FcgammaRIIa, IIIa and IIIb gene polymorphisms in Behçet's disease: do they have any clinical implications?

OBJECTIVE: Behçet's disease (BD) is a unique systemic vasculitis involving both arteries and veins of all sizes. Since Fcgamma receptors (FcgammaR) are important in mediating various immune effector functions, FcgammaR gene polymorphisms may affect the susceptibility to systemic inflammatory diseases such as BD. The aim of this study was to show the distribution of FcgammaRIIa, IIIa ve IIIb receptor gene polymorphisms in BD, and to investigate possible genotype-phenotype relationships. METHODS: In this cross-sectional study, FcgammaRIIa (H/H131, H/R131, R/R131), IIIa (F/F158, F/V158, V/V158), and IIIb (NA1/NA1, NA1/NA2, and NA2/NA2) receptor gene polymorphisms were investigated in 216 unrelated Turkish BD patients (M/F: 130/86) and in 241 healthy subjects, using an allele-specific polymerase chain reaction. RESULTS: The FcgammaRIIa R/R131 (p=0.019) and FcgammaRIIIa F/F158 genotypes (p=0.001) were found to be significantly more frequent in BD compared with healthy controls, whereas the FcgammaRIIIb genotypes were not (p=0.108). Allele analysis showed that the FcgammaRIIIa 158 (p=0.001) and FcgammaRIIIb NA2 (p=0.016) alleles were more frequent in BD than in healthy controls. In BD patients the FcgammaRIIIa V/V158 genotype was significantly associated with the presence of arthritis (p=0.002) and with an earlier disease onset (p=0.008), while the FcgammaRIIIb NA2/NA2 genotype was significantly associated with disease severity (p=0.02), vascular involvement (p=0.014), and pathergy positivity (p=0.02). CONCLUSION: We found that the genotype frequencies and allelic distributions of the FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb gene polymorphisms were significantly different between BD patients and healthy controls. In addition, certain FcgammaRIIIa and FcgammaRIIIb gene polymorphisms appear to be associated with an early disease onset, disease severity, the presence of arthritis, and vascular involvement in BD.

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.

Endothelial nitric oxide synthase gene Glu298Asp polymorphism is associated with Behçet's disease.

OBJECTIVE: The 894 G-->T (Glu298Asp) polymorphism in exon 7 of the endothelial nitric oxide synthase (eNOS) gene was previously reported to be associated with Behçet's Disease (BD) susceptibility in Italian origin and Korean patients, but not in a group of unrelated Turkish patients. We analyzed whether this polymorphism is associated with BD, in another group of Turkish patients. METHODS: We studied 132 consecutive Turkish BD patients being followed up by Ege University Rheumatology Department and 91 healthy controls. All individuals were genotyped by PCR-RFLP for 894 G-->T in exon 7 (Glu298Asp). RESULTS: The frequency of the T allele in BD group (101/264) was significantly higher than in healthy controls (OR 1.88, %95 CI 1.27-2.49, p < 0.001). The frequency of the homozygote (TT) Glu298Asp polymorphism in BD (27/132) was also significantly higher than in healthy controls (5/91) (OR 3.72, %95 CI 3.44-4.0, p < 0.001). However, no association was found between the Glu298Asp polymorphism and clinical parameters in BD. CONCLUSION: In this study, we found that Glu298Asp polymorphism of the eNOS gene was associated with BD in Turkish patients.

Pulmonary hypertension in rheumatoid arthritis.

Using Doppler echocardiography (DE), we measured pulmonary arterial systolic pressure (PASP) in rheumatoid arthritis (RA) patients without coexisting cardiopulmonary diseases. Accepting the normal upper limit of PASP as 30 mmHg, we found elevated PASP in 11 out of 40 (27.5%) RA patients, values being mostly 30-40 mmHg, indicating mild pulmonary hypertension (PHT). Although estimation of PASP by DE is not as reliable as cardiac catheterisation, it is possible that mild elevations in PASP may contribute to the high incidence of cardiovascular events not explained by traditional cardiac risk factors in patients with RA. Long-term follow-up will be obviously necessary to ascertain the impact of mild PHT on the prognosis and mortality rate of RA patients.

