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A Systematic Overview of Contraindications and Special Warnings for Biologic and Targeted Synthetic Disease Modifying Antirheumatic Drugs: Establishing a Framework to Create a “Safety Checklist”

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Abstract

Background/Aim

The purpose of this review is to provide an overview of the contraindications, special warnings, and boxed warnings with the aim to establish a framework to create a prescription safety checklist for a class of drugs or disease indication. This study covers biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs).

Methods

We identified contraindications, boxed warnings, and special warnings provided by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The study included b/tsDMARDs approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (SpA), and juvenile idiopathic arthritis (JIA) within the drug-classes anti-CD20, tumor necrosis factor inhibitors (TNFi), interleukin-1 inhibitors (IL-1i), cytotoxic T-lymphocyte-associated protein (CTLA) 4, interleukin-12/23 inhibitors (IL-12/23i), interleukin 6 receptor inhibitors (IL-6Ri), Janus kinase inhibitors (JAKi), phosphodiesterase 4 inhibitors (PDE4i), interleukin-17 inhibitors (IL-17i), and interleukin-23 inhibitors (IL-23i).

Results

All drug classes, except PDE4i, had contraindications and/or warnings related to infections, including tuberculosis. A warning about herpes zoster was listed for anti-CD20, IL-1i, IL-6Ri, and JAKi, while a warning about hepatitis reactivation was listed for anti-CD20, TNFi, IL-1i, CTLA4-Ig, IL-6Ri, and JAKi. Malignancy risk was mentioned for all drug classes except PDE4i, IL-17i, and IL-23i. Other warnings included demyelinating disease (TNFi, CTLA4-Ig, and IL-6Ri), heart failure (anti-CD20 and TNFi), major adverse cardiac events (JAKi and IL-12/23) and venous thromboembolism (JAKi), hyperlipidemia (IL-6Ri and JAKi), liver impairment (TNFi, IL-1i, IL-6Ri, and JAKi), kidney impairment (IL-1i, JAKi, and PDE4i), inflammatory bowel disease (IL-17i), gastrointestinal perforation (IL-6Ri, JAKi), cytopenia (anti-CD20, TNFi, IL-1i, IL-6Ri, JAKi), and depression (PDE4i). Contraindications and warnings appeared to increase with the passage of time since the drug’s approval.

Conclusion

This review provides an overview to establish the framework to create an easily accessible and actionable prescription safety checklist from individual medical product prescription information provided by regulatory medical authorities.

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Abbreviations

ACR:

American College of Rheumatology

AE:

Adverse events

ALC:

Absolute lymphocyte count

ALT:

Alanine aminotransferase

AMI:

Acute myocardial infarction

ANC:

Absolute neutrophile count

AST:

Aspartate aminotransferase

bDMARDs:

Biologic disease modifying antirheumatic drugs

BID:

Bis in die/twice daily

CD:

Cluster of differentiation

CI:

Confidence interval

COPD:

Chronic obstructive pulmonary disorder

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

EMA:

European Medicines Agency

EULAR:

European Alliance of Associations for Rheumatology

FBC:

Full blood count

FDA:

US Food and Drug Administration

GFR:

Creatinine/calculated glomerular filtration rate

GI:

Gastrointestinal

Hb:

Hemoglobin

IBD:

Inflammatory bowel disease

IL:

Interleukin

ILD:

Interstitial lung disease

JAKi:

Janus kinase inhibitor

JIA:

Juvenile idiopathic arthritis

MACE:

Major adverse cardiac event

MAS:

Macrophage activation syndrome

MedDRA:

Medical Dictionary for Regulatory Activities

MS:

Multiple sclerosis

PASS:

Postauthorization safety studies

PC:

Platelet count

PDE:

Phosphodiesterase

PI:

Prescribing information

PML:

Progressive multifocal leukoencephalopathy

PSUR:

Periodic safety updates

PsA:

Psoriatic arthritis

RA:

Rheumatoid arthritis

REMS:

Risk evaluation and mitigation strategies

RMP:

Risk management plan

SAEs:

Serious adverse events

SLR:

Systematic literature review

SmPC:

Summary of product characteristics

SOCs:

System Organ Classes

SpA:

Spondyloarthritis

TNFi:

Tumor necrosis factor inhibitor

tsDMARDs:

Targeted synthetic DMARDs

UC:

Ulcerative colitis

VTE:

Venous thromboembolism

References

  1. Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3–18.

