Treatment for Interstitial Lung Disease Associated with Systemic Sclerosis

Abstract

ABSTRACT: Systemic sclerosis (SSc) is the disease that causes various symptoms caused by the interaction of fibrosis, inflammation, and vasculopathy. SSc has various complications, including reflux esophagitis, pulmonary hypertension, renal lesions, and interstitial lung disease (ILD). ILD associated with SSc (SSc-ILD) is the most common SSc complication with a high mortality rate. Several treatments, including immunosuppressants, antifibrotic agents, and biologics, have been investigated for SSc-ILD. Mycophenolate mofetil, nintedanib, rituximab, and tocilizumab have recently been attracting attention for their efficacy in SSc-ILD. However, the management of SSc-ILD has remained challenging, and adverse treatment events must be considered. Therefore, a better understanding of the current evidence of treatments for patients with SSc-ILD is required. In this study, we outlined the characteristics of the current treatments for SSc-ILD in terms of efficacy and safety, focusing on key existing studies.

Introduction

Systemic sclerosis (SSc) is characterized by sclerosis in the connective tissue and various symptoms caused by the interaction of fibrosis, inflammation, and vasculopathy. Patients with SSc present several symptoms, including skin lesions (e.g., skin thickening and hardening), musculoskeletal lesions (e.g., polyarthritis and myositis), gastrointestinal lesions (e.g., reflux esophagitis and dysfunctions of the small intestine and colon), pulmonary lesions (e.g., interstitial lung disease (ILD) ), cardiac lesions (e.g., cardiac myopathy and pulmonary hypertension (PH) ), and renal lesions (e.g., renal crisis). The symptoms associated with a poor prognosis are ILD, PH, renal crisis, gastrointestinal symptoms, heart diseases, and multiorgan failure.¹⁾ ILD has the highest complication rate (52%) and a high mortality rate (35%).^2,3) In Japan, the overall prevalence of SSc and SSc-ILD per 100,000 persons is 37.0 and 13.9, respectively.⁴⁾ SSc treatment depends on what symptoms the patient has and their severity. This review discusses treatments for SSc-associated ILD (SSc-ILD).

Classification of SSc

SSc is classified into two main subtypes according to the distribution of skin involvement. In patients with diffuse cutaneous SSc (dcSSc), skin thickening extends proximal to the elbows and knees, whereas in those with limited cutaneous SSc (lcSSc), skin thickening is limited to the hands, face, feet, and forearms. Raynaud's phenomenon develops at approximately the same time as the onset of the skin thickening in most patients with dcSSc. Skin thickening and hardening progress within 6 years. The involvement of other organs, including ILD, occurs during this time. In most lcSSc patients, Raynaud's phenomenon develops several months to years before the skin thickening onset, while organ involvement occurs in some patients more than 5 to 10 years after the disease onset.⁵⁾ ILD develops more frequently in patients with dcSSc than in patients with lcSSc (dcSSc, 53.4%; lcSSc, 34.7%).⁶⁾ The anti-Scl-70 (anti-topoisomerase I) antibody specific to SSc is detected as 40% in dcSSc when compared to less than 10% in lcSSc. Patients with the anti-Scl-70 antibody are at an increased risk of severe SSc-ILD.^7,8) Patients with SSc-ILD are classified as having limited or extensive disease based on the extent of pulmonary fibrosis on high-resolution computed tomography (HRCT) (Fig. 1) or percent predicted forced vital capacity (%FVC) if it is an indeterminate disease extent on HRCT: extensive disease; >20% disease extent on HRCT or %FVC <70% (if it is an indeterminate disease extent on HRCT), limited disease; and <20% disease extent on HRCT or %FVC >70% (if it is an indeterminate disease extent on HRCT).⁹⁾ As reported, the 10-year survival rate decreased to 43% when pulmonary fibrosis exceeded 20% in HRCT.⁹⁾ Therefore, this classification is important for predicting the patient outcomes.

Fig. 1

Typical imaging features of SSc–ILD.

A. Typical imaging features of the extensive disease of SSc–ILD. Chest computed tomography (CT) shows diffuse bilateral ground-glass opacities and reticular opacities. B. Typical imaging features of the limited disease of SSc–ILD. Chest CT shows bilateral reticular opacities limited to a peripheral distribution. All images are provided with consent from the patients.

