Naifold capillaroscopy in mixed connective tissue disease patients.

INTRODUCTION: Mixed connective tissue disease (MCTD) is a rare systemic disease characterized by overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermato-/polymyositis (DM/PM), and rheumatoid arthritis (RA). Naifold capillaroscopy (NFC) is a non-invasive test for evaluating the capillaries of the nail shaft used in the diagnosis of rheumatic diseases. OBJECTIVES: To determine whether there are characteristic abnormalities in NFC in MCTD patients, and whether the type of NFC lesions correlates with organ involvement in these patients. METHODS: Clinical picture and NFC patterns were analyzed in 43 patients with MCTD. Capillaroscopic images were divided into scleroderma-like pattern (SD-like pattern) according to the Cutolo classification, non-specific lesions, and normal images. Relationships between the clinical aspects considered in the MCTD classification criteria and the changes in the capillaroscopic images were evaluated. RESULTS: SD-like pattern was present in 20 MCTD patients (46.51%) with a predominance of the "early" pattern. Giant, branched, dilated capillaries and reduced capillary density were found more frequently in MCTD patients compared to the control group (p-values 0.0005, 0.005, 0.02, < 0.0001 respectively). There were associations found between the presence of a reduced number of vessels, avascular areas, and SD-like pattern with the presence of sclerodactyly in MCTD patients (p = 0.002, p = 0.006, p = 0.02, respectively), alongside an association between the presence of branched vessels and the subpapillary plexus with pulmonary arterial hypertension (PAH) (p = 0.04 and p = 0.005, respectively). CONCLUSIONS: MCTD patients are significantly more likely to have abnormalities upon NFC. It is worthwhile to perform capillaroscopic examination in MCTD patients. Key Points • Scleroderma-like pattern was found in more than half of the MCTD patients. • Reduced capillary density was found to be a significant predictor of the diagnosis of MCTD. • There were relationships between the presence of reduced capillary density, avascular areas, and SD-like with the presence of sclerodactyly in the MCTD patients. • There was an association between the presence of branched vessels and the visibility of the subpapillary plexus and pulmonary arterial hypertension (PAH).

Liver involvement in rheumatic diseases.

Liver involvement in rheumatic diseases may occur as a primary liver disease, primary rheumatic disease with hepatic manifestations or antirheumatic drug-induced liver disease. The aim of our article is to underline the importance of monitoring and control of the level of aminotransferases and cholestatic enzymes in rheumatic disorders. Some of the rheumatic diseases with constantly elevated liver enzymes need to be investigated in consideration of concomitant primary autoimmune liver disease (such as autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis) or drug hepatotoxicity. Also, we should be aware of hepatitis B reactivation or hepatitis C flare when immunosuppressants are used.

Observational study of inflammatory arthritis treatment by etanercept originator switched to an etanercept biosimilar.

OBJECTIVES: The aim of the study was to assess the safety and efficacy of switching an etanercept originator to an etanercept biosimilar in rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis patients. MATERIAL AND METHODS: In 162 patients etanercept originator treatment had been replaced with the biosimilar (Group 1), and in six patients the biosimilar was initiated as the first biological agent (Group 2). The efficacy and safety of the treatment were monitored at 3-6 months. RESULTS: In the majority of patients in Group 1 (n = 138) the etanercept biosimilar was well tolerated, whereas in 24 patients a switch back to the originator was required. The loss of efficacy was confirmed in nine patients using clinical scoring system, and nine patients reported subjective loss of efficacy; 13 patients reported adverse events, most often headache (n = 3) and skin lesions (n = 3). In four patients injection site reactions were present. The adverse events (AE) and/or the loss of the biosimilar efficacy were more commonly observed in women, patients with rheumatoid arthritis (especially in those who did not receive methotrexate), and in patients with a previous history of any other biological treatment. In patients in Group 2 the therapy was effective and no adverse events were observed. CONCLUSIONS: The etanercept biosimilar seems to be effective and well-tolerated in the majority of patients. Nevertheless, in some cases, switching from the originator to the biosimilar was associated with AEs or loss of efficacy.

