Mycophenolate Mofetil in the Management of Oral Mucocutaneous Diseases: Current Evidence and Future Perspectives

Abstract

Background/Objectives: Mycophenolate mofetil (MMF) has emerged as a valuable immunosuppressive agent used in the management of oral mucocutaneous diseases, particularly in autoimmune and inflammatory conditions, such as pemphigus vulgaris (PV), oral lichen planus (OLP), mucous membrane pemphigoid (MMP), systemic lupus erythematosus (SLE), erythema multiforme (EM) and recurrent aphthous stomatitis (RAS). This review consolidates the current evidence regarding MMF’s efficacy, safety and clinical applications across these conditions. Methods: A comprehensive review of literature was performed, focusing on the mechanism of action, dosing strategies, therapeutic outcomes and adverse effects associated with MMF therapy in oral mucocutaneous diseases. The potential of therapeutic drug monitoring (TDM) in optimizing MMF therapy and minimizing adverse effects was also explored. Results: The review demonstrates that MMF is effective in inducing disease remission in up to 80% of patients with PV, with notable steroid-sparing effects. In OLP, MMF provided significant clinical improvement, especially in patients with severe and refractory forms of the disease. For MMP, MMF showed an 89% response rate, particularly when combined with corticosteroids, though gastrointestinal side effects were noted in some patients. In SLE, MMF was effective in managing both renal and non-renal manifestations, with favorable remission rates observed in patients receiving MMF therapy. For EM, MMF’s effectiveness was limited, with only a small number of patients responding to therapy. In RAS, there is limited evidence of MMF’s efficacy, with only partial improvement in severe cases reported. MMF is a promising immunomodulatory therapy for oral mucocutaneous diseases, particularly in reducing corticosteroid dependence and improving patient outcomes. However, the variability in the study designs, dosages and patient populations complicates the generalization of these findings. Conclusions: There is a pressing need for randomized controlled trials to validate MMF’s efficacy and long-term safety across all disease categories. The integration of therapeutic drug monitoring (TDM) shows potential for improving disease control and minimizing adverse effects, making it a key consideration for future research.

1. Introduction

Given its anatomical position, rich vasculature and range of functions, the oral cavity is subjected to a multitude of insults. These involve dental traumas, irritation secondary to certain foods or medications, exposure to systemically ingested substances (into the bloodstream), infections and effects from systematic or immune dysfunction [1]. Accordingly, the oral mucosa often represents the first site of onset of such immune-mediated disorders before spreading to other mucosal or skin sites. In many instances, involvement of the oral mucosa is the sole manifestation of the disease [2,3].

Autoimmunity is characterized by a multilevel disturbance in the functioning order of the host’s immune system. This eventually leads to loss of self-tolerance and initiation of an immune response against the body’s own cells, proteins and tissues. Although the triggering factors for immune-mediated diseases are often unknown, Oral mucocutaneous and inflammatory disease encompasses a diverse group of immunological disorders affecting the oral mucosa and adjacent skin, presenting significant challenges in terms of diagnosis and management [4,5,6].

These conditions include recurrent aphthous stomatitis [7], lichenoid lesions and related conditions [8], systemic lupus erythematosus [9], vesiculobullous disease [10] (pemphigus vulgaris [11] and mucous membrane pemphigoid [12]) and erythema multiforme [13]. The clinical presentations of the lesions are usually nonspecific, subtle and constantly changing in appearance; for a definitive diagnosis, they typically require a thorough evaluation of patient histories, histopathologic studies and multidisciplinary consultations [14,15]. Consequently, early detection and diagnosis of autoimmune disorders are crucial for improved treatment outcomes with minimal side effects. Otherwise, treatments may yield inconsistent or disappointing results and cause considerable morbidity, impacting patients’ quality of life [16,17].

To overcome both short- and long-term adverse effects associated with the prolonged use of corticosteroids, such as osteoporosis, diabetes, hypertension, weight gain and increased susceptibility to infections [18,19,20]. The use of steroid-sparing agents in chronic autoimmune or inflammatory conditions is crucial to establish effective disease control, while preserving the overall health and wellbeing of patients. This has given rise to the frequent utilization of immunomodulatory agents, namely, cyclosporine A (CsA), methotrexate (MXT) and azathioprine (AZA) [21]. These agents function by targeting specific components of the immune system rather than initiating nonspecific broad immunosuppressive effects, inducing disease remission through inhibition of lymphocytic activity and reduction in inflammatory response [22]. Another potent non-steroidal immune-modulating agent is mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), has a rooted history in the prophylaxis against organ transplant rejection and an extended use as an established medication in the management of autoimmune disorders [23,24,25,26,27,28,29]. Mycophenolic acid (MPA) appears to inhibit autoimmune activity by selectively and noncompetitively blocking inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, thus limiting the proliferation of T and B lymphocytes and reducing antibody production by B cells [30]. Several randomized controlled trials (RCTs) have shown mycophenolate’s efficacy in treating autoimmune diseases, with the most substantial evidence supporting its use in lupus nephritis. While some trials indicate that mycophenolate was not superior to other treatments, the majority demonstrate that it was as effective as cyclophosphamide and azathioprine (AZA) in both inducing and maintaining remission in lupus nephritis [31,32,33,34,35,36,37,38,39]. The role of mycophenolate mofetil (MMF) in other autoimmune conditions, such as immunoglobulin A (IgA) nephropathy, ANCA-associated vasculitis, pemphigus vulgaris and foliaceus, erythema multiforme, multiple sclerosis and autoimmune liver diseases remains less well-established [40,41,42,43,44,45,46,47,48,49,50,51,52]. Nevertheless, mycophenolate presents an alternative for patients who either do not respond to or cannot tolerate standard treatments.

