literature review on oral candidiasis

• Open access
• Published: 26 October 2023

Efficacy of photodynamic therapy in the treatment of oral candidiasis: a systematic review and meta-analysis

• Qiaoyu Hu 1 ,
• Ting Li 1 ,
• Jiadi Yang 1 ,
• Yanhui Peng 1 ,
• Qing Liu 1 &

BMC Oral Health volume  23 , Article number:  802 ( 2023 ) Cite this article

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To evaluate the clinical efficacy of photodynamic therapy (PDT) as an adjunct or alternative to traditional antifungal drugs in the treatment of oral candidiasis, and to provide evidence-based medical evidence for its use in the treatment of oral candidiasis.

Computer combined with manual retrieval of China Academic Journals Full-text Database (CNKI), China Biomedical Literature Database (CBM), Chinese Science and Technology Journal Database (VIP), Wanfang Database, PubMed, Web of Science, Cochrane Library, Embase, Scopus retrieval for articles published before January 2023, basic information and required data were extracted according to the inclusion and exclusion criteria, and the Revman V5.4 software was used to conduct Meta-analysis of the included literature.

A total of 11 articles were included, 7 of which used nystatin as an antifungal drug, 2 of which were combined treatment of PDT and nystatin, 2 of the remaining 4 articles were treated with fluconazole, and 2 were treated with miconazole. Meta results showed that PDT was superior to nystatin in reducing the number of oral candida colonies in the palate of patients MD  =  -0.87, 95%CI  =  (-1.52,-0.23), P  =  0.008 , the difference was statistically significant, and the denture site MD  =  -1.03, 95%CI  =  (-2.21, -0.15), P  =  0.09 , the difference was not statistically significant; compared with the efficacy of fluconazole, RR  =  1.01, 95%CI  =  (0.56,1.83), P  =  0.96 ; compared with miconazole RR  =  0.55, 95%CI  =  (0.38, 0.81), P  =  0.002 ; PDT combined with nystatin RR  =  1.27, 95%CI  =  (1.06, 1.52), P  =  0.01 ; recurrence rate RR  =  0.28, 95%CI  =  (0.09, 0.88), P  =  0.03 .

Conclusions

PDT was effective in the treatment of oral candidiasis; PDT was more effective than nystatin for the treatment of denture stomatitis in the palate, while there was no significant difference between the two for the denture site; The efficacy of PDT for oral candidiasis was similar to that of fluconazole; PDT was less effective than miconazole for oral candidiasis; Compared with nystatin alone, the combination of PDT and nystatin is more effective in treating oral candidiasis with less risk of recurrence.

Peer Review reports

Introduction

Oral candidiasis (OC) is a fungal infectious disease of the oral mucosa caused by Candida [ 1 ]. In recent years, with the application of broad-spectrum antibiotics, glucocorticoids, and immunosuppressants, organ transplantation, and tumor treatment, the number of patients with impaired immune function has increased, and the incidence of oral candidiasis has continued to increase, becoming the most common infectious disease of the oral mucosa [ 2 ]. Patients with oral candidiasis are often associated with burning, unpleasant bitter or salty taste, altered taste, and sometimes pain and discomfort, difficulty swallowing, nausea, vomiting, and diarrhea. These symptoms may affect the patient's ability to eat and lead to changes in the patient's quality of life [ 3 ].

The current effective treatments for oral Candida infections are topical and systemic treatments. For mild cases of infection, topical antifungal drugs such as nystatin are recommended [ 4 ]. The treatment period of nystatin is long, usually 14–28 days or even longer, with occasional adverse effects such as nausea, diarrhea or loss of appetite after taking it [ 5 ]. For patients who are immunocompromised or at risk of disseminated candidiasis, systemic antifungal therapy, such as azoles, can be used [ 6 ]. However, the increasing use of azoles has led to an increase in Candida resistance to antifungal drugs [ 7 ], necessitating the search for new therapeutic approaches. Alternative antifungal drugs that have been considered include colloidal solutions of metal nanoparticles (silver, gold), ozone therapy, photo biomodulation and photodynamic therapy, of which photodynamic therapy is a promising new therapy [ 8 ].

Photodynamic therapy (PDT) is a treatment method in which a photosensitizer is applied to the diseased tissue and a photochemical reaction is produced by irradiation with a specific wavelength light source to achieve a therapeutic effect. Reactive oxygen species (ROS) produced in photochemical reactions can react with a variety of biomolecules such as phospholipids, nucleic acids and proteins of cells to produce toxicity thereby inactivating cells and other microorganisms [ 9 , 10 , 11 ]. In recent years, as PDT continues to be used in clinical practice, its anti-Candida effect has received increasing attention. The main benefits of PDT over conventional antifungal therapy include its broad antimicrobial spectrum, short therapeutic course, strong targeting, high selectivity, and low impact on surrounding normal tissue cells [ 1 ]. Additionally, studies have shown that Candida is susceptible to photoinactivation, including drug-resistant strains, which can treat recurrent infections brought on by drug-resistant Candida [ 12 , 13 , 14 ]. Therefore, PDT shows potential applications in the treatment of oral infections.

The light source chosen for PDT is usually a low-energy laser with a power of less than 500mW and a wavelength range of 630 ~ 750 nm, which can be precisely regulated in terms of output power and produces only a localized effect, and therefore does not require any special protection and will not burn the surrounding tissues [ 15 ]. A variety of light sources have been used for PDT therapy, and semiconductor lasers, which have the advantages of being easy to operate, portable, and cost-effective, have been more and more widely used; in addition, non-laser light sources, such as incandescent lamps, quartz halogen lamps, and light-emitting diodes, have been used to a certain extent as well [ 16 ]. Photosensitizer is an important factor in the successful application of photodynamic therapy, commonly used in the clinic is the second generation of photosensitizers, mostly porphyrin compounds derivatives, such as 5-amino ketoglutaric acid; as well as stains and dyes, such as bracketed toluidine blue, methylene blue, rose red, erythrosine, and peacock green, which have strong photoinactivation effect [ 17 ]. Photosensitizers increase the inhibition rate with incubation time, reaching a peak plateau at 30 ~ 90 min [ 18 ].

The current clinical effectiveness of PDT for oral candidiasis is variable, and Mima [ 19 ] and Senna [ 20 ] conducted a randomized controlled trial of PDT for oral candidiasis comparing the efficacy of PDT with that of mycophenolate and found no significant difference between the two in terms of clearance of oral Candida, but the PDT group required a shorter course of treatment to achieve the same effect. Maciel [ 21 ] et al. compared PDT combined with a low-energy laser with miconazole gel in the treatment of oral Candida and showed that although the PDT group had some efficacy, its cure rate was significantly lower than that of the miconazole group. Therefore, this study used Meta-analysis to systematically evaluate PDT for the treatment of oral Candida and to provide a basis for clinical application.

Different from previous systematic reviews, this study is not limited to single-drug control and outcome indicators, but compares PDT with nystatin, fluconazole, and miconazole, and more comprehensively evaluates the effects of PDT and antifungal drugs on oral candida. disease treatment effect. The possible mechanisms of PDT in combination with nystatin for the treatment of oral candidiasis were also explored, as well as the recurrence after treatment and the safety of the treatment approach.

Materials and methods

This Meta-analysis is based on the PRISMA 2020 Statement: Updated Guidelines for the Reporting of Systematic Reviews guidance [ 22 ] for asking questions, registered with INPLASY (registration number INPLASY2022120053), asking “Is photodynamic treatment of oral Candida effective compared to conventional antifungal drugs?”.

Inclusion criteria

The criteria for inclusion in the study were based on the PICOS strategy.

P: Patients diagnosed with oral candidiasis (e.g., denture stomatitis, HIV with Candida infection)

I: PDT of any type of light source and photosensitizer

C: Use of topical or systemic traditional antifungal drugs (e.g., nystatin, fluconazole)

O: Primary outcomes included a reduction in the number of Candida colonies in the patient’s palate and denture or resolution of inflammation in the palate.

S: Randomized Controlled Trial.

Exclusion criteria:

1. Documents in languages other than English and Chinese

2. Duplicate literature

3. Studies unable to provide original data

Search strategy

A combination of computer and manual searches were conducted electronically for literature published in the Chinese Academic Journal Full Text Database (CNKI), Chinese Biomedical Literature Database (CBM), Chinese Science and Technology Journal Database (VIP), Wanfang Database, PubMed, Web of science, Cochrane Library, and Embase as of January 2023. A manual search was also conducted for the incorporated literature of relevant systematic evaluations. Combination of subject terms and free words according to Boolean logic operation, Search terms are as follows:

Photochemotherapy OR Photochemotherapies OR Photodynamic Therapy OR Therapy, Photodynamic OR Photodynamic Therapies OR Therapies, Photodynamic OR Antibacterial photodynamic therapy OR Photodynamic antimicrobial chemotherapy OR Photodynamic inactivation OR PDT OR APDT OR PAD OR PDI

Candida OR Candidiasis OR Candidiases OR Candidiasis, Oral OR Candidiases, Oral OR Oral Candidiases OR Oral Candidiasis OR Thrush OR Moniliasis, Oral OR Moniliases, Oral OR Oral Moniliases OR Oral Moniliasis OR Stomatitis, Denture OR Denture Stomatitides OR Denture Stomatitis OR Stomatitides, Denture OR AIDS-related oral candidiasis randomized controlled trial OR randomized OR placebo

Literature screening

Screening and study selection were independently performed by two researchers, all records were imported into the literature management software, duplicate literature was deleted, and the titles and abstracts of all retrieved literature were pre-screened for potentially eligible studies. A detailed assessment was then carried out according to pre-determined eligibility criteria for inclusion in the review. Disagreeing documents were resolved through consultation or with the assistance of relevant experts, and the final decision was made on whether to include them until a consensus was reached.

Data extraction

The following data were obtained from the included studies: author, publication year, study design, sample size, light source characteristics, pre-irradiation time, photosensitizer type, antifungal drug characteristics, follow-up period and safety, etc. Two researchers performed the data collection process independently. Collect data electronically using Excel sheets.

Literature quality evaluation

The risk of bias of each study was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 [ 23 ], including: method of randomization, concealment of allocation, blinding of participants and researchers, blinding of outcome assessments, completeness of outcome data, selective publication, and other sources of bias. The above results were assessed by two researchers for the quality of the included literature, and inconsistencies were discussed and determined by the superior physician.

Efficacy evaluation index

The indicators for evaluating the efficacy of oral candidiasis include clinical evaluation and microbiological evaluation [ 24 ], clinical evaluation refers to the clinical improvement of patients after treatment, the microbiological evaluation focuses on the effectiveness of this treatment measure by assessing the change in Candida colony forming units per milliliter (CFU/ml).

Statistical analysis

Meta-analysis of the included literature was performed using Review Manager (Revman, version 5.4, Cochrane Community) software, In this study, the clinical efficacy is an ordered classification data(Ineffective, Effective, Significant, Cured), which is converted into a binary classification variable for analysis (i.e., ineffective vs. total effective, total number of effective = effective + significantly effective + cured), and the RR value and 95% confidence interval are used to indicate the size of the effect; Colony forming unit (CFU) is a continuous variable, which is grouped and analyzed according to follow-up time, and the effect size is represented by mean difference MD and 95% confidence interval (CI); A random-effects model was used for the analyses, taking into account the large clinical variation between population and treatments among studies.

