New treatments for immune-mediated skin diseases has led to the so-called biologics era. However, although the efficacy and safety of most biologics have been proven, sporadic cases of serious fungal infections related to the use of tumor necrosis factor (TNF)-α inhibitors during the treat- ment of certain diseases, such as rheumatoid arthritis, have steadily been reported^1-3. TNF-α inhibitors have also been used to treat psoriasis and psoriatic arthritis at similar doses as those used for rheumatoid arthritis. Moreover, indications for the use of these new drugs, such as JAK inhibitors, which were first approved for treating rheumatologic diseases, are being expanded to other immunologic skin diseases, including atopic dermatitis and alopecia areata.

Therefore, this article reviews the reported incidences of fungal infections and their possible mechanisms according to the types of biologics and small-molecule inhibitors used during dermatological treatments, including their fungal sources. Table 1 summarizes the commonly used drugs, in-cluding TNF inhibitors, interleukin (IL) inhibitors, small-molecule inhibitors, the cluster of differentiation (CD) inhibitors, and immune checkpoint inhibitors for treating skin diseases. Table 2 summarizes the possible mechanism associated with fungal infection and susceptible fungal infection according to the biologics and small molecule inhibitors.

2.1. TNF-α inhibitors

TNF-α inhibitors are used to treat autoimmune diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases. Hence, drugs, such as etanercept, infliximab, adalimumab, golimumab, and certolizumab, are TNF-α in- hibitors. The blockade of TNF-α exerts an antiinflammatory effect by reducing cytokine production and inducing the impairment of monocyte recruitment1. Simultaneously, TNF also influences the recognition of fungal antigens, phago- cytosis during fungal removal, and granuloma formation⁴. Thus, the blockade of TNF-α can be a double-edged sword, thereby increasing the risk of viral, bacterial, and fungal in- fections.

In patients treated with TNF-α inhibitors, the prevalence of serious fungal infections differed among patients with different diseases. Interestingly, patients with rheumatoid arthritis showed higher infection rates than those with Crohn's disease or severe psoriasis and psoriatic arthritis. Nevertheless, the dosage and interval of treatment with TNF-α inhibitors were the same between the different disease groups^_5-8. For TNF-α inhibitor users diagnosed with Crohn's disease, TNF-α inhibitors did not raise the risk of serious infections, even with concomitant use of immunomodulators or steroids8. However, in rheumatoid arthritis patients, the risk of serious infections with TNF-α inhibitors increased dose-dependently6. Additionally, rheumatoid arthritis patients with concomitant use of disease-modifying antirheumatic drugs or high-dose systemic corticosteroids recorded increased susceptibility to opportunistic or serious infections. Hence, rheumatoid arthritis itself is proposed to be a risk factor for other serious infections compared with Crohn's disease or psoriasis.

2.2. IL-17 inhibitors

IL-17 inhibitors include brodalumab, secukinumab, and ixekizumab. They are used for treating psoriasis, psoriatic arthritis, and rheumatoid arthritis⁹. IL-17 influences the innate immune defense. IL-17 also facilitates neutrophil recruitment to the skin from systemic circulations by stimulating the ex- pression of neutrophil-recruiting chemokines (e.g., CXCL1 and CXCL5). Additionally, IL-17A contributes to mucocutaneous host defenses against fungal infections, especially candidiasis¹⁰. Hence, patients with an inborn deficiency of IL-17 experience chronic mucocutaneous Candida infections¹¹. Furthermore, a study by Burstein et al. supported the causal relationship between IL-17 inhibitors and dermatophytosis in that IL-17-deficient mouse was found not to develop protective skin barrier functions against Microsporum canis¹². Another study has shown that IL-17 also participated in the defense against endemic mycoses, such as histoplasmosis and coccidioido- mycosis¹³. Literature has also shown that approximately 50% of patients diagnosed with adult T-cell leukemia and lymphoma develop cutaneous fungal infections¹⁴, which is proposed to result from decreased serum IL-17 levels.

Psoriatic patients treated with secukinumab, an anti-IL-17A monoclonal antibody, developed oral, esophageal, skin, or vaginal candidiasis at a rate of 1% to 5%. A pooled analysis of 10 clinical studies has also reported that the exposure-adjusted incidence rates per 100 subject-years were 3.55, 1.85, and 1.37 for 150 and 300 mg secukinumab and eta- nercept, respectively¹⁵. From another study, the infection rate of Candida infections was 2.6% in psoriatic arthritis patients treated with ixekizumab and 0.4% in the placebo group¹⁶.

