Increased risk of superficial fungal infections among psoriasis patients receiving systemic treatment: A nationwide retrospective population-based cohort study

doi:10.21203/rs.3.rs-4097562/v1

Previous meta-analyses or large cohort studies of risk for onychomycosis or mucocutaneous candidiasis in psoriasis patients has been reported. We conducted the retrospective nationwide population-based cohort study to assess the incidence and risk of superficial fungal infections among patients with psoriasis receiving systemic treatment. Our study showed an increased risk of superficial fungal infection among patients with psoriasis receiving systemic treatment regardless of treatment type.

Health sciences/Diseases

Health sciences/Medical research

psoriasis

fungal infection

immunomodulator

biologics

acitretin

Whether psoriasis predisposes patients to superficial fungal infection remains controversial. The immunomodulatory effects of systemic treatments, microbiota dysbiosis of the skin and nails, and immunologic disturbance of capillary units are contributing factors, while the abundance of antimicrobial peptides and fast turnover of the skin and nails are inhibitory factors^1-3. Previous meta-analyses or large cohort studies were limited to onychomycosis or mucocutaneous candidiasis^{2, 4, 5}. Therefore, we conducted this retrospective nationwide population-based cohort study to assess the incidence and risk of superficial fungal infections among patients with psoriasis receiving systemic treatment. The data used in this study were obtained from the Korean National Health Insurance (NHID), in which contains nationwide claims data. This study was approved by the Institutional Review Board (IRB) of Kyung Hee University (KHUH 2020-03-091) a waiver of informed consent was approved from IRB due to the retrospective nature of the big datasets. All methods were performed in accordance with the relevant guidelines and regulations.

Our study used data recorded in the Korean NHID claims database between January 2014 and December 2018. Participants aged ≥18 years who: (1) received a psoriasis diagnosis according to the International Classification of Diseases 10^th Revision (ICD-10); and (2) received systemic treatment were enrolled. The psoriasis group was subdivided by treatment type: (1) biologics (tumor necrosis factor alpha [TNF-α], interleukin [IL]-12/23); (2) immunosuppressants (cyclosporine, methotrexate); and (3) acitretin. The control group included age- and sex-matched hospital outpatients without dermatological diseases (ICD-10 codes L00–99). We determined the incidence of overall superficial fungal infections (ICD-10 codes B35–36) and individual infections (onychomycosis, tinea pedis, tinea corporis, tinea cruris, and candidiasis) per 1000 person-years from enrollment to December 2019. The risk of superficial fungal infection was estimated using uni- and multivariate Cox proportional hazards regression models after the adjustment for age, sex, and comorbidities. Values of p≤0.05 were considered statistically significant.

The incidence of superficial fungal infection was higher in the psoriasis versus control group (5.31 versus 2.45 per 1000 person-years) (Table 1). The risk of superficial fungal infection was significantly higher in the psoriasis than control group (adjusted hazard ratio [aHR], 1.97; 95% confidence interval [CI], 1.88–2.06). When further stratified by treatment type, the risk was significantly higher for all groups than control: biologics (aHR, 1.44; 95% CI, 1.18–1.76), immunosuppressants (aHR, 1.90; 95% CI, 1.80–2.01), acitretin (aHR, 2.07; 95% CI, 1.96–2.19), TNF-α inhibitor (aHR, 1.75; 95% CI, 1.28–2.40), and IL-12/23 inhibitor (aHR, 1.33; 95% CI, 1.02–1.72). As an additional result, IL -17 inhibitor increased risk (aHR, 4.33; 95% CI, 2.51–7.47) (Supplementary Table 1).

In the subgroup analyses, all individual superficial fungal infections presented significantly increased risks among psoriasis patients versus controls: tinea pedis (aHR, 1.76; 95% CI, 1.65–1.87), onychomycosis (aHR, 1.83; 95% CI, 1.70–1.96), tinea corporis (aHR, 2.34; 95% CI, 2.14–2.56), tinea cruris (aHR, 1.83; 95% CI, 1.59–2.12), and candidiasis (aHR, 1.18; 95% CI, 1.10-1.27) (Table 2).

Our study showed an increased risk of superficial fungal infection among patients with psoriasis receiving systemic treatment regardless of treatment type. Low cellular immune function and disruption of the normal structure of the psoriatic skin can increase the fungal colonization, and fungal superantigens can prolong psoriasis.³ Limitations include the small number of IL-17 inhibitor group due to short period of domestic approval, lower accuracy of outcome measures by reliance on ICD-10 codes rather than diagnostic examinations, and lack of individualized analyses of methotrexate and cyclosporine. As nail deformity and skin manifestations in psoriasis resemble onychomycosis and superficial dermatophytosis, clinicians should carefully monitor superficial fungal infections in patients with psoriasis receiving systemic treatment.

Author contribution statement

JI Seo performed the research and wrote the paper.

Hasung Kim and Jungkuk Lee analysed the data.

HJ Ahn analysed the data and wrote the paper.

KH Jeong and MK Shin designed the research and wrote the paper.

