Continuing Education Activity

This activity examines the wide-ranging applications of tocilizumab, a humanized monoclonal antibody approved by the FDA for managing rheumatoid arthritis (RA), giant cell arteritis (GCA), polyarticular juvenile idiopathic arthritis (PJIA), systemic juvenile idiopathic arthritis (SJIA), and COVID-19 pneumonia. The program elucidates the intricate mechanisms of action underlying tocilizumab's efficacy, detailing its authorized uses across diverse patient populations. Emphasis is placed on the interprofessional healthcare team's pivotal role in comprehending therapeutic considerations, potential adverse effects, and nuanced decision-making associated with tocilizumab, particularly in off-label contexts such as COVID-19 treatment.

This educational initiative underscores the need for healthcare professionals to critically analyze tocilizumab's roles and limitations, fostering a deeper understanding of its implications for patient care in rheumatological conditions and infectious diseases. Participants will gain insights into optimizing tocilizumab's use, considering the interprofessional team's collaborative efforts and coordinated approaches. The activity aims to empower healthcare practitioners with the knowledge necessary for informed prescription and strategic implementation of tocilizumab in diverse clinical settings, contributing to improved patient outcomes and management across a spectrum of rheumatological and infectious diseases.

Objectives:

• Identify patients suitable for tocilizumab therapy based on their clinical presentation and disease characteristics.

• Implement appropriate protocols for administering tocilizumab, including dosage adjustments and tailored treatment strategies.

• Assess patient response to tocilizumab therapy, monitoring therapeutic efficacy and potential adverse effects.

• Implement effective communication with patients about tocilizumab therapy's benefits, risks, and potential outcomes, ensuring informed decision-making.

Indications

FDA-Approved Indications

• Cytokine release syndrome (Severe or life-threatening, CAR T-Cell therapy)
  • Patients ≥2 years of age with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS)

• Giant cell arteritis
  • Adult patients
  • Stone JH et al conducted a clinical trial where 251 patients were randomly assigned treatment with tocilizumab weekly or every other week given subcutaneously at a dose of 162 mg, which was combined with a 26-week tapering of prednisone or placebo combined with a tapering of prednisone over 26 weeks or 52 weeks. The primary outcome of the clinical trial was the measurement of prednisone-free remission at week 52 in each tocilizumab cohort, which was compared with the placebo cohort undergoing the 26-week prednisone tapering. The secondary outcome of the clinical trial was the remission rate in each tocilizumab group compared with the placebo group participating in the 52-week prednisone taper. Long-term use of prednisone can cause undesirable adverse effects, eg, Cushing syndrome. Therefore, drugs that can maintain immunosuppression of the disease while decreasing the need for prednisone could help treat patients with giant cell arteritis. The researchers observed sustained immunosuppressive activity at 52 weeks in weekly treatment of tocilizumab in 56% of the patients and 53% in those treated with tocilizumab every other week. The placebo cohorts had much less sustained remissions. In the 26-week prednisone tapering cohort receiving a placebo, 14% of the patients demonstrated sustained immunosuppressive activity, and in the 52-week prednisone tapering cohort receiving a placebo, 18% of the patients demonstrated sustained immunosuppressive activity. Tocilizumab versus placebo in both the 26 and 52-week treatment cohorts were found to be statistically significant. Stone JH et al concluded that tocilizumab supported immunosuppressive activity while tapering the prednisone dose was clinically better than prednisone tapering receiving placebo.[1]

• Polyarticular juvenile idiopathic arthritis
  • Patients ≥2 years old
  • Brunner H. et al conducted a 2-year clinical trial on patients (ages 2 to 17) with systemic juvenile idiopathic arthritis with tocilizumab treatment who did not respond to methotrexate therapy. The trial was divided into 3 parts. In part 1 (N = 188), patients received tocilizumab every 4 weeks at a dose of 8 or 10 mg/kg, depending on body weight. In part 2 (N = 166), patients who responded well to treatment (based on JIA-ACR30 response, ie, 30% improvement) at week 16 were randomly assigned to continued tocilizumab treatment or placebo until week 40. In part 3 (N = 160), all patients received treatment with tocilizumab. At week 104, tocilizumab efficacy was assessed using the JIA-ACR50/70/90 response criteria, ie, 50%, 70%, or 90% improvement. Brunner H. et al concluded that tocilizumab provided therapeutic efficacy.[2]

