Effect of Anti-Psoriatic Biologics on Risk of Anogenital Warts (CONDYPSO)

Overview

This study aims to assess the impact of anti-TNF-α, anti-IL-17, and anti-IL-23 biologic therapies on the risk of development or recurrence of anogenital warts (AGW) in patients with moderate to severe psoriasis. By modulating systemic and mucosal immunity, these treatments may alter host defenses against human papillomavirus (HPV) infections, which are responsible for AGW. In particular, inhibition of Th1 pathways (by anti-TNF-α) and Th17 pathways (by anti-IL-17 and anti-IL-23), both central to the antiviral response, may reduce local production of pro-inflammatory cytokines (such as IFN-γ, IL-17, and IL-22), decrease the activity of CD8+ cytotoxic T lymphocytes, and impair dendritic cell function, thereby compromising viral clearance at the genital mucosa. AGW are a frequent and recurrent manifestation of HPV infection, and their incidence may be influenced by these immunomodulatory treatments. The retrospective component will review cases already documented in medical records and analyze, to the extent permitted by available data, the same risk factors as in the prospective component, including history of sexually transmitted infections (STIs), risk behaviors, treatments used (systemic or topical), and time to onset or recurrence of AGW. This analysis will be conducted as a retrospective case-control study, matching each patient who developed AGW with one or more controls receiving biologics who did not develop AGW, in order to identify factors associated with their occurrence. The prospective follow-up will assess, over 24 months, risk factors for occurrence or recurrence of AGW in patients with moderate to severe psoriasis, according to the treatment received: no treatment, topical treatment, systemic non-immunomodulatory treatment, or immunomodulatory treatment, including biologics. Acceptability of HPV vaccination will also be evaluated in this adult population treated with immunomodulators, which remains insufficiently targeted by current vaccination recommendations.

Scientific Rationale Anogenital warts (AGW) are a frequent manifestation of human papillomavirus (HPV) infection. Their course is generally benign, but they may cause significant discomfort and carry a high risk of recurrence, particularly in the context of immunomodulation. Psoriasis is a chronic inflammatory skin disease affecting approximately 2-3% of the global population. Biologic therapies targeting IL-17 and IL-23, now widely used, profoundly modulate mucosal immunity by acting on the Th17 axis. This pathway plays a central role in defense against viral and fungal pathogens on mucosal surfaces, notably through the production of IL-17 and IL-22. Their inhibition leads to a decrease in these cytokines, which could theoretically impair local viral clearance, particularly with respect to HPV, thereby promoting persistence or recurrence of AGW. Anti-TNF-α agents, long used in dermatology, also influence antiviral immunity by reducing the activity of cytotoxic CD8+ T lymphocytes and the production of IFN-γ, a key Th1 cytokine. This rationale is supported by experimental data showing the essential role of Th1 and Th17 pathways, CD8+ lymphocytes, dendritic cells, and IFN-γ in the control of HPV infections. A cross-sectional study in 222 patients with psoriasis or inflammatory bowel disease, including 104 treated with anti-TNF-α, did not demonstrate a significant increase in the prevalence of anogenital HPV infections compared with patients receiving alternative therapies or no treatment. At baseline, the analysis combined grouped anogenital swabs (penis or vulva, perianal area, and cervix in women) with broad-spectrum HPV PCR, together with serology for neutralizing antibodies against genotypes 6, 16, and 18. However, this study does not allow conclusions on the long-term safety of these treatments, nor on the risk associated with individual molecules, due to sample size and the cross-sectional design. Another, more recent cross-sectional study suggested an increased prevalence of oral HPV infections in psoriatic patients treated for at least 6 months with anti-IL-17, particularly after prolonged exposure (\>8 years), compared with patients receiving topical treatments or other biologics (anti-TNF-α or ustekinumab). HPV PCR on oral rinse was performed at a single time point at inclusion. Genital infections were also investigated using perineal swabs with PCR analysis, but results were less conclusive, with no statistically significant differences between groups. Several case reports have described the occurrence or worsening of AGW in patients receiving anti-IL-17 or anti-TNF-α, suggesting a possible negative impact on viral clearance. These remain isolated observations and do not establish causality. Conversely, elevated levels of interleukins 17 and 23 have been detected in HPV-induced lesions, particularly in the cervix and anal canal. Their inhibition might therefore exert a protective effect against the progression of HPV-induced lesions. Cases of regression of warts, including AGW and cutaneous warts, have indeed been reported under anti-IL-17, as well as a case of regression of high-grade HPV-associated dysplasia after switching from an anti-IL-12/23 (ustekinumab) to a selective anti-IL-23 (risankizumab). To