GRADE quality of evidence assessment

Referring to the GRADE quality of evidence grading system [ 25 ] to grade the evidence for outcome indicators, which contains 5 downgrading factors and 3 upgrading factors, the literature included in this study were all RCTs with the highest level of evidence, so they were not upgraded. The quality of evidence was categorized into 4 levels of High, Moderate, Low, and Very Low based on the 5 dimensions of risk of bias, inconsistency, indirectness, imprecision, and publication bias.

Literature search and screening results

Through a combined computer and manual search, 98 literatures were initially retrieved, 33 duplicates were removed, a total of 52 were excluded after further reading of the title and abstract, and 2 were excluded after reading the full text, and finally a total of 11 literatures met the inclusion criteria, as shown in Fig.  1 .

Flow chart of search

Characteristics of the included literature

In total, there were 11 literatures, 7 of which the antifungal drug was nystatin, 2 of which were PDT in combination with nystatin, and 2 of the remaining 4 were fluconazole treatment and 2 were miconazole treatment (Table 1 ).

Eleven studies used randomized controlled methods, of which two implemented allocation protocol concealment, two clearly described blinding of patients and principal investigators, two did not, and five were blinded to the study outcome measure. The results of the quality evaluation of the studies are shown in Fig.  2 .

Risk bias graph of the included literature

Meta-analysis results

Comparison of pdt and nystatin.

Palatal efficacy assessment: a total of 4 studies were included, and heterogeneity test showed heterogeneity among studies (P  <  0.00001, I 2  =  81%) , and the random effect model was used for Meta analysis: MD  =  -0.87, 95% CI  =  (-1.52, -0.23) , MD combined with 95% CI horizontal line to the left of the null vertical line. Therefore, it can be concluded that PDT cleared more colonies of oral Candida compared to nystatin, with a statistically significant different ( Z  =  2.65, P  =  0.008 ), Fig.  3 .

Palatal forest plot of PDT vs. nystatin. (Random effects model)

Denture site efficacy assessment: a total of 4 studies were included and heterogeneity test showed heterogeneity among studies ( P  <  0.00001, I 2  =  77% ), and the random effect model was used for Meta analysis: MD  =  -1.03, 95% CI  =  (-2.21, -0.15) , the 95% CI horizontal line for MD combined was on the null line, the difference was not statistically significant ( Z  =  1.71, P  =  0.09 ), Fig.  4 .

Denture sites forest plot of PDT vs. nystatin (Random effects model)

Comparison of PDT and fluconazole

Efficacy assessment: 2 studies were included, heterogeneity test showed heterogeneity between studies (P  =  0.10, I 2  =  63%) , and the random effect model was used for Meta analysis: RR  =  1.01, 95% CI  =  (0.56,1.83) , RR combined with 95% CI horizontal line on the null line (Z  =  0.05, P  =  0.96) , the difference was not statistically significant. PDT has similar efficacy to fluconazole in the treatment of oral candidiasis, Fig.  5 .

Forest plot of PDT vs. fluconazole (Random effects model)

Comparison of PDT and miconazole

Efficacy assessment: a total of 2 studies were included, the random effect model was used for Meta analysis: RR  =  0.55, 95% CI  =  (0.38,0.81) , RR combined with 95% CI horizontal line on the left side of the null line, the results showed that PDT was less effective in treating oral candidiasis than miconazole (Z  =  3.03, P  =  0.002) , Fig.  6 .

Forest plot of PDT vs. miconazole (Random effects model)

PDT + nystatin combination therapy

Efficacy assessment: 2 studies were included, the random effect model was used for Meta analysis: RR  =  1.27, 95% CI  =  (1.06, 1.52) , 95% CI horizontal line for RR combined was to the right of the vertical line of ineffectiveness, the difference was statistically significant ( Z  =  2.58, P  =  0.01 ), sufficient evidence exists to suggest that the combination of PDT + mycobacterium is more effective in the treatment of oral candidiasis compared to mycobacterium alone, Fig.  7 .

Forest plot of efficacy of PDT + nystatin combination therapy (Random effects model)

Recurrence rate: 2 studies were included, the random effect model was used for Meta analysis: RR  =  0.28, 95% CI  =  (0.09, 0.88) , RR combined with 95% CI horizontal line located to the left of the null vertical line, results showed that compared to mycobacterium toxin alone, PDT + nystatin combination for oral candidiasis had a lower recurrence rate with a statistically significant difference ( Z  =  2.19,P  =  0.03 ), Fig.  8 .

Forest plot of recurrence rate for PDT + nystatin combination treatment (Random effects model)

Evaluation of the quality of GRADE evidence

The quality of evidence was classified using the GRADEpro GDP software, which showed that the efficacy of nystatin palate was of low quality of evidence (Low), the efficacy of nystatin denture site was of very low quality of evidence (Very low), the efficacy of fluconazole was of low quality of evidence (Low), the efficacy of miconazole was of moderate quality of evidence (Moderate), and the efficacy of the combination of PDT + nystatin as well as recurrence rate was of moderate quality of evidence (Moderate), Fig.  9 .

GRADE evidence quality assessment

The results of this meta-analysis showed that compared with nystatin, when the treatment area was on the palate, there was a statistically significant difference in the reduction of Candida colonies between the two groups ( P  <  0.05 ), suggesting that PDT is more effective in removing oral Candida in the palate, but there was no statistically significant difference in the denture area. The process of microbial adhesion to the denture surface is related to the surface properties of the material, such as hydrophobicity and surface roughness [ 34 ], and the porous structure and irregular inner surface of the acrylic resin denture act as a reservoir for microorganisms, as well as difficulties in hygienic maintenance and disinfection [ 35 ], resulting in more rapid regeneration of Candida in the patient's denture than in the treated palate [ 36 ]. The use of PDT technique in the study affected only the palatal mucosa, while treatment with drugs could act on other areas such as the oral mucosa and the tongue, possibly due to dilution of saliva resulting in a weakened effect on Candida and the penetration of the mycelium into the epithelial cells before starting colonization of the palate within 48 h [ 37 ]. All of these reasons may cause PDT to be more effective on the palate than on the denture site. The role of PDT in reducing Candida counts is insufficient if the denture surface is not mechanically cleaned [ 38 ]. Other topical medications such as nystatin can be used for treatment, but the movement of the oral muscles makes it difficult to keep the medication in the treated area thus reducing the level of treatment [ 27 ]. However, systemic antifungals like amphotericin B can be used, but they are not very effective in removing fungal colonies from the surface of the denture [ 39 ]. Therefore, it is recommended that all wearers clean all surfaces of the denture regularly to minimize denture-related fungal infections [ 38 ]. At the 15-day follow-up of the denture site, there was a statistically significant difference in the reduction of Candida colonies between the two groups, but there was no statistically significant difference at 30 and 60 days, which may be due to the recolonization of Candida on the denture surface after treatment.

Azoles are commonly used in the treatment of Candida infections, but with the massive and unregulated use of antifungal drugs, the resistance rate of Candida to azoles is now gradually increasing, and the phenomenon of cross-resistance between azoles is obvious [ 40 ]. Mechanisms of Candida resistance to azoles include altered drug targets, overexpression of drug efflux pumps, altered metabolic pathways and initiation of adaptive stress responses. Mutation or overexpression of the azole target enzyme gene ERG11 in Candida albicans maintains target enzyme activity and produces drug resistance [ 41 ]. The results of this Meta showed that the efficacy of PDT in oral candidiasis was similar to that of fluconazole and that miconazole was superior to PDT, but considering that the increasing use of azoles has led to an increase in the resistance of Candida to them, and the fact that PDT can treat recurring infections caused by drug-resistant Candida, this is one of the advantages of PDT over azoles.

For the treatment of candidiasis, the use of topical antifungal agents provides temporary relief, but recurrence is a common problem, especially in the case of immunodeficiency [ 21 ]. Mima [ 19 ] et al. showed recurrence of palatal inflammation in 75% and 78% of patients in the NYT and PDT groups, respectively, during follow-up, Scwingel [ 33 ] et al. showed recurrence of signs and symptoms in 72% of patients in the control group on day 30, and Macial [ 21 ] et al. found recurrence in 25% of patients in the experimental group and 12.5% in the control group, which may be related to improper denture cleaning and Candida recolonization in patients with denture stomatitis. With regard to safety, no adverse reactions were reported in Macial [ 21 ], while there were varying degrees of nausea and burning tongue in the studies of Yue Zhao [ 31 ] and Jinmei Tan [ 32 ], which may be related to immunodeficiency in HIV-infected patients.

Due to the widespread use of antifungal drugs such as nystatin and drug resistance in some patients, the clinical effectiveness of their treatment of oral candidiasis still needs to be improved [ 42 ]. PDT has a wide antibacterial spectrum, short therapeutic course and strong targeting, and can cause death of Candida by changing the permeability of Candida [ 43 ]. Combining the two methods may have more significant effects, so it is of great clinical significance to explore the combined application of PDT and mycobacterium. The results of this Meta-analysis showed that the combination of PDT and nystatin was more effective than nystatin alone in the treatment of oral candidiasis, and the recurrence rate was lower, which may be related to the mechanism of fungal inactivation by PDT interacting with the mechanism of antifungal drugs. Nystatin is a polyene antibiotic that interacts with ergosterol in fungal cell membranes, making them porous and susceptible to cracking, thus exerting its antifungal action [ 44 ]. PDT, on the other hand, is a photochemical reaction to excite a photosensitizer to produce reactive oxygen species, which can react with a variety of biomolecules such as proteins and phospholipids of fungal cells to produce activity and eventually inactivate the cells [ 45 ]. Therefore, the synergistic effect of the two treatment measures makes the combination more effective than a single antifungal drug. Regarding the safety of the combination therapy, the results of the Chen Chong [ 29 ] study showed that the incidence of adverse reactions during treatment was similar in both groups, and the adverse reactions resolved on their own without treatment, suggesting that the combination therapy was safe and reliable. The combination of PDT and antifungal drugs is recommended in clinical treatment and may be a more reliable measure for reducing the recurrence of oral candidiasis.

Smoking was identified as one of the important risk factors for increased oral Candida carriage in the included studies [ 46 ]. A meta-analysis by Nader [ 47 ] showed that smokers had significantly higher rates of oral Candida carriage than non-smokers. Smoking reduces the activity of oral leukocytes, decreases gingival exudate, and reduces the load of immunoglobulins and leukocytes, thus contributing to the colonization of Candida in the oral cavity [ 48 ]. Abduljabbar [ 38 ] conducted a clinical trial on the presence of smoking as a risk factor in patients with denture stomatitis and found that PDT was significantly more effective in non-smokers than in smokers.

This Meta has some limitations to consider, the lack of an appropriate number of RCTs included in each subgroup, as well as the small sample size included in some studies and the differences in follow-up time between studies to the extent that bias may result in subgroup analysis. There is a lack of standardization in the use of PDT across studies, such as differences in photosensitizers, activation wavelengths, power output, irradiation duration, and energy dose. In addition, the choice of the optimal synergistic treatment modality of PDT with other drugs still needs to be studied in depth.

Availability of data and materials

All data generated or analyzed during this study are included in this article.

Abbreviations

Photodynamic Therapy

Oral Candidiasis

Denture stomatitis

Reactive Oxygen Species

Deoxyribonucleic Acid

Human Immunodeficiency Virus

Colony forming units

Relative Risk

Mean Difference

Confidence Interval

Fixed-effects Model

Random-effects Model

Preferred Reporting Item for Systematic Reviews and Meta-analyses

Randomized Controlled Trial

Rose Bengal

Photosensitive Diazine

Methylene Blue

Dimethyl Methylene Blue

Indocyanine Green

Low-power laser

Low-level laser therapy

Grading of Recommendations Assessment, Development and Evaluation

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Acknowledgements

All authors were fully responsible for the validity and reliability of the data, the analysis and the writing of the manuscript.

