Nintedanib, a multi-target tyrosine kinase inhibitor, is a small molecule designed as an ATP-competitive inhibitor of platelet-derived growth factor receptor (PDFGR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR), recently approved for the treatment of idiopathic pulmonary fibrosis (IPF) [13]. SSc-ILD and IPF share some similar fibrogenic mechanisms that include fibroblast activation, migration, proliferation, and differentiation into myofibroblasts, resulting in excessive collagen deposition [14]. The phase III, multi-center, randomized, double-blind, placebo-controlled SENSCIS (Safety and Efficacy of Nintedanib in Systemic SClerosIS) trial evaluated nintedanib safety and efficacy in patients affected by SSc-ILD (NCT02597933).

The primary endpoint was the annual rate of forced vital capacity (FVC) decline (ml/year) assessed over 52 weeks [15]. In the primary end-point analysis, the adjusted annual rate FVC change was −52.4 mL/year in the treated group and −93.3 mL/year in the placebo group (difference, 41.0 mL per year; 95% confidence interval (CI), 2.9 to 79.0; p = 0.04). The adjusted mean annual rate of FVC change as a percentage of the predicted value at week 52 was −1.4% in the nintedanib arm and −2.6% in the placebo arm (difference, 1.2 percentage points: 95% CI, 0.1 to 2.2). Patients in the arm treated with MMF at baseline had a better performance. Furthermore, the decrease in FVC differed in the placebo group and it is associated with MMF use. Although a randomization according to MMF administration was not used, these data suggest a potential additional benefit of MMF use with nintedanib on lung function [10]. However, additional studies are necessary to explore the combined use of MMF and nintedanib in SSc-ILD patients. In a post hoc analysis of the SENSCIS trial, the authors assessed the proportions of patients with categorical changes in % predicted FVC at week 52 and the time to absolute decline in FVC of ≥5% predicted or death and absolute decline in FVC of ≥10% predicted or death. Over 52 weeks, the hazard ratio (HR) for an absolute decline in FVC of ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% confidence interval [95% CI] 0.66−1.06) (p = 0.14), and the HR for an absolute decline in FVC of ≥10% predicted was 0.64 (95% CI 0.43−0.95) (p = 0.029), confirming that nintedanib has a clinically significant advantage in reducing the progression of SSc-ILD [16].

Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody of the immunoglobulin G1k subclass, that binds interleukin 6 (IL-6) receptor, thus blocking its signaling. The molecule is genetically engineered and is produced by grafting the complementarity determining region of mouse anti-human IL-6 R to human IgG1 [17]. TCZ is approved in Europe for the treatment of selected forms of rheumatoid arthritis and analogous diseases non-responsive to methotrexate or other disease-modifying anti-rheumatic drugs and it is under evaluation in other diseases sharing inflammatory pathogenesis [18]. The rationale for targeting IL-6 starts from the observation of high levels of IL-6 in skin and lung tissues of SSc-patients [19,20]; moreover, IL-6 levels tightly correlate with skin thickness scores supporting a causal relationship [21]. Starting from these data the faSScinate trial (NCT01532869) was designed. FaSScinate is a phase 2, randomized, double-blind, placebo-controlled trial enrolling 87 SSc patients [11]. Patients were assigned into different groups using randomization (1:1) to receive weekly subcutaneous treatment with TCZ 162 mg or placebo for 48 weeks followed by open-label weekly TCZ for additional 48 weeks. The primary efficacy endpoint was the difference in mean change from baseline in modified Rodnan skin score (mRSS) at week 24. Despite the primary endpoint was not achieved, with a difference of −2.70 mRSS units (95% CI: −5.85, 0.45) in favor of TCZ and in absence of a statistical significance (p = 0.0915), the study evidenced that fewer patients in the TCZ arm had a decline in % predicted FVC than in the placebo arm with respect to cumulative distribution (week 48, p = 0.0373). Overall, after 48 weeks of treatment, safety in faSScinate was coherent with the natural history of SSc and the known safety profile for TCZ [10]. Following these encouraging results, a phase 3 study, the focuSSced trial (NCT02453256), was designed [22]. The primary endpoint was the difference in change from baseline to week 48 in modified Rodnan skin score (mRSS), while % predicted FVC, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. The change in mRSS was higher in the TCZ arm (−6.1 vs. −4.4) but it did not meet significance (p = 0.1). On the other hand, the TCZ group showed a significant stabilization of FVC compared to placebo, according to the subgroup analysis that considered only SSc participants with ILD (−14 mL vs. −255 mL at 48 weeks, p < 0.001). These findings were also associated with a reduced number of SSc-ILD patients having a ≥10% decline in % predicted FVC in the TCZ compared to placebo (5 vs. 14). Taken all together, these results support the use of TCZ in SSc patients with early ILD, as already approved by the Food and Drug Administration.