Recent advancements in nanotechnology have highlighted the potential of magnesium oxide nanoparticles (MgO NPs) due to their potent antimicrobial activity against oral pathogens. With their biocompatibility, broad-spectrum antimicrobial properties and minimal cytotoxicity, even at high doses, MgO NPs can effectively reduce bacterial and fungal loads in the oral environment. A key aspect of their antimicrobial action is the production of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide radicals. These ROS disrupt bacterial cell walls and interfere with cellular functions, making MgO NPs highly effective against both Gram-positive and Gram-negative bacteria. This makes them a promising adjunct in the management of mucocutaneous diseases, particularly where infections complicate the clinical picture [53,54,55,56]. Incorporating MgO NPs into mouth washes and dental materials, such as polymeric denture bases, has been shown to significantly reduce microbial adherence of key pathogens like Candida albicans and Streptococcus mutans, both frequently associated with conditions such as oral lichen planus and pemphigus vulgaris. This suggests that MgO NPs could be used alongside immunomodulatory agents like MMF to manage autoimmune pathologies of secondary infections, potentially mitigating MMF-related adverse effects. Furthermore, the anti-inflammatory properties of MgO NPs, particularly their ability to modulate nitric oxide production (NO) and cytokine expression, enhance their therapeutic potential. These nanoparticles can inhibit the migration of inflammatory cells to tissue sites, making them a valuable complementary therapy in autoimmune conditions characterized by prominent inflammation [57,58,59].

The aim of this study was to review the current evidence on mycophenolate mofetil’s (MMF) use in oral mucocutaneous and inflammatory immune-mediated disease, addressing its mechanism of action, efficacy, safety profile and optimal dosing.

2. Methods

To achieve a comprehensive understanding of the role and effectiveness of mycophenolate mofetil (MMF) in the management of oral mucocutaneous and inflammatory immune-mediated diseases, a structured literature search was conducted using the following three electronic databases: PubMed, Web of Science and Google Scholar. The search was conducted during the time period from January 2024 to October 2024, employing a combination of relevant keywords and Boolean operators, such as ‘mycophenolate mofetil’ OR ‘mycophenolic acid’; ‘MMF’ OR ‘Enteric-coated mycophenolate sodium (EC-MPS)’; OR ‘Cellcept’ OR ‘Myfortic’ AND ‘oral mucocutaneous disease’ OR ‘Oral medicine’ OR ‘oral ulcers’ OR ‘pemphigus vulgaris’ OR ‘lichen planus’ OR ‘autoimmune disease’ AND ‘mechanism of action’ AND ‘pharmacokinetics’ AND ‘pharmacodynamics’ AND ‘therapeutic drug monitoring’. Studies were eligible for inclusion if they were published in English, peer-reviewed and constituted original research involving human subjects, either in vivo or in vitro (including studies conducted on human cells or tissues). Additional inclusion criteria required that the studies involve MMF therapy for autoimmune diseases with orofacial manifestations and include evaluations of MMF’s pharmacological profile, including the mechanism of action, pharmacokinetics, pharmacodynamics and adverse reactions. The exclusion criteria included review articles, editorials, conference abstracts, animal-only studies and studies not addressing relevant clinical, cellular or pharmacological outcomes. The initial search yielded 321 articles. After removing duplicates, 177 unique articles remained and were screened by title and abstract. Of these, 103 articles met the eligibility criteria and were further assessed. After full-text evaluation, 86 articles were included for final review.

3. History

Initially explored for its antibacterial and antifungal properties, mycophenolic acid was first derived from cultures of the fungus Penicillium stoloniferum in the 1890s [60,61]. However, it was not until the early 1970s that researchers discovered the metabolic pathway of the inosine monophosphate dehydrogenase enzyme (IMPDH) and its role in the immune response in autoimmunity and organ transplant rejection [62,63]. Recognizing the immunosuppressive potential of mycophenolic acid through the inhibition of lymphocyte proliferation, researchers sought to improve its bioavailability and reduce its side effects. In the late 1980s, mycophenolate mofetil, the prodrug of mycophenolic acid, was developed [64,65,66,67,68]. The prodrug form allowed for better absorption and conversion to the active compound in the body. Eventually studies in the early 1990s demonstrated its efficacy in combination with other immunosuppressive agents for kidney, heart and liver transplant recipients [69,70,71]. Mycophenolate mofetil became a cornerstone in organ transplant immunosuppression because of its effectiveness and favorable side effect profile compared to some traditional immunosuppressants. Its use also extended to autoimmune disorders, making it a versatile medication in rheumatology and dermatology. Finally, in 1995, the U.S. Food and Drug Administration approved it for use in kidney transplant, followed by the European Union a year later [72,73]. Currently there are two commercially available mycophenolic-acid-based products, as follows: CellCept, by Roche [74], which is offered in the form of oral capsules and an oral suspension, and Myfortic, by Novartis [75], which, on the other hand, is offered in the form of delayed-release tablets. Other generic versions of MMF have been developed with the same active ingredient and strength, but their availability varies by country.