• Rheumatoid arthritis (Moderate to severe)
  • Adults experiencing poor management with disease-modifying antirheumatic drug (DMARD) treatment
  • Finzel S. et al conducted a prospective observational clinical trial that was not randomized in 66 patients with rheumatoid arthritis who received either combination therapy of methotrexate/adalimumab (N = 33) or monotherapy of tocilizumab (N =33). Bone erosion volumes were measured in metacarpal heads, and the radius was measured by CT scan at baseline and after 52 weeks. Methotrexate/adalimumab and tocilizumab treatments reduced bone erosion in the metacarpal heads and radius. Finzel S. et al concluded that tocilizumab monotherapy demonstrated better repair of existing bone erosions than the combination treatment of methotrexate/adalimumab.[3]

• Systemic juvenile idiopathic arthritis
  • Patients ≥2 years old

• Systemic sclerosis-associated interstitial lung disease
  • Decrease the rate of decline of pulmonary lung function in adults

Off-Label Uses

• SARS-CoV-2 (COVID-19) - Emergency Use Authorization (EUA)
  • The Infectious Diseases Society of America recommends treatment with tocilizumab and a glucocorticoid (eg, dexamethasone) in hospitalized adults with declining blood oxygen saturation levels (eg, pulse oximetry ≤94%) and patients on mechanical ventilation or oxygenation with signs of increased systemic inflammation (eg, C-reactive protein).
  • The National Institutes of Health recommends treatment with tocilizumab and a glucocorticoid (eg, dexamethasone) in hospitalized patients with rapidly declining pulmonary function. For example, hospitalized patients who are candidates for intensive care unit (ICU) admission and require mechanical ventilation or oxygenation or hospitalized patients with rapidly declining pulmonary function requiring ventilation or oxygenation with signs of increased systemic inflammation.
  • A clinical trial by Gordon et al observed that ICU COVID-19 pneumonia patients had improved clinical outcomes, including survival with tocilizumab treatment.[4]
  • A clinical trial by Salama C. et al observed that in hospitalized COVID-19 pneumonia patients who were not on mechanical ventilation, tocilizumab treatment reduced the risk of progression to mechanical ventilation or death. However, the drug did not increase patient survival.[5]

• Cytokine release syndrome (Severe or life-threatening, BiTE therapy)
  • Tocilizumab may effectively treat adult and pediatric patients with cytokine release syndrome caused by bi-specific T-cell engaging (BiTE) cancer therapy.[6]

Mechanism of Action

Tocilizumab is a monoclonal antibody that selectively binds to the interleukin-6 receptor and prevents IL-6 from binding to its receptor (IL-6R) on the liver, lung, and synovial fibroblasts, as examples, to treat autoimmune and inflammatory conditions.[7] IL-6 is an important mediator of chronic inflammation. In the liver, IL-6 can increase the production of C-reactive protein (CRP), serum amyloid A, fibrinogen, and hepcidin and decrease albumin synthesis. These liver mediator effects can cause amyloidosis, cardiovascular events, edema, and anemia. Tocilizumab's IL-6R blocking effects in the lungs are the mechanism for treating COVID-19 pneumonia. IL-6 can activate synovial fibroblasts in the joints to increase angiogenesis, vascular permeability, and the production of vascular endothelial growth factor (VEGF). This can lead to increased edema and joint swelling, most commonly in the hands. Thus, tocilizumab's blocking of IL-6 effects in synovial fibroblasts would be beneficial in treating rheumatoid arthritis.[8]

Pharmacokinetics

Absorption

In clinical trials, the mean observed steady-state predose tocilizumab concentrations in week 24 were 40 μg/mL and 7.4 μg/mL for subcutaneous weekly and bi-weekly dosing, respectively, and 18 μg/mL for IV dosing. These studies found that body weight was an important factor affecting clearance and volume of distribution. These trials supported the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.[9]

Distribution

Tocilizumab has a central volume of distribution approximately between 3.5 L and 4.09 L, with a steady-state volume of distribution of 6.4 L in adult patients. In pediatric patients, the central volume of distribution is approximately 2.0 L, and the steady-state volume of distribution is around 4.0 L.

Metabolism

As with other monoclonal antibodies, tocilizumab is metabolized into smaller proteins and amino acids by proteolytic enzymes and has minimal hepatic metabolism via the CYP450 enzymatic system.

Elimination

Tocilizumab's half-life is 5 to 13 days. Clearance appears to be dose-dependent, non-linear at lower doses, and linear at higher doses.

