key: cord-286132-ag2l1xa7
authors: Akiyama, Shintaro; Yamada, Akihiro; Micic, Dejan; Sakuraba, Atsushi
title: The risk of respiratory tract infections and interstitial lung disease with IL-12/23 and IL-23 antagonists in patients with autoimmune diseases: a systematic review and meta-analysis
date: 2020-08-11
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2020.08.026
sha: 
doc_id: 286132
cord_uid: ag2l1xa7

Abstract Background Respiratory tract infections (RTIs) and interstitial lung disease (ILD) secondary to interleukin (IL)-12/23 or IL-23 antagonists have been reported in autoimmune diseases. Objective To assess the risk of RTIs and non-infectious ILD with these drugs. Methods We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Risk of RTIs and non-infectious ILD was compared to placebo by Mantel-Haenszel (MH) risk difference (RD). We divided RTIs into upper RTIs (URTI), viral URTIs, and lower RTIs (LRTIs) including infectious pneumonia. Non-infectious ILD included ILD, eosinophilic pneumonia, and pneumonitis. Results We identified 54 RCTs including 10,907 patients with six IL-12/23 or IL-23 antagonists and 5,175 patients with placebo. These drugs significantly increased the risk of RTIs (MH RD 0.019, 95% confidence interval 0.005-0.033, P = 0.007) which was attributed to URTIs, but not viral URTIs or LRTIs. There was no significant difference in infectious pneumonia and non-infectious ILD between two groups. Limitations Due to the rarity of infectious pneumonia and ILD, sensitivity analysis was required. Conclusion The use of IL-12/23 or IL-23 antagonists for autoimmune diseases increased the risk of URTIs, but not viral URTIs, LRTIs, and non-infectious ILD.

The clinical benefit of interleukin (IL)-12 and IL-23 inhibition has been demonstrated in psoriasis 2 and Crohn's disease (CD) by briakinumab 1, 2 or ustekinumab. 3, 4 Furthermore, IL-23-specific antagonists, such 3 as tildrakizumab, 5, 6 risankizumab, 7, 8 guselkumab, 9, 10 and brazikumab, 11 have completed phase 2 or 3 trials. 4

Currently, IL-12/23 or IL-23 antagonists are the second most commonly prescribed category of biologics for 5 psoriasis and CD, behind anti-tumor necrosis factor agents. 12 6 However, randomized controlled trials (RCTs) of these drugs reported respiratory tract infections 7 (RTIs) as the most common adverse events. 13 Furthermore, the surveillance conducted by Food and Drug 8 Administration (FDA) reported the development of non-infectious interstitial lung disease (ILD) following 9 ustekinumab. 14 Hence, physicians need evidences to decide whether to continue or hold these drugs 10 particularly during the current COVID-19 pandemic. 15-17 11 This systematic review and meta-analysis aimed to determine the risk of RTIs and non-infectious 12

We evaluated the presence of heterogeneity across trials by using the I 2 statistic. An I 2 value of <25% 1 indicated low heterogeneity, 25-75% as moderate heterogeneity and >75% as considerable heterogeneity, 2 respectively. 29 Heterogeneity was evaluated by using Cochran's Q-statistics with a significance level of 3 P<0. 10 . 30 Begg's and Egger's tests were performed to access publication bias and funnel plots were 4 constructed to visualize possible asymmetry when three or more studies were available. 31, 32 5 Statistical analyses were performed using the Comprehensive Meta-Analysis Software (version 2.0; 6

Biostat, Englewood, NJ, USA). All statistical tests used a two-sided a value of 0.05 for significance. characteristics and outcomes of the included studies are summarized in Table 1 The percentage of studies which permitted to use concomitant drugs (e.g. corticosteroids, budesonide, 13 thiopurines, methotrexate, calcineurin inhibitors, or aminosalicylates) during the trials was 40.0% for 14 risankizumab, 38.5% for ustekinumab, 37.5% for briakinumab, 0% for guselkumab, and 0% for tildrakizumab. 15

As for brazikumab, one study for CD was included in this analysis and permitted concomitant drugs (Table 1) . 16

Meta-analysis with a random-effects model showed that the overall risk of RTIs with 1 anti-IL-12/IL-23 or anti-IL-23 agents was significantly higher than that of placebo (MH RD 0.019, 95% 2 confidence interval [CI] 0.005-0.033, P = 0.007) ( Figure 2 ). The number needed to harm of RTIs was 58.8. 3

Subgroup analysis revealed a significantly increased risk of RTIs with briakinumab (MH RD 0.021, 95% CI 4 0.001-0.041, P = 0.036) and risankizumab (MH RD 0.040, 95% CI 0.005-0.076, P = 0.026). Heterogeneity 5 was absent (I 2 = 0%) in overall and subgroup analyses except for briakinumab (I 2 = 31%). Funnel plot 6 demonstrated no asymmetry, therefore suggesting there was no small-study effects or publication bias, which 7 was supported by Begg's and Egger's tests ( Figure S1 ). We also assessed the differential risk of RTIs by 8 underlying disease and showed a significantly increased risk of RTIs in psoriasis (MH RD 0.023, 95% CI We divided RTIs into URTIs, viral URTIs, and LRTIs and investigated each risk with IL-12/23 or 12 IL-23 inhibitors. The overall risk of URTIs was significantly higher in the treatment group compared to Anti-IL-12/IL-23 or anti-IL-23 agents did not increase the overall risks of viral URTIs (MH RD 17 0.001, 95% CI -0.002-0.003, P = 0.60) and LRTIs (MH RD 0, 95% CI -0.002-0.002, P = 0.71) ( Figure S4A , 18 S5A). Heterogeneity was absent (I 2 = 0%) in these analyses. Publication bias was indicated in the analysis of 19 viral URTIs (Begg: P < 0.001, Egger: P = 0.019) ( Figure S4B ) and LRTIs (Begg: P < 0.001, Egger: P = 0.55) 1 ( Figure S5B ), but the funnel plots did not appear asymmetric on visual inspection. 2 3