Treatment of SSc-ILD

Up to date, several treatments for SSc-ILD have been assessed. The treatment options are categorized into glucocorticoids, immunosuppressants, antifibrotic agents, biologics, and transplantations (Table 1). According to the treatment algorithm (draft) provided by the Japanese guide for SSc-ILD,¹⁰⁾ patients with extensive disease without end-stage lung disease are treated with cyclophosphamide (CY), mycophenolate mofetil (MMF), and nintedanib, while patients with limited disease and risk factors for progression are treated with tocilizumab (TCZ) in addition to the above. Rituximab (RTX) and peripheral blood stem cell transplantation should be considered for patients who are refractory to the abovementioned treatments.¹⁰⁾ However, the treatment choice should be based on risks and benefits for each patient. The currently widely available therapeutic agents are described in detail below. The summary of the induction therapy treatments in SSc-ILD recommended in the Japanese guide for SSc-ILD¹⁰⁾ and the approval status of SSc-ILD are shown in Table 2.

Table 1

Category of treatment options for SSc–ILD

Steroids	Immunosuppressants	Biologics	Antifibrotic agents	Transplantation
PBSCT, peripheral blood stem cell transplantation
Glucocorticoid	Cyclophosphamide	Rituximab	Nintedanib	PBSCT
	Mycophenolate mofetil	Tocilizumab	Pirfenidone	Lung transplantation
	Azathioprine

Table 2

Summary of the treatment options for induction therapy in SSc–ILD

	Trial	Study design	Conclusions	Approval year
				Japan	US†	EU‡
†Approved by the Food and Drug Administration. ‡Approved by the European Medicines Agency. DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; POCY, oral cyclophosphamide; RDBPCT, randomized, double-blinded, placebo-controlled trial; RTX, rituximab; SC, subcutaneous injection; SSc, systemic sclerosis; TCZ, tocilizumab
POCY	SLS-I; POCY (≤2 mg/kg/day) vs. placebo for 1 year13)	RDBPCT	%FVC was higher in patients who received POCY compared to placebo	2010	-	-
IVCY	Comparing IVCY and POCY using SLS-I and -II and the EUSTAR registry15)	Indirect comparison	No difference in %FVC and DLCO change between POCY and IVCY	2010	-	-
MMF	SLS-II; MMF (≤3 g/day, for 2 years) vs. POCY (≤2 g/day for 1 year, followed by placebo for 1 year) 19)	RDBPCT	No differences in %FVC change between MMF and POCY, and MMF had less adverse events	2024	-	-
Nintedanib	SENSCIS study; nintedanib (300 mg/day) vs. placebo23)	RDBPCT	Nintedanib reduced the annual decline rate in FVC compared with placebo	2019	2019	2020
RTX	DESIRES study; RTX (375 mg/m2) vs. placebo, 4 times every week26)	RDBPCT	RTX improved both %FVC rate and HRCT findings	2021	-	-
TCZ	focuSSced trial; TCZ (162 mg/week SC for 48 weeks) vs. placebo30)	RDBPCT	TCZ reduced %FVC decline compared with placebo	-	2021	-

Glucocorticoids

Although glucocorticoids are useful for treating most rheumatic diseases, their efficacy on SSc-ILD as single agent is limited. Less than a moderate dose of glucocorticoids has been reported effective when administrated in combination with immunosuppressants, such as CY¹¹⁾ or MMF.¹²⁾ However, glucocorticoids are associated with a high risk of renal crisis; therefore, blood pressure and renal function should be closely monitored after glucocorticoid administration.¹³⁾

CY

CY is a nitrogen mustard that cross-links deoxyribonucleic acid by alkylation. It is used in chemotherapy and immunosuppressive therapy. Oral CY (POCY) has the most convincing evidence among the medications used to treat SSc-ILD. The Scleroderma Lung Study I (SLS-I) conducted by the Scleroderma Lung Study Group is a randomized, double-blind, placebo-controlled trial (RDBPCT) that examined the effects of POCY on pulmonary function and health-related symptoms.¹⁴⁾ A total of 158 patients with symptomatic SSc-ILD, including exertional dyspnea, were enrolled. %FVC ranged between 45% and 85%. Patients received POCY (≤2 mg/kg/day) or a matching placebo for 1 year and were followed up for one more year. After 1 year, %FVC was found to be 2.53% higher in patients who received POCY compared to those who received a placebo. This difference in %FVC was maintained for 1 year after the POCY cessation. Moreover, dyspnea and the quality of life (QOL) index of the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study 36-item Short-form General Health Survey (SF-36) significantly improved in patients receiving POCY. In other words, SLS-I revealed the effectiveness of POCY for SSc-ILD.

