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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 26  |  Issue : 1  |  Page : 55-61

Steroid sparing regimens for management of oral immune-mediated diseases


Department of Oral Medicine and Radiology, Mahatma Gandhi Postgraduate Institute of Dental Sciences, Pondicherry, Puducherry (UT), India

Date of Submission05-Jun-2014
Date of Acceptance11-Sep-2014
Date of Web Publication26-Sep-2014

Correspondence Address:
Arti Agrawal
Department of Oral Medicine and Radiology, Mahatma Gandhi Postgraduate Institute of Dental Sciences, Pondicherry, Puducherry (UT)
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-1363.141857

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   Abstract 

Immune-mediated mucocutaneous disease may present oral symptoms as a first sign of the disease. The primary etiology could be the cellular and/or humoral immune responses directed against epithelial or connective tissue, in a chronic and recurrent pattern. Lichen planus, pemphigus vulgaris and bullous pemphigoid are the most frequent immunologically mediated mucocutaneous diseases. More often than not, patients present with complaints of blisters, oral ulcers, pain, burning sensation, and bleeding from the various oral sites. Steroids, whether topical or systemic, are the treatment of choice as they have both anti-inflammatory and immune-suppressant properties; however, challenges in the treatment of autoimmune diseases are the complexity of symptoms, the need to manage long-term medications for preserving organ function, and the long-term adverse effects of steroids. In such situations steroid sparing agents, such as, tacrolimus, dapsone, azathioprine, cyclosporine, and so on, may be helpful. Here an attempt is made to review various treatment regimens that could be used as alternatives to steroids for management of such diseases.

Keywords: Bullous pemphigoid, corticosteroid, immune-mediated diseases, lichen planus, pemphigus vulgaris, steroid sparing agents


How to cite this article:
Agrawal A, Daniel MJ, Srinivasan SV, Jimsha VK. Steroid sparing regimens for management of oral immune-mediated diseases . J Indian Acad Oral Med Radiol 2014;26:55-61

How to cite this URL:
Agrawal A, Daniel MJ, Srinivasan SV, Jimsha VK. Steroid sparing regimens for management of oral immune-mediated diseases . J Indian Acad Oral Med Radiol [serial online] 2014 [cited 2019 May 26];26:55-61. Available from: http://www.jiaomr.in/text.asp?2014/26/1/55/141857


   Introduction Top


Immune-mediated diseases are represented by a large group of immune system diseases and a large group of the diseases are also directly or indirectly associated with the immune system. The diseases of the immune system include immunodeficiency (primary or inherited and secondary or acquired) disorders, immune-proliferative disorders, such as, malignancies of the immune system (multiple myloma, lymphomas, and leukemia), autoimmune diseases, and immune hypersensitivities (allergies). Allergic diseases or immune hypersensitivity-related conditions are one of the largest groups of immune system diseases. [1]

Immune-mediated inflammatory diseases are used to describe immune-mediated diseases associated with inflammatory pathogenesis mechanisms and are characterized by immune dysregulation, which results in acute or chronic inflammation causing organ or tissue damage. One causal manifestation in immune dysregulation is the inappropriate expression of pro-inflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor alpha. [1],[2]

In most of the patients with immunologically-mediated disorders the oral cavity is the site of the earliest manifestations and can be difficult to diagnose and treat. They may share similar clinical manifestations (e.g., desquamative gingivitis and/or oral ulceration), and as a consequence there may be a delay in the definitive diagnosis. [3]


   Immunologically Mediated Diseases that Affect the Oral Mucosa Top


Immunologically mediated diseases that affect the oral mucosa present with inflammation and loss of epithelial integrity, through a cellular and/or humoral immunity mediated attack on the epithelial-connective tissue targets. The main clinical features are ulceration and reddening, with pain that can be severe and debilitating. In many patients these lesions are chronic and/or present a marked tendency to recur, and they often significantly interfere with such basic activities as eating, drinking, talking, and oral hygiene habits. [2]

Two dimensions in the advances of therapy for these diseases deserve attention. First and most important are the recent advances in drug therapy. Conventional therapy suggests that these diseases can be treated with high-dose, long-term, systemic corticosteroids. However, significant side effects are associated with high-dose and long-term use, some of which can be catastrophic and occasionally fatal. The second important and often neglected dimension of treatment is topical care. [4]

Therefore, the overall goals of treatment of immune-mediated diseases are to relieve symptoms, preserve organ function, and control the autoimmune process. Meanwhile, the challenges in the treatment of autoimmune diseases are the complexity of symptoms, the need to manage long-term medications for preserving organ function, and the long-term adverse effects of immunosuppressant drugs.