This work was supported by the S&T Program of Hebei [grant number 20377799D]; the academic leader training program of Hebei Provincial government [grant number 2018133206–2]; the Medical Science Research subject of Health Commission of Hebei Province [grant number 20191079].

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Qiaoyu Hu: Conceived and designed the experiments; Performed the experiments; Analysed and interpreted the data; Wrote the manuscript.Ting Li and Jiadi Yang: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data. Yanhui Peng: performed the experiments. Na Liu and Qing Liu: conceived and designed the experiments; performed the experiments; interpreted the data; review and edit the manuscript. All authors reviewed the manuscript.

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Hu, Q., Li, T., Yang, J. et al. Efficacy of photodynamic therapy in the treatment of oral candidiasis: a systematic review and meta-analysis. BMC Oral Health 23 , 802 (2023). https://doi.org/10.1186/s12903-023-03484-z

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Current treatment of oral candidiasis: A literature review.

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• Garcia-Cuesta C 1
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Journal of Clinical and Experimental Dentistry , 01 Dec 2014 , 6(5): e576-82 https://doi.org/10.4317/jced.51798   PMID: 25674329  PMCID: PMC4312689

Abstract 

Free full text , current treatment of oral candidiasis: a literature review, carla garcia-cuesta.

1 Dentist. Postgraduate in Oral Medicine

Maria-Gracia Sarrion-Pérez

2 Associate profesor of Oral Medicine Unit. Department of Stomatology. University of Valencia

Jose V. Bagán

3 Chairman of Oral Medicine. Oral Medicine Unit. Department of Stomatology. University of Valencia. Head of the Department of Stomatology and Maxilofacial Surgery. Valencia University General Hospital

Candidiasis or oral candidosis is one of the most common human opportunistic fungal infections of the oral cavity. This pathology has a wide variety of treatment which has been studied until these days. The present study offers a literature review on the treatment of oral candidiasis, with the purpose of establish which treatment is the most suitable in each case. Searching the 24 latest articles about treatment of candidiasis it concluded that the incidence depends on the type of the candidiasis and the virulence of the infection. Although nystatin and amphotericin b were the most drugs used locally, fluconazole oral suspension is proving to be a very effective drug in the treatment of oral candidiasis. Fluconazole was found to be the drug of choice as a systemic treatment of oral candidiasis. Due to its good antifungal properties, its high acceptance of the patient and its efficacy compared with other antifungal drugs. But this drug is not always effective, so we need to evaluate and distinguish others like itraconazole or ketoconazole, in that cases when Candida strains resist to fluconazole.

Key words: Candidiasis, treatment, miconazole, fluconazole, nystatin.

Introduction

The incidence of fungal infections has been increasing over the last decades, being more prevalent in developed countries ( 1 ). An increase incidence of the infections is associated with some predisposing factors ( Table 1 ) as the use of dentures, xerostomia, prolonged therapy with antibiotics, local trauma, malnutrition, endocrine disorders, increased longevity of people, among other states that diminish the quality of defense of the individual ( 2 ). Oral candidiasis is one of the most common clinical features of those patients infected with the human immunodeficiency virus [HIV], this manifestation was seen in up to 90% of individuals infected with HIV ( 3 ).

Oropharyngeal candidiasis is caused by the genus Candida ; it is possible to isolate about 150 species. Many of these remain as a commensal micro-organism in humans, which could act as an opportunistic pathogens often associated with predisposing factors attributed to the organism, thereby causing acute or chronic infections ( 4 ). The most important of these species is C. albicans , which is most commonly isolated from the oral cavity and is believed to be more virulent in humans, occurring in approximately 50% of the cases of candidiasis.

Clinically there are a number of different types of oral candidiasis ( Table 2 ). Therefore the choice of therapy is guided by the type of candidiasis.

The diagnosis of oral candidiasis is essentially clinical and is based on the recognition of the lesions by the professional, which can be confirmed by the microscopic identification of Candida ( 5 ). The techniques available for the isolation of Candida in the oral cavity include direct examination or cytological smear, culture of microorganisms and biopsy which is indicated for cases of hiperplasic candidiasis because this type could present dysplasias ( 6 ).

The treatment of oral candidiasis is based on four fundaments ( 7 ): making an early and accurate diagnosis of the infection; Correcting the predisposing factors or underlying diseases; Evaluating the type of Candida infection; Appropriate use of antifungal drugs, evaluating the efficacy / toxicity ratio in each case.

When choosing between some treatments it will take into account the type of Candida , its clinical pathology and if it is enough with a topical treatment or requires a more complex systemic type ( 8 ), always evaluating the ratio efficacy and toxicity ( 9 ). The different drugs are contained in Table 3 .

Regular oral and dental hygiene with periodic oral examination will prevent most cases of oral candidiasis, so it is need to make the patient aware of oral hygiene measures. Oral hygiene involves cleaning the teeth, buccal cavity, tongue, and dentures. As well as the use of anti- Candida rinses such as Chlorhexidine or Hexetidine, so that they can penetrate those areas where the brush does not. In addition, the need to remove the dentures at night and wash it consciously, leaving it submerged in a disinfectant solution like Chlorhexidine ( 10 ).

This study provides a literature review of the treatment of oral candidiasis and its objectives are to establish general guidelines for treatment of oral candidiasis; Assess the drug of choice for local treatment of oral candidiasis; Assess the systemic treatment for oral candidiasis.

Material and Methods

A Medline-PubMed search was made using the following key words: “ oral candidiasis” OR “oral candidosis” AND amphotericin, “oral candidiasis” OR “oral candidosis” AND nystatine, “oral candidiasis” OR “oral candidosis” AND miconazole, “oral candidiasis” OR “oral candidosis” AND ketoconazole, “oral candidiasis” OR “oral candidosis” AND clotrimazole, “oral candidiasis” OR “oral candidosis” AND fluconazole, “oral candidia-sis” OR “oral candidosis” AND itraconazole, “oral candidiasis” OR “oral candidosis” AND treatment, “oral candidiasis” OR “oral candidosis” AND “antifungal therapy”.The key words were validated by the MeSH [Me-dical Subject Headings] dictionary, with use of the boolean operator “AND” to relate them.

The following limits for inclusion of the studies were established: articles published from 2000, publications in English and Spanish and publications of studies in humans. All systematic reviews, clinical trials, meta-analysis and comparative studies were considered in this review.

A total of 109 articles were identified, of which 30 were selected after reading the abstracts. Following analysis of the 30 articles, we finally included a total of 24, since those publications that did not fit the aims of the present study were excluded.

A total of 24 articles were found about antifungal treatment, of which 20 were clinical trials, 3 systematic re-views and 1 a clinical case ( Table 4 , Table 4 (Cont) ).

Table 4 (Cont)

Candida infection today is highly prevalent, especially the increase in carriers of removable dentures and poor oral hygiene society. Depending on its virulence, location and type of candidiasis there will carry on one treatment or another.

First has been supported the use of conservative measures before starting drug treatment, promoting good oral hygiene along with removing the dentures at night, thereby it will benefit the removal of the biofilm layer generated in the prosthetic surface ( 11 ). Dentists should also correct the predisposing factors and underlying diseases and try to promote the use of oral antiseptic and antibacterial rinses such as Chlorhexidine or Hexetidine ( 12 ). These measures are very effective in patients with denture stomatitis ( 12 ). It was also found in the study of Cross et al. ( 13 ) that in patients with good oral hygiene the recurrence of candidiasis after 3 years was lower.

Regarding the pharmacological treatment of candidiasis can be distinguished between two procedures. Topical drugs, which are applied to the affected area and treat superficial infections and systemic drugs those that are prescribed when the infection is more widespread and has not been enough with the topical therapy.

As first choice for local treatment has been for years the nystatin at doses of 100 000 IU/ml [5ml 4 times daily] and amphotericin b at 50mg [5ml 3 times per day]. This choice is because they are poorly absorbed by the intestinal tract and therefore most of the antifungal is excreted without undergoing any change, thereby reducing hepatotoxicity ( 14 ). However, the unpleasant taste and prolonged pattern compromise treatment compliance by the patient ( 14 - 16 ).

Throughout the years it has been studying the effectiveness of other drugs like fluconazole oral solution. Many authors have focused on evaluating the efficacy and safety of fluconazole oral solution for the treatment of oropharyngeal candidiasis, especially pseudomembranous type, giving good results, although many studies are still needed ( 14 - 18 ).

In a recent study conducted in 19 patients with pseudomembranous candidiasis show that fluconazole suspension in distilled water [2mg/ml] reaches a 95% cure.

The guideline was to rinse with 5ml of the drug solution for 1 minute and then spit it out and repeat this action 3 times a day for 1 week. Another study which included 36 children with pseudomembranous candidiasis showed that fluconazole oral suspension 10mg/ml dose gave better results than nystatin. The main problem was the poor adherence of the nystatin to the oral mucosa and thus the quick ingestion of the suspension, resulting in a lower efficiency ( 14 ).

On the other hand, in another study comparing amphotericin b suspension, the fluconazole oral suspension gave better results in terms of the eradication of Candida ( 16 ). The same was corroborated by Taillandier et al. ( 18 ), which reported that fluconazole oral suspension was as effective as amphotericin b, but it was better accepted by the patient.

Fluconazole oral suspension is administered in a dosage of 10 mg / ml aqueous suspension by administering 5 ml daily for 7 or 14 days. Different studies show that it is a very effective drug against pseudomembranous candidiasis, as it has good adhesion to the surface of the oral mucosa and a rapid symptomatic response. It also offers the convenience of a one-daily dosing, which may explain the better patient compliance ( 14 - 18 ).

Another topic drug widely used is miconazole ( 19 ). We found it in the form of gel, applying it directly on the affected area, at doses of 200-500 mg per day, divided into 4 times. Despite its good properties it has the draw-back of possible interaction with other drugs, such as warfarin. This is because the antifungal inhibit the enzyme cytochrome P-450, which affects the clearance of certain drugs ( 20 , 21 ). In addition, this drug is absorbed by the intestine, therefore care must be taken when is administrated.

It has been introduced in the market an alternative presentation of miconazole. A one-daily miconazole 50 mg mucoadhesive buccal tablet. It has a limited systemic absorption. Its performance is mostly local and it has a convenient application form. Patients are instructed to apply the rounded side of the 50 mg tablet to the upper gum region just above the right or left incisor following brushing of teeth in the morning. The tablet should be held in place until dissolved ( 22 , 23 ). It has the advantage of being applied once daily instead 5 times a day with clotrimazole ( 24 ), and 4 times daily with nystatin ( 25 ).

It has been demonstrated the effectiveness of this new form of administration in the study of Bensadoun et al. ( 26 ). 141 patients with head and neck cancer with clinical signs and symptoms of oropharyngeal candidiasis received 50 mg mucoadhesive tablets of miconazole daily or 125 mg miconazole gel four times per day. Clinical improvement was not significant between the two groups, but the mucoadhesive tablets exhibited higher salivary concentrations and better tolerance for the patient. Despite being more expensive, offers an effective, safe, and well tolerated topical treatment for oropharyngeal candidiasis ( 22 , 23 , 26 ).

- Systemic treatment:

In spite of knowing the efficacy of the drugs listed above, when it comes to a more generalized candidiasis or immunocompromised patients, these would not be sufficient. For those cases would have to resort to treatment with systemic drugs ( 25 ).

