Systemic Sclerosis With Associated Interstitial Lung Disease: Management Considerations and Future Directions

Elana J. Bernstein, MD, MSc

,
J. Terrill Huggins, MD

,
Laura K. Hummers, MD, ScM

,
Gary M. Owens, MD

Supplements and Featured Publications, New Directions in the Management of Interstitial Lung Disease, Volume 27, Issue 7

Systemic sclerosis (SSc), also referred to as scleroderma, is a rare autoimmune disease associated with vasculopathy, inflammation, and fibrosis of the skin and/or internal organs. Interstitial lung disease (ILD) is a frequent complication and is the leading cause of death in patients with SSc. Although economic data are limited, available data suggest that SSc-ILD is associated with significant cost implications. Treatment of SSc-ILD has historically been with immunosuppressive agents. In 2019, however, the treatment landscape expanded with the FDA approval of the tyrosine kinase inhibitor nintedanib. A lack of codified treatment guidelines for patients with SSc-ILD creates significant challenges in improving outcomes at the patient level and, more generally, in reducing disease burden to the health care system. As the treatment landscape continues to evolve, it is likely that to reduce lung volume loss in patients, a combination of immunosuppressive and antifibrotic approaches will need to be used. Additionally, a greater emphasis on risk-stratification strategies may allow for more efficient follow-up, monitoring, and assessment of treatment response.

Am J Manag Care. 2021;27(suppl 7):S138-S146. https://doi.org/10.37765/ajmc.2021.88656

__________________________________________________________________________________________________________

Systemic sclerosis (SSc), also referred to as scleroderma, is a rare autoimmune disease associated with vasculopathy, inflammation, and fibrosis of the skin and/or internal organs.1 The prevalence of SSc is estimated to be 276 cases per million adults, disproportionately affecting adult women, with 389.8 cases per million compared with 84.1 cases per million in adult men. SSc is also more prevalent among African American compared with Caucasian individuals.2 A frequent complication of SSc is interstitial lung disease (ILD), which is the leading cause of death in this population and is sometimes associated with pulmonary hypertension (PH). The prevalence of pulmonary involvement in SSc is high, although the rate reported in clinical studies varies depending on the mode of detection. ILD is diagnosed in 40% to 75% of patients with SSc.3 This article reviews the clinical background and evolving treatment spectrum of SSc-ILD. Additionally, it explores the clinical, psychological, and economic implications of SSc-ILD and offers considerations for the rapidly evolving research and therapeutic landscape.

Disease Overview

Pathophysiology

Although the specific inciting events in SSc-ILD are incompletely understood, there is evidence to suggest that activation of the immune system plays a key role in early disease development, with involvement of a number of cytokines that function to both drive profibrotic disease activity and limit the body’s natural defense mechanisms against that same activity.1 Injury to the alveolar epithelial and endothelial cells may be one of the earliest pathogenic events in SSc-ILD.4 The pathophysiology of pulmonary disease in SSc is characterized by the activation of immune cells and proliferation of fibroblasts that have increased capacity to produce collagen, coupled with diminished collagen breakdown, resulting in fibrosis.4 The activation of T cells directly and indirectly results in overexpression of proinflammatory mediators that stimulate proliferation of fibroblasts, resulting in a perpetual profibrotic state.5

Classification and Phenotypes

Three phenotypes of SSc have been identified: limited cutaneous (lcSSc), diffuse cutaneous (dcSSc), and systemic sclerosis sine scleroderma (ie, SSc without skin involvement). SSc can co-occur with other systemic autoimmune rheumatic diseases.5 The degree of skin involvement may predict the risk for pulmonary complications, as well as survival.1,6 Although ILD has been identified among individuals with both lcSSc and dcSSc, epidemiologic studies suggest that ILD is more prevalent among patients with dcSSc than lcSSc.1 Increased age at disease onset, shorter disease duration, lower hemoglobin levels, higher serum creatine levels, African American race, and the presence of pulmonary arterial hypertension (PAH) or cardiac involvement have been independently associated with the presence of ILD among individuals with SSc.6 Additionally, positivity for anti–topoisomerase I antibody and increased levels of serum IL-6, Krebs von den Lungen-6, chemokine (C-X-C motif) ligand 4, surfactant protein D, pulmonary and activation-regulated chemokine, chitinase 1, tenascin-C, lysyl oxidase, and IL-33, as well as the absence of anti-centromere antibodies, have been associated with greater risk of ILD.1,7-12

