Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome

Objective To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with antisynthetase syndrome and progressive interstitial lung disease (ASS-ILD). Methods Multicentre observational retrospective longitudinal study of a cohort of patients with ASS-ILD that started treatment with RTX due to recurrent or ongoing progressive ILD despite therapy with glucocorticoids and immunosuppressants. Results Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: triangle%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and triangle%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013). Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: triangle%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and triangle%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued. The frequency of adverse events reached 28.5% of cases. Results Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: triangle%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and triangle%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013). Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: triangle%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and triangle%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued. The frequency of adverse events reached 28.5% of cases. Conclusion Based on our results, RTX appears to be effective as rescue therapy in most patients with recurrent or progressive ASS-ILD unresponsive to conventional treatment. The use of RTX was well tolerated in the majority of patients

Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review

Interstitial lung disease (ILD) is one of the most serious pulmonary complications of connective tissue diseases (CTDs) and it is characterized by a deep impact on morbidity and mortality. Due to the poor knowledge of CTD-ILD's natural history and due to the difficulties related to design of randomized control trials, there is a lack of prospective data about the prevalence, follow-up, and therapeutic efficacy. For these reasons, the choice of therapy for CTD-ILD is currently very challenging and still largely based on experts' opinion. Treatment is often based on steroids and conventional immunosuppressive drugs, but the recent publication of the encouraging results of the INBUILD trial has highlighted a possible effective and safe use of antifibrotic drugs as a new therapeutic option for these subjects. Aim of this review is to summarize the available data and recent advances about therapeutic strategies for ILD in the context of various CTD, such as systemic sclerosis, idiopathic inflammatory myopathy and Sjogren syndrome, systemic lupus erythematosus, mixed connective tissue disease and undifferentiated connective tissue disease, and interstitial pneumonia with autoimmune features, focusing also on ongoing clinical trials

Efficacy and safety of mycophenolate mofetil in the treatment of rheumatic disease-related interstitial lung disease: a narrative review

Mycophenolate mofetil (MMF) is an antimetabolite with a potent inhibitory effect on proliferation of T and B lymphocytes used since the early 1990s for the prevention of acute allograft rejection after organ transplant. MMF is also widely used for the treatment of a variety of rheumatic diseases (RDs) and their pulmonary involvement. Interstitial lung disease (ILD) is a heterogeneous group of progressive fibrotic diseases of the lung, which is often secondary to RD and represents a major cause of morbidity and mortality. MMF is considered the main alternative to cyclophosphamide as a first-line agent to treat RD-related ILD or as possible maintenance therapy after cyclophosphamide, with a lower rate of side-effects. However, as for other immunosuppressive agents, the use of MMF in RD-ILD is supported by poor scientific evidence. In this narrative review, we describe the available data and recent advances on the effectiveness and safety of MMF for the treatment of ILD related to RD, including rheumatoid arthritis, systemic sclerosis, primary Sjögren syndrome, systemic lupus erythematosus, idiopathic inflammatory myopathies, undifferentiated connective tissue disease, interstitial pneumonia with autoimmune features and antineutrophil cytoplasmic antibody-associated vasculitis

Efficacy and safety of a step-down regimen of low dosage of glucocorticoids combined with early administration of synthetic or biologic immunosuppressants in anti-synthetase syndrome: A pilot study

Introduction: Anti-synthetase syndrome (ASS) is a rare autoimmune disease characterized by the presence of antiaminoacyl-transfer-RNA synthetase antibodies (ARS) and the involvement of muscles, skin, joints, and lungs. Despite increasing interest and evidence, optimal clinical management remains unclear due to a lack of randomized control trials. This study aims to evaluate the efficacy and safety of a treatment regimen involving early co-administration of glucocorticoids and immunosuppressants, with rapid prednisone tapering. Materials and methods: We prospectively enrolled patients referred to our multidisciplinary "Myositis Clinic" with a diagnosis of ASS. Clinical, serological, instrumental and medications data were collected at baseline and at 6 and 12 months follow-up. According to treatment protocol, patients were treated with traditional synthetic immunosuppressants or rituximab (RTX) depending on clinical manifestations. Prednisone (PDN) was gradually tapered and eventually discontinued within 6 or 12 months. Results: A total of twenty-seven subjects were enrolled: arthritis, myositis and ILD were assessed in 9, 16 and 18 patients, respectively, and all of them had an active disease. RTX was administered after methotrexate (MTX) in 4 cases of refractory joint involvement and co-administration of a second immunosuppressant was necessary in 2 patients. When muscle involvement was present, first-line therapy was MTX, followed by mycophenolate mofetil (MMF) or RTX, which allowed to achieve low disease activity or remission, respectively. Eight ILD-patients were treated with MMF and switched to RTX in 5 cases of inefficacy, but all patients were in clinical remission at the end of follow-up. At 12 months, 12 patients discontinued PDN. Conclusions: This study is the first to prospectively report on the efficacy and safety of a stepwise, steroid-sparing treatment ASS encompassing various domains. MTX, as well as other synthetic immunosuppressants, showed limited efficacy in ASS-related arthritis, while RTX emerged as a promising option. This study recommends early RTX use in case of arthritis, suggesting it as a pivotal treatment for ILD too, and raises questions regarding maintenance therapy and treatment-free remission

