Treatment for Systemic Sclerosis-Associated Interstitial Lung Disease

Abstract

Purpose of review:

This review provides an overview of the current treatments for systemic sclerosis-interstitial lung disease (SSc-ILD) and proposes a conceptual framework for disease management with case scenarios.

Recent findings:

Broad treatment categories include traditional cytotoxic therapies, biologic disease modifying rheumatic drugs, anti-fibrotic agents, autologous hematopoietic stem cell transplant, and lung transplantation. The optimal use of each option varies depending on SSc-ILD severity, progression, and comorbidities of individual patients. A high quality randomized controlled trial demonstrated nintedanib’s ability to retard decline of lung function in patients with limited and diffuse cutaneous disease, with established ILD. Tocilizumab, recently approved by the FDA, provides a unique intervention in those with early SSc associated with ILD with elevated acute-phase reactants: two well-designed trials showed lung function preservation in Phase II and Phase III trials.

Summary:

Stratifying patients based on key SSc-ILD characteristics (e.g., severity, risk of progression, co-morbid disease presentation) may provide a useful guide for practitioners treating SSc-ILD.

Systemic Sclerosis-Associated Interstitial Lung Disease

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a common disease feature^1,2 and among the most common causes of death in patients with systemic sclerosis^3–7. It is the consequence of an autoimmune-mediated inflammatory and fibrotic nexus, leading to pulmonary fibrosis⁸. Traditional SSc-ILD therapies include cytotoxic medications typically initiated in those with clinically impactful disease, aiming to attenuate disease severity or retard disease progression^9–11. These therapies, to date, have demonstrated modest benefit¹². The advent of rationally repurposed anti-fibrotic medication and biologic therapies offer a cache of treatments often without the limiting side effects associated with traditional cytotoxic agents^13–15. Hematopoietic autologous stem cell transplantation and lung transplantation remain options for a select population of the most severe and treatment-refractory cases^16,17.

Treatment Options

Disease modifying anti-rheumatic drugs

Treatment with immunomodulatory agents like cyclophosphamide (CYC) and mycophenolate mofetil (MMF) have proven benefit in key studies in SSc-ILD: Fibrosing Alveolitis in Scleroderma Trial (FAST), Scleroderma-Lung studies I, and II (SLS-I and SLS-II)^18–20. The paucity of sustained benefit after CYC was discontinued in the SLS-I study provided an impetus to identify a less toxic, long-term strategy to stave off disease progression²¹. The SLS-II trial provided clinicians an equally efficacious treatment for SSc-ILD with MMF, in the absence of significant toxicity or long-term fertility concerns associated with CYC. Historically, these treatments have been reserved for patients with clinical or progressive ILD²²; patients treated with these agents typically exhibited a significant burden of disease and were treated with a goal to stabilize lung decline/attenuate disease progression.

Biologic disease modifying anti-rheumatic drugs

Rituximab (RTX) is a chimeric monoclonal antibody targeting the B cell associated marker CD20 approved for the treatment of adult patients with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis among other indications²³. RTX therapy has an increasingly substantive body of evidence to support its use for SSc-ILD^24,25. An open-label, randomized, controlled trial with head-to-head comparison of RTX vs. monthly pulse IV CYC in a population of 60 early, treatment-naive, anti-SCL-70+, dcSSc-ILD patients examined the benefit of RTX on FVC% predicted as its primary endpoint. The average baseline FVC% in the RTX arm was 61.3 (±11.28), placebo arm 59.5 (±12.96). Patients in the CYC group received 500mg/m² IV pulses every 4 weeks for 24 weeks; patients in the RTX group received two pulses of 1000mg at 0 and 15 days. At the end of 6 months, the RTX arm had improved FVC% (improved, 61.3–67.5%) while the CYC arm did not (59.3–58.1%), p=0.002²⁴. A meta-analysis of RTX’s treatment effects (a total of 597 participants) on cutaneous (including 13 studies) and pulmonary (including 12 studies) outcomes showed long-term improvement in mRSS and stabilization of the FVC and Dlco²⁵. A different meta-analysis of RTX’s treatment effects (a total of 575 participants) focusing specifically on RTX’s pulmonary (identifying 20 studies) found RTX was not just associated with stabilization, but rather a significant improvement in FVC and DLCO during the first year of treatment²⁶. A recent prospective cohort study did not confirm RTX’s pulmonary effect; a well-designed randomized controlled trial is needed to properly explore the effects of RTX on lung involvement in SSc²⁷.

