Objective
Behçet's disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical ...diagnostic criteria led to their reassessment.
Methods
An International Team for the Revision of the International Criteria for BD (from 27 countries) submitted data from 2556 clinically diagnosed BD patients and 1163 controls with BD‐mimicking diseases or presenting at least one major BD sign. These were randomly divided into training and validation sets. Logistic regression, ‘leave‐one‐country‐out’ cross‐validation and clinical judgement were employed to develop new International Criteria for BD (ICBD) with the training data. Existing and new criteria were tested for their performance in the validation set.
Results
For the ICBD, ocular lesions, oral aphthosis and genital aphthosis are each assigned 2 points, while skin lesions, central nervous system involvement and vascular manifestations 1 point each. The pathergy test, when used, was assigned 1 point. A patient scoring ≥4 points is classified as having BD. In the training set, 93.9% sensitivity and 92.1% specificity were assessed compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated an unbiased estimate of sensitivity of 94.8% (95% CI: 93.4–95.9%), considerably higher than that of the ISG criteria (85.0%). Specificity (90.5%, 95% CI: 87.9–92.8%) was lower than that of the ISG‐criteria (96.0%), yet still reasonably high. For countries with at least 90%‐of‐cases and controls having a pathergy test, adding 1 point for pathergy test increased the estimate of sensitivity from 95.5% to 98.5%, while barely reducing specificity from 92.1% to 91.6%.
Conclusion
The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD.
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.
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 > or = 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.
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 cyclosporin A in eye involvement and interferon (IFN)alpha in mucocutaneous involvement. There were no RCTs with IFNalpha or tumour necrosis factor (TNF)alpha antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking.
Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.
To develop evidence-based European League Against Rheumatism (EULAR) recommendations for the management of Behçet disease (BD) supplemented where necessary by expert opinion.
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.
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".
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.
To investigate whether the CD4+CD25+ regulatory T cell (Treg) population, which plays important role in autoimmune diseases is related to the pathophysiology of Behçet's disease (BD).
Forty-two ...patients with BD (20 patients in active disease) fulfilling the criteria of the International Study Group of BD. Twenty age-matched healthy controls were studied. We analyzed CD4+CD25+/high T cells and the mRNA expression of Foxp3, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and transforming growth factor beta (TGF-beta) in BD. We have studied the ability of CD4+CD25+ (Treg) to regulate proliferation of CD4+CD25- T cells during active BD stage.
Active BD patients had significantly higher CD4+CD25+/high T cells, as compared with BD in the remission stage, and healthy controls. There was no significant differences in the CD4+ CD25+/high T cells expression between healthy controls and remission BD. In active BD, mRNA for Forkhead box p3 (Foxp3) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were highly expressed when compared to remission BD and healthy controls. There was no differences in the mRNA expression for TGF-beta in active BD, remission BD and healthy controls. Functionally, CD4+CD25+/high T cells in active BD were impaired in their proliferative responses and could suppress the proliferation of their CD4+CD25- counterparts.
These data demonstrate that CD4+CD25+ Treg cells, with the potential to regulate suppression of effector T cells, were increased in the peripheral circulation of active BD patients. The role of CD4+CD25+/high T cells in the regulatory process of the inflammation in active BD, could be taken in account.
The manifestations of BD are considered to have developed as a result of immunological dysfunction, which is suggested to be induced by microbial pathogens. The Toll-like receptor (TLR) genes were ...known to be associated with a variety of infectious diseases due to their central role in both innate and adaptive immunity. In this report, we investigated the possible association between BD patients and genetic variations within the TLR 2, 4 and 9 genes in a Tunisian population.
135 Tunisian BD patients and 159 healthy blood donors from the same geographical area were genotyped by polymerase chain reaction for the TLR polymorphisms.
Among the TLR polymorphisms, only the distribution of TLR9 1486 T/C genotype (p=0.07; chi2=3.30; OR=1.54; 95% CI=0.94-2.51) and allele (p=0.08; chi2=2.91; OR=1.34; 95% CI=0.94-1.92) frequencies was different between BD patients and healthy controls, but did not reach statistical significance. For the TLR9 1237 T/C, the distribution of genotypes and alleles were not significantly different comparing total patients with controls. There were no associations between the studied polymorphisms and the main clinical manifestations of BD. The G, T and A allele of the TLR4 1896 A/G, TLR4 11196 C/T and TLR2 12408 G/A polymorphisms were uncommon and absent in the Tunisian population.
Our results showed that SNPs in the TLR2, 4 and 9 genes were not significantly associated with susceptibility to BD.
