TNFR1-383 A˃C polymorphism association with clinical manifestations in primary Sjögren's syndrome patients.

Primary Sjögren's syndrome is an autoimmune disease affecting the function of exocrine glands. Tumor necrosis factor receptor-1 (TNFR1) is involved in apoptosis through extrinsic pathway initiation. The level of soluble TNFR1 is reported increased in rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome patients. The TNFR1 gene contains a polymorphism that replaced an adenine with a cytosine at the -383 in promoter region position. The TNFR1-383 A˃C polymorphism has been associated with rheumatic diseases. We examined the association between the TNFR1-383 A˃C polymorphism and TNFR1 soluble (sTNFR1) levels and laboratory and clinical characteristics in primary Sjögren's syndrome patients. Eighty-two patients with primary Sjögren's syndrome classified using the American-European criteria and 84 healthy subjects were studied. Sjögren's Syndrome Disease Activity Index (SSDAI) and Sjögren's Syndrome Disease Damage Index were performed for all patients. Genotypic and allelic frequencies were similar in both groups (P = 0.317 and P = 0.329, respectively). sTNFR1 levels were similar in patients and healthy subjects (P = 0.051). High levels of C-reactive protein (P = 0.045) and rheumatoid factor (P = 0.040) in patients with the A˃C genotype were observed. In these patients, the SSDAI score was higher than in A˃A genotype carriers (P = 0.045). This is the first study that to examine the TNFR1-383 A˃C polymorphism in primary Sjögren's syndrome patients. Clinical parameters and SSDAI index were associated in A˃C genotype carriers. However, further studies with a larger sample are necessary to verify the association between primary Sjögren's syndrome and the TNFR1-383 A˃C polymorphism.

FAS -670A>G promoter polymorphism is associated with soluble Fas levels in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Soluble Fas receptor (sFas) has been suggested as a Fas-mediated apoptosis blocker that could impair clonal deletion in infiltrated autoreactive cells. The FAS -670A>G promoter polymorphism has been studied in pSS. However, a relationship between FAS -670A>G promoter polymorphism and sFas levels in pSS had not been found. We examined this relationship in 77 Mexican pSS patients and 84 healthy subjects were included. Genotypes were identified by PCR-RFLP, and Fas soluble levels were quantified by ELISA. No significant differences between allele and genotype frequencies were found between these two groups. The sFas levels in the serum of pSS patients were significantly higher than in controls (9961 vs 8840 pg/mL, respectively). In addition, AA genotype carriers had significantly higher levels of sFas than GG carriers (pSS: 10,763 and 9422 pg/mL; controls: 9712 and 8305 pg/mL, respectively). An additive model analysis between genotypes (AG+GG vs AA) in both groups, demonstrated a significant association between carriers of the A allele and high sFas levels. In conclusion, carrying the double dose of A allele of FAS -670A>G polymorphism is associated with high levels of sFas in pSS, but it is not a susceptibility marker for pSS.

Expression of BAFF and BAFF receptors in primary Sjögren's syndrome patients with ectopic germinal center-like structures.

B cell-activating factor (BAFF) is an essential cytokine in primary Sjögren's syndrome (pSS) physiopathology. It has been reported that pSS patients develop germinal center-like (GC-like) structures in their minor salivary glands (MSGs). BAFF, BAFF-R, TACI, and BCMA expression was analyzed in MSGs from 29 subjects (nonspecific chronic sialadenitis and focal lymphocytic sialadenitis with the presence [pSS-GC(+)] or absence [pSS-GC(-)] of GC-like structures). Twenty-four percent of patients showed ectopic GC-like structures and a high focus score [p < 0.001 vs pSS-GC(-)]. BAFF serum levels (sBAFF) were high in pSS patients (p = 0.025 vs healthy subjects). However, the pSS-GC(-) group showed higher sBAFF levels than pSS-GC(+) patients. BAFF and BAFF-R glandular expression levels were higher in pSS-GC(+) patients, without significant differences compared to pSS-GC(-) patients. Soluble levels of BAFF correlated with anti-La/SSB antibodies and disease duration. Our results showed that BAFF could contribute to focal lymphocytic infiltration. The role of BAFF-binding receptors in MSGs is proposed as a mechanism for the possible establishment of ectopic GC-like structures and disease progression in some patients. In conclusion, this study supports previous evidence that considers the active BAFF system role in the pathogenesis of pSS and the need for strong biomarkers in this disease.

High BAFF expression associated with active disease in systemic lupus erythematosus and relationship with rs9514828C>T polymorphism in TNFSF13B gene.

