ulcerative colitis (UC) and 21 healthy volunteers. A commercial ELISA kit was used (Inova Diagnostics). RESULTS: It was only the patients with CD who had significantly higher levels of antibodies compared with the rest of the group (ANOVA: ASCA IgG, p = 0.0001; ASCA IgA, p = 0.0001). 42% of CD, 4% of BS, 4% of UC and 15% of AS patients had a positive IgG+IgA ASCA. There was a significant trend for patients with gastrointestinal (GI) involvement with BS (n = 8) to be more positive for IgG and IgG+IgA ASCA compared to the rest of the patients with BS (n = 77) (Chi-square, IgG, p = 0.02, IgG+IgA, p = 0.001). CONCLUSION: The rate of positivity of ASCA in BS is comparable to that observed among patients with UC and AS. Patients with BS who have GI involvement may have higher levels of ASCA and this needs to be further studied.

Fibrinolytic activity and d-dimer levels in Behçet's syndrome.

OBJECTIVE: Thrombophlebitis occurs in a third of patients with Behçet's syndrome (BS). The thrombotic tendency in BS has been studied with inconclusive results perhaps due to the inadequate numbers of patients studied during the acute phase of the thrombosis as well as the lack of appropriate diseased controls. We have studied tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and d-dimer levels in BS patients with and without thrombosis both in the acute and chronic phases along with suitable diseased and healthy controls. METHODS: t-PA and PAI-1 were studied by ELISA and d-dimer by semiquantitative latex agglutination slide test in 30 BS patients without deep vein thrombosis (DVT), 10 BS with acute DVT (ADVT), 25 BS with chronic DVT, 27 with ankylosing spondylitis, 26 diffuse systemic sclerosis, 15 patients with ADVT due to other causes, 10 patients with sepsis, and 23 healthy controls. RESULTS: The t-PA levels in BS with ADVT were significantly lower than those in patients with ADVT due to other causes (7.4 +/- 6.2 vs. 13.4 +/- 6.3, P = 0.027) while PAI-1 levels did not show significant differences between the groups (P = 0.60). The numbers of patients with d-dimer levels of > or = 0.5 microg/ml in BS with ADVT were similar to those found in patients with ADVT due to other causes (9/10 vs. 14/14). CONCLUSION: The relatively low t-PA levels point to a defect in fibrinolysis in BS. d-dimer levels are increased in the acute phase of thrombosis in BS.

Management of aneurysms in Behçet's syndrome: an analysis of 24 patients.

BACKGROUND: The surgical therapy of Behçet aneurysms is often unsuccessful, resulting in graft occlusions, anastomoses, and/or new aneurysms. METHODS: Twenty-nine aneurysms were documented in 24 Behçet's patients during a period of 19 years. All patients were male, ranging in age from 20 to 53 years (mean, 35 +/- 7.3 years). The mean duration of disease was 9 +/- 5 years. There were nine abdominal aorta, four iliac, three common femoral, five superficial femoral, four popliteal, one subclavian, one carotid, and one posterior tibial artery aneurysm. In addition, in one patient an aneurysm developed from the arterialized venous conduit that had been inserted for a common femoral artery aneurysm elsewhere. Five patients were already under immunosuppressive therapy for ocular problems at the time of diagnosis. Fifteen patients received immunosuppressive therapy after operation. We performed one abdominal aneurysmorrhaphy, two iliac artery PTFE graft interpositions, two aortobiliac bypasses (PTFE), six aortic tube graft (three PTFE, three Dacron) interpositions, one avrtofemoral bypass (PTFE), two iliofemoral bypasses (PTFE), two superficial femoral artery graft (PTFE) interpositions, and three popliteal graft interpositions (one PTFE, two vein graft). Also as an initial procedure one carotid, one subclavian, four superficial femoral, one popliteal, and one posterior tibial artery were ligated. RESULTS: Nineteen patients were followed up for a mean duration of 47.3 +/- 27 months (range, 1 to 108 months). The patient with a subclavian aneurysm died of massive bleeding on postoperative day 15. Four patients were lost to follow-up. In the abdominal aortic aneurysm group one patient died of gastrointestinal bleeding 4 years after the operation. Another patient from the same group died 5 years after operation without any vascular disease. In the common femoral artery group the patient with an occluded iliofemoral graft died of an exsanguinating pulmonary artery aneurysm in the first year after operation. Overall, there were five anastomotic aneurysms. In addition, after the initial operation two iliofemoral, one aortofemoral, and one popliteal interposition graft were occluded without disabling ischemia. CONCLUSIONS: Aneurysms limited to the extremities could be ligated without disabling ischemia. Abdominal aortic aneurysms could be treated with tube graft insertion, giving satisfactory results. Patients could tolerate graft occlusion without major ischemia.