There is a wide variationin the natural history of systemic lupus erythematosus(SLE) among different ethnic and geographicalgroups. Studies in Arabs are few and those in North Africans and ...especiallyin the Tunisian population do not exist. This study aims to demonstrate the demographic, clinical and laboratory characteristics of SLE Tunisian patients and to identify those at high risk for renal and neuropsychiatricinvolvements. One hundred patients with SLE (American College of Rheumatology criteria), seen at the Department of Internal Medicine of the University Hospital La Rabta in Tunisia over a 15-year period (1987 to 2001) were retrospectivelyenrolled. There were 92 women and eight men with an average age at the onset of disease of 32 years. Nineteen patients were aged over 50 years at the moment of SLE diagnosis(late-onsetSLE). Of the patients,78% had articularinvolvement,53% photosensitivityand 63% malar rash. Serositis occurred in 45 patients of whom 16 had pericarditisand 29 had pleuritis. Nephritis was diagnosed in 43% of the cases and consisted always of glomerular nephritis, in three cases of which tubulointerstitiallesions were also observed. Comparison of patients with and without renal involvement showed that lupus nephritis was significantly associated with pericarditis (P 0.03), arterial blood hypertension (P < 0.0001), cryoglobulinemia (P 0.07) and antiphospholipid syndrome (P 0.03). The SLEDAI at SLE diagnosis was significantly higher for lupus nephritis patients. Twelve patients with lupus nephritis died compared with three patients in the remaining group (P < 0.0001). Neuropsychiatric manifestations were observed in 25% of the cases. The mean age at SLE onset was significantly lower, the mean SLEDAI at SLE diagnosis and the mortality were significantly higher in the neuropsychiatric group than in the remaining group. Immunological features included antinuclear antibodies (100%), anti-DNA antibodies (56%), anti-Sm antibodies (61%), anticardiolipin antibodies (62%), anti-b2GP1 (13%) anti-Rnp (23%) and hypocomplementemia (48%). The frequencies of pulmonary hypertension (25 versus 2%, P < 0.00001) and vascular thrombosis (25 versus 2%, P < 0.00001) were significantly higher in patients with positive anti b2GPI antibodies. The five-year survival rate in our series was 86%. The most frequent causes of death were active SLE and infections.
Inflammatory optic neuropathy (ON) is a rare event in Behçet's disease (BD). We report herein a series of ten BD Tunisian patients with ON and describe its clinical features among them. A ...retrospective review of BD patients (International Study Group for BD criteria) was performed. The patients were divided into two groups: those presenting an inflammatory ON, and those none. The diagnosis of inflammatory ON was based on the clinical examination, visual field and visual evoked potentials. We analyzed the characteristics of the two groups. Ten patients (2.3%) presented an inflammatory ON among our 440 patients. Inflammatory ON was inaugural in 8 cases. Clinical manifestations were as follows: blurred vision (7 cases) and periorbital pain (3 cases). In two cases, the patients did not complain from ophthalmological symptoms. The fundus revealed a papilledema (2 cases), papillary pallor (4 cases), and was normal in 5 cases. Visual field realized in only three patients showed a scotoma in all cases. Visual evoked potentials revealed increased latency in all cases. All patients received corticosteroids associated to an immunosuppressive agent. The comparative study between the two groups revealed that inflammatory ON was significantly more associated to neurological involvement (p<0.0001) and that the disease was more severe in the ON group (p<0.0001). Inflammatory ON in BD is rare and may occur at an early stage of the clinical course of the disease. Its prevalence is certainly underestimated. A systematic visual evoked potential may be interesting as a screening tool.
Interleukin‐15 (IL‐15) is a novel proinflammatory cytokine, involved in the pathogenesis of inflammatory/autoimmune disease. The objective of our study was to measure serum and cerebrospinal fluid ...(CSF) IL‐15 levels in patients with Behçet's disease (BD). CSF/serum IL‐15 ratio was introduced to assess the origin of elevated IL‐15 levels. We measured serum and CSF‐IL‐15 levels in 40 patients with BD (20 patients in active stage). Inflammatory and non‐inflammatory neurological disease patients acted as controls. Active BD patients have significantly higher serum IL‐15 levels (median 10.4 pg/ml; range 5.3–17.4) compared with BD in remission (6.05 pg/ml; 4–10.4) and healthy controls (4.65 pg/ml; 3.9–6.2). Similar serum IL‐15 levels were found in active neuro‐BD and inflammatory neurological disease (9.5 pg/ml; 5–13). Elevated levels of IL‐15 were observed in CSF samples from neuro‐BD patients (11 pg/ml; 8.5–15) and inflammatory neurological disease patients (10 pg/ml; 6.5–14) compared with patients with non‐inflammatory neurological disease (4 pg/ml; 4–5.5; P < 0.001). Vascular cerebral BD lesions were associated with high CSF/serum IL‐15 ratio. Our findings suggest that IL‐15 is involved in BD inflammatory process, particularly in vasculitis foci, as an elevated CSF/serum IL‐15 ratio characterizes vascular cerebral lesions.
Serum levels of the B-cell activating factor in the tumor necrosis factor family (BAFF), a potent contributor to B-cell survival, are elevated in patients with systemic autoimmune diseases. The ...objective of this study was to determine serum BAFF levels and to link the results to the clinical features in patients with skin manifestations.
Serum BAFF levels were examined by an enzyme-linked immunosorbent assay (ELISA) in 42 patients with BD (16 with active disease), 20 healthy controls, and in 20 patients with systemic lupus erythematosus (SLE) and 15 patients with multiple sclerosis (MS), who served as the disease control groups. Expression of BAFF messenger RNA (mRNA) in the skin was quantified by a real-time reverse transcription-polymerase chain reaction; the expression of BAFF receptor (BAFF-R) on CD19+ B cells was assessed by flow cytometry; and ELISA was used to evaluate the production of IgG, interleukin-6 (IL-6) and IL-10 by isolated B cells.
Serum BAFF levels were elevated in patients with active BD compared to the healthy controls, and correlated positively with the extent of skin lesions. Disease remission was accompanied by decreased BAFF levels. SLE patients had the highest serum BAFF levels. Skin biopsies showed BAFF mRNA expression to be up-regulated in active BD patients. BAFF-R expression on B cells was increased in BD patients with vasculitis. Furthermore, in BD patients the ability to produce IgG and IL-6 (but not IL-10) was enhanced in BAFF-stimulated B lymphocytes.
These results suggest that BAFF and its signalling in B cells contribute to B cell abnormalities and the development of skin disease in patients with BD.
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