Corticosteroids play a central role in the treatment of oral immune-mediated diseases. They act as an anti-inflammatory and immunosuppressants. The adverse effects associated with the use of systemic corticosteroids have led to the increased use of topical corticosteroids; but they still have some local and systemic adverse effects. [5]

Adverse effects from corticosteroids arise both from their long-term use and abrupt discontinuation. [6] Two patterns of corticosteroid toxicity were observed by Huscher et al., in 2009: A 'linear' pattern, in which the reported toxicity increased proportionally with the dose and a 'threshold' pattern in which the toxicity was only observed above a certain dose. [7]

With long-term use, corticosteroids can cause altered response to physical stress, steroid withdrawal syndrome, infection, gastrointestinal ulcers or bleeding, osteoporosis, weight gain, insomnia, mood changes, fluid retention, and elevated blood pressure, elevated blood sugar, and aseptic necrosis. [7]

To overcome the adverse effects of long-term use of corticosteroids, steroid sparing agents can be used in replacement therapy or as adjuvant therapy in the management of oral immune-mediated diseases.


   Steroid Sparing Therapy Top


Use of non-steroid immune-suppressive drugs that permits partial withdrawal of corticosteroids is known as steroid sparing therapy. To date, 'steroid sparing' therapies are simply additional non-glucocorticoid immunosuppressive drugs, permitting partial withdrawal of glucocorticoids, and no mechanism-based approach in improving glucocorticoid sensitivity or producing glucocorticoid beneficial effects, with reduced adverse effects, have been identified. [7]

Steroid sparing agents

Azathioprine

0Azathioprine is a purine analog used as a steroid sparing agent. It is a prodrug, which is converted first to 6-mercaptopurine and then to 6-thioguanine, the active metabolite. Azathioprine acts during the S-phase of the cell cycle and inhibits the formation of adenine and guanine nucleotides. [6],[8],[9] Dosages range from 3 to 4 mg/kg [Table 1]. The onset of action is slow, as it usually takes between six to eight weeks to take effect. [6] Initial monitoring should consist of a complete blood count (CBC) and liver enzymes, every two weeks. [6],[10]
Table 1: Summary of the steroid sparing agents[6,8-11]

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Side effects from azathioprine are uncommon, but include gastrointestinal toxicity, hepatotoxicity, alopecia, and pancreatitis. [6],[9] In addition, the lymphoproliferative diseases and infection rates may be elevated. Azathioprine is metabolized by several enzymes, including hypoxanthine guanine phosphoribosyltransferase (HGPRT), xanthine oxidase (XO), and thiopurine methyltransferase (TPMT). As genetic polymorphisms exist, the TPMT levels must be measured prior to therapy. In those with low levels of TPMT, the drug will be more readily metabolized by the HGPRT pathway, leading to higher drug levels. Therefore, appropriate dosing depends on this enzyme level. [6],[8],[10] When prescribing azathioprine, certain drugs, such as, allopurinol, which inhibits XO and shunts the azathioprine metabolism toward the HGPRT pathway, must be avoided. This increases the risk of bone marrow suppression. [6]

Cyclophosphamide

Cyclophosphamide is an alkylating agent that binds to the DNA non-specifically during the cell cycle and suppresses the B-cell function more than the T-cell function. [6],[8],[9] Dosage is 1 gm intravenously every four weeks, with corticosteroid combination. [6] These drugs are most destructive to rapidly proliferating tissues and appear to cause cell death when they tend to divide. [8] Laboratory monitoring consists of renal function, complete blood count with platelets, and urine analysis. [6]

The toxicity of cyclophosphamide is significantly higher than that of azathioprine and mycophenolate mofetil (MMF). [6] Acute myelosuppression is common. Other side effects include mucosal ulcers, alopecia, nephrotoxicity, cardiotoxicity, hepatotoxicity, carcinogenicity, teratogenicity, and interstitial lung fibrosis [Table 1]. Rarely, male patients may develop azoospermia. [6],[8],[9]