ILD can be radiographically and/or histopathologically classified as nonspecific interstitial pneumonia (NSIP, the most common form in patients with SSc-ILD), usual interstitial pneumonia (UIP), diffuse alveolar damage, organizing pneumonia, or lymphocytic interstitial pneumonia.1,13 High-resolution CT (HRCT) scan of the chest is considered the gold standard for diagnosing ILD and may also have prognostic value and guide treatment decisions.14

Experts in the field have recommended that all patients with SSc be screened for ILD using HRCT,15 yet the use of HRCT varies widely among rheumatology practices.16 Despite their frequent use as a noninvasive screening test, pulmonary function tests (PFTs) are not sufficiently sensitive for the detection/diagnosis of SSc-ILD.17 PFTs are typically used in patients with SSc to follow ILDs.17,18 For example, PFTs can test for diffusing capacity of the lungs for carbon monoxide (DLCO), as functional decrement may be apparent prior to symptom onset.1

Mortality Risk

SSc is notable for its devastating clinical course and risk of mortality.19 Risk of mortality is approximately 250% higher among individuals with SSc compared with age- and sex-matched controls.19 Since the introduction of angiotensin-converting enzyme inhibitors as treatment for scleroderma renal crisis in the 1980s, pulmonary complications (specifically ILD and PAH) have become the leading causes of death among individuals with SSc.5,20 Findings from a study examining trends in causes of death in systemic sclerosis from 1972 to 1997 indicated that improvements in survival for patients from 1982 to 1991 were more pronounced compared with improvements between 1972 and 1981.21 Although the frequency of deaths due to renal crisis decreased substantially over the full 30-year period, the proportion of patients with SSc who died of pulmonary fibrosis increased from 6% to 31%.21 In a large, prospective European cohort of patients with SSc, pulmonary fibrosis was the leading cause of death directly related to SSc, followed by PH and cardiac causes. SSc-related complications (eg, pneumonia, sepsis, gastrointestinal hemorrhage) were believed to have contributed in 25% of cases.20

Approximately 80% of patients with SSc develop lung involvement (including ILD and PAH) with
heterogeneity in the disease course. ILD and PAH are the most common causes of mortality in
patients with SSc."

One study estimated that the 5-year survival rate associated with SSc-ILD was 82% in patients with UIP and 90% in patients with NSIP.22 In this study, the pattern of cutaneous involvement (limited vs diffuse) did not affect outcomes but lowered forced vital capacity (FVC) and DLCO predicted a greater risk of mortality.22 Advanced age, FVC, DLCO, bronchoalveolar lavage (BAL) neutrophilia, HRCT scan fibrosis extent, and PAH have been identified as risk factors for death in patients with SSc-ILD in unadjusted analyses.23 A multivariable analysis identified presence of proteinuria, presence of PH, FVC less than 80% of predicted, presence of dyspnea on exertion, reduced DLCO, older age of SSc onset, and higher modified Rodnan skin score (mRSS) as independent risk factors associated with mortality in SSc.20

Findings from another study showed that the development of PH within the first 3 years of SSc was associated with a nearly 7-fold greater hazard of death.6 Baseline DLCO has been consistently shown to predict mortality in multivariable models, while one study found that change in DLCO after 3 years was predictive following adjustment for baseline pulmonary function and BAL eosinophil level.22,24-26 A study estimating prevalence, incidence, survival, and characteristics of SSc in the United States identified poorer survival among men compared with women, which was attributed, in part, to pulmonary disease.2