TNF-308 G/A polymorphism and risk of systemic lupus erythematosus in the Polish population.

OBJECTIVES: Numerous studies have been performed with TNF-α-308 G/A (rs1800629) single nuclear polymorphism (SNP) to evaluate the risk of SLE in various ethnicities. However, the significance of TNF-α-308 G/A in both clinical and laboratory studies of the disease remains unclear. METHODS: Using a high-resolution melting curve analysis, we assessed the prevalence of TNF-α-308 G/A SNP in SLE patients (n = 262) and controls (n = 528) in a Polish population. We also assessed the contribution of this SNP to various clinical symptoms and the presence of autoantibodies in SLE patients. RESULTS: The p-value obtained using a χ(2) test for the trend of TNF-α-308 G/A was statistically significant (ptrend = 0.0297). However, using logistic regression analysis for the presence of the HLA-DRB1*03:01 haplotype, we observed that the TNF-α-308 G/A SNP may be the DRB1*03:01-dependent risk factor of SLE in the Polish population. There was a significant contribution of TNF-α-308 A/A and A/G genotypes to arthritis OR = [2.692 (1.503-4.822, p = 0.0007, pcorr = 0.0119)] as well as renal SLE manifestation OR = [2.632 (1.575-4.397, p = 0.0002, pcorr = 0.0034)]. There was a significant association between TNF-α-308 A/A and A/G genotypes and the presence of anti-Ro antibodies (Ab) OR = 3.375(1.711-6.658, p = 0.0003, pcorr = 0.0051). However, the logistic regression analysis revealed that only renal manifestations and the presence of anti-anti-Ro antibodies remained significant after adjustment to the presence of the HLA-DRB1*03:01 haplotype. CONCLUSION: Our studies indicate that the TNF-α-308 G/A polymorphism may be a DRB1*03:01 haplotype-dependent genetic risk factor for SLE. However, this SNP was independently associated with renal manifestations and production of anti-Ro Ab.

Genetic variants of DNMT3A and systemic lupus erythematosus susceptibility.

OBJECTIVES: A significant increase in DNA methyltransferase 3A (DNMT3A) transcript levels has recently been demonstrated in peripheral blood mononuclear cells from systemic lupus erythematosus (SLE) patients as compared to healthy individuals. METHODS: Employing high resolution melting curve analysis (HRM) and PCR-restriction fragment length polymorphism analysis, we assessed the frequency of five single nucleotide polymorphisms (SNPs) of this gene: rs2289195, rs7590760, rs13401241, rs749131 and rs1550117, situated in different linkage disequilibrium blocks of the DNMT3A gene in two hundred and fifty seven women with SLE and six hundred and twenty five controls. RESULTS: The lowest p values of the trend test were observed for the DNMT3A -448A> G (rs1550117) SNP (ptrend = 0.0111). We also found that, in a dominant inheritance model, the DNMT3A -448A> G SNP may protect from SLE development [odds ratio (OR) = 0.494 (0.294-0.830), p = 0.0068, pcorr = 0.034]. Furthermore, we observed that the DNMT3A -448A > G SNP in dominant inheritance models may protect from immunologic manifestations of SLE [OR = 0.1753 (95% CI = 0.04976-0.6176, p = 0.0026, pcorr = 0.0468). CONCLUSIONS: Our study demonstrates that the DNMT3A -448A> G SNP might protect from SLE and its immunologic manifestations in a sample from the Polish population.

The FCRL3 -169T>C polymorphism might be associated with some autoantibody presence in patients with SLE in a Polish population.