Tocilizumab (TCZ) is an anti-IL6 receptor monoclonal antibody, approved for the treatment of adult patients with rheumatoid arthritis, giant cell arteritis, and juvenile idiopathic arthritis, among other indications [37]. Two large double-blind randomized control trials ((faSScinate study, NCT01532869) and (focuSSced study, NCT02453256)) examining TCZ failed to meet their primary endpoints, a reduction in the modified Rodnan skin score (mRSS). Importantly, both met the key secondary endpoint on FVC% to support TCZ’s use in patients with early SSc-ILD^28,29. The faSScinate trial (n=87) was a phase II trial in early (within 5 years from onset of the first non-Raynaud’s Phenomenon), diffuse cutaneous, skin-fibrosis progressive SSc patients with a primary endpoint focused on mRSS change²⁸. The average baseline FVC (% predicted) in the TCZ arm was 80 (±14), placebo arm 82 (±13). While the primary endpoint was not met, there was evidence of benefit in the study drug arm in secondary analyses showing fewer patients had a decline in FVC% predicted at 48 weeks compared to the placebo arm: TCZ reduced FVC% decline at 48 weeks: −2.6% (−5.2 to −0.1), compared to −6.3% (−8.9 to −3.8) in the placebo arm. The focuSSced phase III trial (n=210) targeted a similar population of early diffuse cutaneous patients with mild baseline FVC% predicted deficits and clinical and biological signs of active inflammatory disease. No concomitant immunosuppressant was allowed at baseline and previous immunomodulating therapies had to be discontinued with an appropriate washout period. The average baseline FVC% predicted in the TCZ arm was 80 (±14), placebo arm 84 (±15). Secondary analyses showed preservation of lung function in the treatment arm compared to the significant worsening seen in the placebo arm: −0.6% (−2.4 to 0.9) in the TCZ arm, compared to −3.9% (−4.8 to −1.6) in the placebo arm. Among the intention-to-treat population and those with SSc-ILD (as determined by a thoracic radiologist’s visual read), the TCZ arm demonstrated preserved FVC over 48 weeks, whereas the placebo arm demonstrated a decline: the least squared means (LSM) of FVC change was −0.1% for TCZ, and −6.3% for placebo. The difference between treatment group was 6.2% (P<0.0001). This preservation was seen in those patients ranging from mild to severe extent of lung involvement (quantitative ILD, or QILD) and lung fibrosis (quantitative lung fibrosis, or QLF). Importantly, TCZ demonstrated its benefit using quantitative HRCT: at 48 weeks, the overall QILD for the TCZ arm showed a statistically significant improvement (mean change (95% CI) −1.8 (−3.5, −0.2), p=0.02). In terms of fibrosis, there was a statistically significant increase in QLF scores at 48 weeks in the PBO arm (0.7 (0.3, 1.1), p<0.01) that was not seen in the TCZ arm (−0.5 (−1.1, 0.2), p=0.12)³⁰.

RTX and TCZ present important additions to cytotoxic therapy options for SSc-ILD. The TCZ was recently approved by the FDA for management for SSc-ILD and the data represent an important option to initiate therapy in early ILD and prevent decline of lung function before it happens, rather than waiting until patients show clinical symptoms and a functional decline to initiate cytotoxic therapy.

Anti-fibrotics

Nintedanib (NIN) is a tyrosine kinase inhibitor approved for use in idiopathic pulmonary fibrosis (IPF) by the US Food and Drug Administration in 2014, and the European Medicines Agency in 2015³¹. This medication stops intracellular signalling by competitively binding to ATP–binding pockets of receptors (PDGF receptor alpha and beta, FGF receptor 1–3, and VEGF receptor 1–3). It prevents the release of growth factors that would lead to fibrotic consequences, with demonstration of benefit in vitro and in vivo ^32,33 NIN became the first FDA medication approved for SSc-ILD in 2019. The Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial was a 52-week randomized double-blind, placebo-controlled trial of patients with SSC–ILD, with a minimum of 10% of lung involvement as determined by HRCT³⁴. The NIN arm was 150 mg twice daily (N = 288) compared to a placebo arm (N = 288), in a population of patients with an average baseline FVC% predicted in the nintedanib arm of 72.4 (±16.8), and placebo arm 72.7 (±16.6). At 52-week follow-up, NIN demonstrated a statistically significant reduction in the annual rate of decline of FVC in the treatment arm (−52.4mL (−1.4%), compared to −93.3mL (−2.6%) in the placebo arm). The adjusted mean annual rate of decline in FVC% predicted was −1.4% (±0.4) in the NIN arm and −2.6% (±0.4) in the placebo arm (difference 1.2; 95% CI, 0.1–2.2). There was no effect of NIN on skin score and respiratory and other patient-reported outcomes³⁴.

