Treatment Approach to Connective Tissue Disease-Associated Interstitial Lung Disease

Abstract

Interstitial lung disease (ILD) is a common manifestation in connective tissue diseases (CTD), such as rheumatoid arthritis (RA), systemic sclerosis (SSc) and inflammatory myositis (IM). ILD is associated with significant morbidity and mortality in nearly all CTD highlighting the critical need for effective treatment strategies in this patient population. In this review, we will summarize the approach to treatment when there is concern for CTD-ILD and highlight recent advancements in therapeutics within various specific CTD-ILDs.

Introduction

Pulmonary disease is commonly reported in association with connective tissue disease (CTD) including rheumatoid arthritis (RA), systemic sclerosis (SSc), inflammatory myositis (IM), mixed connective tissue disease (MCTD), Sjogren’s syndrome (SjS), and systemic lupus erythematosus (SLE)^{1 2}. Pulmonary involvement in CTD can have an adverse effect on a patient’s quality of life and contribute to mortality thus highlighting the importance of clinical management and treatment. One of the more severe forms of pulmonary involvement in CTD is interstitial lung disease (ILD) which refers to varying degrees of inflammation and fibrosis involving the interstitial compartment of the lung. ILD in CTD (CTD-ILD) can range from an incidental finding on radiographic imaging to a rapidly progressive illness leading to respiratory failure and death. The spectrum of interstitial involvement in CTD is reviewed in detail elsewhere³. The pattern of interstitial involvement varies by underlying CTD. For example, SSc and the IM spectrum of disease commonly display a more inflammatory pattern of nonspecific interstitial pneumonia (NSIP) with or without organizing pneumonia (OP) while patients with RA are more likely to have a predominately fibrotic pattern of usual interstitial pneumonia (UIP). In this review we will discuss the recent advancements in treatment strategies pertaining to the clinical management of patients CTD-ILD.

Who to Treat

The decision to initiate therapy is a difficult one and should consider severity of disease, availability of affective therapies and patient preference. Though many patients with CTD-ILD are diagnosed after respiratory symptoms that lead to further evaluation, a subset of patients will have subclinical CTD-ILD, defined as radiographic abnormalities without symptoms or physiologic abnormalities. Up to 60% of CTD patients are reported to have evidence of subclinical ILD depending on the specific CTD^4–6. Currently, data regarding the progression of these changes over time are limited, and therefore no established treatment guidelines for subclinical CTD-ILD exist. However, a detailed monitoring plan is recommended for these patients as it is likely that a subset will have progressive ILD. Our practice is to monitor lung spirometry with diffusing capacity for carbon monoxide (DLCO) every 3 months and chest high-resolution computed tomography (HRCT) every 6 to 12 months for at least the first 2 years. Disease progression can occur at any point in subclinical CTD-ILD, though there is data in SSc to suggest that if patients are going to progress, they will do so within 2–5 years of their diagnosis of SSc⁷.

In CTD patients with ILD and respiratory symptoms, not all will benefit from pharmacotherapy; therefore, the clinician must consider a combination of subjective and objective measurements when deciding whether to initiate therapy. In general, treatment is reserved for those with significant disease at presentation which is often defined as radiographic abnormalities in the setting of restrictive physiology, or for those who demonstrate evidence of disease progression as manifested by any combination of radiographic, physiologic, or symptomatic worsening over time. In addition, the specific pattern of lung involvement can provide insight into a patient’s likelihood of response to therapy. While there are exceptions, the more inflammatory patterns of ILD including OP and cellular NSIP (cNSIP) generally respond better to immunosuppression compared to those with less inflammation and more fibrosis such as fibrotic NSIP and UIP which may respond better to anti-fibrotic agents. Finally, while subjective symptoms attributable to ILD such as breathlessness are considered in determining who should be treated, these symptoms can be misleading, especially in the setting of comorbid pulmonary manifestations such as pulmonary hypertension or extra-thoracic disease that limits a patient’s activity level. Consider a patient with RA-ILD who has severe joint disease significantly limiting mobility – relying on clinical symptoms of breathlessness could underestimate the severity of lung disease and lead to delayed therapy.

Disease-specific treatment strategies

Systemic Sclerosis

SSc is a systemic autoimmune disease highlighted by tissue fibrosis and vasculopathy within various organs such as the skin, gastrointestinal tract, kidneys, heart, and lungs. Patients are typically classified as having diffuse SSc or limited SSc based on the pattern of skin/internal organ involvement and autoantibody profiles, although disease patterns within these clinical phenotypes are highly variable. ILD is relatively common in SSc (up to 80% of patients⁸) with an increased risk specifically in males, diffuse SSc, and those with anti-topoisomerase 1 (anti-Scl-70) antibodies^9–11. SSc-ILD is often identified early in the disease, thus it is critical to monitor for any change in a patient’s respiratory symptoms or radiographic and physiologic progression.