    CAS  PubMed  Google Scholar 

  2. Fraenkel L, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924–39.

    PubMed  Google Scholar 

  3. Gossec L, et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update. Ann Rheum Dis. 2024.

  4. Singh JA, et al. Special Article: 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis. Arthritis Care Res (Hoboken). 2019;71(1):2–29.

    PubMed  Google Scholar 

  5. Ramiro S, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis. 2022.

  6. Ward MM, et al. 2019 update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2019;71(10):1599–613.

    PubMed  PubMed Central  Google Scholar 

  7. FDA. Homepage. Available from: https://www.fda.gov/.

  8. EMA. Homepage. Available from: https://www.ema.europa.eu/en.

  9. European Commission Enterprise and Industry Directorate-General. A guideline on summary of product characteristics (SmPC). 2009.

  10. ACR Convergence Meeting. A label is worth a thousand words: exploring FDA communication methods 2021. 2021.

  11. FDA. Guidance for industry warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products—content and format. 2011. Available from: https://www.fda.gov/files/drugs/published/Warnings-and-Precautions--Contraindications--and-Boxed-Warning-Sections-of-Labeling-for-Human-Prescription-Drug-and-Biological-Products-%E2%80%94-Content-and-Format.pdf.

  12. EMA. Periodic safety update reports 2023. [09.01.23]. Available from: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/periodic-safety-update-reports-psurs.

  13. EMA. Guideline on good pharmacovigilance practices (GVP) module VII—periodic safety update report (Rev 1). 2013. [09.01.23]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vii-periodic-safety-update-report_en.pdf.

  14. EMA. EMA pharmacovigilance system manual Version 1.3. 2021. [09.01.23]. Available from: https://www.ema.europa.eu/en/documents/other/european-medicines-agency-pharmacovigilance-system-manual_en.pdf.

  15. FDA. Drug label. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.

  16. Thoenes A, et al. Discrepancies between the labels of originator and generic pharmaceutical products: implications for patient safety. Drugs Real World Outcomes. 2020;7(2):131–9.

    PubMed  PubMed Central  Google Scholar 

  17. MEDDRA. Medical dictionary for regulatory activities. [05.10.22]. Available from: https://admin.meddra.org/sites/default/files/page/documents_insert/essentials_on_meddra.pdf.

  18. Flint J, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2016;55(9):1693–7.

    CAS  PubMed  Google Scholar 

  19. Ogbu EA, Brunner HI. Treatment guidelines in pediatric rheumatic diseases. Rheum Dis Clin North Am. 2022;48(3):725–46.

    PubMed  Google Scholar 

  20. EMA. Rituximab. Sept 2023 [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/mabthera#product-information-section.

  21. FDA. Rituximab. Jun 2021 [27.11.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103705s5464lbl.pdf.

  22. EMA. Adalimumab. Okt 2022 [27.11.22]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/humira.

  23. FDA. Adalimumab. Feb 2021 [27.11.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125057s417lbl.pdf.

  24. EMA. Infliximab. Sept 2022 [27.11.22]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/remicade#product-information-section.

