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Keywords:

  • medicine;
  • craniofacial;
  • oral diseases;
  • azathioprine;
  • mycophenolate

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Azathioprine
  5. Mycophenolic acid and Mycophenolate mofetil
  6. Conclusions
  7. Author contributions
  8. References

Systemic non-biological agents (NBAs) have been extensively used for immunosuppression in clinical medicine, often with considerable efficacy, although sometimes accompanied with adverse effects as with all medicines. With the advent of biological agents, all of which currently are restricted to systemic use, there is a rising need to identify which agents have the better therapeutic ratio. The NBAs include a range of agents, most especially the corticosteroids (corticosteroids). This article reviews the purine synthesis inhibitors (azathioprine and mycophenolate), which are currently the most commonly used systemically immunosuppressive agents in the management of orofacial mucocutaneous diseases. Subsequent articles discuss other corticosteroid-sparing agents used in the management of orofacial disease, such as calcineurin inhibitors, and the cytotoxic and other immunomodulatory agents.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Azathioprine
  5. Mycophenolic acid and Mycophenolate mofetil
  6. Conclusions
  7. Author contributions
  8. References

Various purine analogues that affect purine synthesis and thereby lymphocyte proliferation are used in the treatment of patients requiring immunosuppression for the prevention of organ transplant rejection and for the control of autoimmune and inflammatory diseases. The purine synthesis inhibitors azathioprine and mycophenolate are the medications most commonly used as steroid-sparing agents in the treatment of orofacial diseases. This article discusses their properties and the evidence for their application in oral diseases.

Azathioprine

  1. Top of page
  2. Abstract
  3. Introduction
  4. Azathioprine
  5. Mycophenolic acid and Mycophenolate mofetil
  6. Conclusions
  7. Author contributions
  8. References

Azathioprine was the first immunosuppressive agent which, in combination with prednisone, facilitated successful human renal allotransplantation (Murray et al, 1963). Synthesized in 1957 by G.H. Hitchings and G. Elion, these workers, together with Sir J.W. Black, received the Nobel Prize in Physiology or Medicine in 1988 for this advance (Nobelprize.org).

Clinical uses of azathioprine

Azathioprine is officially approved for the management of renal homotransplantation and for the treatment of rheumatoid arthritis (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf accessed May 2013), but it is also prescribed as an off-label indication in many other conditions.

Pharmacology

Azathioprine is a purine antimetabolite which, by reducing lymphocyte proliferation, is immunosuppressive (Cara et al, 2004). Azathioprine is actually a prodrug, which is metabolized to 6-mercaptopurine (6-MP) – the active metabolite. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) then activates 6-MP to thio-inosine monophosphate (TIMP) (Elion, 1993) and active 6-thioguanine nucleotides (Figure 1). The latter bind to DNA and inhibit purine synthesis – resulting in cell cycle arrest and apoptosis especially in lymphocytes (Cara et al, 2004).

image

Figure 1. The metabolism of Azathioprine. TIMP, thio-inosine monophosphate; ITPA, inosine triphosphate pyrophosphatase; TPMT, thiopurine S-methyltransferase

Download figure to PowerPoint

Azathioprine is well absorbed via the oral route, and the plasma half-life is ~5 h. The level of circulating azathioprine is not an index of toxicity, such effects depending mainly on the thiopurine nucleotide levels in the tissues. (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2265&loc=ec_rcs accessed May 2013) 6MP is inactivated by the enzyme thiopurine S-methyltransferase (TPMT) (Meggitt et al, 2011), the activity of TPMT varying between individuals.

Adverse effects of azathioprine

The most significant adverse effects of azathioprine are haematological, gastrointestinal, infectious and malignancies. Adverse effects are dependent on the dose and duration of treatment and are also influenced by the patients underlying disease (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf accessed May 2013) (Table 1).