Since its introduction, fluconazole has been used to treat systemic Candida infections because of its efficacy and good tolerability. The appropriate dose is between 50-100 mg daily ( 27 ). Furthermore, when dealing with immunocompromised patients, such as those HIV-infected, or cancerous, this drug has good effects doubling the dose ( 28 , 29 ). Its efficacy has been demonstrated ( 27 ). The dose was individualized depending on the severity and type of candidiasis. Patients with pseudomembranous type started with 100 mg fluconazole daily; patients with erythematous variety started with 50 mg fluconazole. Therefore, according to the clinic and the virulence of the infection the dose would be titrated, giving good results, and increasing the guideline in those cases where the fungal infection did not decrease ( 27 ).

To support the efficacy of this drug it has been compared with other systemic antifungal agents ( 29 ). In one randomized study, the efficacy of fluconazole [100mg per day for 10 days] and itraconazole [200mg per day for 15 days] was compared in patients with oropharyngeal candidiasis. The results were a clinical and mycological improvement of 66% for the first group and 54% for those treated with itraconazole. The main conclusion of this study is that in patients with oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole. The failures of itraconazole may be explained by drug interactions and the unpredictable absorption of itraconazole capsules. But when fluconazole failed, itraconazole was prescribed to these patients, having good results. So it is said that it was a good drug for fluconazole-resistant Candida strains ( 29 ).

As it has been suggested above, it may happen that the Candida strains were not susceptible to fluconazole, and it has not any effect. In that case it will be used other drugs like itraconazole or newest ones as voriconazole ( 30 ). Keeping always in mind that strains which were resistant to fluconazole were also resistant to other drugs ( 31 ).

The new triazol antifungal voriconazole [200 mg per day] has been shown to be a potent drug. Ally et al. ( 32 ) compared the efficacy of voriconazole and fluconazole in the treatment of esophageal candidiasis. The success rate was 98.3% for voriconazole and 95.1% for fluconazole. The results show clearly that voriconazole is at least as effective as fluconazole in the treatment of candidiasis. It suggests that this new agent may be a useful alternative for fluconazole-resistant Candida strains ( 32 ). Because of being a new there are little strains resistant to voriconazole. The voriconazole has an important role in the treatment of candidiasis ( 30 ), although it is still not fully established in the market, so many more studies and research would be needed.

There have been several studies comparing topical and systemic drugs. In a study to treat denture stomatitis have been compared the use of ketoconazole tablets [200mg daily] with topical ketoconazole [2% twice daily] and miconazole mucoadhesive tablets ( 33 ). Due to the adverse effects of ketoconazole ( 31 ) like nausea, vomiting and gastrointestinal problems it has been supported the use of other drugs when treating prosthetic candidiasis ( 34 ). Thus the use of miconazole mucoadhesive tablet was established as the drug of first line of defense for this type of candidiasis.

General treatment guidelines include after the completion of an early diagnosis, the correction of predisposing factors or underlying diseases and maintaining a good oral hygiene. Moreover using antiseptic agents such as Chlorhexidine or Hexetidine, as well as removing dentures at night. All of that in order to obtain well results in the treatment of oral candidiasis as first line of defense, continuing the application of antifungal drugs. Beginning with local treatment and keeping up the systemic ones for those patients who do not respond to topical treatment or in immunocompromised patients.

It has recently been found that fluconazole oral suspension as a local treatment, at a dose of 2 mg/ml 3 times daily or 10 mg /ml once daily, gives good clinical results, besides the better patient compliance due to the dosage and its pleasant taste. Despite not being currently the most widely used locally because it requires further clinical studies. Nowadays the most used drugs remains in nystatin solution which contain 100 000 IU / ml [5ml 4 times daily] and miconazole gel [200 to 500 mg per day divided into 4 doses]. Moreover miconazole mucoadhesive tablets [50 mg once daily] which are considered effective in the treatment of oropharyngeal candidiasis, but their high cost is one of the main problems.

Fluconazole at doses between 50-100 mg per day is the systemic drug of choice because it has high efficacy and tolerability by the patient. However it is important to think about the voriconazole which is as effective as fluconazole but is still under study. Also it is need to know about other drugs such as itraconazole, which are effective when Candida strains are resistant to fluconazole.

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A Practical Guide to the Management of Oral Candidiasis in Patients with Plaque Psoriasis Receiving Treatments That Target Interleukin-17

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• April W. Armstrong 1 ,
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Plaque psoriasis is an immune-mediated inflammatory skin disease associated with the dysregulation of cytokines, especially those involved in the interleukin (IL)-23/IL-17 pathways. In recent years, there has been growing interest in developing biologic therapies that target these pathways. However, inhibition of the cytokines of the IL-23/IL-17 pathways may increase patients’ risk of developing fungal infections, particularly oral candidiasis. Therefore, it is important that dermatology practitioners can effectively diagnose and treat oral candidiasis. In this review, we examine the role of the IL-23/IL-17 pathways in antifungal host defense, and provide a practical guide to the diagnosis and treatment of oral candidiasis in patients with psoriasis. Overall, while treatment with anti-IL-17 medications leads to an increased incidence of oral candidiasis in patients with psoriasis, these cases are typically mild or moderate in severity and can be managed with standard antifungal therapy without discontinuing treatment for psoriasis. If applicable, patients with psoriasis should also be advised to practice good oral hygiene and manage or control co-existing diabetes, and should be provided with information on smoking cessation to prevent oral candidiasis.

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Avoid common mistakes on your manuscript.

Introduction

Psoriasis is an immune-mediated inflammatory skin disease associated with dysregulation of inflammatory cytokines that affects approximately 41 million people worldwide [ 1 , 2 ]. The cytokines of the interleukin (IL)-23/IL-17 pathways have been identified as key mediators of psoriasis pathogenesis [ 3 ]. Subsequently, there has been growing interest in developing biologic therapies that target these pathways [ 4 , 5 ]. However, as a result of the roles of IL-17 and IL-23 in antifungal host defense at the oral mucosa, targeting these cytokines may increase patients’ risk of developing fungal infections, particularly oral candidiasis [ 6 ].

Here, we provide an overview of the role of the IL-23/IL-17 pathways in antifungal host defense, as well as a practical guide to the treatment of oral candidiasis in patients with psoriatic disease.

This review article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors

The IL-23/IL-17 Pathways and Immunity

Overview and role in psoriasis.

The main producers of IL-17, along with T cytotoxic 17 (Tc17) cells, are T-helper (Th)17 cells—a subset of Th cells that differentiate from naïve CD4 + T cells upon exposure to proinflammatory cytokines [ 7 , 8 ]. The IL-17 family consists of six ligands (IL-17A to IL-17F) that bind to receptors (IL-17R) expressed ubiquitously throughout the body [ 9 , 10 , 11 , 12 , 13 ]. IL-17A and IL-17F share the closest homology and can exist as homodimers or heterodimers [ 5 ]. While not required for the induction of the Th17 and Tc17 lineages, IL-23 is required for the stabilization and proliferation of these cells [ 7 , 8 ].

Although the etiology of psoriasis is not fully understood, genetic and environmental factors appear to contribute to atypical activation of the immune system, resulting in disease [ 14 , 15 ]. The cytokines IL-17A and IL-17F in particular have been identified as key upregulated proinflammatory cytokines in psoriatic lesions; they are thought to recruit immune cells to psoriatic skin, stimulating the hyperproliferation of keratinocytes [ 16 , 17 ].

Role in Host Defense Against Candida

One of the major roles of the IL-23/IL-17 pathways is host defense against fungal infections [ 18 ]. The most common species involved, Candida albicans , is usually commensal; however, upon conversion to a hyphal state it can cause mucocutaneous candidiasis [ 19 ].

The key role of IL-17 signaling in host defense against Candida is supported by observations from patients with primary immunodeficiencies leading to defects in the Th17 pathway, who present with a form of chronic mucocutaneous candidiasis (CMC) termed CMC disease (CMCD) [ 20 ]. These patients are prone to recurrent oral and esophageal candidiasis, suggesting a pivotal role of IL-17 in defense against candidiasis in the mucosa of the upper digestive tract [ 20 ]. However, these patients are not prone to systemic or vulvovaginal candidiasis, leading to an emerging consensus that the IL-23/IL-17 pathways are not essential to immune defense against these infections [ 19 , 21 , 22 , 23 ]. These patients also rarely display any other severe diseases [ 24 ].

According to the current model of host defense against oral candidiasis, conversion of C. albicans to a hyphal state results in the activation of immune cells in response to damage [ 25 ]. These cells then produce proinflammatory cytokines such as IL-23, inducing the proliferation of Th17 cells and the release of IL-17A and IL-17F as well as IL-22. Neutrophils are then recruited to the infection site by these cytokines, inducing the secretion of antifungal proteins (Fig.  1 ) [ 19 , 26 ]. Therefore, through the inhibition of IL-17 or its receptors, anti-IL-17 medications prescribed for psoriasis can increase the risk of oral candidiasis through inhibition of these Th17 cell-mediated antifungal pathways.

Simplified model of host defense against oral candidiasis. Colonization of the oral mucosal epithelium by Candida results in the activation of macrophages and DCs, either directly or indirectly, via alarmins such as IL-1α, IL-1β, and IL-36, which are released in response to tissue damage by the peptide candidalysin. This then triggers the expression and secretion of IL-6, IL-1β, and IL-23, which induce the differentiation and proliferation of Th17 cells from naïve CD4 + T cells. These Th17 cells produce the cytokines IL-17A, IL-17F, and IL-22, which recruit neutrophils to the site of infection and act on epithelial cells to induce the release of antifungal β-defensins. Through the inhibition of IL-17 or its receptors, anti-IL-17 medications prescribed for psoriasis can increase the risk of oral candidiasis through inhibition of Th17 cell-mediated antifungal pathways. DC dendritic cells, IL interleukin, R receptor, Th17 T-helper cell type 17

Epidemiology of Candida Colonization and Infection in Psoriasis

There is some evidence of increased Candida colonization of the oral cavity in patients with psoriasis versus those without psoriasis. In a systematic literature review and meta-analysis of nine studies, statistically higher rates of Candida colonization of mucosal membranes were observed in patients with psoriasis [ 27 ]. For example, rates were reported as 69% versus 44% for those without psoriasis in a study conducted in Jordan [ 28 ], and 47.2% versus 19.5% in a study conducted in Germany [ 29 ]. This trend was consistent with another study where patients with psoriasis receiving systemic treatment were excluded (20.0% versus 2.8%) [ 30 ]. The reason for this association is unclear. Notably, there was considerable heterogeneity in these studies, and most measured the presence of Candida colonization rather than true candidiasis [ 27 ].

Risk of Candidiasis in Patients Receiving Biologic Treatments for Psoriasis

In recent years, several monoclonal antibodies targeting IL-17 (e.g., brodalumab, ixekizumab, and secukinumab), IL-23 (e.g., guselkumab, risankizumab, and tildrakizumab), and IL-12/23 (e.g., ustekinumab) have been approved for treatment of psoriatic disease [ 4 ].

A systematic review of previous trials of anti-IL-17 medications in psoriatic disease found that overall incidence of candidiasis was increased in patients treated with anti-IL-17 medications versus placebo (1.7–4.0% versus 0.3%, respectively) [ 31 ]. The majority of Candida infections were oral and not vulvovaginal. Moreover, most oral candidiasis cases were mild to moderate in severity [ 31 ]. There was also no increase in the risk of esophageal or systemic candidiasis, further supported by a systematic review of all IL-17 and IL-23 inhibitors [ 31 , 32 ].

