Abstract
BackgroundThe treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities. MethodsHere, we describe a series of 10 SSc patients (4M and 6F, mean age 46±13.5SD years, mean disease duration 6.3±2.7SD years; 5 pts had limited and 5 diffuse SSc cutaneous subset) treated with one or more cycles of RTX (4 weekly infusions of 375mg/m2). The main indications to RTX were interstitial lung fibrosis, cutaneous, and/or articular manifestations unresponsive to previous therapies; ongoing treatments remained unchanged in all cases. The effects of RTX were evaluated after 6months of the first cycle and at the end of long-term follow-up period (37±21SD months, range 18–72months). An updated review of the world literature was also done. ResultsRTX significantly improved the extent of skin sclerosis in patients with diffuse SSc at 6months evaluation (modified Rodnan skin score from 25±4.3 to 17.2±4.6; p=.022). A clinical improvement of other cutaneous manifestations, namely hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6) was observed. Moreover, arthritis revealed particularly responsive to RTX showing a clear-cut reduction of swollen and tender joints in 7/8 patients; while lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up. Pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, evaluated in 3 patients with diffuse cutaneous SSc, showed a more or less pronounced reduction after the first RTX cycle.These observations are in keeping with the majority of previous studies including 6 single case reports and 10 SSc series (from 5 to 43 pts), which frequently reported the beneficial effects of RTX on some SSc manifestations, particularly cutaneous sclerosis, along with the improvement/stabilization of lung fibrosis. Possible discrepancies among different clinical studies can be related to the etiopathogenetic complexity of SSc and not secondarily to the patients' selection and disease duration at the time of the study. ConclusionThe present study and previous clinical trials suggest a possible therapeutical role of RTX in SSc, along with its good safety profile. The specific activity of RTX on B-cell-driven autoimmunity might explain its beneficial effects on some particular SSc clinical symptoms, namely the improvement of skin and articular involvement, and possibly the attenuation of lung fibrosis.
Highlights
Systemic sclerosis (SSc) is a connective tissue disease characterized by specific autoimmune abnormalities, diffuse microangiopathy, and accumulation of collagen and other matrix constituents in the skin and target internal organs [1, 2]
Standard pulmonary function tests (PFTs), namely FVCnd a DLCO, 6minute walking test, high-resolution computed tomography (HRCT), trans-thoracic echo-color-Doppler cardiography (ECHOcg), and nailfold videocapillaroscopy were performed in all patients at baseline, after 6 months of RTX treatment, and at the end of follow up
Demographic and clinico-epidemiological features of 10 SSc patients treated along with the main indications to RTX therapy are shown in Tab. 1.Five patients presented limited cutaneous scleroderma with serum ACA, while the other five showed a diffuse cutaneous involvement with circulating anti Scl-70 in 4 and ANoA in one
Summary
Systemic sclerosis (SSc) is a connective tissue disease characterized by specific autoimmune abnormalities, diffuse microangiopathy, and accumulation of collagen and other matrix constituents in the skin and target internal organs [1, 2]. SSc appears as multifaceted disorder consequent to the variable contribution of the above pathogenetic mechanisms, through a multistep process responsible for different clinical phenotypes These latter represent a variable combination and degree of typical SSc symptoms: from vascular manifestations, i.e. skin ulcers, pulmonary arterial hypertension, and/or renal scleroderma crisis, to fibrotic cutaneous and visceral organ involvement [1,2,3,4]. The effects of nonselective immunosuppressive treatments, usually employed during the early phases of SSc to control skin and lung inflammation, are often unpredictable They tend to lose their efficacy once the disease enters a chronic phase, and their long-term treatment is not recommendable considering their potential severe side-effects [4]. RTX significantly improved the extent of skin sclerosis in patients with diffuse SSc at 6 months evaluation
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