Table 1. Azathioprine possible adverse events
Early
Arrhythmias
Fatigue
Gastrointestinal
Haematological (leukopenia early usually)
Hypersensitivity (in 3–42 days fever, myalgia, arthralgia, liver/kidney)
Hypotension
Liver damage (hepatitis)
Nausea
Pancreatitis
Renal damage (nephritis)
Medium term
Haematological: neutropenia in 20% (5–30%)
Hair loss
Infections
Liver damage
Rash
Long term
Oncogenicity
Non-melanoma skin cancer (>10 year and UV radiation)
Non-Hodgkin lymphoma [often year 1 and in those with EBV infection or IBD (inflammatory bowel disease)]

About 0.3% of the general population are TPMT deficient, and these people are at particular risk of severe myelosuppression if given azathioprine, because of the accumulation of excessive amounts of cytotoxic 6-thioguanine nucleotide. TMPT screening is therefore indicated in all patients who are scheduled for treatment with azathioprine (or 6-MP) (Anstey et al, 2004).

It has been suggested that the enzyme inosine triphosphate pyrophosphatase (ITPA) also plays a role in the digestion of thiopurines and that defective activity resulting from polymorphisms in the ITPA-encoding genes may be associated with thiopurine-induced adverse effects. However, one meta-analysis does not show a correlation between the development of thiopurine toxicity and the ITPA 94C[RIGHTWARDS ARROW]A polymorphism, implying that there is no clinical relevance at this time to determining ITPA polymorphisms in thiopurine-treated patients (van Dieren et al, 2007).

Haematological

The haematological disorders associated with azathioprine use range from mild leukopenia to severe myelotoxicity and pancytopenia. The rate of leukopenias is as high as 50% in renal transplant patients treated with azathioprine and 28% in patients with rheumatoid arthritis on azathioprine, while severe leukopenias (<2500 cells mm−3) are reported in 16% and 5% of the above categories of patients, respectively (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf accessed May 2013). The rate of myelotoxicity is higher among individuals with low TPMT activity, and when some other drugs are coadministered (see below). The time of onset of the haematological adverse effects is unpredictable: some cases have occurred within a few weeks of starting treatment with azathioprine, but others only after several months and even years. For this reason, regular complete blood count monitoring is recommended throughout treatment with azathioprine. Mild cytopenias may reverse with dose reduction, while severe reductions are an indication for azathioprine cessation.

Gastrointestinal

The most common adverse effects of azathioprine are mild gastric irritation with nausea, dyspepsia and vomiting. The nausea usually appears early in treatment and resolves spontaneously without dose alteration but, in order to avoid this symptom, clinicians may initiate the drug treatment with progressive dose escalation to allow the patient better to tolerate the drug (Meggitt et al, 2011). This approach although common is not sufficiently evidenced (Meggitt et al, 2011). More severe gastrointestinal tract symptoms present with diarrhoea, fever and myalgias, and these may require cessation of azathioprine treatment. In a few patients, abdominal pain and vomiting may be the result of pancreatitis – when azathioprine should be withdrawn.

Hepatotoxicity (as evidenced by raised serum alkaline phosphatase, bilirubin and transaminases) may occur early in people receiving azathioprine after organ transplantation (<6 months) and is reversible when azathioprine is withdrawn. The rate of hepatotoxicity in patients with other conditions such as rheumatoid arthritis treated with azathioprine is fortunately low (1%). Liver damage is typically mild and resolves on drug cessation, but occasional patients develop severe idiopathic drug-induced liver damage and, more rarely, nodular regenerative hyperplasia (Lopez-Martin et al, 2011). Thus, regular and frequent liver function monitoring is indicated for all patients taking azathioprine.

Infections

The risk of infections is an important consideration in all immunocompromised patients, especially when they receive a combination of immunosuppressive agents. Azathioprine is no exception – a range of infections (bacterial, viral and fungal/new or reactivations of latent infections) may be observed. The British Association of Dermatology has issued recommendations for the management of varicella-zoster virus infections in patients taking azathioprine, which include drug withdrawal, oral antivirals and IV antivirals for ophthalmic infections (Meggitt et al, 2011).

Malignancies

Azathioprine in long-term use carries a risk for malignancies (FDA box-warning) (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf accessed May 2013). Patients on azathioprine are prone to skin cancers and lymphomas and are thus recommended to avoid UV exposure and to wear sun protection. The risk of developing such malignancies is highest among transplant recipients treated with azathioprine and is positively correlated with the duration of exposure to the drug (Wise and Callen, 2007).

