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.

Differences in pain and fatigue perception among a group of rheumatoid arthritis patients in the United States and in Turkey who have similar disease activity and functional status.

OBJECTIVES: The concordance of patient reported outcomes in rheumatoid arthritis (RA) among different countries has not been studied in detail. We tried to determine the differences in pain and fatigue perception among a group of RA patients in the US and in Turkey who had similar disease activity and functional score in multidimensional health assessment questionnaire (MDHAQ FN). METHODS: One hundred and thirty seven RA patients from Turkey and 129 from the US were studied. An MDHAQ was obtained and a DAS28 was calculated for each patient. Pain and fatigue perception was compared between the two groups after adjusting for age, sex, MDHAQ FN and DAS 28. RESULTS: Turkish patients had less pain than their US counterparts when adjusted for MDHAQ FN, DAS 28, age and sex (3.56 (2.24) vs. 4.35 (2.23), p=0.005) whereas there was no difference in fatigue between the two groups (3.85 (2.44) vs. 4.25 (2.45), p=0.194). When the patients with a DAS28 score of above 5.1 and below 2.6 were compared in both groups, Turkish patients had again less pain albeit less in the high disease activity group. CONCLUSIONS: This study suggests that Turkish patients have less pain than the US patients when controlled for age, gender and MDHAQFN and DAS28 scores. This is at odds to the conventional wisdom that pain perception is increased among the non-Western cultures.

Takayasu's arteritis in Turkey - clinical and angiographic features of 248 patients.

OBJECTIVE: Takayasu's arteritis (TA) is a chronic, inflammatory vasculitis affecting the aorta and its major branches. Although it is more prevalent in Far-East Asia, the distribution of the disease is worldwide with different vascular involvement patterns and clinical manifestations. The objective of this study was to evaluate the demographic, clinical, angiographic and prognostic features of TA patients in Turkey. METHODS: Clinical and angiographic findings of 248 TA patients (228 female, 27 male) followed at 15 Rheumatology Centers were prospectively evaluated according to a predefined protocol. RESULTS: The mean age was 40.1 years (30.2 years at the clinical onset). Clinical manifestations included constitutional symptoms in 66%, absent or diminished pulses in 88%, bruits in 77%, extremity pain in 69%, claudication in 48%, hypertension in 43% and cerebrovascular accidents (CVA) in 18% of the patients. Renal artery stenosis, aortic regurgitation and pulmonary hypertension were present in 26%, 33% and 12%, respectively. According to the new angiographic classification, type V (50.8%) and Type I (32%) were the most frequent types of involvement. Corticosteroids were the main treatment in 93% of the patients alone (9%) or in combination with immunosuppressive agents (84%). Most frequently preferred immunosuppressive agents were methotrexate (63%), azathioprine (22%) and cyclophosphamide (13%). Remission was observed at least once in 94% of the patients and sustained remission in 71% during follow-up. CONCLUSION: The demographical, clinical and angiographic findings of TA patients in our series were similar to those reported from Japan, Brazil and Colombia. Combination therapies with immunosuppressive agents were the preferred choice of treatment in Turkey.

PTPN22 gene polymorphism in Takayasu's arteritis.

OBJECTIVE: Takayasu's arteritis (TA) is a chronic, rare granulomatous panarteritis of unknown aetiology involving mainly the aorta and its major branches. In this study, genetic susceptibility to TA has been investigated by screening the functional single nucleotide polymorphism (SNP) of PTPN22 gene encoding the lymphoid-specific protein tyrosine phosphatase. METHODS: Totally, 181 patients with TA and 177 healthy controls are genotyped by PCR-RFLP method for the SNP rs2476601 (A/G) of PTPN22 gene. Polymorphic region was amplified by PCR and digested with Xcm I enzyme. RESULTS: Detected frequencies of heterozygous genotype (AG) were 5.1% (9/177) in control group and 3.8% (7/181) in TA group (P = 0.61, odds ratio: 0.75, 95% CI: 0.3, 2.0). No association with angiographic type, vascular involvement or prognosis of TA was observed either. CONCLUSION: The distribution of PTPN22 polymorphism did not reveal any association with TA in Turkey.

