Clinical Experience with IV Tocilizumab

Safety and efficacy of IV tocilizumab have been evaluated in 5 randomized, double-blind studies in adults (≥18 years of age) with moderate to severe active rheumatoid arthritis.(1)(3)(4)(5)(6)(8) In these studies, tocilizumab was administered as monotherapy, in combination with methotrexate or other nonbiologic DMARDs in patients with an inadequate response to these drugs, or in combination with methotrexate in patients with an inadequate response to TNF blocking agents.(1) Patients included in these studies had 8 or more tender joints and 6 or more swollen joints.(1)(3)(4)(5)(6) Those receiving low stable dosages of corticosteroids (equivalent to 10 mg or less of prednisone daily) and/or stable dosages of nonsteroidal anti-inflammatory agents (NSAIAs) could continue such agents.(3)(4)(5)(6)(8) Tocilizumab was administered IV at a dosage of 4 or 8 mg/kg once every 4 weeks.(1)(3)(4)(5)(6)

The American College of Rheumatology (ACR) criteria for improvement (ACR response) in measures of disease activity were used as the principal measure of clinical response in studies evaluating the efficacy of tocilizumab.(1)(3)(4)(5)(6) An ACR 20 response is achieved if the patient experiences a 20% improvement in tender and swollen joint count and a 20% or greater improvement in at least 3 of the following criteria: patient pain assessment, patient global assessment, physician global assessment, patient self-assessed disability, or laboratory measures of disease activity (i.e., erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP] level).(2) An ACR 70 response is defined using the same criteria but with a level of improvement of 70%.(16)(17)(18) The proportion of patients who achieved an ACR 20 response at week 24 was the primary end point in the studies of tocilizumab.(1)(3)(4)(5)(6) In one longer-term study, the total Sharp-Genant score (a composite score of erosions and joint space narrowing in hands, wrists, and forefeet) was used as the principal measure of joint damage, and the Health Assessment Questionnaire Disability Index (HAQ-DI) was used to assess physical function and disability.(1)

Clinical evaluations of tocilizumab indicate that, in adults with active rheumatoid arthritis despite therapy with methotrexate or other nonbiologic DMARD(s), the addition of tocilizumab to the DMARD regimen is associated with greater efficacy than use of the nonbiologic DMARD(s) alone.(1)(4)(5) In addition, therapy with tocilizumab in conjunction with methotrexate has been more effective than methotrexate alone in patients with an inadequate response to prior therapy with TNF blocking agents.(1)(6) In patients with an inadequate response to prior therapy with nonbiologic DMARDs or TNF blocking agents, response rates were higher in those receiving tocilizumab 8 mg/kg IV every 4 weeks compared with those receiving 4 mg/kg IV every 4 weeks.(1)(4)(6) When tocilizumab was compared with methotrexate as monotherapy in patients with active rheumatoid arthritis, tocilizumab was more effective than methotrexate.(1)(3) Response to tocilizumab can occur 2–4 weeks following initiation of therapy in some patients.(3)(4)(5)(6)(11)

In the study evaluating efficacy of tocilizumab as monotherapy (AMBITION), patients were randomized to receive either tocilizumab (8 mg/kg IV every 4 weeks) or methotrexate (7.5 mg weekly, increased up to 20 mg weekly).(1)(3) Patients were excluded if they had received methotrexate in the past 6 months, had previously discontinued methotrexate because of lack of response or clinically important toxicity, or had previously discontinued therapy with a TNF blocking agent because of inadequate response.(1)(3) About two-thirds of the patients in the study had never received methotrexate therapy.(1)(3) An ACR 20 response was achieved in 70% of patients receiving tocilizumab and 53% of those receiving methotrexate for 24 weeks.(1)(3)

In 2 studies (OPTION and LITHE), therapy with tocilizumab given in combination with methotrexate was evaluated in patients who had not responded adequately to methotrexate; patients in these studies were randomized to receive tocilizumab 4 mg/kg IV every 4 weeks, tocilizumab 8 mg/kg IV every 4 weeks, or placebo, each given in conjunction with a stable dosage of methotrexate (10–25 mg weekly).(1)(4)(29) Patients who had been treated unsuccessfully with a TNF blocking agent were excluded from these studies.(4)(8)(29) In one study (OPTION), ACR 20 responses were achieved at 24 weeks in 59, 48, or 27% of those receiving tocilizumab 8 mg/kg and methotrexate, tocilizumab 4 mg/kg and methotrexate, or placebo and methotrexate, respectively.(1)(4) The other study (LITHE) was longer term (2 years with an optional 3-year extension phase) and was designed to assess changes in signs and symptoms of rheumatoid arthritis at 24 weeks, with subsequent assessments of joint damage and physical functioning at 1 and 2 years of treatment.(1)(8)(29) Following 1 year of treatment with the randomly assigned regimen, patients received open-label treatment with tocilizumab 8 mg/kg for an additional year or had the option to continue their double-blind treatment if improvement in swollen and tender joint count was maintained above 70%.(1) Planned interim analyses indicated that ACR 20 responses were achieved at 24 weeks in 56, 51, or 27% and at 1 year in 56, 47, or 25% of those receiving tocilizumab 8 mg/kg and methotrexate, tocilizumab 4 mg/kg and methotrexate, or placebo and methotrexate, respectively.(1) At 1 year, 7, 4, or 1% of patients receiving tocilizumab 8 mg/kg and methotrexate, tocilizumab 4 mg/kg and methotrexate, or placebo and methotrexate, respectively, had achieved major clinical responses (defined as ACR 70 responses for a continuous 24-week period).(1)(29) Findings at 1 year also indicated that treatment with tocilizumab 4 or 8 mg/kg and methotrexate inhibited progression of structural damage compared with placebo and methotrexate.(1)(29) At 1 year, 78 or 83% of patients receiving tocilizumab 4 or 8 mg/kg and methotrexate, respectively, exhibited no radiographic progression, as determined by change in total Sharp-Genant score, compared with 66% of patients receiving placebo and methotrexate.(1) Patients receiving tocilizumab 4 or 8 mg/kg and methotrexate also experienced greater improvements in physical function and disability, as assessed using HAQ-DI scores, at 1 year compared with those who received placebo and methotrexate.(1)(29) By the end of the 2-year study, most patients in the placebo and methotrexate group had crossed over to tocilizumab and methotrexate treatment.(1)