Cyclophosphamide has been the traditional steroid sparing agent of choice for patients with severe disease or rapid progression. [6]

Cyclosporine

Cyclosporine is an immunosuppressive agent with anti-T-cell lymphocyte activity. It forms a complex with cytoplasmic cyclophilin and blocks its ability to activate calcineurin [Table 1]. Activated calcineurin normally phosphorylates NFAT-1, a transcription factor that initiates IL-2 production and promotes proliferation of the helper and cytotoxic T-cells. [6],[8],[9] Laboratory monitoring consists of renal- and liver-function tests, complete blood count, electrolytes, lipid profile, and blood pressure. [6],[10]

The most common side effects are electrolyte abnormalities, such as, hyperkalemia, hyperuricemia, and hypomagnesemia. [6],[9] The drug is metabolized by the hepatic cytochrome P450 system and has the potential for many drug interactions. [6],[8] Cyclosporine is nephrotoxic, which is dose-related and may initially be reversible. However, long-term use often leads to irreversible kidney damage and hypertension. Renal toxicity may be potentiated by the concomitant use of aminoglycosides, nonsteroidal anti-inflammatory drugs, amphotericin B, and vancomycin. Other side effects include tremors, hirsutism, hyperlipidemia, hypertension, and gingival hyperplasia. [6],[8],[9]

Dapsone

Dapsone is a sulfone antibiotic with an anti-inflammatory activity, primarily against polymorphonuclear leukocytes. The drug inhibits neutrophil toxicity and chemotaxis by blocking the myeloperoxidase activity. [6],[9],[11]

Dapsone commonly causes hemolytic anemia and methemoglobinemia in varying degrees, in all patients. It is dose-related, but it is most severe in patients with glucose-6-phosphate dehydrogenase deficiency. [6],[9] These patients are extremely sensitive to oxidative stress from dapsone metabolites. Cimetidine and vitamin E may provide some protection against methemoglobinemia. Dapsone is also associated with idiosyncratic peripheral motor neuropathy and psychosis. Agranulocytosis is a rare, but serious reaction, occurring in the first three months of therapy. Finally, a dapsone hypersensitivity syndrome may develop, comprising of severe mononucleosis-like reactions, such as fever, erythroderma, hepatitis, eosinophilia, or death [Table 1]. Complete blood count should be monitored weekly for the first month, monthly for six months, and semi-annually thereafter. Renal- and liver-function tests should be obtained every three months, for potential toxicity. [6],[9],[11]

Tacrolimus

Tacrolimus is the newer immunosuppressant that acts by inhibiting T-cell activation and cytokine release. It is available in 0.1 and 0.3% ointment form [Table 1]. Its adverse effects include nephrotoxicity, neurotoxicity (tremor, headache, motor disturbances and seizures), GI complaints, hypertension, hyperkalemia, hyperglycemia, diabetes, irritation, and burning sensation of the applied area. [6],[8],[10]

Mycophenolate mofetil

It inhibits de-novo purine synthesis by noncompetitively inhibiting inosine monophosphate dehydrogenase (IMPDH). Both B-cell and T-cell lymphocytes are most affected by MMF because these cells lack a purine salvage pathway [Table 1]. This drug may be considered safer than other immunosuppressive agents. Dosages range from 0.5 to 1.5 g twice daily. After ingestion, MMF is converted to mycophenolic acid, which is metabolized by the liver. [6],[8],[9],[10],[11],[12]

Mycophenolate mofetil is well tolerated, with the most common side effect being gastrointestinal distress. Patients may experience dose-related and reversible anemia, leukopenia, and thrombocytopenia [Table 1]. Additionally, there is a slight increase in the incidence of infections. Complete blood count and liver enzymes should be monitored monthly. [6],[8],[10],[11]

Methotrexate

Methotrexate is an anti-metabolite that suppresses DNA and RNA synthesis during the S-phase of the cell cycle. [6],[9] Patients should be started on a low dose (often with an initial test dose) that is cautiously increased every week to the target dose. Laboratory monitoring consists of a complete blood count, electrolytes, and renal- and liver-function tests. Additionally, methotrexate is a teratogen, affecting both egg and sperm production. [6],[9]