Administration of azathioprine

Azathioprine is available as tablets for oral use. If the oral route is compromised, other agents should be considered. The dosing of azathioprine is relevant to the underlying disease and is 3–5 mg kg−1 per daily for renal transplants and 1 mg kg−1 per daily for conditions such as rheumatoid arthritis. The dose used for other inflammatory diseases is usually similar to that used in rheumatoid arthritis (50–100 mg) (Meggitt et al, 2011). Many clinicians prefer to gradually increase the drug dosing although there is no hard evidence that such a practice is necessary. Similarly, the drug does not require tapering to be stopped.

The treatment effects of azathioprine are not immediately evident, and thus, azathioprine is usually started together with, or immediately after, high doses of glucocorticosteroids (Boura et al, 2007; Wise and Callen, 2007). Azathioprine usually requires a few weeks (3–6) to establish its effects, when glucocorticoids may be gradually tapered off (Wise and Callen, 2007). The duration of azathioprine treatment is dependent on the disease activity and control. The drug can be stopped as soon as after 3 months, if the condition is controlled, or may be continued for years if necessary (Meggitt et al, 2011). Treatment is generally stopped when symptoms are resolved, and no or minimal steroids are required to maintain the therapeutic result, or if adverse effects indicate.

Monitoring azathioprine use

As noted above, azathioprine should not be administered to patients without prior assessment of TPMT activity. In patients with reduced TPMT activity, lower levels of azathioprine can still be administered with close monitoring (Table 2). Also, the pretreatment assessment should include: complete blood count and liver function tests, urea, electrolytes and creatinine tests.

Table 2. Modification of azathioprine dose according to TPMT levels
TMPT levelAzathioprine daily dose mg kg−1
AbsentAvoid
Intermediate1–1.5
Normal2–3

Patients on azathioprine should be monitored with complete blood count and liver function tests weekly for the first 6 weeks of treatment and then every 2 weeks, until their treatment dose in stable for 6 weeks, after which these tests may be carried out monthly. If the dose of the drug increases, complete blood count and liver function tests should be repeated after 2 weeks and then monthly. If dose and test results are stable for 6 months, one could consider complete blood count and liver function tests every 3 months. In patients heterozygote for TPMT, monitoring should be performed monthly throughout treatment. Also, it is advisable to perform urea, electrolytes and creatinine tests every 6 months. http://www.rheumatology.org.uk/includes/documents/cm_docs/2009/d/dmard_grid_november_2009.pdf, accessed May 2013.

Azathioprine should not usually be prescribed in pregnant women (Category D). If it is imperative to use the drug in a pregnant woman, the patient must be informed of the potential risk of injury to the foetus; fully informed consent is always essential.

Azathioprine coadministration with other drugs

All systemic immunosuppressive agents coadministered with azathioprine may result in severe immunosuppression and an increased risk for infections (Meggitt et al, 2011). Azathioprine also has a significant synergistic action with angiotensin-converting enzyme inhibitors, which may result in severe neutropenia (Hodsman and Johnston, 1987). The coadministration of azathioprine with allopurinol increases the risk of severe myelotoxicity due to decreased metabolism of 6-MP to 6-thiouric acid (el-Gamel et al, 1998). Azathioprine may compromise the antithrombotic effect of heparin and the anticoagulant effect of warfarin (Ng and Crowther, 2006). Drug interactions of azathioprine are summarized in Table 3.