Furthermore, mucocutaneous candidiasis was more com- mon in patients with psoriasis treated using brodalumab (3.5~4%) versus placebo, ustekinumab, or etanercept groups, as reported by another study9. Therefore, various studies have shown that this class of drugs increases susceptibility to fungal infections, especially Candida.

2.3. IL-12 and IL-23 inhibitors

IL-12 and IL-23 inhibitors have been used for treating psoriasis, psoriatic arthritis, and inflammatory bowel diseases. However, ustekinumab inhibits both the IL-12 and IL-23 pathways, whereas guselkumab and tildrakizumab block only the IL-23 pathway. By contrast, risankizumab more selectively targets IL-23A. Studies have shown that IL-23 but not IL-12 is involved in optimal antifungal responses against certain fungi, such as Candida albicans (C. albicans). Theoretically, the blockade of the IL-23 pathway should therefore increase susceptibility to Candida infections¹⁷. However, compared with secukinumab, guselkumab did not increase the suscep- tibility to mucocutaneous Candida infections¹⁸. Additionally, no increase in deep fungal infections related to IL-23 in- hibitors has been reported through observational studies of more than 5 years¹⁹,²⁰.

2.4. CD20 inhibitors

CD receptors are cell surface molecules present on hemato- poietic cells. CD20 inhibitors are used for treating pemphigus, leukemia, lymphoma, and multiple myeloma. Rituximab is a first-generation CD20 monoclonal inhibitor. It does not immediately block the production of immunoglobulins be- cause CD²⁰ antigens are not expressed on B-cell precursors or plasma cells²¹.

Invasive candidiasis and aspergillosis have thus rarely been reported in rituximab users. Still, Pneumocystis jirovecii pneumonia was once suggested to be related to the use of rituximab. Nevertheless, Pneumocystis jirovecii pneumonia was reported only in two of 1085 pemphigus vulgaris patients in a systematic review of rituximab use over 16 years²¹.

It is therefore difficult to attribute fungal infections directly to CD20 inhibitors, considering the effects of the concomitant use of immunosuppressive drugs, neutropenia, and under- lying diseases on infection risks. A recent study supporting this fact also reported that rituximab itself did not increase Pneumocystis jirovecii pneumonia infections, including those in lymphoma patients²². However, patients on rituximab taking at least 20 mg of corticosteroids longer than 4 weeks required anti-Pneumocystis prophylaxis^22.

2.5. JAK inhibitors

Various small-molecule inhibitors are used for treating autoimmune diseases and cancers²³. JAK/STAT inhibitors are among these representative small-molecule inhibitors that are used in treating rheumatoid arthritis, polycythemia vera, myelofibrosis, alopecia areata, atopic dermatitis, psoriasis, and psoriatic arthritis. The JAK inhibitor drugs include tofacitinib, baricitinib, and ruxolitinib. Newer JAK inhibitors, such as upadacitinib and abrocitinib, which inhibit various combi- nations of the JAK/STAT pathway, have also been developed.

Systematic reviews and retrospective multicenter database analyses have reported that cryptococcosis, aspergillosis, and Candida esophagitis were rarely reported in patients treated with tofacitinib, baricitinib, and ruxolitinib regardless of the underlying diseases²³. Furthermore, no studies have evaluated fungal infections in patients with alopecia areata or atopic dermatitis treated with JAK inhibitors. Interestingly, ruxolitinib turned out to have a therapeutic effect on chronic mucocutaneous candidiasis patients related to STAT1 gain-of-function by blocking the JAK/STAT pathway²⁴.

2.6. Immune checkpoint inhibitors

Programmed cell death-1 (PD-1 and CD270) is an immune inhibitory receptor belonging to the CD28:B7 family of costimulatory molecules. PD-1 inhibitors and anticytotoxic T-lymphocyte-association protein 4 (CTLA-4) antibodies have been used for treating various malignancies, such as malig- nant melanoma, non-small cell lung cancer, and hematologic malignancies. Ipilimumab is an anti-CTLA-4 antibody, and pembrolizumab in addition to nivolumab are representative PD-1 inhibitors widely used for treating melanoma.

