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Mitigating treatment risks in IBD – opportunistic infection, demyelination and skin problems

Updated on: 14 Feb 2020   First published on 14 Aug 2019

Tuberculosis in aTNF-exposed patients is thought to be due to reactivation of latent infection. Screening for tuberculosis infection when IBD is diagnosed is, therefore, recommended. However, in patients receiving glucocorticoid treatment the QUANTIferon Gold in-tube assay can be impaired, leading to indeterminate results.2 After treatment of tuberculosis, aTNF therapy may be used without the risk of reactivation.

The incidence of herpes zoster following reactivation of varicella zoster virus infection is increased in patients with IBD. Those who are taking thiopurine or glucocorticoids are at particular risk of infection reactivation. Tofacitinib, a JAK1 and JAK3 inhibitor, is also associated with a dose-dependent increase in risk of herpes zoster.5 Filgotinib, a JAK1 inhibitor, does not appear to have the same associated risk.6 Advances in vaccines against herpes zoster might reduce this risk in the future.4

Immunisation can reduce the risk of opportunistic infections. Patients should be encouraged to get influenza vaccinations annually and a one-off pneumococcal vaccination.

Screening for chronic viral infections (eg, HIV, Hepatitis B and Hepatitis C viruses) before aTNF therapy is started avoids the need for live vaccination and allows the infection to be treated.2

Demyelination
The concerns about demyelination extend beyond medications. There is a reciprocal 1.5-fold increased risk of multiple sclerosis in people with IBD,7 and in patients taking aTNF the risk is increased twofold (cumulative incidence is 0.35% at 5 years8). Multiple sclerosis is associated with a single-nucleotide polymorphism in TNFRSF1A that leads to direct expression of a soluble form of TNFR1. This novel form of the protein antagonises the effect of TNF. This action may be mimicked by aTNF drugs,9 and avoiding these in patients with known multiple sclerosis is advised. Axonal myopathy without evidence of demyelination has also been reported in patients treated with infliximab for IBD.10

If patients develop neurological symptoms, physicians are advised to stop aTNF treatment and seek the opinion of a neurologist. The withdrawal of the biologic therapy might be sufficient to induce remission, but corticosteroids, with or without immunoglobulins and/or plasma exchange, are sometimes required. Overall, 66% of cases have favourable outcomes.10 

Skin 
There are two principal skin conditions associated with the treatments of IBD:

  • Malignancy
  • Psoriasis

The risk of non-melanoma skin cancer is raised in patients with IBD, particularly Crohn’s disease, and is further increased in those older than 50 years.11 Thiopurines are associated with non-melanoma skin cancer, and risk grows with increasing length of exposure and cumulative dose.13 The risks also persist after discontinuation.12 Thiopurines increase the risk of squamous-cell cancers by replacing a small amount of guanine in DNA, causing mutations and increased reactivity to ultraviolet light.13
Similar processes are seen in basal-cell cancer,14 although the incidence is raised among IBD patients how have not received thiopurines.11 

Melanoma is 37% more common in IBD patients than the general population, but there is no clear link between melanoma and biologic use.15 Findings were similar in patients with rheumatoid arthritis.16 The pragmatic approach to limiting the risk of skin cancers is to encourage sun protection and dermatological screening.15

Although aTNF drugs are used in the treatment of psoriasis, they can paradoxically cause psoriasiform rashes, particularly in females. Infliximab is the most commonly associated agent.17 These lesions are seen more frequently in patients taking immunomodulators and in those with Crohn’s disease.18 A suggested approach for management is as follows:

  1.  Topical treatment – effective in 64% of patients17
    2.    Systemic therapy (eg, low-dose oral steroids, antibiotics, anti-fungals or methotrexate)
    3.    Withdrawal of aTNFs – resolves the rash in 67% of patients.17
    4.    Change to another aTNF –recurrence is seen in 64% of patients with this strategy17
    5.    Consider changing to ustekinumab, particularly in patients with a high Dermatology Life Quality Index scores

Other paradoxical skin reactions can occur (Figure 1) and the balance needs to be struck between managing symptoms and manifestations while maintaining control of IBD. Withdrawal of the offending agent frequently improves the skin reaction.19

Figure 1: Classification and pathogenesis of cutaneous paradoxical reactions to biologic agents and related key immune-response/cytokine patterns

Garcovich, S., et al. (2019). Paradoxical skin reactions to biologics in patients with rheumatologic disorders. Frontiers in Pharmacology.

Conclusions
A proactive approach can mitigate the side effects of aTNF drugs. Opportunistic infections are largely preventable with timely screening and immunisation. Demyelination is generally reversible if recognized early and treated if required. Skin lesions may be treated but might require cessation of the associated aTNF agent.


About the authors

James Morgan

James graduated from the University of Manchester (MBChB) in 2011. He completed his Foundation years in Stockport before moving to the Mersey deanery for his medical training. He obtained MRCP (UK) in 2014 and entered Gastroenterology Specialty training in 2015. James has developed an interest in Inflammatory Bowel Disease (IBD) during his higher training and undertook a year in a tertiary IBD centre at the Royal Liverpool University Hospital, which included 3 months attached to the Intestinal Failure unit at Salford Royal NHS Foundation Trust.

Chris Probert

After graduating from University of Birmingham (MBChB 1985) and obtaining MRCP (UK) in 1988. Chris was awarded MD by University of Leicester, in 1993, for the study of the epidemiology of inflammatory bowel disease in South Asian migrants.