Hyperhomocysteinaemia in Behçet's disease.

OBJECTIVE: Arterial and venous thrombosis are among the clinical features of Behçet's disease (BD), the pathogenesis of which is not completely understood. In this study, we investigated whether hyperhomocysteinaemia, being a well known risk factor for thrombosis, is also a contributive risk factor for the arterial and venous thrombosis of BD. METHODS: Eighty-four patients fulfilling the criteria of the International Study Group for Behçet's Disease (54 males, 30 females, mean age 36+/-9 yr) were enrolled. All the patients were carefully screened for a history of venous thrombosis and were separated into two groups with respect to thrombosis history. Thirty-six healthy individuals (23 males, 13 females), matched for age and sex with the BD group, were included as a negative control group. Patients were excluded if they had any condition that might affect plasma homocysteine concentration. As methotrexate (MTX) causes hyperhomocysteinaemia, we also included 29 rheumatoid arthritis patients (five males, 24 females) receiving MTX weekly. Fasting plasma homocysteine concentrations were measured by high-performance liquid chromatography. The data were analysed with the chi(2) test and Student's t-test. RESULTS: The highest homocysteine concentrations were found in the MTX group (17.5+/-5.3 micromol/l). Mean plasma homocysteine concentrations in BD patients were significantly higher than in the healthy controls (11.5+/-5.3 vs. 8.8+/-3.1 micromol/l, P<0.001). Among BD patients with a history of thrombosis, 20 of 31 (64%) had hyperhomocysteinaemia, and this was significantly higher than in those without thrombosis (9%). On the other hand, there was no significant difference between patients with non-thrombotic BD and healthy controls (P>0.05). In patients with thrombosis, we found no correlation between the duration of the post-thrombotic period and homocysteine concentration. Among all the variables investigated, only hyperhomocysteinaemia was found to be related to thrombosis. CONCLUSION: Hyperhomocysteinaemia may be assumed to be an independent risk factor for venous thrombosis in BD. Unlike the factor V Leiden mutation, hyperhomocysteinaemia is a correctable risk factor. This finding might lead to new avenues in the prophylaxis of thrombosis in BD.

Analysis of meatal location in 300 boys.

The high incidence of anterior hypospadias and the consideration of some of the parents that this location is a normal variation and the resistance to the surgical treatment led us to investigate the normal meatal location in boys. The location of external meatus was analyzed in 300 boys. The meatal location was classified as type A (anterior third/tip of the glans) type B (middle third) and type C (posterior third/glandular hypospadias). Of the 300 boys taken into study, in 282 (94%) meatus was located at the tip of the glans in 14 patients (4.6%) on the middle third, 'type B' and in 2 patients (0.6%) on the posterior third, 'type C'. The present study clearly demonstrated that the true location of urethral meatus should be at the tip of the glans. Type B is an acceptable location, which requires no operation and is seen in a very small percentage. Type C is a true glandular hypospadias and should certainly be corrected by glanuloplasty and meatal advancement. We are of the opinion that after surgery for anterior hypospadias meatal position presenting elsewhere than at the tip of the glans should not be considered a successful intervention.

Activated Protein C Resistance in Behçet's Disease.

We investigated activated protein C resistance (aPCR) using modified activated partial thromboplastin time (aPTT) in 32 patients with Behçet's disease (BD) and 9 healthy controls. None of the healthy controls were found to have aPCR. However, 11 out of 32 Behçet's patients (34.3%) were found to have aPCR. The frequency of aPCR was increased to 44.4% among 18 Behçet's patients having a history of venous thrombosis. In the subgroup of 14 patients without venous thrombosis, aPCR frequency was %22.2. Our findings show that, besides other factors, aPCR may also predispose patients to venous thrombosis in BD. The detection of aPCR, using modified aPTT may serve as a routine screening test to determine the necessity of prophylactic anticoagulation reatment in patients with BD.

A case of Lafora's disease associated with cardiac arrhythmia.