A study reported that PD-1 not only acts as an immune inhibitory receptor but also serves as a negative regulator of α-(1,3)-glucan-mediated regulatory T-cell polarization, which is important in Aspergillus infections²⁵. Theoretically, another study reported that patients who received PD-1 inhibitors had their regulatory T-cell responses and polarized T helper-1 immune responses suppressed²⁶. In another invasive pul- monary aspergillosis mouse model, treatment with PD-1 inhibitors significantly improved survival and decreased the fungal burden²⁷. However, invasive aspergillosis (n = 2), invasive candidiasis (n = 1), and Pneumocystis pneumonia (n = 3) were reported in 740 melanoma patients who received PD-1 inhibitors. The main risk factors of serious infections, including invasive fungal infections, were also associated with the simultaneous use of corticosteroids or infliximab²⁸. Thus, host factors and the concomitant use of the drugs should be considered in determining the risk of PD-1 inhibitors.

3.1. The incidence of invasive fungal infections in patients using biologics for dermatological diseases is rare.

Deep fungal infections are extremely rare. However, delayed diagnosis can be life-threatening. Thus, physicians should be aware of the clinical symptoms of deep fungal infections and strive to make an early diagnosis.

Invasive fungal infections that developed among patients on biologics and small-molecule inhibitors were all taking concomitant immunosuppressants or had an immunocom- promised status, such as graft-versus-host disease after hematopoietic stem cell transplantations1,²⁹. Furthermore, the development of deep fungal infections in patients with skin diseases taking biologics is much more rarely reported. For example, the overall incidence of serious infections, in- cluding deep fungal infections in patients with rheumatoid arthritis, has been reported to be approximately 1.97/100 person-years for patients taking adalimumab and 2.47/100 person-years for those taking infliximab2. By contrast, the incidence of deep fungal infections in patients diagnosed with psoriasis taking adalimumab or infliximab was close to zero after the analysis of long-term follow-up data of 19 random- ized clinical trials2.

Next, we reviewed the incidence of deep fungal infection depending upon the fungal sources, which was reported to be related to the use of biologics and small-molecule inhibitors for treating skin diseases. Below are some of the important infectious fungal microbes.

3.1.1. Cryptococcosis

The incidence of cryptococcosis was reported to arise in 5.08 cases/100,000 persons of the overall patients treated with infliximab³⁰,_³¹. Among the reported cases, pulmonary cryptococcosis was the predominant manifestation. Add- itionally, among the patients on TNF-α inhibitors for treating skin diseases, only a case of cutaneous deep fungal crypto- coccosis, which occurred in a 14-year-old boy on the scalp mimicking a kerion, was reported to be related to the use of etanercept for treating psoriasis³². A 65-year-old male patient with psoriasis also developed pulmonary cryptococcosis during treatment with tofacitinib³³. Furthermore, a case of dissem- inated cryptococcosis was reported in a patient with severe psoriasis who was treated with methotrexate, cyclosporine, and efalizumab (an anti-CD11a antibody)³⁴. However, no case reports of cryptococcosis related to the use of interleukin inhibitors have been reported to date.

3.1.2. Aspergillosis

Aspergillosis developed at a rate of 6.19 to 8.63 cases/ 100,000 persons among the general users of TNF-α inhibitors ³⁰,³¹. One case of cutaneous aspergillosis was reported in a psoriasis patient taking TNF-α inhibitors³⁵. However, no case reports of aspergillosis related to the use of interleukin in- hibitors, JAK inhibitors, or rituximab have been reported in patients with skin diseases.

3.1.3. Histoplasmosis^36,37

Life-threatening histoplasmosis has been reported in patients taking TNF-α inhibitors³⁷. Subsequently, the Food and Drug Administration (FDA) requested a black box warning for histoplasmosis. However, among the patients diagnosed with psoriasis, only one case of histoplasmosis was reported in a patient who concomitantly received infliximab, methotrexate, and corticosteroid, in addition to living in an endemic histo- plasmosis area. The patient was treated with amphotericin B36. Besides this case, no other case reports of histoplasmosis related to the use of interleukin or JAK inhibitors in patients with skin diseases have been reported.