All authors have read and approved the final manuscript.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Funding sources: This work was supported by a grant from Kyung Hee University in 2022."(KHU-20220710), Republic of Korea.

Conflict of interest: None

IRB approval status: Reviewed and approved by Institutional Review Board of Kyung Hee University; approval #2020-03-091

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Table 1. Risk of superficial fungal infection among psoriasis patients receiving systemic treatment

				Univariable analysis		Multivariable analysis
Group	Fungal infection diagnosis, n (%)	Median time of onset (IQR) (days)	Incidence rate (per 1000 person-years)	Crude HR (95% CI)	p value	aHR (95% CI)	p value
Psoriasis vs CTR
Psoriasis (total)	4669 (20.26)	14.9 (24.3)	5.31	2.01 (1.92-2.10)	<0.05	1.97 (1.88-2.06)	<0.05
CTR	3732 (16.14)	32.5 (36.1)	2.45	1 [Reference]		1 [Reference]
BIO, IMS, ACT vs CTR
Psoriasis (BIO)	99 (13.43)	14.9 (23.1)	4.56	1.54 (1.26-1.88)	<0.05	1.44 (1.18-1.76)	<0.05
Psoriasis (IMS)	2332 (18.73)	14.9 (23.4)	4.98	1.88 (1.78-1.98)	<0.05	1.90 (1.80-2.01)	<0.05
Psoriasis (ACT)	2238 (22.7)	14.5 (25.6)	5.74	2.19 (2.08-2.31)	<0.05	2.07 (1.96-2.19)	<0.05
CTR	3732 (16.14)	32.5 (36.1)	2.45	1 [Reference]		1 [Reference]
Biologics vs CTR
TNF-α inhibitor	40 (16.88)	15.5 (29.8)	5.03	1.99 (1.46-2.72)	<0.05	1.75 (1.28-2.40)	<0.05
IL-12/23 inhibitor	59 (11.8)	14.9 (18.6)	3.83	1.50 (1.16-1.94)	<0.05	1.33 (1.02-1.72)	<0.05
CTR	3732 (16.14)	32.5 (36.1)	2.45	1 [Reference]		1 [Reference]

ACT, acitretin; aHR, adjusted hazard ratio; CI, confidence interval; BIO, biologics; CTR, control; IL, interleukin; IMS, immunosuppressants; IQR, interquartile range; TNF-α, tumor necrosis factor alpha

Table 2. Subgroup analyses of association of superficial fungal infection risk with systemic treatment.

	Tinea pedis		Onychomycosis		Tinea corporis		Tinea cruris		Candidiasis
Group	aHR (95% CI)	p value	aHR (95% CI)	p value	aHR (95% CI)	p value	aHR (95% CI)	p value	aHR (95% CI)	p value
Psoriasis vs CTR
Psoriasis (Total)	1.76 (1.65-1.87)	<0.05	1.83 (1.70-1.96)	<0.05	2.34 (2.14-2.56)	<0.05	1.83 (1.59-2.12)	<0.05	1.18 (1.10-1.27)	<0.05
CTR	1 [Reference]		1 [Reference]		1 [Reference]		1 [Reference]		1 [Reference]
BIO, IMS, ACT vs CTR
Psoriasis (BIO)	1.47 (1.11-1.95)	<0.05	1.33 (0.95-1.85)	0.09	1.04 (0.64-1.68)	0.89	1.23 (0.63-2.39)	0.55	0.97 (0.67-1.40)	0.85
Psoriasis (IMS)	1.53 (1.41-1.66)	<0.05	1.71 (1.57-1.87)	<0.05	2.23 (2.00-2.47)	<0.05	1.95 (1.64-2.31)	<0.05	1.22 (1.13-1.32)	<0.05
Psoriasis (ACT)	2.00 (1.86-2.16)	<0.05	1.96 (1.80-2.13)	<0.05	2.51 (2.26-2.78)	<0.05	1.75 (1.47-2.08)	<0.05	1.13 (1.02-1.25)	<0.05
CTR	1 [Reference]		1 [Reference]		1 [Reference]		1 [Reference]		1 [Reference]
BIO vs CTR
TNF-α inhibitor	1.49 (0.93-2.37)	0.10	1.98 (1.24-3.16)	<0.05	1.47 (0.73-2.98)	0.28	1.53 (0.56-4.13)	0.41	0.64 (0.31-1.36)	0.25
IL-12/23 inhibitor	1.46 (1.04-2.07)	<0.05	1.02 (0.63-1.62)	0.95	0.89 (0.46-1.72)	0.72	0.99 (0.41-2.43)	0.99	1.19 (0.78-1.83)	0.42
CTR	1 [Reference]		1 [Reference]		1 [Reference]		1 [Reference]		1 [Reference]

ACT, acitretin; aHR, adjusted hazard ratio; CI, confidence interval; BIO, biologics; CTR, control; IL, interleukin; IMS, immunosuppressants; IQR, interquartile range; TNF-α, tumor necrosis factor alpha

No competing interests reported.

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Increased risk of superficial fungal infections among psoriasis patients receiving systemic treatment: A nationwide retrospective population-based cohort study

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