To the Editor:
Interleukin(IL)-17 and IL-23 inhibitors* are common treatments for psoriasis and other inflammatory disorders,1 but may increase risk for invasive fungal infections (IFI), particularly candidiasis, as IL-17 and IL-23 are critical to innate antifungal immunity.2–5 Yet, most safety data come from clinical trials, which may not reflect real-world safety in broader populations.2–4 We estimated IFI incidence and describe IFI risk factors in patients starting IL-17 and IL-23 inhibitors.
Using Merative™ MarketScan® Research Databases, we identified patients who filled an outpatient IL-17 or IL-23 inhibitor prescription during 7/1/2016–1/31/2022, creating seven cohorts (one per drug) and following patients one year from index prescription to ascertain IFI diagnoses and calculate incidence.† By drug class, we compared demographics, drug indications, underlying conditions, and concurrent immunosuppressive medications for IFI vs. non-IFI patients using χ2 or Fisher exact tests (α=0.05).
Of 33,536 patients prescribed an IL-17 (n=13,834) or IL-23 (n=19,702) inhibitor, 125 had an IFI (incidence: 3.7/1,000 patient-years) (Table 1). Median time to diagnosis was 172 days (interquartile range 79–280); most diagnoses (84%) were in outpatient settings. The most frequent IFI types were candidiasis (64% [incidence: 2.4], mostly esophageal candidiasis), histoplasmosis (11%) and “unspecified mycoses” (10%). Aspergillosis, pneumocystosis, coccidioidomycosis, sporotrichosis, and “other specified mycoses” each composed ≤5% of IFIs. IFI incidence by drug ranged from 0.8 (guselkumab)–5.1 (secukinumab).‡
Table 1.
Incidence of Invasive Fungal Infections (IFI) in Patients within the First Year of Initiating an IL-17 or IL-23 Inhibitor — United States, July 2016‒January 31, 2022
| Drug* | No. patients with IFI/population at risk (incidence per 1,000 person-years) | Time to 1st IFI diagnosis, median, (IQR), days | No. (%) hospitalized at time of 1st IFI diagnosis | IFI types diagnosed within 1 year (no. patients)† |
|---|---|---|---|---|
| All patients | 125/33536 (3.7) | 172 (79–280) | 20 (16) | Aspergillosis (6), Candidiasis (80), Coccidioidomycosis (6), Histoplasmosis (14), Pneumocystosis (4), Sporotrichosis (1), Other specified mycosis (1), unspecified mycosis (13) |
| IL-17 inhibitors | ||||
| Secukinumab | 48/9329 (5.1) | 133 (73.5–284.5) | 6 (13) | Aspergillosis (5), Candidiasis (27), Coccidioidomycosis (3), Histoplasmosis (5), Pneumocystosis (2), Sporotrichosis (1), Unspecified mycosis (5) |
| Ixekizumab | 19/4461 (4.3) | 254 (180–296) | 0 (0) | Candidiasis (18), Histoplasmosis (1) |
| Brodalumab | 0/44 (0) | n/a | n/a (n/a) | n/a |
| IL-23 inhibitors | ||||
| Ustekinumab | 50/11998 (4.2) | 160 (79–266) | 13 (26) | Aspergillosis (1), Candidiasis (30), Coccidioidomycosis (3), Histoplasmosis (6), Pneumocystosis (2), Other specified mycosis (1), Unspecified mycosis (7) |
| Guselkumab | 3/3663 (0.8) | 274 (61–330) | 1 (33) | Candidiasis (1), Histoplasmosis (1), Unspecified mycosis (1) |
| Tildrakizumab | 0/92 (0) | n/a | n/a | n/a |
| Risankizumab | 5/3949 (1.3) | 123 (120–180) | 0 (0) | Candidiasis (4), Histoplasmosis (1) |
Patient drug cohorts are mutually exclusive.
