Impact of rituximab on humoral response to SARS-CoV-2 vaccination in previously vaccinated patients with autoimmune diseases.

SARS-CoV-2 infection is more severe in patients undergoing rituximab (RTX) treatment. Humoral response to vaccination is severely impaired in patients already treated with RTX, but data on antibody persistence in patients initiating RTX are lacking. We evaluated the impact of RTX initiation on humoral response to SARS-CoV-2 vaccination in previously vaccinated patients with immune-mediated inflammatory diseases. We performed a retrospective, multicenter study evaluating the evolution of anti-spike antibodies and breakthrough infections after initiation of RTX in previously vaccinated patients with protective levels of anti-SARS-CoV-2 antibodies. Threshold for anti-S antibodies positivity and protection were 30 and 264 BAU/mL, respectively. We included 31 previously vaccinated patients initiating RTX (21 female, median age 57 years). At first RTX infusion, 12 (39%) patients had received 2 doses of vaccine, 15 (48%) had received 3 doses, and 4 (13%) had received 4 doses. The most frequent underlying diseases were ANCA-associated vasculitis (29%) and rheumatoid arthritis (23%). Median anti-S antibody titers at RTX initiation, 3 months, and 6 months were 1620 (589-2080), 1055 (467-2080), and 407 (186-659) BAU/mL, respectively. Overall, antibody titers waned by almost two-fold at 3 months and four-fold at 6 months. Median antibody titers were significantly higher in patients who received ≥3 doses compared to those who received only 2 doses. Three patients developed SARS-CoV-2 infection without any severe symptom. Anti-SARS-CoV-2 antibody titers in previously vaccinated patients decline after RTX initiation similarly to general population. Specific monitoring is useful to anticipate prophylactic strategies. Key Points • Anti-SARS-CoV-2 antibody titers in previously vaccinated patients decline after rituximab initiation similarly to the general population. • The number of dose of vaccine before rituximab initiation is associated with higher antibody titers at month 3. • Monitoring antibody levels is mandatory to initiate prophylactic strategies in this population.

The predictable chaos of slow earthquakes.

Slow earthquakes, like regular earthquakes, result from unstable frictional slip. They produce little slip and can therefore repeat frequently. We assess their predictability using the slip history of the Cascadia subduction between 2007 and 2017, during which slow earthquakes have repeatedly ruptured multiple segments. We characterize the system dynamics using embedding theory and extreme value theory. The analysis reveals a low-dimensional (<5) nonlinear chaotic system rather than a stochastic system. We calculate properties of the underlying attractor like its correlation and instantaneous dimension, instantaneous persistence, and metric entropy. We infer that the system has a predictability horizon of the order of days weeks. For the better resolved segments, the onset of large slip events can be correctly forecasted by high values of the instantaneous dimension. Longer-term deterministic prediction seems intrinsically impossible. Regular earthquakes might similarly be predictable but with a limited predictable horizon of the order of their durations.

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.

INTRODUCTION: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

Classification, categorization and essential items for digital ulcer evaluation in systemic sclerosis: a DeSScipher/European Scleroderma Trials and Research group (EUSTAR) survey.

BACKGROUND: A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc). METHODS: DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked. RESULTS: A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU. CONCLUSIONS: For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted. TRIAL REGISTRATION: Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263 , posted on April 19, 2013).

Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid arthritis: A 12-year longitudinal multi-center study.

OBJECTIVE: Rituximab (RTX) is an anti-CD20 monoclonal antibody that selectively depletes B-cell population. Thus, it presents a potential risk for the development of hypogammaglobulinemia and related infectious events. Our aim was to identify predictors of hypogammaglobulinemia in RA patients long-term treated with RTX. METHODS: Multicenter observational usual care study of patients with RA on RTX maintenance therapy (minimal exposition of 30 months). Serum protein electrophoresis was performed before each RTX infusion. Hypogammaglobulinemia and severe hypogammaglobulinemia were defined as total gammaglobulin <6g/L and <4g/L, respectively. The primary outcome was the occurrence within the follow-up period of hypogammaglobulinemia. RESULTS: 134 patients met inclusion criteria and were followed-up for 79.5 ± 24.6 months. Hypogammaglobulinemia occurred during the follow-up period in 23 patients (2.7 events per 100 pt-yrs). The mean time to development of hypogammaglobulinemia was 64 ± 23 months. Patients who developed hypogammaglobulinemia were more likely to experience severe infections (26.1% vs. 6.3%, P = 0.033). Multivariate Cox analysis identified gammaglobulin levels <8g/L at baseline as an independent predictor of hypogammaglobulinemia (HR 7.34 [95% CI: 2.00-26.90], P = 0.003). Concomitant methotrexate (MTX) intake was also predictive of a reduced risk of hypogammaglobulinemia occurrence (HR 0.26 [95% CI: 0.08-0.87], P = 0.03). CONCLUSION: Our results show that gammaglobulin levels of less than 8g/L at baseline is a strong independent risk factor for developing subsequent hypogammaglobulinemia, whereas concomitant MTX therapy seems to be a protective factor in RA patients treated long-term with RTX.