ILD-targeted therapies in SSc have largely focused on the use of cytotoxic drugs cyclophosphamide (CYC) and mycophenolate mofetil (MMF) based on data from two prior randomized controlled trials, Scleroderma Lung Study I (SLS-I) and Scleroderma Lung Study II (SLS-II). In SLS-I where patients were randomized to 1 year of oral CYC vs placebo, there was a statistically significant FVC% difference of 2.53% in favor of the CYC group¹². This difference persisted at 18 months but was lost at 24 months¹³. In SLS-II, patients were randomized to oral CYC for 1 year versus MMF for two years. Both the CYC and MMF arms had a significant improvement in pulmonary function and modified Rodnan skin score (mRSS) though MMF was better tolerated with less toxicity¹⁴.

More recent clinical trials have focused on treatments outside of CYC and MMF, namely biologics and anti-fibrotic agents. One specific class of biologics of interest are interleukin-6 (IL-6) inhibitors given the accumulating evidence suggesting the potential role of IL-6 in modulating pathogenesis of SSc^{15 16}. In the phase II, double blind, placebo-controlled faSScinate trial, efficacy of subcutaneous tocilizumab was assessed using the primary endpoint of mRSS after 24 weeks. While there was no effect on mRSS at 24 weeks, there were less patients in the tocilizumab arm experiencing a decline in percent predicted forced vital capacity (FVC% predicted) compared to placebo arm at 48 weeks¹⁷. In the subsequent phase III focuSSced trial, the impact of subcutaneous tocilizumab on mRSS was evaluated at 48 weeks in addition to a secondary analysis of change in FVC% predicted. The primary endpoint of change in mRSS was not met but subjects on tocilizumab had a stabilization of FVC% predicted over 48 weeks compared to a 6.4% decline in FVC% predicted in those on placebo, suggesting efficacy of tocilizumab in early stages of ILD^{18 19} **. In 2021, based on the results of the faSScinate and focuSSced trials, the FDA approved tocilizumab for the treatment of SSc-ILD.

The antifibrotic agents nintedanib and pirfenidone were initially approved for use in idiopathic pulmonary fibrosis (IPF), though recent studies have proven efficacy in various CTD-ILDs. In the SENSCIS trial, 576 SSc-ILD patients were randomized to receive nintedanib or placebo over a 52-week period with a primary outcome of change in FVC over time²⁰*. The nintedanib arm experienced a significant decrease in annual rate of decline in FVC compared to the placebo group (−52.4 mL vs. −93.3 mL, respectively). There were no differences in other scleroderma-related outcomes and though the rate of adverse and serious adverse events did not differ between groups, patients treated with nintedanib experienced a higher rate of adverse drug reactions, such as diarrhea, compared to the control group (75.7% vs. 31.6%, respectively). SSc-ILD patients were also included in the INBUILD trial which evaluated efficacy of nintedanib compared to placebo in non-IPF patients with progressive fibrosing ILD²¹**. The nintedanib arm experienced significantly less annual rate of decline in FVC compared to placebo (−80.8 mL vs. −187.8 mL, respectively), with a higher rate of GI-related side effects. Based on the SENSCIS trial, nintedanib also became FDA approved for the treatment of SSc-ILD.

Rheumatoid Arthritis

ILD is one of the most common extra-articular manifestations in RA, seen in 20 to 30% of patients and contributing to death in up to 10% of RA patients^22–24. There are several risk factors known to be associated with the development of ILD in RA, such as age, male sex, history of smoking, higher autoantibody levels and the presence of a promoter variant within the MUC5B gene^25–27. Despite the significant advancements in the therapeutics for articular disease in RA, the shared efficacy in ILD has not been apparent and in some cases there has been an association of the development of ILD with various drugs²⁸. Thus, when choosing biologic disease modifying antirheumatic drugs (DMARDs) for the articular disease in RA-ILD patients, consideration should be given to those with efficacy data in ILD such as the non-tumor necrosis factor (TNF) inhibitor agents Rituximab, Abatacept, or Tocilizumab. Several studies have shown the association of non-TNF inhibitor biologic use with improved mortality and survival specifically in RA-ILD compared to those using TNF inhibitors^{29 30}. There has been considerable focus on the use of abatacept in RA-ILD, with several studies having shown an association with ILD disease specific stability and or improvement in a significant portion of patients^31–33. In addition, and open label studies of Rituximab in progressive RA-ILD showed stabilization or improvement in lung function^{34 35}. However, there have been no randomized controlled trials to date using conventional, synthetic or biologic DMARDs in RA-ILD.

As in SSc-ILD, antifibrotics are currently being investigated for use in RA-ILD. Like SSc-ILD, RA-ILD subjects were included in the recently completed INBUILD trial and made up the highest proportion of patients within the autoimmune ILD group^{21 36 37}. As such, nintedanib is approved for use in RA patients with a progressive fibrosing phenotype. Additionally, the TRAIL1 (NCT02808871) phase 2 trial recently completed in which approximately 270 patients with RA-ILD were randomized to pirfenidone or placebo with the primary outcome being progression free survival at 52 weeks³⁸. Preliminary results presented at the 2021 American College of Rheumatology Convergence meeting reported that while the study did not meet the primary endpoint (composite outcome of FVC% decline from baseline ≥10% or death at 52 weeks), it did find that pirfenidone slowed the rate of lung function decline in RA-ILD patients based on a pre-defined secondary endpoint (FVC: −66 mL vs. −146 mL, p=0.0082 in the pirfenidone and placebo group respectively)³⁹. It is likely that a better understanding of the pathogenesis of RA-ILD, particularly differences in the UIP and NSIP patterns of lung involvement that likely have distinct underlying mechanisms of pathogenesis, will lead to improved therapeutic strategies moving forward.