IL-6 receptor, IL-8 receptor and TNF-alpha238 (G/A) polymorphisms are not associated with Behçet's disease in patients of German or Turkish origin.

OBJECTIVE: To assess the association of polymorphisms of the IL-6 receptor gene (+24013A/G:Ala31Ala; +48892 A/C:Asp358Ala), the IL-8 receptor gene (+2607G/C:Ser/Thr IL-8RA), and TNF-alpha 238 (G/A) single nucleotide polymorphism (SNP) with Behçet's disease in patients of German or Turkish origin. METHODS: DNA was extracted from blood samples taken from patients in Germany (n=93) and Turkey (n=28), as well as from 51 German and 20 Turkish healthy controls. The polymorphisms were analysed by PCR with the LightCycler system. RESULTS: No significant association was found between TNF-alpha 238, +2607 IL-8RA, +48892 IL-6R or +24013 IL-6R- polymorphisms and nationality or disease. Statistically there was no difference between the patients and controls (TNF-alpha 238: p = 0.86; +2607 IL-8RA: p=0.23; +48892 IL-6R: p=0.087; +24013 IL-6R: p = 0.80) nor between Germans and Turks (TNF-alpha 238: p=0.13; +2607 IL-8RA: p=0.68; +48892 IL-6R: p=0.32; +24013 IL-6R: p=0.65). CONCLUSION: The single nucleotide polymorphisms of the IL-6 and IL-8 receptor genes and the TNF-alpha gene analysed here do not appear to be associated with Behçet's disease.

The role of HLA-DRB1 shared epitope alleles in predicting short-term response to leflunomide in rheumatoid arthritis.

OBJECTIVES: To investigate the role of shared epitope (SE) alleles in the short-term clinical response to leflunomide for the treatment of active RA. METHODS: In an open-label, multi-centre study of 16-weeks duration, 93 patients (82% female) fulfilling ARA 1987 RA criteria were treated with leflunomide (100 mg loading dose for 3 days, then 20 mg/day as the maintenance dose). The primary efficacy criterion was the response status according to the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score-28 (DAS28) activity measure. SE determinations have been undertaken by polymerase chain reaction and sequence-specific oligonucleotide genotyping methods. RESULTS: The mean (s.d.) Disease Activity Score-28 (DAS28) was 5.1 (1.3) before the treatment, which was significantly decreased after 16 weeks [3.0 (1.1), P < 0.001]. According to the EULAR response criteria, 55 patients (59.1%) were classified as good responders. SE was positive in 51 (54.8%) of the patients, with 13 (13.9%) having SE homozygosity or carrying any two SE alleles. Among SE-positive patients, 68.6% (35/51) were good responders, compared with 47.6% (20/42) in SE negatives (P = 0.04). No difference was present according to SE hetero- or homozygosity (68.4 vs 69.2%). RF was also present significantly more frequently in the SE-positive group compared with negatives (78.4 vs 57.1%, P = 0.03). However, no significant difference was observed in the prevalence of RF positivity in patients with a good clinical response (72.7 vs 63.2%, P = 0.32). CONCLUSIONS: The results suggest that HLA-DRB1 SE presence may favourably affect the outcome of leflunomide monotherapy in an unselected group of RA patients with an active disease and naive to leflunomide.

Interleukin (IL)-12, IL-2, and IL-6 gene polymorphisms in Takayasu's arteritis from Turkey.

Takayasu's arteritis (TA) is a chronic arterial inflammation of unknown etiology involving mainly the aorta and its major branches. Genetic polymorphisms of cytokines are screened as susceptibility factors for TA in Turkey. A total of 94 patients with TA were investigated for the genetic polymorphisms of the interleukin genes IL12, IL2,and IL6 and were compared with 108 healthy control subjects using polymerase chain reaction-sequence-specific primer method. The frequencies of IL12B 1188 C allele (p = 0.03, OR = 1.7) and CC genotype (p = 0.007, OR = 3.7) were both higher in TA patients than in control subjects. TT genotype at IL2-330 (p = 0.006, OR = 2.4) and GG genotype at IL6-174 (p = 0.04, OR = 1.9) were more frequent in TA patients. Lower prevalence of GT genotype at IL2-330 (p = 0.005, OR = 0.4), CG genotype at IL6-174 (p = 0.001, OR = 0.4), and AG genotypes at IL6-598 (p = 0.01, OR = 0.4) were also detected. The polymorphism of IL-12 as well as IL-6 and IL-2 genes may contribute to susceptibility and pathogenesis of TA by altering cytokine production and inducing inflammation.