In one study (TOWARD) in patients who had not responded adequately to treatment with one or more nonbiologic DMARDs, tocilizumab (8 mg/kg IV weekly) or placebo was added to the stable background DMARD regimen.(1)(5) For 76% of patients in the study, the background regimen contained one DMARD, most commonly methotrexate (mean dosage of 15 mg weekly).(5) Patients who had been treated unsuccessfully with a TNF blocking agent or had previously received any cell-depleting therapy were excluded.(5) At 24 weeks, an ACR 20 response was achieved in 61 or 24% of those receiving tocilizumab or placebo, respectively, in conjunction with the nonbiologic DMARD(s).(1)(5)

Tocilizumab, given in combination with methotrexate, also was evaluated in one study (RADIATE) in patients with rheumatoid arthritis who had not responded adequately to, or who had not tolerated, one or more TNF blocking agents.(1)(6) Patients in this study were randomized to receive tocilizumab 4 mg/kg IV every 4 weeks, tocilizumab 8 mg/kg IV every 4 weeks, or placebo, each given in combination with methotrexate 10–25 mg weekly; tocilizumab was initiated following discontinuance of any other DMARDs and stabilization of the methotrexate dosage.(1)(6) At 24 weeks, an ACR 20 response was achieved in 50, 30, or 10% of those receiving tocilizumab 8 mg/kg and methotrexate, tocilizumab 4 mg/kg and methotrexate, or placebo and methotrexate, respectively.(1)(6)

Analysis of long-term data from the 5 studies showed that improvements from baseline in clinical measures of efficacy generally were sustained through at least 4.2 years of tocilizumab therapy.(30)

General health status was assessed by the Short Form Health Survey (SF-36) in these 5 studies.(1) Patients receiving tocilizumab demonstrated greater improvement from baseline compared with placebo in the physical and mental component summaries and in all 8 domains of the SF-36.(1)

A phase 4, multicenter, open-label randomized trial evaluated the efficacy of tocilizumab compared to rituximab in 161 patients with rheumatoid arthritis who demonstrated an inadequate response to TNF-blocking agents.(73) In this study, 161 patients were stratified based on results of synovial B-cell status determined by biopsy, and randomized to receive two 1000-mg rituximab infusions 2 weeks apart or 8 mg/kg tocilizumab monthly infusions; baseline synovial biopsies from all participants were also subjected to RNA sequencing. (73) In patients who were histologically classified as B-cell rich, no statistically significant difference between treatments was observed in the number of patients who achieved the primary outcome (50% improvement from baseline in the Clinical Disease Activity Index [CDAI]).(73) However, in patients who were classified as having poor B-cell status based on RNA sequencing, a significantly higher response rate for the primary outcome was observed in those who received tocilizumab (63%) than those who received rituximab (36%).(73)

Clinical Experience with Subcutaneous Tocilizumab

Efficacy and safety of subcutaneous tocilizumab have been evaluated in 2 double-blind, controlled studies in adults with moderate to severe active rheumatoid arthritis.(1)(22)(23) One study was a noninferiority study that compared tocilizumab 162 mg subcutaneously every week with tocilizumab 8 mg/kg IV every 4 weeks.(1)(23) The other study was a placebo-controlled superiority study evaluating tocilizumab 162 mg subcutaneously every other week.(1)(22) In these studies, the effects of subcutaneously administered tocilizumab on clinical response and progression of joint damage were consistent with the effects observed in studies evaluating IV administration of the drug.(1)

In the active-control study (SUMMACTA), 1262 patients with moderate to severe active rheumatoid arthritis were randomized in a 1:1 ratio to receive subcutaneous tocilizumab (162 mg every week) or IV tocilizumab (8 mg/kg every 4 weeks) for 24 weeks in conjunction with a stable dosage of one or more nonbiologic DMARDs.(1)(23) To be included in the study, patients were required to have at least 4 tender and 4 swollen joints and to have had an inadequate response to at least one DMARD.(1)(23) Patients receiving stable dosages of NSAIAs and/or low stable dosages of corticosteroids (equivalent to 10 mg or less of prednisone daily) could continue such agents.(23) Approximately 21% of patients included in the study had experienced an inadequate response to prior TNF-blocking agent therapy.(23) ACR 20 response at 24 weeks (the primary measure of efficacy) was observed in 69 or 73% of patients receiving subcutaneous or IV tocilizumab, respectively, establishing noninferiority of the subcutaneous regimen.(1)(23) ACR 50 and ACR 70 responses were observed in 47 and 24%, respectively, of those receiving subcutaneous tocilizumab and 49 and 28%, respectively, of those receiving IV tocilizumab.(1)(23) At 24 weeks, similar proportions of patients receiving subcutaneous or IV tocilizumab (38 or 37%, respectively) had a low level of disease activity, as defined by a Disease Activity Score in 28 joints (DAS 28) of less than 2.6.(1)(23) The mean decrease in HAQ-DI score from baseline to week 24 was 0.6 in both treatment groups, and similar proportions of patients receiving subcutaneous or IV tocilizumab (65 or 67%, respectively) achieved clinically important improvement in HAQ-DI score (change from baseline of at least 0.3 units).(1)(23)