Surgical therapy of pulmonary arterial aneurysms in Behçet's syndrome.

Two patients with Behçet's syndrome were operated for exsanguinating pulmonary artery aneurysm into a bronchus. Lower lobectomy was performed in the first patient. He died of hypoxia and sepsis on the 8th postoperative day. Pneumonectomy was undertaken in the second patient, who is well 30 months after the operation.

Behçet's disease: diagnostic and prognostic aspects of neurological involvement.

This study was conducted to describe clinical and prognostic aspects of neurological involvement in Behçet's disease (BD). Patients referred for neurological evaluation fulfilled the criteria of the International Study Group for Behçet's Disease. We analyzed disability and survival by the Kaplan-Meier method, using Kurtzke's Extended Disability Status Scale (modified for BD) and the prognostic effect of demographic and clinical factors by Cox regression analysis. We studied 164 patients; of the 107 diagnostic neuroimaging studies: 72.1% showed parenchymal involvement, 11.7% venous sinus thrombosis (VST) and the others were normal. CSF studies were performed in 47 patients; all with inflammatory CSF findings (n = 18) had parenchymal involvement. An isolated increase in pressure was compatible with either VST or normal imaging. The final diagnoses were VST (12.2%), neuro-Behçet syndrome (NBS) (75.6%), isolated optic neuritis (0.6%), psycho-Behçet syndrome (0.6%), and indefinite (11%). VST and NBS were never diagnosed together. Ten years from onset of BD 45.1% (all NBS) reached a disability level of EDSS 6 or higher, and 95.7 +/- 2.1% of the patients were still alive. Having accompanying cerebellar symptoms at onset or a progressive course is unfavorable. Onset with headache or a diagnosis of VST is favorable. Two major neurological diagnoses in BD are NBS and VST. These are distinct in clinical, radiological, and prognostic aspects, hence suggesting a difference in pathogenesis.

CNS involvement in neuro-Behçet syndrome: an MR study.

BACKGROUND AND PURPOSE: Behçet disease (BD) is a multisystem vasculitis of unknown origin in which neurologic involvement has been reported in the range of 5% to 10% in large series. Reports on clinical and radiologic aspects of neuro-Behçet syndrome (NBS) are in general limited in number. Our purpose was to determine the MR patterns in patients with NBS who had neural parenchymal involvement and to correlate our findings with possible vascular pathophysiology. METHODS: The MR images of 65 patients with NBS and neural parenchymal involvement were reviewed. In a subgroup of patients who had serial MR studies, we evaluated the anatomic-radiologic location and distribution of the lesions and whether they corresponded to any vascular territory, and studied their extension, enhancement patterns, and temporal course. RESULTS: The most common imaging finding in NBS patients who had neural parenchymal involvement was a mesodiencephalic junction lesion with edema extending along certain long tracts in the brain stem and diencephalon in 46% of the patients. The next most common location of involvement was the pontobulbar region, seen in 40% of the cases. Three primary cervical spinal cord lesions and one case of isolated optic nerve involvement were observed. CONCLUSION: The parenchymal distribution of lesions in NBS appears to support the hypothesis of small-vessel vasculitis; mainly, venular involvement. The anatomic distribution of intraaxial veins of the CNS explains the predominant involvement of the brain stem structures observed in our patients. This pattern of lesion distribution might help to differentiate NBS from other vasculitides as well as from the inflammatory-demyelinating diseases of the CNS, such as multiple sclerosis.

Low dose cyclosporin A versus pulsed cyclophosphamide in Behçet's syndrome: a single masked trial.

A single masked trial of cyclosporin A 5 mg/kg/day versus monthly 1 g intravenous boluses of cyclophosphamide was conducted among 23 patients with Behçet's syndrome and active, potentially reversible uveitis. The trial was unmasked after a mean of 12 (SD 2) months for the cyclosporin A group (n = 12) and a mean of 10 (SD 3) months for the cyclophosphamide group (n = 11). During the initial 6 months the visual acuity significantly improved (p < 0.001) in the cyclosporin A group whereas this was not observed in the cyclophosphamide group. The subsequent follow-up of patients up to 24 months suggested that the initial improvement in visual acuity with cyclosporin A was not sustained. More extensive and especially long-term studies of cyclosporin A in the uveitis of Behçet's syndrome are warranted.

Inefficacy of azapropazone in the acute arthritis of Behçet's syndrome: a randomized, double blind, placebo controlled study.