The predictive value of disease duration and baseline fibrosis (assessed using HRCT) on decline in FVC can be inferred from an analysis of placebo-treated patients in Scleroderma Lung Study I. The study evaluated factors associated with decline in FVC for the purpose of cohort enrichment in future therapeutic trials. Investigators found no difference in the unadjusted rates of decline in the FVC percentage predicted among groups of patients with disease durations of 0 to 2 years, 2 to 4 years, or more than 4 years.27 However, when patients were stratified by maximum HRCT fibrosis score (defined as the score from a patient’s lung zone with the worst extent of abnormality), severe fibrosis was associated with greater mean ± SD decline in FVC percentage predicted vs those with no or moderate fibrosis.27

Clinical, Psychological, and Economic Implications

SSc and Quality of Life

SSc has been shown to have a negative impact on quality of life (QOL). Findings from a systematic review that included 1127 patients with SSc showed notable impairment in both physical and mental health. Compared with lcSSc, dcSSc had a greater impact on physical indices of health care–related QOL, but there was no difference according to subtype on patients’ mental well-being.28 Patients with SSc have been shown to be more unsatisfied with health care than other chronically ill patients because of physical disfigurement, psychological impact, and the increased costs required for health care access.29,30 Although physicians tend to use clinical parameters to assess the impact of SSc, patients more commonly focus on metrics related to how their disease impacts daily living, such as limitations in mobility and hand function, pain, fatigue, sleep disturbance, depression, sexual dysfunction, and impact on body image.30,31 Indeed, symptoms of depression and anxiety are prevalent among patients with SSc. In a cross-sectional survey of 114 patients with SSc, 24 (21.0%) had mild mood disturbances, 25 (22.0%) had borderline clinical depression, 22 (19.3%) experienced moderate depression, 4 (3.5%) had severe depression, and 3 (2.6%) had extreme depression per Beck Depression Inventory scores. Moreover, 56 (49.1%) patients had moderate anxiety, 20 (17.5%) had severe anxiety, and 7 (6.1%) needed psychiatrist assistance to manage anxiety.32 Patients with dcSSc were more likely to develop depressive symptoms compared with patients with lcSSc. Additionally, dyspnea was significantly associated with depressive symptoms.32

Economic Impact of SSc

Although data are limited on the economic implications of SSc, the few studies available demonstrate a significant cost burden associated with the disease. In one study, the total cost burden of SSc on the US economy was estimated to be $1.5 billion.33 Direct costs were estimated to be $462 million (32%) for patients with SSc, or $4694 per person annually.33 Morbidity costs, which included work loss days, job loss, unemployed activity loss, and disability and sick leave costs, were estimated to be $819 million annually, or 56% of total costs.33 Indirect costs attributable to mortality and morbidity were estimated to be $998 million, and the value of lifetime earnings lost because of SSc-related death was $180 million.33

Recently, a large US commercial claims database was used to investigate health care resource utilization, work loss, and annual direct and indirect costs among patients with SSc. Among the 2192 patients with SSc included in the analysis, 21% had comorbid rheumatic disease other than SSc (compared with 1.6% among the healthy control group), and 14.5% had chronic pulmonary disease (compared with 5.8% of healthy controls).34 Baseline total costs were significantly higher among patients with SSc compared with matched controls ($9382 vs $3058; P < .0001).34 During 12 months of follow-up, patients with SSc had more inpatient, outpatient, and emergency department visits compared with matched controls.34 Correspondingly, direct health care costs were found to be $12,819 higher for patients with SSc compared with matched controls ($18,069 vs $5250), with significant differences in both annual direct medical costs ($13,024 vs $3268) and annual pharmacy costs ($4625 vs $1684).34 Patients with SSc had significantly higher disability costs ($1513 vs $151) and medically related absenteeism ($3362 vs $1333) than matched controls.34