The safety and tolerability of the anti-fibrotic medication pirfenidone (PFD) were assessed in a multinational, open-label, randomized, parallel-group, 16-week phase 2 study in patients with SSc-ILD (the LOTUSS trial)³⁵. All patients received PFD and were randomized 1:1 to either a 2- or 4-week titration period. No safety or tolerability signal was detected in this pilot study, notably in patients with concomitant use of MMF (63.5% of the population). Scleroderma Lung Study-III (SLS-III) (clinicaltrials.gov: NCT03221257) is thus examining the combination of MMF and PFD in SSc-ILD. It will examine efficacy with the primary endpoint of change in FVC% predicted over 18 months; secondary endpoints include change in DLco% predicted, mRSS, the extent of fibrosis and total ILD on HRCT, and patient-reported outcomes³⁶.

Hematopoietic autologous stem cell transplantation

In the last decade, three key trials have examined the use of autologous hematopoietic stem cell transplantation (ASCT) for treatment of SSc-ILD: Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial (ASSIST), Autologous Stem Cell Transplantation International Scleroderma (ASTIS), and Scleroderma Cyclophosphamide or Transplantation (SCOT) studies^37–39. These interventions are the only treatments listed here with demonstrated survival benefit, although the modest benefits noted in the other trials may be framed in the context of a limited window of observation (1 year), as compared to the transplant trials (several years). In the ASTIS trial, despite early treatment-related mortality (10.1%) and an increase in serious adverse events, the transplant arm demonstrated a long-term survival benefit at year 1, year 2, and year 4. In the SCOT trial, survival at 54 months post-treatment showed 91% of transplant patients were alive, compared to 77% of the comparator arm of monthly CYC.

The SCOT trial was a multi-center, randomized phase III trial including 75 patients with early dcSSc; 100% of patients in the HSCT group had ILD. HSCT patients (n=36) were conditioned with CYC (120mg/kg), anti-thymocyte globulin, received total body irradiation (800 cGy) and received a stem cell transplant (CD34þ selected); the comparator arm received CYC (750mg/m²) x12 months (n=39). At baseline, the two groups had similar FVC% predicted averages: 74.5% (±14.8) in the ASCT arm compared with 73.8 (±17) in the CYC arm. More patients receiving ASCT improved in FVC than those in the CYC group at 54 months: 36% of the ASCT patients improved (relative increase of FVC by ≥10%) compared to 23% of the CYC patients. Conversely, fewer patients in the ASCT group worsened (relative decrease by ≥10%) compared to the CYC group (17% vs. 41%, respectively)³⁹. The percentage of patients who had an adverse event of grade 3 or more was higher in the ASCT group than in the CYC group suggesting that careful patient selection and monitoring is needed for ASCT.

Lung transplantation

Analysis of survival or chronic lung allograft dysfunction (CLAD) in carefully selected patients with SSc-ILD highlights that SSc-patients undergoing lung transplantation (LT) have short-term and long-term mortality comparable to other ILD-groups (predominantly including patients with IPF) as well as similar freedom from CLAD duration^17,40,41. These data suggest that LT may be considered for specific SSc-ILD patients with non-severe extra-pulmonary disease but severe clinical SSc-ILD refractory to first-line therapy, although controlled studies are still lacking.

Framework for Treatment

In our practice, treatment algorithms are based on data from clinical trials and expert opinion¹². We recommend stratifying treatment based on disease severity (subclinical vs. clinical ILD) and tailoring therapy in the context of a patient’s risk of developing progressive SSc-ILD and the severity/extent of extra pulmonary disease (e.g., lung predominant vs. multi-organ involvement). Figure 1 outlines a recommended treatment strategy based on this approach. The overall strategy aims to identify patients as early as possible in the course of SSc-ILD, prevent symptomatic disease when possible, and retard progression if already present.

Figure 1:

Treatment algorithm for SSc-ILD based on evidence-based recommendations and expert opinion/unpublished clinical experiences.