4. Pharmacokinetics and Pharmacodynamics

Currently, there are two available forms of the morpholino ethyl ester-structured prodrug of mycophenolic acid (MPA), as follows: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). These were developed to increase MPA’s bioavailability to approximately 94% [76]. Although both formulations are bioequivalent and promptly converted into the active drug form (i.e., MPA), the enteric coating in EC-MPS is designed to uphold the release of MPA until reaching the small intestine to reduce MPA-related gastrointestinal adverse events [77,78]. After MMF administration, it is rapidly absorbed and hydrolyzed into the active drug form, MPA, by the gastrointestinal tract. It undergoes a primary peak in plasma concentration levels within the 1st hour. This occurs in relation to pre-systemic de-esterification by carboxylesterases 1 and 2 and achievement of a maximal concentration (Cmax) of 24.3 ± 5.7 mg/L at 0.6 ± 0.1 h. However, plasma concentration reaches plateau within 3 to 4 h after swift distribution to tissues. A second peak is initiated 6 to 12 h later when the enterohepatic product MPA-7-O-glucuronide (MPAG) of the primary MPA metabolite is re-hydrolyzed back into MPA by bacterial de-glucuronidase activity and recirculated into the gastrointestinal tract to be reabsorbed into the bloodstream [23,79,80,81,82,83,84]. Enterohepatic recirculation (EHC) presumably contributes to a range of 10 to 60 percent of MPA exposure. In regard to clinical relevance, the percentages of MPA and MPAG bound concentrations in plasma albumins are 97% and 82%, respectively [82,85,86,87].

Mycophenolic acid (MPA) is predominantly processed in the liver and other tissues (e.g., gut wall and kidneys) by uridine diphosphate glucosyltransferases (UGTs). This metabolic process involving phase II bio-transformation reactions is facilitated by uridine diphosphate glucosyltransferases (UGTs). The main metabolite generated by UGT isoforms 1A8 and 1A9 is MPA glucuronide (MPAG), a non-pharmacologically active metabolite. On the other hand, the pharmacologically active metabolite MPA acyl glucuronide (AcMPAG) is primarily produced by isoform 2B7 [88,89,90]. MMF-administered doses have an elimination half-life of approximately 17 h. MPA has a range of 8 to 16 h, while there is a reported range of 13 to 17 h for MPAG [78,82]. In addition, clearance of the administered dosage from the body is primarily through the active tubular secretion of MPAG into the urine (60 to 87%) [91,92]. Organic anion transporters (OATs), transport proteins, and multidrug-resistance protein 2 (MRP-2), which are both expressed in renal tubular cells, have a combined action of enhancing the elimination of MPAG [93,94,95,96,97,98].

The area under the concentration–time curve (AUC) is a pharmacokinetic parameter that provides a comprehensive measure of drug exposure over time. It represents the total exposure of a drug in the bloodstream over a specific period. For MPA, a target therapeutic exposure of 0 to 12 h post-dose (dAUC12) ranges between 30 and 60 mg·h/L [78,84,99]. However, in the case of mycophenolate, therapeutic drug monitoring (TDM) of the AUC is often preferred over assessing individual concentrations (Cmax or Cmin) because of its concentration-dependent pharmacokinetics [80,100]. For example, studies of allograft rejection and lupus management consistently demonstrate clinical advantages when mycophenolic acid’s (MPA) AUC concentration exceeds 30 mg·h/L [23,78,80]. Despite the evident relationship between concentration and effectiveness, existing pharmacokinetic data for MPA, primarily obtained from human transplant investigations, indicate that patients may encounter a variability in drug exposure exceeding ten-fold [101].

Gender, body weight, ethnicity, renal and hepatic functions, serum albumin, bilirubin and hemoglobin levels, genetics, simultaneous use of other immunosuppressant agents, drug–drug interactions, patient noncompliance and time elapsed since transplantation are all additional factors that may influence MPA plasma concentrations [85,102,103,104]. Other factors, such as food, have been shown to affect Cmax, but they do not influence systemic exposure (AUC) of MPA for either MMF or EC-MPS; thus, it is recommended to take MMF on an empty stomach [102,103,104]. Moreover, antibiotics, including ciprofloxacin, amoxicillin/clavulanic acid and bowel decontamination types (co-amoxiclav, metronidazole, norfloxacin and rifampicin), affecting UGT enzymes diminish the activity of the gut bacteria β-glucuronidase, which inhibits the de-glucuronidation of the inactive MPA-7-O-glucuronide metabolite to MPA and thereby possibly preventing its enterohepatic recirculation [105,106,107,108,109,110,111]. Also, antiacids containing aluminum and magnesium hydroxide have been reported to cause reductions in MPA Cmax by 33% and AUC24 by 17%, while another study reported continuous decreases in MPA concentrations from the time of the first absorption peak until 9 h post-dose in patients taking NSAIDs [112,113,114]. Other contraindicated medications are cholestyramine, antiepileptic drugs, clozapine and antiviral drugs such as acyclovir and valaclovir [106,115].

5. Adverse Effects

A generally well-tolerated immunosuppressive, the active metabolite of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) selectively targets lymphocytes and demonstrates a more acceptable safety profile compared to other immunosuppressive agents, like methotrexate (Mtx), cyclosporine (CSA) and azathioprine (AZA) [116,117,118,119,120]. Information regarding the side effects of these two formulations is mainly derived from renal transplant patients, whose risk of adverse reactions may differ from that of the general population [23,79,121]. Transplant recipients may also be prescribed MPA-based medications as part of a combined immunosuppressive regimen, often at doses higher than those typically used in dermatological conditions [122]. Some studies report that MMF exhibits a safety profile comparable to NSAIDs [123].

MPA’s most commonly reported side effects in patients are typically confined to various gastrointestinal (GI) issues, such as diarrhea, nausea, abdominal cramps and vomiting [23,76,124,125,126]. However, the literature consistently indicates that GI intolerance is of dosage-dependent origin and can be reversed upon discontinuation of therapy [23,125,127]. Accordingly, it has been reported that 20% of patients suffer from gastrointestinal upset on a 2 g dose [119]. Despite several proposed causes, the precise mechanism responsible for MPA-related GI toxicity remains incompletely understood, and whether this toxicity is local or systemic in nature is unclear. Different hypothesis has been introduced as possible causes, and epithelial cells present in the GI tract are relatively dependent on de novo purine synthesis, which affects their proliferation. The acyl glucuronide metabolite of mycophenolic acid (MPA), known as acyl-MPAG, may possess proinflammatory properties and its local distribution in the intestinal epithelium or transport to the intestine with bile can contribute to GI toxicity [124,128,129]. Additionally, it could be attributed to the antibacterial properties of MPA and its possible alterations in the normal micro-flora of the GI tract, inducing tissue damage [124,130].