Health care costs among patients with lung involvement secondary to SSc were studied in a retrospective cohort analysis of a claims database encompassing data between 2003 and 2014. Over a 5-year period, all-cause health care costs were found to be substantially higher among individuals with SSc-ILD (n = 219, $191,107 ± $322,193) or SSc-PAH (n = 108, $254,425 ± $240,497) compared with individuals with SSc and no documented lung involvement (n = 1957, $101,839 ± $167,155).35 Over the same period, patients with SSc incurred average annual costs of $18,513 to $23,268 compared with $31,285 to $55,446 in patients with SSc-ILD and $44,454 to $63,320 in patients with SSc-PAH.35 An important caveat to the study was that among patients with SSc-ILD, 25.2% received a diagnosis of PAH in the year following their ILD diagnosis; 41.8% in the PAH group were given a diagnosis of ILD within 1 year of PAH diagnosis. The latter demonstrates that pulmonary involvement in SSc can be multifactorial. For the purpose of the study, the overlap in cohorts precluded standard statistical analysis.35 Nevertheless, a higher percentage of patients in the PAH (64%) and ILD (53%) cohorts had at least 1 inpatient admission during the 5-year follow-up period compared with the SSc-only cohort (44%). Inpatient admissions were 1 of 3 factors found to drive higher 5-year health care costs among patients with lung involvement, with “other outpatient services” and “outpatient pharmacy claims” also contributing. Moreover, 5-year health care costs were highest among patients with PAH ($254,425 ± $240,497; median, $171,192), followed by patients with ILD ($191,107 ± $322,193; median $98,297), and SSc alone ($101,839 ± $167,155; median, $55,819). During this time frame, outpatient pharmacy costs for patients with SSc-PAH were approximately 4 times those of patients with SSc and double those compared with patients with SSc-ILD.35 A similar trend was noted pertaining to average annual costs over the 5-year period, with trends suggesting escalating costs in all groups from year 3 to year 5.35 SSc may also negatively impact productivity at home and at work. In one study, employed individuals (n = 60) with SSc missed 2.6 days per month of work, had an average of 2.2 days per month in which SSc affected their work, and had 2.5 days per month in which their productivity was cut in half.36 A similar impact was noted with respect to household work; patients with SSc (n = 162) reported missing a mean of 8 days of housework per month and productivity reductions of 50% or greater on 6 additional days per month.36

Current Treatment Options in SSc-ILD

Treatment of SSc-ILD has historically been with immunosuppressive agents. In 2019, however, the treatment landscape expanded with the FDA approval of the tyrosine kinase inhibitor (TKI) nintedanib. Current treatment options for SSc-ILD are reviewed in the following sections.

Immunosuppressive Agents

Immunosuppressive agents, such as mycophenolate mofetil (MMF), are frequently used in the treatment of SSc-ILD. MMF is an inhibitor of T and B lymphocyte proliferation that is often used in the treatment of manifestations of rheumatic diseases. In observational studies, MMF has been shown to possibly prevent deterioration of pulmonary function in SSc-ILD37,38 while also being well tolerated.39 In the double-blind Scleroderma Lung Study II, patients with SSc-ILD were randomized to receive MMF for 24 months or cyclophosphamide (CYC) for 12 months followed by placebo for 12 months.39 Both the MMF and CYC groups had improvements in lung function over 24 months, but there was no difference in FVC between treatment arms (P = .24).39 The improvement in percentage predicted FVC was 2.19% (95% CI, 0.53-3.84) for the MMF group and 2.88% (95% CI, 1.19-4.58) for the CYC group.39

Although total adverse events (AEs) and serious AEs were comparable between the groups, time to withdrawal from the study drug or treatment failure was significantly shorter in the CYC group (P = .019).39 There were 11 deaths in the CYC group compared with 5 in the MMF group.39 Most patients in the MMF group achieved and maintained close to the target dose, whereas the tolerated dose of CYC declined over time to approximately 75% of the target dose.39 Although MMF did not demonstrate statistical superiority to CYC, its favorable AE profile compared with CYC and the ability to use MMF long term, unlike CYC, makes MMF preferred to CYC as a treatment option for SSc-ILD.