Progressive myoclonic epilepsies are rare, genetically transmitted diseases characterized by epileptic seizures, myoclonus, and progressive neurologic deterioration. Unverricht-Lundborg disease, Lafora's disease, neuronal ceroid lipofuscinosis, mitochondrial disorders, and sialidosis are included in this group. Lafora's disease is a progressive disorder of the central nervous system with onset in the late first or second decade of life and is inherited in an autosomal-recessive pattern. The first clinical manifestation is generalized tonic-clonic seizures, myoclonus, or both, usually seen between the ages of 11 and 18 years. The other clinical manifestations are progressive dementia and limb ataxia. Diagnosis is based on showing the typical inclusions in the brain, liver, skin, or muscle tissue specimens. The case of a 6-year-old male patient, who was admitted with the clinical findings of third-degree atrioventricular block and dementia and eventually diagnosed with Lafora's disease, is presented.

Prevalences of hepatitis A, B, C and E viruses in Behçet's disease.

OBJECTIVE: To determine whether Behçet's disease (BD), being a systemic vasculitis of unknown aetiology, is associated with hepatitis viruses (HAV, HBV, HCV and HEV). METHODS: In addition to 124 patients [male:female (M/F): 73/51], all fulfilling the diagnostic criteria of the International Study Group for BD (1991), 14 patients with systemic necrotizing vasculitis (M/F: 7/7), 47 patients with ankylosing spondylitis (M/F: 36/11) and 51 healthy controls (M/F: 22/29) were also included in this study. Serological markers of four different types of hepatitis (anti-HAV IgM, total anti-HAV, HBsAg, anti-HBs, total anti-HBc, anti-HBc IgM, anti-HCV and anti-HEV) were studied in all cases. RESULTS: There was no difference between the groups with respect to HAV, HCV and HEV serologies. Anti-HBs positivity was observed less frequently in BD compared with healthy controls and systemic vasculitis (P<0.05). CONCLUSION: Serological evidence of previous HAV, HCV and HEV infections was not significantly different between Behçet's patients and other groups. However, previous HBV infection was found in a significantly lower number of BD patients as compared with healthy controls and systemic vasculitic patients.

Serum prolactin levels in Behçet's Syndrome.

Since prolactin (PRL) has been implicated as playing a role in the pathogenesis of certain autoimmune diseases and since Behcet's Syndrome (BS) is a unique systemic vasculitis, we investigated serum PRL levels in patients with BS. We found that mean PRL levels in patients with clinically active BS, were not significantly higher than patients with clinically inactive BS and healthy controls. This finding may be regarded as evidence that a contribution of hyperprolactinemia to the aetiopathogenesis of BS seems unlikely.

Adhesive arachnoiditis causing cauda equina syndrome in ankylosing spondylitis: CT and MRI demonstration of dural calcification and a dorsal dural diverticulum.

We present the radiological features of a 42-year-old man with long-standing inactive ankylosing spondylitis (AS), demonstrating that arachnoiditis is a cause of a cauda equina syndrome (CES) in this disease. CT showed a dorsal arachnoid diverticulum causing scalloped erosion of the laminae, and punctate and curvilinear dural calcification. MRI revealed adhesion and convergence of the cauda equina dorsally into the arachnoid pouch, causing the dural sac to appear empty canal. To the best of our knowledge, dural calcification on CT is a new finding in AS, which may be related to the CES. Our findings support the hypothesis that chronic adhesive arachnoiditis with subsequent loss of meningeal elasticity may be the main cause of CES in AS.

Transcranial Doppler detection of microembolic signals in patients with Behçet's disease.

