Susanna Cappelli

Prevalence of Pulmonary Hypertension in Systemic Sclerosis in European Caucasians and Metaanalysis of 5 Studies

Objective. To measure the prevalence of different types of pulmonary hypertension (PH) and to identify patients with systemic sclerosis (SSc) at highest risk in a multicenter European sample, with a metaanalysis of relevant studies. Methods. Consecutive patients with SSc recruited at 11 French and Italian centers underwent detailed evaluations, including Doppler echocardiography, chest computed tomography, pulmonary function tests, and right-heart catheterization (RHC), to detect the presence and causes of PH. A metaanalysis was performed, including data from 4 other studies. Results. Among 206 patients in whom it was suspected, PH was confirmed by RHC in 83 patients (7%). Precapillary PH was found in 64 patients (5%), of whom 42 had pulmonary arterial hypertension (PAH) and 22 had PH secondary to interstitial lung disease (ILD). RHC identified 17 patients (1%) with postcapillary PH secondary to left-heart disease. Patients with DLCO/alveolar volume < 70% were more likely to have precapillary PH (87.5% vs 42%; p < 0.0001). Precapillary and postcapillary PH were associated with advanced age (68 ± 14 vs 59 ± 12 yrs, p < 0.0001, and 74 ± 16 vs 61.5 ± 10 yrs, p < 0.0001, respectively). The metaanalysis of 3818 patients showed a prevalence of precapillary PH of 9% (95% CI 6%–12%) and identified advanced age, longer disease duration, and limited cutaneous disease subset as risk factors for this condition. Conclusion. The prevalence of precapillary PH in our multicenter study of SSc was 5%, and in the metaanalysis 9%. Our observations support use of RHC to confirm the presence of precapillary PH suspected by noninvasive testing. We also identified patients at high risk who should be carefully monitored.

To be or not to be, ten years after: evidence for mixed connective tissue disease as a distinct entity.

OBJECTIVES To determine if mixed connective tissue disease (MCTD) can be considered an independent clinical entity, to compare 3 different classification criteria for MCTD (Kasukawa, Alarcón-Segovia, and Sharp), and to define predictors (clinical features and autoantibodies) of potential evolution toward other connective tissue diseases (CTDs). METHODS One hundred sixty-one MCTD patients were evaluated retrospectively at the diagnosis and in 2008. They were classified, at the diagnosis, according to the 3 classification criteria of MCTD (Sharp, Alarcón-Segovia, and Kasukawa) and reclassified in 2008 according to their evolution. Statistical analyses were performed to find out predictors (clinical features and autoantibodies) of evolution into other CTDs. RESULTS After a mean of 7.9 years of disease, 57.9% of patients still satisfied MCTD classification criteria of Kasukawa; 17.3% evolved into systemic sclerosis, 9.1% into systemic lupus erythematosus, 2.5% into rheumatoid arthritis, 11.5% was reclassified as affected by undifferentiated connective tissue disease, and 1.7% as suffering from overlap syndrome. Kasukawas criteria were more sensitive (75%) in comparison to those of Alarcón-Segovia (73%) and Sharp (42%). The presence of anti-DNA antibodies (P = 0.012) was associated with evolution into systemic lupus erythematosus; hypomotility or dilation of esophagus (P < 0.001); and sclerodactyly (P = 0.034) with evolution into systemic sclerosis. CONCLUSIONS MCTD is a distinct clinical entity but it is evident that a subgroup of patients may evolve into another CTD during disease progression. Initial clinical features and autoantibodies can be useful to predict disease evolution.

Associated Autoimmune Diseases in Systemic Sclerosis Define a Subset of Patients with Milder Disease: Results from 2 Large Cohorts of European Caucasian Patients

Objective. To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID). Methods. A multicenter study was performed in France and Italy to recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases. Results. We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren’s syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren’s syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers. Conclusion. Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.

Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria

OBJECTIVES Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc. STUDY DESIGN AND SETTING A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs). RESULTS Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90). CONCLUSIONS Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.

Interstitial lung disease in systemic sclerosis: where do we stand?

Interstitial lung disease (ILD) is common in systemic sclerosis (SSc) patients and despite recent advances in the treatment is, at present, the major cause of death. Today, an early diagnosis of ILD is possible, and is mandatory to improve the prognosis of the disease. Pulmonary function tests and high-resolution computed tomography remain the mainstay for the diagnosis of SSc-ILD, but there is a growing interest in lung ultrasound. Recently, the correlation between severity of fibrosis and some peripheral blood biomarkers has been described. Nonselective immunosuppressors are still the main treatment for ILD, with cyclophosphamide (CYC) most widely used to obtain remission. Novel therapies towards specific molecular and cellular targets have been suggested; in particular, rituximab (RTX) has shown promising results, but further research is needed. It is of paramount importance to define the severity of the disease and the risk of progression in order to define the need for treatment and the treatment intensity. We propose the division of the treatment strategies at our disposal to induce remission into three categories: high intensity (haematopoietic stem cell transplantation), medium intensity (CYC and RTX) and low intensity (azathioprine (AZA) and mycophenolate mofetil (MMF)). After obtaining remission, maintenance treatment with AZA or MMF should be started. In this review we explore new advances in the pathogenesis, diagnosis and treatment of SSc-ILD. Early diagnosis of ILD is possible, and is mandatory to improve the prognosis of the disease http://ow.ly/P28JH