The most common adverse effect of methotrexate is hepatotoxicity [Table 1]. The drug may cause bone marrow suppression, ulcers, alopecia, interstitial pneumonitis and fibrosis, and nephrotoxicity. The predisposing factors for toxicity include alcohol consumption, renal insufficiency, diabetes, and increasing cumulative doses. [6],[9]

Patients should avoid drugs that inhibit folic acid metabolism. Certain drugs may also displace plasma proteins and increase methotrexate levels. These include tetracycline, phenytoin, phenothiazines, chloramphenicol, non-steroidal anti-inflammatory drugs, and salicylates. An acute methotrexate overdose may cause bone marrow suppression or gastrointestinal mucositis. In these cases, folinic acid can be administered as a rescue treatment. [6],[9]


   Immune-Mediated Oral Diseases and Steroid Sparing Treatment Regimens Top


To best of our knowledge there is no proper documentation regarding the epidemiology of immune-mediated oral diseases in India. An epidemiological study of immune-mediated skin diseases affecting the oral cavity was conducted in Brazil (2010) and of all the cases registered. Eighty-two (0.8%) corresponded to immune-mediated skin diseases, with the symptoms affecting the oral cavity. The diseases found in this study were: Oral lichen planus, pemphigus vulgaris, and benign mucous membrane pemphigoids [Table 2]. [13]
Table 2: Distribution of immune-mediated diseases affecting the oral cavity[13]

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Lichen planus

Oral Lichen Planus (OLP) is a common chronic inflammatory disease associated with cell-mediated immunological dysfunction. Atrophic and ulcerative (erosive) forms of OLP can cause symptoms ranging from burning sensation to severe pain with remission being rare. [14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24]

According to a study done by Riano et al., 0.1% tacrolimus (topical application) in cases of oral erosive lichen planus, refractory to numerous treatments (mainly corticosteroids), responded well, within 15 days of therapy. [20] Yet another comparative study conducted by Javed A Qazi showed that topical tacrolimus ointment induced a better initial therapeutic response than triamcinolone acetonide ointment. However, a relapse was reported within six to eight weeks of cessation of therapy. [25] In the study conducted by Verma et al., 77.8% patients had an excellent response with azathioprine and none of the patients with complete healing of lesion had a relapse over the six-to-nine-month follow-up period after stopping treatment. [26]

A recent clinical study done by Raj et al. on the response to dapsone for resistant oral erosive lichen planus demonstrated a significant improvement in the burning sensation and reduction in size of the erosive areas within three months of therapy. Reduction in hemoglobin percentage, by 0.92 gm from the baseline values, was the only observed side effect. Therefore, it was concluded that dapsone could be used as a steroid sparing agent, with minimal adverse effects. [27]

According to the Cochrane database, oral lichen planus treatment aims to provide symptomatic relief, as there is no cure for this disease. Although topical steroids are considered to be the first line of treatment, there are no randomized control trials that compare steroids with placebo in patients with symptomatic OLP. Trials in this review are not suggestive of any one steroid being more effective than the other. There is only weak and unreliable evidence that cyclosporin may reduce pain and clinical signs of OLP. Compared to steroids or placebo, other calcineurin inhibitors (tacrolimus, pimecrolimus) were not effective in reducing pain [Table 3]. From the 28 trials included in this systematic review and the wide range of interventions compared, there is insufficient evidence to support the effectiveness of any specific treatment being superior. [28]
Table 3: Use of steroid sparing agents in the order of preference[6,26]

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Pemphigus vulgaris

Pemphigus is a group of rare, chronic, potentially life-threatening autoimmune blistering disease characterized by widespread blistering and erosions of the skin and mucous membranes. [17],[18],[19],[29],[30],[31] The first sign of the disease appears in the oral mucosa in approximately 60% of the cases. Chronic blistering can result in pain, dehydration, secondary infection, and in rare instances, death.

