Reduced type I collagen gene expression by skin fibroblasts of patients with systemic sclerosis after one treatment course with rituximab.

OBJECTIVES: There is evidence that B lymphocytes play a role in the pathogenesis of systemic sclerosis (scleroderma). Stimulatory autoantibodies targeting and activating normal human fibroblasts in vitro have been demonstrated in sera from scleroderma patients. Rituximab is a monoclonal antibody which selectively targets and depletes CD20+ B lymphocytes. We investigated the biological effects of rituximab in six patients affected by scleroderma with severe skin involvement. METHODS: Six patients with severe skin fibrosis, unresponsive to immunosuppressive treatment, were treated with 375 mg/m2 per week of intravenous rituximab for a total of four doses. Serum stimulatory autoantibodies to the PDGF receptor were detected. Fibroblast activation was evaluated in fibroblasts grown from skin biopsies performed at baseline and at months 3 and 6 post-treatment. The modified Rodnan's skin score, health assessment questionnaire (HAQ) and visual analogic scale (VAS) for global wellness and B lymphocyte count were performed monthly. RESULTS: A significant reduction of anti-PDGF receptor autoantibodies was observed in the serum of all patients 3 months after treatment. Fibroblasts showed a significant downregulation of type I collagen gene expression and of the intracellular signalling triggered by anti-PDGFR autoantibodies. A decrease of the skin score and an improvement of disability indexes matched with the in vitro results. A single course of rituximab reduced scleroderma fibroblast activation in vitro and the serum levels of anti-PDGFR stimulatory autoantibodies. CONCLUSIONS: These data provide further evidence of B-cell involvement in the pathogenesis of scleroderma. Targeting B cells may be a promising treatment for scleroderma patients, and controlled clinical trials are warranted.

An observational cohort study of patients with newly diagnosed digital ulcer disease secondary to systemic sclerosis registered in the EUSTAR database.

OBJECTIVES: This study describes clinical characteristics, prognostic factors, and quality of life in patients with newly diagnosed (incident) digital ulcers (DU). METHODS: Observational cohort study of 189 consecutive SSc patients with incident DU diagnosis identified from the EUSTAR database (22 centres in 10 countries). Data were collected from medical charts and during one prospective visit between 01/2004 and 09/2010. RESULTS: Median age at DU diagnosis was 51 years, majority of patients were female (88%), and limited cutaneous SSc was the most common subtype (61%). At incident DU diagnosis, 41% of patients had one DU and 59% had ≥2 DU; at the prospective visit 52% had DU. Pulmonary arterial hypertension (PAH) and multiple DU at diagnosis were associated with presence of any DU at the prospective visit (odds ratios: 4.34 and 1.32). During the observation period (median follow-up was 2 years) 127 patients had ≥1 hospitalisation. The event rate of new DU per person-year was 0.66, of DU-associated complications was 0.10, and of surgical or diagnostic procedures was 0.12. At the prospective visit, patients with ≥1 DU reported impairment in daily activities by 57%, those with 0 DU by 37%. The mean difference between patients with or without DU in the SF-36 physical component was 2.2, and in the mental component 1.4. DU patients were not routinely prescribed endothelin receptor antagonists or prostanoids. CONCLUSIONS: This real world cohort demonstrates that DU require hospital admission, and impair daily activity. PAH and multiple DU at diagnosis were associated with future occurrence of DU.

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study.

INTRODUCTION: Pulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy. METHODS: Thirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A "good response" was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DLCO) >15% and PaO2 > 90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved. RESULTS: Twenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease. CONCLUSIONS: Lung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics. TRIAL REGISTRATION: ClinicalTrials.gov NCT00573326. Registered 13 December 2007.

Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies.

OBJECTIVES: A higher incidence of cancer in scleroderma patients compared with the general population has been suggested by several observational studies, reporting, however, different estimates. Therefore, we aimed to perform a systematic review and meta-analysis to definitely assess this association. METHODS: We searched MEDLINE and Embase for all original articles of observational studies on cancer incidence in scleroderma patients without language restriction published up to December 2011. Two independent authors reviewed all titles/abstracts and retrieved detailed full-text of potentially relevant articles to identify studies according to predefined selection criteria. Summary estimates were derived using random-effects model and reported as relative risk (RR). Publication bias was evaluated by trim and fill analysis. RESULTS: From articles initially identified, 16 original studies, involving more than 7000 patients, were included in the present review. Compared with the general population, the summary RR to develop all invasive cancers in scleroderma patients was 1.75 (95% CI 1.41, 2.18). The results for selected cancer sites indicated a strong association with lung cancer (RR 4.35; 95% CI 2.08, 9.09), and a significant increased risk also for haematological neoplasms (RR 2.24; 95% CI 1.53, 3.29). The relation with breast cancer, suggested in some previous epidemiological studies, was not confirmed (RR 1.05; 95% CI 0.86, 1.29). CONCLUSION: The present meta-analysis, the first on scleroderma and cancer risk, provides definite estimates on the association between scleroderma and cancer.

A management of blunt thoracic trauma in an emergency department observation unit: pre-post observational study.

BACKGROUND: The best management of patients with isolated blunt thoracic trauma at high risk of pulmonary complications (HRPC-BTT: ≥3 isolated rib fractures, sternal fracture, single or few pulmonary contusions or minimal pneumothorax) is still unclear. We compared efficacy and cost-effectiveness of a new clinical pathway involving an Emergency Department Observation Unit (EDOU) with routine care. DESIGN: Retrospective before-after study. SETTING: Level II Trauma Center within a Regional Teaching Hospital. PARTICIPANTS: A consecutive series of patients with HRPC-BTT. INTERVENTIONS: a new clinical pathway involving EDOU was implemented. MAIN OUTCOMES: Death rate, tube thoracostomy, and re-admission of discharged patients. Hospital admission rate, length of hospital occupancy, overall costs, and cost-effectiveness were also compared in pre- and post-EDOU period. RESULTS: Two hundred forty patients were eligible for the study: 110 patients in the pre-EDOU period and 130 in the post-EDOU period. Thirteen (12%) of the treated patients were re-admitted to the ED in the pre-EDOU period compared with only five (4%) when the EDOU was available (p = 0.03). The rate of tube thoracostomy performed in admitted patients significantly increased after EDOU implementation: 1 of 54 (1.9%) versus 4 of 32 (12.5%; p < 0.05). The rate of hospitalization decreased from 49% in the pre-EDOU period to 24% in the post-EDOU period (p < 0,005) and the length of stay in hospital in the pre-EDOU period was longer than in the EDOU period: mean 94.7 ± 79.6 versus 65.7 ± 60.6, respectively (p < 0.02). Cost analysis revealed no relevant change in cost-effectiveness per patient (median; interquartile range): €487; €103 to 1959 versus €616; €124 to 1455, respectively, in the pre- and post-EDOU period. CONCLUSIONS: In managing patients affected by HRPC-BTT, a clinical pathway involving the EDOU seems to be more effective than routine care with little impact on cost.