Table 3. Azathioprine potential drug interactions
ACEI (angiotensin-converting enzyme inhibitors)
Allopurinol
Aspirin
Ciclosporin
Clozapine
Co-trimoxazole
Cyclophosphamide
Febuxostat
Immunosuppressants
Mesalazine
Methotrexate
Osalazine
Ribavirin
Sulphasalazine
Trimethoprim
Warfarin
Grapefruit juice and cytochrome p450 inhibitors

Azathioprine use in oral diseases

Azathioprine may be used in the treatment of bullous diseases as a corticosteroid-sparing agent (Table 4) (Wise and Callen, 2007). Azathioprine is approved for the management of pemphigus vulgaris (PV), although the evidence is not very strong (Martin et al, 2009; Meggitt et al, 2011). In PV, the drug was the first immunosuppressive agent to be introduced and is used in combination with corticosteroids and maintained until the disease is controlled with minimal steroids (Meggitt et al, 2011). A few cases of patients with PV successfully treated with azathioprine as a monotherapy have also been reported (Harman et al, 2003). A current systematic review of 11 studies of interventions for PV and pemphigus foliaceus suggested that there is evidence to confirm the steroid-sparing effect of azathioprine (Chams-Davatchi et al, 2007). Also, the most recent Cochrane review of interventions for PV demonstrated that azathioprine is more effective than cyclophosphamide or mycophenolate mofetil (MMF) (Martin et al, 2009). Conversely, there is inadequate evidence to suggest that azathioprine and the other immunosuppressive agents (comprising also cyclophosphamide and mycophenolate) are more effective than glucocorticoids as monotherapy (Martin et al, 2009). Data from two non-blinded, randomized controlled trials concluded that mycophenolate and azathioprine showed similar effects in achieving disease remission (Beissert et al, 2006; Chams-Davatchi et al, 2007). Nonetheless, the intention-to-treat (ITT) analysis of the Beissert et al study advocated that mycophenolate is perhaps more successful than azathioprine in accomplishing disease control (Beissert et al, 2006; Martin et al, 2009; Meggitt et al, 2011).

Table 4. Azathioprine clinical applications in mucocutaneous and other diseases
FDA IndicationsDosagesOral diseasesPrice/unit

Renal transplantation

Rheumatoid arthritis

3–5 mg kg−1 daily, tapered to 1–3 mg kg−1

1.0 mg kg−1 (50–100 mg) for Rheumatoid arthritis

PV

MMP

BP

Crohn's disease and OFG

Behcet disease

LE

OLP

GVHD

Linear IgA BD

Wegener's granulomatosis

Giant cell arteritis

$25–86 for 100 tablets of 50 mg

Azathioprine is the first-choice treatment as a steroid-sparing agent for mucous membrane pemphigoid (MMP) patients with severe mucosal involvement and is used in doses of 1–2 mg kg−1 (Knudson et al, 2010). Azathioprine has been also used with variable reported success in limited numbers of patients with severe mucocutaneous lupus erythematosus (LE), oral lichen planus (OLP), epidermolysis bullosa aquisita (EBA), bullous pemphigoid (BP), linear IgA bullous disease (IgABD), graft vs host disease (GVHD) and Adamantiades-Behçet disease (Wise and Callen, 2007; Hatemi et al, 2008).

Azathioprine has also been tried in few patients with refractory orofacial granulomatosis (OFG) and in people with the oral manifestations of Crohn's disease (1 mg kg−1 day−1) as monotherapy or in combination with systemic steroids, with moderate results (up to 50% remission rate) (Plauth et al, 1991; Leao et al, 2004). Some authors recommend that azathioprine should be reserved for patients with OFG unresponsive to other treatments; three of seven patients in one report developed mild adverse effects from azathioprine (Al Johani et al, 2010).

Azathioprine has also successfully been used in the treatment of patients with oral manifestations of giant cell arteritis and Wegener granulomatosis (Maahs and Fabricio, 2007; Almouhawis et al, 2013).

Azathioprine is probably still the most commonly used steroid-sparing agent for oral diseases with an immune-mediated pathogenesis. It has been in clinical use for decades and has a well-known drug profile. The cost of azathioprine is low in comparison with other steroid-sparing agents, such as mycophenolate. It is important to note that as many potential patients are older people and may have comorbidities, their treatment regimen should be decided and monitored in collaboration with other medical specialties (Sami, 2011).