The immunosuppressive effects of MMF can lead to an increased risk of infections, in particular, infections involving the respiratory system, wounds of patients and genitourinary symptoms, such as urinary tract infections, hematuria, polyuria and dysuria [131,132]. In addition, the risk of opportunistic infections, especially those caused by the human herpesvirus (HHV) family [133], leukopenia, thrombocytopenia and anemia, is among the reported hematological side effects but only accounts for less than 5% [120,134,135]. Regarding susceptibility to oral infections in chronic autoimmunity, long-term treatment with immunosuppressive medications will diminish the patient’s overall capacity to initiate an immune response. Thus, the consideration of prophylactic measures, such as the use of antifungal agents, may be necessary [136]. Malignancy (lymphoma) presents the most significant concern associated with long-term MMF immunosuppressive therapy. However, it is infrequently reported in the literature and correlated to the duration and intensity of immunosuppression [137,138,139,140,141]. Skin cancer (non-melanoma) has an approximate incidence rate of 4% in transplant patients taking MMF, and patients are advised to abstain from excessive sunlight exposure and wear a sun protective factor (SPF) of at least 30 and a star rating of 4 [131,134].

Mycophenolate mofetil (MMF) is classified as Pregnancy Category D because of the evidence of fetal harm and significant risk during pregnancy. It is associated with an increased risk of congenital malformations, birth defects and spontaneous abortions. Fertility issues in both men and women have been reported; thus, there is a need for effective contraception 4 weeks prior to treatment with MMF and for 6 weeks after the conclusion of therapy [132,134]. Furthermore, it is generally not recommended to administer live vaccines to individuals on immunosuppressive therapy, including MMF. The weakened live virus in the vaccine, including MMR (measles, mumps and rubella), chickenpox, polio, shingles, yellow fever and nasal flu vaccines, may pose a risk of causing infection in individuals with a weakened immune response [142]. Finally, guidance from the British Association of Dermatologists suggests regular monitoring of mycophenolate mofetil (MMF) through weekly assessments of a complete blood count, urea, electrolytes and liver function tests during the initial month, followed by less frequent monitoring. The mitigation of adverse effects is achievable through dose reduction and concurrent use of other immunosuppressant agents [133,134].

6. MMF’s Role in Oral Mucocutaneus and Inflammatory Disease

6.1. Oral Lichen Planus

Lichen planus (LP) is a potentially malignant, chronic inflammatory disorder that can affect the skin, mucous membranes, hair and nails [143]. It is characterized by autoreactive T lymphocytes targeting basal layer antigens. Systemic and topical corticosteroids are commonly utilized as first-line therapy because of their effectiveness in managing oral lichen planus (OLP) with the aim of relieving symptoms, promoting healing and managing any associated discomfort [144]. The involvement of activated T cells in LP’s pathogenesis is evident through dermal lymphocytic infiltrate, leading to keratinocyte damage and eventually lesion development [145]. Mycophenolate mofetil (MMF) is used as an adjunctive immunosuppressive steroid-sparing medication, as it specifically targets the proliferation of activated T cells and reversibly inhibits its synthesis [146].

A study conducted by Wee et al. explored the off-label utilization of mycophenolate mofetil (MMF) at a dental hospital in the UK, assessing ten patients with severe mucocutaneous lichen planus. The researchers demonstrated the effectiveness of MMF in cases of severe ulcerative lichen planus and suggested that the symptomatic and clinical benefits of MMF may require up to one year of treatment, with daily dosages reaching a maximum of 1500 mg to 2500 mg [27]. Another recent study by Sin et al. [147] reported similar outcomes, indicating clinical improvement in 80% of patients with oral lichen planus (OLP) after receiving MMF treatment for at least 13 months, with dosages ranging from 500 mg to 2000 mg daily. However, their study showcased a slightly lower MMF dosage, and most patients ceased systemic corticosteroids after receiving MMF. This can be potentially explained by the confined oral cavity’s involvement in 10 out of 12 patients [147]. Additionally, the presence of both oral and genital lichen planus in nine out of ten patients in Wee et al.’s study [27], along with the association of the HLA-DBQ1*0201 allele [148] in eight patients, suggested a more severe and refractory form of lichen planus. To enhance patient compliance and set realistic expectations, it is crucial to inform patients that MMF therapy may be prolonged, and disease control may take up to a year. Azizpour et al. [149] conducted a retrospective cohort study assessing the clinical efficacy of MMF on 52 patients suffering from lichen planopilaris (LLP). A daily dosage of 2 mg was administered for a period of at least 6 months. The LLP index (LPPAI) was calculated before and after treatment and demonstrated a statistically significant improvement in disease activity from a range of 4 to 6 toward a range of 0–2 after 6 months (p < 0.001). Their study concluded that MMF is an efficient treatment modality for LPP patients and exhibits a relatively safe profile. In a different approach to MMF, 27 patients with ulcerative OLP were administered a 2% MMF mucoadhesive patch on the lesion twice daily for a period of 4 weeks. For monitoring lesion proregression and follow-up, a sterile digital caules (mm) was used to measure the lesion size, while the visual analogue scale (VAS; cm) measured the level of pain and burning sensation. In week 4, there was a significant reduction in pain, burning sensation and lesion size (p = 0.004), with no reported side effects. The authors stated that the MMF in the 2% mucoadhesive patch form achieved disease remission but its effects were time-dependent [150].