OBJECTIVES: The Fcrl3 -169T>C (rs7528684) polymorphism has been shown to be a risk factor of various autoimmune diseases, including systemic lupus erythematosus (SLE); however, these results are inconsistent between distinct ethnicities. METHODS: Using PCR-RFLP we studied the distribution of the FCRL3 -169T>C polymorphism in SLE patients (n = 263) and controls (n = 528) in a sample from the Polish population. RESULTS: We found no significant differences of FCRL3 -169T>C genotypes and alleles between patients with SLE and healthy individuals. However, in the dominant model we found a significant association between the FCRL3 -169T>C polymorphism and the presence of anti-Scl-70 antibody (Ab) [OR = 4.747 (95 % CI = 1.639-13.749), p = 0.0011, p corr = 0.0198]. Moreover, in the dominant model we observed a significant contribution of FCRL3 -169T>C to the presence of either anti-La or anti-Scl-70 Abs [OR = 4.378 (95 % CI = 1.793-10.690, p = 0.0003, p corr = 0.0054)]. CONCLUSIONS: Our study demonstrated that the FCRL3 -169T>C polymorphism is not a risk factor of SLE in the Polish population, but this polymorphism may contribute to autoantibody production in this disease.

The FCRL3 -169T>C polymorphism might be associated with some autoantibody presence in patients with SLE in a Polish population.

OBJECTIVES: The Fcrl3 -169T>C (rs7528684) polymorphism has been shown to be a risk factor of various autoimmune diseases, including systemic lupus erythematosus (SLE); however, these results are inconsistent between distinct ethnicities. METHODS: Using PCR-RFLP we studied the distribution of the FCRL3 -169T>C polymorphism in SLE patients (n = 263) and controls (n = 528) in a sample from the Polish population. RESULTS: We found no significant differences of FCRL3 -169T>C genotypes and alleles between patients with SLE and healthy individuals. However, in the dominant model we found a significant association between the FCRL3 -169T>C polymorphism and the presence of anti-Scl-70 antibody (Ab) [OR = 4.747 (95 % CI = 1.639-13.749), p = 0.0011, p corr = 0.0198]. Moreover, in the dominant model we observed a significant contribution of FCRL3 -169T>C to the presence of either anti-La or anti-Scl-70 Abs [OR = 4.378 (95 % CI = 1.793-10.690, p = 0.0003, p corr = 0.0054)]. CONCLUSIONS: Our study demonstrated that the FCRL3 -169T>C polymorphism is not a risk factor of SLE in the Polish population, but this polymorphism may contribute to autoantibody production in this disease.

Contribution of toll-like receptor 9 gene single-nucleotide polymorphism to systemic lupus erythematosus.

There are several studies on the association of TLR9 polymorphisms with systemic lupus erythematosus (SLE) in different ethnicities; however, the results are inconsistent. Therefore, we studied the distribution of the TLR9 C > T (rs352140) polymorphism in patients with SLE (n = 254) and controls (n = 521) in a Polish population. We did not observe significant differences in the prevalence of the TLR9 C > T genotype and alleles between patients with SLE and controls. However, we found a contribution of the T/T and T/C genotypes to renal [OR = 2.949 (95 % CI = 1.523-5.711, p = 0.001), (p corr = 0.017)] and immunologic disorders [OR = 2.938 (95 % CI 1.500-5.755, p = 0.0012), (p corr = 0.0204)] in SLE patients. Moreover, we observed a significant association between the TLR9 T/T and T/C genotypes and the presence of anti-dsDNA Ab [OR = 3.682 (1.647-8.230, p = 0.001), (p corr = 0.017)]. Our studies suggest that the TLR9 C > T (rs352140) polymorphism might contribute to renal and immunologic disorders and to the presence of anti-dsDNA Ab.

Vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of systemic lupus erythematosus.

Recently, several studies have demonstrated the role of vitamin D receptor (VDR) polymorphisms in the development of systemic lupus erythematosus (SLE); however, these results are inconsistent between different cohorts. Therefore, we studied the prevalence of the VDR FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) genotypes and alleles in SLE patients (n = 258) and healthy individuals (n = 545) in a Polish population. We did not observe significant differences for either the VDR FokI, BsmI, ApaI and TaqI genotype and allele frequencies in patients with SLE and healthy individuals. However, the frequency of the VDR F/F and F/f genotypes of FokI was statistically different between patients with renal disease and patients without this symptom OR = 3.228 (1.534-6.792, p = 0.0014), p (corr) = 0.0476)]. There was no association of the studied VDR BsmI, ApaI and TaqI polymorphisms with clinical manifestations and laboratory profiles in patients with SLE. Our study indicates that the studied VDR FokI variant might increase the risk of some clinical presentations in patients with SLE.

Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population.

The STAT4 has been found to be a susceptible gene in the development of systemic lupus erythematosus (SLE) in various populations. There are evident population differences in the context of clinical manifestations of SLE, therefore we investigated the prevalence of the STAT4 G > C (rs7582694) polymorphism in patients with SLE (n = 253) and controls (n = 521) in a sample of the Polish population. We found that patients with the STAT4 C/G and CC genotypes exhibited a 1.583-fold increased risk of SLE incidence (95 % CI = 1.168-2.145, p = 0.003), with OR for the C/C versus C/G and G/G genotypes was 1.967 (95 % CI = 1.152-3.358, p = 0.0119). The OR for the STAT4 C allele frequency showed a 1.539-fold increased risk of SLE (95 % CI = 1.209-1.959, p = 0.0004). We also observed an increased frequency of STAT4 C/C and C/G genotypes in SLE patients with renal symptoms OR = 2.259 (1.365-3.738, p = 0.0014), (p (corr) = 0.0238) and in SLE patients with neurologic manifestations OR = 2.867 (1.467-5.604, p = 0.0016), (p (corr) = 0.0272). Moreover, we found a contribution of STAT4 C/C and C/G genotypes to the presence of the anti-snRNP Ab OR = 3.237 (1.667-6.288, p = 0.0003), (p (corr) = 0.0051) and the presence of the anti-Scl-70 Ab OR = 2.665 (1.380-5.147, p = 0.0028), (p (corr) = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease.

Asp327Asn polymorphism of sex hormone-binding globulin gene is associated with systemic lupus erythematosus incidence.

Endogenous sex hormones have been observed to have a role in systemic lupus erythematosus (SLE) predisposition. Sex hormone-binding globulin (SHBG) regulates the bioavailability of sex hormones to target tissues. Therefore, we examined the distribution of the SHBG functional polymorphism Asp327Asn (rs6259) in SLE patients (n = 150) and controls (n = 150) in a Polish population. We found a contribution of the SHBG327Asn variant to the development of SLE. Women with the Asp/Asn and Asn/Asn genotypes displayed a 2.630-fold increased risk of SLE (95% CI = 1.561-4.433, P = 0.0003). SHBG has a much higher affinity for testosterone than estradiol, and the SHBG327Asn variant displays a reduction of estradiol clearance. Therefore we suggest that the opposing effects of estrogens and testosterone on the immune system and imbalance in the levels of these hormones in SLE patients can be enhanced by the SHBG327Asn protein variant.

IL-18 105 A>C polymorphism contributes to renal manifestations in patients with SLE.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune connective tissue disorder characterized by various aberrations including increased production of IL-18. As IL-18 105 A>C polymorphic variants have been linked to increased production of this cytokine, we investigated the prevalence of IL-18 105 A>C (rs549908) polymorphic variants in SLE patients (n = 111) and controls (n = 152). There were no significant differences in the distribution of IL-18 105 A>C polymorphic variants in SLE patients and controls. However, there was a significant association between the IL-18 105 AA genotype (recessive model) and renal manifestations OR = 3.360 (1.523­7.415, P = 0.0039) and the P value remained statistically significant after Bonferroni correction (P corr = 0.0351).Our findings indicate that the IL-18 105 AA genotype variant can contribute to renal manifestations in patients with SLE.

Genetic variation in the interleukin-10 gene promoter in Polish patients with systemic lupus erythematosus.