date, no cases of AGW have been reported with the newer anti-IL-23 agents such as guselkumab, risankizumab, or tildrakizumab, while a single isolated case under ustekinumab was published in 2021. A review of the literature confirms the lack of robust quantitative data in patients treated with IL-17 and IL-23 inhibitors and highlights the scarcity of studies focusing on anogenital sites. In addition, the use of topical corticosteroids or calcineurin inhibitors in the anogenital area may locally reduce mucosal immunity and contribute to persistent or recurrent HPV infection. The role of biologics targeting TNF-α, IL-17, and IL-23 in the course of HPV infections therefore remains uncertain, complex, and likely dependent on immunological mechanisms that are still not fully understood. These considerations justify systematic studies to assess their specific impact on the incidence and recurrence of anogenital warts in psoriatic patients. Finally, very limited data are available regarding risk perception of HPV infection and acceptability of HPV vaccination in this adult population receiving immunomodulatory treatments, despite the fact that prevention could be relevant. Study Design Type: Mixed study (retrospective + prospective) Total duration: 32 months (2025-2028) Retrospective phase: 3 months (Oct-Dec 2025) Prospective phase: 27 months (Oct/Nov 2025 - Dec 2027) Analysis phase: 5 months (Jan-May 2028) The retrospective phase will consist of a case-control study, matching each patient who developed anogenital warts (AGW) with one or more controls receiving biologic therapy who did not develop AGW, in order to identify factors associated with their occurrence and to more precisely estimate the relative risk of AGW under biologic therapies, beyond simple case description. Enrollment period (prospective phase): Patients will be enrolled between October and December 2025. Each patient will be followed for 24 months after enrollment, during their routine dermatology visits for psoriasis management. No additional visits will be required by the study. Relevant data will be collected during routine consultations. All data will be available prior to the start of the analysis phase. An anonymous questionnaire on HPV vaccination acceptability will be offered during the prospective phase to all enrolled patients, regardless of vaccination status, whether or not they are receiving systemic immunomodulatory therapy (anti-TNF-α, anti-IL-17, anti-IL-23, methotrexate, cyclosporine, deucravacitinib, dimethyl fumarate). The purpose of this approach is not to promote vaccination, but to collect data on risk perception of HPV and willingness to be vaccinated, while enabling a comparative analysis between treated and untreated patients. The acceptability rate will be defined as the proportion of patients who state they would accept vaccination if it were offered. These timelines are indicative and may be adjusted depending on the actual number of inclusions or potential delays related to ethical or logistical processes. To ensure sufficient homogeneity in the prospective phase, both in terms of diagnosis and management, precise clinical definitions as well as a therapeutic reference document will be provided to investigators: Anogenital wart (AGW): papillomatous lesion suggestive of HPV infection, clinically diagnosed by a dermatologist; histological confirmation may be performed in atypical or doubtful cases. Recurrence: reappearance of lesions clinically compatible with AGW, after documented complete resolution of the initial episode. Management of AGW will be based on French recommendations from the Haute Autorité de Santé (HAS), adapted to the Belgian therapeutic context. In particular, podophyllotoxin, recommended as first-line therapy in France, is currently unavailable in Belgium. It will therefore be replaced in the reference grid by Veregen®, which is widely used in local practice. This adaptation is intended to guarantee a minimum level of treatment homogeneity while respecting local prescribing realities. The adapted grid will be communicated to investigators involved in the prospective phase, in order to ensure harmonization of AGW management practices during the study. Data Collected Common data (retrospective + prospective): Sex, age, phototype, BMI Type and duration of psoriasis (plaque, guttate, pustular), mode of diagnosis (clinical/histological) Disease severity (BSA, PASI) HPV vaccination status (vaccine, dates, and number of doses) Current and past treatments (antipsoriatic and others, continuous or not) Genital involvement of psoriasis: yes/no Topical use in the genital area: molecule, duration, frequency Comorbidities (notably HIV, diabetes, immunosuppression, chronic inflammatory diseases, etc.) Gynecological-obstetrical status (for female patients): current pregnancy, recent pregnancy (\<12 months), breastfeeding Sexual history (relationship status, gender of sexual partners, multiple partners, unprotected intercourse, PrEP use, chemsex practices) Addictive behaviors (smoking, drug use, alcohol) History of STIs and anogenital warts (clinical/histological diagnosis, localization, number of lesions, dates, treatment) History of HSIL or invasive carcinoma (cervical, anal, vulvar, vaginal, penile, Prospective (during routine consultations): Efficacy and adherence