Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2024;14(2):e2024107 1 Oral Diseases During Systemic Psoriatic Drugs: A Review of the Literature and Case Series Annunziata Raimondo1, Federica Di Spirito1, Serena Lembo1 1 Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Italy Key words: psoriasis, anti-psoriatic drugs, oral health, oral adverse drug reactions Citation: Raimondo A, Di Spirito F, Lembo S. Oral Diseases During Systemic Psoriatic Drugs: A Review of the Literature and Case Series. Dermatol Pract Concept. 2024;14(2):e2024107. DOI: https://doi.org/10.5826/dpc.1402a107 Accepted: November 29, 2023; Published: April 2024 Copyright: ©2024 Raimondo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Annunziata Raimondo, M.D., Research Fellow, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy. E-mail: araimondo@unisa.it Introduction: The oral health of psoriatic patients seems to be compromised compared to that of control individuals: many published studies have investigated the relationship between psoriatic disease and gingivitis, periodontitis, and missing teeth. However, data from these studies are not consistent nor exhaustive. Moreover, no study has considered the possible specific effects of conventional and biological systemic psoriatic treatments. Objective: We report a narrative review of the literature about the possible link between anti- psoriatic drugs and oral disease onset and present case series of patients that have experienced oral disease during systemic therapy for psoriasis. Methods: This is a narrative review. The literature search was performed using the MEDLINE data- base. From the selected articles, additional references were identified by a manual search among the cited literature. Results: Oral adverse events during psoriatic therapies can be found in sporadic cases. The specific mechanisms of interplay between oral anatomic structures and the pathway targeted by the systemic agents will be investigated in depth. Conclusion: All psoriatic patients who are candidates for conventional or biological systemic therapy should have regular oral health check-ups with a dentist and a dermatologist to prevent oral compli- cations. Dermatologists and oral medicine specialists should be ready to recognize and manage this increasing number of oral adverse drug reactions during systemic treatments for psoriatic disease so as to provide patients with sufficient information about this risk and to stress the fundamental importance of regular dental assessments and good oral hygiene. ABSTRACT 2 Review | Dermatol Pract Concept. 2024;14(2):e2024107 Introduction Psoriatic disease is a complex and multifactorial disorder with systemic involvement and auto-inflammatory patho- genesis [1]. Oral psoriatic lesions do not follow a predict- able pattern: angular cheilitis and fissured white-coated geographic tongue lesions are examples of oral clinical manifestations associated with psoriasis [2, 3]. Patients with psoriasis also have an increased risk of developing other illnesses, such as inflammatory bowel disease, cardio- vascular disease, metabolic syndrome, and diabetes as well as articular and bone inflammation [2-6]. Moreover, many published studies have reported that oral health in psori- atic patients seems to be compromised compared to that of control individuals. Based on a recent meta-analysis, peri- odontal disease is more frequent in psoriasis patients, with a reported statistically significant increase in odds ratio, with differing severity [7]. Psoriasis represents a risk factor for periodontitis in these patients. Although there are similari- ties in the risk factors and comorbidities between psoriasis and periodontal disease, their relationship's pathophysiol- ogy is still speculative [2, 8]. Current systemic therapeu- tic strategies, including disease-modifying anti-rheumatic drugs (DMARDs) and biological agents, permit the almost or complete clearance of psoriatic skin manifestations, with an improvement in quality of life. Biological agents are categorized by their target in anti-TNF-α, anti-IL17, and anti-IL23. Moreover, oral therapy for psoriatic disease is available: an inhibitor of the enzyme phosphodiesterase E4 (PDE4). The possible specific effects on the oral health of DMADRs, biologics, and small-molecule systemic psori- atic treatments are underestimated and reported as sporadic cases in the literature. Objective and Methods The purpose of this narrative review was to collect the liter- ature on this topic, focusing on studies that describe oral ad- verse drug reactions (ADRs) in the context of systemic drug therapy for psoriasis. The literature search was performed on MEDLINE via PubMed and Google Scholar databases using these search terms: “oral diseases,” “psoriasis,” “pso- riatic systemic drugs,” “biologic therapy,” and “oral adverse event,” with diverse matches among them. The inclusion criteria were all types of articles indexed on PubMed and related to psoriatic patients. The exclusion criteria were full text not available and not in English. From the selected arti- cles, additional references were identified by a manual search among the cited literature. Moreover, we report a case series of psoriatic patients that have experienced oral disease during anti-psoriatic sys- temic therapies. DMADRs, Psoriasis, and Oral Disease Conventional systemic therapies are used