6.2. Pemphigus Vulgaris

Pemphigus vulgaris is a rare type of autoimmune bullous dermatosis and the main clinical form of pemphigus, representing 70% of cases [151]. A life-threatening condition, PV is a B-cell-mediated disease distinguished by an antibody reaction targeting the structural elements of the epithelium, leading to the development of vesicles and bullae [152,153,154]. Since the introduction of corticosteroids, it remains the recommended first-line therapy in the management of PV [155]. It significantly contributed to the reduction in mortality rates from PV from 95% to around 10–40% [156,157]. However, complications from corticosteroid therapy became the leading cause of mortality in PV (5%) rather than the disease itself [158,159]. Thus, immunosuppressive agents play a vital role through immune-modulation and as steroid-sparing agents. MMF is effective in managing PV and recommended as first-line adjunctive therapy at 2–3 g per day by the British Association of Dermatologists [160]. Moreover, its reported to reduce the risk of relapse by 29%, more effectively than other adjunctive immune-modulating agents [161].

Sin et al. [147] reported complete disease remission in all PV patients, with a favorable response to MMF treatment at maximal dosage of 1500 mg to 2000 mg per day. Moreover, MMF enabled patients to maintain a tapered steroid dose of 3–5 mg/day. In a study of childhood PV, 47 cases, with an age range of 2 to 12 years, have successfully been treated, with durable disease remission, via an initial dose of 500 mg of MMF, with a subsequent gradual increase of up to 1200 mg daily, in combination with a low dose of prednisone at 5 mg/day [162]. Recent guidelines for PV indicate that the recommended dosage of MMF is 2–3 g/day, divided into two doses [161,163,164,165,166].

Furthermore, an international, multicenter and randomized controlled trial involving 94 patients, with all participant groups receiving oral prednisolone, revealed that the inclusion of MMF resulted in more prolonged effects and a quicker disease response. Another advantage for the MMF group was that patients could be maintained on lower doses of prednisolone, leading to a slightly reduced overall exposure to steroids. The study further indicated a preference for MMF at a daily dosage of 2 to 3 g/day, with an increase in the daily dose by 1 capsule (500 mg) per week until the final target dose per day was reached, primarily because of the lower GI side-effect burden. Otherwise, MPA can be used at 720–1080 mg twice daily for better gastrointestinal tolerance [167]. Sukanjanapong et al. [168] conducted a comparative study of azathioprine (AZA) and mycophenolate mofetil (MMF) as adjunctive immunosuppressants to prednisolone steroid therapy in 62 PV patients. Their findings were based on complete remission on and off therapy (immunological remission). The study indicated the superiority of MMF in terms of a shorter disease remission period and greater steroid-sparing effects than AZA, with clinical significance both on and off therapy (p = 0.007 and p = 0.043, respectively). The authors stated that MMF has the potential to lower the risk of chronic steroid use. They also added that the AZA group had a higher recurrence rate but with no statistical significance due to the small sample size. The authors also attributed the difference in results from previous studies, in favor of AZA, to their measuring parameters of complete remission, where their definition of complete remission was based on a lower cumulative steroid dosing rather than complete re-epithelization of all lesions. In contrary, rituximab outperformed mycophenolate mofetil in achieving complete remission at the 52-week mark among patients with PV. Rituximab led to a more substantial decrease in corticosteroid usage compared to mycophenolate mofetil, although there were more reported serious adverse events in the rituximab group [169].

6.3. Mucous Membrane Pemphigoid

Similar to pemphigus vulgaris in etiology, mucous membrane pemphigoid (MMP) is classified within the category of subepidermal blistering disorders and characterized by the presence of immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM) or complement factor 3 autoantibodies. The deposition of these immune reactants against basement membrane epithelium leads to the complete detachment of the mucosa (epidermis) from the submucosa (dermis), resulting in the formation of subepithelial bullae affecting the body’s mucosal surfaces [170,171,172].

MMF was effective in managing mucous membrane pemphigoid (MMP) in a study in which 78% of MMP patients showed clinical improvement after nine months of treatment. The maximal administered dosage was 500 mg to 2000 mg daily. Two-thirds of patients became independent from steroid therapy once MMF treatment commenced, highlighting MMF’s steroid-sparing effect. Their study concluded that MMF is recommended as a second-line therapy in patients suffering from mild to moderate MMP [147]. Another study reviewed six patients with MMP-related oral lesions. A low-dose combination regime of dapsone, MMF and prednisolone demonstrated efficacy in disease remission [173]. In addition, Fin et al. conducted a study with 42 MMP patients. A group of 13 patients received MMF, and a response rate of 46.2% was reported [174].

Hrin et al. [175] explored the efficacy of MMF in a study with 38 patients with MMP. Twenty-nine patients were administered MMF in combination with prednisone, while nine patients received MMF as monotherapy. The authors reported an 89% response rate for the monotherapy group during a 12-month evaluation period, while the group with concomitant prednisone therapy reported response rates of 65%, 70% and 74% during evaluation periods of 3, 6 and 12 months, respectively. Adverse effects such as gastrointestinal upset, fatigue, thrombocytopenia and difficulties in urination led to the discontinuation of MMF therapy in seven patients. However, MMF was recommended as an effective therapy for late stage, mild to moderate active inflammation in mucous membrane (cicatricial) pemphigoid. Fremont et al. reported an overall MMF efficacy in treating ocular cicatricial pemphigoid (OCP) of 67% (complete remission), stating that response rates were the highest for MMF but with a 33% discontinuation rate due to adverse effects (AEs) [176]. The existing literature reports success rates in controlling inflammation with MMF of 71%, 58% and 59% in cohorts consisting of 18, 10 and 34 patients, respectively [177,178,179]. The safety profile was generally favorable, with 1% to 15% of patients discontinuing treatment because of adverse events [178,179].