Oxidative burst response to monosodium urate crystals in patients with Behçet's syndrome.

OBJECTIVE: An erythematous response to intradermal injection of monosodium urate crystals (MSU) has been demonstrated in Behçet's syndrome (BS). To further elucidate the pathogenesis of this response, the effects of MSU on in vitro oxidative burst reaction of neutrophils and monocytes were investigated. METHODS: Peripheral blood mononuclear cells from patients with Behçet's syndrome (BS), rheumatoid arthritis (RA), familial Mediterranean fever (FMF) and healthy controls (HC) were incubated with 100 ng/ml phorbol myristate acetate (PMA) and MSU at different dosages (25-500 microg/ml). Oxidative burst reaction was evaluated in neutrophils and monocytes by flow cytometry. RESULTS: In patients with BS, oxidative burst of neutrophils was significantly increased compared to HC at 125 microg/ml and 250 microg/ml dosages of MSU (p < or = 0.001 and 0.004 respectively). In patients with FMF; there was also an increased oxidative burst reaction at 75 microg/ml, 250 g/ml and 500 microg/ml (p < or = 0.007; 0.001 and 0.004 respectively). In patients with BS, oxidative burst of monocytes was increased only at 125 g/ml dosage of MSU (p < or = 0.002). However, in patients with FMF monocyte burst response was increased at 25 microg/ml, 75 microg/ml and 125 g/ml (p < or = 0.004; < 0.0001; < 0.0001 and 0.002 respectively). In RA group, stimulation with PMA resulted in a higher oxidative burst reaction than FMF and BS (p < or = 0.000 and p < or = 0.008). No correlation was observed between oxidative burst of neutrophils or monocytes and intradermal responses to MSU crystals. CONCLUSION: Oxidative burst reaction with MSU is augmented in neutrophils and monocytes of BS. However, the response is not specific and is unassociated with skin dermal test which has a high specificity for 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.

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.

Reversible decrease of dopamine D2 receptor density in the striatum of rats with acute hepatic failure.

The binding of a D2 receptor ligand, [3H]spiperone, was measured in striatal membranes derived from rats in which acute hepatic failure induced with thioacetamide (TAA) was associated with symptoms of hepatic encephalopathy (HE), and during recovery from HE. A 28% decrease of Bmax for the binding was measured in a symptomatic stage of HE, 1 day after TAA administration. The B(max) for [3H]spiperone binding was no longer different from control 7 days after TAA administration, when blood and brain biochemical correlates of HE were already absent. At 21 days after TAA administration, the B(max) was increased by 31% above the control level, consistent with other aspects of metabolic activation of the brain characteristic of the late recovery period from acute HE.

Nailfold capillary abnormalities in patients with familial Mediterranean fever.

OBJECTIVE: To determine the frequency and the degree of the nailfold capillary abnormalities in patients with familial Mediterranean fever (FMF). METHODS: We studied 67 (M/F: 28/39) patients with FMF. Thirty-seven healthy subjects (16/21), 19 patients (0/19) with systemic lupus erythematosus (SLE), and 8 patients (0/8) with scleroderma (PSS) were also studied. All participants were questioned for the presence of Raynaud's phenomenon (RP). Capillary loops of eight fingers were evaluated and scored with respect to avascular areas, tortuosity, enlargement and extravasations by the conventional capillary microscopy. Both FMF patients and healthy controls were examined in a blind manner. RESULTS: FMF patients differed from healthy controls by the presence of increased tortuosity and enlargement of capillary loops, but not by microhemorrhages. Being female and the presence of RP were the factors that correlated with the capillaroscopic findings. CONCLUSION: Capillary abnormalities are seen in patients with FMF.

Behçet's syndrome. The Cerrahpasa experience. Members of the Behçet's Syndrome Research Centre.