Regarding intravenous CY (IVCY), a previous study showed that IVCY (750 mg/m², monthly, 1 year), followed by maintenance therapy [MMF or azathioprine (AZA) ] stabilized the pulmonary function over 3 years in 75 patients with SSc-ILD.¹⁵⁾ A comparative study of IVCY and POCY in patients with SSc using randomized controlled trial (RCT) databases (SLS-I and II) and the European Scleroderma Trials and Research registry reported no significant differences in %FVC, diffusing capacity of the lung for carbon monoxide (DLCO), or skin conditions between IVCY and POCY after a 1-year follow-up, indicating a similar efficacy between IVCY and POCY.¹⁶⁾

Although CY is an effective treatment, it is carcinogenic and may cause infertility. The use of CY increased the malignancy risk in bladder cancer, nonmelanoma skin cancer, and hematological malignancies, with long-term use and high total dose of CY, especially more than 36 g.¹⁷⁾ Regarding infertility, the risk of ovarian failure increases with age: it was observed in 14% of patients who started CY at younger than 30 years, in 28% of those aged 30-39 years, and in 50% of those aged 40 or older.¹⁸⁾ Therefore, caution must be exercised with CY usage.

MMF

MMF is an antimetabolite that inhibits purine synthesis by selectively inhibiting inosine 5′-monophosphate dehydrogenase expressed in activated T and B lymphocytes. MMF has not been approved in the EU or the US for SSc-ILD treatment, but the UK guidelines listed it as an alternative therapy to CY or as a maintenance therapy after CY administration.¹⁹⁾ In Japan, MMF was newly approved for public knowledge-based application in February 2024 based on the outcome of the SLS-II study, and received regulatory approval in June 2024. The SLS-II study is a RDBPCT that compared the efficiencies and the safety of MMF and POCY. The MMF group (n = 69) that received MMF (up to 3 g/day) for 2 years was compared with the POCY group (n = 73) that received POCY for 1 year, followed by a placebo for 1 year. After 2 years, no significant differences were noted in the change in %FVC from baseline between the MMF and POCY groups (＋2.19% vs.＋2.88%), indicating that MMF was not inferior to POCY. Moreover, the treatment discontinuation rate caused by adverse events (AE), such as leukopenia and thrombocytopenia, was lower in the MMF group than in the POCY group (35% vs. 42%).²⁰⁾

MMF increases the risks of congenital malformations and spontaneous abortion;²¹⁾ therefore, it must be avoided during pregnancy, and female patients of reproductive age must be made aware of its risks.

AZA

AZA is a prodrug of 6-mercaptopurine (6-MP), an antimetabolite, that functions as an inhibitor of nucleic acid synthesis after being degraded to 6-MP. A randomized open-label study evaluated the efficiency of AZA (2.5 mg/kg/day for 1 year, and then maintained at 2 mg/kg/day) versus POCY (2 mg/kg/day for 1 year, and then maintained at 1 mg/kg/day) in 60 patients with SSc-ILD. The findings obtained demonstrated that AZA was inferior to POCY because FVC and DLCO remained unchanged in the POCY group, but significantly worsened in the AZA group after 18 months of treatment.²²⁾ Therefore, AZA is not recommended as a first-line therapy for SSc-ILD, but it is useful as maintenance therapy following induction therapy with CY.²³⁾

Nintedanib

Nintedanib is an antifibrotic agent approved as SSc-ILD treatment in Japan in December 2019. The SENSCIS trial is a global phase III RDBPCT that confirmed the efficiency and the safety of nintedanib for SSc-ILD in 2019.²⁴⁾ At baseline, participants had ≥10% fibrosis on HRCT, %FVC ≥40%, and DLCO of 30%-89%. The primary endpoint was the annual decline rate in FVC assessed over 52 weeks. A total of 576 patients were recruited and received nintedanib (150 mg twice daily, n = 288) or a placebo (n = 288), and a low dose of prednisone (≤10 mg/day) and/or stable therapy with MMF or methotrexate (≥6 months) was permitted. The declines in FVC in the nintedanib and placebo groups were 52.4 and 93.3 mL, respectively, suggesting that nintedanib suppressed the SSc-ILD progression. The secondary outcomes included the QOL index of the total score on the St. George's Respiratory Questionnaire, the HAQ-Disability Index (HAQ-DI), and the Functional Assessment of Chronic Illness Therapy (FACIT)-Dyspnea questionnaire, which were evaluated and did not significantly differ. In addition, a subanalysis of Asian patients revealed the nintedanib efficacy.²⁵⁾

The most common AE with nintedanib is gastrointestinal symptoms, such as nausea and diarrhea. In the SENSCIS trial, diarrhea developed in 75.7% of participants treated with nintedanib. Nausea, vomiting, abdominal pain, and weight loss were also often observed.^24,26) When gastrointestinal symptoms were noted in patients with SSc-ILD receiving nintedanib, dose reductions and/or the use of antidiarrheal agents must be considered. Additionally, nintedanib must be used cautiously in patients who already have gastrointestinal symptoms caused by SSc.