Patients could receive >1 IFI diagnosis. Among all patients with candidiasis (n=80), subtypes diagnosed included esophageal candidiasis (n=68), candidal sepsis (n=8), Candida enteritis (n=3), and pulmonary candidiasis (n=1).
IFI patients (vs. non-IFI patients) in both groups more frequently had concurrent corticosteroid use (IL-17: n=15 [22.4%] vs. n=1,577 [11.5%], p=0.005; IL-23: n=21 [36.2%] vs. n=2,245 [11.4%], p<0.001). (Table 2). In the IL-23 group, IFI patients were more frequently Western U.S. residents (26% vs. 12%, p=0.001) and had psoriatic arthritis (19% vs. 9%, p=0.006) (but less frequently had psoriasis in general [41% vs. 61%, p=0.003]), Crohn’s disease (53% vs. 26%, p<0.0001), and stem cell transplant (2% vs. 0%, p=0.018).
Table 2.
Factors associated with invasive fungal infection (IFI) development in patients within one year after initiating IL-17 or IL-23 inhibitors, United States, July 2016‒January 31, 2022*
| Characteristic | IL-17 inhibitor | IL-23 inhibitor | ||||
|---|---|---|---|---|---|---|
| IFI (n=67) | No IFI (n=13,767) | P-value | IFI (n=58) | No IFI (n=19,644) | P-value | |
| Age group (years) | 0.054 | 0.447 | ||||
| 0–17 | 0 (0) | 88 (1) | 1 (2) | 605 (3) | ||
| 18–44 | 13 (19) | 4690 (34) | 23 (40) | 8742 (45) | ||
| 45–64 | 48 (72) | 8227 (60) | 29 (50) | 9383 (48) | ||
| ≥65 | 6 (9) | 762 (6) | 5 (9) | 914 (5) | ||
| Female | 41 (61) | 7333 (53) | 0.194 | 27 (47) | 10082 (51) | 0.468 |
| U.S. census region † | 0.806 | 0.003 | ||||
| Northeast | 9 (14) | 2245 (16) | 0.525 | 4 (7) | 3674 (19) | 0.021 |
| South | 36 (55) | 6690 (49) | 0.401 | 29 (50) | 9463 (48) | 0.781 |
| Midwest | 12 (18) | 2844 (21) | 0.579 | 10 (17) | 4097 (21) | 0.499 |
| West | 9 (14) | 1968 (14) | 0.841 | 15 (26) | 2356 (12) | 0.001 |
| Indications for IL-17 or IL-23 inhibitor | ||||||
| Psoriasis | 49 (73) | 10236 (74) | 0.820 | 24 (41) | 11909 (61) | 0.003 |
| Psoriatic arthritis | 22 (33) | 4493 (33) | 0.972 | 11 (19) | 1707 (9) | 0.006 |
| Ankylosing spondylitis | 8 (12) | 1493 (11) | 0.774 | 1 (2) | 117 (1) | 0.295 |
| Inflammatory bowel disease | 0 (0) | 85 (1) | >0.999 | 33 (57) | 6033 (31) | <.0001 |
| Crohn's disease | 0 (0) | 39 (0) | >0.999 | 31 (53) | 5147 (26) | <.0001 |
| Ulcerative colitis | 0 (0) | 48 (0) | >0.999 | 6 (10) | 1821 (9) | 0.780 |
| Behçeťs disease | 0 (0) | 8 (0) | >0.999 | 0 (0) | 9 (0) | >0.999 |
| Pyoderma gangrenosum | 0 (0) | 7 (0) | >0.999 | 1 (2) | 54 (0) | 0.150 |
| Hydradenitis suppuritiva | 1 (1) | 93 (1) | 0.367 | 1 (2) | 187 (1) | 0.427 |
| Lichen planus | 0 (0) | 22 (0) | >0.999 | 0 (0) | 34 (0) | >0.999 |
| Seborrheic dermatitis | 0 (0) | 246 (2) | 0.635 | 1 (2) | 473 (2) | >0.999 |
| Juvenile arthritis | 0 (0) | 51 (0) | >0.999 | 0 (0) | 40 (0) | >0.999 |
| Rheumatoid arthritis | 10 (15) | 1412 (10) | 0.209 | 1 (2) | 601 (3) | >0.999 |
| Other underlying conditions (present during the 180 days before starting IL-17 or IL-23 inhibitor) | ||||||
| Diabetes mellitus | 14 (21) | 1964 (14) | 0.122 | 5 (9) | 2059 (10) | 0.644 |