to antipsoriatic therapies (if patient is treated) Occurrence/recurrence of AGW: date, localization, treatment Occurrence/recurrence of HSIL or invasive carcinoma (cervical, anal, vulvar, vaginal, penile, or perineal) Organization Research nurse: administrative support Principal investigator: recruitment, validation of inclusions, clinical supervision Co-investigators: recruitment Data manager: data management, anonymization, secure storage Statistician: statistical analyses and assistance with interpretation Statistical Analysis Sample size calculation For the prospective phase, the power calculation was based on an expected incidence of anogenital warts (AGW) of 2% in the "topical treatments" group versus 8% in the "biologics" group (two-group design with pooled biologics; estimated distribution 50% biologics / 50% others), derived from literature data. To ensure 80% power and a two-sided alpha risk of 5%, 207 patients per group are required using either the z-test for proportions or the log-rank test (Kaplan-Meier). Allowing for a 20% loss to follow-up over 24 months, the target sample size is 498 patients in total. For the retrospective phase, the case-control study aims to identify at least 50 cases of AGW under biologics, matched to controls at a 1:3 ratio, allowing robust multivariable analyses. Analysis plan Analyses will be performed on an intention-to-treat basis (all enrolled patients) and per protocol (patients with at least two years of routine follow-up). Continuous variables will be described by median and interquartile range. Categorical variables will be expressed as counts and percentages. Primary analyses Prospective phase: Cumulative incidence of AGW will be estimated using Kaplan-Meier methods, with comparisons between treatment groups using the log-rank test. A proportional hazards Cox model will evaluate the association between treatments and risk of AGW, adjusted for the most relevant variables. The proportional hazards assumption will be checked using Schoenfeld residuals. Results will be expressed as hazard ratios with 95% confidence intervals. Secondary analyses Predefined subgroup analyses will examine the specific effect of each therapeutic class and individual molecule. For patients with multiple recurrences, a frailty model (a survival model designed to analyze recurrent/repeated events within individuals) will be used to account for intra-individual correlation. A sensitivity analysis excluding patients who changed treatment during follow-up will assess the robustness of the main results. HPV vaccination acceptability will be analyzed using logistic regression, considering potential explanatory variables. Handling of missing data Missing data will be described and their mechanism explored. If \<5% of data are missing for a variable, analyses will be conducted on complete cases. For 5-20% missing data, multiple imputation using chained equations will be performed. If \>20% of data are missing, the variable will be excluded from analysis. A sensitivity analysis will compare results from complete-case and imputed datasets. Statistical considerations To control for inflation of type I error related to multiple comparisons, the Benjamini-Hochberg procedure will be applied. The significance threshold will be set at p\<0.05 after adjustment. Analyses will be conducted using R (version 4.3 or later) or SAS (version 9.4). Results will be reported according to STROBE guidelines for observational studies, ensuring transparency and reproducibility of analyses. Ethical Considerations Submission to the ethics committee prior to any enrollment Written informed consent required for the prospective phase only GDPR compliance (anonymization, secure database, retention for 10 years) The study does not impose any additional consultations. All data are collected exclusively during visits scheduled as part of routine clinical practice. Appendix: Exploratory Sub-study - Storage of Condyloma Fragments for HPV Genotyping In certain cases, when an interventional treatment of anogenital warts (such as CO₂ laser, curettage, or other) is performed as part of routine clinical management, a small fragment may be preserved for the purpose of HPV genotyping. These samples, collected without any additional procedure for the patient, will be stored under appropriate conditions (e.g., freezing at -80 °C or, more rarely, paraffin embedding) for possible future virological analysis in an accredited partner laboratory (likely AML Laboratory, 113 Avenue Henri Jaspar, 1160 Saint-Gilles). The number of samples collected will depend on clinical situations encountered and technical feasibility. This exploratory sub-study is not a primary objective of the trial but may be subject to complementary analysis if a sufficient number of samples is obtained. This possibility has been explicitly mentioned in the patient information sheet and the informed consent form, in order to ensure transparency with participants, including in the event that no analysis is ultimately performed. No additional costs or travel will be incurred by patients. DLQI Perception and acceptability of HPV vaccination: specific questionnaire at baseline (M0) Evolving gynecological-obstetrical status (for female patients): new pregnancies, current breastfeeding Clinical examination of oral and anogenital mucosa