Administration

Adult Dosing, Dosage Forms and Strength

Tocilizumab is administered intravenously (IV) or subcutaneously (SQ).

• Cytokine release syndrome
  • >30 kg: 8 mg/kg IV, maximum 800 mg/dose; may be used as monotherapy or in combination with a glucocorticoid.
  • If no clinical improvement occurs after the first dose, 3 additional doses may be administered in at least 8-hour intervals.
• Giant cell arteritis
  • 162 mg SQ once weekly, combined with a tapering dose of a glucocorticoid.
  • 6 mg/kg/dose IV every 4 weeks; maximum 600 mg/dose in combination with a glucocorticoid. 
• Rheumatoid arthritis
  • 4 mg/kg IV once every 4 weeks may increase to 8 mg/kg IV once every 4 weeks, with a maximum dosage of 800 mg/dose, monotherapy, or with methotrexate or a nonbiologic DMARD.
  • >100 kg: 162 mg SQ once every week, <100 kg, 162 mg SQ once every other week, monotherapy or with methotrexate or a nonbiologic DMARD.
• Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
  • 162 mg SQ once every week.
• Polyarticular juvenile idiopathic arthritis (PJIA)
  • <30 kg: 10 mg/kg IV once every 4 weeks; >30 kg: 8 mg/kg IV once every 4 weeks, maximum 800 mg/dose.
  • <30 kg: 162 mg SQ once every 3 weeks; >30 kg: 162 mg SQ once every 2 weeks.
• Systemic juvenile idiopathic arthritis (SJIA)
  • <30 kg: 12 mg/kg IV once every 2 weeks; >30 kg: 8 mg/kg IV once every 2 weeks.
  • <30 kg: 162 mg SQ once every 2 weeks; >30 kg: 162 mg SQ once every week.
• COVID-19
  • 8 mg/kg/dose IV for a single dose.

When the absolute neutrophil count (ANC) <2,000/mm³, platelet count <100,000/mm³, alanine aminotransferase (ALT) or aspartate (AST) >1.5 times the upper limit of normal (ULN), the manufacturer recommends that tocilizumab not be initially given to patients with rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, or systemic sclerosis-associated interstitial lung disease. The manufacturer recommends discontinuing tocilizumab therapy if the ALT or AST becomes more than 5 times the ULN, ANC <500 cells/mm³, or platelets <50,000 cells/mm³.

A clinical study by Salama C. et al treated adult COVID-19 pneumonia patients at a dose of 8 mg/kg IV, similar to treating cytokine release syndrome. Seven days before or during the study, 80% of the tocilizumab cohort and 88% of the placebo cohort received a glucocorticoid (eg, dexamethasone). Also, about 79% of the patients in the tocilizumab or placebo treatment arms received antiviral treatment (eg, remdesivir).[5]

Special Patient Populations

Hepatic impairment

For COVID-19: avoid use in patients with baseline AST/ALT >10 times the upper normal limit.

Renal impairment

No adjustment is necessary for patients with CrCl >30. For CrCl <30, dose adjustments are undefined.

Pregnant women

Clinicians should weigh the risk vs benefit in pregnant patients. Insufficient human data is available, but there is a possible risk of embryo-fetal toxicity based on animal studies.

Breastfeeding women

Tocilizumab can be used while breastfeeding; no human data exists, but based on drug characteristics, there is no risk of infant harm. There is no human data regarding the effects on milk production.

Pediatric patients

See dosing for juvenile patients above.

Older patients

A study determined older patients experienced therapeutic improvement similar to younger patients with only slightly higher adverse event rates, demonstrating a favorable risk-benefit ratio with tocilizumab therapy regardless of age.[10]

Adverse Effects

Common (>10 %)

• Increased plasma cholesterol (19% to 20%)
  • Children, teenagers (<2%)
• Increased plasma ALT (<36%) and AST (<22%) [11]
• SQ injection site reaction (7% to 10%)
  • Children, teenagers (15% to 44%)
• Infusion-related reaction (4% to 20%)

Less Common (1% to 10%)

