Risk factors for malignancy in systemic sclerosis patients.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with multisystem involvement. An increased incidence of cancer in SSc patients compared with the general population has been reported in several reports. Our aims in this study were to determine the most common malignancies and to investigate the possible risk factors for the development of malignancy in patients with SSc. Three hundred forty SSc patients from 13 centers were included to the study. Data of the patients were obtained by evaluating their medical records retrospectively. A total of 340 patients with SSc were evaluated. Twenty-five of the patients had 19 different types of malignancy. Bladder cancer was the most common type of cancer with four patients and was followed by breast cancer with three patients, and cervix cancer and ovarian cancer with two patients each. Other types of cancers such as squamous cell skin cancer, adenocancer with an unknown origin, multiple myeloma, chronic myeloid leukemia, papillary thyroid cancer, larynx cancer, non-small cell lung cancer, follicular type non-Hodgkin lymphoma (NHL), endometrium cancer, colon cancer, uterus cancer, neuroendocrine tumor, glioblastoma multiforme, and soft tissue sarcoma were diagnosed in one patient each. The only cancer type that showed an association with cyclophosphamide dose was bladder carcinoma. Other malignancies did not show a correlation with age, sex, smoking, type and duration of the disease, autoantibodies, organ involvement, and dose and duration of cyclophosphamide therapy. Cancer may develop in any organ in patients with SSc. Continuous screening of the patients during a follow-up period is necessary for the early detection of the tumor development.

Complement C5a receptor gene 450 C/T polymorphism in renal transplant recipients: association of the CT genotype with graft outcome.

Complement-mediated humoral rejection has become the main focus of research in organ transplantation. The aim of this study was to investigate the possible association of the complement C5aR gene 450 C/T polymorphism in antibody-mediated renal allograft rejection. This polymorphism was investigated in 290 first deceased donor kidney graft recipients with well functioning grafts and no rejection treatment during the first transplant year (WFG), 265 recipients with graft failure within the first transplant year (F), and 187 healthy controls. Frequency of the 450 CT genotype was lower in the total population of 555 kidney recipients (4.7%) than in 187 healthy controls (8.6%), but the difference was not statistically significant (P = 0.065). A significantly higher frequency of CT genotype was found in F patients (CT: 6.8%) when compared to WFG patients (CT: 2.8%, P = 0.027). The CT genotype was also significantly lower in WFG patients than in healthy controls (P = 0.009). Low frequency of the C5aR 450 CT genotype, which apparently is a feature of certain kidney diseases, appears to be associated with good graft outcome in kidney transplantation and might be helpful for identifying recipients who are at low risk for graft rejection.

Diffuse soft tissue and vascular calcification in systemic lupus erythematosus with chronic kidney disease.

The systemic disorder of mineral and bone metabolism which is related to chronic kidney disease (CKD) is called mineral and bone disorder (MBD). Calcifications related to CKD-MBD may occur in ophthalmic tissue, arterial walls, subcutaneous and periarticular soft tissues and organs. The vascular calcifications are the most important causes of mortality and morbidity in CKD. Here, we present a case of systemic lupus erythematosus with early and disseminated calcifications of vascular and periarticular soft tissues related to CKD-MBD.

Circadian rhythm of serum phosphate, calcium and parathyroid hormone levels in hemodialysis patients.

BACKGROUND: Serum levels of Phosphate (P), Calcium (Ca) and Parathyroid hormone (PTH) show circadian rhythms in healthy people. The aim of this study is to investigate whether there is also a rhythm in Hemodialysis (HD) patients. METHODS: We studied 15 (11 M, 4 F) HD patients, ages were 26 - 70 (mean 53 +/- 15) years. Two of the patients had history of parathyroidectomy operation. Serum levels of phosphate, calcium, albumin and PTH were evaluated six times at 07.00, 11.00, 15.00, 19.00, 23.00 and 03.00 on the second day after scheduled HD session. RESULTS: The lowest serum phosphate levels were found at 15.00 (5.41 +/- 1.76 mg/dL), the highest levels were 5.97 +/- 1.77 mg/dL at 03.00. The lowest serum Ca levels were 7.90 +/- 1.31 mg/dL at 03.00, the highest levels were 8.39 +/- 1.20 mg/dL at 15.00. Serum levels of PTH increased two times in a day and then decreased. The lowest levels were 330.07 +/- 203.57 pg/mL at 07.00, the highest levels were 418.30 +/- 206.24 pg/mL at 15.00. The results of two patients who had parathyroidectomy history disclosed that the lowest levels of phosphate were 2.87 +/- 0.12 mg/dL at 15.00, the highest levels were 4.37 +/- 1.25 mg/dL at 07.00. Serum Ca levels were as; the lowest levels: 8.29 +/- 3.5 mg/dL at 03.00, the highest levels 9.30 +/- 3.50 mg/dL at 19.00. As expected, serum PTH levels were constantly low during the day disclosing no correlation with other parameters. CONCLUSIONS: These results show that serum P, Ca and PTH levels exhibit a circadian rhythm also in HD patients. The rhythm predominantly depends on endogen factors and intravascular volume.

