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Annals of the American Thoracic Society logoLink to Annals of the American Thoracic Society
. 2024 Feb 1;21(2):328–337. doi: 10.1513/AnnalsATS.202301-056OC

Tocilizumab in Patients with Systemic Sclerosis–associated Interstitial Lung Disease: A Systematic Review and Meta-Analysis

Marya Ghazipura 1,2,3,✉, Madalina Macrea 5,6, Derrick Herman 7, Hayley Barnes 8,9,10, Shandra L Knight 11, Richard M Silver 12, Sydney B Montesi 13, Ganesh Raghu 14,15, Tanzib Hossain 4
PMCID: PMC12042949  PMID: 37773003

Abstract

Background

The American Thoracic Society (ATS) convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis–associated interstitial lung disease (SSc-ILD).

Objective

To conduct a systematic review and evaluate the literature to determine the impact of treating patients with SSc-ILD with tocilizumab on prespecified critical and important outcomes determined by the ATS guideline panel.

Data Sources

A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through June 2022 for studies using tocilizumab to treat patients with SSc-ILD.

Data Extraction

Mortality and disease progression were determined to be critical outcomes of focus, with quality of life and adverse events important outcomes. Data on these outcomes were extracted and meta-analyses performed using the generic inverse variance method when possible. The Grading of Recommendations, Assessment, Development, and Evaluation Working Group method was used to assess the quality of evidence.

Synthesis

The literature review resulted in five studies for inclusion. The absolute decrease from baseline in forced vital capacity (FVC) for the tocilizumab arm was 118 ml, 241 ml, and 129 ml less than the placebo arm at 24, 48, and 96 weeks, respectively, favoring tocilizumab. The mean decrease in FVC% predicted at 48 weeks was 6.50% less and the risk of decrease >10% was 66% less in the tocilizumab arm, whereas patients were 1.97 times more likely to have any increase in FVC% predicted if they received tocilizumab in place of placebo. When the placebo arm was given tocilizumab from 48 to 96 weeks, the mean change in absolute FVC was 54.90 ml less and the mean change in FVC% predicted was 1.30% less. For diffusing capacity of the lung for carbon monoxide (DlCO)% predicted, at 48 weeks there was 1.50% less change and from 48 to 96 weeks there was 5.40% less change in the tocilizumab arm. Quantitative Interstitial Lung Disease scores and Quantitative Lung Fibrosis scores at 48 weeks and modified Rodnan skin scores at 72 weeks all favored the tocilizumab arm, as did several adverse event parameters, including serious adverse events (mean difference, −27.40; 95% confidence interval, −30.10 to −24.70). The quality of evidence was very low grade.

Conclusions

Tocilizumab use in patients with SSc-ILD is associated with less disease progression and a better toxicity profile than placebo. However, the quality of evidence is very low, and large prospective studies dedicated to assessing tocilizumab specifically for SSc-ILD are needed.

Keywords: tocilizumab, interstitial lung disease, systemic sclerosis, SSc-ILD, systematic review

The development of interstitial lung disease (ILD) is a well-recognized manifestation of systemic sclerosis (SSc) (1, 2). SSc-associated ILD (SSc-ILD) can be found in up to 30% of patients with SSc and is a leading cause of morbidity and mortality, with changes in lung function parameters on pulmonary function tests indicative of progression (1, 3, 4). However, at this time, clinical practice guidelines for the treatment of SSc-ILD are primarily consensus based, with variations in the treatment of choice (4, 5). Therefore, the American Thoracic Society (ATS) convened an international and multidisciplinary committee of experts to develop evidence-based clinical practice guidelines for the treatment of SSc-ILD.

Tocilizumab, a monoclonal antibody that targets the IL-6 (interleukin-6) receptor, is believed to have benefit in SSc, in which elevated concentrations of IL-6 have been associated with skin fibrosis and development of SSc-ILD (6). In March 2021, tocilizumab was approved by the U.S. Food and Drug Administration (FDA) for use in SSc-ILD for slowing the rate of decline in lung function (4, 7). To inform the 2023 ATS clinical practice guideline on treatment for SSc-ILD (8), this systematic review examined the existing literature, including data from the studies that led to FDA approval, to determine the treatment effects of tocilizumab on predetermined patient outcomes of mortality, disease progression, quality of life, and adverse events (AEs) in patients with SSc-ILD.

Methods

Research Question and Outcomes

This systematic review was conducted to provide evidence for the ATS 2023 clinical practice guidelines on SSc-ILD (8). It was registered with the International Prospective Register of Systematic Reviews database (registration number CRD42022323797) and conducted in accordance with the Cochrane Handbook for Systemic Reviews of Intervention (9). The overarching research question asked by the guideline committee was: “Should patients with SSc-ILD be treated with tocilizumab?”