Following the 24-week double-blind period in the SUMMACTA study, patients who had received subcutaneous tocilizumab were randomized in an 11:1 ratio to receive subcutaneous or IV tocilizumab, while those who had received IV tocilizumab were randomized in a 2:1 ratio to receive IV or subcutaneous tocilizumab in a 72-week open-label extension of the study.(24) The proportions of patients who achieved ACR responses, DAS 28 score indicating a low level of disease activity, and clinically important improvement in HAQ-DI score were maintained through week 72 (97 weeks of tocilizumab treatment) and were similar across treatment groups.(24)

In the placebo-controlled study (BREVACTA), 656 patients with moderate to severe active rheumatoid arthritis were randomized in a 2:1 ratio to receive subcutaneous tocilizumab (162 mg every other week) or placebo for 24 weeks in conjunction with a stable dosage of one or more nonbiologic DMARDs.(1)(22) To be included in the study, patients were required to have at least 8 tender and 6 swollen joints and to have had an inadequate response to at least one DMARD.(1)(22) Patients receiving stable dosages of NSAIAs and/or low stable dosages of corticosteroids (equivalent to 10 mg or less of prednisone daily) could continue such agents.(22) Approximately 21% of patients included in the study had experienced an inadequate response to prior TNF-blocking agent therapy.(22) ACR 20 response at 24 weeks (the primary measure of efficacy) was observed in 61% of patients receiving tocilizumab compared with 32% of those receiving placebo.(1)(22) In addition, ACR 50 and ACR 70 responses were observed at 24 weeks in 40 and 20%, respectively, of tocilizumab-treated patients compared with 12 and 5%, respectively, of placebo recipients.(1)(22) At 24 weeks, 32 or 4% of patients receiving tocilizumab or placebo, respectively, had a low level of disease activity, as defined by a DAS 28 score of less than 2.6.(1)(22) Less progression of joint damage, as assessed radiographically by the change in van der Heijde-modified Sharp score (a composite score of structural damage that measures joint erosions and joint space narrowing in the hands, wrists, and feet(25) ), was observed in patients receiving tocilizumab compared with those receiving placebo.(1)(22) The mean decrease in HAQ-DI score from baseline to week 24 was 0.4 or 0.3, and the proportion of patients who achieved clinically important improvement in HAQ-DI score (change from baseline of at least 0.3 units) was 58 or 47% for patients receiving tocilizumab or placebo, respectively.(1) In an open-label continuation of this study, efficacy and safety of tocilizumab were maintained for up to 2 years in patients receiving tocilizumab every 2 weeks.(74) Escalation to weekly dosing demonstrated response and tolerability in prior nonresponders.(74)

In the SUMMACTA study, the proportion of patients achieving responses (ACR responses and DAS 28 scores indicating low disease activity) to either IV tocilizumab (8 mg/kg every 4 weeks) or subcutaneous tocilizumab (162 mg every week) generally were similar regardless of body weight, but tended to be lower and more variable in the small subset of patients weighing 100 kg or more.(23) However, in the BREVACTA study, patients weighing 100 kg or more had poorer ACR responses to subcutaneous tocilizumab (162 mg every other week) than did patients in 2 lower-weight categories.(22)

Other randomized clinical studies have also demonstrated efficacy of weekly dosing of subcutaneous tocilizumab in patients with inadequate response to every-other-week dosing.(75)(76) Additionally, maintenance of efficacy has been shown in studies of tocilizumab alone (after discontinuation of methotrexate) in patients with low disease activity on methotrexate plus tocilizumab.(77)(78)

Clinical Perspective

The American College of Rheumatology issued guidelines for the treatment of rheumatoid arthritis in 2021.(2003) Recommendations for disease-modifying treatments for rheumatoid arthritis include conventional DMARDs (e.g., hydroxychloroquine, leflunomide, methotrexate, sulfasalazine), biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab, sarilumab, rituximab), and/or targeted synthetic DMARDs (e.g., Janus kinase inhibitors).(2003) Specific agents for rheumatoid arthritis treatment are selected according to current disease activity, prior therapies used, and the presence of comorbidities.(2003) A “treat-to-target” approach is typically employed, with the goal of achieving low disease activity or remission.(2003)

IL-6 inhibitors used in the treatment of rheumatoid arthritis include tocilizumab and sarilumab.(2003) Methotrexate monotherapy is strongly recommended over biologic DMARD monotherapy for DMARD-naive patients with moderate to high disease activity, because of its established safety and efficacy and lower cost.(2003) Add-on therapy with biologic DMARDs (including IL-6 inhibitors) and targeted synthetic DMARDs is conditionally recommended over triple therapy (i.e., addition of sulfasalazine and hydroxychloroquine) for patients who are taking maximally tolerated doses of methotrexate and are not at target.(2003) Recommendations for the use and selection of biologic DMARDs in rheumatoid arthritis vary based on the presence of certain comorbidities (e.g., heart failure, previous serious infection, nontuberculous mycobacterial lung disease).(2003)