Familial Takayasu arteritis in a mother and daughter. A report of two cases.

Takayasu arteritis (TA) is a chronic granulomatous panarteritis, predominantly affecting the aorta and its main branches. Infections, genetic factors as suggested by familial clustering, and autoimmunity may play a role in its pathogenesis. In this report, we describe familial TA in a mother and daughter with diverse clinical manifestations. In addition to being a familial form of vasculitis, both of our cases demonstrated amyloidosis, chronic renal disease thought to be due to ischemic nephropathy, and hypertensive nephrosclerosis.

The impact of smoking on clinical features of Behçet's disease patients with glutathione S-transferase polymorphisms.

OBJECTIVES: Various cancer studies have suggested that polymorphism of GSTM1 may influence the ability to detoxify chemicals in cigarette smoke. In the present study the effect of smoking on clinical features of Behçet's disease were investigated in patients having GST-M1 and/or -T1 null polymorphisms. METHODS: Ninety-seven patients meeting International Study Group Criteria for Behçet's disease (63 male, 34 female) and 172 healthy controls (94 male, 78 female) were included into the study. GST-M1 and -T1 polymorphisms were investigated using polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Frequency of GSTM1- and/or GSTT1-null polymorphisms were comparable between the Behçet and the control groups. Smoking patients with GSTM1 null-polymorphism have decreased risk of developing papulopustuler lesions (OR=0.227 [0.063-0.818], χ2=5.463, p=0.019). Non-smoking patients with GSTM1 null-polymorphism has increased risk for having chronic arthritis (OR=5.988 [0.845-43.478]) but smoking patients with GSTM1 null-polymorphism have decreased risk (OR=0.741 [0.593-0.926]). GSTT1 null-polymorphism is associated with the presence of venous insufficiency (χ2=6.273, p=0.012, OR=2.740 [1.224-6.135]); smoking further increases the risk (χ2=7.840, OR=3.333 [1.412-7.874], p=0.005). GSTM1 null-polymorphism seemed to effect development of large vessel vasculitis (OR=1.158 [0.981-1.367], χ2=4.760, p=0.029). Male smoker Behçet patients even have more risk (OR=1.250 [0.971-1.610]). CONCLUSIONS: Several manifestations of Behçet's disease may be influenced by smoking, and this effect can be augmented in patients carrying GST gene polymorphism, which code enzymes crucial for the detoxification of chemicals.

Analysis of vascular endothelial growth factor gene 936 C/T polymorphism in patients with familial Mediterranean fever.