to treat moderate-severe psoriatic patients who are not responsive to topical medications and/or to phototherapy. These therapies include acitretin, cyclosporine, and methotrexate. Acitretin This is an oral retinoid, which is a synthetic form of vita- min A, and it is approved to treat psoriasis. Possible side effects are hair loss, dry skin and eyes, increased sensitivity to sunlight, peeling fingertips and nail changes, depression, headache, and decreased night vision. Regarding potential oral ADR, chapped lips and dry mouth are common, as are bleeding gums [9]. There are few data in the literature about other oral ADRs in psoriatic patients during acitretin ther- apy. However, we report two cases of destructive periodonti- tis resulting in tooth loss. Case 1 A 52-year-old female with severe recalcitrant palmoplantar psoriasis was started on 25 mg of acitretin daily. She is a smoker and had a personal history of periodontal disease in follow-up. After two months, clinical psoriatic manifes- tations significantly improved, but the patient experienced a rapid worsening of her periodontal status with the loss of three teeth of the lower arch. Case 2 A 53-year-old female with moderate psoriasis localized at the palmoplantar, elbow, and pretibial areas was started on 25 mg of acitretin daily. No signs of psoriatic arthritis or pain were present. The patient is a heavy smoker (about 15 cigarettes per day). After one month, as she achieved a good clinical response, the dosage was reduced to 20 mg/ day. However, after three months, the therapy was discon- tinued due to the onset of significant side effects, including telogen effluvium, dyspepsia with weight loss (about 14 kg in 6 months), acute sacroiliitis, and a rapid worsening of pre- existing chronic periodontitis that led to the loss of five upper jaw teeth. After discontinuing acitretin, the patient started a biological drug. Cyclosporin Cyclosporin (CsA) is an immunosuppressive drug approved for the treatment of moderate-to-severe psoriasis. The most common side effects are decreased kidney function, head- ache, high blood pressure, the elevation of cholesterol serum level, hypertrichosis, and tingling or burning of the arms or legs. The most common oral ADR is gingival hyperplasia, re- ported in about 15% of psoriatic patients and in up to 80% of transplant patients [10]. This well-recognized ADR is not related to the dose or to the duration of treatment. Predictive Review | Dermatol Pract Concept. 2024;14(2):e2024107 3 factors are the level of dental plaque and gingival inflam- mation. For this reason, correct oral hygiene and meticulous plaque control are indispensable to prevent this ADR. Der- matologists should be more sensitive to this aspect, and they should recommend the patient to consult a dentist before starting CsA therapy to correct some risk factors, such as ap- propriate oral hygiene, smoking cessation, adequate diet, and possible concurrent medication interaction. The combination of CsA and nifedipine exponentially increase the severity of gingival hyperplasia. Interestingly, it has been shown that fe- males have a higher risk of developing ADRs during CsA therapy [17]. Female physiology, such as hormonal status and menopause, seems to have an important role that should be considered; hormonal changes are reflected in differing oral health related to estrogen and progesterone levels. It has been supposed that menstrual cycles, pregnancy, and meno- pause influence drug pharmacokinetics and pharmacody- namics, with an effect on its tolerability [11]. Methotrexate Methotrexate (MTX) it is an antagonist of folic acid with immunomodulator action. At high doses, it is used as a che- motherapeutic drug, while at a low dose (no more than 25 mg/week), it has anti-inflammatory effects, and it represents a valid therapeutic option for many inflammatory disorders. The addition of folic acid is the most important antidote to managing acute MTX toxicity, improving gastrointestinal tolerance, and preventing severe hematological disorders [12]. Regarding oral ADR, mucositis or oral ulcers are the most frequent events, which appear in 11-17% of MTX- treated patients [14,15]. The severity of these oral side effects of MTX can range widely, and it is seldom easy to treat them. What the most efficient care for patients with oral ulcers who take MTX at low doses is has been addressed by a system- atic review of oral ulcers caused by low doses of MTX. The systematic review consists of sixteen research papers with a total of 24 individuals who experienced mouth ulcers while receiving low-dose MTX therapy. The mean patient age was 65.45 years, the mean MTX treatment duration was 52.91 months (SD: 80.75), and the average MTX dose was 10.93 mg/week (SD: 5.45). Except for one patient, all patients took MTX orally. The lingual dorsum, hard palate, gingiva, ret- romolar region, keratinized gingiva, and lip were the sites of the lesion. The lesions typically appeared after 35.63 days on average (SD: 52.57). The average recovery duration was 19.9 days (SD=10.63). Only three out of the 24 patients identified themselves as non-smokers. Moreover, only 50% of the patients mentioned using any concurrent medications. The most common management was MTX withdrawal and supplementation of folic acid, followed by only interrup- tion of MTX. Some authors associated the abandonment of MTX with