5Relevance of immunomodulatory therapy for interstitial lung disease in systemic sclerosis
Introduction
All forms of systemic sclerosis (SSc) are systemic autoimmune diseases characterized by fibrosis [[1], [2], [3]]. The sever fibrotic phenotype distinguishes them from other connective tissue diseases (CTDs), which include systemic lupus erythematosus, primary Sjögren's syndrome, dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myositides, and mixed connective tissue diseases. The term CTDs is therefore debatable; SSc is probably the only disease that can be appropriately referred to as a connective tissue disease. Hence, relating the CTDs to antinuclear antibodies (ANA) is important. More specifically, the autoimmune response of SSc is denoted by autoantibodies to topoisomerase (Scl-70), centromere-protein B, RNA polymerase III, or fibrillarin [4,5].
All these facts provide only circumstantial evidence. However, the essential point is proven by the success of autologous stem cell transplantation (ASCT) [6,7]. This therapeutic option is hampered by early mortality-associated with the procedure, but usually leads to long-lasting effects. The success of ASCT also pertains to SSc interstitial lung disease (ILD), which at present constitutes the most common fatal organ manifestation of SSc [[8], [9], [10]]. In the U.S. SCOT trial, 97% of patients had ILD. Five patients suffered from respiratory failure following ACST, as compared with 13 patients in the cyclophosphamide control arm [7]. In the European ASTIS trial, 86% of patients had SSc-ILD [6]. In the area under the curve analysis, forced vital capacity (FVC) improved after the ASCT. Since it is difficult to hypothesize a way in which ASCT would directly influence tissue fibrosis, the success of this immunoablative approach is a strong argument for SSc-ILD being driven by autoimmunity.
In 2020, the first ever drug for SSc-ILD was approved, both by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This first approved drug, nintedanib, is antifibrotic in its mechanism, and does not appear to have relevant immunomodulatory effects. This mode of action is focused on by another review in this issue [11]. In contrast to nintedanib, all immunomodulatory action mechanisms were off-label until March 5th, 2021, when the FDA approved tocilizumab. The approval of nintedanib and tocilizumab make this the appropriate time to investigate the evidence for immunomodulatory treatment for SSc-ILD. After all, physicians who treat patients with SSc and an interstitial lung manifestation will have to decide, whether they suggest an antifibrotic or an immunomodulatory treatment approach, or a combination of both. This review will therefore analyze the evidence for immunomodulatory therapy for SSc-ILD, with a particular focus on randomized controlled trials (Table 1).
Section snippets
Cyclophosphamide
ASCT uses high-dose cyclophosphamide as a source of treatment [6,7]. Moreover, the cyclophosphamide control arms in both the ASCT trials showed indications of efficacy. In the SCOT trial, cyclophosphamide was not inferior in any regard to the ongoing monthly intravenous cyclophosphamide bolus therapy (750 mg/m2). Events of organ failure and deaths occurred in patients after years, but one death occurred after a year when cyclophosphamide was stopped, without maintenance therapy. In the ASTIS
Mycophenolate
Mostly because of the second scleroderma lung trial (SLS II), mycophenolate has become the alternate immunomodulatory standard therapy in SSc-ILD. Several groups had suggested before that mycophenolate mofetil (MMF) [[29], [30], [31], [32], [33], [34], [35]], and also mycophenolic acid [35,36], can stabilize or even improve SSc-ILD. SLS II in 2016 confirmed this fact. Given the SLS (I) results and the fatal consequences of worsening ILD, it was considered unethical to test MMF against placebo.
Rituximab
In various centers, the B-cell depleting anti-CD20 monoclonal antibody rituximab has been used as a rescue therapy [[39], [40], [41], [42], [43]]. A EUSTAR case control study in 2013 found 63 rituximab-treated SSc patients [44]. Of these, 9 patients had ILD with a FVC <70% predicted. While the matched controls showed a decline in FVC, the rituximab-treated patients were stable, resulting in a significant difference (p = 0.02) [44]. In 2017, another EUSTAR approach already identified 254 SSc
Tocilizumab
In a report on two cases, the monoclonal anti-interleukin-6 receptor antibody tocilizumab was originally reported to act on SSc skin involvement, not lung involvement [49]. Such findings led to a phase II randomized controlled trial, faSScinate, which tested weekly subcutaneous tocilizumab (162 mg) against placebo, with modified Rodnan's skin score (MRSS) as the primary endpoint [50]. The trial included 87 SSc patients with active, diffuse cutaneous SSc (MRSS 15–40), who had less than 5 years
Current recommendations
There are several sets of recommendations available, which stem from different years and partially come to differing conclusions. On SSc-ILD, the 2016 updated EUSTAR recommendations [53] stated, “In view of the results from two high-quality RCTs and despite its known toxicity, cyclophosphamide should be considered for treatment of SSc-ILD, in particular for patients with SSc with progressive ILD.” A recent survey showed an agreement of 8.0 ± 2.0 of SSc experts on this statement [54]. In
Summary
At a time when anti-fibrotic treatment offers new options for patients with SSc-ILD, there are important arguments that immunomodulatory approaches should not be given up. In line with the idea that SSc always constitutes a systemic autoimmune disease, and that ILD is one important manifestation of the involved autoimmune processes, there is convincing evidence for efficacy of cyclophosphamide, mycophenolate, rituximab, and tocilizumab as induction treatment for patients with SSc-ILD. In
Funding
No funding was received for the preparation of this manuscript.
Declaration of competing interest
Martin Aringer reports advisory boards and has been an investigator for Boehringer Ingelheim and Roche. Gabriela Riemekasten reports advisory boards for Boehringer Ingelheim.
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