RTX

RTX is a chimeric monoclonal antibody that targets CD20 expressed on the B-cell surface and depletes B cells through cytotoxic effects. In Japan, RTX was approved for SSc treatment in 2021. The DESIRES study, a multicenter RCT aimed at evaluating the safety and the efficacy of RTX in patients with SSc, has been conducted in Japan since 2017. A total of 56 patients with SSc were divided into the RTX (total; n = 28, including 25 patients with SSc-ILD) and placebo (total; n = 28, including 23 patients with SSc-ILD) groups. Patients received RTX 375 mg/m² or a placebo intravenously four times every week. The findings obtained as secondary endpoint revealed significant improvements in SSc-ILD in the RTX group compared to the placebo group. The %FVC recovered by 0.09% in the RTX group, but decreased by 2.9% in the placebo group after 24 weeks. Additionally, the area occupied by interstitial shadows on HRCT decreased by 0.32% in the RTX group, but increased by 2.4% in the placebo group.²⁷⁾ Additionally, RTX was effective on the primary endpoint of skin symptoms. There were no significant differences found in the QOL index of SF-36 and HAQ-DI compared to the placebo. Based on this study, RTX was approved for SSc, including SSc-ILD, by the Japanese Ministry of Health, Labour and Welfare and covered by the health insurance system in Japan.

A randomized open-label study enrolled 60 patients with SSc-ILD in 2018 to compare the efficacies of RTX and IVCY. The patients in the RTX group received 1,000 mg of RTX on days 0 and 15, while those in the IVCY group received 500 mg/m² of IVCY every 4 weeks for 24 weeks. After 6 months of treatment, %FVC improved from 61.3 to 67.5% in the RTX group, but decreased from 59.3% to 58.1% in the IVCY group. Moreover, serious AE, such as scleroderma and renal crisis, were more frequently observed in the IVCY group than in the RTX group, indicating that RTX was more effective and safer than IVCY.²⁸⁾

The contraindication of administrating RTX for severe SSc-ILD is listed in the package insert published by the Pharmaceuticals and Medical Devices Agency in Japan. In a study assessing the efficacy of RTX versus CY in SSc-ILD patients in Japan, one patient who received RTX died of acute ILD exacerbation, which was suspected to be caused by the development of infection or drug-induced ILD due to RTX. This patient had severe SSc-ILD with %FVC of 64% and DLCO of 30% before RTX administration.²⁹⁾ Therefore, patients with %FVC <60% or DLCO <40% were excluded from entry into the DESIRES study.²⁷⁾ The severity of SSc-ILD must be carefully assessed when using RTX to treat SSc-ILD.

TCZ

TCZ is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor. It is often used in treating SSc and SSc-ILD because the IL-6 overexpression may be a predictor of the SSc-ILD exacerbation and the patient outcomes.³⁰⁾ The US Food and Drug Administration approved TCZ for SSc-ILD treatment in March 2021 according to the focuSSced trial, an RDBPCT. A total of 210 early dcSSc patients were assigned to the TCZ (n = 104) and placebo (n = 106) groups in this trial. A significant difference was observed in %FVC between the two groups (−0.6% vs. −4.6%) at 48 weeks, suggesting the TCZ efficacy for SSc-ILD.³¹⁾ However, in Japan, TCZ is not currently approved for SSc-ILD.

Regarding the AE of TCZ, a cohort study investigating the efficacy and safety of TCZ reported that the most common AE were leukopenia and thrombocytopenia; however, neither were severe enough to warrant TCZ discontinuation. Other frequent AE were infection, skin ulcers, and acute heart failure.³²⁾

Conclusion

SSc is a progressive and refractory autoimmune disease. The number of new and effective drugs for SSc-ILD, including nintedanib, RTX, and TCZ, recently increased. Moreover, MMF is covered by the health insurance system in Japan. As the usage of MMF increases, more evidence supporting its use in Japanese patients with SSc-ILD is expected to accumulate in the future. The further development of more effective therapies with fewer AE is expected for SSc-ILD patients.

Disclaimer: Toshihiro Nanki is one of the Editors of Toho Journal of Medicine. He was not involved in the editorial evaluation or decision to accept this article for publication at all.

Authors' contribution: AS and EW wrote the manuscript. TN supervised the manuscript. All authors read, discussed, and approved the manuscript.

Conflicts of interest: AS, none; EW, none; TN received grant/research support from Chugai Pharmaceutical Co., Ltd., Asahikasei Pharma Corp., Ayumi Pharmaceutical Corp., Nippon Kayaku Co., Ltd., AbbVie GK, Taisho Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. and consultant fees and speaker fees from Chugai Pharmaceutical Co., Ltd.

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