Cardiac autonomic profile in rheumatoid arthritis and systemic lupus erythematosus.

Neurological involvement is a well-documented issue in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, little is known about the involvement of the autonomic nervous system. This study was conducted to investigate autonomic nervous system dysfunction in patients with RA and SLE. Twenty-six RA patients, 38 SLE patients and 40 healthy controls were recruited from our in- and out-patient departments. Heart rate variability (HRV) parameters (the power of the high- [HF] and low-frequency [LF] band of haemodynamic time series, the ratio between low- and high-frequency components [LF/HF ratio], the power spectral density), baroreflex sensitivity (BRS) and beat-to-beat blood pressures were assessed by a novel non-invasive haemodynamic monitoring tool (Task Force Monitor [TFM], CNSystems Medizintechnik GmbH, Graz, Austria). Autonomic nervous system dysfunction was determined according to classical Ewing autonomic test battery. Furthermore, we implemented a secondary autonomic test score by modifying the Ewing test battery with additional criteria. Both the classical and modified Ewing test batteries have revealed that the frequencies of autonomic neuropathy were significantly higher in patient groups compared with controls (p < 0.001). Evaluation by TFM revealed that deterioration of sophisticated autonomic parameters (such as HRV and BRS) were more pronounced in the patient groups compared with controls. There was a significant association between BRS and Ewing test scores and abnormal BRS results were more frequent in patients with autonomic dysfunction according to Ewing test batteries. No relation was found between autonomic neuropathy and disease duration, disease activity and autoantibody positivity. Consequently, we believe that further large-scale studies investigating cardiovascular autonomic neuropathy in rheumatic diseases should be carried out to verify our findings and manifest clinical consequences beyond these results.

The numbers of Foxp3 + Treg cells are positively correlated with higher grade of infiltration at the salivary glands in primary Sjogren's syndrome.

This study was designed to investigate whether Foxp3( +) regulatory T (Treg) cells play a role in the histopathologic changes of primary Sjögren's Syndrome (pSS) and to evaluate other factors possibly associated with Foxp3(+) Treg cells in pSS patients. The number of FoxP3-expressing T cells in peripheral blood (PB) of 39 patients with pSS, 40 patients with rheumatoid arthritis (RA), and 28 healthy controls was measured by flow-cytometer analysis. FoxP3-expressing CD4(+)CD25(+) Treg cells were analyzed in minor salivary gland (SG) tissues of 39 pSS patients. Histopathologic changes were examined by light microscopy according to Chisholm's classification. Immunohistochemistry and immunofluorescence were performed to assess the Foxp3(+) Treg in SG biopsy specim-ens. The numbers of CD4(+) T cells and FoxP3-expressing CD4(+) T cells in PB were similar in all groups. Expression of CD25 on CD4(+) T cells in PB of patients with pSS and RA was significantly higher than in healthy controls, especially for RA patients. Immunohistochemistry and immunofluorescence showed that FoxP3(+) Treg were enriched in the SGs of pSS patients, with a positive correlation between the increase in FoxP3(+) Treg in SG and the Chisholm score in pSS (p < 0.001, r = +0.605). The increase of FoxP3( +) Treg cells in the SGs of pSS patients, which is correlated with gland infiltration, suggests that natural regulatory T cells play an important role in the pathogenesis of pSS. Further studies are required to explore the mechanisms that mediate the relationship between Treg and the pathogenesis of pSS.

Bone marrow infection caused by Mycobacterium avium complex in a patient with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a disease with wide range of signs and symptoms. SLE patients have increased infective diathesis, and infections are a very important cause of death in these patients. Infections can sometimes mimic the signs and symptoms of SLE. Thus, it is important to recognize that infection can induce a lupus flare-up or can be difficult to distinguish from a lupus flare-up. We describe a 36-year-old female patient with SLE, who presented with skin lesions and pancytopenia, and clinical manifestations similar to a flare-up of SLE. Bone marrow examination revealed infection with Mycobacterium avium complex (MAC). The patient had no history or clinical evidence of pulmonary involvement. This patient is the first case of invasive bone marrow MAC infection in SLE. With this unique case, we would like to emphasize that SLE patients can also be infected by non-tuberculous mycobacteria, and that bone marrow examination for tuberculosis as well as for non-tuberculosis mycobacteria should be considered in SLE patients with refractory pancytopenia.

Clinical importance of antineutrophil cytoplasmic antibody positivity during propylthiouracil treatment.

BACKGROUND: Propylthiouracil (PTU) is the mainstay of antithyroid drug therapy. Previous studies reported antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis in patients treated for Graves' disease. ANCA has been associated with either PTU or to the disease itself. However, this issue has not been investigated in toxic multinodular goitre (TMNG). The aim of this study was to evaluate the frequency of ANCA positivity in both TMNG and Graves' disease patients treated with PTU, and to investigate the clinical importance of this issue. PATIENTS AND METHODS: We studied the presence of ANCA in 46 patients treated with PTU (30 Graves' disease, 16 TMNG). Two years after the discontinuation of PTU, ANCA was re-evaluated in 29 patients (18 Graves' disease, 11 TMNG). RESULTS: By indirect immunofluorescence, 19 of the 46 patients (41.3%) on PTU treatment were ANCA positive [13 of the 30 patients in Graves disease (43.3%), six of the 16 patients in TMNG (37.5%)]. There was no statistically significant difference between Graves' disease and TMNG patients for ANCA positivity (p = 0.362). ANCA positivity was not related to gender, thyroid autoantibodies, alanine aminotransferase, aspartate aminotransferase, neutrophil count and PTU dose. Two years after withdrawal of PTU treatment, 10.3% of patients continued to have positive ANCA (p < 0.0001). Signs and symptoms of vasculitis could not be detected in any of the ANCA-positive patients. CONCLUSION: Our study suggests that PTU but not Graves' disease itself is the most important factor for ANCA development. The frequency of ANCA positivity is 41.3% in our country which was not different in Graves' disease and TMNG patients. The dose of PTU and ethnic factors are not associated with ANCA positivity. After cessation of PTU, vasculitis did not develop during the 2 years of follow-up despite positive ANCA.