Tyrosine Kinase Inhibitors

There is some evidence that tyrosine kinase activity may be involved in the pathogenesis of SSc. First, abnormal signaling in the transforming growth factor β (TGF-β) pathway has been implicated, particularly with respect to downstream effects on the intracellular tyrosine kinase c-Abl. Second, abnormalities in the platelet-derived growth factor (PDGF) axis via the PDGF receptor appear to be important. Thus, interest in evaluating tyrosine kinase inhibition as a therapeutic strategy in patients with SSc has been high.40

Although it must be recognized that treatment decisions are multifactorial and individualized,
clinicians would benefit from cogent, evidence-based guidance on when to initiate therapy,
what type of therapy to initiate, and when to switch to alternate approaches. Such a paradigm
would likely improve specific measures of lung function, with attendant potential to reduce
cause-specific mortality."

In 2019, nintedanib, a multitargeted TKI that has shown anti-inflammatory and anti-fibrotic effects, became the first pharmacologic agent to secure FDA approval for the treatment of SSc-ILD based on the results of the randomized, double-blind, placebo-controlled SENSCIS trial. The trial evaluated 576 patients with SSc-ILD (mean age of 54 ± 12.2 years),41 with the primary outcome being the annual rate of decline in FVC over 52 weeks. At baseline, 48.4% of patients were receiving MMF. The results showed that those who received nintedanib had a lower rate of FVC decline over 52 weeks (–52.4 mL/year) compared with those who received placebo (–93.3 mL/year) (95% CI, 2.9-79.0; P = .04).41 The rates of change in FVC over 52 weeks in patients receiving MMF at baseline were –40.2 mL and –66.5 mL per year in the nintedanib and placebo groups, respectively, compared with –63.9 mL and –119.3 mL, respectively, in patients not receiving MMF.41 The authors observed that the data potentially suggest a beneficial effect of MMF on lung function.41

The safety profile in the nintedanib group was consistent with the agent’s known safety profile. Diarrhea was the most common AE, occurring in 75.7% of patients in the nintedanib group and 31.6% in the placebo group.41 Severe AEs were reported in 18.1% and 12.5% of patients in the nintedanib and placebo groups, respectively, while serious AEs were reported in 24% and 21.5% of patients in the nintedanib and placebo groups, respectively.41 The most frequent serious AE reported in patients treated with nintedanib was pneumonia (2.8% compared with 0.3% in the placebo group).42 Additionally, investigators noted that AEs leading to permanent dose reductions were seen in 34% and 4% of patients in the nintedanib and placebo groups, respectively.42 Finally, 5 fatal AEs were reported in the nintedanib group (1.7%) compared with 4 (1.4%) in the placebo group.41

Inhibition of IL-6

Elevated serum IL-6 has been observed in patients with SSc,43 with positive correlations noted between IL-6 levels, extent of skin involvement,44 and SSc-ILD progression.7 In March 2021, the FDA approved tocilizumab subcutaneous injection for slowing the rate of decline in pulmonary function in adult patients with SSc-ILD. In the phase 2 faSScinate study, fewer patients in the tocilizumab group compared with placebo had a decline in FVC at 48 weeks.45 In the phase 3 focuSSced trial, tocilizumab did not reach its primary end point of change from baseline to week 48 in mRSS. Nevertheless, investigators noted clinically relevant differences in FVC preservation that favored the tocilizumab group.46

Experimental and Pipeline Agents

As noted above, the limited number of viable treatment options for patients with SSc-ILD has spurred research for a number of potential therapeutic targets that will, hopefully, lead to the development of novel agents.

Tyrosine kinase inhibitors. Another TKI that has been investigated in SSc-ILD is imatinib. In clinical studies, imatinib improved mRSS and at least stabilized PFT outcomes in patients with early- and late-stage diffuse SSc.40 Despite showing improvements in FVC in a phase 2 trial, AEs were common, with 171 total AEs that were considered related to imatinib.47

