What are the recommendations for using Interleukin-6 (IL-6) blocking medications, such as tocilizumab (Actemra), in adult patients with a history of chronic inflammatory conditions, like rheumatoid arthritis or giant cell arteritis?

IL-6 Blocking Medications: Clinical Overview

What Are IL-6 Inhibitors?

IL-6 blocking medications are humanized monoclonal antibodies that target the interleukin-6 receptor, effectively treating multiple inflammatory rheumatic diseases by interrupting the IL-6 inflammatory pathway. 1

The primary IL-6 receptor antagonist is tocilizumab (Actemra), with sarilumab representing another agent in this class 2. These medications work by binding to both soluble and membrane-bound IL-6 receptors, preventing IL-6 from triggering inflammatory cascades 2, 3.

FDA-Approved Indications

Tocilizumab is approved for:

• Rheumatoid arthritis (RA) in adults with moderately to severely active disease who have inadequate response to one or more DMARDs 1
• Giant cell arteritis (GCA) in adult patients 1
• Systemic sclerosis-associated interstitial lung disease (SSc-ILD) to slow pulmonary function decline 1
• Polyarticular juvenile idiopathic arthritis (pJIA) in patients ≥2 years old 1
• Systemic juvenile idiopathic arthritis (sJIA) in patients ≥2 years old 1
• Cytokine release syndrome (CRS) in patients ≥2 years old with CAR T-cell induced severe or life-threatening disease 1
• COVID-19 in hospitalized adults receiving systemic corticosteroids and requiring supplemental oxygen or mechanical ventilation 1

Dosing and Administration

Rheumatoid Arthritis

Intravenous dosing:

• Start at 4 mg/kg every 4 weeks, then increase to 8 mg/kg every 4 weeks based on clinical response 1
• Maximum dose: 800 mg per infusion 1

Subcutaneous dosing:

• Patients <100 kg: 162 mg every other week, increase to weekly based on response 1
• Patients ≥100 kg: 162 mg weekly 1

Giant Cell Arteritis

• Maximum dose: 600 mg per infusion 1
• Can be used as monotherapy or with non-biologic DMARDs 1

Critical Pre-Treatment Requirements

Do not initiate tocilizumab if: 1

• Absolute neutrophil count (ANC) <2000/mm³ (for RA, GCA, SSc-ILD, pJIA, sJIA)
• ANC <1000/mm³ (for COVID-19)
• Platelet count <100,000/mm³ (for RA, GCA, SSc-ILD, pJIA, sJIA)
• Platelet count <50,000/mm³ (for COVID-19)
• ALT or AST >1.5× ULN (for RA, GCA, SSc-ILD, pJIA, sJIA)
• ALT or AST >10× ULN (for COVID-19)

Guideline Recommendations by Disease

Rheumatoid Arthritis

• Tocilizumab is firmly established as effective therapy for adults with moderate to severe active RA, leading to rapid and sustained improvement in clinical and radiographic outcomes 2, 4
• Can be used as monotherapy or combined with methotrexate, with extensive clinical experience supporting both IV and subcutaneous regimens 2
• For patients well-controlled on an IL-6 receptor inhibitor, continue the medication when available; only switch to a different biologic if unable to access 2

Giant Cell Arteritis

• IL-6 receptor inhibitors should be continued in GCA patients with an indication, if available, even during the COVID-19 pandemic 2
• Tocilizumab greatly increases the rate of sustained remission over 1 year compared to glucocorticoids alone 5, 6
• In a phase 2 trial, 85% of tocilizumab patients achieved complete remission by week 12 versus 40% with placebo (risk difference 45%, p=0.0301) 6
• Relapse-free survival at 52 weeks was 85% with tocilizumab versus 20% with placebo (risk difference 65%, p=0.0010) 6
• Cumulative glucocorticoid dose was dramatically reduced: 43 mg/kg with tocilizumab versus 110 mg/kg with placebo (p=0.0005) 6

Adult-Onset Still's Disease (AOSD)

• EULAR strongly recommends tocilizumab as first-line biologic therapy for AOSD, not reserved for refractory cases 7
• Tocilizumab demonstrates efficacy in controlling all aspects of AOSD, including systemic manifestations and joint involvement 7
• Initiate tocilizumab before 3 months from symptom onset to optimize outcomes and potentially prevent chronic persistent disease 7
• For patients with severe polyarthritis, tocilizumab achieves articular improvement in 86% of cases 7

