Real-life efficacy and safety of nintedanib in systemic sclerosis-interstitial lung disease: data from an Italian multicentre study

Abstract

IntroductionNintedanib (NTD) has been shown to be effective in systemic sclerosis (SSc)-interstitial lung disease (ILD). Here we describe the efficacy and safety of NTD in a real-life setting.MethodsPatients with SSc-ILD treated with NTD were retrospectively evaluated at 12 months prior to NTD introduction; at baseline and at 12 months after NTD introduction. The following parameters were recorded: SSc clinical features, NTD tolerability, pulmonary function tests and modified Rodnan skin score (mRSS).Results90 patients with SSc-ILD (65% female, mean age 57.6±13.4 years, mean disease duration 8.8±7.6 years) were identified. The majority were positive for anti-topoisomerase I (75%) and 77 (85%) patients were on immunosuppressants. A significant decline in %predicted forced vital capacity (%pFVC) in the 12 months prior to NTD introduction was observed in 60%. At 12 months after NTD introduction, follow-up data were available for 40 (44%) patients and they showed a stabilisation in %pFVC (64±14 to 62±19, p=0.416). The percentage of patients with significant lung progression at 12 months was significantly lower compared with the previous 12 months (60% vs 17.5%, p=0.007). No significant mRSS change was observed. Gastrointestinal (GI) side effects were recorded in 35 (39%) patients. After a mean time of 3.6±3.1 months, NTD was maintained after dose adjustment in 23 (25%) patients. In nine (10%) patients, NTD was stopped after a median time of 4.5 (1–6) months. During the follow-up, four patients died.ConclusionsIn a real-life clinical scenario, NTD, in combination with immunosuppressants, may stabilise lung function. GI side effects are frequent and NTD dose adjustment may be necessary to retain the drug in patients with SSc-ILD.

Biomarkers in Systemic Sclerosis: An Overview

“…Through the identification of B-lines, vertical hyperechogenic lines arising from pleural line, LUS may help to discover signs of lung interstitial syndrome [97-99] (Figure 2). Significant or progressive SSc-ILD usually requires therapy [6,88,89,[95][96][97][98][100][101][102][103][104][105][106][107][108]. The PFT-based OMERACT (outcome measures in rheumatic diseases) detects progression of SSc-ILD defined as a ≥10% decline in forced vital functions (FVC) or ≥5% to <10% decline in FVC with a decline relative ≥15% DLCO [84,87,[99][100][101][102][103][104][105].…”

“…Significant or progressive SSc-ILD usually requires therapy [6,88,89,[95][96][97][98][100][101][102][103][104][105][106][107][108]. The PFT-based OMERACT (outcome measures in rheumatic diseases) detects progression of SSc-ILD defined as a ≥10% decline in forced vital functions (FVC) or ≥5% to <10% decline in FVC with a decline relative ≥15% DLCO [84,87,[99][100][101][102][103][104][105]. Importantly, with effective therapy for SSc-ILD, pulmonary fibrosis is stabilized or the rate of decline in lung function is reduced [84,87,[101][102][103][104][105][106].…”

“…The drugs typically used to treat SSc-ILD are non-specific immunosuppressants (cyclophosphamide, mycophenolate), more specific immunosuppressive drugs including anti-IL-6 agents (tocilizumab) and anti-B-cell drugs (rituximab), and antifibrotics agents (nintedanib-a tyrosine kinase inhibitor) [6,88,89,[95][96][97][98][101][102][103][104][105][106][107][108]. The non-specific immunosuppressants, mycophenolate, an inhibitor of guanosine nucleotide synthesis, and cyclophosphamide, an alkylating agent, decrease the proliferation of fibroblasts, T helper cells and B cells and thus have significant anti-fibrotic effects [6,88,89,[95][96][97][98][100][101][102][103][104][105][106][107][108]. Indeed, mycophenolate is currently considered the standard and baseline therapy for SSc-ILD.…”

“…In particular, the antifibrotic effect associated with the action of Tocilizumab is linked to the inhibition of the IL-6 receptor, which determines the activation of myofibroblasts and the reduction of the M2 macrophage polarization [6,88,89,[95][96][97][98][101][102][103][104][105][106][107][108]. In SSc-ILD, anti-B cell agents, such as Rituximab, are used with the rationale that B cell depletion suppresses pro-fibrotic macrophage differentiation and consequently inhibits fibrosis [6,88,89,[95][96][97][98][100][101][102][103][104][105][106][107][108]. Nintedanib, a tyrosine kinase inhibitor, is an antifibrotic drug that inhibits PDGF, FGF and vascular endothelial growth factor (VEGF) receptors, reducing fibrosis [6,88,89,[95][96][97][98][100][101][102][103][104][105]…”

“…It is unusual to find two different SSc-specific autoantibodies simultaneously in the same individual [29][30][31][32][33][48][49][50][51][52][53][54][55][92][93][94][95][96][97][98][99]. Mortality in SSc patients is significantly increased and usually related to the life-threatening manifestations of SSc, including PAH, ILD, SRC, cardiac involvement, tumors, and infections, which are also related to immunosuppressive drugs [8,9,34,48,[56][57][58][100][101][102][103][104][105][106][107][108][109].…”