For the systematic review, and the guideline as a whole, SSc was defined using the American Rheumatology Association 1980 criteria or the 2013 American College of Rheumatology Criteria and European League Against Rheumatism criteria (10, 11). ILD was defined by radiologic presence of the following: reticulation, traction bronchiectasis, traction bronchiolectasis, honeycomb cysts, ground-glass opacities and/or air space consolidation, other interstitial lung abnormalities, or any of the recognized patterns of interstitial pneumonias (8). SSc-ILD was defined as having SSc and ILD by these criteria. Three subgroups of patients were assessed: 1) at initial diagnosis of SSc-ILD; 2) with stable SSc-ILD; and 3) with progressive SSc-ILD. Progressive SSc-ILD is defined in the guideline document as manifesting two of the following criteria: 1) worsening dyspnea or cough; 2) physiological evidence of disease progression; or 3) radiological evidence of disease progression (8).

The intervention in this review was tocilizumab. The appropriate comparator was selected to be either placebo or standard of care, which was determined to be mycophenolate based on the Scleroderma Lung Study II (12). Critical and important outcomes were determined a priori by consensus from the guideline committee. Critical outcomes of interest included mortality and disease progression. The latter was determined by changes in lung function parameters, including forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DlCO), the modified Rodnan skin score (mRSS) (which was used as an indirect measure of disease progression because of its use in SSc) (13), and parameters of lung fibrosis (Quantitative Lung Fibrosis [QLF] and Quantitative ILD [QILD] scores). Important outcomes included quality-of-life indices (assessed using the 5-D Itch, the Health Assessment Questionnaire–Disability Index [HAQ-DI], Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, and the Patient Global Visual Analog Scale [VAS] scores) and AEs.

Literature Search, Study Selection, and Data Extraction and Synthesis

With the assistance of a medical librarian, a literature search was conducted through June 2022 across MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases focusing on the use of tocilizumab in patients with SSc-ILD (see data supplement). Two authors independently screened the titles, abstracts, and full texts of the studies. Any disagreements were resolved by consensus with a third author. Studies in English that enrolled patients with SSc-ILD and provided treatment with tocilizumab were included. The focus was on finding randomized controlled trials (RCTs), so only prospective studies were included, and case reports and case series were excluded.

Studies that were included underwent data extraction by two authors and were reviewed by additional authors to verify accuracy. Extracted data included study background characteristics (including year, location, type, duration, and funding source), population characteristics (including criteria used to diagnose SSc-ILD, number of participants in the tocilizumab and control arms, and details of the treatment provided), and all relevant outcomes. When possible, data from studies were pooled and meta-analyses performed using the generic inverse variance method; R Studio was used for all calculations. Individual effect estimates were pooled using random-effects models. Relative risk (RR) scores were obtained to report the results for binary outcomes, and mean differences (MDs) were obtained to report the results for continuous outcomes, accompanied by a 95% confidence interval (CI). Statistical heterogeneity was assessed using the I2 test, with I2 of 50% or higher indicating significant heterogeneity.

The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group method was used to assess the risk of bias for each individual study and the certainty of evidence (very low, low, moderate, or high) for each intervention on the outcomes of interest (14–19). Study quality was downgraded for high risk of bias (such as baseline differences in demographics between intervention and control groups in randomized trials), inconsistency in data (significant heterogeneity), indirectness to interventions and outcomes of interest, imprecision of results (wide confidence intervals), and the likelihood of publication bias (16).

Results

Literature Review and Characteristics of Included Studies

The literature review resulted in 271 total articles. After 2 duplicates were removed, 261 were excluded upon initial title and abstract screen (Figure 1). Eight full-text studies were assessed for eligibility, and three were removed for overlapping patient populations and data, resulting in five articles meeting inclusion criteria for data extraction (see Table 1 and Table E1 in the data supplement). The included studies were the faSScinate trial (20) and its open-label extension (21), the focuSSced trial (6) and its open-label extension (22), and a post hoc analysis of data from the focuSSced trial (23).

Figure 1.

Figure 1.

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Preferred reporting Items for systematic reviews and meta-analyses flow diagram.

Table 1.

