Abstract
Systemic sclerosis (SSc) is an immune-mediated disease characterized by progressive, and often severe, inflammation and fibrosis of the skin and internal organs, such as the lungs, heart, kidneys, and gastrointestinal tract. There is an unmet medical need to treat patients with SSc given the high SSc-related mortality rate. Furthermore, disease-modifying therapies are lacking, and current treatment options focus on the management of individual organ-specific complications associated with the disease. Immunosuppressive therapies are the mainstay of pharmacologic management of major SSc-associated complications, such as skin and lung manifestations, but their overall effectiveness is limited and toxicity issues are common. Advances in understanding of the pathological processes involved in the immunologic and fibrotic mechanisms of SSc have led to clinical research focusing on targeted immunotherapies, in an effort to develop much needed disease-modifying treatment options. The interleukin-6 receptor-alpha antagonist tocilizumab has demonstrated promising efficacy in a phase 2 trial and is being investigated in a phase 3 trial. This article provides an overview of current pharmacologic treatment options for the management of SSc-related complications and discusses tocilizumab for the treatment of SSc in clinical trials.
Keywords
Introduction
Systemic sclerosis (SSc) is a heterogeneous, immune-mediated disease characterized by clinical features that include Raynaud's phenomenon and inflammation, fibrosis, and microvascular injury of the skin and internal organs (1). Patients may have pulmonary, cardiac, gastrointestinal, and renal complications, with lung involvement a major contributor to mortality in patients with SSc. For example, pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) account for approximately 60% of SSc-related deaths (2, 3).
The two main subtypes of SSc can be classified based on the extent of skin involvement and differ in natural history and prognosis (1, 4). Patients with skin involvement confined to the face, neck, and skin distal to the elbows and knees are classified as having limited cutaneous SSC (lcSSc), whereas those with proximal skin involvement including the upper arms, thighs, and/or trunk are classified as having diffuse cutaneous SSc (dcSSc). lcSSC is often associated with a long history of Raynaud's phenomenon before diagnosis, followed by frequent later-stage serious complications such as PAH and severe gut disease. In contrast, dcSSc is associated with a short history of Raynaud's phenomenon, rapid early progression of skin thickening, and internal organ involvement early in disease progression with early increased risk for renal crisis and cardiac involvement and a higher frequency of severe lung fibrosis.
There is an unmet medical need for efficacious treatment for patients with SSc given the high SSc-related mortality rate (3) and the lack of disease-modifying treatment options (5). Current treatments focus on the management of organ-specific complications, but none has demonstrated efficacy across multiple SSc-associated organ manifestations in a randomized controlled clinical trial. This article provides an overview of current treatments for SSc and focuses on recent clinical research evaluating anti-interleukin-6 receptor alpha (IL-6Rα)-targeted therapy with tocilizumab.
Current treatment options for SSc complications
What follows is a brief overview of results from key randomized controlled clinical trials evaluating currently available pharmacologic therapies used to treat patients with SSc (Fig. 1) (4–5–6).
Overview of the proposed treatment options for major complications associated with systemic sclerosis (4). Level A or B recommendations (7) for key pharmacologic treatment options for major complications of systemic sclerosis are shown. aShould be performed in expert centers. CCBs = calcium channel blockers; EULAR = European League Against Rheumatism; HSCT = hematopoietic stem cell transplantation; MMF = mycophenolate mofetil; PDE-5 = phosphodiesterase-5; PPI = proton pump inhibitor. Reprinted from The Lancet, 390(10103), Denton CP, Khanna D, Systemic Sclerosis, 1685-1699, Copyright 2017, with permission from Elsevier.
