OBJECTIVE: To assess bladder toxicity of cyclophosphamide (CYC) and uroprotective effect of mesna in rheumatic diseases.; METHODS: Data of 1018 patients (725 women/293 men) treated with CYC were evaluated in this retrospective study. All of the following information was obtained: the cumulative CYC dose, route of CYC administration, duration of therapy, concomitant mesna usage, and hemorrhagic cystitis. Cox proportional hazard model was used for statistics.; RESULTS: We identified 17 patients (1.67%) with hemorrhagic cystitis and 2 patients (0.19%) with bladder cancer in 4224 patient-years. The median time for diagnosis to hemorrhagic cystitis was 10 months (4-48) and bladder cancer was 8 years (6-10.9). There were 583 patients (57.2%) who received mesna with intravenous CYC therapy. We observed similar incidence rate for hemorrhagic cystitis in both patient groups concomitantly treated with or without mesna [9/583 (1.5%) vs 8/425 (1.8%) respectively, p =3D 0.08]. Cumulative CYC dose (HR for 10-g increments 1.24, p < 0.001) was associated with hemorrhagic cystitis.; CONCLUSION: Cumulative dose was the only risk factor for hemorrhagic cystitis in patients treated with CYC. No proof was obtained for the uroprotective effect of mesna in our cohort.=20

Background In systemic lupus erythematosus (SLE) sustained CD40L expression by T cells and platelets activates a variety of cells via its receptor CD40 contributing to disease pathogenesis. Although CD40 has recently been identified in genome-wide association study as a novel rheumatoid arthritis susceptibility gene such an association has not been documented for SLE. Objective To investigate whether the rs4810485 CD40 single nucleotide polymorphism (SNP) is associated with increased risk for SLE and its impact on CD40 expression. Materials and methods The primary sample set consisted of 351 patients with SLE and 670 matched healthy controls of Greek origin. 158 patients with SLE and 155 controls from Turkey were used as a replication sample. Genotyping of rs4810485 was performed by restriction fragment length polymorphism and the Sequenom MassArray technology. The expression of CD40 mRNA and protein was assessed in unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells by quantitative real time PCR and flow cytometry, respectively. Results The minor allele T of CD40 rs4810485 SNP was significantly under-represented in Greek patients with SLE compared with healthy controls (OR=3D0.65, 95% CI 0.54 to 0.79). The association was replicated in the Turkish cohort (OR=3D0.57, 95% CI 0.41 to 0.80; meta-analysis of 509 patients with SLE and 825 healthy controls: OR=3D0.63, 95% CI 0.53 to 0.74, p =3D 2x10(-8)). In both cases and controls, the rs4810485 G/T and T/T genotypes were associated with significantly reduced CD40 mRNA and protein expression in peripheral blood CD14+ monocytes and CD19+ B cells compared with G/G genotype, both under basal conditions and following stimulation. Conclusions CD40 has been identified as a new susceptibility locus in Greek and Turkish patients with SLE. The rs4810485 minor allele T is under-represented in SLE and correlates with reduced CD40 expression in peripheral blood monocytes and B cells, with potential implications for the regulation of aberrant immune responses in the disease.

Objective. To evaluate the genetic background of systemic sclerosis ( SSc) in the Turkish population.Methods. There were 354 cases and 718 unaffected controls from Turkey genotyped for the most relevant SSc genetic markers ( IRF5-rs10488631, STAT4-rs3821236, CD247-rs2056626, DNASE1L3-rs35677470, IL12A-rs77583790, and ATG5-rs9373839). Association tests were conducted to identify possible associations.Results. Except for ATG5, all the analyzed genes showed either significant associations ( IRF5: p =3D 1.32E-05, OR 1.76; CD247: p =3D 2.20E-03, OR 0.75) or trends of association ( STAT4: p =3D 0.066, OR 1.21; IL12A: p =3D 0.079, OR 4.07; DNASE1L3: p =3D 0.097, OR 1.41) with the overall disease or with specific phenotypes.Conclusion. The genetic component of SSc seems to be similar between Turks and Europeans.

Plasma cells (PCs) are one of the two major cell types generated during germinal center reactions. To test the hypothesis that PCs express a unique repertoire of immunoglobulin (Ig) genes resulting from intensive antigenic stimulation and selection, the mutational pattern and distribution of VH gene segments within 178 transcripts amplified from individual IgM and IgA secreting tonsil PCs were analyzed. The results demonstrated that both mu and alpha transcripts expressed repertoires with limited diversity. Moreover, both mu and alpha transcripts were heavily mutated, with a significantly increased mutational frequency noted for alpha compared to mu transcripts (5.0X10-2 vs 1.8X10-2, P<0.001). In addition, both mu and alpha transcripts showed significantly greater targeting of mutations to RGYW motifs (purine/guanine/pyrimidine/A or T) compared to memory B cells. Finally, clonally expanded cells were detected in alpha but not mu PC compartments. These results indicate that antigen driven stimulation and selection shape the entire expressed PC repertoire, but the impact is greater in alpha expressing PCs.

