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Comorbidities in Psoriatic Arthritis
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Maria J. Antonelli, Marina Magrey
Given the concern for increased cardiovascular events with the use of NSAIDs, it is recommended that NSAIDs be used for the shortest time at the lowest possible dose in patients with PsA and known CVD or multiple known risk factors (Ogdie et al. 2015). Similarly, both NSAIDs and glucocorticoids should be limited in patients with known congestive heart failure (CHF), as they may increase the risk of CHF exacerbations (Ogdie et al. 2015). Likewise, glucocorticoids should be avoided in patients with diabetes given their hyperglycemic effects. Methotrexate should be used with caution in patients with obesity and/or diabetes, as there may be an increased risk of elevated liver function test abnormalities and liver fibrosis (Ogdie et al. 2015). For patients with known CHF New York Heart Association (NYHA) class III or IV, TNF antagonists should be avoided due to limited data (Ogdie et al. 2015). Observational data do not suggest a risk of new-onset CHF in patients being treated with TNF antagonist (Ogdie et al. 2015). Although initial studies with interleukin (IL) 12/23 antagonist therapy, briakinumab and ustekinumab, raised interest in a possible increased risk for cardiovascular events, extended studies with ustekinumab have not demonstrated substantial cardiovascular risk in PsO patients and rare events in PsA clinical trials (McKeage 2014).
Risankizumab for the treatment of moderate to severe psoriasis
Published in Expert Opinion on Biological Therapy, 2019
Andrea Chiricozzi, Luca Antonioli, Salvatore Panduri, Matteo Fornai, Marco Romanelli, Corrado Blandizzi
No safety concerns related to the use of risankizumab have emerged from the phase III trials, even though the occurrence of rare cases of MACEs will make long-term evaluations of this important, class of AEs. Since the clinical development of briakinumab, a fully human monoclonal antibody directed against the IL-12/IL-23p40 subunit, was discontinued due to higher rates of MACEs as compared to placebo, the IL-12/IL-23 inhibition was hypothesized to induce instability of atherosclerotic plaques. However, no warning signals about MACEs have been associated with ustekinumab over the 9 years of clinical usage, which has shown, across national and international registries, the safest profile among the antipsoriatic systemic drugs to date. When compared to ustekinumab, risankizumab is able to inhibit selectively the pathogenic signal mediated by IL-23, thus preserving the IL-12/IFN-γ signaling that is pivotal to both anti-viral and anti-cancer immune-surveillance. However, the robust safety profile, generated by long-term registry data related to the clinical use of ustekinumab, does not support any advantage of blocking the p19 subunit, in terms of safety implications, as compared to the p40 inhibition [42–45]. By contrast, risankizumab might be advantageous over the IL-17/IL-17-receptor blockers in terms of risk of candida infections. Indeed, no harmful signals, in the short- and mid-term period, have been associated with risankizumab, even though mice models do suggest a central role of IL-23 in candida infections [19,46].
Targeting IL-23 in Crohn’s disease
Published in Expert Review of Clinical Immunology, 2018
Silvia Sedda, Gerolamo Bevivino, Giovanni Monteleone
The first study investigating the effect of a neutralizing IL-12/IL-23p40 antibody in CD was a multicenter, randomized, placebo-controlled, phase II clinical trial, which was conducted to assess safety and efficacy of ABT-874/J695 (briakinumab), in patients with active CD [41]. Briakinumab is a recombinant full-length IgG1 antibody targeting IL-12/IL-23p40 and, hence, preventing binding of these two cytokines with their receptors. Seventy-nine patients with moderate-to-severe CD were randomized to receive 7 weekly subcutaneous injections of 1 mg or 3 mg of briakinumab per kilogram of body weight or placebo. Cohort 1 received one injection followed 4 weeks later by one injection per week for 6 weeks, and Cohort 2 received one injection per week for seven weeks [41]. Patients in Cohort 1 were seen two weeks after the first injection and at weekly intervals coinciding with the next six injections; patients in Cohort 2 were seen weekly during the 7-week treatment phase. All patients were followed for 18 weeks after the final injection of study drug and were seen at 6, 12, and 18 weeks. In patients in cohort 1, the rates of clinical response and remission did not differ between the two doses of the drug and placebo at weeks 4, 9, and 18. In contrast, in cohort 2, the clinical response rate was higher in patients receiving 3 mg briakinumab than in those treated with 1 mg briakinumab or placebo at week 7, but were no longer significant at the end of follow up (week 18). The low dose of monoclonal antibody used in the trial may have contributed to the limited benefit of the treatment. Patients receiving briakinumab exhibited reduced production of inflammatory cytokines (i.e. IL-12, IFN-γ, TNF-α) in the gut. The adverse events were documented in more than 10% of patients but were not significantly different among groups, with the exception of skin reaction at injection site, which in cohort 2 was more frequent among patients receiving briakinumab than in those treated with placebo [41].
A drug safety evaluation of risankizumab for psoriasis
Published in Expert Opinion on Drug Safety, 2020
Phase 1, 2 and 3 clinical trials have demonstrated the superior efficacy of risankizumab compared to ustekinumab and adalimumab. In a meta-analysis, risankizumab is the most effective IL-23 blocker [38]. More importantly, its safety is not compromised despite its favorable efficacy. Indeed, the safety profile is generally well tolerated. Previous studies discussed an increased number of MACEs of briakinumab as compared with ustekinumab [39], although both drugs work through the inhibition of IL-12/IL-23. One possible explanation is the higher efficacy of briakinumab. Similar probable association between better efficacy and safety concern is not observed in risankizumab so far. The same as observed in guselkumab, another IL-23 blocker, the most common adverse event of risankizumab was upper respiratory tract infection [8]. For guselkumab, the three-year data does not show a disproportionate increase in malignancies, major infections or MACE over time [40], whereas only two-year safety data is currently available for risankizumab in phase 3 pivotal studies. Although direct head-to-head comparisons have not been performed, no increased risk of mucocutaneous candidiasis or inflammatory bowel disease was observed in risankizumab when compared to the IL-17 blockers. In a small subset of patients with latent tuberculosis (positive for Quantiferon TB gold assay), no active tuberculosis developed after risankizumab treatment for 55 weeks despite the lack of tuberculosis prophylaxis [33]. This is the first study of all biologics blocking IL-12/23, IL-17 and IL-23 to allow patients with latent TB without prophylaxis. Nonetheless, the study groups were mainly from low TB burden countries, and it also took several years of experience in real-world practice to find the TB risk of ustekinumab [41–45]. In particular, recent studies also find the role of IL-23 in the defense against tuberculosis [46–48]. More data is needed to determine whether the tuberculosis risk is really minimal or more favorable than IL-17 blockers in this regard [49,50]., and whether routine tuberculosis prophylaxis or monitoring is necessary even in countries with higher TB prevalence.