Immunosuppressive therapy
Immunosuppressive therapy is the mainstay of pharmacologic treatment for skin and lung manifestations associated with SSc (8). Early evidence from a small study of methotrexate in patients with SSc receiving weekly injections for 24 weeks reported a significantly higher proportion of patients with favorable response (defined as ≥30% improvement in total skin score, ≥15% improvement in single breath diffusion capacity [DLCO], or ≥30% improvement in visual analog scale (VAS) score of general well-being, without persistence of digital ulcerations or worsening of DLCO by ≥15%) compared with placebo (53% vs. 10%; p=0.03) (9). Significant improvements in University of California Los Angeles (UCLA) skin scores were also noted after 3 months’ treatment with oral methotrexate (p<0.05) in a trial of early diffuse SSc, but statistical significance was lost by 12 months. No significant improvements in the modified Rodnan skin score (mRSS) were noted at 12 months, but significant improvement in the Physician Global Assessment (VAS) was reported (p<0.035) (10). Retrospective reanalysis of data from this trial using Bayesian analysis indicated that methotrexate treatment resulted in better mean outcomes than placebo treatment; the probability (odds ratio) of a beneficial effect of methotrexate compared with placebo was 94% (15.7:1) for mRSS, 96% (24:1) for UCLA skin score, and 88% (7.3:1) for Physician Global Assessment VAS (8).
Cyclophosphamide therapy for patients with SSc-related ILD resulted in modest but significant improvements in lung function (percent predicted forced vital capacity [%pFVC]) at 12 months compared with placebo (mean absolute difference 2.53% predicted; p<0.03) in the Scleroderma Lung Study (SLS)-I (11). Cyclophosphamide plus prednisone followed by azathioprine treatment demonstrated a trend toward improvement in lung function over placebo (FVC, 4.19% predicted; p=0.08) in patients with SSc-associated pulmonary fibrosis, but this did not reach statistical significance (12). Based on these trial results, cyclophosphamide is recommended for the treatment of SSc-related ILD, despite its known toxicity (13). Recently, the head-to-head SLS-2 trial comparing mycophenolate mofetil (MMF) and cyclophosphamide reported similar efficacy with regard to lung function (FVC) at 24 months (2.19% vs. 2.88% predicted; p=0.24) in patients with SSc-related ILD, though MMF was marginally better tolerated (14). Post hoc analyses of patients with dcSSc from the SLS-I and SLS-2 trials showed that MMF and cyclophosphamide treatment resulted in statistically significant improvements in mRSS compared with placebo; mean (standard error) change from baseline in mRSS was -3.7 (1.1) for placebo, -7.2 (0.8) for cyclophosphamide, and -6.4 (1.1) for MMF at 2 years (both treatments p<0.05 vs. placebo) (15).
Hematopoietic stem cell transplantation (HSCT) has also been evaluated in diffuse SSc. Treatment with autologous HSCT was associated with a significantly higher proportion of patients achieving disease improvement (≥25% decrease in mRSS or >10% increase in FVC) versus pulse cyclophosphamide (odds ratio [OR], 110; p=0.00001) in patients with SSc in a trial in North America (16). In a European study of patients with early diffuse SSc, autologous HSCT was associated with significant improvement in longer-term event-free survival (occurrence of all-cause death or development of persistent major organ failure) versus cyclophosphamide at 2 (OR, 0.35; p=0.006) and 4 (OR, 0.34; p=0.006) years; however, treatment-related mortality was increased during the first year of follow-up (relative risk 1.59) (17). A third randomized controlled trial of HSCT versus placebo has supported the data from the European study (18).
Β-cell depletion with the monoclonal antibody rituximab has shown promise in patients with SSc, with improvements in skin thickening observed in a case series of 10 patients though improvement in lung function was not observed (19).
Other treatments
Several pharmacologic treatment options have also shown promise or have been recommended for the management of other complications associated with SSc.
A number of targeted agents are available for the management of PAH, including endothelin receptor antagonists, epoprostenol analogs, phosphodiesterase-5 (PDE-5) inhibitors, a soluble guanylate cyclase stimulator, and a selective IP prostacyclin receptor antagonist (4, 13, 20, 21). Recommendations for the management of digital vasculopathy include calcium channel blockers, nifedipine, epoprostenol analogs, PDE-5 inhibitors and iloprost for Raynaud's phenomenon, and PDE-5 inhibitors or iloprost for digital ulcers (4, 13, 20, 21).