Scanning for therapeutic targets within the cytokine network of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNF, LT, BAFF), Interferons (IFN//), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNF treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNF agents to treat other diseases, pointing to the complex effects of TNF neutralization. Treatment with anti-IFN has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction

A Narrative Review of Interstitial Lung Disease in Anti-Synthetase Syndrome: A Clinical Approach

Anti-synthetase syndrome (AS) is a rare autoimmune disorder characterized by the presence of aminoacyl-transfer RNA synthetase antibodies in conjunction with clinical features such as interstitial lung disease (ILD), Raynaud\u27s phenomenon, nonerosive arthritis, and myopathy. AS distinguishes itself from other inflammatory myopathies by its significant lung involvement and rapidly progressive interstitial lung disease (AS-ILD), therefore the management of AS-ILD requires careful clinical, serologic and radiologic assessment. Glucocorticoids are considered the mainstay of therapy; however, additional immunosuppressive agents are often required to achieve disease control. Patient prognosis is highly dependent on early diagnosis and symptom recognition as the antibody profile is thought to influence therapy response. Since progressive ILD is the leading cause of morbidity and mortality, this review will discuss the clinical approach to patient with suspected AS, with particular emphasis on diagnosis and management of AS-ILD

Antisynthetase syndrome with anti-glycyl tRNA synthetase antibodies in a patient with axial spondyloarthritis treated with tumor necrosis factor-α inhibitors

We present a case of interstitial lung disease arising in the course of antisynthetase syndrome (ASSD) in a patient with axial spondyloarthritis (ax-SpA) undergoing tumor necrosis factor-α (TNF-α) inhibitors therapy. Only two cases of ASSD in ax-SpA patients have been described in the literature, although with a different autoantibody profile. Only in one case, ASSD manifested with lung involvement, without the possible implication of TNF-α inhibitors in the pathogenesis, as it occurred concurrently with spondyloarthritis. Our case is the first to emphasize the coexistence of ASSD with anti-glycyl tRNA synthetase antibodies and ax-SpA, reminding us of the possible, although rare, adverse effects on the lungs with TNF-α inhibitors

A glance into the future of myositis therapy

The idiopathic inflammatory myopathies are chronic diseases of the skeletal muscle that comprise various conditions, including dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and the antisynthetase syndrome. Although there are a number of distinguishing features, all these disorders are characterized by an immune and inflammatory response mainly directed against the muscle. Hence, therapy is geared toward curbing the autoimmune and inflammatory response. A quite wide range of medications are currently available to treat these disorders, but despite all therapeutic progress still a number of patients are unable to maintain a sustained remission. In this review article, we have marshaled a variety of potential therapeutic agents that may hold promise for the future treatment of the idiopathic inflammatory myopathies. It is to be expected that by increasing the therapeutic armamentarium with agents that have different mechanisms of action even challenging cases could be successfully managed, thus reducing disease burden and disability

Current pharmacological treatment of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies are uncommon and heterogeneous disorders. Their classification is based on distinct clinicopathologic features. Although idiopathic inflammatory myopathies share some similarities, different subtypes may have variable responses to therapy, so it is very important to distinguish the correct subtype. There are few randomised, double blind placebo controlled studies to support the current treatment. High dose corticosteroids continue to be the first-line therapy and other immunosupressive drugs are used in refractory cases, as well as steroid-sparing agents. Some novel therapeutic approaches have emerged as potential treatment including tacrolimus, intravenous immunoglobulin and rituximab, following good outcomes reported in case studies. However, more randomised controlled trials are needed. This review considers the current and the potential future therapies for inflammatory myopathies