Mycophenolic acid and Mycophenolate mofetil

  1. Top of page
  2. Abstract
  3. Introduction
  4. Azathioprine
  5. Mycophenolic acid and Mycophenolate mofetil
  6. Conclusions
  7. Author contributions
  8. References

Mycophenolate – both as MMF and Mycophenolic acid (MPA) – is an antiproliferative agent. MPA was originally used in the treatment of psoriasis in the 1970s, but severe adverse effects – gastrointestinal and infections – dissuaded its use (Zwerner and Fiorentino, 2007). MMF was produced in the 1990s (Cellcept), and this and the MPA mycophenolate sodium enteric-coated tablets (Myfortic) proved to have much better tolerance profiles, earning FDA approval (Zwerner and Fiorentino, 2007).

Clinical uses of mycophenolate

Both MMF and MPA are strong immune response inhibitors, and they have been used successfully in solid organ transplant rejection in combination with other immunosuppressants http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf accessed May 2013. They also have been used in numerous other immune-mediated conditions as off-label indications (Park, 2011).

Pharmacology of mycophenolate

Mycophenolic acid sodium (C17H20O6) and MMF (C23H31NO7) inhibit the enzyme inosine monophosphate dehydrogenase – resulting in reduced guanosine nucleotide synthesis – which leads to reduced purine synthesis (Zwerner and Fiorentino, 2007; Park, 2011). As purines are also synthesized via the salvage pathway (hypoxanthine-guanine phosphoribosyl pathway), the effects of MPA and MMF in lymphocytes (which lack this salvage pathway) are greatest. In addition, MMF blocks the inosine monophosphate dehydrogenase type II isoform with greater affinity, and this is the main relevant enzyme found in lymphocytes (Park, 2011). Mycophenolate thus especially blocks lymphocyte proliferation.

Mycophenolate mofetil is produced as the 2-morpholino-ethyl ester of MPA. MMF given orally is rapidly absorbed and reaches high plasma concentration (94%) http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf accessed May 2013. Esterases in the plasma, liver and kidney convert MMF to MPA which is the active agent, bound in plasma to albumin http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf accessed May 2013, then follows a persistent cycle of transformations between active and inactive forms of MPA mediated by the enzyme glucuronidase (Zwerner and Fiorentino, 2007). The active and inactive MPA is repeatedly absorbed and secreted from the enterohepatic circulation, a process that keeps the plasma concentrations of MPA fairly constant, until it is finally cleared as the inactive MPA phenolic glucuronide in the urine; the half-life is around 18 h http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf accessed May 2013. Glucuronidase is found mainly in the gastrointestinal tract and skin – hence, the efficacy in treating cutaneous inflammatory conditions and also the common adverse gastric effects of diarrhoea and discomfort (Zwerner and Fiorentino, 2007).

Mycophenolate adverse effects

Table 5 summarizes the possible adverse effects of MMF and MPA.

Table 5. Possible adverse effects of MMF and MPA
Adverse effects of MMF and MPA
Acne
Chest pain
Cough
Dyspnoea
Exanthemas
Gastrointestinal tract irritation
Haematological abnormalities
Headache
Hypercholesterolaemia
Hyperglycaemia
Hypertension
Hypo/hyperkalemia
Hypophosphatemia
Infections
Insomnia
Malignancies
Palpitations
Pedal oedema
Tinnitus
Gastrointestinal

Mycophenolate-related gastrointestinal tract adverse events are fairly common, seen in 20% of patients, and include nausea, vomiting, diarrhoea and abdominal pain, while in rare cases, gastrointestinal tract bleeding and perforation have been recorded (Mimouni and Nousari, 2002). In renal transplant patients receiving MMF, adverse effects are more common, and result in the need for MMF dose reduction or withdrawal in 40–50% of patients (Bunnapradist and Ambuhl, 2008). The enteric-coated mycophenolate sodium (an enteric-coated formulation for transporting and releasing mycophenolic acid in the intestine-Myfortic) has been created with the aim of improving gastrointestinal tract tolerability and has been proved to be as therapeutically as effective as MMF (Sollinger, 2004; Kobashigawa et al, 2006).

Haematological

Haematological adverse effects, such as leukopenia, anaemia and thrombocytopenia, have been reported in less than five per cent of patients receiving MMF (Park, 2011). In addition, any haematological disturbances related to MMF are usually mild, and dose dependent, and are reversible when the drug is discontinued or dose is reduced (Schanz et al, 2002; Lee and Cooper, 2004). MMF causes leukopenia in 34.5% of patients treated with higher doses such as 3 g daily (Park, 2011).