  25. FDA. Infliximab. Okt 2021 [27.11.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103772s5401lbl.pdf.

  26. EMA. Golimumab. Jul 2023 [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/simponi#product-information-section.

  27. FDA. Golimumab. Feb 2021 [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125433s032lbl.pdf.

  28. EMA. Certolizumab Pegol. Apr 2023 [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/cimzia-0.

  29. FDA. Certolizumab Pegol. Dec 2022 [18.09.23]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125160s305lbl.pdf.

  30. EMA. Etanercept. Aug 2023 [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/enbrel.

  31. FDA. Etanercept. Jun 2023 [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103795s5594lbl.pdf.

  32. EMA. Anakinra. Jul 2023 [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/kineret#product-information-section.

  33. FDA. Anakinra. Dec 2020 [01.12.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/103950s5189lbl.pdf.

  34. EMA. Canakinumab. Aug 2023 [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ilaris#product-information-section.

  35. FDA. Canakinumab. Aug 2023. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125319s107lbl.pdf.

  36. EMA. Abatacept. Jun 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/orencia.

  37. FDA. Abatacept. Dec 2021. [01.12.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125118s240lbl.pdf.

  38. EMA. Ustekinumab. Jul 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/stelara#product-information-section.

  39. FDA. Ustekinumab. Jul 2022. [01.12.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125261s161lbl.pdf.

  40. EMA. Tocilizumab. Apr 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/roactemra#product-information-section.

  41. FDA. Tocilizumab. Dec 2023. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125276s138lbl.pdf.

  42. EMA. Sarilumab. Jul 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/kevzara#product-information-section.

  43. FDA. Sarilumab. Feb 2023. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761037s013lbl.pdf.

  44. EMA. Tofacitinib. Jun 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/xeljanz.

  45. FDA. Tofacitinib. Dec 2021. [01.12.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203214s028,208246s013,213082s003lbl.pdf.

  46. EMA. Baricitinib. Aug 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/olumiant.

  47. FDA. Baricitinib. Jun 2022. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207924s007lbl.pdf.

  48. EMA. Filgotinib. May 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/jyseleca.

  49. EMA. Upadacitinib. Aug 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/rinvoq.

  50. FDA. Upadacitinib. Jun 2023. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211675s017lbl.pdf.

  51. EMA. JAK. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/janus-kinase-inhibitors-jaki.

  52. FDA. JAK. Available from: https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death.

  53. EMA. Apremilast. Jul 2022. [01.12.22]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/otezla.

  54. FDA. Apremilast. Jul 2023. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/205437s012lbl.pdf.

  55. EMA. Secukinumab. Aug 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/cosentyx#product-information-section.

  56. FDA. Secukinumab. Jul 2023. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125504Orig1s054s055s067lbl.pdf.

  57. EMA. Ixekizumab. Feb 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/taltz.

  58. FDA. Ixekizumab. Jul 2022. [18.09.23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125521s024lbl.pdf.

  59. EMA. Bimekizumab. Jun 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/bimzelx.

  60. EMA. Guselkumab. Jul 2022. [01.12.22]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tremfya.

  61. FDA. Guselkumab. Jul 2020. [01.12.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761061s007lbl.pdf.

  62. EMA. Risankizumab. Sep 2023. [18.09.23]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/skyrizi.

  63. FDA. Risankizumab. Jan 2022. [01.12.22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761105s014lbl.pdf.

  64. Lexchin J. How safe are new drugs? Market withdrawal of drugs approved in Canada between 1990 and 2009. Open Med. 2014;8(1):e14–9.

    PubMed  PubMed Central  Google Scholar 

  65. Riley TR, George MD. Risk for infections with glucocorticoids and DMARDs in patients with rheumatoid arthritis. RMD Open. 2021;7(1).

  66. Dey M, et al. Infection profile of immune-modulatory drugs used in autoimmune diseases: analysis of summary of product characteristic data. RMD Open. 2022;8(2).

  67. Ytterberg SR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316–26.

    CAS  PubMed  Google Scholar 

  68. Li X, et al. Comparative risk of serious infections among real-world users of biologics for psoriasis or psoriatic arthritis. Ann Rheum Dis. 2020;79(2):285–91.

