LAUDES Study: impact of digital ulcers on hand functional limitation, work productivity and daily activities, in systemic sclerosis patients.

The objective of this study was to evaluate the impact of digital ulcers (DUs) in daily life of systemic sclerosis (SSc) Spanish patients. We developed a multicenter observational study to compare functional disability in SSc patients with active DUs vs. those without DUs. An additional correlation between perception of patients and physicians on disability due to DUs was performed. A total of 199 patients were enrolled, 70 (35%) with DUs. Patients with DUs were younger (48 vs. 58 years; p < 0.001) and had more frequently the diffuse subtype of SSc (45 vs. 24%; p = 0.004) than patients without DUs. Patients with DUs showed significantly higher scores in the Cochin Hand Function Scale overall (p < 0.002) and for each of its five dimensions. They also showed higher scores in the Systemic Sclerosis Health Assessment Questionnaire items related to hand function such as, dress and self-care (p < 0.013), eat (p < 0.013) and grip (p < 0.03), and higher Visual Analogic Scale scores for pain (p < 0.013), trouble related with Raynaud's Phenomenon (p < 0.001) and sense of severity (p < 0.004). Impact on daily activities was significantly higher in patients with DUs (p = 0.002), with a non-significant trend to experience higher impact on work productivity (p = 0.07). A high correlation was found between DUs patients and physicians opinion on the impact of DUs (daily life: Pearson R = 0.86; work productivity: Pearson R = 0.87). Study findings show an impaired hand function and increased disability for daily life activities and work productivity in SSc patients with DUs compared with patients without DUs in Spanish population.

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway.

OBJECTIVES: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc. METHODS: This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method. RESULTS: Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants. CONCLUSIONS: We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology.

Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis.

OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88x10(-2), OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89x10(-2), OR=1.13; p=1.69x10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00x10(-4), OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.

COVID GEAS: COVID-19 National Survey in Patients With Systemic Autoimmune Diseases.

OBJECTIVES: COVID-19 outcomes in population with systemic autoimmune diseases (SAD) remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 infection in people with rheumatic disease. METHODS: Two phases cross-sectional survey of individuals with rheumatic disease in April 2020 and October 2020. COVID infection, severity of disease, age, sex, smoking status, underlying rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analyzed. RESULTS: A total of 1,529 individuals with autoimmunity disease diagnosis were included. Out of 50 positive patients, 21 required telephone medical assistance, 16 received assessment by primary care physician, 9 were evaluated in Emergency Department and 4 patient required hospitalization. Multivariate analysis was performed without obtaining differences in any of the systemic autoimmune diseases. Regarding the treatments, significant differences were found (p 0.011) in the treatment with anti-TNF-alpha agents with OR 3.422 (1.322-8.858) and a trend to significance (p 0.094) was observed in patients receiving mycophenolate treatment [OR 2.016 (0.996-4-081)]. CONCLUSIONS: Anti-TNF-alpha treatment was associated with more than 3-fold risk of suffering from SARS-CoV-2 infection, although in all cases infection was mild. Cumulative incidence in patients with SAD was up to 5 times higher than general population but with great differences between autoimmune diseases.

Effect of bosentan in pulmonary hypertension development in systemic sclerosis patients with digital ulcers.

Systemic sclerosis is a disease where microcirculation damage is critical in their beginning and vascular complications have similar pathogenic findings. Digital ulcers are a frequent complication in systemic sclerosis patients and pulmonary hypertension is one of the leading causes of death. The use of bosentan has been shown to be useful for the treatment of pulmonary arterial hypertension and to prevent new digital ulcers. However, is unknown if bosentan can prevent pulmonary hypertension. Our objective was to determine if bosentan is useful to prevent pulmonary hypertension in SSc patients. A retrospective study in 237 systemic sclerosis patients with digital ulcers history treated or not with bosentan to prevent it was made. We analyzed the occurrence of pulmonary hypertension defined by an echocardiogram pulmonary arterial pressure > 40 mmHg in the entire cohort. Demographic, clinical, and treatment variables were recorded for all patients. Statistical significance was denoted by p values < 0.05. Fifty-nine patients were treated with bosentan a median of 34 months. 13.8% of treated patients had pulmonary hypertension vs 23.7% of untreated patients (p 0.13) during the follow up. In multivariate analysis patients not treated with bosentan had 3.9fold-increased risk of pulmonary hypertension compared with patients under bosentan treatment (p < 0.02). Moreover the percentage carbon monoxide diffusing capacity (DLCO) in bosentan treated patients did not decrease from baseline to the end of follow-up (61.8±14% vs 57±20.1%, p = 0.89). We concluded that Systemic sclerosis patients with digital ulcers treated with bosentan seems to have less risk to develop pulmonary hypertension and to stabilize DLCO.

Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations.

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.

[Usefulness of oral pilocarpin therapy in the treatment of xerostomia and xerophthalmia in patients with primary Sjögren's syndrome]. / Pilocarpina oral en el tratamientode la xerostomía y xeroftalmía en pacientes con síndrome de Sjögren primario.