| Hematologic malignancy | 0 (0) | 60 (0) | >0.999 | 1 (2) | 57 (0) | 0.157 |
| Solid malignancy | 3 (4) | 289 (2) | 0.167 | 1 (2) | 354 (2) | >0.999 |
| Neutropenia | 0 (0) | 20 (0) | >0.999 | 0 (0) | 27 (0) | >0.999 |
| Stem cell transplant | 0 (0) | 1 (0) | >0.999 | 1 (2) | 5 (0) | 0.018 |
| Solid organ transplant | 0 (0) | 10 (0) | >0.999 | 1 (2) | 29 (0) | 0.085 |
| HIV infection | 0 (0) | 17 (0) | >0.999 | 0 (0) | 43 (0) | >0.999 |
| Concurrent immunosuppressive medications (prescription filled at least once during period during which the patient started the IL17 or IL23 inhibitor to 365 days later or to development of IFI, whichever occurred earlier) | ||||||
| Corticosteroids | 15 (22) | 1577 (11) | 0.005 | 21 (36) | 2245 (11) | <0.001 |
| Tacrolimus | 0 (0) | 278 (2) | 0.647 | 1 (2) | 334 (2) | >0.999 |
| Cyclosporine | 1 (1) | 229 (2) | >0.999 | 0 (0) | 203 (1) | >0.999 |
| Methotrexate | 11 (16) | 1696 (12) | 0.309 | 7 (12) | 1233 (6) | 0.094 |
| Mycophenolate mofetil | 0 (0) | 46 (0) | >0.999 | 1 (2) | 47 (0) | 0.132 |
| Small molecule kinase inhibitors | 3 (4) | 298 (2) | 0.179 | 0 (0) | 211 (1) | >0.999 |
| Antifungal prophylaxis (≥21 days’ supply during the 90 days before starting IL-17 or IL-23 inhibitor) | ||||||
| Pneumocystis prophylaxis | 0 (0) | 46 (0) | >0.999 | 1 (2) | 107 (1) | 0.273 |
| Voriconazole, posaconazole, or isavuconazole | 0 (0) | 2 (0) | >0.999 | 0 (0) | 4 (0) | >0.999 |
| Fluconazole | 0 (0) | 56 (0) | >0.999 | 0 (0) | 85 (0) | >0.999 |
IFIs and underlying conditions were identified using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. A full list of ICD-10-CM codes used is available as a supplemental table. Patients could have more than one underlying condition. P values were calculated using chi-square or Fisher’s exact tests (for small cell sizes) for proportions.
U.S. census region of primary beneficiary’s residence. Map of U.S. census regions: https://www2.census.gov/geo/pdfs/maps-data/maps/reference/us_regdiv.pdf. U.S. census region was unknown or missing for 21 patients on IL-17 inhibitors and 54 patients on IL-23 inhibitors.
Within the first year of initiating anti-IL-17 or IL-23 therapy, few patients (0.37%) developed an IFI (primarily candidiasis), a rate lower than or comparable to previous studies. In a meta-analysis of 11 IL-17 inhibitor randomized controlled trials (RCTs), candidiasis incidence (including non-invasive forms) was 1.5% among 7,387 IL-17 inhibitor-treated patients.3 A study pooling three placebo-controlled RCTs for tildrakizumab (IL-23 inhibitor) found candidiasis incidence rates were 0.1% (n=705, 100mg) and 0.3% (n=708, 200mg).4
We found higher IFI incidence in IL-17 and IL-23 inhibitor patients receiving corticosteroids and in IL-23 inhibitor patients with Crohn’s disease, psoriatic arthritis, or stem cell transplant, possibly reflecting greater background immunosuppression and suggesting a need for increased clinical vigilance for IFI in such patients. Although non-Candida IFIs were less common, continued physician awareness is necessary given potential disease severity.