Figure 1 is modified from the EULAR Online Course on Systemic Sclerosis, In depth discussion Module 9 (Management of SSc-ILD), updated 2020.

*: In those with early SSc with progressive skin and elevated acute phase reactants

No standardized definitions of clinical ILD exist at this time. It may be conceptualized as a disease state that affects how a patient feels, functions, or survives, in the setting of mild-to-severe extent of ILD on HRCT. These patients have symptomatic SSc-ILD (e.g., cough or dyspnea attributed to the ILD) or impact on day-to-day functioning, although significant arthritis and other disease features may preclude exertion, making this a challenging disease feature to reliably identify. These patients may show impairment on spirometry and DLco (below the lower limit of normal, and/or a clinically meaningful decline in FVC% or DLco%), and may show desaturation during cardiopulmonary exercise testing⁴². Subclinical ILD may be characterized by minimal-to-mild extent of ILD on HRCT in the setting of absent SSc-ILD symptoms or impact on day-to-day functioning, FVC% and DLco% above the lower limit of normal, and without clinically meaningful declines within the previous 12 months⁴³. There are several risk factors for developing SSc-ILD including demographics (African-American ethnicity, older age at disease onset, male gender) and disease-specific features (short disease duration, presence of anti-SCL 70 antibody or RNA polymerase III and/or absence of anti-centromere antibody)^44–47. Elevated C-reactive protein (CRP) represents an important serological marker associated with progressive ILD and has been demonstrated in dcSSc to be predictive of severe disease worsening (including new onset internal organ involvement and death)^48,49. The Goh staging algorithm⁵⁰ provides a prognostic risk stratification by combining pulmonary function testing and extent of ILD on HRCT. Progressive ILD is a worsening in terms of disease severity, identified by an expanding extent of fibrosis on HRCT and deficits in FVC and DLco. An advancing HRCT extent (>20% involvement on HRCT (fibrosis/ground-glass opacifications on transverse cuts)) and impaired pulmonary function testing (%FVC < 70%), or those with significant declines in the preceding 12-months FVC (% >10% or FVC >5% to <10% with >15% decline in DLco) have demonstrated correlates with morbidity and mortality ^50–52.

All patients with SSc during their initial visit should receive an HRCT, even in the absence of respiratory symptoms⁵³. Preclinical interstitial abnormalities present in this high-risk population⁵⁴ allows for risk stratification in Figure 1. For those meeting the above definition of subclinical ILD with low risk of progression (e.g., mild extent of disease on HRCT, no elevation in CRP, anti-centromere antibody positivity), we recommend frequent monitoring of respiratory symptoms, with routine PFTs every 4–6 months and serial 6-minute walk distance (6MWD) assessments for the first 3–5 years following their first non-Raynaud’s Phenomenon¹. Deficits on PFTs should be interpreted in the context of symptoms and concomitant electrocardiogram and echocardiography, as well as alternative causes for restrictive lung disease (such as inflammatory myopathy) and declining Dlco (such as pulmonary SSc-associated vasculopathy). A repeat HRCT should be performed if the PFT deficits and advancing respiratory symptoms are suspected to be due to advancing parenchymal lung disease⁴³.

Patients with early and subclinical ILD with other risk factors (e.g., dcSSc, elevated CRP, or anti-SCL-70 positivity) should be considered for immunomodulatory treatment. TCZ is supported by data from two RCTs and is now FDA-approved. Currently, we utilize MMF in this scenario but TCZ is now available for this indication. Patients with early clinical SSc-ILD with risk factors above should also be offered TCZ. Those with clinical ILD who are absent active skin or musculoskeletal symptoms (a small subset in clinical centers) can be considered for nintedanib monotherapy. Gastrointestinal upset is a common side effect and may lead to discontinuation of treatment³². In our practice, we typically offer induction therapy with CYC or MMF, with preference for MMF given its favourable side effect profile relative to CYC, and the ability to transition to mycophenolic acid for those unable to tolerate GI side effects. About half of patients in the SENSCIS trial were on background MMF; these patients tend to benefit from combination therapy with a decreased decline in FVC (−40.2mL/year) compared to those on NIN monotherapy (−63.9mL/year). Nonetheless, at present, there are insufficient data to discern if upfront combination therapy (MMF+NIN) is more efficacious than monotherapy.