• Hypertension (6%)
• Peripheral edema (<2%)
• Rash
• Hypothyroidism (<2%)
• Diarrhea
  • Children, teenagers (>5%)
• Gastric ulcer (<2%)
• Gastritis (1%)
• Oral mucosl ulcers (2%)
• Stomatitis (<2%)
• Upper abdominal pain (2%)
• Weight gain (<2%)
• Leukopenia (<2%)
• Neutropenia
  • Children, teenagers <30 kg, grade 3 (26%)
  • Children, teenagers >30 kg, grade 3 (4%)
  • Adults, grade 3 (3% to 4%)
• Thrombocytopenia (1%)
• Neutralizing antibody development (<1%)
• Herpes simplex infection (<2%)
• Dizziness (3%)
• Headache (7%)
• Conjunctivitis (<2%)
• Nephrolithiasis (<2%)
• Bronchitis (3%)
• Cough (<2%)
• Dyspnea (<2%)
• Nasopharyngitis (7%)
• Upper respiratory tract infection (7%)

The following are reported postmarketing adverse drug reactions: Stevens-Johnson syndrome, cellulitis, diverticulitis, pancreatitis, urinary tract infection, hepatic failure, hepatitis, anaphylaxis, hypersensitivity reaction, aspergillosis, candidiasis, cryptococcosis, tuberculosis, pneumocystis pneumonia, varicella-zoster infection, chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis.

Drug-Drug Interactions

Tocilizumab is contraindicated with live vaccines and with talimogene laherparepvec. The drug should not be used concomitantly with many other immunosuppressive monoclonal antibodies due to the risk of severe infection. Tocilizumab may also decrease the effectiveness of oral hormonal contraceptives. Tocilizumab may increase the serum levels of metabolized drugs via the hepatic CYP450 system. Careful medication reconciliation is necessary when placing patients on tocilizumab.

Contraindications

A contraindication tocilizumab therapy is a hypersensitivity reaction to the tocilizumab dosage form. Some of the tocilizumab dosage forms may contain polysorbate 80. Polysorbate 80 can cause a delayed hypersensitive reaction in allergic patients.[12][13][14] In premature infants with a hypersensitivity reaction, it can cause damage to the lungs, liver, and kidneys, as well as cause thrombocytopenia and ascites.[15][16]

Box Warning

Tocilizumab carries an FDA box warning for an increased risk of serious infections. Many patients taking tocilizumab may also take an immunosuppressant, eg, methotrexate, glucocorticoid, etc. Examples of potential infections are tuberculosis, aspergillosis, candidiasis, cryptococcosis, and varicella-zoster infection. Therefore, the healthcare team needs to monitor for signs of infection.

Monitoring

Monitoring parameters depend on the indication:

• For RA, giant cell arteritis, or SSc-ILD:
  • Patients should have the following baseline tests: hepatitis B serology, including HBsAg, TB test, AST/ALT, alkaline phosphatase, and total bilirubin every 4 to 8 weeks for 6 months, then every 3 months. They should also have a baseline ANC and platelets at 4 to 8 weeks, then every 3 months. Finally, a lipid panel should be performed 4 to 8 weeks following treatment initiation.
• For PJIA:
  • Patients should have the following baseline tests: hepatitis B serology, including HBsAg, TB test, AST/ALT, alkaline phosphatase, total bilirubin, ANC, and platelets, then at the 2nd infusion, then every 4 to 8 weeks. A lipid panel should be performed 4 to 8 weeks following treatment initiation.
• For SJIA:
  • Patients should have the following baseline tests: hepatitis B serology, including HBsAg, TB test, AST/ALT, alkaline phosphatase, total bilirubin, ANC, and platelets, then at the 2nd infusion, then every 2 to 4 weeks. A lipid panel should be performed 4 to 8 weeks following treatment initiation.
• For COVID-19:
  • Patients should have AST/ALT, ANC, and platelets at baseline and during treatment.[17]

The healthcare team should monitor the patient for signs or symptoms of infection, eg, tuberculosis, candidiasis, etc.[18]

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team, including physicians, advanced practitioners, nurses, and pharmacists, must work collaboratively to ensure the safety and efficacy of tocilizumab therapy. The healthcare team must monitor for signs of infection, eg, aspergillosis, candidiasis, pneumocystis, tuberculosis, etc. The pharmacist should verify the dosing and perform a thorough medication reconciliation. Nurses can monitor adverse events and make preliminary assessments of treatment effectiveness on subsequent visits.

Both nurses and pharmacists need to have an open communication line with the prescribing clinician to report or discuss concerns regarding tocilizumab therapy or the patient drug regimen. This interprofessional healthcare team communication type is necessary to optimize patient outcomes with minimal adverse events for tocilizumab therapy.