Important study limitations were lack of information on non-commercially–insured patients, race/ethnicity, drug dosing, laboratory values, and clinical outcomes. Further, administrative data are subject to under-coding and misclassification.
In summary, IFIs were rare among patients beginning IL-17 and IL-23 inhibitor therapy, and our study could help physicians stratify IFI risk when prescribing these medications. Clinical vigilance for IFIs may be particularly warranted in patients with Crohn’s disease, psoriatic arthritis, stem cell transplant, or corticosteroid use.
Supplementary Material
Acknowledgements:
We thank Malavika Rajeev, PhD, and Dallas J. Smith, PharmD, MAS, for assistance with study design and review of this manuscript.
Funding Sources:
Dr. Bahr receives funding from the National Institute of Neurological Disorders and Stroke, K23 NS110470.
Abbreviation List:
- IL
interleukin
- IFI
invasive fungal infection
- ICD-10-CM
(International Classification of Diseases, 10th Revision, Clinical Modification)
- IBD
(inflammatory bowel disease)
- RCT
(randomized controlled trial)
Footnotes
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.
Note: This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy (e.g., 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq).
Potential Conflicts of Interest: Dr. Lipner has served as a consultant for Ortho-dermatologics, Eli Lilly, Moberg Pharmaceuticals, and BelleTorus Corporation. The other authors declare no potential conflicts.
Statement of prior presentation: None.
IRB: This study is IRB exempt.
Patient Consent: not applicable
U.S. Food and Drug Administration (FDA)-approved IL-17 inhibitors are secukinumab, ixekizumab, and brodalumab; FDA-approved IL-23 inhibitors are ustekinumab, guselkumab, tildrakizumab, and risankizumab.
The Merative™ MarketScan® Research Commercial Database and the Medicare Supplemental Database are deidentified and included approximately 49 million unique commercially insured outpatients during the study period. We excluded patients who switched to a different IL-17 or IL-23 inhibitor and patients who received IFI diagnosis <180 days before initial IL-17 or IL-23 prescription and required continuous insurance coverage during the 180 before to 365 days after the index prescription. IFI diagnoses were ascertained using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes (Supplemental Material: https://data.mendeley.com/datasets/83hw75sy3k/1).
Cohorts with zero IFIs (brodalumab, tildrakizumab) had <100 total patients each.
References:
- 1.Lee MP, Wu KK, Lee EB & Wu JJ Risk for deep fungal infections during IL-17 and IL-23 inhibitor therapy for psoriasis. Cutis 106, 199–205 (2020). 10.12788/cutis.0088 [DOI] [PubMed] [Google Scholar]
- 2.Sticherling M et al. Secukinumab in Pediatric Patients with Plaque Psoriasis: Pooled Safety Analysis from Two Phase 3 Randomized Clinical Trials. Am J Clin Dermatol 24, 821–835 (2023). 10.1007/s40257-023-00782-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Feng Y et al. Risk of Candida Infection and Serious Infections in Patients with Moderate-to-Severe Psoriasis Receiving Biologics: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Clin Pract 2022, 2442603 (2022). 10.1155/2022/2442603 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Blauvelt A et al. Safety of tildrakizumab for moderate-to-severe plaque psoriasis: pooled analysis of three randomized controlled trials. Br J Dermatol 179, 615–622 (2018). 10.1111/bjd.16724 [DOI] [PubMed] [Google Scholar]
- 5.Saunte DM, Mrowietz U, Puig L & Zachariae C Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol 177, 47–62 (2017). 10.1111/bjd.15015 [DOI] [PubMed] [Google Scholar]
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