Characteristics of studies evaluating tocilizumab versus placebo in systemic sclerosis–associated interstitial lung disease

Study Details faSScinate faSScinate Open Label focuSSced focuSSced Post Hoc focuSSced Open Label
Publication year 2016 2018 2020 2021 2022
Primary author (reference) Khanna (20) Khanna (21) Khanna (6) Roofeh (23) Khanna (22)
Design RCT RCT open-label extension RCT RCT post hoc RCT open-label extension
Intervention Tocilizumab 162 mg/wk subcutaneously Tocilizumab 162 mg/wk subcutaneously Tocilizumab 162 mg/wk subcutaneously Tocilizumab 162 mg/wk subcutaneously Tocilizumab 162 mg/wk subcutaneously
Control Placebo weekly subcutaneously Placebo Weeks 0–48, Tocilizumab 162 mg Weeks 48–96 Placebo weekly subcutaneously Placebo weekly subcutaneously Placebo Weeks 0–48, Tocilizumab 162 mg Weeks 48–96
Numbers Intervention 43, control 44 Intervention 30, control 31 Intervention 68, control 68 Intervention 68, control 68 Intervention 60, control 54
Key outcomes Mean change from baseline in mRSS at 24 wk Mean change from baseline in mRSS at 96 wk Changes in FVC, FVC% predicted, and QLF/QILD score Whole-lung QILD and QLF scores Changes in FVC, FVC and DlCO% predicted, mRSS, AE
Duration 48 wk 96 wk 48 wk 48 wk 96 wk
Location 5 countries 5 countries 20 countries 20 countries 20 countries
Funding Roche, Genentech Roche, Genentech Roche N/A Roche
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Definition of abbreviations: AE = adverse events; DlCO = diffusing capacity of the lung for carbon monoxide; FVC = forced vital capacity; mRSS = modified Rodnan skin score; N/A = not applicable; QILD = Quantitative Interstitial Lung Disease; QLF = Quantitative Lung Fibrosis; RCT = randomized controlled trial; SSc-ILD = systemic sclerosis–associated interstitial lung disease.

The faSScinate trial (20) was a phase 2 RCT that assigned patients with SSc to tocilizumab or placebo over 48 weeks. The study enrolled 87 participants across five countries, with 43 assigned to tocilizumab and 44 to placebo. Participants received weekly subcutaneous injections of tocilizumab at 162 mg or placebo. SSc was determined using the American Rheumatology Association 1980 criteria (10), and participants were those with <5 years of symptoms, mRSS of 15–40 with documented worsening within the 6 months before enrollment unless diagnosed within a year of enrollment, and skin involvement proximal to the elbows or knees with documented worsening. The primary outcome was the mean change from baseline in the mRSS at 24 weeks. Secondary outcomes included change from baseline in mRSS at 48 weeks and change at 24 and 48 weeks for patient- and physician-reported scores for the HAQ-DI, patient and physician global VAS, FACIT-Fatigue, and 5-D Itch. Exploratory outcomes included change from baseline to 24 and 48 weeks in the FVC and FVC% predicted and change from baseline to 48 weeks in the DlCO% predicted.

The faSScinate trial open-label extension (21) extended treatment to 96 weeks. From the original study, 30 participants in the tocilizumab arm were included and continued to get weekly subcutaneous injections of tocilizumab at 162 mg from Weeks 48 to 96. In addition, 31 participants in the original placebo arm were also given tocilizumab at 162 mg weekly from 48 to 96 weeks. Outcomes included change from baseline to 96 weeks in mRSS, FVC% predicted, DlCO% predicted (corrected for hemoglobin), HAQ-DI, patient global VAS, FACIT-Fatigue, 5-D Itch, and AEs.

The focuSSced trial (6) was a phase 3 RCT that assigned patients with SSc to tocilizumab or placebo over 48 weeks. The study enrolled 210 participants across 20 countries, with 104 in the tocilizumab arm and 106 in the placebo arm. Participants received subcutaneous tocilizumab 162 mg or placebo weekly. SSc was determined using the 2013 American College of Rheumatology/European League Against Rheumatism criteria (11), with patients required to have disease for <5 years duration and active disease during the time of enrollment. From the 210 total participants, 136 (with 68 in each arm) had ILD on visual read of high-resolution computed tomography (HRCT) by a thoracic radiologist. Outcomes included: difference in mean and median change from baseline in percentage predicted FVC at 48 weeks, patients with FVC decrease from baseline ⩾10% predicted, patients with FVC increase from baseline ⩾0% predicted, difference in mean absolute FVC change from baseline at 24 and 48 weeks, difference in change from baseline in observed HRCT QLF for the most affected lung (QLF-LM) at 48 weeks, difference in change from baseline in observed HRCT QLF for the whole lung (QLF-WL) at 48 weeks, and difference in change from baseline in observed HRCT QILD whole lung (QILD-WL) at 48 weeks.