Bimekizumab, an anti-IL-17 medication recently authorized in Europe for the treatment of moderate to severe plaque psoriasis [ 33 ], inhibits IL-17F in addition to IL-17A [ 34 ]. Dual inhibition of IL-17A and IL-17F has demonstrated superior levels of skin clearance compared with targeting IL-17A alone with secukinumab in a head-to-head in patients with plaque psoriasis [ 35 ]. As expected, as a result of the roles of both cytokines in antifungal host defense, dual neutralization was also associated with an increased incidence of mild to moderate oral candidiasis as compared with previously approved anti-IL-17 medications [ 36 , 37 , 38 ].

Despite both bimekizumab and brodalumab inhibiting the activity of IL-17A and IL-17F, differences have been observed in the rates of oral candidiasis. This could be a consequence of the mechanistic differences between these two biologics. One hypothesis is that, as brodalumab inhibits IL-17R, it blocks the function of all additional IL-17 cytokines, including IL-17E which may indirectly suppress Th17 responses [ 13 ]. Furthermore, if IL-17R is not fully blocked at the end of a dosing cycle, it is possible that residual IL-17 may confer host protection against Candida . However, further research into this topic is needed.

Anti-IL-23 biologics do not seem to increase the risk of Candida infections as much as anti-IL-17 biologics [ 39 ]. This may be because anti-IL-23s do not block IL-23-independent sources of IL-17, such as IL-17 produced by innate lymphoid cells [ 3 , 39 ]. However, IL-23-independent sources of IL-17 are increasingly thought to play a significant role in the pathogenesis of immune-mediated inflammatory diseases, which may explain the higher efficacy of some anti-IL-17 medications compared with IL-23 blockers axial spondyloarthritis and joint outcomes in psoriatic arthritis [ 40 , 41 ].

Diagnosis and Treatment of Oral Candidiasis

Given the increased risk of oral candidiasis in patients with psoriasis treated with anti-IL-17 medications, it is important that dermatology practitioners can effectively diagnose and treat these infections. On the basis of a review of the literature and clinical experience, we propose the diagnosis and treatment algorithm for oral candidiasis shown in Fig.  2 .

Algorithm for the diagnosis and management of oral candidiasis in patients with plaque psoriasis. a In the case that administration of anti-IL-17 treatment falls on the same day in which the antifungal treatment for oral candidiasis is initiated, administration of anti-IL-17 can be postponed for 3–4 days to prioritize resolution of oral candidiasis

Clinical Presentations of Oral Candidiasis

Pseudomembranous candidiasis.

Pseudomembranous candidiasis (or “thrush”) is sometimes referred to as the classic presentation of candidiasis [ 42 ], and in our clinical experience is most commonly identified in patients with psoriasis receiving anti-IL-17 treatment. It is characterized by the presence of white, curd-like plaques that can be dislodged with gentle scraping, revealing underlying erosions of the oral mucosa (Fig.  3 A) [ 43 , 44 , 45 , 46 ]. Patients are often asymptomatic; however, pain, a burning sensation, and in some cases a metallic taste may be present [ 46 ].

Clinical presentations of oral candidiasis. A Pseudomembranous candidiasis in a male patient receiving anti-IL-17A treatment for plaque psoriasis; this patient was also a smoker. Patient image was provided courtesy of Dr Gisondi. B Acute erythematous candidiasis of the tongue. Patient image was borrowed from the Mount Sinai collection

Erythematous Candidiasis

Erythematous candidiasis is the most common form of oral candidiasis [ 46 ]. There are four subtypes: acute erythematous candidiasis, chronic erythematous candidiasis, angular cheilitis, and median rhomboid glossitis.

Acute erythematous candidiasis presents as painful reddened lesions which occur throughout the oral cavity (Fig.  3 B) [ 43 , 44 , 45 , 46 ]. In chronic erythematous candidiasis (or “denture stomatitis”), these lesions are localized to the fitting surface of dentures [ 43 , 44 , 45 , 46 ]. Angular cheilitis, most commonly seen in elderly patients with over-closure of the jaw, is characterized by reddened lesions at the corner of the mouth [ 43 , 44 , 45 , 46 ]. Finally, the least common subtype, median rhomboid glossitis, presents as a rhomboid-shaped area of atrophy and erythema on the midline posterior tongue dorsum [ 43 , 45 ].

Chronic Hyperplastic Candidiasis

Chronic hyperplastic candidiasis is a rare form of oral candidiasis that presents as a thickened white plaque, most frequently at the commissural region of the mouth or the dorsum of the tongue. However, unlike in pseudomembranous candidiasis, this plaque cannot be removed by gentle scraping [ 42 , 43 , 44 , 45 , 46 , 47 ]. Plaques may be smooth and isolated (homogeneous) or nodular and speckled (heterogeneous) [ 45 , 46 , 47 ].

Risk Factors for Oral Candidiasis

The presence of predisposing factors, other than treatment with anti-IL-17 medications, can also inform diagnosis of oral candidiasis. These factors are divided into two categories: local factors that affect the local oral environment and microflora and systemic factors that affect the host’s immune status (for a full list see Table  1 ) [ 43 ].

Local Predisposing Risk Factors

One of the most common local risk factors is the use of dentures, which can create a favorable environment for Candida growth, especially if denture hygiene is poor [ 43 , 48 , 49 ]. It is estimated that up to 75% of adults who wear dentures have some form of erythematous candidiasis, although most are unaware of it [ 48 ].

Another common local predisposing factor is the use of steroid inhalers, which may cause alterations in the oral microflora and is commonly associated with pseudomembranous candidiasis [ 42 , 43 , 49 , 50 ]. Incidence of oral candidiasis in users of steroid inhalers generally ranges from 1% to 7% in the literature [ 51 ].

Patients who use or smoke tobacco have significantly increased oral Candida carriage levels and rates of oral candidiasis [ 49 , 52 ]. Hyperplastic candidiasis is almost exclusively found in patients who smoke [ 47 ]; however, the exact underlying mechanism remains unclear [ 52 ].

Systemic Predisposing Risk Factors

The best-characterized systemic predisposing factors for oral candidiasis are human immunodeficiency virus (HIV) and chemotherapy and radiotherapy for cancer [ 49 , 53 , 54 ]. Antibiotic use is also associated with oral candidiasis, particularly acute erythematous candidiasis (commonly referred to as “antibiotic sore mouth”) [ 43 , 44 , 45 , 46 , 49 ].

Other major systemic predisposing factors for oral candidiasis are extremes of age; both elderly patients and infants have increased risk of oral candidiasis due to lower levels of protective salivary defenses [ 43 ]. Elderly patients may also have a loss of vertical dimension of occlusion, increasing the risk of developing angular cheilitis [ 43 ].

Diabetes and poor glycemic control have also been associated with oral candidiasis; patients with poorly controlled diabetes often exhibit reduced salivary pH and increased salivary glucose levels, facilitating Candida proliferation [ 49 , 55 ].

Confirmation of Diagnosis

Oral candidiasis is typically diagnosed according to the presence of clinical signs and symptoms in patients with predisposing factors [ 45 , 56 ]. If there are diagnostic doubts, diagnosis can be confirmed via microbiologic examination [ 45 , 49 ]. Fresh samples from the oral tissues can be taken and examined microscopically using 10% potassium hydroxide (KOH) [ 45 ]. This method is useful for distinguishing erythematous manifestations of oral candidiasis from conditions with similar presentations, such as thermal traumatic lesions, lupus erythematosus, erythema multiforme, or epithelial dysplasia [ 57 ]. Alternatively, it is possible to culture samples using Sabouraud dextrose agar (SDA), from which the Candida species can be identified [ 45 , 47 ]. This can be useful if infection shows resistance to antifungal agents, as some rarer Candida species (e.g., Candida glabrata ) may show enhanced resistance to treatment [ 47 ].

In rare cases (0.32% of otherwise healthy individuals in a retrospective single-center study of 88,125 individuals in South Korea) [ 58 ], oral Candida infections may extend to the esophagus. Esophageal candidiasis appears endoscopically as thick white plaques on the esophageal mucosa. Symptoms include difficulty or pain upon swallowing or pain behind the sternum [ 49 , 59 ]. Patients presenting with these symptoms should be referred for esophagoscopy to exclude esophageal candidiasis [ 49 , 60 ].

If a patient presents with clinical signs of hyperplastic candidiasis, a biopsy should be conducted because of the proposed link between this presentation and malignancy [ 56 ].

Treatment of Oral Candidiasis

Patients with psoriasis are encouraged to practice good oral and denture hygiene to prevent the occurrence of oral candidiasis. However, if oral candidiasis occurs, a number of treatments are available, with some applied topically and others administered orally [ 56 ]. Generally, as per guidelines from the Infectious Diseases Society of America and Centers for Disease Control and Prevention in the USA, and the UK National Institute for Health and Care Excellence, initial topical antifungal treatment for 7–14 days is recommended [ 49 , 56 , 61 , 62 ]. This can include miconazole oral gel (50 mg mucoadhesive tablet applied daily [USA], or 2.5 mL, four times daily [UK]), clotrimazole troches (10 mg, five times daily [USA]) or “swish and swallow” treatments such as nystatin suspension (100,000 U/mL, 4–6 mL [USA] or 1 mL [UK] four times daily) [ 61 , 62 ]. If candidiasis does not resolve, oral fluconazole (100–200 mg once daily for 7–14 days [USA], or 50–100 mg once daily for 7 days [UK]) is recommended [ 49 , 61 , 62 ]. Itraconazole (200 mg once daily [USA] or 100–200 mg twice daily [UK]) can be prescribed as an alternative to fluconazole [ 61 , 62 ]. As the labels of anti-IL-17 medications recommend pausing administration until an infection is resolved, if administration of anti-IL-17 treatment falls on the same day as initiation of antifungal treatment, administration of anti-IL-17 can be postponed for a few days to prioritize resolution of oral candidiasis.

Depending on local guidelines, fluconazole may be prescribed as a first-line treatment for oral candidiasis, as it is highly effective in treating fungal infections and has a simpler dosing schedule compared with topical antifungal treatments [ 56 ]. In our experience, shorter durations of fluconazole treatment (e.g., 100–200 mg daily for 3–5 days) can be an effective first-line treatment for oral candidiasis. However, any potential drug–drug interactions should be carefully considered, especially if a patient with psoriasis presents with other comorbidities. If oral candidiasis shows resistance to fluconazole, fungal characterization via SDA culture can be carried out, as previously described [ 45 , 47 ]. In the case that a fluconazole-resistant Candida species is identified, alternative antifungal treatment should be prescribed.

While the majority of patients respond to these antifungal treatments with quick resolution [ 56 ], in certain cases oral candidiasis may be recurrent. If recurrent, measures should be taken to confirm adherence to antifungal treatment and correct any predisposing factors if applicable. This includes education in proper oral and denture hygiene, smoking cessation, rinsing the mouth after use of steroid inhalers, and proper management of diabetes [ 62 ]. Poor oral and denture hygiene, in particular, are key risk factors of oral candidiasis and so should be amended in order to prevent reinfection if relevant.

If recurrence continues within a 3-month period following initial treatment, and there is insufficient treatment response with alternative modes of psoriasis treatment, initiation of prophylaxis can be considered. In our clinical experience, this could include administration of any of the aforementioned treatment measures repeated once weekly or monthly for short or longer periods, guided by need and response.