Immunosuppression for interstitial lung disease in systemic sclerosis

The efficacy of immunosuppressors in the treatment of systemic sclerosis-interstitial lung disease is still matter of controversy. In this review we will analyse the evidence that immunosuppressors, despite not being able to reverse fibrotic changes, may help in slowing disease progression. Induction treatment with cyclophosphamide should be started as soon as possible in patients at risk for progression. Mycophenolate mofetil and rituximab have to be considered in patients who are unable to tolerate cyclophosphamide. After remission, maintenance treatment with mycophenolate mofetil or azathioprine should be started in order to preserve the benefits achieved during the induction treatment.

Treatment options in systemic sclerosis

Introduction: The treatment of systemic sclerosis (SSc) still represents a challenge for all physicians because of the complexity of this disease. However, new insights into pathophysiology are driving new approaches to its treatment by acting on key targets of pathogenesis. Areas covered: The management of SSc consists of a symptomatic therapy and a disease modifying therapy. The aim of symptomatic treatment is to control different symptoms, clinical manifestations and organ-based complications while disease modifying therapy interferes with the main pathogenetic mechanisms in order to obtain remission, to stop disease progression and if possible to reverse disease-related skin and internal organ changes. This article will provide an overview of the different treatments for the most common features of SSc. A Medline search was focused on most relevant treatment literature contribution published in the past decade. Expert opinion: As for symptomatic treatment, calcium channel blockers (CCBs) should be considered as the first-line therapy for Raynauds phenomenon (RP). In case of intolerance or ineffectiveness, a phosphodiesterase type 5 (PDE5) inhibitor alone or in association with CCB can be started. As for pulmonary arterial hypertension (PAH), both bosentan, ambrisentan and sildenafil, can be used as first-line treatments. In patients with organ involvement at risk for progression, cyclophosphamide (CYC) should be considered the disease modifying agent of choice. In case of contraindications to CYC, rituximab (RTX) and mycophenolate mofetil (MMF) have to be taken into account. After induction treatment, maintenance with MMF or azathioprine (AZA) has to be started.

THU0306 Predictors of outcome in a cohort of italian children/adolescents with primary raynaud’s phenomenon: A multicenter study

Background Raynaud’s phenomenon (RP) is a benign reversible vasospasm of the extremities that may occur in the absence of any underlying connective tissue disease (CTD), mostly systemic lupus erythematosus, juvenile dermatomyositis and systemic scleroderma. Predictors of a favorable outcome are still unraveled in primary RP (pRP): the causative role of various autoantibodies remain to be elucidated mostly for pRP starting in childhood or adolescence. Objectives To identify the possible predictors of outcome in a cohort of children and adolescents with pRP. Methods We performed a prospective data collection of demographic, clinical, laboratory and treatment characteristics of 76 Italian children/adolescents with pRP (54 females, 22 males, median age at disease onset: 13.3 years, median age at diagnosis: 14.7 years), managed in 4 pediatric rheumatologic centres and 1 transition clinic during the last three years. Demographic characteristics included sex, age and ethnicity. The evaluation included clinical pictures, eventual disease associations, pubertal status, laboratory data and nailfold videocapillaroscopy (NVC) at baseline and at regular 6-month-follow-up. Laboratory examinations included erythrosedimentation rate, C-reactive protein, transaminases, creatinine, hemoglobin, complement fractions C4 and C3, renal and thyroid function and specific serum autoantibodies (anti-nuclear antibodies [ANA], anti-DNAds, anti-ENA, anti-cardiolipin, anti-Scl-70 and anti-centromere antibodies). Screening for coeliac disease was performed at the first evaluation. Treatment details included the eventual specific drug used, its dosage and overall treatment duration. Out of 76, 14 patients were treated with hydroxicloroquine, 10 with calcium blockers, 1 with low-dose aspirin, 3 with iloprost, while the remaining 48 did not receive any drug.A forward stepwise multiple logistic regression analysis was used to find any association among sex, pubertal status, inflammatory parameters, NVC abnormalities, all serum autoantibodies and the risk of developing a CTD at baseline and at 36-month-follow-up. The software used was STATA 10. A p-value <0.05 was considered significant Results ANA positivity at baseline was significantly associated with the risk of developing a CTD (p<0.05). No NVC abnormalities was related to specific patients’ outcome. No patient resulted positive at the screening for coeliac disease. Conclusions Our data show that only ANA positivity is the potential predictor of poor outcome and progression to CTD in children and adolescents with pRP. References Nigrovic PA, Fuhlbrigge RC, Sundel RP. Raynaud’s phenomenon in children: a retrospective review of 123 patients. Pediatrics 2003;111:715-21. Disclosure of Interest None Declared