Inflammatory myositis

IM is a heterogeneous autoimmune disease highlighted by inflammation of the proximal skeletal musculature in addition to other organs including the skin, joints, gastrointestinal tract, heart and lungs. ILD can be seen in up to 80% of patients, although this manifestation is more often associated with specific subtypes, such as anti-synthetase syndrome, or specific autoantibodies, such as anti-melanoma differentiation-associated 5 protein (anti-MDA5)⁴⁰. Given that the predominant pattern of ILD in IM is OP or NSIP, first line therapy is nearly always glucocorticoids in combination with a steroid-sparing agent. There are no prior clinical trials comparing the use of specific steroid sparing agents and thus the decision to which adjunctive therapy to use is often based on overall severity and presence of other manifestations, such as skin, muscle or joint involvement. IM-ILD outcomes are generally more favorable compared to other forms of CTD-ILD, where the five-year survival has been reported to be as high as 80–90%^{41 42}. A notable exception to this is anti-MDA5-associated ILD where a significant portion of patients develop rapidly progressive respiratory failure, which is resistant to many forms of immunosuppression resulting in >50% mortality at 6 months^{43 44}. Combination therapy of calcineurin inhibitors, cyclophosphamide and glucocorticoids are often the preferred initial therapy, although there are recently published recommendations regarding the treatment of anti-MDA5 associated ILD using research-based evidence and expert opinion.⁴⁵. In a single-center open-label trial, patients with newly diagnosed (<3 months) anti-MDA5+ IM with ILD were treated with tofacitinib and prednisone and compared to a historical cohort of a similar patient population. In the treatment arm, 100% of patients survived at 6 months compared to 78% in the historical arm⁴⁶. B-cell and antibody-targeted therapies are also of interest as higher autoantibody levels have been associated with disease severity and normalization after treatment associated with disease remission^47–49*. While limited primarily to case reports and case studies, rituximab and plasmapheresis have shown benefit in survival when used as first line treatment or rescue therapy in refractory cases^50–53. Further studies are needed to better understand the pathophysiology of anti-MDA-5 associated ILD which would likely contribute to improved treatment strategies.

Ongoing Clinical Trials

Table 1 outlines the ongoing clinical trials and different therapies being studied in the treatment of CTD-ILD. Considering the scarcity of published trials in this area, findings from these trials will undoubtedly expand our understanding of key mechanisms involved in CTD-ILD pathogenesis and improve our management of CTD-ILD patients going forward.

Table 1.

Ongoing clinical trials in CTD-ILD

	Trial	Phase	Therapeutic Interventions
SSc	NCT04948554	I/II	ACE-1334 vs. placebo; 52 weeks
	NCT05270668	II	PRA023 vs placebo; 50 weeks
	NCT04837131	II	MMF +/− Ixazomib; 6 cycles × 28 days each
	NCT03630211	II	Autologous stem cell transplant
	NCT03221257* (SLS III)	II	MMF +/− Pirfenidone; 18 months
RA	NCT03084419 (APRIL)	II	Abatacept (no placebo); 20 weeks
	NCT04311567 (PULMORA)	IV	Tofacitinib vs. MTX; 24 weeks
IIM	NCT03215927 (ATtackMy-ILD)	II	Abatacept vs. placebo; 24 weeks
	NCT04966884	IV	Tofacitinib + steroids (no placebo); 52 weeks
CTD-ILD	NCT04928586	IV	DMARD +/− Pirfenidone; 52 weeks
	NCT04988087	II	MHV370 vs. placebo; 24 weeks

^*Active, not recruiting

Duration of therapy and monitoring

Though duration of treatment for CTD-ILD isn’t well established, therapies are utilized for at least 6 to 12 months but often longer with duration dictated by clinical response. Many of the proposed agents take many months to start being effective. A general guideline is that radiographic and/or physiologic stability is considered success of therapy, especially when dealing with the more fibrotic subtypes of CTD-ILD like UIP. Frequent follow-up of patients on therapy is indicated both to monitor for medication tolerance as well as efficacy. It is our practice to monitor symptoms, physiology and gas exchange every 3 to 6 months and HRCT at 6 to 12 months. In those who have therapy stopped due to intolerance or lack of efficacy, an alternate agent should be considered. In patients with acute signs or symptoms on treatment, drug reaction or infection needs to always be considered.

Conclusion

In summary, the decision to initiate ILD-specific therapies in various CTDs is complex and is generally reserved for those with respiratory symptoms, impaired pulmonary physiology, or progressive disease. The specific agent to use is largely dependent on the CTD and can include immunosuppression, anti-fibrotic agents, or combination therapy. While there are have been significant recent advancements in therapeutics for CTD-ILD, there are many active, ongoing clinical trials that will further enhance treatment strategies.