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.

Nail changes in connective tissue diseases: do nail changes provide clues for the diagnosis?

OBJECTIVE: To evaluate the frequency and the specificity of nail changes associated with connective tissue diseases (CTD). METHODS: In a case-control study, 190 patients including those with systemic lupus erythematosus (SLE; 56), rheumatoid arthritis (RA, 47), primary Sjögren's syndrome (pSS; 35), systemic sclerosis (SSc; 39), and dermatomyositis/polymyositis (DM/PM; 13) were enrolled in the study. Patients with SLE and other CTDs were compared with two different control groups. Twenty nails were examined. Nail features were noted and classified. Nail samples were collected for mycological cultures. RESULTS: In patients with SLE, erythema of proximal nailfold (P<0.01), splinter haemorrhages in fingernails (P<0.01), capillary loops in proximal nailfold (P<0.05), periungual erythema (P<0.05), and thin nail plates (P<0.05) were more common than those in controls. Only splinter haemorrhages were associated with the disease activity. In patients with SSc and DM/PM, splinter haemorrhages (P<0.05) and capillary loops in proximal nailfold (P<0.01) in fingernails were common as well. Increase in longitudinal curvature (P<0.001), transverse curvature (P<0.01), and white dull colour in fingernails were other frequent findings in patients with SSc. Increase in transverse curvature was associated with the disease activity in SSc. In patients with RA, splinter haemorrhages (P<0.05), red lunula (P<0.05), and white dull colour (P<0.05) in fingernails were frequent. The sensitivity values of all these changes were very low. However, their specificity values were found to be relatively high. CONCLUSION: Proximal nailfold is the most important site of affection in CTDs. These nail changes can be used in combination with highly sensitive diagnostic modalities to establish an accurate diagnosis.

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.

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.

Increased thickness of the carotid artery intima-media assessed by ultrasonography in Behçet's disease.

OBJECTIVE: Behçets disease (BD), is a unique systemic vasculitis, which affects almost all types and sizes of blood vessels. Carotid intima-media thickness (IMT) is an endothelial cell dysfunction (ECD) parameter which may also be associated with atherosclerosis. We aimed to search carotid IMT and plaque formation in BD, using high-resolution B-mode Doppler ultrasonography (USG). METHODS: We studied 114 BD patients (M/F: 68/46; mean age 38.15 +/- 9.44 years; disease duration 121 +/- 79 months), being followed up by Ege University Rheumatology Department. Age and sex-matched, 77 healthy controls, and as the disease control group 46 non-matched SLE patients were also included. Exclusion criteria for all the study participants were hypertension, hyperlipidemia, diabetes mellitus, obesity and history of cardiovascular or cerebrovascular disease. Comparison of the three groups were made by ANOVA and for post-hoc confirmation, Bonferoni test was used. RESULTS: The carotid IMT in BD (mean +/- SD, 0.55 +/- 0.14 mm) was significantly higher than in healthy controls (0.48 +/- 0.09 mm) (p = 0.004), but significantly lower than in SLE (0.66 +/- 0.24 mm) (p = 0.001). Likewise, plaque frequency in BD (5/114) was significantly higher than in healthy controls (0/77), but significantly lower than in SLE (8/46) (p < 0.001). CONCLUSION: Despite significantly higher carotid IMT and plaque frequency in BD compared with healthy controls, these parameters in BD were not as marked as in SLE. Less severe carotid artery abnormalities in BD, may partially explain why cardiovascular morbidity and mortality do not seem to be increased in BD, unlike in SLE.

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.

The urinary excretion of glycosaminoglycans and heparan sulphate in lupus nephritis.

Renal involvement in systemic lupus erythematosus (SLE) affects the disease outcome. In order to advance the diagnosis and the initiation of therapy, non-invasive diagnostic techniques are required. In this study, urinary glycosaminoglycans (GAG) and heparan sulphate (HS) were measured in 26 patients with biopsy-proven lupus nephritis and compared to 16 healthy controls. Uronic acid as a representative of GAGs in urine was determined spectrophotometrically with the meta-hydroxydiphenyl, following acid treatment. HS was determined as hexosamine by the method of Smith and Gilkerson. The median values of GAG (3.99 mg/g crea./day) and HS (2.41 mg/g crea./day) in patients were significantly ( P = 0.001) higher than in the control group (1.98 and 0.87, respectively). There was a positive correlation between GAG and HS values ( P = 0.000, r = 0.924) in SLE patients. There were no differences in HS excretion, microalbuminuria and SLE-DAI scores between different classes of lupus nephritis. However, GAG values in class 3 nephritis were significantly ( P = 0.033) higher than from both class 2 and class 4 lupus nephritis. There were no differences in all the measured parameters between normoalbuminuric, microalbuminuric and macroproteinuric patients. Furthermore, there were no correlations between GAG, HS excretions and SLE-DAI scores or microalbuminuria. These results suggest that urinary GAG and HS may serve as useful, independent and non-invasive markers of lupus nephritis.