CTLA-4 gene polymorphism of exon 1(+49 A/G) in Turkish systemic lupus erythematosus patients.

Cytotoxic T lymphocyte-associated antigen-4 is a cell-surface molecule providing a negative signal for T cell activation. CTLA-4 gene polymorphisms are known to be related with genetic susceptibility to various autoimmune diseases, including systemic lupus erythematosus (SLE). However, the effects of this polymorphism on clinical features of SLE have not been defined. We analysed the CTLA-4 gene +49 A/G polymorphisms in patients with SLE by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and investigated the effect of polymorphisms on clinical outcomes. Blood was collected from 47 unrelated Turkish SLE patients, all fulfilling the American College of Rheumatology criteria for SLE, and 100 ethnically matched healthy volunteers. The AA genotype was a predominant genotype in the Turkish population and genotype frequencies of CTLA-4 AA were significantly higher in SLE patients (70%) than healthy controls (47%) (P = 0.015). There was a statistically significant difference in the AA genotype [odds ratio (OR): 2.66, confidence interval (CI) 95%: 1.27-5.56, P = 0.014] distribution among patients and controls. There was also an increase in A allele frequency in SLE and controls, but the difference was not statistically significant (81% vs. 70%, P = 0.068, OR = 1.8, CI 95%: 0.99-3.28). Interestingly, mean age and mean age of onset disease was higher in AA homozygote SLE patients compared to non-AA (39.2 +/- 11.5 vs. 31.6 +/- 10.6, P = 0.044; 32.38 vs. 24.31, P = 0.046, respectively). There was no association between genotype and the other clinical features of SLE. Our results suggested that CTLA-4 +49 AA genotype might be a risk factor for the development of SLE in Turkish population and G allele might be involved in early development of SLE. No association with clinical features was found for polymorphism of the promoter region in CTLA-4 +49.

Development of Crohn's disease following anti-tumour necrosis factor therapy (etanercept).

Inhibition of tumour necrosis factor (TNF)-alpha is effective in the treatment of rheumatoid arthritis and other inflammatory rheumatic diseases. Anti-TNF antibodies such as infliximab, etanercept and adalimumab are commonly used. There are structural and functional differences among these agents. We describe development of Crohn's disease in a patient with ankylosing spondylitis receiving anti-TNF therapy. This case suggests that the appearance of gastrointestinal symptoms in patients on anti-TNF therapy must be evaluated to find out whether this is a new onset or an exacerbation of underlying inflammatory bowel disease.

Cutaneous alternariosis in a patient with systemic lupus erythematosus.

Alternaria species are common saprophytic fungi that naturally subsist on decaying plant materials, and occasionally may cause diseases in human beings and domestic animals. They can be a potential opportunistic pathogen in immunocompromized hosts or those with significant underlying disease. However, rarely they are also pathogen in otherwise healthy hosts. We report here the first case of cutaneous alternariosis in a 30-year-old woman who was on systemic steroid therapy for active systemic lupus erythematosus. The patient was referred to our department with purple papules and ulcerated nodules on the dorsum of the hands, wrists and ankles. Skin biopsy showed granulomatous reaction with fungal elements that were subsequently identified as Alternaria species. Individual lesions were successfully treated with oral itracanozole 200mg daily for six weeks. Besides the patient's own disease, the use of systemic steroid use might be a possible predisposing factor for the development of cutaneous alternariosis.

Concurrent gene therapy strategies effectively destroy synoviocytes of patients with rheumatoid arthritis.

Objectives. Rheumatoid arthritis (RA) is characterized by the chronic inflammation of the synovial joints resulting from the hyperplasia of synovial cells and the infiltration of lymphocytes, macrophages and plasma cells. Currently, the aetiology of RA is not known, and new treatment modalities are needed to prevent the disease progression. Apoptosis induction of synovial cells through the use of death ligands has been explored as a treatment modality for RA. Thus, the primary objective of this study was the testing of the efficacy of adenovirus delivery of human TRAIL (Ad5hTRAIL) for the treatment of patients with RA. Methods. Primary synovial cell cultures were established from eight patients with RA. Adenovirus permissiveness of synovial cells was determined by the infection of synoviocytes with adenovirus vector encoding green fluorescent protein (AdEGFP). TRAIL sensitivity of synoviocytes was assessed through the infection with Ad5hTRAIL vector using Live/Death Cellular Viability/Toxicity kit from Molecular Probe. TRAIL receptor profiles of synoviocytes were revealed by real-time RT-PCR assays followed by flow cytometric analyses. Results. While the presence of TRAIL death receptors were necessary for the induction of cell death, high levels of TRAIL-R4 decoy receptor expression on surface were correlated with TRAIL resistance. A DcR2 siRNA approach in combination with Ad5hTRAIL infection eliminated apoptosis-resistant RA synovial fibroblasts. Conclusion. Because a DcR2 siRNA approach in combination with Ad5hTRAIL infection exterminated RA synoviocytes to a greater extent than Ad5hTRAIL alone, the modulation of TRAIL receptor expression might be a new gene therapy strategy to sensitize RA synoviocytes to TRAIL.