folic acid and systemic corticosteroid therapy. Frequently, patients who experienced this ADR did not re- assume MTX. All these studies have many risks of bias, a lack of important information on patient history, and a short follow-up (the average follow-up period for these patients was 19.2 months, with an SD of 17.81). Moreover, differ- ential diagnosis with other entities, including lichenoid re- actions, is very difficult due to incomplete medical history. Indeed, overdosage and interactions with other medicines, particularly nonsteroidal anti-inflammatory medications, are the most frequent causes of MTX toxicity. Oral ulcers due to MTX therapy is an ADR that the specialists do not underestimate because these ulcers can be associated with a lymphoproliferative disorder, and they can cause malnutri- tion and the death of the fragile patient. Case 1 We have previously described a 60-year-old female with palmoplantar psoriasis who was unresponsive to topical therapy and was switched to MTX 10 mg/week adminis- tered subcutaneously, along with 10 mg of folate the next day. The patient's palmar-plantar psoriasis manifestations significantly improved three months later, but the challenge was managing the medication and concurrent SARS-CoV-2 vaccination. After that, we advised stopping MTX one week before and one week after receiving the COVID-19 vaccine. The patient experienced diffuse erythema over the entire body surface three days after the immunization, swelling on the right periocular area and in the mouth, and ulcer on the soles of the her feet (Figure 1). Corticosteroids (40 mg/day) and antihistamines (10 mg/day) were then administered to the patient, with full recovery in one month [22]. Case 2 A 61-year-old female with plaque psoriasis, psoriatic arthri- tis, and mild comorbidities (hypertension and dyslipidemia) started methotrexate treatment at a dose of 15 mg/week plus 10 mg of folate the day after. However, after one month, the therapy was discontinued because of the emergence of nu- merous adverse outcomes like myalgia, pulpitis, and gingival bleeding. The patient experienced severe ulcerative gingival stomatitis with ulcers and erosions that affected the buccal mucosa, the gingiva, and the tongue. Clinical oral manifes- tations resolved after suspension of MTX and appropriate topical therapy with antiseptic and corticosteroid agents. Biological Agents, Small Molecules, Psoriasis, and Oral Disease Biological therapies are agents that have specific targets, in- cluding cytokines, receptors, and signaling molecules. They have revolutionized the therapeutic approach to psoriasis, obtaining clearance or near clearance of clinical manifes- tations. To date, the literature lacks documents that report 4 Review | Dermatol Pract Concept. 2024;14(2):e2024107 of moderate-severe psoriasis. Regarding the IL-17 inhibitors (secukinumab, ixekizumab, brodalumab, and bimekizumab) and oral ADRs, the most frequently reported event is Can- dida infection. This side effect is due to the important role that IL-17A plays in innate and adaptative responses against Candida infections. However, in most cases, the appropriate local and occasionally systemic antifungal therapy resolves the infection without biological drug withdrawal. Accord- ing to a recent comprehensive study, individuals receiving brodalumab, secukinumab, or ixekizumab had a risk of developing a Candida infection of 4%, 1.7%, or 3.3%, re- spectively. The frequent localizations are oral and genital, with forms of mild to moderate severity [20]. Candida is a commensal, and many factors can promote its transition to a pathological condition. Recognizing predisposing fac- tors (medical conditions, a prior history of recurrent oral candidiasis, etc.) and acting on them can reduce risk. There are reported cases of a severe form of candidiasis, such as the mucocutaneous form, and atypical clinical manifesta- tions for which the differential diagnosis with leukoplakia, oral lichen planus, or non-specific lichenoid reaction is not easy and requires other diagnostic procedures, including bi- opsy [20, 21]. Considering the high prevalence of psoriatic diseases in the general population and the large group of patients who undergo biological therapy with these agents, a well-structured randomized control study is necessary to evaluate in depth the adverse effects of long-term IL-17 in- hibitor therapy on oral health. To date, no oral ADRs are reported in patients during anti-IL-23 biological therapies (guselkumab, tildrakizumab, risankizumab) as well as small molecule agents (apremilast). oral ADRs in the course of biological therapy for psoriasis. Many papers have described the possible link between pso- riasis and periodontal disease (PD) but not the possible ef- fects on the latest biological drugs. Recently, this aspect has been investigated in patients with rheumatoid arthritis (RA) suffering from concomitant PD in therapy with anti-TNF-α biologic agents (infliximab, adalimumab, etanercept, cer- tolizumab pegol, golimumab) [16, 17]. These studies in accordance with the evidence that anti-TNFα inhibitors worsen periodontal parameters and gingival inflammation and slightly increase concentrations of antibodies against P. gingivalis. However, they decrease the gingival destruction of bone. A recent study reported that biological therapy, such as anti-TNF-α and anti-IL6 