We evaluated the prevalence of microembolic signals (MES) in patients with Behçet's disease (BD). We also attempted to determine the frequency of MES in BD patients with or without neurological involvement. This study enrolled 55 patients fulfilling the diagnostic criteria of International Study Group for BD. Bilateral transcranial Doppler ultrasound of the middle cerebral arteries was performed. MES were identified based on the criteria of International Consensus group on Microembolus Detection. Patients with BD were divided into two groups in respect of the presence of neurological involvement (n = 10) or not (n = 45), and counts of MES in the two were compared with each other and with normal subjects. We found MES in 16 patients (29%) with BD. The frequency was higher in patients with neurological involvement than in those without (80% vs. 17%, P< 0.001). In patients with neurological involvement there was a positive correlation in regression analysis between the prevalence of MES and disease duration (P = 0.025). There was a significantly higher prevalence of MES in BD patients than in control subjects. The frequency of MES was higher in patients with neurological involvement than in those without. TCD detection of MES may allow the recognition of subset of patients at high risk for the appearance of neurological involvement.

Two siblings with juvenile hyaline fibromatosis: case reports and review of the literature.

In this paper, we describe two siblings with Juvenile Hyaline Fibromatosis (JHF) who were diagnosed at the age of 34 and 29 years respectively. JHF is a very congenital disease, mainly diagnosed in the first few years of life, with less than 40 published cases in literature. All the main clinical features of this syndrome, which may be summarised as multiple subcutaneous tumours, marked gingival hypertrophy, flexion contractures and osteolytic lesions were present in both of these cases. Clinical, radiological and histological differential diagnosis of JHF were made. Recent information about histopathology, treatment and prognosis of JHF was also reviewed.

Zinc tolerance test patterns in normal children and in moderate and severe zinc deficiency states.

Twenty-six normal, 38 moderately and 14 severely zinc-deficient children, aged 2-12 years, were examined by clinical and laboratory approaches. After fasting-blood sampling, 120 mg zinc sulphate (25 mg elemental zinc) were administered orally to each group of children, to obtain zinc tolerance curve patterns. Sampling proceeded to the 2nd and 4th hours of the loading-test period. Plasma zinc was assessed on an atomic absorption spectrophotometer. In normal children, at the 2nd hour of loading, a significant (p < .001) elevation (1.764 +/- 0.133 mg/l) in the mean (+/- SEM) plasma zinc level was noted; also at the 4th hour a significant (p < .001) decrease (1.506 +/- 0.123 mg/l) in the mean plasma zinc level was shown. The mean plasma zinc level at the 4th hour was found higher than the mean fasting plasma zinc level (1.054 +/- 0.061 mg/l), but lower than the mean level found at the 2nd hour. In moderately zinc-deficient children, the rise in the 2nd hour and the fall in the 4th hour in the plasma zinc level were highly significant (p < .001 and p < .001, respectively) in relation to fasting blood level. However, in severely zinc-deficient children, the intensity of the increase (0.746 +/- 0.147 mg/l) in plasma zinc level at the 2nd hour was of lesser significance (p < .006) and the fall (0.424 +/- 0.061) mg/l) at the 4th hour was not significant. Therefore, in children with normal plasma zinc levels, an increase of more than 0.50 mg/l was seen at the 2nd hour of loading. This rise was seen to persist at the 4th hour. However, in children with moderate zinc deficiency, although again an increase of 0.50 mg/l was seen at the 2nd hour this increase did not persist at the 4th hour; and the 4th-hour value showed a significant decrease in relation to the 2nd hour value. Whereas, in children with severe zinc deficiency the rise of plasma level at the 2nd hour was less than 0.5 mg/l and the fall at the 4th hour was to such a level which was not significant in relation to fasting zinc level. This could be due to enhanced uptake of zinc off the circulation by the depleted tissues in severe zinc deficiency.

Multicentric reticulohistiocytosis.

We describe a 42-year-old man with a five-year history of arthritis mutilans-like destructive joint changes and with a one-year history of nodules on the fingers, ears, oral mucosa, pharynx, larynx, vocal cords, some being ulcerated and haemorrhagic. He was diagnosed as having rheumatoid arthritis; however, biopsies from the nodules on the oral mucosa and ear revealed multicentric reticulohistiocytosis. The large nodule over the olecranon process, simulating a rheumatoid nodule but diagnosed as multicentric reticulohistiocytosis with biopsy; ulcerated and haemorrhagic nodules on the oral mucosa; and rapidly progressive joint destructions make our case interesting.