Vascular endothelial growth factor (VEGF) is a cytokine that promotes endothelial cell proliferation, leucocyte chemotaxis and expression of adhesion molecules and is a major mediator of vascular permeability. It has been demonstrated that VEGF directly activates neutrophils and it could promote acute recruitment of leucocytes. It is known that neutrophils are the major cell population involved in acute inflammation in familial Mediterranean fever (FMF) and the role of VEGF in these cells may be crucial. The aim of this study was to investigate whether the 936 C/T functional polymorphism of the VEGF gene is associated with susceptibility to FMF and its relationship with the main clinical features of the disease. Polymerase chain reaction-restriction fragment length polymorphism technique was used to determine 936 C/T polymorphism within the VEGF gene in 75 patients with FMF and 122 non-related healthy controls. Genotype and allele frequencies of the VEGF 936 C/T polymorphism between patients with FMF and healthy control groups were not significantly different (OR = 0.74, 95% CI = 0.40-1.37, P = 0.335 for CT genotype; OR = 1.11, 95% CI = 0.67-1.83, P = 0.700, for T allele). Although VEGF 936 TT genotype was found to be more frequent in patients with FMF than in healthy controls (6.7% vs. 1.6%, respectively), the difference was not significant (OR = 4.28, 95% CI = 0.81-22.67, P = 0.108). No associations were found between the studied polymorphism and either the clinical features such as arthritis, abdominal pain, pleuritis, myalgia, arthralgia and erysipelas-like erythema of the disease or the four common studied exon 10 mutations (M694V, M680I, V726A, M694I) of the Mediterranean fever gene. Present results suggest that VEGF gene 936 C/T polymorphism does not seem to be associated with susceptibility to FMF and its clinical manifestations.

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.

Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's disease.

In this study we aimed to investigate IVS3 +17T/C single nucleotide polymorphism (SNP) of CD28 gene, +49A/G and -318C/T SNPs of CTLA-4 gene in patients with Behçet's disease (BD) and their potential association to the main clinical features of the disease. These polymorphisms were investigated in a Turkish population of 123 patients with BD and 179 healthy controls, by using PCR-RFLP technique. HLA-B*51 genotype was also studied in both groups by using PCR-SSP. The frequency of IVS3 +17TC genotype of the CD28 gene was significantly increased in BD patients compared to controls (43.6% vs. 31.2%, OR = 1.663, 95% CI = 1.033-2.679, P = 0.039). CTLA-4 +49GG genotype frequency was found to be significantly lower in patients with BD than those of healthy controls (4% vs. 10.6%, OR = 0.357, 95% CI = 0.130-0.983, P = 0.05). Genotype and allele frequencies of the CTLA-4-318C/T polymorphism between the BD and healthy control groups were not significantly different (12.2% vs. 10.6%, OR = 1.170, 95% CI = 0.570-2.402, P = 0.713). There were no associations between the studied polymorphisms and the main clinical features of BD. The frequencies of HLA-B*51 were 60.3% and 30.7% in BD and control groups, respectively (OR = 3.429, 95% CI = 2.115-5.559, P = 0.0001). Association between HLA-B*51 and each studied polymorphism did not reach to significant levels (OR = 0.479, 95% CI = 0.228-1.004, P = 0.064 for CD28 IVS3 +17TT genotype; OR = 2.180, 95% CI = 1.025-4.639, P = 0.061 for TC genotype; OR = 1.570, 95% CI = 0.870-2.836, P = 0.146 for C allele). These results may suggest that CD28 IVS3 +17TC genotype may be a risk factor for the development of BD, on the contrary CTLA-4 +49GG genotype may be protective in the studied Turkish population.

Vasculitis induced by zafirlukast therapy.

Zafirlukast is a leukotriene inhibitor that has recently been approved for the prophylaxis of asthma. Although this new product has been well accepted because of its convenient dosing and relatively few side effects, several cases of Churg-Strauss syndrome have been reported to be associated with its use. In this paper we describe the case of a 54-year-old white man with no history of corticosteroid therapy in whom leukocytoclastic vasculitis, hepatitis and eosinophilia developed while he was on zafirlukast therapy for mild asthma.

Smoking and Behçet's disease.

It has recently been claimed that some of the symptoms in patients with Behçet's disease (BD) can be activated after the patient has stopped smoking. In this study we investigated the effect of smoking on the symptoms of Behçet's disease. Fifty asymptomatic current smokers (CS) who promised to stop smoking (group 1) and 60 current non-smokers (NS) (group 2) (21 of them ex-smokers) with BD were examined at the beginning and a week later for the presence of symptoms of BD. Forty-seven of the 50 CS completed the study. Oral aphthous ulcers were observed in 31 (65.9%) of them at the end of the study period. Besides oral aphthous lesions, genital ulcers were detected in two and erythema nodosum in two other patients. Only 15 (25%) group 2 patients developed oral aphthous ulcers during the study period. The difference between the frequencies of oral aphthous lesions in these groups was significant (p=0.0002). We concluded that cessation of cigarette smoking can activate the mucocutaneous symptoms, especially oral aphthous lesions, in patients with BD.

Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1.

Heterozygous germ-line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer. The disease susceptibility of individuals who constitutionally lack both wild-type alleles is unknown. We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age, and at least two of them displayed signs of neurofibromatosis type 1 (NF1). DNA sequence analysis and allele-specific amplification in two siblings revealed a homozygous MLH1 mutation (C676T-->Arg226Stop). Thus, a homozygous germ-line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and/or lymphoma associated with neurofibromatosis type 1.

Serum soluble interleukin-2 receptor levels in familial Mediterranean fever.

OBJECTIVE: To investigate serum soluble interleukin-2 receptor (sIL-2R) in familial Mediterranean fever (FMF) and assess its role in acute FMF crisis. METHODS: Serum sIL-2R concentrations were measured in patients with FMF during acute crises and during inactive periods of the disease, using an immunoenzymatic assay kit. Twenty four FMF patients during acute crisis (active FMF), 17 patients with inactive FMF, 24 healthy controls, and 20 active patients with rheumatoid arthritis (as a disease control group) were studied. RESULTS: Serum sIL-2R concentrations were increased during an acute FMF crisis compared with the values in inactive FMF patients and healthy controls (P = 0.0105 and P = 0.0012 respectively), while there was no significant difference between the mean values in active FMF and rheumatoid arthritis patients (P = 0.7325). In 14 of the FMF group whose blood samples were available in both active and inactive phases, sIL-2R concentrations were significantly higher in an acute attack than in an attack-free period (P = 0.027). CONCLUSIONS: An increase in sIL-2R may be a result of hyperreactivity of IL-2R-expressing cells during an acute inflammatory attack of FMF.

Iliopsoas transfer in cerebral palsy: the long-term outcome.

Thirty-three patients with cerebral palsy had iliopsoas transfers as part of their surgery for hip instability. All had total-body involvement, spastic cerebral palsy and none could walk. At the time of surgery, eight hips were subluxated and 39 were dislocated or severely subluxated. Mean follow-up was 8 years in patients between 8-25 years old. Forty-five of the 47 hips were located. Thirty patients had an accompanying scoliosis, and, in 10 patients, the rib cage impinged on the pelvis. Hip flexion had decreased in most patients. Sitting ability had not improved in any patient, and had in fact deteriorated in 50%.

Circulating corneal epithelium antibodies and immune complexes in immunologic eye disorders.

We investigated the incidence of circulating corneal epithelial antibodies and the serum levels of immune complexes in patients with immunologic disorders associated with the eye. Fifty patients with autoimmune diseases, 29 of whom had Behcet disease, were included in our study. Twenty healthy subjects were used as controls. Twenty-four patients (48%) had detectable levels of circulating antibodies against the corneal epithelium compared with two (10%) of the control subjects. Patient age had a negative effect on the induction of antibodies, whereas there were neither positive nor negative associations of antibody positivity rates with factors such as gender, the duration of the illness, the activity of the disease, the occurrence rate of the attacks, immune suppressant therapy, and the levels of circulating immune complexes. This study clearly demonstrated the high incidence of corneal antibodies in certain diseases of immunologic origin, including Behcet disease. Further investigations should be done to reveal clues about the presumed effects of local and systemic factors on the production of anticorneal antibodies.

The association between HLA B5 and ocular involvement in Behçet's disease in southern Turkey.

HLA B5 plays an important role in the aetiology of Behçet's disease. The frequency of HLA B5 differs between racial groups and geographical regions. Ocular involvement, which could lead to serious complications, is a very important feature of Behçet's disease. Various racial groups having different genetic properties live in the Cukurova region, located in southern Turkey. To investigate the role of HLA B5 in Behçet's disease in Cukurova region, HLA B5 antigens were investigated by lymphocytotoxicity assay in 65 patients and 200 healthy controls. A significantly higher frequency was found in the patient group. Neither ocular involvement, nor the type of uveitis showed any correlation with HLA B5, but it was found that patients presenting with frequent ocular attacks had significantly higher HLA B5 positivity than the patients with rare attacks. This observation suggests that HLA B5 would be a negative factor in visual prognosis in Behçet's disease.