Clinical Experience with IV Tocilizumab in Polyarticular Juvenile Idiopathic Arthritis

IV tocilizumab has been evaluated in a randomized, double-blind treatment-withdrawal study (CHERISH) in patients 2–17 years of age with active polyarticular JIA who had not responded adequately to or had not tolerated treatment with methotrexate.(1)(20) Patients included in this study had at least 6 months of active disease, with at least 5 joints with active arthritis (swollen or limitation of movement with pain and/or tenderness) and limitation of motion in at least 3 of the active joints.(1)(20) Disease subtypes included rheumatoid factor-positive or -negative polyarticular JIA and extended oligoarticular JIA.(1)(20) Patients receiving low stable dosages of corticosteroids (equivalent to 0.2 mg/kg or less [maximum of 10 mg] of prednisone daily) and/or a stable dosage of NSAIAs or methotrexate (10–20 mg/m² per week) could continue such therapy;(1)(20) however, concomitant use of other nonbiologic or biologic DMARDs was not permitted.(1) Approximately 32% of patients had received prior biologic DMARD therapy.(20)

During a 16-week lead-in period, all 188 patients enrolled in the study received IV tocilizumab; those weighing 30 kg or more received a dosage of 8 mg/kg every 4 weeks, while those weighing less than 30 kg were randomized to receive a dosage of either 8 or 10 mg/kg every 4 weeks.(1)(20) At week 16, all patients with JIA-ACR 30 response were randomly assigned in a 1:1 ratio (stratified by concomitant methotrexate and corticosteroid use) to continue receiving tocilizumab at the previously assigned dosage or to receive placebo for 24 weeks.(1)(20) JIA-ACR responses are defined as the percentage improvement (e.g., 30, 50, 70, or 90%) in 3 of any 6 core outcome variables compared with baseline, with worsening in no more than 1 of the remaining variables by 30% or more.(1)(20) Core outcome variables consist of physician global assessment, parent or patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and physical function (as assessed using the disability index of the Childhood Health Assessment Questionnaire [CHAQ-DI]).(1)(21)

At the end of the lead-in period, 91% of patients receiving tocilizumab in combination with methotrexate and 83% of those receiving tocilizumab monotherapy (a total of 163 patients) achieved a JIA-ACR 30 response and entered the treatment-withdrawal period; JIA-ACR 50 and JIA-ACR 70 responses were observed at the end of the lead-in period in 84 and 64%, respectively, of patients receiving tocilizumab in combination with methotrexate and 80 and 55%, respectively, of those receiving tocilizumab monotherapy.(1) Response rates for children weighing less than 30 kg and receiving the 8-mg/kg dose were numerically lower than those for the other 2 treatment groups.(20)

During the treatment-withdrawal period, a greater proportion of patients receiving placebo (48%) compared with those receiving tocilizumab (26%) experienced a JIA-ACR 30 flare (the primary measure of efficacy).(1)(20) JIA-ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to the start of the treatment-withdrawal period.(1)(20) At the end of the treatment-withdrawal evaluation period, JIA-ACR 30, 50, and 70 responses were observed in a greater proportion of patients receiving tocilizumab compared with those receiving placebo.(1)

Follow-up of patients in a subsequent open-label extension period is ongoing.(1)(20)

Clinical Experience with Subcutaneous Tocilizumab in Polyarticular Juvenile Idiopathic Arthritis

Subcutaneous tocilizumab was evaluated in pediatric patients with polyarticular JIA in a 52-week, open-label, multicenter, pharmacokinetic, pharmacodynamic, and safety study to determine the appropriate subcutaneous dosage of tocilizumab that achieves comparable pharmacokinetic/pharmacodynamic profiles as the IV tocilizumab regimen.(1) Polyarticular JIA patients 1–17 years of age with an inadequate response to or inability to tolerate methotrexate, including patients with well-controlled disease on IV tocilizumab therapy and tocilizumab-naive patients with active disease, were treated with subcutaneous tocilizumab based on their body weight.(1) Patients weighing 30 kg or more (25 patients) received 162 mg of tocilizumab given subcutaneously every 2 weeks and patients weighing less than 30 kg (27 patients) received 162 mg of tocilizumab subcutaneously every 3 weeks for 52 weeks.(1) Of these 52 patients, 71% were naive to tocilizumab and 29% had been receiving IV tocilizumab and were switched to subcutaneous tocilizumab at baseline.(1) The manufacturer states that the efficacy of subcutaneous tocilizumab in pediatric patients 2–17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of IV tocilizumab in pediatric patients with polyarticular JIA and subcutaneous tocilizumab in adults with rheumatoid arthritis.(1)

Clinical Experience with IV Tocilizumab in Systemic Juvenile Idiopathic Arthritis

