Differences associated with age at onset in early systemic sclerosis patients: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR) database.

OBJECTIVE: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years' duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets. METHOD: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud's SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud's phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31-59, and ≥ 60 years. We performed descriptive and bivariate analyses. RESULTS: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud's. CONCLUSION: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice.

Malnutrition and sarcopenia in a large cohort of patients with systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease which may lead to malnutrition. Previous studies have defined it with different criteria. No thorough evaluations of sarcopenia in SSc are available. The aim of the present study was to assess the prevalence and the potential association of malnutrition and sarcopenia in a large cohort of SSc cases. A total of 141 SSc consecutive outpatients were enrolled. Body composition was analyzed by densitometry. Malnutrition was defined according to recently published ESPEN criteria, whereas sarcopenia was diagnosed in patients with reduced skeletal muscle index. Malnutrition was diagnosed in 9.2% of patients (95% CI, 4.4-14.0%). Malnourished patients had worse gastrointestinal symptoms according to UCLA SCTC GIT 2.0 questionnaire (p = 0.007), lower physical activity (p = 0.028), longer disease duration (p = 0.019), worse predicted DLCO/VA and FVC (p = 0.009, respectively), worse disease severity according to Medsger severity score (p < 0.001), lower hemoglobin (p = 0.023), and fat-free mass (p < 0.001) and were more often sarcopenic (p < 0.001). In multivariate analysis, only FVC (p = 0.006) and disease severity (p = 0.003), in particular for the lungs (p = 0.013), were confirmed to be worse in malnourished patients. Sarcopenia was diagnosed in 29\140 patients (20.7%; 95% CI, 14.0-27.4%); 11\29 were also malnourished. In multivariate analysis, sarcopenic patients had longer disease duration (p = 0.049), worse DLCO/VA (p = 0.002), and lung (p = 0.006) and skin (p = 0.014) involvement. In SSc, malnutrition defined with ESPEN criteria was found to be lower than previously reported. Sarcopenia was found to be somewhat common. Lung involvement was significantly associated with nutritional status and may not be explained only by muscle weakness.

Adherence to recommendations for cervical and breast cancer screening in systemic sclerosis.

The aim of the study was to evaluate the adherence of systemic sclerosis (SSc) female patients to cervix and breast cancer screening procedures, as suggested by local guidelines. A cohort of 84 SSc women was asked if they had undergone mammography and Pap test during the previous 2- and 3-year intervals, as indicated according to the Italian recommendations. The results were compared with those collected in patients affected by other chronic rheumatic disorders and in the general population. More than 85% of SSc women declared to comply with an age-related cervix and breast cancer screening schedule. The data were similar to those collected in patients affected by other chronic rheumatic disorders, whereas the subjects belonging to the general population reported to undergo breast cancer screening more frequently. Among SSc women, neither the educational level, nor the lung and skin involvement influenced their cancer screening program compliance. Only a positive history of ischemic digital ulcers seemed to interfere with mammography. Our study reported a very high percentage of SSc female patients who adhered to programs for the early detection of cervical and breast cancer. The significant adherence to guidelines may be due to the schedule adopted by the local health public service, which regularly invites eligible subjects by mail to undergo cancer screening at no charge.

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.

Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement.

OBJECTIVE: The aim of this study was to investigate the relationship between SP-D and KL-6 serum concentrations and the extent of interstitial lung involvement, as measured by a quantitative HRCT score and the functional impairment, in patients with systemic sclerosis (SSc). Moreover we analysed the association between these lung-specific biomarkers and skin involvement, anti-Scl-70 antibody titres and an index of disease activity. METHODS: Serum SP-D, KL-6 and anti-Scl-70 concentrations were determined by ELISA in 25 SSc patients. Disease activity and lung function parameters were assessed, and the extent of ILD was measured by a HRCT score. RESULTS: SP-D and KL-6 concentrations were higher in patients with SSc and lung fibrosis than in healthy controls. KL-6 correlated positively with the HRCT-fibrosis score (r=0.68, p<0.001), SP-D showed a weaker correlation (r=0.44, p=0.025). Increased KL-6 concentrations were associated with decreased DLCO and decreased FVC in SSc patients, SP-D showed no association. Furthermore KL-6, but not SP-D, showed a strong association with skin involvement as expressed by the modified Rodnan skin score (r=0.71, p<0.0001) and a disease activity index (r=0.73, p<0.0001). CONCLUSION: KL-6 is more strongly associated than SP-D with the HRCT-fibrosis score, and, different from SP-D, it correlates with skin involvement and disease activity. We suggest that KL-6 may be a useful biomarker in the assessment of scleroderma patients.

