What is the role of Tocilizumab (Interleukin-6 receptor antagonist) in treating scleroderma?

Tocilizumab in Systemic Sclerosis

Tocilizumab should be considered for SSc-associated interstitial lung disease (SSc-ILD) and may be considered for skin fibrosis in early, inflammatory diffuse cutaneous SSc, but it is not a first-line therapy in treatment-naïve patients. 1, 2

Role in SSc-ILD Treatment

Tocilizumab is FDA-approved for slowing the rate of decline in pulmonary function in adult patients with SSc-ILD. 3 The evidence supporting this indication comes from phase 2 and phase 3 trials where lung function was assessed as a prespecified secondary endpoint:

• In the 24-week phase 2 trial, tocilizumab demonstrated significantly smaller FVC decline compared to placebo (−34 mL vs −171 mL; p=0.0368) 1
• In the 48-week phase 3 trial, the difference in FVC% predicted change was 4.2% (95% CI 2.0 to 6.4; nominal p=0.0002) favoring tocilizumab 1
• Long-term data through 96 weeks showed sustained preservation of lung function, with mean FVC change of -0.5% in continuous tocilizumab versus -3.3% in placebo-tocilizumab groups 4

The magnitude of effect was substantial despite tocilizumab being investigated without background immunosuppressive therapy in an early, inflammatory population. 1

Treatment Algorithm for SSc-ILD

First-Line Options (Choose Before Tocilizumab)

Mycophenolate mofetil (MMF), cyclophosphamide, or rituximab should be considered as first-line treatment for SSc-ILD. 1, 2 The 2025 EULAR guidelines and ACR/ATS guidelines conditionally recommend mycophenolate as the preferred first-line therapy across all systemic autoimmune rheumatic disease-associated ILD subtypes. 2

• MMF 1-1.5g twice daily has Level 1A evidence as first-line therapy 2
• Rituximab 375 mg/m² weekly for 4 weeks is an alternative first-line option, particularly if musculoskeletal involvement is prominent 2
• Nintedanib should be considered alone or in combination with MMF for progressive fibrosing ILD 1

When to Consider Tocilizumab

Tocilizumab becomes appropriate for SSc-ILD in two specific scenarios: 1, 2

1. Disease progression despite first-line treatment with MMF, rituximab, or cyclophosphamide 2
2. Early inflammatory dcSSc with contraindications or intolerance to first-line agents, characterized by:
   • Disease duration <5 years 2
   • Elevated CRP/ESR 2
   • Progressive skin thickening with mRSS >10 2

Role in Skin Fibrosis

Tocilizumab may be considered for skin fibrosis in patients with early, inflammatory diffuse cutaneous SSc, but the evidence does not support it as first-line therapy. 1

Evidence for Skin Involvement

• Phase 2 trial (87 patients with mRSS>15): LSM change in mRSS at 48 weeks was −6.33 for tocilizumab vs −2.77 for placebo (difference −3.55,95% CI −7.23 to 0.12; p=0.0579) 1
• Phase 3 trial (210 patients with mRSS>10): LSM change at 48 weeks was −6.14 for tocilizumab vs −4.41 for placebo (difference −1.73,95% CI −3.78 to 0.32; p=0.10) 1
• Neither trial met statistical significance for the primary skin endpoint, though a trend toward benefit was observed with satisfactory safety profile 1
• Real-world data showed mean mRSS improvement of -6.9 ± 5.9 after 1 year in refractory patients (P < 0.001) 5

Preferred First-Line Options for Skin Fibrosis

Methotrexate, MMF, or rituximab should be considered before tocilizumab for skin fibrosis in early disease with significant skin involvement. 1, 6 Rituximab has the strongest evidence with absolute mRSS improvement of −8.44 (95% CI −11.00 to −5.88; p<0.0001) at 24 weeks in a double-blind RCT. 1

Dosing and Administration

For SSc-ILD, the recommended dose is 162 mg subcutaneously every week. 3 The FDA label specifies that tocilizumab should not be initiated in SSc patients with:

• Absolute neutrophil count (ANC) below 2000 per mm³ 3
• Platelet count below 100,000 per mm³ 3
• ALT or AST above 1.5 times the upper limit of normal 3

Safety Profile

Long-term safety through 96 weeks was consistent with the known tocilizumab safety profile. 4 Rates of serious adverse events from weeks 48-96 were 14.8 per 100 patient-years for placebo-tocilizumab and 15.8 for continuous-tocilizumab. 4

Common pitfalls include recurrent digital ulcer infections, which occurred in 3 of 21 patients in real-world experience. 5 The boxed warning emphasizes risk of serious infections including tuberculosis, bacterial, invasive fungal, viral, and opportunistic infections. 3

Critical Pitfalls to Avoid

• Do not use tocilizumab as first-line therapy in treatment-naïve SSc patients without establishing disease severity, inflammatory phenotype, and considering standard first-line options 2
• Do not delay baseline pulmonary function testing including FVC, DLCO, and high-resolution CT chest to quantify ILD severity before initiating any therapy 2
• Do not assume tocilizumab will improve established fibrotic lung disease—the benefit is in slowing decline, not reversing existing fibrosis 1, 4
• Perform testing for latent tuberculosis before initiating tocilizumab and monitor all patients for active TB during treatment 3

Patient Selection Nuances

The pathogenic role of IL-6 differs depending on disease phase and organ involvement. 7 IL-6 influence is greater in:

• Patients at relatively early phase of disease 7
• Patients with lung lesions 7
• Patients with elevated acute-phase reactants 1, 4

Patients with higher IL-13 levels may have already lost the influence of IL-6, making tocilizumab less effective. 7 This underscores the importance of selecting patients with early, inflammatory disease phenotype rather than late-stage fibrotic disease.