Interleukin‐17 inhibitor, is it safer than tumor necrosis factor inhibitor?

Abstract

The efficacy of IL17 inhibitor (IL17i) in inflammatory arthritis (IA) including ankylosing spondylitis (AS) and psoriatic arthritis (PsA) has been ascertained in largescale clinical trials, while safety, especially infections, should be further addressed and paid more attention to by clinicians in longterm administration. In a nationwide populationbased study evaluating the mortality of AS, the proportions for all general comorbidities including infections were substantially higher in the patients with AS. Within the AS cohort, infections were statistically significant predictors of death.1 PsA per se is associated with an increased infectious risk, which is in line with the theory.2 Biological diseasemodifying antirheumatic drugs (bDMARDs) including IL17i as well as tumor necrosis factor inhibitor (TNFi), are approved for treatment in IA. According to current practice for IA,3,4 in patients with predominantly axial disease which is active and has insufficient response to nonsteroidal antiinflammatory drugs (NSAIDs), TNFi should be considered as the first bDMARD, IL17i may be preferred when there is relevant skin involvement. Switching to another TNFi or an IL17i is recommended in case TNFi fails. Although TIght COntrol of Psoriatic Arthritis (TICOPA) showed better responses with treatment adaptations upon tight control compared with standard care, theoretically antidrug antibody would eventually lead to secondary drug failure. Thus switching should be cautious instead of being fond of the new and tired of the old and clinicians must weigh the pros and cons to make the best choice. Relative contraindications should include specific types of infections. Therapeutic effects together with adverse effects (AE) are both due to mode of action, socalled mechanisms of the relevant drugs. The most common AE is infection. Compared with IL17, TNF exerts a more potent and wider effect and might induce more side effects including severe and opportunistic infections. By widespread innate and adaptive system modification, it has been proposed that TNFi increased the risk of tuberculosis and mycobacterial infections as well as causing disruption of tuberculosis granulomas or reactivation of tuberculosis. On the other hand, the mechanism of action of IL17i is more targeted than that of TNFi, with generally fewer warnings and precautions. IL17i proved to be safer in patients with high risk for tuberculosis and hepatitis B virus (HBV). In the case of HBV infection, IL17 can play both protective and pathogenic roles.5 Interestingly, IL17 can enhance the proliferation of HepG2 cells in vitro and in vivo via activating the IL6/STAT3 pathway, demonstrating that the tumorpromoting effect mediated by IL17 might be correlated with a direct action on tumor cells through inducing IL6, which could activate STAT3 in hepatocellular carcinoma (HCC). The IL17/IL6/ STAT3 (signal transducer and activator of transcription 3) signaling pathway is a potential therapeutic target for HBVrelated HCC.6 In another way, IL17i might be protective or at least not harmful in patients with HBV infection who are at risk of HCC. Clinical data show no risk of increased infection with IL17i from specific pathogens, with the exception of candidiasis. Treatment with secukinumab (SEC) (MEASURE 14 in AS 79 and FUTURE 13 in PsA 1012) may increase the risk of infections. In the doubleblinded period, candida infection was reported with incidence of less than 3% in AS and less than 1% in PsA. Treatment with ixekizumab (IXE) (COASTV, COASTW in AS 13,14 and SPIRITP1, SPIRITP2 in PsA 15,16) could consistently increase the risk of infections. In the doubleblinded period, candida infection was also reported with similar incidence. In a bimekizumab (BKZ) trial in AS,17 candida infection was twice higher compared with previous IL17i. In the BKZ trial in PsA,18 the incidence of candida infection was comparable. Of special interest, candida infections (genital candidiasis, oral candidiasis and candida thrush infection) were reported. These events did not lead to study discontinuation and resolved spontaneously or with standard antifungal treatment. Gainoffunction human STAT1 mutations impair IL17 immunity and underlie chronic mucocutaneous candidiasis including skin, nails, oral cavity, oropharynx, genital mucosa.19 The promising neutralizing effect targeting IL17F in addition to IL17A might come up with possible higher risk of candida infection. In the longterm evaluation of SEC trials up to 5 years,2028 the exposureadjusted incidence rate (EAIR) of infections reached the peak with the highest rate of infection and infestation of 81.3% in AS and 76.3% in PsA at 1 year. The rate of serious infection (1.0% in AS and 1.8% in PsA) and candida infection (0.4% in AS and 0.9% in PsA) remained stable at the fifth year. The reported data for extension study of IXE was relatively shorter with up to 1 year in AS 28 and 3 years in PsA,29 the incidence of infections also reached the peak at 1 year (52% in AS and 55% in PsA) with decreasing tendency. As time goes by, the risk of infection might be dosedependent within the first year and drop to a stable level, which might be due to biologics tapering and decreased concomitant treatment after disease control.