Dataset Information

Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: results of a randomised controlled trial (VISARA).

ABSTRACT:

Objective

To evaluate the effect of tocilizumab (TCZ), an interleukin 6 receptor inhibitor, on humoral immune responses to immunisations in patients with rheumatoid arthritis (RA).

Methods

Patients with RA with inadequate response/intolerance to one or more anti-tumour necrosis factor-α agents were randomly assigned (2:1) to TCZ 8 mg/kg intravenously every 4 weeks plus methotrexate (MTX) or MTX alone up until week 8. Serum was collected before vaccination at week 3, antibody titres were evaluated at week 8, and then all patients received TCZ+MTX through week 20. End points included proportion of patients responding to ≥6/12 pneumococcal polysaccharide vaccine (PPV23) serotypes (primary) and proportions responding to tetanus toxoid vaccine (TTV; secondary) at week 8.

Results

91 patients were randomised. At week 8, 60.0% of TCZ+MTX and 70.8% of MTX patients responded to ≥6/12 PPV23 serotypes, with insufficient evidence for any difference in treatments (10.8% (95% CI -33.7 to 12.0)), and 42.0% and 39.1%, respectively, responded to TTV. Two of three TCZ+MTX patients with non-protective baseline TTV antibody titres achieved protective levels by week 8. The safety profile of TCZ was consistent with previous reports.

Conclusions

Short-term TCZ treatment does not significantly attenuate humoral responses to PPV23 or TTV. To maximise vaccine response, patients should be up to date with immunisations before starting TCZ treatment.

Clinicaltrialsgov identifier

NCT01163747.

SUBMITTER: Bingham CO

PROVIDER: S-EPMC4392200 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Publications

Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: results of a randomised controlled trial (VISARA).

Bingham Clifton O CO Rizzo Warren W Kivitz Alan A Hassanali Azra A Upmanyu Ruchi R Klearman Micki M

Annals of the rheumatic diseases 20140121 5

<h4>Objective</h4>To evaluate the effect of tocilizumab (TCZ), an interleukin 6 receptor inhibitor, on humoral immune responses to immunisations in patients with rheumatoid arthritis (RA).<h4>Methods</h4>Patients with RA with inadequate response/intolerance to one or more anti-tumour necrosis factor-α agents were randomly assigned (2:1) to TCZ 8 mg/kg intravenously every 4 weeks plus methotrexate (MTX) or MTX alone up until week 8. Serum was collected before vaccination at week 3, antibody titre ...[more]

