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.

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.

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.

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.

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.

Autoimmune thyroiditis and anti-thyroid antibodies in primary Sjogren's syndrome: a case-control study.

OBJECTIVE: To determine the frequency of antithyroid antibodies and the presence of autoimmune thyroiditis among patients with primary Sjögren's syndrome. DESIGN: A case-control study. METHODS: 53 consecutive patients with primary Sjögren's syndrome, 30 with rheumatoid arthritis, 12 with secondary Sjögren's syndrome associated with rheumatoid arthritis, 17 with autoimmune thyroiditis, and 53 apparently healthy controls were studied for anti-TG and anti-TPO antibodies as well as serum thyroid hormones and TSH levels. RESULTS: The overall frequencies of thyroid antibodies were 6/53 (11%) in primary Sjögren's syndrome, 2/30 (7%) in rheumatoid arthritis, 2/12 (17%) in secondary Sjögren's syndrome, 4/53 (8%) in healthy controls, and 16/17 (94%) in autoimmune thyroiditis. There was no difference in the frequency of the thyroid antibodies among the groups if patients with autoimmune thyroiditis were excluded (p = 0.415 for anti-TPO; p = 0.275 for anti-TG; p = 0.696 for either anti-TG and/or anti-TPO). Only two patients with primary Sjogren's syndrome had clinical hypothyroidism associated with autoimmune thyroiditis. CONCLUSIONS: In this Turkish population, no association between primary Sjögren's syndrome and autoimmune thyroiditis was found.

Enteroclysis findings of intestinal Behcet disease: a comparative study with Crohn disease.

BACKGROUND: The aim of this study was threefold; to define the enteroclysis (EC) findings of intestinal involvement in Behcet disease (BD), to compare these findings with those seen in Crohn disease (CD), and to determine the relation between the duration of BD and severity of the EC findings. METHODS: From 1997 to 2000, 17 BD and 50 CD cases were examined by EC examination. EC was performed with a 13-F balloon catheter via transnasal entubation. Mucosal and mural changes were evaluated. Statistical analysis was performed with the Mann-Whitney U test to determine the relation between duration of BD and severity of the EC findings. P

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.

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.

A double-blind trial of colchicine in Behçet's syndrome.

OBJECTIVE: Colchicine is a widely used treatment for Behçet's syndrome, even though in a previous 6-month controlled study, it was shown to be effective only in controlling erythema nodosum and arthralgias. We reassessed the effect of colchicine in Behçet's syndrome in a study conducted among a larger group of patients for 2 years. METHODS: We randomized 116 patients with Behçet's syndrome (60 male/56 female), who had active mucocutaneous disease without eye or major organ involvement, to receive either placebo or colchicine (1-2 mg/day, adjusted to body weight) in a double-blind trial for 2 years. The primary outcome measure was the sustained absence of any lesions during treatment (complete response). The secondary outcome measure was the difference in the number of mucocutaneous lesions or arthritic joints between the active drug and placebo arms. Women and men were analyzed separately. RESULTS: Eighty-four patients (72%; 45 male, 39 female) completed the 24-month study. Kaplan-Meier analyses showed significantly more complete responses in the colchicine treatment group in terms of reduced occurrence of genital ulcers (P = 0.004), erythema nodosum (P = 0.004), and arthritis (P = 0.033) among the women, and reduced occurrence of arthritis (P = 0.012) among the men. The mean numbers of genital ulcers (P = 0.001), erythema nodosum lesions (P = 0.002), and arthritic joints (P = 0.014) among the women were less in the colchicine group, and the mean number of arthritic joints (P = 0.026) among the men was less in the colchicine group. Adverse effects were similar in both groups. CONCLUSION: Colchicine may be useful for treating some of the manifestations of Behçet's syndrome, especially among women. This might be a reflection of less severe disease among the women.

Papulopustular skin lesions are seen more frequently in patients with Behçet's syndrome who have arthritis: a controlled and masked study.

OBJECTIVE: To determine the prevalence of acneiform skin lesions (comedones, papules, and pustules) in patients with Behçet's syndrome (BS) with arthritis. METHODS: Study groups included 44 patients with BS with arthritis (32 men, 12 women, mean (SD) age 37.8 (8.9)), 42 patients with BS without arthritis (31 men, 11 women, mean age 35.5 (6.4)), 21 patients with active rheumatoid arthritis (five men, 16 women, mean age 48.8 (14)), and 33 healthy volunteers (28 men, five women, mean age 40.1 (8.1)). All probands and controls were examined by a rheumatologist and a dermatologist, in a prospective and masked protocol. An ophthalmological evaluation was performed if necessary. Skin lesions, including comedones, papules, and pustules, were counted and scored as 0: absent, 1: 1-5, 2: 6-10, 3: 11-15, 4: 16-20, and 5: >20. RESULTS: Although there was no significant difference between the four groups in the prevalence of comedones, the number of papules and pustules was significantly higher in patients with BS with arthritis (p=0.0037 for papules and p<0.0001 for pustules) than in the remaining three groups. CONCLUSION: Acneiform skin lesions (papules and pustules) seem to be more frequent in patients with BS with arthritis. This suggest that the arthritis seen in BS may possibly be related to acne associated arthritis.

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.