Slip pulse and resonance of the Kathmandu basin during the 2015 Gorkha earthquake, Nepal.

Detailed geodetic imaging of earthquake ruptures enhances our understanding of earthquake physics and associated ground shaking. The 25 April 2015 moment magnitude 7.8 earthquake in Gorkha, Nepal was the first large continental megathrust rupture to have occurred beneath a high-rate (5-hertz) Global Positioning System (GPS) network. We used GPS and interferometric synthetic aperture radar data to model the earthquake rupture as a slip pulse ~20 kilometers in width, ~6 seconds in duration, and with a peak sliding velocity of 1.1 meters per second, which propagated toward the Kathmandu basin at ~3.3 kilometers per second over ~140 kilometers. The smooth slip onset, indicating a large (~5-meter) slip-weakening distance, caused moderate ground shaking at high frequencies (>1 hertz; peak ground acceleration, ~16% of Earth's gravity) and minimized damage to vernacular dwellings. Whole-basin resonance at a period of 4 to 5 seconds caused the collapse of tall structures, including cultural artifacts.

Prevalence and predictors of small intestinal bacterial overgrowth in systemic sclerosis patients with gastrointestinal symptoms.

OBJECTIVES: There is a paucity of data available on small intestinal bacterial overgrowth (SIBO) in systemic sclerosis (SSc). The objectives of the study were to estimate the prevalence of SIBO in SSc patients exhibiting intestinal symptoms and identify patients at risk of SIBO regarding clinical and biological presentations and gastrointestinal symptoms captured by standardized questionnaires. METHODS: Between 2011 and 2012, patients exhibiting intestinal complaints underwent glucose H2/CH4 breath tests (BT) and blood assays. They were interviewed using the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA SCTC GTI) and the Short Form-36 (SF-36). For patients diagnosed with SIBO, BT was repeated 1 to 4 months after the end of antibiotics. RESULTS: Among 120 consecutive patients, 37 patients (29 women) exhibiting intestinal complaints were included (median age: 60 years). Fourteen patients (38%) were diagnosed with SIBO; patients from this subset had a longer disease duration (p=0.02), a significant weight loss within the past 6 months (p=0.03) and a higher total UCLA SCTC GTI score (p=0.03). The SF-36 assessment was not discriminant. Among the 14 patients treated for SIBO, 6 had a negative control BT, 4 remained positive, 2 failed to repeat the test and 2 patients died due to severe chronic malabsorption. CONCLUSIONS: SIBO is a not uncommon, late onset, severe and not easy to treat complication of SSc. Higher UCLA SCTC GTI score and weight loss appeared to be strongly associated with SIBO.

Threshold for sand mobility on Mars calibrated from seasonal variations of sand flux.

Coupling between surface winds and saltation is a fundamental factor governing geological activity and climate on Mars. Saltation of sand is crucial for both erosion of the surface and dust lifting into the atmosphere. Wind tunnel experiments along with measurements from surface meteorology stations and modelling of wind speeds suggest that winds should only rarely move sand on Mars. However, evidence for currently active dune migration has recently accumulated. Crucially, the frequency of sand-moving events and the implied threshold wind stresses for saltation have remained unknown. Here we present detailed measurements of Nili Patera dune field based on High Resolution Imaging Science Experiment images, demonstrating that sand motion occurs daily throughout much of the year and that the resulting sand flux is strongly seasonal. Analysis of the seasonal sand flux variation suggests an effective threshold for sand motion for application to large-scale model wind fields (1-100 km scale) of τ(s)=0.01±0.0015 N m(-2).

Earth-like sand fluxes on Mars.