B-cell depletion. There is some evidence that B-cell activity plays a role in SSc-ILD pathogenesis. Findings from one study indicated that a higher CD19 percentage count in BAL fluid was associated with greater ILD progression, defined by identification of honeycombing on HRCT, eosinophils, and an inverted CD4-CD8 ratio.48 Rituximab, a chimeric monoclonal antibody against CD20, has been explored as a possible therapeutic agent for SSc-ILD.49-52 In a 20-patient, prospective, open-label observational study, rituximab treatment increased FVC and total lung capacity at 12 months compared with baseline in patients with dcSSc.50 More recently, rituximab was compared with CYC for the potential to halt the progression of ILD and skin manifestations in 60 patients with SSc in an open-label, randomized, controlled trial. Predicted FVC in the rituximab group significantly improved from 61.3% to 67.5% over 6 months, while the predicted FVC in the CYC group declined from 59.3% to 58.0%.53 Patients in the rituximab group had improvement in mRSS from 21.77 to 12.10 (P < .001) over 6 months, while those in the CYC group had improvement from 23.83 to
18.33 during that period (P < .001).53

In the UK-based RECITAL trial, patients with SSc-ILD, idiopathic inflammatory myositis, or mixed connective tissue disease are being randomized to either rituximab or CYC. In this ongoing trial, the primary end point is change in FVC at week 24, while secondary outcomes include FVC analyses at 48 weeks and safety, among others.54

Another monoclonal antibody with B-cell activity that has been investigated for the treatment of SSc is belimumab. In a randomized, double-blind trial, investigators evaluated 20 patients with dcSSc who started MMF therapy and were randomized to receive belimumab or placebo.55 The median mRSS decreased from 27 to 18 in the belimumab group, while in the placebo group, the median mRSS decreased from 27 to 21.55 Only 10% of patients in the belimumab group and 20% of patients in the placebo group had SSc-ILD,55 but the results, nonetheless, warrant future consideration.

Antifibrotic therapy. The antifibrotic agent pirfenidone is believed to have multiple mechanisms of action that may be relevant in SSc-ILD. The pyridine compound exhibits antifibrotic activity against TGF-β in animal models of idiopathic pulmonary fibrosis.56 It also has demonstrated inhibitory activity against various inflammatory mediators, including IL-1β, IL-6, tumor necrosis factor α, monocyte chemoattractant protein-1, and PDGF.56,57 In the phase 2 LOTUSS trial evaluating 63 patients with SSc-ILD receiving pirfenidone, investigators randomized patients to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day.58 Results showed no clinically relevant lung function differences (FVC or DLCO) between groups.58 FVC change from baseline to week 16 was –0.6% in both the 2- and 4-week titration groups and –0.3% in the pirfenidone 2403-mg/day group, while DLCO change from baseline to week 16 was 0.7% in the 2-week titration group, 3.2% in the 4-week titration group, and –0.2% in the pirfenidone 2403-mg/day group.58 Of note, 96.8% of patients experienced at least 1 treatment-emergent AE.58

Pirfenidone is being investigated in combination with MMF in the ongoing Scleroderma Lung Study III (NCT03221257), which is expected to be completed in March 2022.59 In this trial, patients are randomized to receive either MMF and placebo or a combination of MMF and pirfenidone for 18 months.59

Hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation (HSCT) has been studied as a potential treatment option for selected patients with progressive dcSSc with a poor prognosis. In the phase 3 Autologous Stem Cell Transplantation International Scleroderma trial, investigators evaluated the safety and efficacy of HSCT vs 12 successive monthly intravenous pulses of CYC among patients with early diffuse SSc, with a primary end point of event-free survival. Median follow-up was 5.8 years, with 19 deaths and 3 irreversible organ failures reported in the HSCT group and 31 events reported in the control group, including 23 deaths and 8 irreversible organ failures. Notably, during the first year, event and mortality rates were higher in the HSCT group (13 events and 8 deaths) than in the control group (8 events, no deaths).60

In the randomized phase 2 Scleroderma: Cyclophosphamide or Transplantation trial, investigators randomized patients to receive myeloablative CD34+ selected autologous HSCT or 12 monthly infusions of CYC.61 The primary end point was a global rank composite score based on death, event-free survival, FVC, mRSS, and Health Assessment Questionnaire-Disability Index, assessed at 54 months.61 In the intention-to-treat population, transplantation was favored over CYC (67% vs 33%, respectively).61 In the transplantation group, 7 patients died; 2 of the deaths were treatment related.61 Fourteen patients in the CYC group died, 7 of whom had already had an event of respiratory, renal, or cardiac failure.61