For patients with clinical SSc-ILD and active skin or musculoskeletal disease, we prescribe CYC, MMF, RTX, or TCZ with preference given to MMF because of its demonstrated benefit for SSc-ILD, skin, and favorable side effect profile^20,55. TCZ, with recent approval may be an appropriate indication for this. If MMF is unavailable or cannot be tolerated, CYC provides an option with well-established efficacy, based on data from two well-designed clinical trials. The use of IV CYC compared to oral CYC has not demonstrated that one route is superior; IV CYC is associated with a favorable side effect profile and decreased long-term side effects (e.g., ovarian dysfunction, risk of malignancy) with a lower total cumulative dose⁵⁶. When implemented, we recommend IV CYC use consistent with the SCOT trial (IV CYC 750mg/m² monthly) typically for 6 months, followed by transition to MMF therapy, assuming normal renal and hepatic function. Considerations for fertility and hormone-preservation in pre-menopausal women, concomitant liver or renal insufficiency, and inflammatory arthritis may favor use of RTX or TCZ over MMF and CYC as initial therapy. Concerns for medical non-adherence with oral medication may make IV CYC or RTX an attractive option.

Refractory and progressive SSc-ILD represents a considerable challenge in management. Evidence-based decisions regarding management of treatment-refractory patients are limited and recommendations are based on expert opinion. For those patients who have failed MMF, we often consider therapy with CYC⁵⁷ or RTX⁵⁸. A recently published case series identified 24 SSc-ILD patients with progressive disease despite MMF treatment (relative decline of ≥10% in the FVC% or ≥15% in the DLco%, or a relative decline FVC% of 5–10% or DLco% decline of <15% alongside worsening of respiratory symptoms and increased fibrosis on HRCT). After 1 year of treatment with RTX (1000mg/dose, divided by 14 days, administered every 6 months), there was a significant improvement in FVC% (+8.8%, 95% CI: −13.7 to −3.9; p=0.001) and DLco% (+4.6%, 95%CI: −8.2 to −0.8; p=0.018)⁵⁸. The results of this retrospective observational study needs to be evaluated in a randomized, placebo-controlled trial before a stronger recommendation may be made for its use. For those with severe, refractory multi-systemic disease with sufficient renal and cardiac reserve to tolerate transplantation, ASCT should be considered. Although once thought to be a contraindication for lung transplant due to extra pulmonary comorbidities, several studies have demonstrated post-transplant survival rates in SSc similar to other indications for transplant^40,41. Enrollment of SSc-ILD participants in clinical treatment trials may provide an option for investigational use of medications not yet approved by the FDA, for appropriate patients.

Case Scenarios

Case Scenario 1: Subclinical SSc-ILD with High Risk for Progressive Disease

50-year-old male presents with a new diagnosis of dcSSc. His symptoms of puffy hands started 2 years ago. He does not report dyspnea at rest or with exertion. The physical exam shows an mRSS of 18/51. Bloodwork shows a positive anti-SCL-70 antibody; CRP is elevated at 1.4 mg/dL (ULN <0.6 mg/dl). Spirometry shows a normal total lung capacity, a FVC% of 88% and a DLco of 80%; HRCT shows mild ILD (visual read estimates 5% whole lung involvement).

This patient may be classified as subclinical SSc-ILD given the absence of respiratory symptoms, mild extent of involvement on HRCT, and normal FVC% and DLco% (Figure 1). He is considered high risk for progression given his dcSSC status, anti-SCL-70 antibody positivity, and elevated CRP. A potential misstep is the failure to recognize the risk of advancing lung disease in this SSc-ILD subset. Disease monitoring alone would be inappropriate given his high risk for progression. Taking into account the cutaneous disease and the risk for irreversible lung function loss, at this time the data support the initiation of TCZ to prevent decline of FVC% (with a strength of recommendation coming from at least one randomized controlled trial and level of evidence based on two RCTs with positive secondary or exploratory endpoint and large effect size)^29,59. Other immunomodulatory therapies may also be an option, including consideration for MMF or ASCT; at this time, those treatments would not be indicated based on lack of available clinical trial data.

Case Scenario 2: Clinical SSc-ILD

28-year-old female presents with lcSSc and an onset of sclerodactyly 3 years ago. Over the last 6 months, she has developed shortness of breath with moderate exertion. Her physical exam shows crackles at bilateral bases independent of positioning and an mRSS of 5/51. There is no JVP increase, prominent P2 on auscultation, or lower extremity swelling/edema; there are telangiectasias about the face and hands. She is anti-centromere antibody positive; NT-proBNP is normal, as is uric acid. She has restrictive lung disease with a total lung capacity of 70%, FVC% of 66%, and DLCO% of 55%. Her HRCT shows interstitial markings that persist on prone imaging and is read as NSIP pneumonitis.