The effectiveness of prophylaxis for the prevention of recurrent oral candidiasis has most frequently been demonstrated in patients with HIV [ 63 ]. In these patients, fluconazole prophylaxis has been shown to reduce recurrence as compared with no treatment or placebo [ 64 , 65 , 66 , 67 , 68 ]. However, there is concern that continuous treatment may lead to fluconazole resistance. Indeed, one study found decreased susceptibility of Candida isolates to fluconazole in 56% of patients who received continuous therapy. Nevertheless, the vast majority of patients in this study still showed clearance of oral candidiasis in response to fluconazole [ 69 ]. Furthermore, in another study, similar proportions of patients with HIV receiving continuous (4.1%) or episodic (4.3%) fluconazole developed fluconazole-refractory oral candidiasis [ 70 ]. For fluconazole-refractory infections, treatment with non-azole antifungals can be considered [ 61 ].

Conclusions

Given the increased risk of oral candidiasis in patients with psoriasis receiving anti-IL-17s, dermatologists should be attentive to clinical signs of oral candidiasis and aware of how to manage cases appropriately.

Oral candidiasis in patients with psoriasis is typically mild to moderate in severity. In our clinical experience, cases can be managed with standard antifungal treatment without discontinuing biologic psoriasis therapies. Furthermore, anti-IL-17 treatment is generally not associated with an increased risk of systemic candidiasis or serious infections.

To prevent recurrence of oral candidiasis, patients should be advised to practice good oral hygiene and be provided with information on smoking cessation, if applicable. Prophylaxis with antifungal agents can be considered if there is insufficient treatment response with alternative modes of psoriasis treatment.

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Acknowledgements

UCB funded the review and development of the manuscript and reviewed the text to ensure that from the perspective of UCB, the data presented in the publication are scientifically, technically, and medically supportable, that they do not contain any information that has the potential to damage the intellectual property of UCB, and that the publication complies with applicable laws, regulations, guidelines and good industry practice. The authors approved the final version to be published after critically revising the manuscript/publication for important intellectual content. The journal’s Rapid Service Fee was also funded by UCB.

Medical Writing, Editorial and Other Assistance

The authors acknowledge Susanne Wiegratz, MSc, UCB Pharma, Monheim, Germany for publication coordination as well as Kaity McCafferty Layte, BSc, Daniel Smith, BA, and Amelia Frizell-Armitage, PhD, Costello Medical, UK, for writing and editorial assistance funded by UCB Pharma in accordance with Good Publication Practice guidelines. Richard B. Warren, MD, PhD, is supported by the Manchester NIHR Biomedical Research Centre.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Substantial contributions to the review conception and design: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW; substantial contributions to the analysis and interpretation of review findings: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW; drafting the article or revising it critically for important intellectual content: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW; final approval of the version of the article to be published: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW.

Disclosures

April W. Armstrong has served as a data safety monitoring board member for Boehringer Ingelheim/Parexel; received research funding from Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, LEO Pharma, Pfizer, and UCB Pharma; has been a research investigator without compensation for Sanofi Genzyme; has been scientific investigator for AbbVie, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, LEO Pharma, Modernizing Medicine, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, and Sun Pharma; has served as speaker for AbbVie, Regeneron, and Sanofi Genzyme. Andrew Blauvelt has served as a scientific adviser and/or clinical study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Evommune, Forte, Galderma, Incyte, Janssen, Landos, LEO Pharma, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, and Vibliome. Ulrich Mrowietz has served as advisor and/or clinical study investigator for, and/or received honoraria and/or grants from AbbVie, Almirall, Aristea, Boehringer Ingelheim, Celgene, Dr. Reddy’s Laboratories, Eli Lilly, Foamix, Formycon, Forward Pharma, Janssen, LEO Pharma, Medac, Novartis, Phi-Stone, Pierre Fabre, Sanofi Genzyme, and UCB Pharma. Bruce Strober has served as a consultant (honoraria) from AbbVie, Almirall, Amgen, Arcutis, Arena, Aristea, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Equillium, GSK, Janssen, LEO Pharma, Meiji Seika Pharma, Mindera, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB Pharma; has served as speaker for AbbVie, Amgen, Eli Lilly, Janssen, and Ortho Dermatologics; Scientific Director (consulting fee) for CorEvitas Psoriasis Registry; investigator for AbbVie, Cara Therapeutics, CorEvitas Psoriasis Registry, Dermavant, Dermira, and Novartis; Editor-in-Chief (honorarium) for Journal of Psoriasis and Psoriatic Arthritis . Paolo Gisondi has served as a consultant for AbbVie, Abiogen, Almirall, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Sanofi Genzyme, and UCB Pharma. Joseph F. Merola has been a consultant for AbbVie, Amgen, Bayer, Biogen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi-Regeneron, UCB Pharma; principal investigator for Dermavant, LEO Pharma, and UCB Pharma. Richard G. Langley has been a principal investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer, UCB Pharma; served on scientific advisory boards for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer, and UCB Pharma; provided lectures for AbbVie, Amgen, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, and Pfizer. Mona Ståhle has received honoraria for participating in advisory boards and has given lectures for AbbVie, Celgene, Eli Lilly, LEO Pharma, Lipidor, Novartis, Pfizer, and UCB Pharma. Mark Lebwohl is an employee of Mount Sinai and receives research funds from AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen, Ortho Dermatologics, Regeneron, and UCB Pharma and is a consultant for Aditum Bio, Almirall, AltruBio, AnaptysBio, Arcutis, Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy’s Laboratories, Evelo Biosciences, Evommune, Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. Mihai G. Netea is a scientific founder and shareholder for Trained Therapeutix Discovery and Lemba; has served as a consultant (honoraria) for Inflazome, Roche, and UCB Pharma. Natalie Nunez Gomez is an employee and shareholder of UCB Pharma. Richard B. Warren has received consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, UCB Pharma; has received research grants to his institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis, UCB Pharma; honoraria from Astellas, DiCE, GSK, and Union.

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Department of Dermatology, Keck School of Medicine of USC, 1975 Zonal Ave, Los Angeles, CA, 90033, USA

April W. Armstrong

Oregon Medical Research Center, Portland, OR, USA

Andrew Blauvelt

Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

Ulrich Mrowietz

Yale University, New Haven, CT, USA

Bruce Strober

Central Connecticut Dermatology Research, Cromwell, CT, USA

University of Verona, Verona, Italy

Paolo Gisondi

Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

Joseph F. Merola

Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, NS, Canada

Richard G. Langley

Department of Medicine, Unit of Dermatology, Karolinska Institutet, Solna, Sweden

Mona Ståhle

Icahn School of Medicine at Mount Sinai, New York, NY, USA

Mark Lebwohl

Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

Mihai G. Netea

UCB Pharma, Brussels, Belgium

Natalie Nunez Gomez

Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester, UK

Richard B. Warren

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Armstrong, A.W., Blauvelt, A., Mrowietz, U. et al. A Practical Guide to the Management of Oral Candidiasis in Patients with Plaque Psoriasis Receiving Treatments That Target Interleukin-17. Dermatol Ther (Heidelb) 12 , 787–800 (2022). https://doi.org/10.1007/s13555-022-00687-0

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Oral Candidiasis of Tobacco Smokers: A Literature Review

• PMID: 37129200
• DOI: 10.3923/pjbs.2023.1.14

The mouth is a vital point of entry into the human body, the health of the mouth entails mental, physical as well as social well-being. Studying diseases, microbiota and environmental conditions of the mouth is important to maintain oral health and all body. The smoke of tobacco cigarettes is one of the worst habits that affect the health of the mouth and the body. Therefore, this review has been conducted to study the effect of smoking on the balance of the oral microbiota and the opportunistic organisms, one of the most important of them &lt;i&gt;Candida&lt;/i&gt;. Although a few studies have found that cigarette smoking does not influence carriage by &lt;i&gt;Candida&lt;/i&gt; significantly. However, most of the studies had results completely contrary to that, smoking cigarettes affect &lt;i&gt;Candida&lt;/i&gt; pathogenic characteristics such as a transition from yeast to hyphal form, biofilm formation and, virulence-related gene expressions. Tobacco is not only an inducer of the transition process but it considers an excellent medium for this process. Furthermore, smoking was significantly associated with &lt;i&gt;Candida&lt;/i&gt; pathogenicity in patients with clinically suspected oral leukoplakia and smoking worsens oral candidiasis and dampens epithelial cell defense response. Nicotine significantly altered the composition and proportion of yeast cells, as well as the extracellular polysaccharide amounts which increase biofilm matrix and thickness which could promote oral candidiasis. Smoking has the potential to alter the oral condition and cause severe oxidative stress, thereby damaging the epithelial barrier of the mouth. These oxidative molecules during smoking activate epithelial cells proteins called oxidative stress-sensing proteins. If some of these proteins induced, widely thought to have anti-inflammatory properties, inhibit the secretion of pro-inflammatory cytokines and are linked to inflammation and oxidative stress is thought to be a possible therapeutic objective and a crucial regulator for smoking-related oral diseases and mouth candidiasis for instance leukoplakia. Also, it is transported into the cell nucleus in the existence of additional electrophilic chemicals to activate antioxidant enzyme gene expression. Therefore, smoking cigarettes destroys oral health and consequently destroys the health of the whole body.

Keywords: Candida albicans; Candida species; cigarette smokers; mouth health; oral candidiasis; oral microbiota; tobacco smoking; virulence.

Publication types

• Candidiasis, Oral*
• Saccharomyces cerevisiae

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A Practical Guide to the Management of Oral Candidiasis in Patients with Plaque Psoriasis Receiving Treatments That Target Interleukin-17

April w. armstrong.

1 Department of Dermatology, Keck School of Medicine of USC, 1975 Zonal Ave, Los Angeles, CA 90033 USA

Andrew Blauvelt

2 Oregon Medical Research Center, Portland, OR USA

Ulrich Mrowietz

3 Psoriasis-Center at the Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany

Bruce Strober

4 Yale University, New Haven, CT USA

5 Central Connecticut Dermatology Research, Cromwell, CT USA

Paolo Gisondi

6 University of Verona, Verona, Italy

Joseph F. Merola

7 Harvard Medical School, Brigham and Women’s Hospital, Boston, MA USA

Richard G. Langley

8 Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, NS Canada

Mona Ståhle

9 Department of Medicine, Unit of Dermatology, Karolinska Institutet, Solna, Sweden

Mark Lebwohl

10 Icahn School of Medicine at Mount Sinai, New York, NY USA

Mihai G. Netea

11 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

Natalie Nunez Gomez

12 UCB Pharma, Brussels, Belgium

Richard B. Warren

13 Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester, UK

Plaque psoriasis is an immune-mediated inflammatory skin disease associated with the dysregulation of cytokines, especially those involved in the interleukin (IL)-23/IL-17 pathways. In recent years, there has been growing interest in developing biologic therapies that target these pathways. However, inhibition of the cytokines of the IL-23/IL-17 pathways may increase patients’ risk of developing fungal infections, particularly oral candidiasis. Therefore, it is important that dermatology practitioners can effectively diagnose and treat oral candidiasis. In this review, we examine the role of the IL-23/IL-17 pathways in antifungal host defense, and provide a practical guide to the diagnosis and treatment of oral candidiasis in patients with psoriasis. Overall, while treatment with anti-IL-17 medications leads to an increased incidence of oral candidiasis in patients with psoriasis, these cases are typically mild or moderate in severity and can be managed with standard antifungal therapy without discontinuing treatment for psoriasis. If applicable, patients with psoriasis should also be advised to practice good oral hygiene and manage or control co-existing diabetes, and should be provided with information on smoking cessation to prevent oral candidiasis.

Key Summary Points

Introduction.

Psoriasis is an immune-mediated inflammatory skin disease associated with dysregulation of inflammatory cytokines that affects approximately 41 million people worldwide [ 1 , 2 ]. The cytokines of the interleukin (IL)-23/IL-17 pathways have been identified as key mediators of psoriasis pathogenesis [ 3 ]. Subsequently, there has been growing interest in developing biologic therapies that target these pathways [ 4 , 5 ]. However, as a result of the roles of IL-17 and IL-23 in antifungal host defense at the oral mucosa, targeting these cytokines may increase patients’ risk of developing fungal infections, particularly oral candidiasis [ 6 ].

