Ixekizumab is a Safe Option for Long-Term Treatment of Inflammatory Diseases
Psoriasis, psoriatic arthritis (PsA), and axial spondyloarthritis (SpA) are chronic inflammatory diseases that often require long-term treatment. The current pharmacotherapy of these diseases includes conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and targeted biological therapies that inhibit the effects of tumor necrosis factor (TNF) or interleukins IL-23 and IL-17. An analysis published in early 2020 in the journal Rheumatology focused on the safety of long-term inhibition of IL-17A using ixekizumab.
Ixekizumab in Long-Term Therapy
Pathologically elevated concentrations of IL-17A promote keratinocyte proliferation and activation in psoriasis and are associated with the pathogenesis of PsA and axial SpA, where they support inflammation leading to erosive bone damage and pathological new bone formation. Ixekizumab is a monoclonal IgG4 antibody that binds with high affinity and specificity to IL-17A (IL-17A and IL-17A/F) and inhibits these effects. Ixekizumab is indicated for the treatment of moderate to severe psoriasis and active PsA, and it was recently approved for the treatment of active axial SpA.
Long-term disease therapy places high demands on drug safety. Collecting safety data and regularly evaluating it is essential for the rational choice of therapy. An international team of authors conducted an analysis of long-term safety data of ixekizumab regardless of indication. Data for the analysis were obtained from 21 clinical trials from the UNCOVER (psoriasis treatment), SPIRIT (PsA), and COAST (SpA) programs. In total, data from 8,228 patients who were administered ixekizumab for up to 5 years (5,898 patients with psoriasis, 1,401 with PsA, and 929 with axSpA; a total of 20,896 patient-years) were evaluated.
Key Findings
The overall incidence rate of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) did not increase with long-term exposure to ixekizumab. Instead, it showed a decreasing trend (TEAEs) or stabilization (SAEs) over the 5-year follow-up period. The incidence rates of SAEs, deaths, and adverse events leading to treatment discontinuation were low. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and injection site reactions (ISR). Rare cases of intestinal inflammation, malignancies, and significant cardiovascular events were reported. In the first year of treatment, the most common TEAEs were primarily infections, ISRs, and allergic reactions (hypersensitivity). Their frequency decreased significantly with longer exposure to ixekizumab.
Patients with psoriasis, PsA, and SpA have a 1−4× increased risk of developing inflammatory bowel disease (IBD) compared to the healthy population. It is unclear whether IL-17 plays a role in this. The incidence of IBD during ixekizumab treatment in the analyzed studies corresponded to the incidence in the populations of patients with psoriasis, PsA, and SpA. The influence of IL-17 inhibition on the occurrence of IBD was not evident in this analysis.
Infectious Complications
Infections were the most common adverse events throughout the follow-up period. They were more frequent in the first year of treatment and did not increase thereafter. The incidence of serious infections was low and remained stable over the long term. The most frequent infections during treatment were upper respiratory tract infections, bronchitis, and opportunistic infections such as oral and esophageal candidiasis or herpes zoster. No systemic or invasive candidiasis was reported, and herpetic eye involvement was rare. Opportunistic infections are likely caused by the suppression of IL-17A effects in host defense processes against these pathogens.
Patients in the studies were regularly tested for tuberculosis (TB) at annual intervals. A positive result led to the discontinuation of ixekizumab in 67 psoriasis patients and 10 PsA patients. However, no cases of TB reactivation associated with ixekizumab administration were confirmed, even in patients with latent or previously treated Mycobacterium tuberculosis infection.
Conclusion
The information obtained from this integrated data analysis indicates that the safety of ixekizumab is similar regardless of indication. Long-term administration of this drug is not associated with an increase in adverse events, even in the category of infectious complications. The safety profile of ixekizumab described in this analysis is consistent with previous findings. Ixekizumab thus represents a suitable option for long-term therapy of psoriasis, PsA, and SpA.
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Source: Genovese M. C., Mysler E., Tomita T. et al. Safety of ixekizumab in adult patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis: data from 21 clinical trials. Rheumatology (Oxford) 2020 May 25: keaa189, doi: 10.1093/rheumatology/keaa189 [Epub ahead of print].
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