Dear Editor,
We read with interest the article by Roberti et al.,Citation1 who evaluated adverse effects (AEs) of biologic agents in 623 patients with inflammatory bowel disease (IBD) over a two-year period. They identified AEs in 14.8% of patients, including serious AEs (SAEs) in 1.6%, most commonly skin and subcutaneous disorders and infusion reactions. Biologically naive patients were significantly more likely to experience AEs compared with previously exposed patients, however there was no statistical difference in rates of AEs between biologic agents. AEs were prospectively documented via scheduled phone calls, patient diaries and physician/pharmacist review of every AE, including application of the Naranjo Adverse Probability Scale. The number of AEs recorded during the study period was compared with the number reported in the same centres during the preceding two years, and found to be markedly higher (102 vs 35 cases).
Although documentation of AEs from biologic agents in IBD is not novel, this paper elegantly demonstrates the value of pharmacovigilance. Many AEs only become evident post-marketing because drug trials and randomized controlled trials have short follow-up durations and narrow inclusion criteria which excludes patients with comorbidities. This precludes detection of AEs which occur rarely or take longer to develop, and limits real-world applicability. For example, infliximab received United States Food and Drug Administration approval for Crohn’s disease in 1998, however it took until a large French database of nearly 200,000 IBD patients in 2017 to obtain reliable data on the increased risk of lymphoma secondary to IBD medicationsCitation2. This study identified a significantly increased risk of lymphoma with either anti-TNF or thiopurine monotherapy, which was further increased in patients on combination therapy. Prior to this study, there had been some evidence to support thiopurines raising the risk of lymphoma; however, the risk conferred by anti-TNF agents was still uncertain.
As highlighted in this paper, without designated pharmacovigilance programs, under-reporting of AEs is common. Reliance on physicians or patients to proactively report to governing bodies is limited by time pressures, lack of awareness of avenues to pursue AE reporting, small numbers of cases taking several decades and large cohort to detect any increased signal, lack of control groups and selection bias towards patients experiencing more severe AEs, making the denominator uncertain. Furthermore, there is often insufficient data about patient disease phenotype or other factors contributing to the AE, which is particularly challenging for non-specific symptoms with multiple potential causes. Several pharmacovigilance methods exist worldwide, including local health district based systems, national pharmaceutical governance programs and patient reporting platforms. For example, an online patient-reporting system for adverse events has recently been trialled in IBD patientsCitation3. These patients reported a median of 2 AEs each, only 62% of which were reported to a healthcare provider. This is unlikely to be effective as a solo reporting method, however it may improve understanding of which AEs are most burdensome for patients. The Food and Drug Administration Adverse Event Reporting System (FAERS) is another voluntary reporting system for post-marketing adverse events from healthcare workers as well as consumers. However, despite originating from a government organization, this data is not verified and must be interpreted with caution. For example, distorted pharmacovigilance signals have been detected due to excessive attorney reporting of isotretinoin-induced IBD, causing a signal inflation factor of 5.82Citation4. The Psoriasis Longitudinal Assessment and Registry (PSOLAR) is a voluntary observational registry of patients with psoriasis on biologic agents. It was commenced in 2007, involving scheduled follow up visits to proactively detect AEs, so far demonstrating lower rates of infection and malignancy with ustekinumab compared with anti-TNF agentsCitation5,Citation6. Although the inclusion criteria would create some degree of selection bias, the PSOLAR registry still serves as a reliable resource for detecting AEs over a long duration in a large cohort. However, the external validity of this data to the IBD population is uncertain, with lower standard doses (90 mg every 8 weeks vs 45 mg every 12 weeks) and different health issues. To our knowledge, there are no similar pharmacovigilance programs in the IBD population, despite the clear need.
As more biologic and small molecule agents enter the IBD market, it is becoming increasingly important to establish pharmacovigilance systems for ongoing reporting of drug AEs. Instituting this will take a coordinated effort, ideally from multiple countries around the world. Physicians should be informed about these systems and encouraged to utilize them in order to achieve the best outcomes.
Transparency
Declaration of funding
None received.
Declaration of financial/other relationships
No potential conflict of interest was reported by R.L. C.P.S. has disclosed that he has received unrestricted research grants from Warner Chilcott, Janssen and AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda, Fresenius Kabi and Janssen, and had speaker arrangements with Warner Chilcott, Dr Falk, AbbVie, MSD, Pfizer and Takeda.
Author contributions
R.L. and C.P.S. co-wrote the manuscript.
Acknowledgements
None.
References
- Roberti R, Iannone LF, Palleria C, et al. Safety profiles of biologic agents for inflammatory bowel diseases: a prospective pharmacovigilance study in Southern Italy. Curr Med Res Opin. 2020. DOI:10.1080/03007995.2020.1786681
- Lemaitre M, Kirchgesner J, Rudnichi A, et al. Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 2017;318(17):1679–1686.
- Thomas P, West R, Russel M, et al. Inflammatory bowel disease (IBD) patients frequently report adverse drug reactions during biologic therapy: a multicentre, prospective, patient-reported pharmacovigilance monitoring system. J Crohns Colitis. 2020;14(Suppl 1):S319–S319.
- Stobaugh DJ, Deepak P, Ehrenpreis ED. Alleged isotretinoin-associated inflammatory bowel disease: disproportionate reporting by attorneys to the Food and Drug Administration Adverse Event Reporting System. J Am Acad Dermatol. 2013;69(3):393–398.
- Fiorentino D, Ho V, Lebwohl MG, et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol. 2017;77(5):845–854 e5.
- Kalb RE, Fiorentino DF, Lebwohl MG, et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol. 2015;151(9):961–969.