Sixty-three consecutive Behçet's syndrome patients with an acute arthritis of up to 10 days duration were treated either with azapropazone (APZ) 300 mg t.i.d. or placebo for three weeks. Twenty-eight patients (14 males, 14 females: mean age 36.2 +/- 8.1 SD years) from the APZ group and 29 patients (18 males, 11 females; mean age 34.2 +/- 8.4 SD years) from the placebo group completed the trial. At the end of the trial the arthritis persisted in 53.5% (15/28) of the APZ patients and in 41.3% (12/29) of the placebo patients (chi 2 = 0.85; NS). Six patients (6/28; 21%) from the APZ group and 9 patients (9/29; 31%) from the placebo group developed new joint involvement (chi 2 = 0.7; NS). There was no difference in the duration of arthritis between the two groups (19.9 +/- 8.3 SD days in the APZ groups vs. 19.7 +/- 8.2 SD days in the placebo group; NS). The degree of joint swelling, the tender joint score and the visual analogue score for pain significantly improved in both groups, but there was no difference in any of these parameters between the groups except for a significant difference in the visual analogue score for less pain at the first week in the azapropazone group (t = 2.23; p < 0.05). There were also no differences in the mean numbers of acetaminophen tablets used or in the CRP and ESR levels between the two groups. We conclude that azapropazone is not effective in controlling the arthritis of Behçet's syndrome.

Colchicine neuromyopathy: a report of six cases.

Colchicine has been in use for therapeutic purposes for many years. It can, however, cause subacute onset muscle and peripheral nerve toxicity in patients with chronic renal failure. In this report we describe 6 patients who developed neuromyopathy after the administration of colchicine. All patients presented with proximal muscle weakness, elevated serum creatine kinase (CK) levels, and neuropathy and/or myopathy on electromyography (EMG). The diagnosis of colchicine toxicity was confirmed in all cases by the normalization of CK levels and EMG after discontinuation of the drug. Toxicity developed in 4 renal failure patients on therapeutic doses of the drug, while one patient took a massive dose for suicidal reasons, and the other was on high-dose therapy. Patients using colchicine--especially those with renal failure--should be warned about the side effects of the drug and physicians should be careful in the administration of the drug.

Topical alpha interferon in the treatment of oral ulcers in Behçet's syndrome: a preliminary report.

The effect of topical recombinant interferon alfa 2c hydrogel (IFN alpha 2C) in the aphthous lesions of the mouth in Behcet's syndrome was assessed in twenty patients in a twelve-week open trial. IFN alpha 2C applied to the mouth for four weeks significantly reduced the number of aphthae in the post-treatment phase compared to the pretreatment and treatment phases. No side effects were recorded. Topical IFN alpha 2C seems to be effective in the treatment of the aphthae in Behcet's syndrome.

The frequency and clinical characteristics of methotrexate (MTX) oral toxicity in rheumatoid arthritis (RA): a masked and controlled study.

To assess the frequency and clinical characteristics of methotrexate (MTX) oral toxicity in rheumatoid arthritis (RA) patients, 51 RA patients receiving MTX and 46 RA patients not receiving MTX were studied. A questionnaire, the credibility of which was tested on four separate patient groups including a group with Behcet's Syndrome, was used as a tool to determine the prevalence of stomatitis by a blind observer. In this first controlled study of the oral toxicity of MTX, prevalence of stomatitis was found in 37.2% in the group taking MTX and 19.5% in the group not taking MTX (P = 0.054). No statistical differences were detected with respect to number, duration, frequency, and site of stomatitis. Two of the 51 MTX taking patients temporarily reduced their MTX dosage and only one patient temporarily terminated MTX treatment. MTX and toxicity is usually of no major clinical concern in the treatment of RA.

Calciphylaxis: a condition mimicking necrotizing vasculitis.

A patient with end stage renal disease developed ischaemic skin necrosis and digital gangrene. He had diffuse arterial calcification associated with hyperparathyroidism secondary to renal failure. The patient received inappropriate cyclophosphamide therapy as he had been misdiagnosed as having an inflammatory vasculitis. This clinical picture, previously named "calciphylaxis" should come into the differential diagnosis of systemic vasculitis in a uraemic patient with hyperparathyroidism.

Glomerulonephritis in Behçet's disease: report of seven cases and review of the literature.

Despite being recognised much more frequently than in the past, renal involvement has not previously been regarded as a feature of Behcet's disease (BD). In this study we aimed to assess the frequency of renal involvement in BD by performing urinalyses of 674 consecutive BD patients; we also retrospectively evaluated the charts of 4212 BD patients for the incidence of glomerulonephritis (GN). Urinary abnormalities (proteinuria and/or haematuria) were present in 10.8%; and during a period of 23 years GN was detected by renal biopsy in seven (0.16%) BD patients. Two patients with GN were lost to follow-up; end-stage renal failure developed in only one patient, and she underwent renal transplantation. We were unable to determine any pathognomonic feature that was predictive of renal involvement. Although males tend to have a more serious clinical course of BD the incidences of urinary abnormalities and GN were similar in both sexes in our series. According to our results, we can conclude that urinary abnormalities are more frequent in BD; however, serious renal lesions develop in only very few of these patients.