The focuSSced trial open-label extension (22) extended treatment to 96 weeks. From the original study, 60 participants on tocilizumab continued to receive tocilizumab 162 mg subcutaneously weekly from 48 to 96 weeks. In addition, 54 participants in the original placebo arm were also assigned to receive subcutaneous tocilizumab 162 mg weekly from 48 to 96 weeks. Outcomes assessed included: difference in mean absolute FVC change from baseline, difference in mean FVC% predicted change from baseline, difference in mean DlCO% predicted change from baseline, difference in mean mRSS change from baseline, and AEs.

The focuSSced trial post hoc analysis (23) assessed QILD and QLF scores for participants enrolled in the study. QILD scores were further classified to mild (>5–10%), moderate (>10–20%), or severe (>20%) findings. Outcomes measured included difference in mean change from baseline in QILD-WL and QLF-WL scores at 48 weeks.

There were insufficient data to address the predefined subgroups by disease status of SSc-ILD at initial diagnosis, SSc-ILD with stable disease, or progressive SSc-ILD for the included studies.

Systematic Review Outcomes

Critical outcomes

The critical outcomes for this review were mortality and disease progression (Table 2). At 24 weeks, there was no significant difference in mortality between the tocilizumab and placebo arms (RR, 1.02; CI, 0.07–15.84). This was also noted at 48 weeks (RR, 1.02; CI, 0.12–8.94; I2 = 47.4%) (Figure E3) and between 48 and 96 weeks (RR, 0.96; CI, 0.14–6.68; I2 = 0%) (Figure E4).

Table 2.

Summary of critical outcomes for tocilizumab versus placebo in systemic sclerosis–associated interstitial lung disease