Takayasu Arteritis

• For patients with TAK refractory to glucocorticoids alone, conditionally recommend adding a TNF inhibitor over tocilizumab 2
• The voting panel favored TNF inhibitors due to more clinical experience and data in TAK 2
• In the only randomized trial of tocilizumab in TAK, the primary efficacy endpoint was not achieved, though a trend toward longer time to relapse was observed 2
• Tocilizumab may be considered when TNF inhibitors are contraindicated 2

Safety Profile and Monitoring

Boxed Warning: Serious Infections

Serious infections leading to hospitalization or death have occurred, including tuberculosis, bacterial, invasive fungal, viral, and opportunistic infections 1

Critical safety steps:

• Perform latent TB testing before starting tocilizumab (except in COVID-19 patients) 1
• If latent TB is positive, start TB treatment prior to tocilizumab 1
• Monitor all patients for active TB during treatment, even if initial test was negative 1
• If serious infection develops, interrupt tocilizumab until controlled 1

Comparative Safety Data

In pooled analysis of Still's disease patients: 2

• Tocilizumab serious adverse events: 36.5 per 100 patient-years versus 22.6 with IL-1 inhibitors 2, 7
• Infectious adverse events: 104.6 per 100 patient-years with tocilizumab versus 94.5 with IL-1 inhibitors overall and 18.1 with anakinra 2, 7
• Infectious serious adverse events: 12.9 per 100 patient-years with tocilizumab versus 4.1 with IL-1 inhibitors 2

Additional Monitoring Requirements

• Monitor neutrophil counts, platelet counts, and liver enzymes regularly 1
• Assess lipid levels, as tocilizumab increases cholesterol and triglycerides 5
• Watch for gastrointestinal perforations, particularly in patients with diverticulitis history 1

Clinical Decision-Making: IL-6 vs IL-1 Inhibition

When to Choose Tocilizumab

• Prominent articular disease: Tocilizumab demonstrates excellent efficacy for severe polyarthritis 7
• Giant cell arteritis: Tocilizumab is the only FDA-approved biologic for GCA 1, 5
• Established rheumatoid arthritis with inadequate DMARD response: Strong evidence base supports tocilizumab 2, 4

When to Consider IL-1 Inhibitors Instead

• Safety concerns predominate: Anakinra has the most reassuring safety profile with serious adverse events of only 10.4 per 100 patient-years 2, 7
• Predominantly systemic features in Still's disease: Either IL-1 or IL-6 inhibition is appropriate 7

Common Clinical Pitfalls

Do Not Reserve Tocilizumab Only for Refractory Cases

Current guidelines recommend early biologic initiation in appropriate patients, not sequential failure of multiple conventional agents 7. Delaying biologic therapy in patients with high disease activity risks irreversible joint damage 4.

Do Not Continue High-Dose Glucocorticoids Long-Term

Tocilizumab's primary advantage is enabling rapid glucocorticoid taper 7, 6. In the GiACTA trial, tocilizumab reduced cumulative glucocorticoid exposure by 61% 6. Failure to reduce steroids negates a major benefit of IL-6 inhibition 7.

Do Not Ignore the Therapeutic Window

Initiate tocilizumab before 3 months from symptom onset when treating Still's disease 7. Delayed initiation beyond 3 months may result in more patients developing chronic persistent disease 7. Early initiation is associated with very favorable short-term outcomes with high rates of clinical inactive disease off glucocorticoids 7.

Do Not Overlook TB Screening

Perform latent TB testing before starting tocilizumab, and if positive, start TB treatment prior to initiating IL-6 blockade 1. Monitor all patients for active TB during treatment, even if initial test was negative 1.

Do Not Combine with Other Biologics

Avoid using tocilizumab concomitantly with other biologic DMARDs or targeted synthetic DMARDs due to increased infection risk 8.

Off-Label Uses with Supporting Evidence

Tocilizumab has shown efficacy in case series and small studies for: 9, 3

• Adult-onset Still's disease (now with strong guideline support) 7, 9, 3
• Polymyalgia rheumatica 9
• Relapsing polychondritis 9
• Systemic lupus erythematosus 9
• Amyloidosis 9

Mechanism and Biomarkers

IL-6 is a multifunctional cytokine that regulates inflammatory response and immune reaction 3. Overproduction of IL-6 is pathologically involved in RA, juvenile idiopathic arthritis, and other inflammatory conditions 3.

Predictive biomarkers: Patients with highest IL-6 levels and lowest soluble IL-6 receptor (sIL-6R) levels at baseline show the best response to tocilizumab 10. In one study, 17 of 18 patients in this group had good or moderate EULAR response 10.