Combination Therapy with Nintedanib and Sarilumab for the Management of Rheumatoid Arthritis Related Interstitial Lung Disease

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease characterized by joint and extra-articular involvement. Among them, interstitial lung disease (ILD) is one of the most common and severe extra-articular manifestations, with a negative impact on both therapeutic approach and overall prognosis. ILD can occur at any point of the natural history of RA, sometimes before the appearance of joint involvement. Since no controlled studies are available, the therapeutic approach to RA-ILD is still debated and based on empirical approaches dependent on retrospective studies and case series. Here, we report the case of a 75-year-old patient affected by RA complicated by ILD successfully treated with a combination therapy of an antifibrotic agent, nintedanib, and an inhibitor of IL-6 receptor, sarilumab. We obtained a sustained remission of the joint involvement and, simultaneously, a stabilization of the respiratory symptoms and function, with a good safety profile. To date, this is the first report describing a combination therapy with nintedanib and a disease-modifying antirheumatic drug (DMARD) for the management of RA complicated by ILD. Future prospective studies are needed to better define efficacy and safety of this approach in the treatment of these subjects.

Role of Interleukin-6 in Vascular Health and Disease

“…In these patients, acute pulmonary injury is associated with a hyper-inflammatory state that predicts a worse clinical outcome ( Spadaro et al, 2019 ; Herold et al, 2020 ; Liu et al, 2020 ). However, inhibiting IL-6 signaling to limit cytokine-dependent lung injury, using sarilumab or tocilizumab for example, has only been explored in Covid-19 patients ( Rossotti et al, 2020 ; Sinha et al, 2020 ), rheumatoid arthritis-related interstitial lung disease ( Manfredi et al, 2020 ; Vacchi et al, 2020 ), and PAH ( Hernandez-Sanchez et al, 2018 ). More systematic studies clarifying the inflammatory and vascular remodeling effects of IL-6 in the lung is required to fully understand the role of this cytokine in pulmonary diseases.…”

Antifibrotic drugs in connective tissue disease-related interstitial lung disease (CTD-ILD): from mechanistic insights to therapeutic applications

“…Therefore, based on the available evidence, the use of antifibrotics in patients with RA-ILD is likely to be associated with retarded lung disease progression, improved functional outcomes and, ultimately, in increased survival. In addition, given the systemic inflammatory burden and the presence of organized ectopic lymphoneogenesis in lung tissue of patients with RA-ILD, 81 combination therapy with antifibrotic drugs and immunosuppressants is likely to be effective in patients with RA-ILD 10 . Accordingly, remission of symptoms related to articular involvement together with stabilisation of lung functional decline have been reported in the UIP subgroup of patients with RA-ILD receiving antifibrotic drugs, alone or in combination with immunosuppressants.…”

“…Accordingly, remission of symptoms related to articular involvement together with stabilisation of lung functional decline have been reported in the UIP subgroup of patients with RA-ILD receiving antifibrotic drugs, alone or in combination with immunosuppressants. 10 , 82 , 83 …”

“…abatacept) and intravenous immunoglobulins have also been tested in CTD-ILDs, with conflicting results. 10 – 14 Haematopoietic stem cell transplantation and lung transplantation have also proven to be effective, especially in SSc-ILD, 15 , 16 but should be reserved to selected patients with progressive refractory disease in the context of clinical trials conducted in centres with high expertise.…”

Drugs that act on the respiratory tract

“…Pirfenidone has been studied as a perioperative therapy in patients undergoing surgical resection of primary lung cancer ( Kanayama et al, 2020 [c]), as well as a maintenance therapy in patients with unclassifiable progressive fibrosing interstitial lung disease ( Maher et al, 2020 [C]) and systemic sclerosis-related interstitial lung disease ( Acharya et al, 2020 [c]). Nintedanib use has been reported in progressive interstitial lung disease ( Wells et al, 2020 [C]), non-small cell lung cancer with IPF ( Shiratori et al, 2020 [A]), idiopathic-inflammatory-myopathy-related interstitial lung disease ( Liang et al, 2021 [c]), rheumatoid arthritis-related interstitial lung disease ( Narváez et al, 2020 [A]; Vacchi et al, 2020 [A]), systemic sclerosis-related interstitial lung disease ( Azuma et al, 2021 [C]; Bournia et al, 2021 [R]; Highland et al, 2021 [C]; Kuwana et al, 2021 [c]; Seibold et al, 2020 [C]), bronchiolitis obliterans syndrome after allogenic haematopoietic stem cell transplantation ( Tang et al, 2020 [A]), and for pulmonary fibrosis after coronavirus disease 2019 ( Ogata et al, 2021 [A]). The incidence, type, and severity of nintendanib and pirfenidone associated adverse events in these reports is consistent with what has been previously reported for these agents in clinical trials for IPF.…”