receptor therapy, may not lessen the severity of PD in RA patients and does not affect the activity of the disease. Interestingly, this study described a significant negative correlation between PD severity and the therapeutic response of RA patients: PD severity correlated with reduced effectiveness of the biological treatment. Con- sequently, PD therapy strategies may be helpful in enhancing RA patients' therapeutic responses [26]. Another longitudi- nal observation study had as its objective to assess the ef- fect of MTX and etanercept treatment on the periodontal condition of RA patients. The results showed that MTX or anti-TNFα treatment did not improve the periodontal con- dition, demonstrating a negligible influence [17-19]. Future large studies are needed to explore in depth the impact of anti-TNF therapies on PD, especially in the psoriatic pop- ulation. Another important class of biological drugs is the anti-interleukins (IL), including anti-IL-17 and IL-23. They have a good safety and effectiveness profile for the treatment Figure 1. Cutaneous eruption in a psoriatic patient after SARS‐CoV‐2 vaccine during MTX therapy. Review | Dermatol Pract Concept. 2024;14(2):e2024107 5 is correlated to the increase in novel and unexpected ADRs, which need to be managed rapidly and appropriately. Pso- riatic patients frequently have many comorbidities, such as psoriatic arthritis (PsA), which negatively affect oral health. In particular, the involvement of temporomandibular joint (TMJ) causes malocclusion, restricted jaw movement range, preauricular edema, and impaired eating function. The im- pact of this condition on the individual's daily life can be very negative and requires specific therapeutic actions [23]. Recently, the prevalence of atypical oral lesions in the course of conventional as well as biological therapies is enhanced, even if the specific mechanisms of interplay between oral an- atomic structures and the pathway targeted by the systemic agents will be investigated in depth. Dermatologists and oral medicine specialists should be ready to recognize and man- age this increasing number of oral ADRs during systemic treatments for psoriatic disease, providing patients with suf- ficient information about this risk and stressing the funda- mental importance of regular dental assessments and good oral hygiene so as to avoid side effects (Table 1). Psoriatic Case We have previously described the case of a 49-year-old fe- male with severe psoriasis who began biological therapy with ixekizumab in 2018. A PASI 100 score was reported after 12 weeks, and this brilliant result remained constant for approximately one year, after which the patient de- scribed episodes of perionyxes, conjunctivitis, and vulvo- vaginitis with burning symptoms, itching, and foul-smelling discharges. The physical examination revealed a geographic tongue with a red atrophic plaque and whitish-yellow areas that could not be removed by scraping, numerous areas of de-epithelization at the level of the hard palate and the lower gingival arch, and angular cheilitis with erythema and fis- sures (Figure 2) [22]. Conclusions and Perspectives ADRs are potentially harmful side effects associated with the use of drugs. The growth of new target therapies for the management of autoimmune and autoinflammatory diseases Figure 2. During treatment with an anti-IL-17A biological agent, a patient with psoriasis devel- oped Candida infection. A geographic tongue with red atrophic plaque, whitish- yellow patches, and numerous de-epithelization areas at the hard palate level can be observed in the image. Table 1. Key considerations for conducting surveillance on oral health in patients with psoriasis. Regular Dental Check-ups and Oral Health Assessment: encourage patients with psoriasis to schedule routine dental examinations with a dentist who is skilled in any potential oral health complications linked to the skin condition. The best frequency for these examinations should be twice annually. Patient Education: psoriatic patients should be informed by dermatologists and dentists about the value of maintaining proper oral hygiene. This includes using mouthwash, flossing, and brushing the teeth as prescribed. The possible effects of psoriasis and its therapies on dental health should also be discussed with patients. Oral Hydration: encourage patients to maintain adequate oral hydration to help avoid dry mouth, a problem that affects many people with psoriasis. It can be helpful to drink water throughout the day and, if necessary, to use substitutes for saliva. Stress Management: since stress can exacerbate both psoriasis symptoms and oral health problems, it is possible to advise psoriatic patients on stress management techniques. Stress-reduction strategies and exercises for relaxation can be helpful. Patient Communication: ensure that the patient, dermatologist, and dentist are in constant communication. For the proper course of action to be taken, patients should be encouraged to report any oral symptoms or discomfort as soon as possible. 6 Review | Dermatol Pract Concept. 2024;14(2):e2024107 11. Lauritano D, Palmieri A, Lucchese A, Di Stasio D, Moreo G, Carinci F. Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts. Int J Mol Sci. 2020;21(2):595. 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Impact of temporomandibular disorders on oral health-related