Tocilizumab
Tocilizumab is a humanized monoclonal antibody that targets IL-6Rα, blocking both classic and IL-6 trans-signaling (Fig. 2). Tocilizumab binds to membrane-bound IL-6R in cells that express IL-6R, such as hepatocytes, and inhibits homodimerization of IL-6R and gp130, thus blocking downstream IL-6 signaling pathways. In addition, tocilizumab can bind to soluble IL-6R, preventing homodimerization with gp130 in cells such as fibroblasts that do not express IL-6R, again blocking downstream IL-6 signaling pathways.
Tocilizumab blocks IL-6 classic signaling and trans-signaling. IL-6 binds to membrane-bound IL-6R in cells, such as hepatocytes, that express IL-6R and induces homodimerization of gp130 and subsequent activation of downstream IL-6 signaling pathways (classic signaling). In cells that do not express IL-6R, such as fibroblasts, gp130 homodimerization is activated by the binding of IL-6 to soluble IL-6R (trans-signaling). Tocilizumab blocks membrane-bound and soluble IL-6R, thereby blocking downstream signaling pathways. JAK = Janus kinase; IL-6 = interleukin-6; MAPK = mitogen-activated protein kinase; mIL-6R = membrane-bound IL-6 receptor; sIL-6R = soluble IL-6 receptor; STAT = signal transducers and activators of transcription; TCZ = tocilizumab. Figure adapted with permission from Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295, copyright Cold Spring Harbor Laboratory Press, and adapted by permission from Macmillan Publishers Ltd. Clin Transl Immunol, from O'Reilly S, Cant R, Ciechomska M, van Laar JM. Interleukin-6: a new therapeutic target in systemic sclerosis? Clin Transl Immunol. 2013;2(4):e4, copyright 2013.
Approved indications for tocilizumab include rheumatoid arthritis (RA) and systemic and polyarticular juvenile idiopathic arthritis, as well as Castleman's disease in Japan. Tocilizumab has also recently gained approval in the USA for the treatment of patients with giant cell arteritis and has been investigated for the treatment of patients with Takayasu arteritis (22).
Evidence supporting the use of tocilizumab for the treatment of SSc was first observed in case studies of patients who received tocilizumab as an IL-6Rα antagonist. Skin softening was observed in two Japanese patients with SSc who were treated with TCZ for 6 months; both patients experienced decreases in clinical skin thickness as measured by mRSS (23). In a case series from Portugal (24), improvements in mRSS and healing of digital ulcers were also observed in two of three patients with SSc who had been treated with tocilizumab for 9 months, and a Japanese patient with SSc receiving tocilizumab therapy experienced improved range of joint motion and skin softening, suggesting that improved skin scores may be associated with functional improvement (25). Finally, a case study of two patients with SSc treated with tocilizumab in the USA reported improvements in skin scores; however, both also experienced exacerbation of gastrointestinal tract disease, leading to discontinuation of treatment (26).
Supporting evidence for the use of tocilizumab in patients with SSc was also observed in an observational study of 15 patients from the EULAR Scleroderma Trials and Research, or EUSTAR, database (27). Significant improvement in disease activity score based on 28 joint counts (DAS28) was observed after 5 months of tocilizumab treatment, with a median decrease of 2.7. Ten patients achieved EULAR good response and four achieved EULAR moderate response. However, there was no significant change in skin or lung fibrosis. Similar results were observed in patients from the same study who were treated with abatacept, with 11 demonstrating improvement in DAS28 scores and 8 achieving EULAR good or moderate response; as observed with tocilizumab, no significant change in skin or lung fibrosis occurred.
Clinical trials of tocilizumab in patients with SSc
Phase 2 trial: faSScinate
The faSScinate study was the first randomized, placebo-controlled, phase 2 trial of tocilizumab for the treatment of patients with SSc (28). The study enrolled 87 patients who were randomly assigned (1:1) to receive either subcutaneous tocilizumab 162 mg/week or subcutaneous placebo for 48 weeks double-blind, followed by open-label tocilizumab 162 mg/week for another 48 weeks.