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.

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.

Clinical, serologic and instrumental data of ten patients affected by sclerodermatous chronic graft versus host disease: similarities and differences in respect to systemic sclerosis.

Chronic graft versus host disease (cGVHD), the most common late complication of allogeneic haematopoietic stem cell transplantation (HSCT), may present with sclerodermatous lesions resembling in some cases the cutaneous involvement of systemic sclerosis (SSc). Certain pathogenetic findings connect the two diseases. In this report we describe ten subjects affected by cGVHD who underwent the examinations routinely carried out to stage SSc patients. Demographic, clinical, serologic and instrumental data were recorded. These patients showed differences in appearance, extent and progression of the sclerodermatous lesions with greater involvement of the trunk and proximal part of the limbs than the extremities. In seven subjects ANA test was positive; scleroderma-associated autoantibodies were not detected in any of the cases. Moreover, typical organ involvement of SSc was not found. Only one patient developed Raynauds phenomenon after HSCT and only one patient demonstrated a nailfold videocapillaroscopic scleroderma pattern. Except for cutaneous involvement of cGVHD, that may resemble SSc, the clinical features of the two diseases are quite different, suggesting that the fibrotic process characterizing cGVHD and SSc has different etiologies and different initial pathobiologic events.

Systemic lupus erythematosus and strongyloidiasis: a multifaceted connection.

We describe a case of systemic lupus erythematosus complicated by strongyloidiasis. The parasitic infection appeared with diarrhoea, weight loss and peripheral eosinophilia in association with recurrence of polyarthritis, probably due to a flare of systemic lupus erythematosus. The literature about the coexistence of systemic lupus erythematosus and strongyloidiasis has been reviewed.

Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis.

OBJECTIVES: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). METHODS: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. RESULTS: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. CONCLUSION: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective.

Safety and efficacy of etanercept in children with juvenile-onset Behcets disease.

Behcets disease (BD) is a chronic, relapsing, multi-system inflammatory disorder, clinically characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. Other manifestations include arthritis, a positive pathergy test, thrombophlebitis, central nervous system disease and gastrointestinal ulcerations. The majority of affected individuals do not have life-threatening disease, although mortality can be associated with vascular-thrombotic and neurological manifestations. Currently, treatment of BD is symptomatic and empirical, and is tailored according to the severity of clinical features. In the past few years, isolated reports and case-series have been published on adult BD patients suggesting that inhibition of TNF-alpha is a promising therapeutic approach for severe ocular and various extra-ocular manifestations, including central nervous system involvement. In this study we present our promising experience with Etanercept therapy in juvenile-onset BD patients, characterized by refractory multiorgan involvement.

Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study.

OBJECTIVES: To asses risk factors for a first thrombotic event in antiphospholipid antibody (aPL) positive carriers and evaluate the efficacy of prophylactic treatments. METHODS: Recruitment criteria were age 18-65 years, no history of thrombosis, positivity for lupus anticoagulant and/or IgG/IgM anticardiolipin antibody (aCL) on > or =2 occasions at least 6 weeks apart. Demographic, laboratory and clinical parameters were collected at enrolment and at the time of the thrombotic event. RESULTS: 370 patients/subjects (mean (SD) age 34 (9.9) years) were analysed retrospectively for a mean (SD) follow-up of 59.3 (45.5) months. Thirty patients (8.1%) developed a first thrombotic event during follow-up. Hypertension and medium/high levels of IgG aCL were identified by multivariate logistic regression analysis as independent risk factors for thrombosis. Thromboprophylaxis during high-risk and long-term periods was significantly protective. CONCLUSIONS: Hypertension or medium/high titres of IgG aCL are risk factors for a first thrombotic event in asymptomatic aPL carriers and primary prophylaxis is protective.

[Sustained response to infliximab treatment in two cases of early rheumatoid arthritis that has been maintained after drug withdrawal]. / Due casi di artrite reumatoide trattati in fase precoce con infliximab con mantenimento dell'effetto dopo la sospensione del farmaco.

The authors report two cases of active seropositive rheumatoid arthritis who were treated in an early phase of the disease with infliximab plus methotrexate obtaining a clinical remission. The benefit was maintained after the discontinuation of the anti-TNF alpha inhibitor for adverse events, indicating that the early administration of the drug may be followed by a sustained remission.

[Chikungunya arthritis: report of 6 cases]. / Artropatia da Chikungunya: descrizione di 6 casi.