Tocilizumab has been evaluated in a 12-week randomized, double-blind, placebo-controlled study in 112 patients 2–17 years of age with active systemic JIA that had not responded adequately to treatment with NSAIAs and corticosteroids.(1)(21) Patients included in this study had at least 6 months of active disease, with either 5 or more active joints or 2 or more active joints and fever.(21) Patients were randomized in a 2:1 ratio to receive tocilizumab (administered IV every 2 weeks at a weight-adjusted dosage [8 mg/kg in those weighing 30 kg or more, 12 mg/kg in those weighing less than 30 kg]) or placebo and were stratified according to body weight, disease duration, corticosteroid dosage, and methotrexate use.(1)(21) Those receiving stables dosages of NSAIAs, corticosteroids (equivalent to 0.5 mg/kg or less [maximum of 30 mg] of prednisone daily), and methotrexate (20 mg/m² or less per week) could continue such therapy; however, concomitant use of other nonbiologic or biologic DMARDs was not permitted.(21) Approximately 82% of patients had received prior biologic DMARD therapy.(21) Tapering of the corticosteroid dosage was permitted beginning at week 6 in patients who achieved a JIA-ACR 70 response.(1)(21) At week 12, the combined primary end point of JIA-ACR 30 response and absence of fever was observed in 85% of patients receiving tocilizumab compared with 24% of those receiving placebo.(1)(21) JIA-ACR 30, 50, and 70 responses were observed at week 12 in 91, 85, and 71%, respectively, of patients receiving tocilizumab, compared with 24, 11, and 8%, respectively, of those receiving placebo.(1)(21) Tocilizumab therapy also was associated with improvement in systemic manifestations (fever and rash).(1)(21) A greater proportion of patients receiving tocilizumab reduced their corticosteroid dosage by at least 20% without experiencing a subsequent occurrence of systemic symptoms or JIA-ACR 30 flare, compared with placebo recipients (24 versus 3%).(1) In addition, a greater proportion of patients receiving tocilizumab had clinically important improvements in physical function, as assessed using the CHAQ-DI, from baseline to week 12, compared with those receiving placebo (77 versus 19%).(1)

A total of 110 patients subsequently were entered into a long-term, single-group, open-label extension study.(21) At 44 weeks of follow-up, responses to tocilizumab therapy (absence of fever, JIA-ACR response rates, systemic symptoms) were similar to those observed in the 12-week randomized study.(1) By week 44, 43% of patients had discontinued oral corticosteroid therapy; about 50% of these patients had discontinued corticosteroid use for 18 weeks or longer.(1) At 52 weeks of follow-up, 80% of patients had JIA-ACR 70 response and no fever, 59% had JIA-ACR 90 response and no fever, 48% had no joints with active arthritis, and 52% had discontinued oral corticosteroid therapy; the proportion of patients with moderate or severe functional impairment was 38%, compared with 82% at study baseline.(21)

Clinical Experience with Subcutaneous Tocilizumab in Systemic Juvenile Idiopathic Arthritis

Subcutaneous tocilizumab was evaluated in pediatric patients with systemic JIA in a 52-week, open-label, multicenter, pharmacokinetic, pharmacodynamic, and safety study to determine the appropriate subcutaneous dosage of tocilizumab that achieves comparable pharmacokinetic/pharmacodynamic profiles as the IV tocilizumab regimen.(1) Eligible patients received tocilizumab subcutaneously dosed according to body weight, with patients weighing 30 kg or more (26 patients) treated with 162 mg of tocilizumab every week and patients weighing less than 30 kg (25 patients) treated with 162 mg of tocilizumab every 10 days (8 patients) or every 2 weeks (17 patients) for 52 weeks.(1) Of these patients, 51% were naive to subcutaneous tocilizumab and 49% had been receiving IV tocilizumab and were switched to subcutaneous tocilizumab at baseline.(1) Efficacy of subcutaneous tocilizumab in pediatric patients 2–17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of IV tocilizumab in pediatric patients with systemic JIA.(1)

Clinical Perspective

The American College of Rheumatology and the Arthritis Foundation issued a joint guideline in 2019 for the treatment of juvenile idiopathic arthritis manifesting as nonsystemic polyarthritis (including polyarticular disease), sacroiliitis, or enthesitis.(2013) Several drug classes are used to treat juvenile idiopathic arthritis, including NSAIAs, systemic and intra-articular corticosteroids, conventional DMARDs (e.g., methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), and biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab, rituximab).(2013) Specific agents for juvenile idiopathic arthritis treatment are selected according to the presence of certain risk factors (e.g., positive anti-cyclic citrullinated peptide antibodies, positive rheumatoid factor, joint damage), level of disease activity, involvement of specific joints, presence of certain comorbidities (e.g., uveitis), and prior therapies received.(2013)(2022) An individualized “treat-to-target” approach is typically employed, with the goal of achieving remission or minimal/low disease activity.(2014)

Biologic DMARDs, including tocilizumab, are conditionally recommended as an initial therapy option in patients with risk factors and involvement of high-risk joints such as the cervical spine, wrist, or hip; high disease activity; and/or those at high risk of disabling joint disease.(2013) Use of tocilizumab is also conditionally recommended as subsequent therapy in patients with moderate/high disease activity as an add-on therapy to a DMARD or when switching from a TNF blocking agent.(2013) In patients receiving a second biologic DMARD, the guideline conditionally recommends tocilizumab, abatacept, or a TNF blocking agent over rituximab.(2013)

