SSc-ILD

Treatment and management

The goal of treating clinical systemic sclerosis associated interstitial lung disease (SSc-ILD) is to stabilize or prevent progressive disease.

All patients with clinically meaningful SSc-ILD should be offered treatment. Although no consensus definition exists, clinical interstitial lung disease (ILD) may be defined as those patients with symptoms attributable to ILD and non-trivial lung involvement seen on high-resolution computed tomography (HRCT) and/or associated decrements in lung physiology and gas exchange.¹

Disease monitoring¹

Disease monitoring should be rigorous in order to detect the subset of clinical ILD patients with progressive disease, operationalized as a decline in FVC levels of >10% from baseline or ≥5% to <10% relative decline in forced vital capacity (FVC) and ≥15% relative decline in diffusion capacity of the lung for carbon monoxide (DLCO). These patients span a spectrum from mild to rapidly progressive disease. Decisions to initiate or advance treatment often take into consideration the likelihood of progression, patient comorbidities, risk of toxicities, and current data on efficacy.¹ (Figure 1)

Figure 1. Screening and monitoring algorithm for patients with SSc-ILD.¹

General preventative measures^1-3

Before addressing specific therapies, general preventative measures should be considered.

• Yearly influenza vaccination is recommended for all patients along with vaccination for pneumococcal disease.²
• The American College of Rheumatologists’ guidance on SARS-CoV-2 vaccination advises against delaying vaccination for almost all immunosuppressive therapies. Withholding methotrexate or delaying cyclophosphamide for 1 week after vaccination has been proposed to improve vaccine efficacy in patients receiving these treatments based in influenza vaccination. However, patients with ILDs receiving rituximab or cyclophosphamide often have severe or rapidly progressive disease, and it might not be possible to delay the next dose of treatment in someone requiring urgent immunosuppression. Patients with SSc-ILD might require these drugs at some point in the future and therefore are encouraged to have the vaccine at the earliest opportunity.³
• Supplemental oxygen should be provided to those patients requiring it to maintain SpO2 ≥ 88% during ambulation.¹
• Pulmonary rehabilitation has been suggested to be beneficial in exercise capacity, oxygenation and symptoms for patients with SSc (some of whom had ILD).²

Pharmacological treatments

The treatment of SSc-ILD has evolved, reflecting understanding of the biological processes contributing to lung injury and progress in the development of targeted therapies.²

Immunosuppressive therapies²

• Corticosteroids²: Moderate- to high-dose corticosteroid monotherapy (average daily dose of 30 mg prednisolone) was proven to be well tolerated in patients with SSc and resulted in stabilization of pulmonary function over a median follow up of more than 10 years in a small retrospective study. However, the considerable side effects of long-term corticosteroid use, the presence of high-quality studies investigating alternative treatment regimens, and the real possibility of precipitating scleroderma renal crisis all argue against using moderate- dose or high-dose steroids to treat SSc-ILD.²
• Azathioprine²: A few small, uncontrolled studies have showed some promise in using azathioprine in the treatment of SSc-ILD in patients with progressive respiratory decline while taking cyclophosphamide or as first-line therapy. However, the availability of other therapies that are supported by higher quality data have led to decreased use of azathioprine in the treatment of SSc-ILD. Azathioprine might have an adjuvant role in the management of patients with more advanced disease or in those intolerant to cyclophosphamide and mycophenolate.²

• Cyclophosphamide and mycophenolate mofetil²: The best evidence for the value of cyclophosphamide therapy in SSc-ILD came from Scleroderma Lung Studies (SLS) 1 and 2. In the prospective randomized SLS-1 study, oral cyclophosphamide in a dose of up to 2 mg/kg/day or placebo was given for 1 year. Patients in the treatment arm showed less dyspnea, skin thickening, and an improved functional capacity, and better scores in some components of the SF-36 quality of life questionnaire. Moreover, there was a small (2.5%) but statistically significant improvement in FVC compared to placebo. HRCT analysis also showed that cyclophosphamide was associated with lower fibrotic scores. However, side effects were relatively common in the treatment group for only a modest benefit, and most of the improvement seen in the treatment arm had been lost at 2-year follow-up.²