Here, we provide an overview of the role of the IL-23/IL-17 pathways in antifungal host defense, as well as a practical guide to the treatment of oral candidiasis in patients with psoriatic disease.

This review article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors

The IL-23/IL-17 Pathways and Immunity

Overview and role in psoriasis.

The main producers of IL-17, along with T cytotoxic 17 (Tc17) cells, are T-helper (Th)17 cells—a subset of Th cells that differentiate from naïve CD4 + T cells upon exposure to proinflammatory cytokines [ 7 , 8 ]. The IL-17 family consists of six ligands (IL-17A to IL-17F) that bind to receptors (IL-17R) expressed ubiquitously throughout the body [ 9 – 13 ]. IL-17A and IL-17F share the closest homology and can exist as homodimers or heterodimers [ 5 ]. While not required for the induction of the Th17 and Tc17 lineages, IL-23 is required for the stabilization and proliferation of these cells [ 7 , 8 ].

Although the etiology of psoriasis is not fully understood, genetic and environmental factors appear to contribute to atypical activation of the immune system, resulting in disease [ 14 , 15 ]. The cytokines IL-17A and IL-17F in particular have been identified as key upregulated proinflammatory cytokines in psoriatic lesions; they are thought to recruit immune cells to psoriatic skin, stimulating the hyperproliferation of keratinocytes [ 16 , 17 ].

Role in Host Defense Against Candida

One of the major roles of the IL-23/IL-17 pathways is host defense against fungal infections [ 18 ]. The most common species involved, Candida albicans , is usually commensal; however, upon conversion to a hyphal state it can cause mucocutaneous candidiasis [ 19 ].

The key role of IL-17 signaling in host defense against Candida is supported by observations from patients with primary immunodeficiencies leading to defects in the Th17 pathway, who present with a form of chronic mucocutaneous candidiasis (CMC) termed CMC disease (CMCD) [ 20 ]. These patients are prone to recurrent oral and esophageal candidiasis, suggesting a pivotal role of IL-17 in defense against candidiasis in the mucosa of the upper digestive tract [ 20 ]. However, these patients are not prone to systemic or vulvovaginal candidiasis, leading to an emerging consensus that the IL-23/IL-17 pathways are not essential to immune defense against these infections [ 19 , 21 – 23 ]. These patients also rarely display any other severe diseases [ 24 ].

According to the current model of host defense against oral candidiasis, conversion of C. albicans to a hyphal state results in the activation of immune cells in response to damage [ 25 ]. These cells then produce proinflammatory cytokines such as IL-23, inducing the proliferation of Th17 cells and the release of IL-17A and IL-17F as well as IL-22. Neutrophils are then recruited to the infection site by these cytokines, inducing the secretion of antifungal proteins (Fig.  1 ) [ 19 , 26 ]. Therefore, through the inhibition of IL-17 or its receptors, anti-IL-17 medications prescribed for psoriasis can increase the risk of oral candidiasis through inhibition of these Th17 cell-mediated antifungal pathways.

Simplified model of host defense against oral candidiasis. Colonization of the oral mucosal epithelium by Candida results in the activation of macrophages and DCs, either directly or indirectly, via alarmins such as IL-1α, IL-1β, and IL-36, which are released in response to tissue damage by the peptide candidalysin. This then triggers the expression and secretion of IL-6, IL-1β, and IL-23, which induce the differentiation and proliferation of Th17 cells from naïve CD4 + T cells. These Th17 cells produce the cytokines IL-17A, IL-17F, and IL-22, which recruit neutrophils to the site of infection and act on epithelial cells to induce the release of antifungal β-defensins. Through the inhibition of IL-17 or its receptors, anti-IL-17 medications prescribed for psoriasis can increase the risk of oral candidiasis through inhibition of Th17 cell-mediated antifungal pathways. DC dendritic cells, IL interleukin, R receptor, Th17 T-helper cell type 17

Epidemiology of Candida Colonization and Infection in Psoriasis

There is some evidence of increased Candida colonization of the oral cavity in patients with psoriasis versus those without psoriasis. In a systematic literature review and meta-analysis of nine studies, statistically higher rates of Candida colonization of mucosal membranes were observed in patients with psoriasis [ 27 ]. For example, rates were reported as 69% versus 44% for those without psoriasis in a study conducted in Jordan [ 28 ], and 47.2% versus 19.5% in a study conducted in Germany [ 29 ]. This trend was consistent with another study where patients with psoriasis receiving systemic treatment were excluded (20.0% versus 2.8%) [ 30 ]. The reason for this association is unclear. Notably, there was considerable heterogeneity in these studies, and most measured the presence of Candida colonization rather than true candidiasis [ 27 ].

Risk of Candidiasis in Patients Receiving Biologic Treatments for Psoriasis

In recent years, several monoclonal antibodies targeting IL-17 (e.g., brodalumab, ixekizumab, and secukinumab), IL-23 (e.g., guselkumab, risankizumab, and tildrakizumab), and IL-12/23 (e.g., ustekinumab) have been approved for treatment of psoriatic disease [ 4 ].

A systematic review of previous trials of anti-IL-17 medications in psoriatic disease found that overall incidence of candidiasis was increased in patients treated with anti-IL-17 medications versus placebo (1.7–4.0% versus 0.3%, respectively) [ 31 ]. The majority of Candida infections were oral and not vulvovaginal. Moreover, most oral candidiasis cases were mild to moderate in severity [ 31 ]. There was also no increase in the risk of esophageal or systemic candidiasis, further supported by a systematic review of all IL-17 and IL-23 inhibitors [ 31 , 32 ].

Bimekizumab, an anti-IL-17 medication recently authorized in Europe for the treatment of moderate to severe plaque psoriasis [ 33 ], inhibits IL-17F in addition to IL-17A [ 34 ]. Dual inhibition of IL-17A and IL-17F has demonstrated superior levels of skin clearance compared with targeting IL-17A alone with secukinumab in a head-to-head in patients with plaque psoriasis [ 35 ]. As expected, as a result of the roles of both cytokines in antifungal host defense, dual neutralization was also associated with an increased incidence of mild to moderate oral candidiasis as compared with previously approved anti-IL-17 medications [ 36 – 38 ].

Despite both bimekizumab and brodalumab inhibiting the activity of IL-17A and IL-17F, differences have been observed in the rates of oral candidiasis. This could be a consequence of the mechanistic differences between these two biologics. One hypothesis is that, as brodalumab inhibits IL-17R, it blocks the function of all additional IL-17 cytokines, including IL-17E which may indirectly suppress Th17 responses [ 13 ]. Furthermore, if IL-17R is not fully blocked at the end of a dosing cycle, it is possible that residual IL-17 may confer host protection against Candida . However, further research into this topic is needed.

Anti-IL-23 biologics do not seem to increase the risk of Candida infections as much as anti-IL-17 biologics [ 39 ]. This may be because anti-IL-23s do not block IL-23-independent sources of IL-17, such as IL-17 produced by innate lymphoid cells [ 3 , 39 ]. However, IL-23-independent sources of IL-17 are increasingly thought to play a significant role in the pathogenesis of immune-mediated inflammatory diseases, which may explain the higher efficacy of some anti-IL-17 medications compared with IL-23 blockers axial spondyloarthritis and joint outcomes in psoriatic arthritis [ 40 , 41 ].

Diagnosis and Treatment of Oral Candidiasis

Given the increased risk of oral candidiasis in patients with psoriasis treated with anti-IL-17 medications, it is important that dermatology practitioners can effectively diagnose and treat these infections. On the basis of a review of the literature and clinical experience, we propose the diagnosis and treatment algorithm for oral candidiasis shown in Fig.  2 .

Algorithm for the diagnosis and management of oral candidiasis in patients with plaque psoriasis. a In the case that administration of anti-IL-17 treatment falls on the same day in which the antifungal treatment for oral candidiasis is initiated, administration of anti-IL-17 can be postponed for 3–4 days to prioritize resolution of oral candidiasis

Clinical Presentations of Oral Candidiasis

Pseudomembranous candidiasis.

Pseudomembranous candidiasis (or “thrush”) is sometimes referred to as the classic presentation of candidiasis [ 42 ], and in our clinical experience is most commonly identified in patients with psoriasis receiving anti-IL-17 treatment. It is characterized by the presence of white, curd-like plaques that can be dislodged with gentle scraping, revealing underlying erosions of the oral mucosa (Fig.  3 A) [ 43 – 46 ]. Patients are often asymptomatic; however, pain, a burning sensation, and in some cases a metallic taste may be present [ 46 ].

Clinical presentations of oral candidiasis. A Pseudomembranous candidiasis in a male patient receiving anti-IL-17A treatment for plaque psoriasis; this patient was also a smoker. Patient image was provided courtesy of Dr Gisondi. B Acute erythematous candidiasis of the tongue. Patient image was borrowed from the Mount Sinai collection

Erythematous Candidiasis

Erythematous candidiasis is the most common form of oral candidiasis [ 46 ]. There are four subtypes: acute erythematous candidiasis, chronic erythematous candidiasis, angular cheilitis, and median rhomboid glossitis.

Acute erythematous candidiasis presents as painful reddened lesions which occur throughout the oral cavity (Fig.  3 B) [ 43 – 46 ]. In chronic erythematous candidiasis (or “denture stomatitis”), these lesions are localized to the fitting surface of dentures [ 43 – 46 ]. Angular cheilitis, most commonly seen in elderly patients with over-closure of the jaw, is characterized by reddened lesions at the corner of the mouth [ 43 – 46 ]. Finally, the least common subtype, median rhomboid glossitis, presents as a rhomboid-shaped area of atrophy and erythema on the midline posterior tongue dorsum [ 43 , 45 ].

Chronic Hyperplastic Candidiasis

Chronic hyperplastic candidiasis is a rare form of oral candidiasis that presents as a thickened white plaque, most frequently at the commissural region of the mouth or the dorsum of the tongue. However, unlike in pseudomembranous candidiasis, this plaque cannot be removed by gentle scraping [ 42 – 47 ]. Plaques may be smooth and isolated (homogeneous) or nodular and speckled (heterogeneous) [ 45 – 47 ].

Risk Factors for Oral Candidiasis

The presence of predisposing factors, other than treatment with anti-IL-17 medications, can also inform diagnosis of oral candidiasis. These factors are divided into two categories: local factors that affect the local oral environment and microflora and systemic factors that affect the host’s immune status (for a full list see Table  1 ) [ 43 ].

Table 1

Predisposing risk factors for oral candidiasis

HIV human immunodeficiency virus

Local Predisposing Risk Factors

One of the most common local risk factors is the use of dentures, which can create a favorable environment for Candida growth, especially if denture hygiene is poor [ 43 , 48 , 49 ]. It is estimated that up to 75% of adults who wear dentures have some form of erythematous candidiasis, although most are unaware of it [ 48 ].

Another common local predisposing factor is the use of steroid inhalers, which may cause alterations in the oral microflora and is commonly associated with pseudomembranous candidiasis [ 42 , 43 , 49 , 50 ]. Incidence of oral candidiasis in users of steroid inhalers generally ranges from 1% to 7% in the literature [ 51 ].

Patients who use or smoke tobacco have significantly increased oral Candida carriage levels and rates of oral candidiasis [ 49 , 52 ]. Hyperplastic candidiasis is almost exclusively found in patients who smoke [ 47 ]; however, the exact underlying mechanism remains unclear [ 52 ].