Clinical Experience with Subcutaneous Tocilizumab

Efficacy and safety of subcutaneous tocilizumab in the treatment of GCA were demonstrated in a randomized, double-blind, multicenter study of 1 year's duration (the Giant-Cell Arteritis Actemra [GiACTA] trial; NCT01791153) in adults with active GCA.(1)(50) In this study, 251 patients with new-onset or relapsing GCA were randomized in a 2:1:1:1 ratio to one of four treatment arms; 2 subcutaneous dosages of tocilizumab (162 mg every week and 162 mg every other week) with a prespecified 26-week prednisone taper regimen were compared with 2 different placebo control groups (prespecified prednisone taper regimen over 26 weeks and 52 weeks).(1)(50) The study consisted of a 52-week, blinded period followed by a 104-week, open-label extension.(1)(50) All patients concurrently received corticosteroid therapy (i.e., prednisone).(1) Both tocilizumab treatment groups and one of the placebo groups followed a prespecified prednisone taper regimen with the aim to reach 0 mg by 26 weeks, while the second placebo group followed a prespecified prednisone taper regimen with the aim to reach 0 mg by 52 weeks, which was designed to be more in line with standard clinical practice.(1)(50) The primary efficacy end point was the proportion of patients achieving sustained corticosteroid-free remission at 52 weeks.(1)(50) Sustained remission was defined by a patient attaining a sustained absence of GCA signs and symptoms from week 12 through week 52, normalization of the erythrocyte sedimentation rate (ESR) from week 12 through week 52, normalization of CRP from week 12 through week 52, and successful adherence to the prednisone taper defined by not more than 100 mg of excess prednisone from week 12 through week 52.(1)(50)

In the GiACTA trial (NCT01791153), tocilizumab 162 mg weekly and 162 mg every other week plus a 26-week prednisone taper both showed superiority in achieving sustained remission from week 12 through week 52 (56 and 53% of patients, respectively) compared with placebo plus a 26-week prednisone taper (14%) or placebo plus a 52-week prednisone taper (18%).(1)(50) In addition, the estimated annual cumulative prednisone dose was lower in the 2 tocilizumab treatment groups (medians of 1887 and 2207 mg in the once-weekly and every-2-week tocilizumab treatment groups, respectively) compared with the placebo groups (medians of 3804 and 3902 mg in the placebo plus 26-week prednisone taper and the placebo plus 52-week prednisone taper groups, respectively).(1) The overall tolerability profile of tocilizumab in the treatment of GCA was found to be similar to its tolerability profile in other indications.(1)(50) A post-hoc analysis of this study demonstrated sustained remission and a reduction in flares with tocilizumab compared to placebo in subgroups of patients who had either cranial symptoms only, polymyalgia rheumatica symptoms only, or a combination of both at baseline evaluation.(79)

In a 2-year extension study (part 2) of GiACTA, data from 215 of the original 251 randomized patients were analyzed.(53) Participants who were in clinical remission at the end of the 52-week, double-blind period received no further treatment and those not in clinical remission received therapy at the clinician's discretion, which could include tocilizumab and/or corticosteroids.(53) A higher proportion of patients who were originally assigned to receive tocilizumab were treatment-free during this period (with a higher proportion of treatment-free patients among those who received the drug once weekly compared with every 2 weeks) compared with those originally assigned to receive placebo.(53) Retreatment with tocilizumab with or without corticosteroids restored clinical remission in patients who experienced a disease flare.(53) In addition, cumulative corticosteroid doses were lower in patients originally assigned to tocilizumab than in patients originally assigned to placebo.(53) No new safety concerns emerged in the tocilizumab-treated patients during the 3-year study.(53)

Clinical Experience with IV Tocilizumab

IV tocilizumab for the treatment of GCA was assessed in an open-label pharmacokinetic-pharmacodynamic (PK-PD) and safety study (WP41152; NCT03923738) to determine the appropriate IV dose of tocilizumab that would achieve comparable PK-PD profiles to subcutaneous tocilizumab.(1)(93) A total of 24 patients who had received ≥5 doses of tocilizumab 8 mg/kg IV every 4 weeks and achieved remission were enrolled in the study.(1)(93) In period 1 of the study, all patients received tocilizumab 7 mg/kg IV every 4 weeks for 20 weeks.(1)(93) After completion of period 1, 22 patients remained in remission and continued in period 2 to receive tocilizumab 6 mg/kg IV every 4 weeks for 20 weeks.(1)(93) Both dosages of tocilizumab were generally well tolerated.(93) The efficacy of IV tocilizumab 6 mg/kg in adults with GCA is based on pharmacokinetic exposure and extrapolation to the efficacy established for subcutaneous tocilizumab in patients with GCA.(1)

Clinical Perspective

Giant cell arteritis (GCA) is a systemic vasculitis that primarily involves medium-sized and large arteries; the condition can cause a variety of clinical manifestations, including headaches, ischemic visual symptoms (with a risk of vision loss), limb or jaw claudication, polymyalgia rheumatica, aortic aneurysm, myocardial infarction, and stroke.(50)(51)(52)(3000) The condition mainly occurs in adults older than 50 years of age and is 2–3 times more likely to occur in women than in men.(50)(51)(52) Corticosteroids are considered standard first-line initial therapy for GCA and can help control headaches and reduce systemic inflammation, normalize inflammatory markers such as C-reactive protein (CRP), and prevent vision loss.(50)(51)(52) However, long-term corticosteroid therapy can cause severe adverse effects in patients with GCA.(50)(51)

