Clinical presentation of both systemic sclerosis (SSc) and SSc-related interstitial lung disease (ILD) vary. A 2010 survey of 464 patients with SSc found that the chief complaints in terms of both frequency and impact on daily activity were fatigue (89% reported frequency greater than sometimes, 72% reported moderate to severe impact on activities), Raynaud phenomenon (86% and 67%), hand stiffness (81% and 59%), joint pain (81% and 64%), and difficulty sleeping (76% and 59%).1 The most common symptoms of SSc-ILD include exertional dyspnea, fatigue, reduced exercise tolerance, and cough. A 2018 prospective study of the EUSTAR database and Chinese Rheumatism Data Center of 448 patients with SSc, 86% of which had ILD, found that 60.5% of patients had respiratory symptoms, with shortness of breath after exercise being the most common (55.8%), followed by cough (23.7%) and dyspnea (8.5%).2
Because of this variability, potential courses of treatment can vary based on a holistic approach to managing symptom burden as well as disease management while taking into account the potential presence of other SSc-related organ manifestations. There are few options that directly treat SSc-ILD, and those that are available have shown to only marginally improve lung function but not have a discernible effect on survival.
American Thoracic Society (ATS) and the European League Against Rheumatism (EULAR) clinical practice guidelines recommend the use of certain immunosuppressants for the treatment of SSc-ILD.3,4 There is no consensus dosage or duration recommendation. ATS strongly recommends the use of mycophenolate mofetil (MMF) and conditionally recommend cyclophosphamide (CYC), rituximab, tocilizumab, nintedanib, and nintedanib in combination with MMF, advising that not enough research has been done to fully recommend them.3 ATS further advises that there is insufficient evidence to recommend the use of pirfenidone and pirfenidone in combination with mycophenolate. EULAR recommends that CYC be considered for the treatment of SSc-ILD, especially in patients with progressive disease.4
The decision to start medication and the selection of a particular agent should be based on an individual’s disease severity. EULAR recommends that treatment should be considered based on individualized risk-benefit analyses, weighing the benefit of progression of ILD against toxicity and reaction to treatment.4 Clinical presentation of SSc should also be taken into consideration, as side effects can not only reduce quality of life but also complicate other manifestations of SSc (for example, gastrointestinal manifestations).
Mycophenolate and Cyclophosphamide
CYC was the previously established first-line therapy for SSc-ILD, but more recent studies have shown that MMF can be equally beneficial with fewer toxic side effects. The beneficial effects of the immunosuppressants CYC and MMF were shown in the randomized control trials Scleroderma Lung Study I and II (SLS I and II).5,6
SLS I was conducted from 2000-2004 and randomized 145 patients with SSc-ILD to either treatment with CYC or placebo.5 At 12 months, those in the intervention experienced less forced vital capacity (FVC) decline (1.0% vs 2.6% placebo, adjusted mean difference 2.97%, p=0.009), total lung capacity (TLC) decline (0.3% vs 2.8%, adjusted mean difference 4.09%, p=0.026), and dyspnea measured using the Mahler transitional dyspnea index (scale from -9 to +9, +1.4 in intervention vs -1.5 placebo). There was limited difference in reported cough (66.2% vs 67.2%) and no significant difference between diffusing capacity of carbon monoxide (DLCO). Effects of treatment were found to be modest, but significant.
SLS II found that treatment with either MMF or cyclophosphamide resulted in significant increases in FVC.6 SLS II was conducted from 2009-2013 126 patients were followed over 24 months of treatment with either MMF (for 24 months) or cyclophosphamide (for 12 months followed by 12 months of placebo). FVC improvement was similar between the two groups (2.19% MMF and 2.88% CYC). Fewer MMF patients withdrew from treatment (20 vs 32) or qualified as having treatment failure (0 vs 2). Adverse events, including leukopenia and thrombocytopenia, occurred more frequently (30 vs 4 patients; p<0·05) and exclusively (4 vs 0 patients; p<0·05) in the CYC arm, respectively.
A long term observational follow-up study to SLS I and II examined the effect of treatment on survival.7 CYC did not improve long-term survival compared to placebo over a median follow-up of 8 years (37% survival for both, p=0.335) in SLS I. In SLS II, there were no significant differences in long-term survival for patients taking CYC vs MMF over a median of 3.6 years of follow-up (68% vs 74%, p=0.627). Rates of organ failure were higher in placebo than intervention arms for both SLS I (CYC 18% vs placebo 79%) and SLS II (CYC 11% vs MMF 10%).
Rituximab
Rituximab can be used as a rescue therapy when MMF is not effective for individuals with SSc-ILD. A 2022 randomized control trial with 97 patients with connective tissue-related ILD (CTD-ILD; 38% of participants had SSc-ILD) compared treatment with CYC to rituximab.8 While rituximab was not superior to CYC, treatment resulted in increased FVC at 24 weeks (unadjusted mean increase 97 mL for rituximab, 99 mL for CYC). Rituximab was associated with fewer adverse events than CYC (445 vs 646 events, 29 vs 33 serious adverse events). Quality of life (QOL) as assessed by the King’s Brief Interstitial Lung Disease (KBILD, scores 0-100) questionnaire found that rituximab increased scores by a mean of 8.8 points and CYC increased scores by 9.4 points.