Spontaneous bilateral perirenal hematoma as a complication of polyarteritis nodosa in a patient with human immunodeficiency virus infection.

We present a 29-year-old man with polyarteritis nodosa (PAN) having human immunodeficiency virus (HIV) infection. This patient fulfilled the American College of Rheumatology (ACR) 1990 criteria for PAN, and the diagnosis was confirmed by typical arteriographic findings, including microaneurysms. Due to the rupture of microaneurysms, perirenal hematomas occurred in both kidneys. Unilateral nephrectomy was performed, and renal histology confirmed that aneurysm rupture was the etiology of the perirenal hematoma. The occurrence of renal hematomas is a usual complication of PAN. However, bilateral renal hematoma during the course of HIV-associated PAN is quite rare, and to our knowledge, this would be the second case reported in the literature. When compared with other viral agents, the association of HIV with PAN may be considered rare. However, as suggested by various reports in the literature, HIV infection should always be kept in mind while evaluating patients with PAN.

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.

Hypothalamus-hypophysis-thyroid axis, triiodothyronine and antithyroid antibodies in patients with primary and secondary Sjögren's syndrome.

It has been well established that, anti-thyroglobulin antibodies (ATG) and anti-microsomal antibodies (AMC) may be present in various thyroid disorders and other systemic autoimmune diseases, including Sjögren's syndrome (SS). However, presence of circulating autoantibodies to thyroid hormones, i.e. both to triiodothyronine (T3) and tetraiodothyronine (T4), has not been studied extensively in SS. Autoantibodies to T3 and T4 are very important, because serum T3 and T4 levels may be detected spuriously higher or lower, due to the presence of these autoantibodies. Their presence should be suspected when measured serum thyroid hormone levels are not consistent with clinical status of the patient. SS is a slowly progressive, inflammatory autoimmune disease, affecting primarily the exocrine glands. Thyroid gland, being a target in some autoimmune diseases, is well known to be affected in SS as well. Keeping this possibility in mind, we investigated T3 autoantibody levels and thyroid gland involvement in patients with SS. Twenty-six SS patients (F/M:22/4) with a mean age of 46.6 years, were recruited in this study. Twelve of them were accepted as primary SS (pSS), while others had secondary SS (sSS) (7 with rheumatoid arthritis (RA), 3 with systemic lupus erythematosus (SLE), 3 with progressive systemic sclerosis (PSS) and 1 with sarcoidosis). Thyroid function tests, including T3, T4, fT3, fT4, TSH, ATG, AMC, T3 antibody measurements, thyroid scintigraphy, thyroid ultrasonography and TRH stimulation tests were performed in all patients. We compared our results with those of the twenty healthy normal controls. Serum ATG and/or AMC were detected in three patients with pSS (25%) and no patients with sSS. No significant difference could be shown in the other parameters, including T3 autoantibodies and thyroid function tests. TRH stimulation test was also normal, showing that the hypothalamus-hypophysis-thyroid axis was not affected in patients both with pSS and sSS. In conclusion, we found that T3 autoantibody levels in pSS, were not significantly higher than sSS and normal controls.

An unusual presentation of Behçet's disease: intestinal perforation.

Behçet's disease (BD), when first described in 1937, consisted of three symptoms: recurrent oral and genital ulcerations and iridocyclitis. Today, it is known that BD is a multisystemic chronic vasculitic disorder which may involve both arteries and veins of all sizes, as well as the central nervous and gastrointestinal systems. The rate of gastrointestinal involvement of BD varies in different populations, being more common in Japan (50%-60%) and less common in the Mediterranean basin, including Turkey (0%-5%). We present a 34-year-old Turkish woman with BD who had ileal and colonic ulcerations complicated by perforation and gastrointestinal bleeding. Special emphasis was placed on the differential diagnosis between Crohn's disease (CD) and BD with gastrointestinal involvement.

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.

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.

Anticardiolipin antibodies in acute rheumatic fever and chronic rheumatic heart disease: is there a significant association?

OBJECTIVE: The incidence and significance of IgG and IgM anticardiolipin antibodies (aCLa) in patients with acute rheumatic fever (ARF), chronic rheumatic heart disease (CRHD) and streptococcal pharyngitis have been investigated in order to determine whether these antibodies play an important role in the pathogenesis and if they are markers that can be used to confirm disease activity. METHODS: An enzyme-linked immunosorbent assay was used to measure the IgG and IgM aCLa levels. aCLa levels of patients were considered positive if they were greater than 3.0 standard deviations above the mean for healthy children. RESULTS: No significant difference in aCLa levels was found between patients with rheumatic fever or streptococcal pharyngitis and healthy controls, and aCLa concentrations did not correlate with the acute phase reactant levels. CONCLUSIONS: aCLa in patients with ARF and CRHD do not appear to be markers of disease activity, and our data suggest that aCLa do not play an important role in the pathogenesis of rheumatic fever.

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.