  The SLS-2 trial was designed to address concerns regarding the tolerance and toxicity of cyclophosphamide by comparing 12 months of oral cyclophosphamide (up to 2 mg/kg) followed by 12 months of placebo, with 24 months of mycophenolate mofetil (maximum daily dose 3 g). FVC increased by 2–3% at the end of the study, with no medication showing superiority. Most patients in each group had an improvement in FVC during the study, and in those with a positive change in FVC, the average improvement was 7–8%. Beneficial effects were also observed in secondary outcomes such as the modified Rodnan Skin Score and the Transition Dyspnea Index. Unlike SLS-1, the treatment effect persisted at 2 years in the patients who were randomly assigned to cyclophosphamide plus placebo. HRCT fibrosis scores were reduced in both groups to an equal extent, with patients who had the most severe fibrosis at baseline deriving the most benefit. The safety and tolerance data favored mycophenolate over cyclophosphamide. Finally, both DLCO and DLCO divided by alveolar volume tended to improve in the mycophenolate group suggesting a potential effect on vascular remodeling.²

Biological therapies

• Rituximab²: Given the significance of autoantibodies in the pathogenesis of SSc and the multifactorial roles of B cells as regulators of inflammation and fibrosis, B-cell depletion with rituximab has been used as rescue therapy in patients with progressive SSc-ILD. Despite encouraging results from small observational studies, the value of rituximab was challenged in a 2019 prospective study comparing 254 patients enrolled in the EUSTAR database treated with rituximab with 9,575 propensity score-matched controls. Although skin fibrosis improved, no difference in decline in FVC or DLCO was seen. Patients treated with both rituximab and mycophenolate mofetil tended to have better outcomes than those who received rituximab alone or matched controls.²

  Rituximab is currently being investigated in two randomized controlled trials. The EvER-ILD trial (NCT02990286) is comparing 6 months of mycophenolate mofetil (2 g/day) with mycophenolate mofetil (2 g/day) plus rituximab (1g given as an infusion on days 1 and 15) in patients who failed first-line immunosuppressive therapy (defined as corticosteroids, cyclophosphamide, or azathioprine). The RECITAL trial (NCT01862926) is comparing intravenous cyclophosphamide (600 mg/m2 once every 4 weeks for 6 doses) with rituximab (1g given on days 1 and 15) in patients with connective tissue disease-associated ILD, including patients with SSc-ILD.²

• Tocilizumab²: Given that IL-6 appears to be a major driver of inflammation and fibrosis in patients with SSc, its inhibition with the monoclonal antibody, tocilizumab, has also been examined as a potential treatment strategy for skin disease. In the larger, phase 3 FocuSSed trial, tocilizumab did not improve the modified Rodnan Skin Score in patients with early active dcSSc with an inflammatory phenotype. Despite an average disease duration of only about 2 years, 64% of this cohort had evidence of ILD on HRCT with preserved pulmonary function (FVC 82.1% predicted, DLCO 75.6% predicted). A secondary endpoint was a clinically meaningful difference in the cumulative distribution of the percentage of predicted FVC change from baseline to week 48. Among patients with evidence of SSc-ILD, 5 (8.6%) of 58 who were randomly assigned to tocilizumab had a 10% worsening in FVC, compared with 13 (24.5%) of 53 patients in the placebo group. This is additional evidence that early onset ILD is a risk factor for progressive disease. These data were further supported by improvements in quantitative fibrosis scores on HRCT in the tocilizumab cohort.²