Because concentrations of CRP and other acute-phase reactants increase with elevated serum concentrations of interleukin-6 (IL-6), tocilizumab has been studied as a treatment for GCA.(50)(51)(52)(53) Clinical experience with tocilizumab in GCA to date indicates that the drug can produce sustained remission and allow for reductions in corticosteroid doses (i.e., steroid-sparing effect) that are used to control the disease and to maintain remission.(50)(51)(52)(53) Further study is needed to determine the optimal role of tocilizumab therapy in the management of GCA and to evaluate its efficacy when used alone without corticosteroids.(50)(51)(52) Tocilizumab has been shown to be an effective glucocorticoid-sparing agent for GCA.(3000) Therefore, some clinicians recommend that tocilizumab therapy be considered in patients who are experiencing adverse effects from corticosteroid therapy, patients with clinically important preexisting medical conditions that could be adversely affected by long-term corticosteroid therapy (e.g., diabetes mellitus, hypertension, psychiatric conditions, pancreatitis), and patients whose disease is refractory to corticosteroid therapy (i.e., patients who didn't achieve remission or who experienced flares during a corticosteroid taper).(51)(52)

The American College of Rheumatology and Vasculitis Foundation issued a joint guideline in 2021 for the management of GCA.(3000) Medications used to treat GCA include systemic glucocorticoids, non-biologic immunosuppressants (e.g., azathioprine, leflunomide, methotrexate, mycophenolate mofetil, cyclophosphamide), and biologic DMARDs (e.g., TNF blocking agents, abatacept, tocilizumab).(3000) Specific drug regimens are recommended according to the degree of organ involvement.(3000) The guideline conditionally recommends the use of tocilizumab with oral glucocorticoids over oral glucocorticoids alone in patients with newly diagnosed GCA.(3000) A conditional recommendation is also given for adding tocilizumab and increasing the dose of glucocorticoids over adding methotrexate and increasing the dose of glucocorticoids in patients who experience disease relapse with cranial symptoms while receiving glucocorticoids alone.(3000) Choice of therapy should be based on the physician’s experience and the patient’s clinical condition, values, and preferences.(3000)

Clinical Perspective

The American Society of Clinical Oncology (ASCO) issued a guideline in 2021 for the management of immune-related adverse events in patients treated with CAR T-cell therapy. (3001) Specific agents are selected according to grading of fever, hypoxia, and hypotension based on the American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading system.(3001) Management of CRS begins with supportive care (e.g., antipyretics, IV hydration, broad-spectrum antibiotics, granulocyte-colony stimulating factor), but may require pharmacologic treatment for prolonged or severe CRS.(3001) Tocilizumab with or without a corticosteroid is recommended in patients with prolonged or severe CAR T-cell-associated CRS.(3001)

Clinical Experience with Subcutaneous Tocilizumab

Efficacy of tocilizumab in SSc-ILD was evaluated in a phase 3, multicenter, randomized, double-blind, placebo-controlled study (focuSSced) in 212 adults with SSc as defined by the 2013 ACR/EULAR criteria with onset of disease of 5 years or less, modified Rodnan Skin Score (mRSS) of 10–35 units at screening, increased inflammatory markers (or platelets), and active disease.(1)(80) Criteria for active disease included at least one of the following: disease duration 18 months or less, increase in mRSS of 3 or more units over 6 months, involvement of one new body area and an increase in mRSS of at least 2 units over 6 months, or involvement of 2 new body areas within the previous 6 months, or presence of at least one tendon friction rub.(1)(80) Use of biologic agents, alkylating agents, or cyclophosphamide was not permitted.(1)(80)

Patients were randomized to tocilizumab 162 mg or placebo administered weekly by subcutaneous injection for 48 weeks, followed by open-label tocilizumab 162 mg administered subcutaneously every week for another 48 weeks.(1)(80) Rescue treatment was allowed after 16 weeks if there was more than a 10% decline in predicted forced vital capacity (FVC) or after 24 weeks for worsening skin fibrosis.(1)(80) The primary efficacy endpoint was change in mRSS from baseline to week 48.(1)(80) Change from baseline in FVC at week 48 was a secondary endpoint.(1)(80)

Sixty-seven percent of patients in the tocilizumab group and 64% in the placebo group had SSc-ILD.(1)(80) Primary and secondary endpoints were evaluated in the overall population and a post-hoc analysis evaluated outcomes in the subgroup of patients with and without SSc-ILD.(1)(80) No statistically significant difference in the primary outcome of change in mRSS was observed in the overall population or in the subgroup of patients with SSc-ILD.(1)(80) The change from baseline in predicted FVC and observed FVC was substantially improved in the overall population and in SSc-ILD subgroup.(1)(80)

A phase 2/3 multicenter, randomized, double-blind, placebo-controlled study provides supportive information on the efficacy of tocilizumab in adult patients with SSc.(1)(81) Results in terms of mRSS and FVC outcomes were similar to those observed in the principal phase 3 study.(1)(81)