Behçet's syndrome (BS) is a systemic vasculitis of unknown etiology. There are several reasons for doubting a primary autoimmune pathogenesis of this condition. Recent information suggests evidence for genetic anticipation. Although there is heightened inflammatory activity, as exemplified by the pathergy reaction, wound healing in BS is normal. BS also runs a more stormy course in adults and in the young. However, the amount of androgen receptors in scrotal skin have not found to be increased. Another unsolved problem is the nature of acne-like lesions and how they differ from acne vulgaris (AV). Only lesions in "non-acne" areas were compared between the two conditions, and no differences were detected. Mortality is increased in BS, especially among males. Azathioprine proved to be effective in disease control after 8 years of follow-up. We have also recently finished a 24 week controlled trial of two doses of thalidomide, 100 mg and 300 mg per day. Both doses were superior to placebo, with no real differences in efficacy, in controlling the oral and genital ulcers.

Hair diameter in systemic lupus erythematosus.

It is widely appreciated that patients with systemic lupus erythematosus (SLE) get thinner and shorter hair. However little work has been done to quantitate this. We assessed hair thickness of SLE patients and compared this to that of patients with rheumatoid arthritis (RA) and healthy controls (HC). Fifty-seven female patients with SLE (mean age: 32 +/- 8 years) and 77 female patients with RA (mean age: 50 +/- 12 years) were studied along with 75 healthy women (mean age: 27 +/- 6 years). Five strands of hair were taken from each subset and mounted on glass slides. Two independent observers, blind to the sources of the hair, measured the hair strands under a light microscope, using a micrometer. Finally, the mean hair thickness between each of the three groups was calculated. The hair in both SLE and RA patients was found to be thinner than that of HC by both observers (P < 0.001). Age adjusted analysis between SLE and HC showed similar results. However, there was no significant difference in hair thickness between SLE and RA. SLE patients have thinner hair compared to HC. More studies are needed to investigate the effect of disease activity, therapy and other factors on hair diameter.

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

OBJECTIVES: Corticosteroids are widely used in Behçet's syndrome despite the absence of controlled studies. We assessed the effect of depot corticosteroids primarily for genital ulcers and secondarily for the other mucocutaneous manifestations of Behçet's syndrome. METHODS: We randomized 86 patients who had active disease with genital ulcers to receive either intramuscular corticosteroid injections (40 mg methylprednisolone acetate) or placebo every 3 weeks for 27 weeks. RESULTS: Seventy-six patients (88%) completed the treatment. There were no significant differences in the mean number of genital and oral ulcers, or folliculitis between groups. The mean number of erythema nodosum lesions was less in the corticosteroid group as a whole (P = 0.0046); subgroup analyses revealed that this was significant for females (P = 0.0148) but not for males (P = 0.1). CONCLUSION: Low-dose depot corticosteroids did not have any beneficial effect on genital ulcers. However, it was useful in controlling erythema nodosum lesions, especially among the females.

The relationship between arthritis and human parvovirus B19 infection.

In order to evaluate the role of human parvovirus B19 in the etiopathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), synovial fluid and blood specimens were collected at 1-month intervals from 20 patients with early synovitis (ES) and 31 with RA. Blood specimens were also collected from 25 patients with SLE, 25 with osteoarthritis (OA) as the diseased control group, and 50 healthy blood donors (HBD) as the healthy control group. Detection of B19 IgM and B19 IgG were performed by enzyme-linked immunosorbent assay from serum specimens, and B19 DNA was detected by polymerase chain reaction from synovial fluid samples. B19 IgM, B19 IgG, and B19 DNA were found in the three patients of the ES group. Subsequently, two of them were diagnosed with RA and one with SLE. B19 DNA was also detected in the synovial fluid of eight patients in the RA group. Of them, all were positive for B19 IgG and half were positive for B19 IgM. B19 IgM was not detected in either of the control groups. To define the role of B19 in the etiopathogenesis and prognosis of undiagnosed arthritis and other chronic inflammatory diseases such as RA and SLE, we need broader serial and prospective studies based on clinical and laboratory collaboration. In conjunction with case reports, these studies would also serve to detect other possible factors in the etiopathogenesis of chronic inflammatory diseases.