Strong and sustained winds on Mars have been considered rare, on the basis of surface meteorology measurements and global circulation models, raising the question of whether the abundant dunes and evidence for wind erosion seen on the planet are a current process. Recent studies showed sand activity, but could not determine whether entire dunes were moving--implying large sand fluxes--or whether more localized and surficial changes had occurred. Here we present measurements of the migration rate of sand ripples and dune lee fronts at the Nili Patera dune field. We show that the dunes are near steady state, with their entire volumes composed of mobile sand. The dunes have unexpectedly high sand fluxes, similar, for example, to those in Victoria Valley, Antarctica, implying that rates of landscape modification on Mars and Earth are similar.

Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: association with the functional IRAK1 196Phe/532Ser haplotype.

OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. METHODS: We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.

NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.

BACKGROUND: Recent evidence has highlighted a potential role of interleukin 1ß (IL-1ß) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1ß. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. OBJECTIVE: /st> To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. METHODS: NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. RESULTS: Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. CONCLUSIONS: Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

Predictive factors of hand radiographic lesions in systemic sclerosis: a prospective study.

OBJECTIVE: To examine the outcomes of hand radiographic x-rays in patients with systemic sclerosis (SSc) and to identify risk factors for the progression of hand radiographic lesions in a prospective cohort. METHODS: Dual time-point x-rays were systematically performed after a median interval of 5 years (range 4-7 years) in 103 consecutively recruited patients with SSc. Univariate and multivariate Cox proportional hazards models evaluated predictors of progression of hand radiographic lesions. RESULTS: Radiographic progression of erosive arthritis, acro-osteolysis, calcinosis and flexion contracture occurred in 24, 22, 27 and 18 patients, respectively. Multivariate Cox regression analysis did not identify any predictor of the progression of erosive arthritis. Digital ulcers were shown independently to predict the progression of acro-osteolysis and calcinosis (HR 12.43, 95% CI 1.97 to 88.40 and 3.16, 95% CI 1.22% to 9.43%, respectively). The diffuse cutaneous subset was shown to be an independent predictor of the progression of flexion contracture (HR 7.52, 95% CI 1.21 to 43.93). CONCLUSION: The results highlight the striking level of hand radiographic lesions in SSc and suggest close monitoring of patients with the diffuse cutaneous subset for the occurrence or worsening of this complication. The results also show that severe peripheral vascular involvement predicts both acro-osteolysis and calcinosis, highlighting their vascular background.

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group.

OBJECTIVE: To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). METHODS: A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. RESULTS: Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. CONCLUSION: The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.

Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

Influence of flare design on symptomatic efficacy of non-steroidal anti-inflammatory drugs in osteoarthritis: a meta-analysis of randomized placebo-controlled trials.

INTRODUCTION: Non-steroidal anti-inflammatory drugs' (NSAIDs) symptomatic efficacy in osteoarthritis (OA) is often assessed in trials with a "flare design", i.e., including only patients with an increase in their pain after stopping their usual treatment (NSAIDs or analgesic). OBJECTIVE: To evaluate the influence of the "flare design" on NSAIDs apparent symptomatic efficacy in OA. SEARCH STRATEGY: a systematic literature research was performed in Medline, EMBASE and The Cochrane Register up to March 2009. All randomized controlled trials comparing NSAIDs vs placebo symptomatic efficacy in hip, knee, or digital OA were included. DATA COLLECTION AND ANALYSIS: efficacy was evaluated on pain (visual analog scale), and on function (Western Ontario and McMaster Universities OA index or Lequesne index). The magnitude of the treatment effect was evaluated by calculating Cohen's effect size (ES). Meta-analysis of ES according to flare design yes/no was performed. RESULTS: Among the 343 identified studies, 33 (20,915 patients) were included: 27 (18,667 patients) vs 6 (2248 patients) respectively in the group with vs without "flare design". Populations were comparable in each group. ESs were, for pain, -0.66 (95% confidence interval, -0.71 to -0.61), vs -0.45 (-0.54 to -0.36) in the flare design vs "no flare design" group, and for function, -0.50 (-0.55 to -0.44) vs -0.25 (-0.36 to -0.14) respectively. CONCLUSION: Our study suggests that the flare design used in clinical trials evaluating NSAIDs results in a treatment effect of higher magnitude. These results should be considered when designing a trial and/or interpreting the results of a trial.

BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4.

OBJECTIVE: To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene-gene interactions between BANK1 and IRF5 as well as STAT4. METHODS: BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls. RESULTS: The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64-0.93) and an OR of 0.73 (95% CI 0.61-0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57-0.86], P = 3.39 x 10(-4)) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06-1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold. CONCLUSION: Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis.