This patient has clinical ILD based on dyspnea on exertion that may be attributed to symptomatic ILD, restrictive lung disease, and lung fibrosis. Monitoring with no pharmacotherapy is inappropriate given the burden of her disease and the opportunity to attenuate progression of lung decline. Patients with clinical ILD should be initiated on an immunomodulatory agent, anti-fibrotic, or both. Mycophenolate mofetil at 3 grams/day in divided dosing (1,500mg every 12 hours) is a reasonable choice based on the SLS-II data, noting the need for routine lab monitoring and reliable contraception given the risk for teratogenicity with this medication. Nintedanib is another reasonable choice for this patient based on the SENSCIS trial findings in patients with SSc-ILD, at 150mg every 12 hours, also confirming reliable contraception as this medication can cause risk to the fetus if she were to become pregnant. The determination of which agent is initiated may depend on institutional experience and preference, side effect profiles and patient tolerability, and insurance coverage/cost: our preference is to use MMF as the initial agent to target the underlying immune dysfunction. Combination therapy (immunosuppression with MMF and anti-fibrotic therapy with NIN) is supported by data in terms of safety, but there are insufficient data to know if initial combination therapy or step-up therapy should be implemented for routine practice in treating SSc-ILD⁶⁰. In this treatment-naïve patient, lung transplantation would not be the first step in her management.

Case Scenario 3: Rapidly Progressive SSc-ILD

50-year-old female is diagnosed with NSIP pattern SSc-ILD: she has rapidly progressive dcSSc, no scleroderma-specific autoantibodies, and an estimated onset of disease within the last 2 years. Exam shows an mRSS escalation from 12 to 31 in that time period. Renal and cardiac function is unimpaired; she was noted to have elevated platelet levels developing over the last 2 years. Serial spirometry with DLco shows a decline in FVC% by 15% and DLco of 20% over a year despite MMF 3g/day with excellent adherence for the last year. HRCT provides an estimate of 25% whole lung involvement.

This patient clearly has progressive SSc-ILD, alongside progressive cutaneous disease. ASCT is currently the only disease modifying strategy that has demonstrated evidence for improving long-term survival¹⁶. This is reserved for those with early rapidly progressive dcSSc who have yet to progress to severe internal organ involvement, but have a poor prognosis for survival despite adequate therapy. Benefits of treatment in this population also include improved skin scores, FVC, extent of fibrosis on HRCT, and physical and mental health-related quality of life^38,39,61. Other considerations for her include switching therapy to CYC or RTX, or adding in RTX to MMF¹². Tocilizumab may be appropriate for this patient given recently published data showing TCZ stabilizes FVC and attenuates progression of the extent of lung involvement over 48 weeks³⁰. Her clinical scenario is similar to a section of the focuSSced population with early dcSSc, progressive skin disease, elevated acute phase reactants (including elevated CRP and platelet levels), and clinically-significant SSc-ILD: about 1/3^rd of participants in this trial had a severe extent of lung involvement on HRCT (≥20%) and deficits on FVC³⁰. Importantly, the medication was shown to be effective in preserving lung function across a broad extent of lung involvement on HRCT (≥5% to >20%). Tocilizumab’s use in treatment-refractory cases or in addition to mycophenolate mofetil has not been studied. An option like nintedanib may benefit lung disease, but will have no effect on skin progression. There are no data to support adding corticosteroid treatment for fibrotic NSIP, the predominant disease type of SSc-ILD. Escalation therapy may include a clinical trial, but not prior to considering other, established therapies.

Case Scenario 4: Alternative Considerations for Advancing Dyspnea in SSc-ILD

60-year-old female was diagnosed with dcSSc 15 years ago; she has no scleroderma-specific antibodies and NSIP pattern SSc-ILD. She had routine spirometry with DLco for the first 10 years, showing FVC% ranging from 72–77%, and DLco% ranging from 68–78%, with testing every 6 months. Previous treatment included oral CYC for the first year of disease. She was lost to follow-up for the last 5 years and presents to your office on no immunomodulatory therapy. In the last 6 months, she reports advancing dyspnea with mild exertion and a persistent dry cough. Her exam shows telangiectasias on her face and hands; her mRSS is 5/51. EKG shows the presence of right axis deviation and echocardiogram shows a right ventricular systolic pressure of 45mmHg. Serum urate and NT-proBNP are elevated above the upper limit of normal. Repeat testing shows FVC% declining to 60%, DLco declining to 35%.