BACKGROUND AND OBJECTIVE: We aimed to asses the efficacy of pilocarpine tablets as a symptomatic treatment for dry mouth and dry eyes in patients with primary Sjögren's syndrome (SS). PATIENTS AND METHOD: We included 40 patients with SS (38 women and 2 men), mean age 49.2 years (range, 35-68), with severe xerostomia and xerophthalmia. Objective tests (salivary scintigraphy, Schirmer's test, break-up time, Rose Bengal staining) and subjective tests (symptoms' questionnaire) were carried out before starting treatment and 6 months later to evaluate any glandular function improvement. RESULTS: All patients initially received 15 mg daily of pilocarpine. Twelve (30%) patients received 20 mg daily. Dry mouth-related symptoms improved in 57.5% of patients and dry eyes-related ones improved in 35%. Scintigraphic studies demonstrated an objective improvement of the glandular function in 35% patients. Ocular tests showed an improvement in 30% cases. CONCLUSIONS: Pilocarpine therapy is useful to improve xerostomia and xerophthalmia in SS patients with moderate and severe glandular involvement. However, we have not observed a good correlation between subjective improvement of symptoms and the objective test results.

Mortality and survival in systemic sclerosis: systematic review and meta-analysis.

OBJECTIVE: To determine the mortality, survival, and causes of death in patients with systemic sclerosis (SSc) through a meta-analysis of the observational studies published up to 2013. METHODS: We performed a systematic review and meta-analysis of the observational studies in patients with SSc and mortality data from entire cohorts published in MEDLINE and SCOPUS up to July 2013. RESULTS: A total of 17 studies were included in the mortality meta-analysis from 1964 to 2005 (mid-cohort years), with data from 9239 patients. The overall SMR was 2.72 (95% CI: 1.93-3.83). A total of 43 studies have been included in the survival meta-analysis, reporting data from 13,529 patients. Cumulative survival from onset (first Raynaud's symptom) has been estimated at 87.6% at 5 years and 74.2% at 10 years, from onset (non-Raynaud's first symptom) 84.1% at 5 years and 75.5% at 10 years, and from diagnosis 74.9% at 5 years and 62.5% at 10 years. Pulmonary involvement represented the main cause of death. CONCLUSIONS: SSc presents a larger mortality than general population (SMR = 2.72). Cumulative survival from diagnosis has been estimated at 74.9% at 5 years and 62.5% at 10 years. Pulmonary involvement represented the main cause of death.

Early- versus late-onset systemic sclerosis: differences in clinical presentation and outcome in 1037 patients.

Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤ 30 years (early onset), age between 31 and 59 years (standard onset), and age ≥ 60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients.

Latent pulmonary inflammation in patients with systemic sclerosis.

BACKGROUND: Induced sputum is a non-invasive method for studying pulmonary inflammation. OBJECTIVES: To assess pulmonary inflammation by analysis of induced sputum specimens in patients with systemic sclerosis and lung involvement, and to determine whether there is a correlation with the pulmonary function alterations in these patients. METHODS: Twenty-five patients with systemic sclerosis were included (20 women). Patients were divided into 3 groups according to the type of lung involvement: group 1, diffuse interstitial lung disease (n=10); group 2, those with pulmonary arterial hypertension (n=7), and group 3, patients with systemic sclerosis without lung involvement (n=8). All patients underwent a complete lung function study. Induced sputum samples were obtained and differential cell count was performed by optic microscopy. RESULTS: The mean percentage of sputum neutrophils was 85%, 71%, and 75% for groups 1, 2, and 3, respectively. A significant negative correlation between sputum total cell count and DLCO was seen in group 1 and group 3 (r=-0.733, P=.016; and r=-0.893, P=.007, respectively). This negative correlation was not observed in group 2. CONCLUSIONS: Pulmonary inflammation was present in all patients with systemic sclerosis included in the study, regardless of the presence of documented signs of pulmonary involvement. This finding suggests that induced sputum could be helpful for detecting early abnormalities indicative of subclinical pulmonary involvement in patients with systemic sclerosis.

Efficacy of cyclophospamide in the treatment of interstitial lung disease associated with systemic sclerosis.

BACKGROUND: Cyclophosphamide (CYC) stabilizes the parameters of lung function tests (LFT) of patients with (SSc) and interstitial lung disease (ILD) treated for 12 months. There is little information about long-term treatment (24 months). The aim of this study is to analyze the effect of intravenous CYC in LFT parameters in patients with SSc and ILD treated for 24 months. PATIENTS AND METHOD: Retrospective study of 37 patients with ILD associated with scleroderma treated with intravenous CYC for 24 months and regularly assessed by LFT (at baseline, 6, 12 and 24 months) including forced vital capacity (FVC) and transfer capacity of carbon monoxide (DL(CO)). To evaluate response to treatment the recommendations of the ATS and SEPAR were considered. RESULTS: The difference between FVC and DL(CO) values performed at baseline and those performed at 6, 12, and 24 months were less than 10%, which meant that CYC stabilized LFT. There were no differences in LFT when patients treated for 6 months were evaluated according to the type of skin involvement of the SSc (diffuse or limited) and the duration of the ILD. Although patients with severe restriction (FVC<70%) showed more improvement, it was less than 10% in all cases. CONCLUSION: In this series of patients with ILD associated with SSc intravenous CYC was effective in stabilizing LFT in long-term treatment.