    CAS  PubMed  Google Scholar 

  69. Evangelatos G, et al. Tuberculosis and targeted synthetic or biologic DMARDs, beyond tumor necrosis factor inhibitors. Ther Adv Musculoskelet Dis. 2020;12:1759720x20930116.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Redeker I, et al. Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register. Ann Rheum Dis. 2022;81(1):41–7.

    CAS  PubMed  Google Scholar 

  71. Wu KK, et al. Risk of herpes zoster with IL-17 inhibitor therapy for psoriasis and other inflammatory conditions. J Dermatolog Treat. 2020;31(4):359–65.

    CAS  PubMed  Google Scholar 

  72. Vassilopoulos A, et al. The incidence of opportunistic infections in patients with psoriatic arthritis treated with biologic and targeted synthetic agents: a systematic review and meta-analysis. Front Pharmacol. 2022;13: 992713.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Baumrin E, et al. A systematic review of herpes zoster incidence and consensus recommendations on vaccination in adult patients on systemic therapy for psoriasis or psoriatic arthritis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2019;81(1):102–10.

    PubMed  Google Scholar 

  74. Lin TC, et al. Risk of hepatitis B virus reactivation in patients with inflammatory arthritis receiving disease-modifying antirheumatic drugs: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2018;70(5):724–31.

    PubMed  Google Scholar 

  75. Fragoulis GE, et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2022.

  76. Davidson L, et al. Risk of candidiasis associated with interleukin-17 inhibitors: a real-world observational study of multiple independent sources. Lancet Reg Health Eur. 2022;13: 100266.

    PubMed  Google Scholar 

  77. Furer V, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020;79(1):39–52.

    CAS  PubMed  Google Scholar 

  78. ACR. Vaccination guideline. 2024.

  79. Friedman MA, Curtis JR, Winthrop KL. Impact of disease-modifying antirheumatic drugs on vaccine immunogenicity in patients with inflammatory rheumatic and musculoskeletal diseases. Ann Rheum Dis. 2021;80(10):1255–65.

    CAS  PubMed  Google Scholar 

  80. EULAR, OP0045. EULAR points to consider on the initiation of targeted therapies in patients with inflammatory arthritides and a history of cancer. 2023.

  81. Lopez-Olivo MA, et al. Systematic review of recommendations on the use of disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and cancer. Arthritis Care Res (Hoboken). 2020;72(3):309–18.

    PubMed  Google Scholar 

  82. Wetzman A, et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021.

  83. Huss V, et al. Short- and longer-term cancer risks with biologic and targeted synthetic disease-modifying antirheumatic drugs as used against rheumatoid arthritis in clinical practice. Rheumatology (Oxford). 2022;61(5):1810–8.

    CAS  PubMed  Google Scholar 

  84. Kragstrup TW, et al. Waiting for JAK inhibitor safety data. RMD Open. 2022;8(1).

  85. Kunchok A, et al. Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events. JAMA Neurol. 2020;77(8):937–46.

    PubMed  Google Scholar 

  86. Lotan I, McGowan R, Levy M. Anti-IL-6 therapies for neuromyelitis Optica spectrum disorders: a systematic review of safety and efficacy. Curr Neuropharmacol. 2021;19(2):220–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Khoury SJ, et al. ACCLAIM: a randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis. Mult Scler. 2017;23(5):686–95.

    CAS  PubMed  Google Scholar 

  88. Yang V, et al. Managing cardiovascular and cancer risk associated with JAK inhibitors. Drug Saf. 2023.

  89. Delcoigne B, et al. Short-term, intermediate-term and long-term risks of acute coronary syndrome in cohorts of patients with RA starting biologic DMARDs: results from four Nordic countries. Ann Rheum Dis. 2022;81(6):789–97.