This case highlights the need to identify the several potential causes of FVC% and DLco% decline, which may coincide with the presence of SSc-ILD. Progressive shortness of breath may not be due directly to advancing SSc-ILD and failure to identify alternative causes of dyspnea may lead to incomplete or inappropriate management. Measurement inaccuracy should always be considered and ruled out with repeat testing, especially if the spirometry and gas exchange decline do not coincide with reports of development or progression of dyspnea. A repeat set of pulmonary testing should be conducted making sure accuracy and reliability meet the American Thoracic Society standards⁶² and corroborated with ancillary testing like the 6MWD. Late-onset progressive ILD is possible, but not the most likely cause of her progressive dyspnea with spirometry and gas exchange decline. SSc-ILD will typically show progression in the first 3–5 years from the onset of the first non-Raynaud’s Phenomenon; in this patient’s case, she is 15 years from the onset of her disease. Aspiration pneumonitis results from uncontrolled esophageal reflux disease; occult aspiration is suspected to be a contributing factor in SSc-ILD^63,64. An HRCT will be important to provide insight into her disease, as specific CT findings are useful in differentiating the cause of radiographic changes associated with FVC and DLco changes⁶⁵. Pulmonary hypertension (PH) may cause progressive dyspnea and decline in spirometry and DLco⁶⁶. The DETECT algorithm is an evidence-based screening method to detect pulmonary arterial hypertension in patients with SSc⁶⁷. This suspicion should be carefully investigated to determine the underlying cause: Group 1 (pulmonary arterial hypertension), Group 2 (PH related to left-heart disease), Group 3 (PH related to chronic hypoxia), or a combination of the 3. A right heart catheterization, along with degree of ILD on HRCT, must be performed to distinguish amongst these possibilities. Finally, scleroderma-associated myopathy may be seen in 13–25% of patients with SSc⁶⁸ and progressive disease can produce a restrictive lung disease physiology. This is usually common in early disease but should be part of the differential diagnosis. The work-up includes evaluation of biochemical muscle breakdown products, electromyogram and nerve conduction study, as well as maximal inspiratory and expiratory pressures to assess diaphragm weakness.

Conclusions

The clinical course of SSc–ILD is variable^11,69. Early identification to risk stratify, monitor progression, and intervene when necessary is critical in improving our management of this potentially deadly complication of SSc. Features important in risk stratification include patient demographics, SSc specific features like skin distribution and disease duration, serological markers, pulmonary function testing, and extent of lung disease on HRCT. The clinical scenarios presented here provide examples of how we approach these cases, but should not be interpreted as strict guidelines for management. Personalized medicine may become a reality for these patients as our ability to predict which patients are likely to progress improves alongside the development of less toxic, more specific targeted therapies. Advances in understanding the pathophysiology of this disease has led to targeted biologic therapies, which allow for a favorable benefit/risk ratio, which may allow intervention prior to a state where advanced fibrosis has set in and cannot be reversed. At this time, stem cell therapy remains the only intervention with proven survival benefit, but is appropriate only for a narrow province of patients with clinical SSc-ILD.

Key Points.

1. Treatment strategies range from close monitoring of pulmonary function to immunomodulatory/ anti-fibrotic therapies to autologous stem cell and lung transplantations.

2. Understanding which therapy is appropriate involves staging disease severity, risk of progression/inflammatory parameters, burden of extra-pulmonary disease, and need for escalation therapy.

3. Sub-classifying patients based on these factors may allow practitioners an opportunity to intervene before advanced fibrosis sets in and cannot be reversed.

Clinically Meaningful Change:

If >1 PFT available, a clinically meaningful decline is defined as FVC levels of >10% from baseline or decline in FVC >5% to <10% and >15% relative decline in DLco.

Testing Acronyms

FVC%

Forced Vital Capacity percent predicted

DLco%

Diffusion Capacity of Carbon Monoxide percent predicted

HRCT

High Resolution Chest Computerized Tomography

PFT

Pulmonary Function Testing

Disease Acronyms

dcSSc

Diffuse cutaneous systemic sclerosis

ILD

Interstitial Lung Disease