Lenabasum is a synthetic cannabinoid receptor type-2 (CB2) agonist recognized as an inflammation-resolving drug candidate for the treatment of different diseases, thanks to its anti-inflammatory effects, and also for systemic sclerosis [23]. A randomized, double-blind, placebo-controlled, phase II study (NCT02465437) was designed to evaluate the safety and tolerability of lenabasum in patients with active SSc [24]. Lenabasum treatment was safe, well-tolerated, and improved multiple efficacy assessments of overall disease, such as skin involvement and patient-reported outcomes. FVC was used as a lung performance measure and was associated with numerical improvement from baseline in the lenabasum group compared to the placebo group starting at week 8, with a maximal but non-significant mean ± SEM treatment difference of 1.7 ± 1.6% observed at week 12. These data encouraged authors to provide other analyses and patients who had completed the 16-week phase 2 study were enrolled to continue lenabasum treatment at the dose of 20 mg twice a day. Thirty-six patients were enrolled and 26 patients were treated for >92 weeks. Predicted FVC values declined by 3.2% from the start of the study, but the trial design of this “open period” limits the conclusion. Despite the interesting results, the study shows some limitations, including the small number of patients, short-term observation period, and the subsequent open phase. RESOLVE-1 (NCT03398837) was the phase 3 study [25]. This study presents some novel aspects with respect to other studies: the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was assigned as the primary outcome and interim analysis has been presented at the 2021 American College of Rheumatology meeting [26]. The CRISS score involves a two-step process: the first step is to identify relevant disease worsening or the occurrence of new-onset end-organ damage. The second step requires calculating the probability of patient improvement after 1 year of therapy based on a scale ranging from 0 to 1 point according to changes from baseline status in five domains: the mRSS, % predicted FVC, patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI). A responder is defined as a patient having a CRISS score of 0.6 or higher and no significant renal or cardiopulmonary worsening [27]. Despite in the RESOLVE-1 trial the primary outcome was not achieved, post hoc analysis suggests that patients taking lenabasum in association with background MMF for more than 2 years were more likely to have stable % predicted FVC over 1 year compared to MMF and placebo (64% vs. 35%). These findings, however, need to be confirmed in future studies.

Pirfenidone is a small molecule comprising a modified phenyl pyridine with pleiotropic anti-fibrotic, antioxidant and anti-inflammatory properties, although its exact mechanism of action remains unclear. Pirfenidone was initially identified as an anti-inflammatory compound in animal models [28]. However, the unexpected identification of anti-fibrotic effects in animals treated with pirfenidone redefined the interest in this molecule [29]. Pirfenidone has been shown to attenuate fibrosis in different organs, including lung, liver, heart, and kidney [30]; it is actually approved for IPF treatment [31] and has also been tested in SSc-ILD patients in the LOTUSS study (an Open Label, RandOmized, Phase 2 STUdy of the Safety and Tolerability of Pirfenidone when Administered to Patients with Systemic Sclerosis-Related Interstitial Lung Disease) (NCT01933334) [32]. However, pirfenidone use is known to be associated with adverse events (AE) related to the liver, skin, and gastrointestinal (GI) system which are also frequently observed in SSc patients. Reasonably, the primary endpoint was the safety of this treatment in SSc-ILD patients, whereas the secondary endpoint was the effect of pirfenidone on predicted FVC and diffusion capacity of carbon monoxide (DLCO). Data showed an acceptable tolerability profile of pirfenidone in SSc-ILD and this tolerability was not affected by concomitant MMF use. However, FVC and DLCO values were basically unchanged throughout the observation period and no clinically relevant differences were observed in lung function variables between the groups or in any of the subgroup analyses. Lately, another double-blind, randomized, placebo-controlled, pilot study was conducted to evaluate the safety and efficacy of pirfenidone in SSc-ILD. Analogous to the LOTUSS trial, this study was unsuccessful in finding a relevant beneficial effect of pirfenidone over placebo in improving/stabilizing FVC, exercise capacity, symptoms, or skin disease. Nevertheless, the trial is underpowered to allow conclusive evidence [33].