Pemphigus vulgaris is not curable; therapeutic regimens aim to reduce blister formation by suppressing the immune response. Systemic glucocorticoids are the cornerstone of management, however, adjuvant immunosuppressive and anti-inflammatory agents are commonly used [Table 3]. [29],[32]

A recent Cochrane review included data from 11 clinical trials involving 11 different active treatment regimens (prednisolone, pulsed oral dexamethasone, azathioprine, cyclophosphamide, cyclosporine, tacrolimus, dapsone, mycophenolate, plasma exchange, topical epidermal growth factor, and traditional Chinese medicine), but provided limited information due to a very small sample size. Multiple treatments were available, but there was a variation in dosage plan due to the difference in individual response and combination of the drugs used, which made the choice of the treatment schedule complex. The most effective and safest treatment plan could not be concluded due to insufficient information. [33],[34],[35],[36]

According to Vyas et al., MMF was found to be more effective than azathioprine in controlling the disease, although no difference was seen in remission. [37] Azathioprine and cyclophosphamide decreased the amount of glucocorticoids required, while the topical epidermal growth factor reduced the time required for the lesions to heal by six days (median). There was no difference in withdrawal due to adverse events in any study, although differing adverse event profiles were observed for each intervention. [33],[38]

Another evidence-based study conducted by Sanjay Singh in 2011, suggested that oral glucocorticoid along with a steroid sparing agent appears to be the most effective treatment. Azathioprine had the maximum, while cyclosporine had the least efficacy. MMF could have a similar or a lesser effect and a similar safety profile as azathioprine. Intravenous immunoglobulin (IV Ig) had a moderate effect as an adjuvant or when used alone for treatment-resistant pemphigus. He also documented some efficacy of dapsone as a steroid sparing drug in the maintenance phase. [39]

Bullous pemphigoid

Bullous pemphigoid is an autoimmune disease of the skin and mucous membrane, usually occurring in the elderly, with equal sex predilection. Manifestations of oral disease include vesicles, erosions, desquamative gingivitis, and occasionally scarring. [40],[41],[42]

According to the Cochrane collaboration review on 1049 participants, in 10 different randomized controlled trials, oral corticosteroids are most widely used, but may be associated with serious adverse effects, including, some deaths. All the studies involved different comparisons and none had a placebo group. Other treatments included azathioprine, mycophenolate mofetil, dapsone, methotrexate, cyclosporin, cyclophosphamide, plasma exchange, erythromycin, and tetracycline nicotinamide [Table 3]. [43],[44] Different doses and formulations of corticosteroids plus azathioprine showed no significant difference in disease control, although it reduced the amount of prednisone required. There were no significant differences in healing or disease-free intervals in participants taking azathioprine, when compared with MMF, or in the disease response, when comparing tetracycline plus nicotinamide with prednisolone. [45] According to Marzano et al., mycophenolic acid can be used in refractory cases. [46]

Yet another evidence-based systematic review conducted by Sanjay Singh concluded that for bullous pemphigoid, topical corticosteroid is effective for both moderate as well as extensive disease and is even superior to oral corticosteroids. Adding azathioprine to oral corticosteroids may or may not be superior to oral corticosteroid alone. Adjuvant azathioprine and MMF have a similar efficacy but the latter has significantly lesser liver toxicity. A combination of nicotinamide and tetracycline can be a useful alternative to systemic steroids. [39]

In recent times, omalizumab therapy has been used for the management of bullous pemphigoid by Yu et al., as it selectively suppresses the activity of IgE, an important immunoglobulin in the pathogenesis of the disease. The results of the study have shown improvement and control in the disease activity. [47]


   Conclusion Top


With the results of various studies, it can be assumed that immune-mediated diseases with oral manifestations are relatively rare among oral lesions. Prevalence of the principle immune-mediated diseases affecting the oral cavity is 0.8%. Oral corticosteroids are the first line of treatment in the management of immune-mediated diseases. Steroid sparing agents are indicated in patients in whom systemic steroids are ineffective or are contraindicated or have to be discontinued because of side effects. Steroid sparing drugs can be used as an adjuvant to corticosteroids or as a monotherapy, and selection of the drug and outcome of its use in immune-mediated disease is specific for an individual. Therefore, the risk-benefit ratio should be taken into consideration when prescribing a steroid sparing therapy.

As the number of randomized control trials using steroid sparing drugs for management of immune-mediated diseases is scarce, we need to use these drugs with caution.

 
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46.Marzano AV, Dassoni F, Caputo R. Treatment of refractory blistering autoimmune diseases with mycophenolic acid. J Dermatolog Treat 2006;17:370-6.  Back to cited text no. 46
    
47.Yu KK, Crew AB, Messingham KA, Fairley JA, Woodley DT. Omalizumab therapy for bullous pemphigoid. J Am Acad Dermatol 2014;71:468-74.  Back to cited text no. 47
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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