In an alternative approach to investigating MMF’s efficacy in treating MMP, Woillard et al. [180] implemented the therapeutic drug monitoring method to investigate the correlation between exposure and effect by analyzing the area under the curve (AUC) or trough level of mycophenolic acid in patients with mucous membrane pemphigoid (MMP). This approach was justified by the large interindividual variability in PK of MPA that can vary immensely among patients, almost up to 10-fold between exposure and response. Additionally, preforming therapeutic drug monitoring (TDM) relying on the area under the curve (AUC) provides a finer correlation between the AUC of mycophenolic acid (MPA) and treatment outcomes. In contrast to conventional singular concentration-time points, the authors report that adopting AUC-based dose adjustments leads to better disease control and that MMF should not be administered according to patients’ weight, as there was no correlation between weight and the AUC. An improvement was observed in nine patients (70%), two were non-responders and two were in the stabilization phase. After 29 AUC measurements, there was an association between an AUC threshold of 89 mg·h/L for AUC0–24 h and disease remission; on the contrary, an AUC threshold of <89 mg·h/L for AUC0–24 h was associated with stabilization or non-response.

6.4. Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease that is severe and chronic, and it is marked by the deposition of immune complexes in different organ systems, leading to inflammation and functional impairment [181,182]. Activation of type I IFN pathways, B- and T-cell dysfunction, deoxyribonucleic acid and the presence of antinuclear antibodies represent the diagnostic pathogenetic development of SLE [183,184,185]. Estrogen supports the proliferation of these antibodies, hence the increased prevalence in females (8×); however, genetic predisposition is a contributing factor in SLE [186,187,188]. The aim of SLE treatment is to achieve remission or reduced disease activity and, ultimately, prevent flares [189]. The efficacy of enteric-coated mycophenolate sodium (EC-MPS) was compared to azathioprine (AZA) in a randomized clinical trial by Ordi-Ros et al. [190], where all patients (240) suffered from active SLE disease. A target dose of 1440 mg/day was adjusted for the EC-MPS group, while a 2 mg/kg/day target dose was set for the AZA group in adjunction with prednisolone. The authors reported statistical significance (p < 0.001) in terms of the clinical remission rates in patients undergoing EC-MPS therapy (71.2%) vs. those on AZA therapy (48.3%) at 24 months. In addition, statistical significance (p < 0.001) was observed in favor of the EC-MPS therapy group concerning disease flares and reduction in disease activity. They concluded that EC-MPS is a reliable treatment for non-renal SLP, given its ability to achieve clinical remission and maintain clinical response as early as 12 weeks into treatment. Alternatively, Keyes et al. [191] investigated the difference in response rates between methotrexate (MTX) and mycophenolate mofetil (MMF) to subacute and discoid lupus erythematosus. MMF exhibited a favorable response rate in DLE, while the contrary was true in SCLE. The cohort study concluded that the difference in response rates between the two immunosuppressants was comparable and of no statistical significance. In the same manner, a recent retrospective cohort compared mizoribine (MZR) to MMF in 129 patients with SLE [192]. The authors examined the two therapeutic modalities through different efficacy endpoints, such as in the cumulative incidence of lupus low disease activity state (LLDAS), disease remission flares and tapering of the prednisolone dosage. MZR displayed comparable efficacy to MMF in lowering disease activity, with the benefit of a better safety profile.

In SLE, there is usually multiple organ involvement, namely, joints, skin, muscles, lungs, central nervous system and kidneys [182]. The EULAR recommendations support the efficacy of MMF in renal and non-renal SLE, in particular its effectiveness in lupus nephritis (LN) treatment, whether in the induction phase or as maintenance therapy [193]. In an SLE cohort study [194], MMF was administered as a first-line therapy because of the involvement of several disease features. However, the most common type documented was LN (62.3%), followed by musculoskeletal SLE (24.1%). The study evaluated MMF’s retention rate, which suggests that it provides a well-balanced indication of tolerance and efficacy. The authors report that MMF was effective in preventing the progression of chronic damage. Notably their results demonstrate a complete clinical response in more than 80% of patients with musculoskeletal lupus manifestations, which aligns with past literature. Yet 30% of patients reported relapse. Furthermore, a recent retrospective study [195] provided a 20-year overview of the long-term efficacy of MMF in SLE patients, where LN was the main indication (90%). Complete or partial remission was reported in 76% of patients within one year. The main finding of the study was the low flare rates in only 17 out of 101 patients undergoing MMF treatment. The authors attributed this finding to their high targeted daily dose of 3 g, as the administered dose was not tapered unless serious adverse effects were observed. However, patients of African American/Caribbean ethnicity composed the majority (87%) of patients receiving MMF treatment.