Identification of susceptibility genes in systemic lupus erythematosus (SLE) has recently become a topic of interest. The IL-10 promoter contains three single base-pair substitutions at -627C > A, -854C > T and -1117G > A. These single base-pair substitutions produce three different haplotypes, GCC, ACC and ATA, which affect IL-10 expression. We examined the distribution of -627C > A, -854C > T and -1117G > A IL-10 promoter polymorphisms in patients with SLE (n = 103, women only) and matched controls (n = 300). Despite the higher prevalence of the GCC/GCC, GCC/ATA and ATA/ATA genotypes in SLE patients than in controls, we observed that only GCC/GCC genotype frequency distribution was significant between these groups. We observed that women with the GCC/GCC genotype displayed an approximately twofold increased risk of SLE OR = 2.245 (95% CI = 1.354-3.721, P = 0.0022). We did not find any associations between various genotypes of IL-10 promoter haplotypes and clinical manifestations or autoantibody production in patients with SLE. Our observations indicate that the GCC/GCC promoter genotype may contribute to SLE incidence in Polish patients.

Catalase -262C>T polymorphism in systemic lupus erythematosus in Poland.

It has been reported that reactive oxygen species contribute to pathogenesis of systemic lupus erythematosus (SLE). Catalase (CAT) -330C>T transition, known also as -262C>T, generates three genotypes. The CAT -330CC genotype is associated with a significantly lower CAT expression in comparison to -330CT and -330CT genotypes. Therefore, using restriction length fragment polymorphism analysis, we compared the frequencies of CAT -330C>T polymorphic variants between SLE patients (n = 102) and controls (n = 199). We did not observe significant differences in the prevalence of CAT -330C>T polymorphic variants in SLE patients and controls. However, we found that the CAT -330CC genotype (recessive model) showed a significant association with thrombocytopenia OR = 7.314 (1.977-27.057, P = 0.0017). We also observed that the CAT -330CC genotype (recessive model) is linked with leukopenia OR = 3.232 (1.361-7.676, P = 0.0118), renal manifestations OR = 2.403 (1.085-5.321, P = 0.0471) and presence of anti-snRNP Ab OR = 4.206 (95% CI = 1.405-12.590, P = 0.0131), and anti-Scl-70 Ab, OR = 3.143 (95% CI = 1.171-8.433, P = 0.0343) in SLE patients. Our findings suggest that the CAT -330CC genotype may contribute to some clinical manifestations in patients with SLE.

Manganese superoxide dismutase Ala-9Val mitochondrial targeting sequence polymorphism in systemic lupus erythematosus in Poland.

Systemic lupus erythematosus (SLE) is a chronic and progressive autoimmune disease in which reactive oxygen species contribute to pathogenesis. We analysed the distribution of manganese superoxide dismutase (MnSOD2) 47C>T (Ala-9Val) functional polymorphic variants within the mitochondrial targeting sequence in SLE patients (n = 102) and controls (n = 199). We did not find significant differences in the distribution of MnSOD2 47C>T polymorphic variants in SLE patients and controls. However, we found that MnSOD2 Val/Val genotype (recessive model) showed a significant association with Raynaud's phenomenon, odds ratio (OR) = 12.000 [95% confidence interval (CI) = 2.315-62.193], p = 0.0015. We also found that the MnSOD2 Val/Val genotype contributes to immunologic manifestations, OR = 2.957 (95% CI = 1.207-7.243), p = 0.0222, and anti-dsDNA antibody presence OR = 3.365 (95% CI = 1.364-8.304), p = 0.0107, in patients. Our observations indicate that MnSOD2 Val/Val variant can be linked to some clinical manifestations in patients with SLE.

Prevalence of ZAP-70, LAT, SLP-76, and DNA methyltransferase 1 expression in CD4+ T cells of patients with systemic lupus erythematosus.

T cells from systemic lupus erythematosus (SLE) patients exhibit defective function of CD4(+) T cells that can be responsible for improper activation of B cells and antibody biosynthesis against host antigens. We compared the level of ZAP-70, LAT, and SLP-76, transcripts and proteins in CD4(+) T cells from SLE patients (n = 22) and healthy individuals (n = 15). We also determined DNA methyltransferase 1 (DNMT1) protein content in CD4(+) T cells of SLE patients. The CD4(+) T cells were isolated by positive biomagnetic separation technique. The quantitative analysis of messenger RNA (mRNA) was performed by reverse transcription and real-time quantitative polymerase chain reaction (RQ-PCR) SYBR Green I system. The protein level in the CD4(+) T cells was determined by Western blotting analysis. We found that the LAT protein level was significantly higher in SLE CD4(+) T cells than in controls (P = 0.006). Western blot analysis revealed that ZAP-70 protein content in SLE CD4(+) T cells may be reciprocally correlated with disease activity expressed in SLEDAI scale (R = -0.623, P = 0.002) or number of affected organ systems (R = -0.549, P = 0.008). We also observed reciprocal correlation between DNMT1 protein content in CD4(+) T cells and disease activity scored with SLEDAI scale (R = -0.779, P = 0.001) or number of affected organ systems (R = -0.617, P = 0.019), respectively. Our findings might indicate that LAT, ZAP-70, and DNMT1 protein levels in CD4(+) T cells can be associated with SLE disease.