B cell-activating factor (BAFF) promotes the survival, proliferation and maturation of B lymphocytes, which are key elements in the pathogenesis of systemic lupus erythematosus (SLE). This cytokine is encoded on TNFSF13B gene, and diverse single-nucleotide polymorphisms have been associated with susceptibility in different autoimmune disorders. In this study, the relationship of TNFSF13B gene rs9514827T>C, rs1041567T>A and rs9514828C>T polymorphisms, mRNA expression and soluble BAFF levels was investigated in 175 SLE patients and 208 healthy controls (HC). The TNFSF13B polymorphisms were evaluated by PCR-RFLP technique. The TNFSF13B gene expression was quantified through the RT-PCR assays. The soluble BAFF (sBAFF) levels were measured with ELISA test. There were no differences in genotype and allele frequencies for the three TNFSF13B polymorphisms, between SLE patients and HC. SLE patients showed 3.15-fold more TNFSF13B gene expression than HC. The patients who displayed most mRNA expression were those with active disease and the carriers of rs9514828 T variant allele. The sBAFF serum levels were higher in SLE patients compared to HC (2.083 vs. 0.742 ng/mL, p < 0.001). The SLE patients with active disease showed the higher sBAFF serum levels (2.403 ng/mL), mainly patients with lupus nephritis and hematological manifestations. In addition, a correlation of sBAFF with disease activity was found (r = 0.32, p < 0.001). In conclusion, the TNFSF13B gene polymorphisms were not found to be associated with SLE susceptibility in Mexican mestizos. Nevertheless, rs9514828C>T polymorphism seems to increase TNFSF13B gene expression. High BAFF expression is related to active disease, renal and hematological involvement; therefore, it could be considered as follow-up biomarker in SLE patients.

Analysis of IL10 haplotypes in primary Sjögren's syndrome patients from Western Mexico: Relationship with mRNA expression, IL-10 soluble levels, and autoantibodies.

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. Interleukin-10 (IL-10) plays a role in autoimmune diseases by promoting B-cell activation and autoantibodies production. IL10-1082A>G, -819C>T, -592C>A polymorphisms and their haplotypes have been associated with IL-10 production. The aim of this study was to associate IL10 haplotypes with mRNA expression and soluble IL-10 levels with susceptibility to pSS in 111 Mexican patients and 111 healthy subjects (HS). Primary Sjögren's syndrome patients showed high levels of sIL-10 (p=0.0001 vs HS) correlating with anti-Ro and anti-La antibodies (p<0.05). In addition, IL10 mRNA expression in pSS was higher than HS (0.8 vs 0.1, p=0.1537). However, no difference was observed in sIL-10 levels between haplotypes. Patients carriers of GCC haplotype showed higher mRNA expression than ACC+ATA (1.4 vs 0.6, p=0.2424) and high foci number (p=0.04 vs ACC). Our results suggest a strong relationship of IL10 with pSS which is demonstrated by the increased mRNA expression and also high sIL-10 levels positively correlated with autoantibodies. Besides that, the GCC haplotype carriers expressed high mRNA. However, IL10 haplotypes were not associated with sIL-10 in pSS from Western Mexico which suggest that diverse biological factors may regulate the IL10 expression in pSS.

Research in rheumatology: a six-month review of selected medical journals.

Research in rheumatology has dramatically increased in the past decades, and researchers can choose among over 20,000 journals to publish their findings. The purpose of this study was to examine the current extent and impact of rheumatological research on the medical literature. The tables of contents of 1,158 biomedical journals were analyzed during a 6-month period and those with a rheumatology-related title were selected. In total, 2,549 articles from 406 journals were related to rheumatology. The 10 rheumatology journals selected for the analysis contained 769 articles (30% of the total); thus, over two-thirds of the information on rheumatology topics was provided by non-rheumatology journals. Over 65 different journals included information about rheumatoid and systemic lupus erythematosus. It is concluded that research in rheumatology is extensive and widespread. Since articles in rheumatology are scattered over a variety of journals, it is suggested that the periodic publication of a rheumatology reference index may assist rheumatologists in updating information from various sources.

Evaluation of disease activity by laboratory tests in juvenile rheumatoid arthritis.

We studied 29 juvenile rheumatoid arthritis patients with polyarticular onset in order to detect the presence of disease activity by laboratory tests. Laboratory studies included hemoglobin, hematocrit, erythrocyte sedimentation rate (ESR), white blood cell (WBC) and platelet counts. We also determined the levels of IgG, IgA, IgM, C3, C4 and C reactive protein, as well as the presence of rheumatoid factor and antinuclear antibodies. There were 13 patients in the group with polyarticular disease activity, and 16 in the group with asymptomatic juvenile rheumatoid arthritis. Low hematocrit and hemoglobin values, abnormal ESR and elevated WBC and platelet counts occurred in polyarticular juvenile rheumatoid arthritis patients with active disease. Increased levels of IgA, C3 and C4 were also found in the exacerbation stage, as compared to the asymptomatic control group. No differences were found in rheumatoid factor and antinuclear antibodies between the active and inactive juvenile arthritis patients. Our data agreed with previous studies in that a single laboratory test cannot necessarily confirm juvenile arthritis activity, and they suggest that two or more abnormal parameters would be useful in assessing the flare-up of the disease.