6.5. Erythema Multiforme

Erythema multiforme (EM) is a skin disorder characterized by the sudden onset of distinctive skin lesions, either of an acute or recurrent nature, and it is often in response to an immune system reaction. The etiology of erythema multiforme can be associated with various factors, with the most common trigger being infections, particularly herpes simplex virus (HSV) infections. Other causative factors include medications, especially certain antibiotics and anticonvulsants, as well as exposure to certain allergens and underlying medical conditions [196,197,198,199]. The immune system’s response, involving cytotoxic T cells and immune complexes, plays a role in the pathogenesis of erythema multiforme. It is important to promptly identify and address the underlying cause or trigger to manage the condition effectively [200,201]. Treatment of EM should be planned according to the causative factor; for example, any recent infections should be treated and recent medications with probable allergic reactions ceased. Early intervention with antiviral drugs (e.g., Acyclovir) in viral EM or cessation of medication in drug-related EM leads to fewer symptoms and accelerated remission [202,203]. Regarding recurrent EM, current recommendations are 400 mg acyclovir or a miscellaneous treatment administered twice daily for both idiopathic and HSV EM [204]. If the etiology is HSV, then remission is achievable, but recurrence is highly probable; thus, it is advisable to continue treatment for at least 1 to 2 years before discontinuation [198,199]. In the case of a failed response to antiviral treatment, patients with EM should be administered other systemic medications. Within the scope of immune-modulating agents, IV immunoglobulins, azathioprine (AZA) and thalidomide led to an 80% disease remission rate; however, these findings were reported in a small case series [202]. Rituximab was used in another case series, where four out of five patients demonstrated complete remission and only partial remission in the remaining patient. All patients relapsed within a period of 3 to 11 months [205]. Additionally, mycophenolate mofetil (MMF) demonstrated less promising results in the treatment of EM. In a study investigating MMF efficacy, only three out of eight patients responded to therapy [200]. There is a lack of randomized controlled trials (RCTs) in the literature to support a specific recommendation or line of therapy regarding EM. Instead, these recommendations are largely based on case series and expert opinions [202].

6.6. Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) is an oral condition characterized by recurring episodes (≥3 times/year) of single or multiple painful aphthous ulcers, typically affecting non-keratinized oral mucosal surfaces. The ulcers are usually oval or round in shape, with an erythematous border and a yellowish–grayish central pseudo-membrane. Clinically, RAS manifests in one of the following three forms: minor, major and herpetiform [206,207]. While it is of unknown etiology, it is believed to be of a multifactorial origin, underlying a genetic predisposition and potential contributing factors, such as microbial entities (bacterial or viral), dietary elements, certain medications, hormonal influences, nutritional deficiencies, stress and systemic diseases [208,209].

The present literature has little or no evidence to advocate for mycophenolate mofetil (MMF) as an effective medication in the treatment of recurrent aphthous stomatitis (RAS). A single case of RAS was reported in a recent study. The patient was not responsive to previous topical or systemic ulcer treatments, and their condition was debilitating. MMF therapy was administered and a partial improvement in oral ulceration was reported at 11 months of 2000 mg per day. The reported improvements were in the frequency and duration of ulcerations. Prednisolone corticosteroid continued to be slowly tapered to 5 mg daily [147].

An overview of the current evidence and findings is presented in

Table 1. Summary of findings.

Condition	MMF Dosage	Efficacy	Adverse Effects	Study Design Variability
Pemphigus Vulgaris (PV)	2–3 g/day	Complete remission in most cases; steroid-sparing effects reported	GI issues common; manageable with dose adjustments	Randomized controlled trials support efficacy; study designs vary
Oral Lichen Planus (OLP)	500 mg–2 g/day	Clinical improvement in 80% of cases, especially severe/refractory forms	GI upset at higher doses; generally well tolerated	Studies with variable dosing; often retrospective or observational
Mucous Membrane Pemphigoid (MMP)	500 mg–2 g/day	89% response rate; steroid-sparing effects; recommended for mild to moderate cases	GI upset, fatigue and urinary difficulties reported; discontinuation in some cases	Variable study designs; mostly observational or case series
Systemic Lupus Erythematosus (SLE)	1440 mg/day (EC-MPS) or variable for non-renal manifestations	High remission rates, especially in renal involvement (up to 71% in EC-MPS)	GI intolerance and hematological issues at high doses; infection risk noted	Supported by randomized trials in renal SLE; limited for non-renal
Erythema Multiforme (EM)	Not specified	Limited efficacy; response observed in a minority of cases	Minor adverse effects in limited cases	Case series and expert opinions; lack of randomized trials
Recurrent Aphthous Stomatitis (RAS)	2 g/day (reported partial improvement)	Partial improvement in severe cases; insufficient evidence for broad efficacy	Limited data on adverse effects	Anecdotal evidence; no controlled trials available

.

7. Mechanism of Action

Autoimmunity represents a broad spectrum of debilitating diseases characterized by the initiation of autoreactive T and B lymphocytes, autoantibodies formation and immune complex deposition that causes tissue damage and persistent inflammation [210]. Thus, the main goal of treating such chronic conditions is to suppress these immune-mediated processes. Mycophenolic acid (MPA) is reported to selectively inhibit lymphocytic proliferation, hence reducing the severity of immune reactions. Mycophenolate mofetil (MMF), the prodrug of MPA, is an inactive compound that is rapidly and completely converted into the active form of mycophenolic acid after oral administration [211].