Chris undertook a BDF (now CORE) funded research fellowship at Harvard for 2 years, with Prof Rick Blumberg, studying the mucosal immunology of inflammatory bowel disease.

After this fellowship, Chris was appointed to the post of Senior Lecturer, then Reader, in the Department of Medicine at University of Bristol. He was clinical lead for gastroenterology, and later for inflammatory bowel diseases, at University Hospital Bristol NHS Foundation Trust.

In 2007, Chris was appointed to the chair of gastroenterology in Bristol. In 2011, he was appointed Professor of Gastroenterology at University of Liverpool. He has a major research interest in the study of volatile organic compounds (VOCs) for disease diagnosis, funded by Wellcome Trust and Cancer Research UK.

He has published 140 original papers and >45 reviews in peer-reviewed manuscripts, he has edited 5 textbooks and contributed to many others.

He was Vice Chair of the Clinical Advisor’s Committee of Crohn’s and Colitis UK (NACC) and recent past-chair of the IBD Committee of the BSG.


References

1.European Crohn’s and Colitis Organisation (ECCO). Inflammatory Bowel Disease (IBD): check list for the prevention of infections. http://www.e-guide.ecco-ibd.eu/sites/default/files/MASTER_OI_Consensus_UpdateCheckList_OI_guidelines_2014.pdf (accessed August 27 2019).
2.Shivaji UN, Sharratt CL, Thomas T, et al. Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2019;49:664–80, https://doi.org/10.1111/apt.15097.
3.Carpio D, Jauregui-Amezaga A, de Francisco R, et al. Tuberculosis in anti-tumour necrosis factor treated inflammatory bowel disease patients after the implementation of preventive measures: compliance with recommendations and safety of retreatment. J Crohns Colitis 2016;10:1186–93,  https://doi.org/10.1093/ecco-jcc/jjw022.
4.Khan N, Patel D, Trivedi C, et al. Overall and comparative risk of herpes zoster with pharmacotherapy for inflammatory bowel diseases: a nationwide cohort study. Clin Gastroenterol Hepatol 2018; 16:1919–27.e3, https://doi.org/10.1016/j.cgh.2017.12.052.
5.Caldera F, Farraye FA, Kane S. The who and why of herpes zoster vaccination in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2018; 16:1872–75, https://doi.org/10.1016/j.cgh.2018.08.061.
6.Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 2017;389:266–75, https://doi.org/10.1016/S0140-6736(16)32537-5.
7.Kosmidou M, Katsanos AH, Katsanos KH, et al. Multiple sclerosis and inflammatory bowel diseases: a systematic review and meta-analysis. J Neurol 2017;264:254–59, https://doi.org/10.1007/s00415-016-8340-8.
8.Andersen NN, Pasternak B, Andersson M, Nielsen NM, Jess T. Risk of demyelinating diseases in the central nervous system in patients with inflammatory bowel disease treated with tumor necrosis factor inhibitors. JAMA Intern Med 2015;175:1990–92, https://doi.org/10.1001/jamainternmed.2015.5396.
9.Gregory AP, Dendrou CA, Attfield KE, et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 2012;488:508–11 https://doi.org/10.1038/nature11307.
10.Bosch X, Saiz A, Ramos-Casals M. Monoclonal antibody therapy-associated neurological disorders. Nat Rev Neurol 2011;7:165–72, https://doi.org/10.1038/nrneurol.2011.1.
11.Singh H, Nugent Z, Demers AA, Bernstein CN. Increased risk of nonmelanoma skin cancers among individuals with inflammatory bowel disease. Gastroenterology 2011;141:1612–20, https://doi.org/10.1053/j.gastro.2011.07.039.
12.Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 2011;141:1621–28, https://doi.org/10.1053/j.gastro.2011.06.050.
13.Inman GJ, Wang J, Nagano A, et al. The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nat Commun 2018;9:3667, https://doi.org/10.1038/s41467-018-06027-1.
14.Harwood CA, Attard NR, O’Donovan P, et al. PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients. Br J Cancer 2008;99(8):1276-84, https://doi.org/10.1038/sj.bjc.6604665.
15.Singh S, Nagpal SJS, Murad MH, et al. Inflammatory bowel disease is associated with an increased risk of melanoma: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014;12:210–18, https://doi.org/10.1016/j.cgh.2013.04.033.
16.Mercer LK, Askling J, Raaschou P, et al. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers. Ann Rheum Dis 2017;76:386–91, https://doi.org/10.1136/annrheumdis-2016-209285.
17.Mazloom SE, Yan D, Hu JZ, Ya, et al. TNF-α Inhibitor-Induced psoriasis: A decade of experience at the Cleveland Clinic. J Am Acad Dermatol 2018; published online Dec 18, https://doi.org/10.1016/j.jaad.2018.12.018.
18.Melo FJ, Magina S. Clinical management of anti-TNF-alpha-induced psoriasis or psoriasiform lesions in inflammatory bowel disease patients: a systematic review. Int J Dermatol 2018;57):1521–32, https://doi.org/10.1111/ijd.14072.
19.Garcovich S, De Simone C, Genovese G, Berti E, Cugno M, Marzano AV. Paradoxical skin reactions to biologics in patients with rheumatologic disorders. Front Pharmacol 2019;10:282, https://doi.org/10.3389/fphar.2019.00282.


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