Tocilizumab
A randomized control trial tested Tocilizumab in 136 patients with SSc-ILD to evaluate for improvement in skin changes assessed by the modified Rodnan skin score (mRSS). Though the study failed to meet its primary endpoint, a post hoc analysis of lung function outcomes found that the tocilizumab arm had preservation of FVC % over 48 weeks compared to placebo (mean change in FVC -0.1% vs -6.3%, p<0.001).9 Similar preservation was observed independently of fibrosis severity. This data led to the FDA approval of Tocilizumab for SSc-ILD.
Nintendanib
A randomized controlled trial was done to test the effectiveness of nintendanib with 576 patients with SSc-ILD, 48.4% of whom were receiving MMF.10 The annual rate of FVC decline was found to be lower for nintendanib than placebo (-52.4 mL vs -93.3 mL, p=0.04). FVC % of predicted value and DLCO differed marginally between the two groups (72.4 vs 72.7 and 52.9 vs 53.2, respectively). QOL as assessed by St. George’s Respiratory Questionnaire (SGRQ, scores 0-100, where 0 is best and 100 is worst QOL) was not significantly different between the two trial arms (1.69 points higher for nintendanib).
Lung Transplant
Lung transplantation can be an appropriate treatment option in certain patients, namely for patients who have not responded to other treatment with progressive respiratory failure. Careful evaluation should be done for extrapulmonary SSc-related disease before consideration of a transplant. A retrospective review of 90 patients with scleroderma who underwent lung or heart-lung transplantation found that survival rates after 1, 3, and 5 years were 81%, 68%, and 61%, respectively.11 These survival rates are similar to patients who get lung transplants for reasons other than scleroderma.
Stem Cell Transplantation
Stem cell transplantation is currently an experimental treatment for SSc. There is not enough data to support or refute a recommendation of this therapeutic modality to treat SSc-related ILD.3
Non-Pharmacologic Therapies
When indicated, patients with SSc-ILD can be considered to receive adjunctive nonpharmacologic therapies that are used with patients with ILD. ATS practice guidelines recommend that patients be prescribed supplemental oxygen when they have resting hypoxemia to improve quality of life, although evidence that it improves functioning is limited.12 A randomized control trial on 76 patients with fibrotic ILD found that ambulatory oxygen was associated with improvements in total KBILD scores (mean difference 3.7), breathlessness and activity scores (mean difference 8.6), and chest symptoms (mean difference 7.6).13
ATS practice guidelines also recommend that patients be offered pulmonary rehabilitation.12 These programs can include aerobic conditioning, strength and flexibility training, educational opportunities, nutritional aid, and psychosocial support. Evidence has established that these types of interventions are safe and improve QOL, although improvement to disease severity is relatively unknown.
A systematic review of 21 studies on patients with ILD found low to moderate evidence that pulmonary rehabilitation results in improved six-minute walk distance (mean difference of 40.07 meters), dyspnea (mean difference -0.36), and quality of life (Chronic Respiratory Disease Questionnaire 9.29 point improvement, St. George’s Respiratory Questionnaire 7.91 point improvement).14 These improvements were evident 6-12 months following the intervention period. There were no adverse events reported during rehabilitation.
References
- Bassel M, Hudson M, Taillefer SS, Schieir O, Baron M, Thombs BD. Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey. Rheumatology (Oxford). Apr 2011;50(4):762-7. doi:10.1093/rheumatology/keq310
- Hu S, Hou Y, Wang Q, Li M, Xu D, Zeng X. Prognostic profile of systemic sclerosis: analysis of the clinical EUSTAR cohort in China. Arthritis Res Ther. Oct 22 2018;20(1):235. doi:10.1186/s13075-018-1735-4
- Raghu G, Montesi SB, Silver RM, et al. Treatment of Systemic Sclerosis-associated Interstitial Lung Disease: Evidence-based Recommendations. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. Sep 29 2023;doi:10.1164/rccm.202306-1113ST
- Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. Aug 2017;76(8):1327-1339. doi:10.1136/annrheumdis-2016-209909
- Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. Jun 22 2006;354(25):2655-66. doi:10.1056/NEJMoa055120
- Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. Sep 2016;4(9):708-719. doi:10.1016/S2213-2600(16)30152-7
- Volkmann ER, Tashkin DP, Sim M, et al. Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts. Annals of the Rheumatic Diseases. 2019;78(1):122-130. doi:10.1136/annrheumdis-2018-213708
- Maher TM, Tudor VA, Saunders P, et al. Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med. Jan 2023;11(1):45-54. doi:10.1016/s2213-2600(22)00359-9
- Roofeh D, Lin CJF, Goldin J, et al. Tocilizumab Prevents Progression of Early Systemic Sclerosis-Associated Interstitial Lung Disease. Arthritis Rheumatol. Jul 2021;73(7):1301-1310. doi:10.1002/art.41668
- Distler O, Highland KB, Gahlemann M, et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med. Jun 27 2019;380(26):2518-2528. doi:10.1056/NEJMoa1903076
- Pradère P, Tudorache I, Magnusson J, et al. Lung transplantation for scleroderma lung disease: An international, multicenter, observational cohort study. J Heart Lung Transplant. Jul 2018;37(7):903-911. doi:10.1016/j.healun.2018.03.003
- Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. Mar 15 2011;183(6):788-824. doi:10.1164/rccm.2009-040GL
- Visca D, Mori L, Tsipouri V, et al. Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial. Lancet Respir Med. Oct 2018;6(10):759-770. doi:10.1016/s2213-2600(18)30289-3
- Dowman L, Hill CJ, May A, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. Feb 1 2021;2(2):Cd006322. doi:10.1002/14651858.CD006322.pub4