3.1.4. Pneumocystis infection

Patients diagnosed with rheumatoid arthritis receiving infliximab with other immunosuppressants, such as cortico- steroids, methotrexate, or cyclosporine, have been proposed to be at a higher risk of Pneumocystis pneumonia³⁸. Pro- phylaxis has also been indicated for patients using high-dose corticosteroids for prolonged periods with or without biologics³⁸. However, in psoriasis or psoriatic arthritis patients, treatment with TNF-α inhibitors without the use of other immunosuppressants did not increase the incidence of Pneumocystis pneumonia. A case of Pneumocystis pneu- monia was reported in a 54-year-old man diagnosed with refractory pustular psoriasis who received infliximab. The patient workup revealed an IL-36RN deficiency, which was resolved by anakinra treatment39. In another study, a 41-year-old man on etanercept for treating psoriatic arthritis was reported to develop Pneumocystis pneumonia⁴⁰.

Pneumocystis pneumonia was also reported in only two patients in a systematic review and meta-analysis of polycy- themia vera patients taking ruxolitinib⁴¹. Rituximab did not increase the susceptibility to Pneumocystis pneumonia in pemphigus patients. However, two melanoma patients who received immunosuppressants to control ipilimumab-induced adverse effects developed Pneumocystis pneumonia⁴².

3.2. Noninvasive fungal infections are relatively common with the use of some biologics, especially mucocutaneous candidiasis during anti-IL-17 treatment.

3.2.1. Candidiasis

Candidiasis is the most common fungal infection in patients under treatment with biologics and is reported to account for approximately 70% of fungal infections. However, the overall incidence is low. Studies have also shown that C. albicans infections occurring in the oral (42.1%) or genital (41.7%) areas are not serious. However, invasive candidiasis can seldom occur in patients with immunocompromised status.

TNF-α-related candidiasis was reported to occur in 5.31~ 10.15 per 100,000 people between 1998 and 2002, depending on the type of drug, according to the FDA's Adverse Events Reporting System30,31. Candidiasis was also reported in 1.7~4.0% of the patients on IL-17 inhibitors depending on the drugs. Conversely, incidences of 0.3% and 2.3% were reported in patients taking placebo and ustekinumab, respectively⁴³.

3.2.2. Dermatophytosis

It has been difficult to find a causal relationship between biologics and dermatophytosis because dermatophytosis is common in healthy populations. Localized dermatophytosis involving perianal lesions was therefore reported in two female patients diagnosed with psoriasis during treatment with secukinumab⁴⁴. Widespread tinea corporis was also reported in a 38-year-old male patient 4 weeks after starting secukinumab use to treat psoriasis⁴⁵. In another study, a 64-year-old woman developed invasive dermatophytosis during the treatment period of infliximab and corticosteroid⁴⁶. Dermatophyte infections in patients with psoriatic on IL-23 inhibitors have also not been reported.

3.2.3. Malassezia infection

Malassezia infections related to using biologics have rarely been reported. However, small numbers of patients with atopic dermatitis receiving the IL-4 inhibitor, dupilumab, developed facial redness. The cause of the redness was not well known; however, it was assumed to be caused by enhanced Th1 immune responses due to the blocked Th2 response by dupilumab. This redness also triggered severe inflammation in patients with Malassezia hypersensitivity. Reports on dupilumab facial redness were however improved after itraconazole treatment in two of the patients diagnosed with severe atopic dermatitis⁴⁷.

Furthermore, seven of 153 psoriasis patients on TNF in- hibitors were diagnosed with pityriasis versicolor in one institute. In this study, only one patient was cured with topical antifungals, and the other six were treated with systemic antifungal agents⁴⁸.

The use of biologics in treating rheumatoid arthritis increases the risk of opportunistic fungal infections, whereas the use of biologics in treating other skin disorders, such as psoriasis or psoriatic arthritis, does not increase the risk of fungal infections. Sporadic cases of deep fungal infections are also rare in patients diagnosed with psoriasis or psoriatic arthritis. Furthermore, in most of the reported cases, the patients received concomitant immunosuppressants because of disease severity. By contrast, studies showed that noninvasive mucocutaneous candidiasis was common during anti-IL-17 treatment, especially in patients with psoriasis. Therefore, in determining the susceptibility and risk to fungal infections associated with biologics, JAK inhibitors, CD inhibitors, and immune checkpoint inhibitors, individual approaches are needed, considering host factors, such as underlying disease and the concomitant use of other immunosuppressants.