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Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden
  1. Kathrine Lederballe Grøn1,2,
  2. Elizabeth V Arkema3,
  3. Bente Glintborg1,4,
  4. Frank Mehnert5,
  5. Mikkel Østergaard1,2,
  6. Lene Dreyer6,
  7. Mette Nørgaard5,
  8. Niels Steen Krogh7,
  9. Johan Askling3,
  10. Merete Lund Hetland1,2
  11. The ARTIS Study Group
    1. 1 DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Copenhagen, Denmark
    2. 2 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    3. 3 Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
    4. 4 Department of Rheumatology, Gentofte and Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
    5. 5 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
    6. 6 Departments of Clinical Medicine and Rheumatology, Aalborg University and Aalborg University Hospital, Aalborg, Denmark
    7. 7 ZiteLab ApS, Copenhagen, Denmark
    1. Correspondence to Dr Kathrine Lederballe Grøn, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; kathrine.l.groen{at}gmail.com

    Abstract

    Objective To estimate (1) crude and age-and gender-adjusted incidence rates (IRs) of serious infections (SI) and (2) relative risks (RR) of SI in patients with rheumatoid arthritis (RA) initiating treatment with abatacept, rituximab or tocilizumab in routine care.

    Methods This is an observational cohort study conducted in parallel in Denmark and Sweden including patients with RA in Denmark (DANBIO) and Sweden (Anti-Rheumatic Treatment in Sweden Register/Swedish Rheumatology Quality Register) who started abatacept/rituximab/tocilizumab in 2010–2015. Patients could contribute to more than one treatment course. Incident SI (hospitalisations listing infection) and potential confounders were identified through linkage to national registries. Age- and gender-adjusted IRs of SI per 100 person years and additionally adjusted RRs of SI during 0–12 and 0–24 months since start of treatment were assessed (Poisson regression). Country-specific RRs were pooled using inverse variance weighting.

    Results We identified 8987 treatment courses (abatacept: 2725; rituximab: 3363; tocilizumab: 2899). At treatment start, rituximab-treated patients were older, had longer disease duration and more previous malignancies; tocilizumab-treated patients had higher C reactive protein. During 0–12 and 0–24 months of follow-up, 456 and 639 SI events were identified, respectively. The following were the age- and gender-adjusted 12-month IRs for abatacept/rituximab/tocilizumab: 7.1/8.1/6.1 for Denmark and 6.0/6.4/4.7 for Sweden. The 24-month IRs were 6.1/7.5/5.2 for Denmark and 5.6/5.8/4.3 for Sweden. Adjusted 12-month RRs for tocilizumab versus rituximab were 0.82 (0.50 to 1.36) for Denmark and 0.76 (0.57 to 1.02) for Sweden, pooled 0.78 (0.61 to 1.01); for abatacept versus rituximab 0.94 (0.55 to 1.60) for Denmark and 0.86 (0.66 to 1.13) for Sweden, pooled 0.88 (0.69 to 1.12); and for abatacept versus tocilizumab 1.15 (0.69 to 1.90) for Denmark and 1.14 (0.83 to 1.55) for Sweden, pooled 1.13 (0.91 to 1.42). The adjusted RRs for 0–24 months were similar.

    Conclusion For patients starting abatacept, rituximab or tocilizumab, differences in baseline characteristics were seen. Numerical differences in IR of SI between drugs were observed. RRs seemed to vary with drug (tocilizumab < abatacept < rituximab) but should be interpreted with caution due to few events and risk of residual confounding.

    • rheumatoid Arthritis
    • infections
    • DMARDs (biologic)
    • treatment
    • epidemiology

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    Footnotes

    • Handling editor Josef S Smolen

    • Collaborators The ARTIS Study Group: Johan Askling (author), Lars Klareskog (contributor) and Nils Feltelius (contributor) (Karolinska Institutet, Stockholm, Sweden); Eva Baecklund (contributor) (Uppsala University, Uppsala, Sweden); Christopher Sjöwall (contributor) (Linköping University, Linköping, Sweden); Solbritt Rantapää-Dahlqvist (contributor) and Helena Forsblad-d’Elia (contributor) (Umeå University, Umeå, Sweden); Lennart Jacobsson (contributor) (Sahlgrenska Academy, Gothenburg, Sweden); Carl Turesson (author) and Elisabet Lindqvist (contributor) (Lund University, Malmö and Lund, Sweden); Ralph Nisell (contributor) (Register Holder, Swedish Rheumatology Quality Register, Sweden).

    • Contributors KLG, BG, MLH, MN, MØ, LD, EVA and JA contributed to the study design. KLG, BG, MLH, NSK, FM, EVA and JA contributed to data management. All authors contributed to analyses of raw data and interpretation. All authors contributed to and approved the final manuscript.

    • Funding The study is partly funded by NordForsk and Foreum.

    • Competing interests KLG: BMS. EVA: none. BG: Biogen, AbbVie and Pfizer. FM: none. MØ: AbbVie, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Orion, Pfizer, Regeneron, Roche and UCB. LD: UCB, MSD, Eli Lilly and Janssen Pharmaceuticals. MN: none. NSK: none. MLH: AbbVie, Biogen, BMS, Celltrion, MSD, Novartis, Orion, Pfizer, Samsung and UCB. JA: AbbVie, BMS, MSD, Pfizer, Roche, AstraZeneca, Eli Lilly, Samsung Bioepis and UCB, mainly in the context of safety monitoring of biologics via ARTIS. Karolinska Institutet has received remuneration for JA participating in advisory boards arranged by Pfizer and Eli Lilly.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Author note The DANBIO registry has entered into agreements with AbbVie, Biogen, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche and UCB. They receive postmarketing data and had no influence on the data collection, statistical analyses, manuscript preparation or decision to submit. The ARTIS Study Group conducts scientific analyses using data from the Swedish biologics register ARTIS, run by the Swedish Society for Rheumatology. ARTIS has entered into agreements with AbbVie, BMS, Lilly, Merck, Pfizer, Roche, Samsung Bioepis and UCB. These entities had no influence on the data collection, statistical analyses, manuscript preparation or decision to submit. BMS and Roche were allowed to comment upon the findings prior to submission, although all final decisions resided with the investigators.

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