Patients treated with tocilizumab had clinically relevant, though not statistically significant, improvement in skin thickening (Tab. I). The primary end point—difference in mean change from baseline in mRSS to week 24 between tocilizumab and placebo—was not statistically significant: least squares mean change from baseline in mRSS was -3.92 in the tocilizumab group and -1.22 in the placebo group, with a treatment difference of -2.70 (95% confidence interval [CI]: -5.85, 0.45; p=0.0915). At week 48, the end of the double-blind period, the least squares mean change from baseline was -6.33 in the tocilizumab group and -2.77 in the placebo group, with a treatment difference of -3.55 (95% CI: -7.23, 0.12; p=0.0579) (Fig. 3A). At week 48, 37% of tocilizumab-treated patients and 25% of placebo-treated patients also had a clinically relevant decrease in mRSS of ≥4.7 units (p=0.025).
Overview of key results from faSScinate
p values shown for the double-blind period are for tocilizumab versus placebo groups.
AE = adverse event; CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy; HAQ-DI = Health Assessment Questionnaire–Disability Index; mRSS = modified Rodnan skin score; NA = not assessed; NR = not reported; %pFVC = percent predicted forced vital capacity; PROs = patient-reported outcomes; SAE = serious adverse event; VAS = visual analog scale.
A mixed-model repeated-measures analysis that included the fixed categorical effects of treatment, visit, stratification factor of joint involvement at baseline, and treatment-by-visit interaction and the continuous covariates of baseline score and baseline score-by-visit interaction was used for analysis.
Observed data, exploratory analysis.
A negative change from baseline shows improvement, except for the FACIT-Fatigue score, for which positive change indicates improvement.
Safety is shown for baseline to 24 weeks and baseline to 48 weeks for the double-blind period and from weeks 48 to 96 for the open-label period.
Not reported as n (%) for the open-label period.
Change from baseline to week 48 in mRSS (
There was no statistically significant difference between the treatment groups for patient-reported outcomes. Patient global VAS and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores were generally better in the tocilizumab group than in the placebo group. There was no difference in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores between the treatment groups, but at week 48, 28% of patients in the tocilizumab group and 7% of patients in the placebo group had clinically meaningful improvement in HAQ-DI of ≥0.22 (p=0.0111).
Clinically relevant improvement in lung function was observed with tocilizumab treatment, suggesting it may have a disease-modifying effect by slowing lung function decline. At week 24, tocilizumab-treated patients had significantly smaller decreases in FVC than placebo-treated patients (least squares mean difference, 136 mL; 95% CI: 9, 264; p=0.0368). However, the difference was not significant at week 48 (least squares mean difference, 120 mL; 95% CI: -23, 262; p=0.0990). Worsening of %pFVC was reported in fewer tocilizumab-treated than placebo-treated patients at week 24 (p=0.009) and week 48 (p=0.0373) (Figs. 3B, 3C); at week 24, 3% of tocilizumab-treated patients and 19% of placebo-treated patients had >10% decreases in %pFVC, and at week 48, the percentages were 10% and 23%, respectively.
Exploratory analysis of biomarkers associated with SSc fibrosis in serum and skin biopsy samples suggested that tocilizumab may have a direct effect on lung fibrosis but an indirect effect on skin fibrosis; further analysis is required to investigate these hypotheses. Genes associated with M2-macrophages, which mediate inflammation and promote fibrosis (30, 31), were downregulated with tocilizumab treatment, and serum levels of CCL18, a chemokine associated with M2 macrophages and lung fibrosis (32, 33), were reduced in patients treated with tocilizumab. However, serum concentrations of biomarkers of skin fibrosis, including ENPP2, COMP, and POSTN, were not affected.
An exploratory analysis that included the 48-week, open-label period of the faSScinate trial also showed that the trends for improvements in mRSS and stabilization of lung function observed during the double-blind period were maintained in patients treated with tocilizumab who transitioned to open-label treatment and in patients who transitioned from double-blind placebo treatment to open-label tocilizumab treatment (29). Further improvement in mRSS observed in the open-label period resulted in a total mean (SD; 95% CI) change from baseline to week 96 of -9.1 (8.7; -12.5, -5.6) in the tocilizumab treatment arm. Patients who were originally assigned to double-blind placebo treatment experienced a mean (SD; 95% CI) change from baseline to week 96 of -9.4 (5.6; -11.8, -7.0) after receiving 48 weeks of open-label tocilizumab treatment (Fig. 3D). Post hoc analysis of a combined response index for SSc (CRISS) in patients from faSScinate suggested that tocilizumab may be efficacious at week 48 (p=0.01) for this combined response compared with placebo (34).