The total numbers of infectious pneumonia were 9 and 4 cases in the treatment group and placebo, 5 respectively. Mycobacterium tuberculosis and viral pneumonia were not reported. The overall risk of 6 infectious pneumonia was not significantly increased in the treatment group compared to placebo (MH RD 0, 7 95% CI -0.002-0.002, P = 0.87) ( Figure 3 ). Heterogeneity was absent (I 2 = 0%). The funnel plot was not 8 asymmetric, indicating no publication bias, which was supported by Egger's test (P = 0.93) but not Begg's test 9

(P < 0.001) ( Figure S6 ). 10

In terms of non-infectious ILD, 2 and 1 cases were identified in the treatment group and placebo, 11 respectively. All 3 cases were reported in the trials of ustekinumab and occurred within 16 weeks after 12 initiation of the trial. [33] [34] [35] The overall risk of ILD was not significantly increased in the treatment group (MH 13 RD 0, 95% CI -0.002-0.002, P = 0.99) ( Figure 4 ). Heterogeneity was absent (I 2 = 0%). Begg's (P < 0.001), but 14 not Egger's (P = 0.69), test was suggestive of publication bias, but the funnel plot was not asymmetric ( The sensitivity analysis revealed consistent results (Table S1-2, S4-5, S6, S8) except the analysis 17 with 0.5 constant correction of zero-event studies showed a lower risk of infectious pneumonia (Table S3) and

Based on the GRADE, an overall quality of evidence for this analysis was moderate as infectious 3 pneumonia and ILD were rare events (Tables S9 and S10). 4

Our meta-analysis showed that IL-12/23 or IL-23 inhibitors increased the risk of RTIs, especially 2

URTIs, but not viral URTIs and LRTIs, and non-infectious ILD in autoimmune diseases. 3

We found that risankizumab and briakinumab particularly enhanced the risk of RTIs and 4 hypothesized that concomitant therapies during the trials might differentiate the risk of RTIs. In terms of 5 anti-IL-23 agents, risankizumab showed a higher rate of RCTs which permitted concomitant therapies (40.0%) 6 compared with guselkumab (0%) and tildrakizumab (0%). Among RCTs of risankizumab, the only study 7

reporting an increased risk of RTIs was performed in patients with ankylosing spondylitis who were permitted 8 to use conventional disease-modifying antirheumatic drugs or low-dose systemic steroids. 36 This suggests that 9 combination therapy of anti-IL-23 agents with immunosuppressants might work synergistically to surface the 10 risk of RTIs. As for anti-IL-12/IL-23 agents, each of briakinumab and ustekinumab has a similar percentage of 11

RCTs which permitted concomitant drugs (37.5% for briakinumab and 38.5% for ustekinumab). Other 12 potential risk factors such as age and sex were not different among the drugs. Given that briakinumab has 13 been withdrawn from the application with FDA due to severe adverse events, 1 the difference in risk of RTIs 14 among two drugs would be explained by different properties of these drugs. 15

Our study might support that anti-IL-12/23 and anti-IL-23 therapies can be safely used for 16 autoimmune diseases even during the current COVID-19 pandemic. However, given that influenza Respiratory Syndrome coronavirus showed that a patient with a poor outcome had an increased level of IL- 17 15 expression in the lung. 41 These data suggest that IL-12/23 or IL-23 inhibitors might theoretically be preventive 16

for SARS-CoV-2-induced pneumonia rather than detrimental in autoimmune diseases during the COVID- 19 17 pandemic. 18

First, this study did not assess the long-term effect of IL-12/23 or IL-23 antagonists on RTIs and 2 ILD. However, 92.6 % (50/54) of included studies reported RTIs during placebo-controlled phases. FDA 3 reported the onset of ILD was acute or subacute, 14 so our data would most likely include the incidence of these 4 events. Second, regarding infectious pneumonia and ILD, many studies had both-armed zero-event (87% 5 (47/54) and 94% (51/54), respectively). Thus, we undertook comprehensive analyses that either included or 6 excluded double-zero-event studies. The analysis with 0.5 constant correction showed a lower risk of these 7 events in the treatment group. We also used treatment arm correction because this method performed better 8 than 0.5 constant correction to examine rare events. 46 Third, our study may not reflect the risk in patients at 9

high risk for RTIs due to the possible exclusion of patients with recent RTIs or chronic lung disease in clinical 10 trials. Fourth, we categorized RTIs into URTIs, viral URTIs, and LRTIs based on MedDRA which is widely 11 used in clinical trials, but not so much in clinical research. Furthermore, the included studies have been 12 conducted before the pandemic. Hence, it does not provide evidences whether there is an increase in RTIs or 13 ILD during the pandemic in patients receiving IL-12/23 or IL-23 antagonists, nor whether these agents can be 14

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