No reactivation of tuberculosis in patients with latent tuberculosis infection receiving ixekizumab: A report from 16 clinical studies of patients with psoriasis or psoriatic arthritis

To the Editor: Reactivation of latent tuberculosis infection (LTBI) and/or active tuberculosis (TB) has been associated with certain immunomodulatory therapies for psoriasis (Pso) or psoriatic arthritis (PsA).1Kaushik S.B. Lebwohl M.G. CME part II psoriasis: which therapy for which patient: focus on special populations and chronic infections.J Am Acad Dermatol. 2019; 80: 43-53Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Ixekizumab (IXE), a high-affinity anti–interleukin (IL)-17A monoclonal antibody, has shown safety and efficacy in patients with these conditions,2Langley R.G. Kimball A.B. Nakagawa H. et al.Long-term safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis: an integrated analysis from 11 clinical trials.J Eur Acad Dermatol Venereol. 2019; 33: 333-339Crossref PubMed Scopus (44) Google Scholar,3Mease P. Roussou E. Burmester G.R. et al.Safety of ixekizumab in patients with psoriatic arthritis: results from a pooled analysis of three clinical trials.Arthritis Care Res (Hoboken). 2019; 71: 367-378Crossref PubMed Scopus (36) Google Scholar but more data on the risk of TB infection are needed. This post hoc analysis of integrated safety data (derived via naive pooling) from 13 clinical trials in Pso4Gottlieb A, Papp P, Xu W, et al. Long-term safety of ixekizumab with over 18000 patient years of exposure: analysis from 12 moderate-to-severe plaque psoriasis studies and 3 psoriatic arthritis studies. Presented at the American Academy of Dermatology (AAD); Washington, DC, USA; March 1-5, 2019; #P10158.Google Scholar,5Romiti R. Valenzuela F. Chouela E.N. et al.Prevalence and outcome of latent tuberculosis in patients receiving ixekizumab: integrated safety analysis from 11 clinical trials of patients with plaque psoriasis.Br J Dermatol. 2019; 181: 202-203Crossref PubMed Scopus (16) Google Scholar and 3 studies of PsA3Mease P. Roussou E. Burmester G.R. et al.Safety of ixekizumab in patients with psoriatic arthritis: results from a pooled analysis of three clinical trials.Arthritis Care Res (Hoboken). 2019; 71: 367-378Crossref PubMed Scopus (36) Google Scholar evaluated treatment-emergent (TE) LTBI in IXE-treated patients (Fig 1). The purified protein derivative skin test or QuantiFERON-TB Gold assay (Cellestis Inc, Valencia, CA, USA) was used for LTBI assessment. Patients testing negative for LTBI at screening or less than 3 months before baseline were included in this analysis. Patients with a positive LTBI test result at screening could enroll in the studies after initiating LTBI-specific therapy if they met all other study inclusion criteria, but they were otherwise excluded from this analysis. Annual LTBI testing and discontinuation of patients with TE-LTBI after randomization were required per protocol. Amended protocols allowed patients with TE-LTBI to continue IXE treatment if they received LTBI therapy. In this analysis, 7016 IXE-treated patients, 5898 with Pso (16,313 patient-years of IXE exposure; 1010 mean days of exposure) and 1118 with PsA (1822 patient-years of IXE exposure; 596 mean days of exposure) were evaluated for TE-LTBI during the study program (Fig 2). A total of 101 (1.7%) patients with Pso developed TE-LTBI; of these, 65 discontinued according to study protocol. Of the 36 patients who remained in the studies, LTBI-specific therapy was initiated in 30 patients, while 6 patients did not receive LTBI-specific treatment (Fig 2). In total, 5 patients with TE-LTBI subsequently discontinued IXE in the Pso studies, 3 patients in the LTBI-treatment group, and 2 in the group without LTBI treatment. Of the 32 (2.9%) patients who developed TE-LTBI in the PsA studies, 20 were discontinued per protocol. Seven of the 12 patients continuing IXE treatment received LTBI therapy (1 patient discontinued IXE); 5 patients were not treated for LTBI (of these, 3 also discontinued IXE). No reactivation of TB was reported in the 6 patients with TE-LTBI in the absence of LTBI-specific therapy during IXE treatment. This integrated safety analysis, reporting data from one of the largest IXE databases, identified a small number of patients with TE-LTBI, most of whom received LTBI-specific therapy. No cases of reactivation of TB were identified. Limitations of this analysis are the small number of events, a missing control group, and the limited observation period, preventing long-term risk assessment for active TB. Data interpretation needs to take into consideration that these studies were designed to assess the overall safety and the efficacy of IXE and not to investigate the risk of TB reactivation. Nevertheless, these data contribute to the growing evidence for the use of therapeutic antibodies targeting IL-17A, such as IXE, in patients with LTBI. Real-world data are needed to address the clinical question of the potential long-term risk for reactivation of TB under anti–IL-17 therapy.