Chikungunya is an arboviral disease transmitted by Aedes mosquitoes. The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia, that can persist for months. Chikungunya virus, a member of the genus Alphavirus, has recently caused a large outbreak on islands in the Indian Ocean and on the Indian subcontinent. The ongoing outbreak has involved more than 1.5 million patients, including travellers who have visited these areas. We describe our casistic of six travellers with Chikungunya arthropathy. All patients experienced fever and rash of short term during a travel in areas of epidemicity. All patients had peripheral poliarthralgias, which duration was >2 months in 4 cases (66%) and >6 months in 1 case (16%).

Interethnic differences at the thermometric response to cold test: functional disorders of blood circulation in hand fingers and exposure to hand-arm vibration.

OBJECTIVES: To report some notable aspects regarding thermometric response to cold test in black African subjects compared with Caucasians: both groups comprised persons exposed to hand-arm vibration and controls. METHODS: An overall sample of 48 workers was examined in order to study their blood circulation in hand fingers: a control group of 12 healthy Caucasian workers never exposed before to hand-arm vibration; 12 Caucasian workers exposed for several years to vibrating tools and affected by occupational Raynaud's phenomenon; 12 healthy black African workers exposed to hand-arm vibration for almost 3 years; and 12 healthy black African workers never exposed to hand-arm vibration. Computerized skin thermometry was performed and thermometric curves were analyzed according to thermometric interpretation criteria such as the area-over-curve (AOC), the fifth minute of recovery/baseline temperature ratio (5REC/BT) and the temperature at the tenth minute of recovery (10REC) after cold test. RESULTS: Thermometric parameters in Caucasian subjects confirmed the basis of the existing literature in controls (basal finger temperature higher than 32 degrees C and complete recovery to the initial temperature after the cold test) and also in patients with Raynaud's phenomenon (basal temperature often lower than control subjects and slow recovery of finger temperature after cold test). Statistically significant difference was found between healthy Caucasians and healthy black subjects in all the parameters tested: healthy black subjects showed values of AOC and 10REC suggesting almost constantly lower finger temperatures during the thermometry test. Black people, both exposed and non-exposed to hand-arm vibration showed thermometric parameters suggesting poor blood microcirculation, which seems even poorer than in Caucasian people complaining Raynaud's phenomenon. CONCLUSIONS: Our chronothermometric tests suggest some significant interethnic differences in peripheral microcirculation, which seems rather poor in black African subjects in comparison with Caucasians.

Scleroderma patients nailfold videocapillaroscopic patterns are associated with disease subset and disease severity.

OBJECTIVE: To evaluate in a large group of scleroderma patients, the association of nailfold videocapillaroscopic patterns with both demographic and clinical features. METHODS: One hundred and three Italian patients (91 women and 12 men, mean age 54.3 years, median disease duration 7 yrs, 68 with limited and 35 with diffuse subset of disease), consecutively enrolled for the study, underwent nailfold videocapillaroscopy; the microvascular alterations were classified into three different patterns, early, active and late. The nailfold videocapillaroscopic patterns were correlated with such numerous clinical features as sex, age, disease duration, disease subset, disease activity, haematochemical data, involvement of skin, heart, lung and peripheral vessels. RESULTS: Nailfold videocapillaroscopic patterns were significantly associated with disease subsets (P = 0.018). Severity of skin, lung, heart and peripheral vascular involvement progressively increased across nailfold videocapillaroscopic patterns, from early to late pattern (P < 0.001 for cutaneous and peripheral vascular involvement; P = 0.003 and 0.002 for lung and heart involvement, respectively) as well as homocysteine plasma levels (P = 0.02). Patients with late pattern showed an increased risk to have an active disease [OR (odds ratio) 3.50; 95% CI (confidence interval) 1.31-9.39], to present digital ulcers (OR 5.74; 95% CI 2.08-15.89) and moderate to severe skin (OR 5.28; 95% CI 1.93-14.19), heart (OR 5.75; 95% CI 2.04-16.21) and lung involvement (OR 4.41; 95% CI 1.63-11.92). CONCLUSIONS: Our study showed that scleroderma microangiopathy correlates with disease subset and severity of peripheral vascular, skin, heart and lung involvement; patients with late pattern showed an increased risk to have an active disease and to show a moderate/severe skin or visceral involvement compared to patients with early and active patterns. Therefore nailfold videocapillaroscopy, a simple, non-invasive and non-expensive investigation, is useful in staging scleroderma patients and also provides prognostic information.