Lung transplantation. Lung transplantation is often considered a last resort, with an explicit acknowledgment of a patient’s limited life expectancy without the procedure.62 According to a consensus statement from the International Society for Heart and Lung Transplantation, although SSc is often viewed as a contraindication to lung transplantation because of concerns of esophageal dysmotility and gastroparesis—potentially increasing the risk of aspiration—carefully selected patients benefit from the procedure.62 Adult patients undergoing lung transplantation for SSc-ILD or SSc-PAH are at a significantly increased risk for death in the first year following lung transplantation compared with those undergoing transplant for non–SSc-ILD. However, a diagnosis of SSc confers no greater risk of death in the first year following lung transplant compared with those with a diagnosis of non–SSc-PAH.63

Treatment Considerations and Implications

A lack of codified treatment guidelines for patients with SSc-ILD64 creates significant challenges in improving outcomes at the patient level and, more generally, in reducing burden to the health care system. Although it must be recognized that treatment decisions are multifactorial and individualized, clinicians would benefit from cogent, evidence-based guidance on when to initiate therapy, what type of therapy to initiate, and when to switch to alternate approaches. Such a paradigm would likely improve lung function, with attendant potential to reduce cause-specific mortality.

Immunosuppressive agents represent a prevailing treatment approach for patients with newly diagnosed SSc-ILD, but antifibrotic approaches will likely play an important role as the treatment spectrum evolves. The FDA approval of nintedanib may reshape the treatment paradigm, providing physicians with more therapeutic options and new considerations toward treatment selection. To that end, evolving understandings regarding the mechanisms leading to SSc-ILD and drivers of disease progression, such as inflammation and fibrosis, as well as the overall systemic involvement, have identified therapeutic targets and will likely guide approaches to therapy.65 There is no evidence from randomized clinical trials that any treatment approach is capable of reversing architectural changes due to SSc-ILD or significantly improving lung function after disease progression. It is likely that both immunosuppressive and antifibrotic approaches will need to be utilized to reduce lung volume loss in patients.

A lack of guidelines translates to inconsistent use of HRCT,16 which is the current gold standard for detecting fibrosis and assessing its severity. Better biomarkers for disease progression, particularly with respect to when to employ HRCT, would be welcomed. Consideration should be given to the cost and potential AEs of radiation exposure already in patients with an increased risk for cancer.

Early detection, followed by timely initiation of treatment, remains the best approach for minimizing serious and potentially life-threatening pulmonary complications associated with SSc. Pulmonary function testing, which is widely used to screen for pulmonary complications in patients with SSc, is neither specific nor sensitive for ILD.17,18 However, in one survey, only 51% of rheumatologists said they routinely ordered HRCT in all patients with newly diagnosed SSc, and 66% of those who specialize in treating SSc reported the same.16 Furthermore, there was widespread discrepancy in indications used for ordering HRCT.16 From a clinical perspective, guidance or recommendations regarding specific screening methodologies in patients with new diagnoses would provide better direction for care.

In 2020, a European consensus statement for the identification and management of SSc-ILD was issued.15 The consensus suggested that all patients with SSc-ILD should be screened with HRCT, while PFTs offer supporting evidence.15 The consensus also suggests that the severity of SSc-ILD should be measured with more than 1 indicator.15 Regarding treatment, the authors noted some patients do not require pharmacological treatment but that severe cases should be treated.15

Regarding future treatment directions, important considerations remain. The findings from the SENSCIS trial suggest that nintedanib reduced FVC decline in patients with SSc-ILD.41 Given that 48.4% of patients were receiving MMF at baseline,41 the potential role of nintedanib in a frontline setting could be further explored. Nevertheless, because the patient population included those with and without stable background immunosuppression,41 the results suggest that nintedanib may have broad utility in both groups of patients with SSc-ILD.Ongoing long-term studies should further elucidate the role of nintedanib in the treatment paradigm.41