    CAS  PubMed  Google Scholar 

  90. Giles JT, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. 2020;72(1):31–40.

    CAS  PubMed  Google Scholar 

  91. Peters MJ, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69(2):325–31.

    CAS  PubMed  Google Scholar 

  92. Nash P, et al. Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement. Ann Rheum Dis. 2021;80(1):71–87.

    CAS  PubMed  Google Scholar 

  93. Lauper K, Gabay C. Cardiovascular risk in patients with rheumatoid arthritis. Semin Immunopathol. 2017;39(4):447–59.

    CAS  PubMed  Google Scholar 

  94. Bissonnette R, et al. Signal detection and methodological limitations in a Real-World Registry: learnings from the evaluation of long-term safety analyses in PSOLAR. Drug Saf. 2021;44(6):699–709.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kotyla PJ. Bimodal function of anti-TNF treatment: shall we be concerned about anti-TNF treatment in patients with rheumatoid arthritis and heart failure? Int J Mol Sci. 2018;19(6).

  96. Mann DL, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109(13):1594–602.

    CAS  PubMed  Google Scholar 

  97. Listing J, et al. Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum. 2008;58(3):667–77.

    CAS  PubMed  Google Scholar 

  98. Aimo A, et al. Rituximab as a novel treatment for heart failure: evidence from a case series. Eur Heart J Case Rep. 2019;3(4):1–2.

    PubMed  PubMed Central  Google Scholar 

  99. Molander V, et al. Venous thromboembolism with JAK inhibitors and other immune-modulatory drugs: a Swedish comparative safety study among patients with rheumatoid arthritis. Ann Rheum Dis. 2022.

  100. Anger F, et al. Toxic drug-induced liver failure during therapy of rheumatoid arthritis with tocilizumab subcutaneously: a case report. Rheumatology (Oxford). 2017;56(9):1628–9.

    PubMed  Google Scholar 

  101. Navarro G, et al. Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum. 2014;43(4):458–69.

    CAS  PubMed  Google Scholar 

  102. French JB, et al. Hepatotoxicity associated with the use of anti-TNF-α agents. Drug Saf. 2016;39(3):199–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Fauny M, et al. Paradoxical gastrointestinal effects of interleukin-17 blockers. Ann Rheum Dis. 2020;79(9):1132–8.

    CAS  PubMed  Google Scholar 

  104. Burisch J, et al. Risk for development of inflammatory bowel disease under inhibition of interleukin 17: a systematic review and meta-analysis. PLoS ONE. 2020;15(5): e0233781.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Rempenault C, et al. Risk of diverticulitis and gastrointestinal perforation in rheumatoid arthritis treated with tocilizumab compared to rituximab or abatacept. Rheumatology (Oxford). 2022;61(3):953–62.

    CAS  PubMed  Google Scholar 

  106. Harigai M. Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019;58(Suppl 1):i34–42.

    CAS  PubMed  Google Scholar 

  107. Torre Alonso JC, et al. Expert recommendations for the use of apremilast in psoriatic arthritis. Reumatol Clin (Engl Ed). 2022.

  108. de Souza M, et al. Effect of biological disease-modifying antirheumatic drugs on body composition in patients with rheumatoid arthritis: a systematic review and meta-analysis. Adv Rheumatol. 2022;62(1):16.

    PubMed  Google Scholar 

  109. Veeravalli V, et al. Critical assessment of pharmacokinetic drug-drug interaction potential of tofacitinib, baricitinib and upadacitinib, the three approved janus kinase inhibitors for rheumatoid arthritis treatment. Drug Saf. 2020;43(8):711–25.

    CAS  PubMed  Google Scholar 

  110. Liu Y, et al. Impact of renal impairment on the pharmacokinetics of apremilast and metabolite M12. Clin Pharmacol Drug Dev. 2016;5(6):469–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Yang BB, Baughman S, Sullivan JT. Pharmacokinetics of anakinra in subjects with different levels of renal function. Clin Pharmacol Ther. 2003;74(1):85–94.