Infections

There is an increased risk of opportunistic infections reported in patients receiving MMF, especially in doses higher than 2 g daily (Frieling and Luger, 2002). Infections have been reported in approximately 40% of transplant recipients on MMF, but it should be underlined that the majority of cases occurred in patients treated concurrently with other immunosuppressive agents (Park, 2011). The commonly reported infectious diseases in organ transplant recipients treated with MMF include infections with herpes simplex, herpes zoster, human herpes virus type 6, human papillomavirus, aspergillosis, cryptococcosis, candidiasis, mucormycosis, cytomegalovirus and Pneumocystis carinii (Schanz et al, 2002; Lee and Cooper, 2004; Park, 2011). Patients should always be alerted to report any signs or symptoms of infection and have periodic monitoring of complete blood cell count (Mimouni and Nousari, 2002).

Malignancies

Malignancies related to MMF are mainly reported in the organ transplant recipients, when the relative risk of malignancy developing is possibly attributed to the overall collective effect of immunosuppressants’ combination rather than to a single specific agent (Park, 2011). In patients receiving MMF of MPA for skin diseases, a few cases of malignancies have been reported (Orvis et al, 2009). It is possible that for the dermatological conditions for which mycophenolate is indicated, the level of immunosuppression required is less comparing with organ transplants (less dose of MMF), and moreover, the MMF is usually administered as monotherapy (Park, 2011).

Other adverse effects

Other recorded adverse events comprise neurological (mainly mild – like headache, tinnitus and insomnia), dermatological (mainly exanthemas, acne and pedal oedema), cardiorespiratory (dyspnoea, cough, chest pain, palpitations and hypertension) and metabolic (hypercholesterolaemia, hyperglycaemia, hypophosphataemia and hypo/hyperkalemia) (Mydlarski, 2005).

Administration of mycophenolate

Mycophenolate mofetil when administered orally is usually given in doses of up to 2–3 g per daily in two divided doses. The best absorption is achieved when patients take the drug on an empty stomach (Nutley, 1995; Mydlarski, 2005). The MPA sodium usual daily dose is 1.44 g (equivalent to 2 g MMF) and is divided in 2 doses (Kobashigawa et al, 2006). When the oral route is compromised, the IV delivery of MMF is an option but should be performed slowly (over 2 h). In children, MMF should be administered as 600 mg m−2 per dose every 12 h (Assmann and Ruzicka, 2002). In patients with renal insufficiency, there is no evidence of disturbance in pharmacokinetics of MPA, nonetheless a reduced dose should be considered in communication with the treating nephrologist (Assmann and Ruzicka, 2002). In order to avoid disease relapses, some clinicians consider tapering MMF slowly, but it can be stopped immediately if adverse effects occur (Orvis et al, 2009). The drug requires at least 6–8 weeks and sometimes many months to establish the effects (Zwerner and Fiorentino, 2007).

Mycophenolate is contraindicated in pregnant women (category D). Female patients who are of reproductive age and need the drug should be advised to take contraceptive measures as there is a risk of teratogenic affects and miscarriages (Mydlarski, 2005).

Administration is contraindicated in patients with hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (Lesch-Nyhan, Kelley-Seegmiller syndrome) due to hypersensitivity reactions (Nutley, 1995).

Coadministration of mycophenolate with other drugs

Several drugs can affect the metabolism of MMF and MPA (Table 6). Medications that may increase serum MMF levels include salicylates and probenecid; hence, it may be necessary to reduce the dose of MMF with continuous coadministration in order to avoid potential adverse reactions resulting from severe immunosuppression (Mydlarski, 2005). Medications that can decrease the serum level of MMF include rifampin, fluoroquinolones, metronidazole, glucocorticosteroids, ciclosporin, cholestyramine, antacids, iron and calcium (Park, 2011).