Outcome Group Outcome Outcome Measure (95% CI) Arm Favored N Total (Intervention; Control) N Studies (Reference) (Type) Evidence Quality
Subcutaneous tocilizumab vs. subcutaneous placebo for 48 wk
 Disease progression Difference in mean absolute change from baseline FVC (ml) at 24 wk [LS]MD, 118 (31 to 205)* Tocilizumab N = 136 (68; 66) 1 (6) (RCT) Low†
Difference in mean absolute change from baseline FVC (ml) at 48 wk [LS]MD, 241 (124 to 358)* Tocilizumab N = 136 (68; 66) 1 (6) (RCT) Low†
Difference in mean change from baseline in % predicted DlCO at 48 wk MD, 1.5 (0.79 to 2.21)* Tocilizumab N = 100 (57; 43) 1 (22) (open-label extension of RCT) Very low†‡
Difference in mean change from baseline in % predicted FVC at 48 wk MedianD, 3.40 (0.40 to 5.60)* Tocilizumab N = 136 (68; 68) 1 (6) (RCT) Low†
Difference in mean change from baseline in % predicted FVC at 48 wk [LS]MD, 6.50 (3.40 to 9.50)* Tocilizumab N = 136 (68; 68) 1 (6) (RCT) Low†
Difference in mean change from baseline in % predicted FVC at 48 wk MD, 5.00 (4.55 to 5.45)* Tocilizumab N = 103 (53; 50) 1 (22) (open-label extension of RCT) Very low†‡
Difference in mean change from baseline in % predicted FVC at 48 wk MedianD, 3.40 (0.40 to 5.60)* Tocilizumab N = 136 (68; 68) 1 (6) (RCT) Low†
Difference in mean change from baseline in % predicted FVC at 48 wk [LS]MD, 6.50 (3.40 to 9.50)* Tocilizumab N = 136 (68; 68) 1 (6) (RCT) Low†
Difference in mean change from baseline in absolute FVC (ml) at 48 wk MD, 186.10 (168.28 to 203.92)* Tocilizumab N = 103 (53; 50) 1 (22) (open-label extension of RCT) Very low†‡
Patients with a decrease from baseline ⩾ 10% predicted FVC RR, 0.34 (0.13 to 0.88)* Tocilizumab N = 115 (59; 56) 1 (6) (RCT) Low†
Patients with an increase from baseline ⩾ 0% predicted FVC RR, 1.97 (1.14 to 3.42)* Tocilizumab N = 115 (59; 56) 1 (6) (RCT) Low†
Decrease ⩾ 20% from baseline in modified Rodnan skin score at 24 wk RR, 1.36 (0.73 to 2.53) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Decrease ⩾ 20% from baseline in modified Rodnan skin score at 48 wk RR, 1.45 (0.79 to 2.66) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Decrease ⩾ 4.7 units (MCID) from baseline in modified Rodnan skin score at 24 wk RR, 1.64 (0.84 to 3.20) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Decrease ⩾ 4.7 units (MCID) from baseline in modified Rodnan skin score at 48 wk RR, 1.49 (0.78 to 2.83) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Decrease ⩾ 40% from baseline in modified Rodnan skin score at 24 wk RR, 1.02 (0.36 to 2.93) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Decrease ⩾ 40% from baseline in modified Rodnan skin score at 48 wk RR, 3.07 (0.89 to 10.58) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Decrease ⩾ 60% from baseline in modified Rodnan skin score at 24 wk RR, 1.02 (0.15 to 6.94) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Decrease ⩾ 60% from baseline in modified Rodnan skin score at 48 wk RR, 6.14 (0.77 to 48.92) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Difference in mean change from baseline in modified Rodnan skin score at 24 wk MD, −2.70 (−5.85 to 0.45) Neither N = 84 (41; 43) 1 (20) (RCT) Low†
Difference in mean change from baseline in modified Rodnan skin score at 48 wk MD, −1.57 (−3.82 to 0.69) (see Figure E1) Neither N = 188 (95; 93) 2 (6, 20) (2 RCT) Moderate§
Difference in median change from baseline in observed HRCT QILD-WL at 48 wk MedianD, −3.30 (−4.30 to −0.70)* Tocilizumab N = 101 (54; 47) 1 (6) (RCT) Low†
Difference in median change from baseline in observed HRCT QLF-LM at 48 wk MedianD, −1.60 (−3.30 to −0.40)* Tocilizumab N = 71 (35; 36) 1 (6) (RCT) Low†
Difference in median change from baseline in observed HRCT QLF-WL at 48 wk MedianD, −0.60 (−1.20 to −0.30)* Tocilizumab N = 102 (54; 48) 1 (6) (RCT) Low†
Difference in mean change from baseline in whole-lung QILD >10–20% scores at 48 wk MD, −1.80 (−2.27 to −1.33)* Tocilizumab N = 43 (19; 24) 1 (23) (RCT post hoc) Very low†§
Difference in mean change from baseline in whole-lung QILD > 20% scores at 48 wk MD, −3.00 (−4.15 to −1.85) Neither N = 37 (24; 13) 1 (23) (RCT post hoc) Very low†§
Difference in mean change from baseline in whole-lung QILD > 5–10% scores at 48 wk MD, −3.00 (−4.42 to −1.58)* Tocilizumab N = 19 (9; 10) 1 (23) (RCT post hoc) Very low†§
Difference in mean change from baseline in whole-lung QILD scores at 48 wk MD, −3.30 (−3.56 to −3.04)* Tocilizumab N = 103 (55; 48) 1 (23) (RCT post hoc) Very low†§