Systemic Predisposing Risk Factors

The best-characterized systemic predisposing factors for oral candidiasis are human immunodeficiency virus (HIV) and chemotherapy and radiotherapy for cancer [ 49 , 53 , 54 ]. Antibiotic use is also associated with oral candidiasis, particularly acute erythematous candidiasis (commonly referred to as “antibiotic sore mouth”) [ 43 – 46 , 49 ].

Other major systemic predisposing factors for oral candidiasis are extremes of age; both elderly patients and infants have increased risk of oral candidiasis due to lower levels of protective salivary defenses [ 43 ]. Elderly patients may also have a loss of vertical dimension of occlusion, increasing the risk of developing angular cheilitis [ 43 ].

Diabetes and poor glycemic control have also been associated with oral candidiasis; patients with poorly controlled diabetes often exhibit reduced salivary pH and increased salivary glucose levels, facilitating Candida proliferation [ 49 , 55 ].

Confirmation of Diagnosis

Oral candidiasis is typically diagnosed according to the presence of clinical signs and symptoms in patients with predisposing factors [ 45 , 56 ]. If there are diagnostic doubts, diagnosis can be confirmed via microbiologic examination [ 45 , 49 ]. Fresh samples from the oral tissues can be taken and examined microscopically using 10% potassium hydroxide (KOH) [ 45 ]. This method is useful for distinguishing erythematous manifestations of oral candidiasis from conditions with similar presentations, such as thermal traumatic lesions, lupus erythematosus, erythema multiforme, or epithelial dysplasia [ 57 ]. Alternatively, it is possible to culture samples using Sabouraud dextrose agar (SDA), from which the Candida species can be identified [ 45 , 47 ]. This can be useful if infection shows resistance to antifungal agents, as some rarer Candida species (e.g., Candida glabrata ) may show enhanced resistance to treatment [ 47 ].

In rare cases (0.32% of otherwise healthy individuals in a retrospective single-center study of 88,125 individuals in South Korea) [ 58 ], oral Candida infections may extend to the esophagus. Esophageal candidiasis appears endoscopically as thick white plaques on the esophageal mucosa. Symptoms include difficulty or pain upon swallowing or pain behind the sternum [ 49 , 59 ]. Patients presenting with these symptoms should be referred for esophagoscopy to exclude esophageal candidiasis [ 49 , 60 ].

If a patient presents with clinical signs of hyperplastic candidiasis, a biopsy should be conducted because of the proposed link between this presentation and malignancy [ 56 ].

Treatment of Oral Candidiasis

Patients with psoriasis are encouraged to practice good oral and denture hygiene to prevent the occurrence of oral candidiasis. However, if oral candidiasis occurs, a number of treatments are available, with some applied topically and others administered orally [ 56 ]. Generally, as per guidelines from the Infectious Diseases Society of America and Centers for Disease Control and Prevention in the USA, and the UK National Institute for Health and Care Excellence, initial topical antifungal treatment for 7–14 days is recommended [ 49 , 56 , 61 , 62 ]. This can include miconazole oral gel (50 mg mucoadhesive tablet applied daily [USA], or 2.5 mL, four times daily [UK]), clotrimazole troches (10 mg, five times daily [USA]) or “swish and swallow” treatments such as nystatin suspension (100,000 U/mL, 4–6 mL [USA] or 1 mL [UK] four times daily) [ 61 , 62 ]. If candidiasis does not resolve, oral fluconazole (100–200 mg once daily for 7–14 days [USA], or 50–100 mg once daily for 7 days [UK]) is recommended [ 49 , 61 , 62 ]. Itraconazole (200 mg once daily [USA] or 100–200 mg twice daily [UK]) can be prescribed as an alternative to fluconazole [ 61 , 62 ]. As the labels of anti-IL-17 medications recommend pausing administration until an infection is resolved, if administration of anti-IL-17 treatment falls on the same day as initiation of antifungal treatment, administration of anti-IL-17 can be postponed for a few days to prioritize resolution of oral candidiasis.

Depending on local guidelines, fluconazole may be prescribed as a first-line treatment for oral candidiasis, as it is highly effective in treating fungal infections and has a simpler dosing schedule compared with topical antifungal treatments [ 56 ]. In our experience, shorter durations of fluconazole treatment (e.g., 100–200 mg daily for 3–5 days) can be an effective first-line treatment for oral candidiasis. However, any potential drug–drug interactions should be carefully considered, especially if a patient with psoriasis presents with other comorbidities. If oral candidiasis shows resistance to fluconazole, fungal characterization via SDA culture can be carried out, as previously described [ 45 , 47 ]. In the case that a fluconazole-resistant Candida species is identified, alternative antifungal treatment should be prescribed.

While the majority of patients respond to these antifungal treatments with quick resolution [ 56 ], in certain cases oral candidiasis may be recurrent. If recurrent, measures should be taken to confirm adherence to antifungal treatment and correct any predisposing factors if applicable. This includes education in proper oral and denture hygiene, smoking cessation, rinsing the mouth after use of steroid inhalers, and proper management of diabetes [ 62 ]. Poor oral and denture hygiene, in particular, are key risk factors of oral candidiasis and so should be amended in order to prevent reinfection if relevant.

If recurrence continues within a 3-month period following initial treatment, and there is insufficient treatment response with alternative modes of psoriasis treatment, initiation of prophylaxis can be considered. In our clinical experience, this could include administration of any of the aforementioned treatment measures repeated once weekly or monthly for short or longer periods, guided by need and response.

The effectiveness of prophylaxis for the prevention of recurrent oral candidiasis has most frequently been demonstrated in patients with HIV [ 63 ]. In these patients, fluconazole prophylaxis has been shown to reduce recurrence as compared with no treatment or placebo [ 64 – 68 ]. However, there is concern that continuous treatment may lead to fluconazole resistance. Indeed, one study found decreased susceptibility of Candida isolates to fluconazole in 56% of patients who received continuous therapy. Nevertheless, the vast majority of patients in this study still showed clearance of oral candidiasis in response to fluconazole [ 69 ]. Furthermore, in another study, similar proportions of patients with HIV receiving continuous (4.1%) or episodic (4.3%) fluconazole developed fluconazole-refractory oral candidiasis [ 70 ]. For fluconazole-refractory infections, treatment with non-azole antifungals can be considered [ 61 ].

Conclusions

Given the increased risk of oral candidiasis in patients with psoriasis receiving anti-IL-17s, dermatologists should be attentive to clinical signs of oral candidiasis and aware of how to manage cases appropriately.

Oral candidiasis in patients with psoriasis is typically mild to moderate in severity. In our clinical experience, cases can be managed with standard antifungal treatment without discontinuing biologic psoriasis therapies. Furthermore, anti-IL-17 treatment is generally not associated with an increased risk of systemic candidiasis or serious infections.

To prevent recurrence of oral candidiasis, patients should be advised to practice good oral hygiene and be provided with information on smoking cessation, if applicable. Prophylaxis with antifungal agents can be considered if there is insufficient treatment response with alternative modes of psoriasis treatment.

Acknowledgements

UCB funded the review and development of the manuscript and reviewed the text to ensure that from the perspective of UCB, the data presented in the publication are scientifically, technically, and medically supportable, that they do not contain any information that has the potential to damage the intellectual property of UCB, and that the publication complies with applicable laws, regulations, guidelines and good industry practice. The authors approved the final version to be published after critically revising the manuscript/publication for important intellectual content. The journal’s Rapid Service Fee was also funded by UCB.

Medical Writing, Editorial and Other Assistance

The authors acknowledge Susanne Wiegratz, MSc, UCB Pharma, Monheim, Germany for publication coordination as well as Kaity McCafferty Layte, BSc, Daniel Smith, BA, and Amelia Frizell-Armitage, PhD, Costello Medical, UK, for writing and editorial assistance funded by UCB Pharma in accordance with Good Publication Practice guidelines. Richard B. Warren, MD, PhD, is supported by the Manchester NIHR Biomedical Research Centre.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Substantial contributions to the review conception and design: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW; substantial contributions to the analysis and interpretation of review findings: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW; drafting the article or revising it critically for important intellectual content: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW; final approval of the version of the article to be published: AWA, AB, UM, BS, PG, JFM, RGL, MS, ML, MGN, NNG, RBW.

Disclosures

April W. Armstrong has served as a data safety monitoring board member for Boehringer Ingelheim/Parexel; received research funding from Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, LEO Pharma, Pfizer, and UCB Pharma; has been a research investigator without compensation for Sanofi Genzyme; has been scientific investigator for AbbVie, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, LEO Pharma, Modernizing Medicine, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, and Sun Pharma; has served as speaker for AbbVie, Regeneron, and Sanofi Genzyme. Andrew Blauvelt has served as a scientific adviser and/or clinical study investigator for AbbVie, Abcentra, Aligos, Almirall, Amgen, Arcutis, Arena, Aslan, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Evommune, Forte, Galderma, Incyte, Janssen, Landos, LEO Pharma, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma, and Vibliome. Ulrich Mrowietz has served as advisor and/or clinical study investigator for, and/or received honoraria and/or grants from AbbVie, Almirall, Aristea, Boehringer Ingelheim, Celgene, Dr. Reddy’s Laboratories, Eli Lilly, Foamix, Formycon, Forward Pharma, Janssen, LEO Pharma, Medac, Novartis, Phi-Stone, Pierre Fabre, Sanofi Genzyme, and UCB Pharma. Bruce Strober has served as a consultant (honoraria) from AbbVie, Almirall, Amgen, Arcutis, Arena, Aristea, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Equillium, GSK, Janssen, LEO Pharma, Meiji Seika Pharma, Mindera, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB Pharma; has served as speaker for AbbVie, Amgen, Eli Lilly, Janssen, and Ortho Dermatologics; Scientific Director (consulting fee) for CorEvitas Psoriasis Registry; investigator for AbbVie, Cara Therapeutics, CorEvitas Psoriasis Registry, Dermavant, Dermira, and Novartis; Editor-in-Chief (honorarium) for Journal of Psoriasis and Psoriatic Arthritis . Paolo Gisondi has served as a consultant for AbbVie, Abiogen, Almirall, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Sanofi Genzyme, and UCB Pharma. Joseph F. Merola has been a consultant for AbbVie, Amgen, Bayer, Biogen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi-Regeneron, UCB Pharma; principal investigator for Dermavant, LEO Pharma, and UCB Pharma. Richard G. Langley has been a principal investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer, UCB Pharma; served on scientific advisory boards for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer, and UCB Pharma; provided lectures for AbbVie, Amgen, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, and Pfizer. Mona Ståhle has received honoraria for participating in advisory boards and has given lectures for AbbVie, Celgene, Eli Lilly, LEO Pharma, Lipidor, Novartis, Pfizer, and UCB Pharma. Mark Lebwohl is an employee of Mount Sinai and receives research funds from AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen, Ortho Dermatologics, Regeneron, and UCB Pharma and is a consultant for Aditum Bio, Almirall, AltruBio, AnaptysBio, Arcutis, Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy’s Laboratories, Evelo Biosciences, Evommune, Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. Mihai G. Netea is a scientific founder and shareholder for Trained Therapeutix Discovery and Lemba; has served as a consultant (honoraria) for Inflazome, Roche, and UCB Pharma. Natalie Nunez Gomez is an employee and shareholder of UCB Pharma. Richard B. Warren has received consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, UCB Pharma; has received research grants to his institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis, UCB Pharma; honoraria from Astellas, DiCE, GSK, and Union.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.