OBJECTIVE: Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5. METHODS: Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects. RESULTS: STAT4 rs7574865 was shown to be associated with SSc (P=0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with >or=3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P=2.2x10(-4), OR 1.97, 95% CI 1.28-3.04). CONCLUSION: Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.

Association of hypoxia-inducible factor 1A (HIF1A) gene polymorphisms with systemic sclerosis in a French European Caucasian population.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease characterized by generalized microangiopathy leading to chronic hypoxia. The aim of this study was to determine whether polymorphisms of the hypoxia-inducible factor 1A gene (HIF1A) affects susceptibility to SSc in a large French European Caucasian population. METHODS: A case-control study was performed in 659 SSc patients and 511 healthy matched controls. Three tag single nucleotide polymorphisms (SNPs) of the HIF1A gene (rs12434438 A/G, rs1957757 C/T, and rs11549465 C/T) were genotyped allowing whole gene coverage according to HapMap data. RESULTS: The frequency of genotypes carrying at least one G allele (A/G and/or GG) of the rs12434438 SNP was significantly higher in SSc patients than in controls [p(corr) = 0.018, odds ratio (OR) 1.44, 95% confidence interval (CI) 1.08-1.91]. Regarding SSc subgroup analyses, the heterozygous genotype A/G was associated with SSc (p(corr) = 0.012, OR 1.47, 95% CI 1.13-1.9), with the limited cutaneous form of SSc (p(corr) = 0.04, OR 1.43, 95% CI 1.08-1.91), and with positive anti-centromere antibodies (ACA; p(corr) = 0.016, OR 1.61, 95% CI 1.16-2.23). No association was detected for the remaining two HIF1A SNPs tested. Haplotype analyses did not detect any association with SSc. CONCLUSIONS: We observed an association between the HIF1A gene and SSc in a European Caucasian population, supporting a role for HIF1 in the pathophysiology of SSc.

Critical analysis of rituximab-induced serological changes in connective tissue diseases.

A survey of PUBMED and EMBASE supplied 21 articles dealing with the effect of rituximab (RTX) on immunoglobulin (Ig) and autoantibodies (Abs) in nonorgan-systemic autoimmune diseases, and another 12 articles were found by hand search. No statistics could be performed due to the lack of numerical data in the articles. RTX tended to diminish total Ig but still within the normal ranges, more for IgM than IgG and IgA. Rheumatoid factor level decreased by 30 to 60% 3-6 months after RTX, whereas anti-cyclic citrullinated peptide Ab titers declined modestly. In contrast, anti-DNA and anti-C1q Ab levels showed a marked decrease, whereas the other anti-extractable nuclear antigens Ab (anti-SSA, SSB, SM, RNP...) were stable. There are claims for an increase in the BAFF level by approximately 2.5 to 3-fold at 3-4 months, and a return to pre-treatment value at 8-12 months. RTX-induced changes in the serum bring about new insights into mechanisms of action. Therefore, more attention should be paid to such parameters in clinical trials.

EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR).

PURPOSE: The optimal treatment of systemic sclerosis (SSc) is a challenge because the pathogenesis of SSc is unclear and it is an uncommon and clinically heterogeneous disease affecting multiple organ systems. The aim of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR) was to develop evidence-based, consensus-derived recommendations for the treatment of SSc. METHODS: To obtain and maintain a high level of intrinsic quality and comparability of this approach, EULAR standard operating procedures were followed. The task force comprised 18 SSc experts from Europe, the USA and Japan, two SSc patients and three fellows for literature research. The preliminary set of research questions concerning SSc treatment was provided by 74 EUSTAR centres. RESULTS: Based on discussion of the clinical research evidence from published literature, and combining this with current expert opinion and clinical experience, 14 recommendations for the treatment of SSc were formulated. The final set includes the following recommendations: three on SSc-related digital vasculopathy (Raynaud's phenomenon and ulcers); four on SSc-related pulmonary arterial hypertension; three on SSc-related gastrointestinal involvement; two on scleroderma renal crisis; one on SSc-related interstitial lung disease and one on skin involvement. Experts also formulated several questions for a future research agenda. CONCLUSIONS: Evidence-based, consensus-derived recommendations are useful for rheumatologists to help guide treatment for patients with SSc. These recommendations may also help to define directions for future clinical research in SSc.