The metabolite mycophenolic acid is a selective, reversible and non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), a key enzyme involved in the de novo synthesis of guanosine monophosphate (GMP) nucleotides; this, in turn, causes the suppression of the de novo synthesis of purines (guanosine and adenosine) in lymphocytes, consequently blocking their proliferation and inducing the apoptosis of activated B and T lymphocytes [212,213] [Figure 1]. Compared with other immunosuppressive drugs used in oral medicine, MMF targets the DNA replication of T and B lymphocytes relatively specifically, as these rapidly growing cells are almost entirely dependent on de novo purine synthesis, unlike other cell lines, which can rely on different salvage pathways [102,214,215]. Beyond its impact on lymphocyte proliferation, MPA has additional anti-inflammatory effects through the depletion of guanosine triphosphate (GTP), contributing to the downregulation of pro-inflammatory cytokines and reduced expression of adhesion molecules on the surface of immune cells, namely, monocytes, a type of white blood cell that can differentiate into macrophages or dendritic cells. This leads to the modulation of chemotaxis and affects the migration of inflammatory cells to tissues [79,214,216]. In addition, several studies have suggested that MMF can influence the expression of nitric oxide synthase (iNOS), an enzyme that catalyzes the production of nitric oxide (NO) in response to inflammatory stimuli through the depletion of deplete tetrahydrobiopterin [214,217,218,219]. Finally, immunoinflammatory diseases often involve a cascade of immune responses leading to tissue damage and, in some cases, fibrosis. MPA has been shown to exert anti-fibrotic effects through interfering with the growth of various nonimmune cells, such as smooth muscle cells, renal tubular cells and mesangial cells. Inhibiting their proliferation may contribute to the prevention of vascular and glomerular changes associated with fibrosis [220,221,222]. Recent insights highlighting the involvement of type II isoform of inosine-5′-monophosphate dehydrogenase (IMPDH2) in the development of different cancer types have sparked renewed interest in mycophenolic acid (MPA) as a potential anticancer treatment. Its effectiveness against cancer was validated in vivo using a xenograft model with the gastric AGS cell line. Further in vitro examinations utilizing AGS cells revealed that MPA has a potent capability to induce cell cycle arrest and apoptosis, as well as inhibit cancer cell proliferation. This is attributed to reductions in several cell cycle regulators, including CDK4, BUB1, BOP1, Aurora A, and FOXM1. However, the specific signaling pathways responsible for MPA’s actions remain unclear [223,224,225,226].

8. Limitations

Despite the valuable information presented in this review regarding the use of mycophenolate mofetil (MMF) in oral autoimmune diseases, it is essential to acknowledge several limitations that are inherent in the available literature. A notable constraint lies in the limited number of well-designed and adequately powered clinical trials dedicated explicitly to MMF in the context of oral autoimmune diseases. The existing body of literature often exhibits heterogeneity in study designs, methodologies and outcome measures, making it challenging to conduct a standardized synthesis of the findings. Furthermore, publication bias may influence the overall perception of MMF’s efficacy, as positive results may be disproportionately represented. The variability in disease definitions, patient populations and follow-up durations across the studies adds complexity to the interpretation of the outcomes. The influence of combination therapies and the potential underrepresentation of negative outcomes also pose challenges. The quality of reporting, language bias and the evolving nature of knowledge in the field further contribute to a nuanced landscape of limitations that should be considered when interpreting the results of this review.

9. Recommendations and Emerging Strategies

Future investigations should delve into the long-term safety and efficacy of MMF, particularly in combination therapies, with a focus on embracing a personalized medicine approach based on individual patient characteristics. This could be achieved through therapeutic drug monitoring (TDM) in MMF therapy, which is strongly advised because of the diverse inter-individual pharmacokinetics of MMF. Integrating TDM with clinical endpoints, especially in combination therapies, holds promise for dose standardization and the refinement of treatment regimens. A more reliable method to correlate the area under the curve (AUC) of mycophenolic acid (MPA) with response to an administered dosage (i.e., exposure/effect relationship based on the AUC) would be particularly valuable. Such efforts could lead to breakthroughs in minimizing MMF-related side effects, which are often related to MPA exposure. In this regard, targets of AUC0–24 h ≥ 89 mg·h/L and AUC0–12 h ≥ 45 mg·h/L have been suggested for patients with autoimmune vesiculobullous diseases and organ transplant recipients, respectively. Routine monitoring protocols, including blood sample collection and MPA plasma concentration measurements, should be established to ensure exposure levels align with therapeutic targets, particularly in transplant recipients and patients with autoimmune disease.

Furthermore, the integration of nanotechnology-based treatments, such as magnesium oxide nanoparticles (MgO NPs), into existing therapeutic protocols for oral mucocutaneous diseases was not reported in any study. Their antimicrobial and anti-inflammatory properties are pivotal to enhance the safety and efficacy of current immune-modulatory treatments. Finally, studies exploring the use and efficacy of enteric-coated mycophenolate sodium (EC-MPS) are recommended, as the literature reports fewer side effects and slower release compared to MMF, which may lead to longer exposure durations and potentially improved outcomes. Randomized controlled clinical trials are imperative to solidify the findings in the literature, particularly in the context of oral medicine.

10. Conclusions

This review highlights the clinical utility of mycophenolate mofetil (MMF) as an effective immunomodulatory therapy in managing oral mucocutaneous diseases, specifically pemphigus vulgaris (PV), oral lichen planus (OLP), mucous membrane pemphigoid (MMP), systemic lupus erythematosus (SLE), erythema multiforme (EM) and recurrent aphthous stomatitis (RAS). The evidence suggests that MMF significantly induces remission in PV and OLP, with steroid-sparing benefits, particularly at dosages between 2 and 3 g/day for PV and 500 mg and 2 g/day for OLP. Similarly, MMP shows promising response rates, while SLE patients benefit from MMF’s efficacy in managing both renal and non-renal manifestations.

However, the findings also highlight the variability in patient responses and the lack of standardized treatment protocols. MMF’s efficacy in EM and RAS remains limited, underscoring the need for further research in these areas. Gastrointestinal side effects were common but manageable, particularly with the potential use of therapeutic drug monitoring (TDM) to optimize treatment regimens and minimize adverse effects.

A critical takeaway is the need for randomized controlled trials (RCTs) to confirm MMF’s long-term safety and efficacy across these diseases. The heterogeneity in current study designs and patient populations limits the generalizability of results. Future research should focus on standardized dosing, longer follow-up periods and incorporating TDM to individualize patient care. In conclusion, MMF holds significant promise as a cornerstone therapy for autoimmune conditions with oral manifestations, offering both effective disease control and reduced corticosteroid reliance. Further investigations are necessary to fully establish its role in oral medicine.