A 3-Year Observational Study of Patients with Progressive Systemic Sclerosis Treated with an Intensified B Lymphocyte Depletion Protocol: Clinical and Immunological Response

Abstract

Background: B-cells have been suggested to play a role in the pathogenesis of systemic sclerosis (SSc), representing, therefore, a potential therapeutic target.

Objectives: We aimed at investigating the 36-month outcomes of 20 SSc patients who underwent an intensified B-depletion therapy (IBCDT) scheme, including both Rituximab (RTX) and cyclophosphamide (CYC).

Methods: Data from 20 severe patients (18 females and 2 males, mean age 66.7 ± 11.0 years) with diffuse SSc (anti-topoisomerase I antibody in 95%) patients with multiorgan involvement including interstitial lung disease (ILD) treated with an IBCDT were prospectively collected. IBCDT comprehended: RTX 375 mg/m² administered for four weekly doses (on days 1, 8, 15, and 22), followed by two additional doses after 30 and 60 days, in addition to two administrations of 10 mg/kg of intravenous CYC plus three methylprednisolone pulses (15 mg/kg) and subsequently followed by oral prednisone rapidly tapered to low minimum dosage of 5 mg daily. In addition, 10 patients with more severe functional respiratory impairment at baseline were also treated with RTX 500 mg every 4 months during the first year and two times a year during the second and the third year.

Results: After 36 months of follow-up, we recorded significant amelioration in N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels (mean 385.4 ± 517 pg/mL at baseline to 279 ± 543 after 36 months). In addition, a significant radiological improvement of ILD in 20% of patients (4/20) and a radiological stabilization with no sign of progression of interstitial involvement in 13/20 (65%) were documented. A total of 3 out of 20 (15%) patients experienced a worsening of the ILD. No patient showed further decrease in functional respiratory parameters, including forced vital capacity, forced expiratory volume in one second, and mean values of diffusing capacity for carbon monoxide Moreover, no patient showed any change in the ejection fraction and pulmonary artery pressure when comparing values at baseline and after 24 and 36 months of observation. No severe infection, renal flare, RTX-related side effects were observed. No patient died.

Conclusions: Our findings support that the IBCDT was well tolerated and might be a promising therapeutic option for the management of SSc, especially in those subjects with multiorgan involvement that includes ILD.

Keywords: intensified B-depletion therapy; rituximab; scleroderma; systemic sclerosis.

Figure 1

Patients characteristics at baseline and after 36 months of follow-up. Results are presented as mean ± standard error of the mean. (a) reduction in N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels, (b) an improvement of the skin involvement as assessed by the Modified Rodnan Skin Score (mRSS) was documented, (c) no statistical significant changes in pulmonary artery pressure when comparing baseline and 36 month levels, (d) no patient showed any change in the ejection fraction, (e) forced vital capacity (FVC), (f) forced expiratory volume in one second (FEV1), (g) mean values of diffusing capacity for carbon monoxide (DLCO).

Figure 2

Response to intensified B-depletion therapy (IBCDT) related to systemic sclerosis (SSc) disease duration. Patients are divided in two groups according to the overall response to IBCDT in at least 2 SSc-domains (Modified Rodnan Skin Score, high resolution computed tomography lung, pulmonary function tests, N-terminal-pro-brain natriuretic peptide). Mean disease duration is significantly shorter in those patients who experienced a response to IBCDT in two or more SSc-domains (mean disease duration 4.2 years vs. 10.125 years). Y axis: Years, years of diseases duration (from diagnosis). Results are presented as mean ± standard error of the mean (SEM).