In the European consensus statement for the identification and management of patients with SSc-ILD, the authors noted that both nintedanib monotherapy and combination therapy utilizing nintedanib and MMF represent effective options at treatment initiation. The role of nintedanib also extends to treatment escalation, according to the expert consensus panel, if MMF or CYC is not a suitable option. Combination therapy utilizing nintedanib and MMF is also a treatment option for patients if MMF or CYC or nintedanib alone is not appropriate.15

As the treatment landscape continues to evolve, it is likely that to reduce lung volume loss in
patients, a combination of immunosuppressive and antifibrotic approaches will need to be
used. Additionally, a greater emphasis on risk stratification strategies may allow for more efficient follow-up, monitoring, and assessment of treatment response."

The recommendations of the European consensus statement were echoed by other recently published treatment recommendations, including one article reviewing the management of SSc within the first 5 years of diagnosis, in which authors suggested that patients with progressive disease who do not tolerate MMF may be treated with nintedanib.66 Authors of another article published in 2020 observed that nintedanib represents an appropriate treatment approach for patients with a predominantly fibrotic pattern on chest CT, whereas MMF or CYC may be most effective for patients with a more inflammatory phenotype.65

Conclusions and Future Directions

The discussion presented herein is intended to paint a realistic picture of the challenges faced by physicians and their patients in the management of SSc-ILD. It should not be forgotten that SSc is unique among systemic autoimmune rheumatic diseases for its devastating clinical course and confers a high risk of mortality.19 Additionally, treatment of SSc is associated with significant economic impact.33-35 On a clinical and psychological level, SSc can have devastating consequences for patients’ QOL,31 leading to depression and anxiety32 and decline in work activity.36 Taken together, the data presented in this article underscore the urgent need to address the significant remaining unmet needs in caring for patients with SSc-ILD.

Developing effective treatments that have better safety profiles is a good start, but there is still work to be done. As the treatment landscape continues to evolve, it is likely that to reduce lung volume loss in patients, a combination of immunosuppressive and antifibrotic approaches will need to be used. A greater emphasis on risk-stratification strategies may allow for more efficient follow-up, monitoring, and assessment of treatment response.66

Approximately 80% of patients with SSc develop lung involvement (including ILD and PAH) with heterogeneity in the disease course. ILD and PAH are the most common causes of mortality in patients with SSc. Complications and comorbidities can increase the cost of health care immensely. Developing and utilizing drugs that have synergistic effects and improve outcomes is essential to reduce the disease burden, both at the individual level and with respect to health care utilization and impact on the health care system in general. The limited number of effective treatments is a significant unmet need for patients with SSc, which places a burden on the health care system, given the high rate of hospitalizations among these patients and the devastating clinical course that persists in the context of currently available treatment strategies. Finally, education regarding the effects of ILD in SSc is needed across the health care spectrum so that approaches to management and development of successful interventions may evolve.

Author affiliations: Columbia University Irving Medical Center, New York, NY (EJB); Medical University of South Carolina, Charleston, SC (JTH); Johns Hopkins University, Baltimore, MD (LKH); Gary Owens Associates, Glen Mills, PA (GMO).

Author disclosures: Dr Bernstein has participated in advisory boards and received research grants from Boehringer Ingelheim. Dr Huggins served as a site primary investigator for the SENSCIS trial, funded by Boehringer Ingelheim. Dr Hummers has participated in advisory boards and has received research funds from Boehringer Ingelheim, and her institution is a potential site for an upcoming trial for Boehringer Ingelheim. Dr Owens reports no relationships or financial interests with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship information: Concept and design (EJB, JTH, LKH, GMO), drafting of the manuscript (LKH, GO), analysis and interpretation of data (EJB, JTH), critical revision of the manuscript for important intellectual content (EJB, JTH, LKH, GMO), supervision (GMO).

Address correspondence to: Laura K. Hummers, MD, ScM. Email: lhummers@jhmi.edu.

Acknowledgments: This supplement was supported by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and/or formatting assistance was provided by MJH Life Sciences™, which was contracted and funded by BIPI. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

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