Difference in mean change from baseline in whole-lung QLF first tertile scores at 48 wk MD, −0.41 (−0.49 to −0.33)* Tocilizumab N = 35 (15; 20) 1 (23) (RCT post hoc) Very low†§
Difference in mean change from baseline in whole-lung QLF scores at 48 wk MD, −1.20 (−1.26 to −1.14)* Tocilizumab N = 104 (55; 49) 1 (23) (RCT post hoc) Very low†§
Difference in mean change from baseline in whole-lung QLF second tertile scores at 48 wk MD, −1.39 (−1.60 to −1.18)* Tocilizumab N = 36 (18; 18) 1 (23) (RCT post hoc) Very low†§
Difference in mean change from baseline in whole-lung QLF third tertile scores at 48 wk MD, −1.40 (−1.84 to −0.96)* Tocilizumab N = 33 (22; 11) 1 (23) (RCT post hoc) Very low†§
 Mortality Adverse events resulting in death at 24 wk RR, 1.02 (0.07 to 15.84) Neither N = 87 (43; 44) 1 (20) (RCT) Low†
Adverse events resulting in death between 0 and 48 wk RR, 1.02 (0.12 to 8.94) (see Figure E3) Neither N = 223 (111; 112) 2 (6, 20) (2 RCT) Moderate§
Continuous subcutaneous tocilizumab for 96 wk vs. subcutaneous placebo from Weeks 0 to 48, subcutaneous tocilizumab from Weeks 48 to 96 (Note the placebo group in this section is mixed)
 Disease progression Absolute decrease from baseline > 0% predicted FVC at 96 wk RR, 1.11 (0.59 to 2.08) Neither N = 50 (26; 24) 1 (21) (open-label extension of RCT) Very low†‡
Absolute decrease from baseline > 10% predicted FVC at 96 wk RR, 0.93 (0.06 to 14.03) Neither N = 50 (26; 24) 1 (21) (open-label extension of RCT) Very low†‡
Difference in mean change between 48 and 96 wk (open-label period) in % predicted FVC MD, −1.30 (−1.66 to −0.94)* Control N = 103 (53; 50) 1 (22) (open-label extension of RCT) Very low†‡
Difference in mean change between 48 and 96 wk (open-label period) in absolute FVC (ml) MD, −54.90 (−67.99 to −41.81)* Control N = 103 (53; 50) 1 (22) (open-label extension of RCT) Very low†‡
Difference in mean change from baseline in % predicted FVC at 96 wk MD, 1.75 (−1.66 to 5.16) (see Figure 2) Neither N = 157 (82; 75) 2 (21, 22) (2 open-label extensions of RCT) Low‡
Difference in mean change from baseline in absolute FVC (ml) at 96 wk MD, 128.70 (110.35 to 147.05)* Tocilizumab N = 104 (54; 50) 1 (22) (open-label extension of RCT) Very low†‡
Difference in mean change between 48 and 96 wk (open-label period) in % predicted DlCO MD, 5.40 (4.77 to 6.03)* Tocilizumab N = 100 (57; 43) 1 (22) (open-label extension of RCT) Very low†‡
Difference in mean change from baseline in % predicted DlCO at 96 wk MD, 3.44 (−3.32 to 10.20) (see Figure 3) Neither N = 146 (76; 70) 2 (21, 22) (2 open-label extensions of RCT) Low‡
Decrease ⩾ 20% from baseline in modified Rodnan skin score at 96 wk RR, 1.26 (0.87 to 1.83) Neither N = 61 (30; 31) 1 (21) (open-label extension of RCT) Very low†‡
Decrease ⩾ 4.7 units (MCID) from baseline in modified Rodnan skin score at 96 wk RR, 1.20 (0.84 to 1.70) Neither N = 61 (30; 31) 1 (21) (open-label extension of RCT) Very low†‡
Decrease ⩾ 40% from baseline in modified Rodnan skin score at 96 wk RR, 1.19 (0.69 to 2.06) Neither N = 61 (30; 31) 1 (21) (open-label extension of RCT) Very low†‡
Decrease ⩾ 60% from baseline in modified Rodnan skin score at 96 wk RR, 0.89 (0.34 to 2.33) Neither N = 61 (30; 31) 1 (21) (open-label extension of RCT) Very low†‡
Difference in mean change between 48 and 96 wk (open-label period) in modified Rodnan skin score MD, 0.80 (0.61 to 0.99)* Control N = 104 (54; 50) 1 (22) (open-label extension of RCT) Very low†‡
Difference in mean change from baseline in modified Rodnan skin score at 72 wk MD, −4.10 (−7.97 to −0.24)* Tocilizumab N = 61 (30; 31) 1 (21) (open-label extension of RCT) Very low†‡
Difference in mean change from baseline in modified Rodnan skin score at 96 wk MD, −0.20 (−0.54 to 0.15) (see Figure E2) Neither N = 166 (84; 82) 2 (21, 22) (2 open-label extension2 of RCT) Low‡
 Mortality Adverse events resulting in death between 48 and 96 wk RR, 0.96 (0.14 to 6.68) (see Figure E4) Neither N = 175 (90; 85) 2 (21, 22) (2 open-label extensions of RCT) Low‡
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Definition of abbreviations: CI = confidence interval; DlCO = diffusing capacity of the lung for carbon monoxide; FVC = forced vital capacity; HRCT = high-resolution computed tomography; LM = lung most affected; LS = least squares; MCID = minimal clinically important difference; MD = mean difference; MedianD = median difference; QILD = Quantitative Interstitial Lung Disease; QLF = Quantitative Lung Fibrosis; RCT = randomized controlled trial; RR = relative risk; WL = whole lung.