Overall, the safety results from faSScinate suggest that tocilizumab has a safety profile in patients with SSc consistent with that established in patients with RA. Safety results were consistent with the natural history of SSc. Serious infections were more common with tocilizumab treatment (rate/100 patient-years [95% CI] 34.8 [18.0, 60.8] during the 48-week, double-blind period, and no serious infections were reported during an additional 48 weeks of open-label treatment) than with placebo (rate/100 patient-years [95% CI] 10.9 [3.0, 27.9] during double-blind placebo treatment and 19.6 [7.2, 42.7] after 48 weeks of open-label tocilizumab) (29). Patients with SSc treated with tocilizumab might be at increased risk for small bone osteomyelitis and infections of digital ulcers because of the susceptibility of patients with SSc to digital ulcers. No patients experienced gastrointestinal perforations, serious hepatic adverse events, anaphylactic reactions, or demyelination serious adverse events during the entire treatment period.
Results of the faSScinate trial supported further investigation of tocilizumab for the treatment of patients with SSc in a phase 3 trial. Four patients died during the double-blind period of faSScinate (in the placebo group, one patient died of cardiac failure; in the tocilizumab group, one patient each died of arrhythmia, multiorgan failure, and lung infection [the lung infection was considered related to tocilizumab]). No patients died during the open-label period.
Phase 3 trial: focuSSced
The focuSSced trial (ClinicalTrials.gov identifier, NCT02453256) is a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial that began after the faSScinate trial and is investigating the efficacy and safety of tocilizumab in patients with SSc over a 48-week, double-blind period followed by a 48-week, open-label period. Patients have been recruited and randomly assigned (1:1) to receive treatment with subcutaneous tocilizumab 162 mg/week or placebo as in faSScinate. The primary end point will be the difference in change from baseline to week 48 in mRSS between the treatment groups. Patient-reported outcomes and lung function will also be investigated, as in the faSScinate trial. Week 48 was selected for trial completion based on results from faSScinate that suggested 24 weeks of treatment may not be sufficient to observe a significant effect on skin sclerosis and lung function. The estimated study completion date for focuSSced is May 2019.
Conclusion
To date, disease-modifying therapies for the treatment of patients with SSc are lacking; therefore, the goal of treatment is to manage organ-specific complications. Current treatments have demonstrated encouraging results in clinical trials, but these options are limited by a general lack of effectiveness and by toxicity issues (methotrexate, cyclophosphamide, azathioprine, and MMF) (6) or the need for expert centers (HSCT). Recent advances in our knowledge regarding the pathological processes involved in the immunologic and fibrotic mechanisms of SSc have led clinical researchers to focus on the development of targeted immunotherapies, including tocilizumab. Recent phase 2 trial data evaluating tocilizumab reported promising effects on both skin and lung involvement, supporting phase 3 development in the SSc setting. Comparison between treatment options for SSc is limited by variations in primary end points and patient populations in different studies. Therefore, prospective studies would have to compare the efficacy and safety of tocilizumab and currently approved/recommended immunosuppressive therapies (eg, methotrexate, cyclophosphamide).
Footnotes
Acknowledgments
Medical writing and editorial assistance was provided by Maxwell Chang and Sara Duggan, PhD, of ApotheCom (Yardley, PA, USA).
Conflict of interest: DK reports personal fees from Actelion, Covis, Cytori, EMD Serono, Gilead, GlaxoSmithKline, Sanofi-Aventis, Corbus, Chemomab, Eicos, and UCB pharma; grants and personal fees from Bayer, Roche/Genentech, and Boehringer-Ingelheim; grants from BMS, NIH K2ARO63120, and Pfizer during the conduct of the study; and personal fees from AstraZeneca outside the submitted work.
AJ is an employee of Genentech and owns stock options in Roche.
DEF has nothing to disclose.