Psoriatic arthritis (PsA) may affect different joints, including the spine. The prevalence of spinal involvement is variable depending on the definition and a subset of patients have been identified in cohorts that do not have clinical features of axial disease and yet have imaging findings. Still, there is not a consensus on how and when to screen axial disease. In this study, we aimed to investigate factors associated with being underdiagnosed for axial psoriatic arthritis (axPsA) and its impacts on outcomes. Disease features and outcomes of axPsA according to the physician (n=3D415) were compared with patients with imaging findings only (sacroiliitis fulfilling the modified New York criteria, n=3D112), using data from a real-life PsA registry. Patients with imaging findings only were more frequently women (83/220 (37.7%) vs 29/122 (23.8%); p=3D0.008). This group also had higher peripheral disease activity (imaging only vs clinical AxPsA: mean (SD) tender joint count 5.3 (6.1) vs 3.3 (4.7), swollen joint count 1.9 (2.9) vs 1.2 (2.4); p<0.001 for both comparisons) and was less often treated using TNF inhibitors (16.1 vs 38.2%; p<0.001) than patients who were classified as axPsA. Patient-reported outcomes were similar in both groups. PsA patients, especially women with more severe peripheral disease, have a higher risk of being underdiagnosed for axPsA. The severity of peripheral symptoms may be a risk factor to mask the spinal features of PsA.=20

A significant source of variability in the literature on systemic lupus erythematosus (SLE) susceptibility genes has been the inability to replicate genetic findings across different racial or ethnic groups. We investigated whether a single nucleotide polymorphism (SNP) of the STAT4 (rs7574865), PTPN22 (rs2476601), TRAF1/C5 (rs10818488), and C1q (rs292001) genes as well as the 27-bp VNTR polymorphism on intron 4 of eNOS, previously associated with SLE in other populations, are also associated with SLE risk in Turkey. A group of 158 SLE patients and 155 healthy controls were included in this study. A genetic association of the TRAF1/C5, C1q, and eNOS gene polymorphism, but not of STAT4 and PTPN22, was found to confer a degree of risk for SLE. These data highlight the importance of comparative studies in different populations to confirm the previously detected genetic associations. (C) 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Inducted sputum (IS) is a non-invasive procedure that can be used for collection of airway secretions. The aim of our study is to evaluate the clinical usefulness of IS for detection of airway inflammation in systemic sclerosis (SSc). Bronchoalveolar lavage and IS were performed to 20 patients with SSc. Eighteen patients who were referred to pulmonary medicine for bronchoalveolar lavage due to other reasons were also recruited for cell counts comparisons. Spirometry, echocardiography and thorax CT (HRCT) imaging were also performed to all patients. Mean macrophage and lymphocyte counts were found to be increased in IS of SSc patients compared with that of control (58.4 =C2=B1 14.5% vs. 31.3 =C2=B1 16.3%, 30.2 =C2=B1 15.4% vs. 15.0 =C2=B1 11.5% P < 0.001), whereas mean neutrophil count was lower in the SSc patients (4.1 =C2=B1 4.5% vs. 17.2 =C2=B1 13.1%, P < 0.05). Significant correlations were noted between BAL and IS findings for macrophage (r =3D 0.55, P =3D 0.02) lymphocyte (r =3D 0.65, P < 0.01) and total cell counts (r =3D 0.45, P =3D 0.06). IS is an easy and reliable method for the detection of alveolitis and can be used for early detection of lung involvement in scleroderma.=20

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.

To assess the effect of mycophenolate mofetil (MMF) on pulmonary functions in patients with systemic sclerosis-associated lung disease (SSc-ILD) who experienced an inadequate response to first line cyclophosphamide (CYC) therapy. Twelve consecutive SSc-ILD patients who received MMF due to inadequate response to CYC as a first line agent, were retrospectively reviewed. Over the course of 2 years, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) scans were performed. Following initial baseline tests, PFTs were continued at a frequency of every 6 months and HRCT scans were performed every 12 months. After MMF treatment, values of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) improved in three (25%) and two (16.6%) patients, respectively. It is also noted that the evaluation of serial HCRT scans showed no change in 54.5% of patients. Our case series suggested that PFT and imaging scores seemed to be stabilized by MMF in SSc-ILD patients who were inadequate responders to CYC. =C2=A9 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Purpose: The authors report a case of necrotizing scleritis associated with Wegener's granulomatosis (WG), which was treated with rituximab for relapsing disease. Method: Observational case report. Results: A 32-year-old male patient presented with necrotizing scleritis in his left eye. The patient was diagnosed as having limited WG. Cyclophosphamide was begun. Under maintenance treatment with azathioprine two relapses of scleritis occurred. Since a high cumulative dose of cyclophosphamide (22.5 g) was utilized initially, two intravenous infusions of rituximab 1 g was given. Complete resolution of scleritis occurred. Conclusions: Rituximab may be effective to induce remission in patients with scleritis due to WG.

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12 +/- 3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.

Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=3D0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55-1.94]; p=3D0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=3D0.019 as compared with controls vs 3 [0.66-5.35]; p=3D0.012). Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.