Pomalidomide (POM) is an immunomodulatory agent structurally similar to thalidomide and lenalidomide. POM had shown immune-modulating activity on myeloid and lymphocyte cells and exhibited anti-fibrotic effects in pre-clinical models of dermal fibrosis [34]. Furthermore, it enhances T cell and natural killer (NK) cell-mediated immunity and inhibits pro-inflammatory cytokines release, such as tumor necrosis factor (TNF) or IL-6. In a study including 11 SSc patients, histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8 (+) T cells following thalidomide treatment. Moreover, thalidomide reduced IL-12 and TNF plasma levels. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, and healing of digital ulcers [35]. Starting from these data and from a similar structure, POM was tested in SSc patients. Due to difficulties in recruiting patients for the study owing to restrictive inclusion and exclusion criteria, the sponsor terminated enrollment. According to the interim analysis data, the study did not show a significant amelioration in any of the co-primary efficacy endpoints (changes from baseline in FVC and mRSS) for patients who concluded blinded treatment [36].

Romilkimab is a bispecific monoclonal (immunoglobulin-G4) antibody that binds and neutralizes both IL-4 and IL-13 [37]. IL-4 and IL-13 are Th2-derived cytokines involved in the pro-fibrotic mechanisms of SSc; in fact, their increased levels have been detected both in serum and in skin biopsies of SSc patients [38]. A phase 2A, randomized, double-blind, placebo-controlled, 24-week trial was performed in SSc patients (NCT02921971) [39] that focused the primary endpoint on evaluating the change from baseline to week 24 in modified mRSS and the secondary endpoints on FVC and DLCO. Romilkimab resulted in a significant reduction in mRSS from baseline to week 24 versus placebo (−4.32 to −0.31; p = 0.0291. The least square mean (SE) change in FVC was −10 (40) mL for romilkimab versus −80 (40) mL for placebo at week 24 resulting in a non-significant mean (SE) difference (95% CI) of 70 (60) mL (−40 to 190; p = 0.10). In this study, romilkimab had a non-significant but favorable effect on lung outcomes, which might justify further assessment. Moreover, in patients treated with a placebo, the evidence of the loss of 80 mL for FVC between baseline and week 24 might supports the hypothesis that patients with early SSc may develop significant lung disease in a very short period of time.

The soluble guanylate cyclase (sGC) stimulator riociguat increases intracellular cyclic guanosine monophosphate (cGMP) and consequently activates protein kinases G, with an effect on the regulation of vascular tone and remodeling [40]. Riociguat was approved for the treatment of pulmonary arterial hypertension [41]. A 52 week, double-blind, placebo-controlled, multi-center, randomized phase 2 study (RISE-SSc, NCT0228376219) was performed in recently diagnosed SSc patients (disease duration ≤ 18 months) in order to investigate the potential effects of riociguat. The primary endpoint was the change in mRSS from baseline to week 52 whereas among secondary endpoints, change in FVC% was evaluated. Among secondary endpoints, DLCO% and FVC% were evaluated overall and (post hoc) in patients with ILD according to medical history and restrictive lung disease (FVC% 50–75% at baseline). The modification in FVC% between baseline and week 52 was −2.38% (SD 7.52) with riociguat and −2.95% (SD 9.73) with placebo (difference of LS means −0.20 (SE 1.61); 95% CI −3.40 to 3.00; nominal p = 0.901). Depending on the diagnosis (patients with ILD or patients with restrictive disease) the mean change in FVC% from baseline to week 52 was −7.6 to −8.7% with placebo and +0.7 to −2.7% with riociguat. Some measures of mRSS, lung function in patients with evidence for pre-existing ILD and the prevention of new Raynaud’s phenomenon and digital ulcers symptoms suggest potential signals for efficacy. It is important to highlight that the results of descriptive analyses of secondary and exploratory endpoints should not be interpreted as the efficacy of riociguat, but as a potential indicator to be examined in further studies [42].

Rituximab (RTX) is a chimeric murine/human monoclonal antibody targeted against CD20, a specific pan-B-cell marker and the only binding site for RTX. RTX binding to the cell surface results in the destruction of lymphocytes through several mechanisms including apoptosis activation, complement-dependent cytotoxicity, or antibody-dependent cytotoxicity.

B cells have been found in the skin and lungs of patients with SSc-ILD, and an increased expression of B cell-related genes has also been demonstrated in the skin [11]. Moreover, in SSc patients, the B cell population is predominantly represented by naïve B cells compared to memory B cells, although the latter are highly active [43].

A multi-center, open-label, comparative study was performed on a total of 51 patients with SSc-ILD and treated with rituximab (RTX) or conventional treatment (azathioprine, methotrexate, and MMF) [44]. Patients treated with RTX showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs. 86.90 ± 20.56 at baseline vs. 2 years, respectively, p = 0.041 compared to baseline). Patients in the control group had no significant change in FVC during the first 2 years of follow-up. At the 7th year, the remaining patients in the RTX group had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group that showed an FVC deterioration (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013).

