Recent progress and missing gaps to achieve goal in the care of systemic sclerosis–associated interstitial lung disease

Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysregulation, microvascular damage, and excessive fibrosis. ¹ SSc affects many critical organ systems, including lung, heart, kidney, and gastrointestinal tract. Of these, interstitial lung disease (ILD) is a common manifestation of SSc and the leading cause of morbidity and mortality in patients with SSc. ² , ³ Currently, the mainstay of treatment for SSc-ILD is non-selective immunosuppression based primarily on evidence from two randomized double-blind trials (Scleroderma Lung Studies I and II).^4,5 In fact, the consensus of experts recommends mycophenolate mofetil and cyclophosphamide as treatment options for SSc-ILD. ⁶ Recently, nintedanib, an intracellular inhibitor of multiple tyrosine kinases involved in fundamental process of excessive fibrosis, immunomodulation, and vasculopathy, ⁷ has been approved for the treatment of SSc-ILD, ⁸ based on the result of a phase III randomized, double-blind, placebo-controlled, parallel group SENSCIS trial. ⁹ Consequently, nintedanib was included in the evidence-based recommendations as a treatment option for SSc-ILD either as monotherapy or in combination with mycophenolate mofetil. ¹⁰ We now have at least two options of treatment modality for SSc-ILD, that is, immunosuppressants and anti-fibrotic, immunomodulatory agents, but there are many missing gaps between current knowledge on SSc-ILD and how to implement anti-fibrotic agents in our clinical practice, that is, in what cases, at what timing, how to use them properly, or in combination with which kind of immunosuppressants.

Anti-fibrotic, immunomodulatory agents were first approved for idiopathic pulmonary fibrosis (IPF). SSc-ILD is considered to share to some extent an overlapping pathophysiology with IPF in terms of the underlying fibrotic cascade, and IPF and SSc-ILD are categorized as a disease entity of chronic fibrosing ILD with a progressive phenotype. However, there are apparent differences in the clinical course, pathogenic process, and treatment response between IPF and SSc-ILD. ¹¹ The most com-mon histological and imaging pattern of SSc-ILD is non-specific interstitial pneumonia, rather than usual interstitial pneumonia. In addition, the fibrogenic process of SSc-ILD is obviously amplified through inflammation and immune activation that promote activation of myofibroblasts. Therefore, evidence and experience of anti-fibrotic/immunomodulatory agents in the treatment of IPF are not necessarily applied to SSc-ILD. Vice versa, some immunosuppressive agents have been shown to be harmful in IPF, while there is evidence for efficacy of immunosuppressants in SSc-ILD. ¹²

The clinical course of SSc-ILD is highly variable, in contrast to IPF, in which almost all patients experience an accelerated decline in lung function over time. Findings from observational cohort studies show that less than one-third of patients with SSc-ILD at diagnosis progress to end-stage lung disease, with the remaining patients exhibiting stable or slowly progressing lung function throughout the disease course. ¹³ , ¹⁴ With new options available for treating patients with SSc-ILD, it is more important than ever to accurately identify patients who have a progressive fibrosing phenotype and derive the most benefit from aggressive treatment regimen. In clinical practice, therapy of SSc-ILD has been reserved for patients exhibiting dyspnea with restrictive ventilatory impairment. Since lung function decline is prominent at an early disease course, early therapeutic intervention in patients prone to progression is becoming realistic and may ultimately improve morbidity and mortality outcomes in patients with SSc-ILD. In this situation, it is essential for clinicians to predict a progression of lung function decline, especially early in the disease course. Of many candidate predictors reported, circulating biomarkers are attractive because of easy accessibility. A number of studies have conducted and reported utility of C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), and CCL18 in predicting subsequent decline of forced vital capacity (FVC).

There has been accumulating evidence of well-designed prospective, randomized controlled trials in patients with SSc-ILD, but it is difficult to compare the findings between the studies because of heterogeneity in the enrollment criteria, background treatment, and endpoints. The rate of FVC decline is often used as an endpoint, but roles of other parameters, such as quantitative scoring of high-resolution computed tomography (CT) imaging and patient-reported outcomes, need to be validated. In addition, minimal clinically important differences (MCID) for improvement or worsening have not been validated for many of those endpoints. Identifying subsets most likely to benefit from the therapy, or enriching cohort populations, might be an effective strategy being implemented to capture maximal treatment benefit, although treatment responders might be profoundly different depending on the type of treatment. Finally, unlike IPF, ILD is not a sole complication leading to disability and mortality in SSc patients. Ideal disease-modifying treatments should suppress progression of the disease, prevent organ failure events, and improve functional disability and survivals. While the approvals of organ-based treatments, as for example for pulmonary arterial hypertension and now newly for ILD, are breakthroughs in the care of SSc patients, it is preferable that therapies proven to be effective for SSc-ILD also had efficacy for the entire disease of SSc including non-ILD complications. Our ultimate goal is to develop evidence-based treatment algorithms, which can be used in clinical practice.

Anti-fibrotic/immunomodulatory agents target molecular pathways that lead to the persistent activation of fibroblasts and differentiation into myofibroblasts. In the case of nintedanib, there is compelling evidence for immunomodulatory (though not immunosuppressive) effects in that it also targets macrophage polarization, T-cell activation, and vascular remodeling. ¹⁵ Inflamma-tory and vascular changes may induce profibrotic responses early in the disease course of SSc, but, in later stage, fibroblast activation can be maintained by cell autonomous mechanisms and may render fibroblasts partially independent from external stimuli. Since there are many potential therapeutic targets identified by pre-clinical researches using human samples and animal models, treatment options of disease-modifying agents will be extended in future.

This supplemental issue of the Journal of Scleroderma and Related Disorders is aimed to cover updated topics and future research agenda on SSc-ILD, which are likely to be useful in achieving goal in the patients’ care.