Antifibrotic therapies^2,4

• Nintedanib^2,4: Nintedanib is a tyrosine kinase inhibitor that has been shown to affect several crucial fibrotic mediators, including the platelet-derived growth factor receptor, fibroblast growth factor receptor, vascular endothelial growth factor receptor, and the kinase Src. In the 2019 SENSCIS trial, 580 patients with SSc-ILD affecting at least 10% of the lungs were randomly assigned to receive 150 mg of nintedanib twice per day or placebo for 52 weeks. 299 (about 50%) of the cohort had dcSSc and 350 (nearly 60%) were positive for anti-topoisomerase antibodies. 279 patients (50%) had also been taking stable doses of mycophenolate for at least 6 months. The rate of FVC decline reduced by 44% in the group receiving nintedanib (–52·4 cm³/year vs. 93·3 cm³/year) with a side effect profile similar to that reported in the previous idiopathic pulmonary fibrosis trials. During 52 weeks, the proportions of patients with any decline in FVC and with an FVC decline of more than 5% or more than 10% of what was predicted were lower in the nintedanib group than in the placebo group. On the basis of these data, nintedanib became the first FDA-approved therapy for SSc-ILD as of September 6, 2019;² and the indication was also approved by TFDA on March 18, 2020.⁴
• Pirfenidone²: Pirfenidone has considerable anti-inflammatory and antifibrotic properties, and although its mechanism of action has not been fully elucidated, it is thought to involve the inhibition of transforming growth factor-β and inflammatory cytokines such as tumor necrosis factor-⍺. In the phase 2 LOTUSS trial, pirfenidone at a dose of up to 2,403 mg/day for 16 weeks was found to be safe in patients with SSc-ILD. However, 32 (60%) of the 56 patients in the treatment arm required a dose interruption or reduction, most commonly because of gastrointestinal side effects. SLS-3 (NCT03221257), a phase 3 clinical trial examining the combination of pirfenidone (up to 2,403 mg/day) with mycophenolate (up to 3,000 mg/day) versus mycophenolate plus placebo for SSc-ILD is currently enrolling patients and is expected to be completed by 2021. Patients will be followed up for 18 months, with FVC change from baseline as the primary outcome.²

Transplantations

Autologous stem cell transplantation (ASCT)^1,2

ASCT represents an emerging treatment option for those patients with SSc-ILD that is severe and refractory to standard therapy, and who are likely to benefit from the procedure while unlikely to develop post-transplant complications. Three key trials (ASSIST, ASTIS, and SCOT) have shown improved survival compared to cyclophosphamide, in addition to improved quality of life, skin thickening, and FVC.1 Given these data, European League Against Rheumatism (EULAR) recommends consideration of ASCT in selected patients with rapidly progressive SSc at risk of organ failure, and the disease is now considered a standard of care indication for ASCT by the American Society for Blood and Marrow Transplantation. However, with the high risk of infection and early treatment-related mortality, careful selection of patients is of paramount importance.²

Lung transplantation^1,2

SSc-ILD and SSc-associated pulmonary arterial hypertension (PAH) are uncommon indications for lung transplantation, accounting for just 1.1% of cases included in the 2016 Registry of the International Society for Heart and Lung Transplantation. This low association is related both to the rarity of the disease and to comorbidities that often render patients with SSc poor candidates.² One nationwide cohort study found an increased 1-year mortality rate in SSc-ILD patients compared to those with non-SSc-ILD. Outcomes of mortality up to 5 years suggested similar outcomes to those with non-SSc fibrotic lung disease.¹ Meticulous planning and careful patient selection are required, although no protocols have been established because of the rarity of disease.²

Treatment algorithm

Nintedanib can be reasonably considered as first line among patients with a predominantly fibrotic pattern on chest CT, and mycophenolate or cyclophosphamide can be considered first line in patients with a more inflammatory phenotype. Combination therapy should be considered in patients showing progression of disease while on a single agent and in patients who have evidence of substantial ground glass opacities and fibrotic changes. Rituximab could be considered for refractory disease, whereas the role of tocilizumab needs to be better defined by future clinical trials. ASCT is a viable treatment option for patients with progressive disease and threatened organ dysfunction, whereas patients with isolated lung involvement or lung disease that is too advanced to be considered for ASCT should be considered for lung transplantation.² (Figure 2)