Of note, a recent trial analyzed the efficacy and safety of RTX in SSc patients. This was a phase II, multi-center, double-blind, parallel-group, investigator-initiated, randomized, placebo-controlled trial (DESIRES) conducted in four Japanese hospitals. The results, despite the limited number of patients, are relevant demonstrating that RTX at the dose of 375 mg/m² every week for 4 weeks produces a significant improvement in mRSS compared to placebo. Additionally, among the secondary endpoints included, FVC% appears to be stable in RTX-treated overall compared to the reported reduction of the placebo, with promising results reported in the subgroup analysis regarding SSc-ILD patients [45].

Based on growing evidence suggesting a key role for T cells in the development of both skin and internal organ damage in systemic sclerosis [46,47], a phase II investigator-initiated, multi-center, double-blind randomized placebo-controlled trial was designed to assess the safety and efficacy of abatacept in 88 early diffuse SSc [48]. mRSS change at 12 months, which was the primary endpoint of the study, was not statistically significant; neither was % predicted FVC. Nonetheless, a significant difference was observed in HAQ-DI and ACR CRISS between abatacept and placebo. These results, together with the superior safety profile of abatacept compared to placebo and the higher number of SSc patients requiring rescue therapy in the placebo group, led to the extension of this trial with an additional 6-month open-label, double-blind, randomized trial [49]. Overall, the authors concluded that both mRSS and FVC% predicted showed numerical improvement in patients assigned abatacept compared with those assigned to placebo which was not statistically significant; moreover, substantial individual heterogeneity should be considered.

RTX has been used in patients with SSc with pulmonary and renal involvement and has shown efficacy in patients refractory to CYC [44,50,51]. A prospective, randomized, open-label, parallel-group trial was performed including SSc patients with skin and lung involvement [52]. This trial offers the unique feature to provide a head-to-head study, including CYC as a comparator for the assessment of endpoints. The primary outcome was the % predicted FVC value at 6 months. There was a significant improvement in the predicted FVC in the RTX group [from 61.30 (11.28) at baseline to 67.52 (13.59) at the end of the study; p = 0.002]. The mean difference in predicted FVC was 9.46 (95% CI: 3.01, 15.90; p = 0.003) in favor of the RTX group. This study met its primary endpoint, demonstrating that RTX improved the % predicted FVC, while CYC was not associated with a % precited FVC stability after 6 months. In fact, % predicted FVC in the RTX group significantly increased from 61.30 at baseline to 67.52 at the end of the study, while in the CYC group FVC showed a non-significant decrease from 59.25 at baseline to 58.06. In conclusion, the authors described a greater increase in % predicted FVC value as well as decreased mRSS in the RTX arm compared with the CYC arm. Since the mean difference in % predicted FVC was in favor of the RTX arm (9.46; 95% CI: 3.01, 15.90; p = 0.003) and the lower limit of 95% CI of the mean difference of % predicted FVC was 3.01, this study met the non-inferiority criterion vs. CYC (margin 2%). Furthermore, RTX therapy was associated with a good safety profile.

Because of its immunosuppressive activity and an acceptable safety and tolerability profile, MMF has been widely employed in uncontrolled studies for the treatment of SSc-ILD in the last years. In fact, Tashkin et al. designed a multi-center randomized, double-blind, clinical trial in order to assess the efficacy and safety of MMF using CYC as a comparator drug in the Scleroderma Lung Study II (SLS II) [8], as the natural evolution of the SLS I [7]. In this trial, 69 SSc-ILD symptomatic patients were treated with MMF for 24 months and 73 with CYC for 12 months followed by placebo for additional 12 months. This preliminary hypothesis was based on the results of SLS I, thus assuming that MMF would be effective as CYC at 18 months, while the 12 months treatment with CYC would be associated with a fall in %-predicted FVC back to untreated values after additional 12 months of placebo treatment. While this trial failed to demonstrate MMF superiority, the results showed that MMF is also not inferior to CYC in producing an improvement in lung function, though modest and measured in an increase in % predicted FVC of 3.0 ± 1.2% and 3.3 ± 1.1% within the CYC and MMF treatment arms, respectively. Additionally, MMF induced significant between-treatment differences in DLCO %-predicted and DL/VA %-predicted supporting a slower decline during the MMF treatment than CYC.

Regarding safety, in the CYC arm, hematopoietic suppression occurred more frequently. On the other hand, the number of pneumonias, infections, systemic adverse events, or deaths, was not different between the treatment arms. Nevertheless, a greater percentage of subjects in the CYC arm prematurely discontinued the drug and the tolerated dose of CYC decreased over time to approximately 75% of the target dose.