Clinical Experience with IV Tocilizumab

Efficacy of tocilizumab for the treatment of COVID-19 was evaluated in a randomized, controlled, open-label, multicenter study (RECOVERY; NCT04381936) in 4116 hospitalized adult patients with severe COVID-19-related pneumonia.(1)(89) The primary efficacy endpoint was time to death through day 28.(1)(89) Patients were randomized to receive either standard of care or IV tocilizumab at a weight-tiered dosing comparable to the recommended dosage in addition to standard of care.(1)(89) At baseline, 0.2% of patients were not on supplemental oxygen, 45% of patients required low flow oxygen, 41% required non-invasive ventilation or high-flow oxygen, and 14% required invasive mechanical ventilation.(1)(89) Initially, 82% of patients were reported to be receiving systemic corticosteroids.(1) Tocilizumab improved survival and clinical outcomes at 28 days.(89) In patients who received tocilizumab, the mortality rate was 31% compared with a mortality rate of 35% in those who received standard of care.(1)(89) Reduction in mortality was observed in a larger proportion of patients receiving systemic corticosteroids compared with those not receiving a systemic corticosteroid at randomization; however, this may have been a chance finding.(89) Patients receiving tocilizumab were also more likely to be discharged from the hospital within 28 days and less likely to require invasive mechanical ventilation.(89)

Efficacy of tocilizumab for the treatment of COVID-19 was additionally supported in a randomized, double-blind, placebo-controlled, multicenter study (EMPACTA; NCT04372186) in 377 hospitalized patients with confirmed COVID-19-related pneumonia who were not receiving mechanical ventilation; the study enrolled a substantial proportion of patients from high-risk and racial and ethnic minority groups.(1)(90) The primary efficacy endpoint was time to progression to mechanical ventilation or death through day 28.(1)(90) At baseline, 9% of patients were not on supplemental oxygen, 64% of patients required low flow oxygen, 27% of patients required high-flow oxygen, and 73% were on corticosteroids.(1)(90) Patients were randomized to receive standard of care plus 1 or 2 doses of IV tocilizumab 8 mg/kg (maximum dose 800 mg) or placebo.(90) The cumulative proportion of patients who required mechanical ventilation or died by day 28 was 12% in those receiving tocilizumab and 19.3% in those receiving placebo.(1)(90) Mortality from any cause at day 28 was 10.4% in those receiving tocilizumab compared to 8.6% in those receiving placebo.(1)(90)

In a phase 3 randomized, double-blind, placebo-controlled, multicenter study (COVACTA trial; NCT04320615), 452 adults hospitalized with severe COVID-19-related pneumonia were randomized 2:1 to receive either a single dose of tocilizumab 8 mg/kg or placebo.(1)(91) The primary efficacy end point was improved clinical status, which was measured using a 7-point ordinal scale to assess clinical status based on the need for intensive care and/or ventilator use and the requirement for supplemental oxygen over a 4-week period.(1)(91) The trial failed to meet its primary end point or several key secondary end points.(1)(91) Key secondary end points included 4-week mortality.(91) Differences in the primary end points between the tocilizumab and placebo groups were not statistically significant.(1)(91) At week 4, mortality rates did not differ between the tocilizumab and placebo groups (19.7 versus 19.4%, respectively).(1)(91)

In a double-blind, placebo-controlled, multicenter study (REMDACTA; NCT04 409262). 649 hospitalized patients with severe COVID-19 pneumonia were randomized 2:1 to receive IV tocilizumab and remdesivir or placebo and remdesivir.(1)(92) Tocilizumab was given as a single IV dose of 8 mg/kg along with IV remdesivir 200 mg on day 1 followed by remdesivir 100 mg once daily for a total of 10 days.(1)(92) The primary efficacy endpoint was time from randomization to hospital discharge or “ready for discharge” up to Day 28.(1)(92) At baseline, 7% of patients were on low flow oxygen, 80% were on non-invasive ventilation or high flow oxygen, 14% were on invasive mechanical ventilation, and 84% were on corticosteroids.(1)(92) At day 28, there was no statistically significant difference between the study groups with respect to time to hospital discharge or “ready for discharge” through Day 28.(1)(92) Mortality at day 28 was 18.1% in the tocilizumab and remdesivir study population compared to 19.5% in the placebo and remdesivir study population.(1)(92)

A meta-analysis of the EMPACTA, COVACTA, REMDACTA and RECOVERY studies evaluated the risk difference through Day 28, estimated by the Kaplan-Meier method, in the subgroup of patients receiving baseline corticosteroids.(1) Patients from the RECOVERY trial represent 78.8% of the total sample size in this meta-analysis.(1) The combined risk difference showed that tocilizumab treatment (n=2261) resulted in a 4.61% absolute reduction in the risk of death at Day 28 compared to standard of care.(1)

Emergency Use Authorization in Pediatric Patients

FDA has issued an emergency use authorization (EUA) that permits use of tocilizumab for treatment of COVID-19 in hospitalized pediatric patients 2–18 years of age who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).(70) FDA states that, based on review of data from an open-label, controlled, platform trial (NCT04381936; RECOVERY); a double-blind, placebo-controlled trial (NCT04320615; COVACTA); a double-blind, placebo-controlled trial (NCT04372186; EMPACTA); and a double-blind, placebo-controlled trial (NCT04409262; REMDACTA]), it is reasonable to believe that tocilizumab may be effective for the treatment of COVID-19 in the pediatric patient population specified in the tocilizumab EUA and, when used under the conditions described in the EUA, the known and potential benefits of tocilizumab when used to treat COVID-19 in such patients outweigh the known and potential risks.(70)  

For additional information about the EUA, the tocilizumab EUA letter of authorization (([Web]),70) EUA fact sheet for healthcare providers (([Web]),71) and EUA fact sheet for patients, parents and caregivers (([Web])72) should be consulted.

For further information on the use of tocilizumab in the treatment of pediatric patients with COVID-19, clinicians also may consult the most recent COVID-19 treatment guidelines from NIH (([Web]).40)