Bosentan in clinical practice for treating digital and other ischemic ulcers in Spanish patients with systemic sclerosis: IBER-DU cohort study.

OBJECTIVE: To describe treatment outcomes and safety experience with bosentan in patients with systemic sclerosis (SSc) and digital ulcers (DU), in a clinical setting in Spain. METHODS: This was a multicenter, noninterventional retrospective cohort study. Data were collected retrospectively from patients with DU, with or without pulmonary arterial hypertension (PAH), who were initiating bosentan therapy in 2003 (n = 26) or 2004 (n = 41) and followed until May 2005. Data were obtained from centers prescribing bosentan. Relevant measures included number of DU, occurrence of new DU, overall DU clinical status (improved, stabilized, worsened), and bosentan-associated adverse events. RESULTS: Sixty-seven patients with SSc and DU or other ulcers were included. PAH was also present in 12 patients (18%). At the start of bosentan treatment, the median number of DU per patient was 3.0. The median change in number of DU was -3.6 and -5.0 at 12 and 24 months, respectively. Sixty-eight percent of the patients did not develop any new DU at 12 months. DU clinical status was reported at 12 months for 22 patients: 18 patients (81.8%) improved and 4 (18.2%) stabilized. The median treatment duration was 13.0 months. The main adverse event was increase of aminotransferase, observed in 5 patients (7%), leading to discontinuation of treatment in 3 patients (4.4%). CONCLUSION: Previously reported results of bosentan efficacy in DU management are reproducible in clinical practice. This efficacy is maintained in the longterm followup. Bosentan treatment was well tolerated and adverse events were comparable with those observed in previous reports.

Palmar fascitis and polyarthritis as a paraneoplastic syndrome associated with ovarian carcinoma: a case report.

This case report concerns a 49-year-old woman whose physical examination was remarkable for symmetrical swollen hands, fingers and palmar fascial thickening with erythema. The fingers showed flexion contractures. Examination also revealed markedly limited bilateral shoulder and limited knee flexion.The patient's symptoms were treated with rehabilitation. The immunological laboratory investigations were normal. A technetium scan showed a slightly increased uptake in both shoulders, wrists, hips, knees and ankles. CT revealed a pelvic solid mass next to the uterus. After the patient underwent a total hysterectomy and anexectomy, the polyarthritis showed a gradual improvement but the contractures in the hands persisted.Palmar fasciitis and polyarthritis syndrome (PFPAS) is an uncommon rheumatic disorder consisting of pain, swelling, stiffness, progressive flexion contractures of both hands and thickening of palmar fascia, with erythrosis. It was first described as a paraneoplastic phenomenon with ovarian carcinoma in 1982.The characteristic hand deformities of PFPA should alert the clinician to search for an underlying malignant disease.

Pilocarpina oral en el tratamiento de la xerostomía y xeroftalmía en pacientes con síndrome de Sjögren primario / Usefulness of oral pilocarpin therapy in the treatment of xerostomia and xerophtalmia in patients with primary Sjögren's syndrome

FUNDAMENTO Y OBJETIVO: Evaluar la eficacia de la pilocarpina en el tratamiento de la xerostomía y xeroftalmía en pacientes afectados de síndrome de Sjögren primario. PACIENTES Y MÉTODO: Se incluyó a 40 enfermos (38 mujeres y 2 varones), con una edad media de 49,2 años (intervalo, 35-68), con xerostomía y xeroftalmía intensas. Se practicaron pruebas objetivas (gammagrafía salival, prueba de Schirmer, tiempo de rotura lagrimal, tinción corneal con rosa de Bengala) y subjetivas (cuestionario de síntomas) para valorar la función glandular antes de inicio del tratamiento y a los 6 meses. RESULTADOS: Todos los pacientes recibieron inicialmente 15 mg/día de pilocarpina distribuidos en 3 tomas; 12 (30 por ciento) recibieron 20 mg/día. El 57,5 por ciento refirió mejoría subjetiva de la xerostomía y el 35 por ciento, de la xeroftalmía. La xerostomía mejoró objetivamente en el 35 por ciento de los pacientes y la xeroftalmía, en el 30 por ciento. CONCLUSIONES: El tratamiento con pilocarpina es beneficioso en pacientes con síndrome de Sjögren primario con moderada o escasa función glandular. No siempre existe una adecuada correlación entre la mejoría objetiva y la subjetiva (AU)