Trichinosis with severe myopathic involvement mimicking polymyositis. Report of a family outbreak.

We describe an outbreak of trichinosis in 3 members of a rural family. In the 3 patients eating raw pork was the source of infection. They presented with myalgias and severe proximal muscle weakness mimicking polymyositis. The diagnosis was made by demonstration of larvae of Trichinella spiralis in the muscle biopsy and also by the presence of anti-Trichinella antibodies detected by double immunodiffusion in their sera. We call attention to the unusual clinical presentation of trichinosis in our patients that was manifested by severe muscle weakness that may be confused with polymyositis.

Therapy with intermittent pulse cyclophosphamide for pulmonary hypertension associated with systemic lupus erythematosus.

The aim of this study was to compare the efficacy of intravenous cyclophosphamide (IVCYC) versus oral enalapril in mild or moderate pulmonary hypertension (PH) in systemic lupus erythematosus (SLE). Thirty-four patients with SLE who had systolic pulmonary artery pressure (SPAP) > 30 mmHg by Doppler echocardiography were randomized to receive IVCYC (0.5 g/mt2 body surface area, monthly), or oral enalapril (10 mg/day) for six months. The primary outcome was the significant decrease in SPAP. An additional outcome measure included the improvement in the heart functional class (NYHA). Sixteen patients received cyclophosphamide and 18 enalapril. IVCYC decreased the median values of SPAP from 41 to 28 mmHg (P < 0.001), and enalapril from 35 to 27 mmHg (P = 0.02). IVCYC reduced more than twice as much SPAP than enalapril (P = 0.04). In those patients with SPAP > or = 35 mmHg, cyclophosphamide decreased from 43 to 27 mmHg (P = 0.003), but enalapril was not effective (P = 0.14). The NYHA functional class improved only in those with cyclophosphamide (P = 0.021). Also IVCYC had a higher frequency of side effects including infections (RR = 1.6; 95% CI, 1.001-2.47), and gastrointestinal side effects (RR = 14.6; 95% CI, 2.15-99.68). We concluded that IVCYC was effective in mild and moderate PH associated with SLE. Further research is needed to evaluate its long-term efficacy.

T(H)1/T(H)2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patients.

During the course of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), several immune and neuroendocrine changes associated with pregnancy may exert positive (amelioration) or negative (exacerbation) effects on the clinical outcome. In order to shed light on the mechanisms underlying these responses, we performed a prospective longitudinal study in RA and SLE pregnant women, including healthy pregnant women as a control group. Cytokine messenger RNA (mRNA) expression assessed by quantitative competitive polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC), cytokine levels and lymphocyte proliferation responses (LPR) following phytohaemagglutinin (PHA) stimulation of PBMC, plasma metalloprotease-9 activity (MMP-9) and hormonal status during pregnancy were determined. TNFa was the most abundant cytokine mRNA expressed in PBMC in all groups studied (healthy pregnant women, RA and SLE pregnant patients). However, a general TH2 response reflected by high IL-10 levels was found in RA, as well as SLE, patients. A significant change in IFN-gamma was observed in RA patients but only during the first trimester of pregnancy. This compared with a major TH1 response in healthy pregnant women. Interestingly, our study showed a homogeneous hormonal pattern in RA and SLE patients. Although decreased cortisol levels were observed in all patients studied, this is possibly related to the remission of disease activity status brought about by steroid treatment before and during pregnancy. In summary, we suggest that complex immune and hormonal networks are involved in pregnancy and that rheumatic diseases are very dynamic immune processes that cannot be described with a clear-cut cytokine profile. Furthermore, the observations in this study may reflect treatment-related immune effects more than those associated with disease.

Evaluation of lipid profile, macular toxicity and clinical manifestations according to APO E genotype in systemic lupus erythematosus and rheumatoid arthritis patients treated with chloroquine.

OBJECTIVE: To investigate the effect of APO E gene polymorphism over lipid profile, macular toxicity and clinical manifestations in RA and SLE patients treated with chloroquine. MATERIALS AND METHODS: We studied 45 RA and 29 SLE patients treated with chloroquine who were classified based on the therapeutic regime of chloroquine into three groups: A) Cumulative dose of 100-300 g, B) >300 g and C) Never received chloroquine. Clinical evaluation, fasting lipid profile, visual field testing and stereoscopic photos of the retina were performed. APO E genotype was determined by PCR-RFLP. RESULTS: Reduced apo B levels in RA and SLE according to the cumulative dose of chloroquine 2/3 APO E genotype in a subset of SLE patients were observed. Macular toxicity was independent of both APO E genotype and cumulative chloroquine dose. CONCLUSIONS: Reduced apo B levels were observed associated to chloroquine treatment and 2/3 APO E genotype.