    CAS  PubMed  Google Scholar 

  112. Hetland ML, et al. Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial. BMJ. 2020;371: m4328.

    PubMed  PubMed Central  Google Scholar 

  113. Espinoza F, Le Blay P, Combe B. Biologic disease-modifying antirheumatic drug (bDMARD)-induced neutropenia: a registry from a retrospective cohort of patients with rheumatic diseases treated with 3 classes of intravenous bDMARD. J Rheumatol. 2017;44(6):844–9.

    CAS  PubMed  Google Scholar 

  114. Souto A, et al. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta-analysis. Arthritis Rheumatol. 2015;67(1):117–27.

    CAS  PubMed  Google Scholar 

  115. Astra Zenica. Roflumilast. Available from: https://www.medicines.org.uk/emc/files/pil.9162.pdf.

  116. Kappelmann N, et al. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23(2):335–43.

    CAS  PubMed  Google Scholar 

  117. Mease PJ, et al. Long-Term safety and tolerability of apremilast versus placebo in psoriatic arthritis: a pooled safety analysis of three phase III, randomized controlled trials. ACR Open Rheumatol. 2020;2(8):459–70.

    PubMed  PubMed Central  Google Scholar 

  118. EMA. Brodalumab. Jul 2020. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/kyntheum#product-information-section.

  119. Lebwohl MG, et al. Psychiatric adverse events during treatment with brodalumab: analysis of psoriasis clinical trials. J Am Acad Dermatol. 2018;78(1):81-89.e5.

    CAS  PubMed  Google Scholar 

  120. Holroyd CR, et al. The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis. Rheumatology (Oxford). 2019;58(2):e3–42.

    CAS  PubMed  Google Scholar 

  121. EMA. Section 4.4: special warnings and precautions for use. Available from: https://www.ema.europa.eu/en/documents/presentation/presentation-section-44-special-warnings-precautions-use_en.pdf.

  122. Lis Y. A comparison of US Food and Drug Administration and European Medicines Agency Regulations for pharmaceutical risk management: report of the International Society for Pharmacoeconomic and Outcomes Research Risk Management Working Group. ISPOR Connections; 2011.

  123. Lis Y, et al. Comparisons of Food and Drug Administration and European Medicines Agency risk management implementation for recent pharmaceutical approvals: report of the International Society for Pharmacoeconomics and outcomes research risk benefit management working group. Value Health. 2012;15(8):1108–18.

    PubMed  Google Scholar 

  124. Reinisch W, et al. Comparison of the EMA and FDA guidelines on ulcerative colitis drug development. Clin Gastroenterol Hepatol. 2019;17(9):1673-1679.e1.

    PubMed  Google Scholar 

  125. WHO. WHO surgical checklist. Available from: WHO Surgical Safety Checklist.

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Acknowledgements

We thank Steffen Thirstrup (Affiliate Professor, Chief Medical Officer, European Medicines Agency), Hanne Larsen (Danish Medical Agency), and Marie Louise Christiansen (Danish Medical Agency) for answering our many questions about the EMA and for taking time to support this manuscript.

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Authors and Affiliations

  1. Department of Biomedicine, Aarhus University, Skou Building, Høegh-Guldbergs Gade 10, 8000, Aarhus C, Denmark

    Lykke Skaarup & Tue W. Kragstrup

  2. Diagnostic Center, Regional Hospital Silkeborg, Silkeborg, Denmark

    Lykke Skaarup, René Østgård & Tue W. Kragstrup

  3. Department of Rheumatology, Austin Health, Melbourne, Australia

    Elvina Ingrid & David F. L. Liew

  4. NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal

    Alexandre Sepriano

  5. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

    Alexandre Sepriano, Elena Nikiphorou & Margreet Kloppenburg

  6. Centre for Rheumatic Diseases, King’s College London, London, UK

    Elena Nikiphorou

  7. Rheumatology Department, King’s College Hospital, London, UK

    Elena Nikiphorou

  8. Division of Rheumatology, Department of Internal Medicine and Department of Medicine, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland

    Kim Lauper

  9. Independent Consultant, Geneva, Switzerland

    Ilona Grosse-Michaelis

  10. DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Centre for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Copenhagen University Hospital-Rigshospitalet, Glostrup, Denmark

    Bente Glintborg

  11. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Bente Glintborg

  12. Department of Clinical Pharmacology and Therapeutics, Austin Health, Melbourne, Australia

    David F. L. Liew

  13. Department of Medicine, University of Melbourne, Melbourne, Australia

    David F. L. Liew

  14. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

    Tue W. Kragstrup

Authors
  1. Lykke Skaarup
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  2. Elvina Ingrid
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  3. Alexandre Sepriano
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  4. Elena Nikiphorou
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  5. René Østgård
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  6. Kim Lauper
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  7. Ilona Grosse-Michaelis
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  8. Margreet Kloppenburg
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  9. Bente Glintborg
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  10. David F. L. Liew
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  11. Tue W. Kragstrup
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Corresponding author

Correspondence to Tue W. Kragstrup.

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Funding

T.W.K. was supported by a grant from Independent Research Fund Denmark (9039-00015B). The Kragstrup lab has recieved funding from Gigtforeningen, Axel Muusfeldts Fond, Beckett Fonden, Bjarne Jensens Fond, Danielsens Fond, Hørslev Fonden, Kong Christian den Tiendes Fond, Fonden til Lægevidenskabens Fremme, Direktør Michael Hermann Nielsens Mindelegat, Civilingeniør Frode V. Nyegaard og Hustru's Fond, and Oda og Hans Svenningsens Fond. This study did not receive direct funding from any of these funding sources.

Conflict of interest

T.W.K. has engaged in educational activities receiving speaking fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, and UCB and has been consultant and advisor for Bristol-Myers Squibb, Lilly, and Gilead. T.W.K. is co-owner and clinical developer in Aptol Pharma. D.F.L.L. is a member of the Drug Utilisation Subcommittee of the Pharmaceutical Benefits Advisory Committee of the Australian Government. A.S. received speaker/consulting fees from UCB, AbbVie, Novartis, and Lilly. K.L.received speaker/consulting fees from Pfizer, Celltrion, AbbVie, Eli Lilly, Viatris, and Galapagos paid to the institution. B.G. received research grants (paid to institution) from Pfizer, AbbVie, and Sandoz. R.O. has engaged in educational activities receiving speaking fees from Janssen, Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, and UCB and has been consultant and advisor for Bristol-Myers Squibb, Pfizer, Novartis, Lilly, and Gilead. E.N. has received speaker honoraria/participated in advisory boards and/or received research grants from: UCB, Pfizer, Gilead, Galapagos, AbbVie, Eli Lilly, Fresenius, and Pfizer. M.K. has contributed to consultancy/advisory boards by Pfizer, Galapagos, CHDR, Novartis, UCB, GSK, and IMI-APPROACH (paid to institution) and received honoraria for presentations from Galapagos and Jansen (paid to institution). L.S., E.I., I.G., and M.K. have no disclosures. D.F.L.L. is an editorial board member of Drug Safety. D.F.L.L. was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Data availability

All data is available via references or on the relevant websites

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Author contributions

L.S. and T.W.K. established the project. All authors were involved in the conception and scope of the manuscript. L.S. and E.I. extracted data from the FDA and EMA documents and wrote the result section. L.S. and T.W.K. made the first draft of the manuscript. All authors were involved in analysis and interpretation of data and critically revising the manuscript for intellectual content. All authors approved the final version of the manuscript and agree to be accountable for the work.

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Skaarup, L., Ingrid, E., Sepriano, A. et al. A Systematic Overview of Contraindications and Special Warnings for Biologic and Targeted Synthetic Disease Modifying Antirheumatic Drugs: Establishing a Framework to Create a “Safety Checklist”. Drug Saf 47, 1075–1093 (2024). https://doi.org/10.1007/s40264-024-01461-1

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