Table 6. MMF and MPA interactions
Mycophenolate interactions
Decrease Mycophenolate levels
Antacids (Al, Mg)
Cholestyramine
Ciclosporin
Corticosteroids
Divalent cations (Ca, Fe)
Fluoroquinolones
Metronidazole
Rifampin
Increase Mycophenolate levels
Aciclovir
Ganciclovir
Probenecid
Salicylates

Monitoring

As with all patients on immunosuppressants, patients on MPA and MMF should be under close monitoring for possible adverse effects. Prior to beginning treatment, a laboratory workout including complete blood count, liver function tests, urea and electrolytes and also a chest radiograph are indicated. A complete blood count should be performed weekly until the dose is stable for 4 weeks, and then fortnightly for 2 months. Even after a patient is stabilized on treatment, a complete blood count should be performed monthly. The patients should also be informed that they should contact their clinician in case they have any features of infection (e.g. fever, cough, dyspnoea) or severe gastrointestinal tract disturbances (vomiting, diarrhoea). http://www.rheumatology.org.uk/includes/documents/cm_docs/2009/d/dmard_grid_november_2009.pdf accessed May 2013

Clinical use of mycophenolate in mucocutaneous diseases

MMF and MPA have been used effectively for the control of oral lesions in PV, MMP and severe lichen planus (Table 7). MMF may improve PV lesions faster than does glucocorticoid monotherapy (Beissert et al, 2010), but there is an increased risk of adverse effects if MMF is used in a dose of 3 mg day−1 or greater (Zwerner and Fiorentino, 2007). MMF overall has a good safety profile when used as a long-term steroid-sparing agent in pemphigus (Doukaki et al, 2011).

Table 7. Mycophenolate mofetil and MPA applications in oral diseases
Mode of actionFDA indicationsDosagesOral diseasesPrice/unit
Inhibition of both T and B lymphocytesTransplants (renal, cardiac, hepatic)

for transplants

2 g day−1 (Mycophenolate mofetil)

1440 mg

Total daily dose (Mycophenolic acid)

PV(Esmaili et al, 2008; Baskan et al, 2009)

MMP, EBA, BP, IgA BD, paraneoplastic pemphigus (Marzano et al, 2006; Beissert et al, 2010)

OLP (Wee et al, 2012)

Cell cept $208–612

100 tablets of 500 mg

Myfortic $153 for 60 tablets of 360 mg

Comparing mycophenolate with azathioprine (the two ‘first-line’ steroid-sparing agents used in PV), they show similar efficacy in controlling PV. MMF appears to be safer than azathioprine, which may have more severe toxicities (Beissert et al, 2006), but the cost of MMF is almost 2.5 times higher than that of azathioprine (Cotes and Swerlick, 2013) (Table 8).

Table 8. Mycophenolate mofetil vs Azathioprine
 AzathioprineMycophenolate
Efficacy++++
High cost++
TPMT screen needed++
Monitor+++
Adverse effects+++
Teratogenicity++++
Infections+++++
Malignancy risk+++
Latency>4 weeks>8 weeks

Also, mycophenolate has been used with variable levels of success in limited numbers of patients with MMP, paraneoplastic pemphigus, IgA bullous dermatoses (IgABD) and epidermolysis bullosa (EBA) (Mydlarski, 2005; Orvis et al, 2009).

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Azathioprine
  5. Mycophenolic acid and Mycophenolate mofetil
  6. Conclusions
  7. Author contributions
  8. References

There is sufficient evidence to support efficacy of purine synthesis inhibitors as steroid-sparing agents mainly in managing autoimmune bullous diseases affecting the oral mucosa. Their use in other immune-mediated orofacial diseases has shown benefit, but the evidence is limited.

All agents can have several considerable adverse effects, and patients should be well educated and compliant to the monitoring schedule to avoid serious complications.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Azathioprine
  5. Mycophenolic acid and Mycophenolate mofetil
  6. Conclusions
  7. Author contributions
  8. References

Prof. Scully designed the manuscript and together with Dr Georgakopoulou wrote and revised it.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Azathioprine
  5. Mycophenolic acid and Mycophenolate mofetil
  6. Conclusions
  7. Author contributions
  8. References