*

Denotes statistical significance.

†

Downgraded for imprecision.

‡

Downgraded for crossover during open-label period.

§

Downgraded for indirectness.

Disease progression was measured through changes in lung function and indirectly using the mRSS. Between the tocilizumab and placebo arms, the decrease in FVC from baseline was less in the tocilizumab arm compared with placebo at 24 weeks (MD, 118 ml; CI, 31 to 205 ml), 48 weeks (MD, 241 ml; CI, 124 to 358 ml), and 96 weeks (open-label period) (MD, 129 ml; CI, 110 to 141 ml). This was also noted with the FVC% predicted, with less decrease in the tocilizumab arm for the mean change from baseline to 48 weeks (MD, 6.50%; CI, 3.40% to 9.50%) and the median change from baseline to 48 weeks (median difference, 3.40%; CI, 0.40% to 5.60%). These met the minimum clinically important difference for FVC change, indicating clinical significance (24). The difference in mean change from baseline in FVC% predicted was not significant at 96 weeks (MD, 1.75%; CI, −1.66% to 5.16%; I2 = 99.5%) when the placebo arm also received tocilizumab (Figure 2). The risk of FVC% predicted decreasing by >10% was less in the tocilizumab arm (RR, 0.34; CI, 0.13 to 0.88), whereas the risk of FVC% predicted increasing was higher in the tocilizumab arm (RR, 1.97; CI, 1.14 to 3.42) at 48 weeks, with no significant difference at 96 weeks (open-label period with placebo arm also receiving tocilizumab). When focusing further on the open-label period from 48 to 96 weeks when both arms received tocilizumab, the mean change in absolute FVC (MD, −54.90 ml; CI, −68.00 to −41.80 ml) and FVC% predicted (MD, −1.30%; CI, −1.66% to −0.94%) both favored the original placebo arm.

Figure 2.

Figure 2.

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Difference in mean change from baseline in forced vital capacity (FVC)% predicted at 96 weeks. CI = confidence interval; MD = mean difference.

From baseline to 48 weeks, the mean change in the DlCO% predicted was less in the tocilizumab arm compared with placebo (MD, 1.50%; CI, 0.79% to 2.21%). Between 48 and 96 weeks, this trend persisted (MD, 5.40%; CI, 4.77 to 6.03). At 96 weeks, this difference was not significant (MD, 3.44%; CI, −3.32% to 10.20%; I2 = 99.8%) (Figure 3).

Figure 3.

Figure 3.

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Difference in mean change from baseline in diffusing capacity of the lung for carbon monoxide (DlCO)% predicted at 96 weeks. CI = confidence interval; MD = mean difference.

The QILD and QLF scores favored the tocilizumab arm across all categories evaluated. These included differences in mean change in baseline to 48 weeks in scores for QILD-WL (MD, −3.30; CI, −3.56 to −3.04) and QLF-WL (MD, −1.20; CI, −1.26 to −1.14) as well as median changes for QILD-WL (median difference, −3.30; CI, −4.30 to −0.70) and QLF-WL (median difference, −0.60; CI, −1.20 to −0.30).

The mRSS change from baseline significantly favored the tocilizumab arm at 72 weeks (MD, −4.10; CI, −7.97 to −0.24) and favored the placebo arm across the period from 48 to 96 weeks (MD, 0.80; CI, 0.61 to 0.99). There was no significant difference between arms for other mRSS parameters, including the difference in mean change in mRSS from baseline at 24 weeks (MD, −2.70; CI, −5.85 to 0.45), 48 weeks (MD, −1.57; CI, 3.82 to 0.69; I2 = 49.5%) (Figure E1), or 96 weeks (MD, −0.20; CI, −0.54 to 0.15; I2 = 0%) (Figure E2).

Important outcomes

Quality-of-life measures assessed using patient questionnaires favored the placebo arm that received tocilizumab when looking at data from the open-label period extending to 96 weeks as noted here: HAQ-DI (MD, 0.16; CI, 0.11 to 0.21), FACIT-Fatigue (MD, −7.11; CI, −8.37 to −5.85), patient global VAS (MD, 12.64; CI, 9.22 to 16.06), and 5-D Itch (MD, 1.20; CI, 0.62 to 1.78) (Table E2). These values were not significant when looking at the data for 48 weeks in the original study (20).

In regard to AEs (Table E2), the tocilizumab arm was associated with a decrease in hypersensitivity events (MD, −3.80; CI, −5.32 to −2.28), AEs (MD, −44.10; CI, −54.84 to −33.36), AEs leading to treatment discontinuation (MD, −7.60; CI, −9.56 to −5.64), infectious serious AEs (MD, −9.10; CI, −10.68 to −7.52), and serious AEs (MD, −27.40; CI, −30.10 to −24.70), all assessed per 100 patient-years from 0 to 48 weeks. Between 48 and 96 weeks, this pattern was also seen with the tocilizumab arm with fewer AEs (MD, −96.70; CI, 105.50 to −87.90), infectious serious AEs (MD, −5.60; CI, −6.72 to −4.48), and serious AEs (MD, −8.60; CI, −10.94 to −6.26), all assessed per 100 patient-years. However, the placebo arm had fewer injection site reactions (MD, 10.20; CI, 8.71 to 11.69) per 100 patient-years at 48 weeks and hypersensitivity events excluding injection site reactions (MD, 6.80; CI, 5.46 to 8.14) per 100 patient-years at 48–96 weeks.