Glucocorticoid receptor beta splice variant expression in patients with high and low activity of systemic lupus erythematosus.

The glucocorticoid receptor (GR) occurs mainly in two alternative splice variants encoding GRalpha and GRbeta. The GRbeta variant does not contain a GC binding domain and cannot mediate anti-inflammatory GC effects. Peripheral blood mononuclear cells (PBMCs) were isolated from venous whole blood of twelve patients with SLE. Ten of the SLE patients exhibited low disease activity while two patients displayed highly active stage of the disease. The quantitative analysis of GRalpha and GRbeta transcripts in PBMC was performed by reverse transcription and real-time quantitative PCR SYBR Green I system. The protein level of GRalpha and GRbeta isoforms in PBMCs was determined by western blotting analysis. We found that the two SLE patients with high disease activity exhibited significantly elevated GRbeta transcript levels and corresponding protein levels in PBMCs. These preliminary findings suggest that increased expression of GRbeta isoform may be associated with relatively more severe clinical presentation of SLE syndrome.

[Antiphospholipid syndrome (APS) primary (PAPS) and secondary (SAPS)]. / Zespól antyfosfolipidowy (APS) pierwotny (PAPS) a wtórny (SAPS).

BACKGROUND: During the last decade, a wide variety of clinical manifestations and serological disturbances have been described associated to APS. However the real prevalence of most clinical manifestations with several autoantibody-cofactor systems still needs precise epidemiological and clinical long-term study. OBJECTIVE: Evaluation of frequency clinical and serological symptoms of SLE and APS in PAPS and SAPS pts. METHODS: Two groups of pts were analyzed: 78 SAPS (76F+2M) and 43 PAPS (32F+11M). All pts met Sapporo criteria for APS and SAPS pts met ARA criteria for SLE. Epidemiological, clinical and serological data were collected during 1995-2005 in the Connective Tissue Disease, Institute of Rheumatology, Warsaw, Poland and modified in 2005 according to actual directive line. RESULTS: PAPS pts were younger at the onset of the disease compare to SAPS pts. Duration time of the disease to set up the diagnosis as well as observation time was shorter in PAPS pts. Separated PAPS pts showed no more than two ARA criteria for SLE. All clinical ARA criteria for SLE occurred more often in SAPS pts. Also recurrent miscarriages, livedo reticularis and anti AnnexinV abs occurred more often in these pts. Pulmonary embolism, deep venous thrombosis and IgM aCL, LAC, anti beta2GP1, oxyLDL abs occurred more often in PAPS pts. Arterial thrombosis, migraine, crural ulceration, thrombocytopenia, false positive VDRL and IgG aCL abs were detected in almost the same percentage in both groups of pts. CONCLUSION: Men are less affected with SAPS. Wide variety of clinical SLE symptoms and immunological disturbances are more frequent in SAPS pts. Also in these pts recurrent miscarriages, livedo reticularis and anti AnnexinV abs occur more often. However pulmonary embolism, deep venous thrombosis with LAC, anti beta2GP1, IgM aCl, anti oxyLDL occur in less frequency in SAPS pts. The presence of arterial thrombosis, migraine, crural ulceration, thrombocytopenia, false positive VDRL and aCL IgG were almost in the same percentage in both groups of pts. Precise determination of the link between clinical symptoms of the APS and antibody-cofactor system needs future study on a bigger sample of pts.