PMID: 24448345

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Project description:BackgroundIn rituximab-treated patients with rheumatoid arthritis, humoral and cellular immune responses after two or three doses of SARS-CoV-2 vaccines are not well characterised. We aimed to address this knowledge gap.MethodsThis prospective, cohort study (Nor-vaC) was done at two hospitals in Norway. For this sub-study, we enrolled patients with rheumatoid arthritis on rituximab treatment and healthy controls who received SARS-CoV-2 vaccines according to the Norwegian national vaccination programme. Patients with insufficient serological responses to two doses (antibody to the receptor-binding domain [RBD] of the SARS-CoV-2 spike protein concentration <100 arbitrary units [AU]/mL) were allotted a third vaccine dose. Antibodies to the RBD of the SARS-CoV-2 spike protein were measured in serum 2-4 weeks after the second and third doses. Vaccine-elicited T-cell responses were assessed in vitro using blood samples taken before and 7-10 days after the second dose and 3 weeks after the third dose from a subset of patients by stimulating cryopreserved peripheral blood mononuclear cells with spike protein peptides. The main outcomes were the proportions of participants with serological responses (anti-RBD antibody concentrations of ≥70 AU/mL) and T-cell responses to spike peptides following two and three doses of SARS-CoV-2 vaccines. The study is registered at ClinicalTrials.gov, NCT04798625, and is ongoing.FindingsBetween Feb 9, 2021, and May 27, 2021, 90 patients were enrolled, 87 of whom donated serum and were included in our analyses (69 [79·3%] women and 18 [20·7%] men). 1114 healthy controls were included (854 [76·7%] women and 260 [23·3%] men). 49 patients were allotted a third vaccine dose. 19 (21·8%) of 87 patients, compared with 1096 (98·4%) of 1114 healthy controls, had a serological response after two doses (p<0·0001). Time since last rituximab infusion (median 267 days [IQR 222-324] in responders vs 107 days [80-152] in non-responders) and vaccine type (mRNA-1273 vs BNT162b2) were significantly associated with serological response (adjusting for age and sex). After two doses, 10 (53%) of 19 patients had CD4+ T-cell responses and 14 (74%) had CD8+ T-cell responses. A third vaccine dose induced serological responses in eight (16·3%) of 49 patients, but induced CD4+ and CD8+ T-cell responses in all patients assessed (n=12), including responses to the SARS-CoV-2 delta variant (B.1.617.2). Adverse events were reported in 32 (48%) of 67 patients and in 191 (78%) of 244 healthy controls after two doses, with the frequency not increasing after the third dose. There were no serious adverse events or deaths.InterpretationThis study provides important insight into the divergent humoral and cellular responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis. A third vaccine dose given 6-9 months after a rituximab infusion might not induce a serological response, but could be considered to boost the cellular immune response.FundingThe Coalition for Epidemic Preparedness Innovations, Research Council of Norway Covid, the KG Jebsen Foundation, Oslo University Hospital, the University of Oslo, the South-Eastern Norway Regional Health Authority, Dr Trygve Gythfeldt og frues forskningsfond, the Karin Fossum Foundation, and the Research Foundation at Diakonhjemmet Hospital.

Project description:IntroductionPatients with rheumatoid arthritis (RA) have decreased survival because of increased cardiovascular risk compared with the general population, and treatment with tocilizumab (TCZ) has been shown to increase lipid levels; however, the relationship between lipids and cardiovascular risk is unknown. This post hoc analysis expanded on previously reported 24-week results by characterizing statin use and subsequent changes in lipid parameters in patients with RA treated with intravenous or subcutaneous TCZ (TCZ-IV or TCZ-SC) over 2 years of treatment.MethodsData were collected from patients with moderate to severe active RA who received ≥1 dose of the study drug in seven international, randomized, double-blind, controlled phase 3 and 4 clinical trials of TCZ-IV or TCZ-SC. Lipid levels and safety events were assessed over 2 years of treatment. Data were summarized for all pooled treatment groups of the intention-to-treat populations in the TCZ-IV and TCZ-SC studies, and results were stratified by concomitant statin use.ResultsData from this descriptive, retrospective, pooled analysis indicated that statins can stabilize lipid levels without a clinically significant increase in adverse events. Approximately 30% of patients in the TCZ treatment arms who never received a statin demonstrated a shift in low-density-lipoprotein cholesterol (LDL-C) from <130 mg/dl at baseline to ≥130 mg/dl at 2 years. However, despite the increased potential cardiovascular risk, <15% of patients with LDL-C ≥100 mg/dl and <35% of patients with a total cholesterol:high-density-lipoprotein cholesterol ratio >5 at 2 years were receiving concomitant statins.ConclusionConcomitant statin use attenuated TCZ-mediated lipid increases; however, a large proportion of TCZ-treated patients potentially at risk of cardiovascular disease were untreated. These findings highlight the need for better understanding of potential risk associated with TCZ-mediated lipid elevations as well as implementation of RA-specific guidelines on the recognition and management of elevated risk of cardiovascular events in patients with RA.FundingF. Hoffmann-La Roche, Ltd.

Dataset Information

Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: results of a randomised controlled trial (VISARA).

Objective

Methods

Results

Conclusions

Clinicaltrialsgov identifier

Publications

Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: results of a randomised controlled trial (VISARA).

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