Quality of evidence

All the above outcomes had very low GRADE because of indirectness of evidence and imprecision. Given the two original studies included did not a priori require presence of ILD as part of the enrollment criteria (although 65% of those in the focuSSced trial were deemed subsequently to have ILD), and because the additional studies were two open-label extensions and a post hoc analysis of the original studies, the majority of evidence was indirect, and the small number of studies with small sample sizes led to imprecision.

Discussion

This systematic review was conducted to assess the effect of treatment with tocilizumab on SSc-ILD to inform an expert panel from the ATS in formulating recommendations for a clinical practice guideline (8). Two RCTs were included together with their open-label extensions and a post hoc analysis to arrive at the findings for this review. There was consistent benefit in the critical outcomes in favor of tocilizumab. Changes in disease progression measurements (lung function, quantitative changes in the lung on HRCT, and, indirectly, mRSS) favored the tocilizumab arm over placebo. In addition, there was a trend toward a reduction in lung function decline in the open-label periods, when placebo arms from the original studies were given tocilizumab. Interestingly, this placebo group that was transitioned to tocilizumab also was found to have improvement in quality-of-life measures as assessed by various questionnaires. Aside from an increase in injection site reactions, AEs were less overall in the tocilizumab arm (including AEs leading to treatment discontinuation, infectious serious AEs, and serious AEs). However, it is worth noting that an RCT setting may actually underestimate the frequency and risk of AEs that may be observed in the real world.

Despite the significant findings, in particular for the critical outcomes, there are several limitations to the data available for this review. First of all, the change in mRSS was the primary outcome for both the faSScinate and focuSSced trials, with changes in lung function parameters and mortality secondary. In addition, the presence of ILD was not an inclusion criterion in these studies (although in the focuSSced trial 65% of participants were deemed to have SSc-ILD based on visual read of HRCT by thoracic radiologists), and baseline descriptions of ILD severity could not be obtained. Given the limited number of studies with small sample sizes, lack of a priori identification of SSc-ILD as an inclusion criterion, lack of lung function parameters and mortality as primary endpoints, and the open-label and post hoc nature of the analyses, the data obtained are imprecise and the evidence indirect. In addition, given the data were aggregated, there was no way to account for immortal time bias. The majority of the outcome measurements came from the focuSSced trial, and a few data points incorporated the faSScinate trial as well. Last, funding for the key studies included was provided by the drug company, potentially introducing biases that cannot be calculated. All these resulted in high statistical heterogeneity in the data meta-analyzed. Therefore, the quality of the evidence as determined by GRADE criteria is very low, so the significant findings noted above should be interpreted with caution, because the confidence in the estimated effects is low.

It is worth noting that, compared with the data available for tocilizumab, other agents also used for treatment of SSc-ILD, including cyclophosphamide, mycophenolate, rituximab, and nintedanib, have more robust data in relation to effects on lung function (12, 25–29). Although the scope of this review focused on evaluating the effect of tocilizumab, separate systematic reviews and meta-analyses were prepared for the guideline committee to evaluate treatment with cyclophosphamide (30), mycophenolate (31), rituximab (32), nintedanib (33), and pirfenidone (34). Because no direct comparison among therapeutic agents was assessed in these reviews, it is difficult to directly address when to use tocilizumab and when to use any of the other agents noted above. Further research is needed comparing the use of tocilizumab to other SSc-ILD therapies. In the interim, tocilizumab remains an effective option for treatment of patients with SSc-ILD that has been approved by the FDA, despite low-quality evidence, because of a high potential for benefit with a limited side effect profile. Given the limitations in the data noted above, consideration for the use of tocilizumab in patients with SSc-ILD should take into account patient characteristics, values, and preferences.

Conclusions

Tocilizumab is associated with reduced disease progression (assessed by changes in lung function, radiologic changes, and, indirectly, mRSS) and fewer serious AEs in patients with SSc-ILD. However, the findings are based on very low-quality evidence so should be interpreted with caution.

Footnotes

Supported by Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service, Career Development Award 1IK2RX003535-01A2 (M.M.); and the American Thoracic Society.

Author Contributions: M.G., G.R., S.B.M., and R.M.S. conceived the manuscript. S.L.K. performed the literature search. M.G. and T.H. screened articles and performed data extraction. M.G. drafted the manuscript, and all authors contributed to changes and approved the final manuscript.

This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

Author disclosures are available with the text of this article at www.atsjournals.org.

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