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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 29  |  Issue : 4  |  Page : 306-313

Immunosuppressants in Oral Medicine: A Review


Department of Oral Medicine and Radiology, Swami Devi Dyal Hospital and Dental College, Barwala, Haryana, India

Date of Submission12-Feb-2017
Date of Acceptance18-Jan-2018
Date of Web Publication15-Feb-2018

Correspondence Address:
Dr. Aravinda Konidena
Department of Oral Medicine and Radiology, Swami Devi Dyal Hospital and Dental College, Barwala, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.JIAOMR_24_17

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   Abstract 


Immunologically mediated mucocutaneous diseases constitute a large group of oral mucosal disorders that compromise the quality of life of patients due to their chronicity. The treatment of these disorders should not only be directed to bring relief from symptoms but also towards treating the underlying immune dysregulation, prevent recurrences, and preserve organ integrity and function. These disorders are largely treated by immunosuppressants. Challenge in treating these disorders lies in existing comorbidities, frequent relapses or short disease-free intervals, and long-term use of medication and their complications. This review focusses on newer immunosuppressants and their role in oral mucosal disorders.

Keywords: Biologics, immunosuppressants, oral mucosal disorders, steroid sparing drugs


How to cite this article:
Konidena A, Sharma S, Patil DJ, Dixit A, Gupta R, Kaur M. Immunosuppressants in Oral Medicine: A Review. J Indian Acad Oral Med Radiol 2017;29:306-13

How to cite this URL:
Konidena A, Sharma S, Patil DJ, Dixit A, Gupta R, Kaur M. Immunosuppressants in Oral Medicine: A Review. J Indian Acad Oral Med Radiol [serial online] 2017 [cited 2019 Jun 19];29:306-13. Available from: http://www.jiaomr.in/text.asp?2017/29/4/306/225554




   Introduction Top


Immunologically mediated mucocutaneous diseases constitute a large group of oral mucosal disorders and are triggered by cellular or humoral responses directed against epithelial or connective tissues in a chronic, recurrent pattern.[1] They may be grouped under the following categories:[1],[2]

  1. Autoimmune disorders: Refer to a disorder with an evidence of an immune response against self-antigens due to either autoantibodies or immune cells, and are characterized by lymphocytic infiltration in a target cell
  2. Hypersensitivity disorders/Allergies: Characterized by hypersensitivity reaction to exogenous antigens such as drugs, restorative materials, and food substances. They are further classified as Type 1 (immediate hypersensitivity), Type 2 (antibody mediated), Type 3 (immune complex mediated), and Type 4 (cell mediated or delayed hypersensitivity)
  3. Primary or secondary immunodeficiencies: These disorders are characterized by immune system not capable of mounting a normal immune response
  4. Immunoproliferative disorders: Malignancies of the immune system (multiple myeloma, lymphoma, leukemia, etc.).


Immune-mediated inflammatory conditions are characterized by immune dysregulation, resulting in acute or chronic inflammation and causing end organ damage. One causal manifestation in immune dysregulation is the inappropriate expression of proinflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor alpha.[3] Often, oral cavity may be the first site of manifestation of these debilitating recurrent diseases, forcefully limiting many oral functions of the patient including nutrition, and thus, compromising their quality of life. The treatment of these disorders should be directed not only toward relief from symptoms but also toward treating the underlying immune dysregulation, prevent recurrences, and preserve organ integrity and function.

Immunomodulators

The control of immune dysregulation can be achieved by the use of immunomodulators, defined as natural or synthetic substances that help regulate or normalize the immune system.[4] In other words, they correct immune systems out of balance, i.e., strengthen weak immune systems or moderate over reactive immune systems.

Immunomodulators may be further classified into immunostimulants and immunosuppressants. The classification of immunomodulators is given in [Table 1]. Immunostimulants are agents that are envisaged to enhance body's resistance against infections; they enhance the basal levels of immune response, especially in immunodeficiency. Immunosuppressants are agents that suppress the immune system and are used for the control of pathological immune response in autoimmune disease or hypersensitivity. This review would focus on newer groups of immunosuppressants and their use in oral mucosal disorders.
Table 1: Classification of immunomodulators

Click here to view


Immunosuppressants

Immunosuppressants are agents used to suppress the over reactive immune system causing damage to the host as in autoimmunity or hypersensitivity. Based on the mode of action and origin, they may be broadly classified as traditional immunosuppressants, steroid sparing drugs, and biologics. The mode of action and indications of these various groups are detailed further.

Corticosteroids

Traditional agents used for immunosuppression are glucocorticoids, acting both systemically or topically as anti-inflammatory immunosuppressants. Glucocorticosteroids exhibit intervention at several points in the immune response and appear to affect many aspects of inflammation. In fact, corticosteroids have evolved and emerged as the mainstay of therapy for numerous oral lesions and conditions with an allergic, immunologic, or inflammatory basis.[5]

Mechanism of action

  1. These drugs inhibit inflammatory mediator release from many cell types involved in inflammation such as macrophages, T-lymphocytes, mast cells, dendritic cells, and neutrophilic leukocytes
  2. Glucocorticoids also reduce prostaglandin production by blocking the phospholipase A2 enzyme
  3. The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes encoding cytokines, chemokines, inflammatory enzymes, receptors, and adhesion molecules
  4. Changes in gene transcription are regulated by proinflammatory transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). These proinflammatory transcription factors switch on inflammatory genes via a process involving the recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation
  5. Glucocorticoids exert their anti-inflammatory effect on responsive cells by binding and activating a cytoplasmic glucocorticoid receptor. The interaction between the activated glucocorticoid receptor and proinflammatory transcription factors may result in deacetylation of histones and repression of inflammatory genes.[6],[7]


Indications

Used commonly but not limited for the treatment of:

  1. Several ulcerative, vesiculobullous lesions involving the oral cavity and perioral areas, including recurrent aphthous stomatitis (RAS), Bechet's syndrome, pemphigus vulgaris, bullous pemphigoid, mucous membrane pemphigoid, erythematous and ulcerative lichen planus, SLE, DLE, linear IgA disease, epidermolysis bullosa, mucositis, erythema multiforme, and Stevens–Johnson syndrome
  2. Intralesional injections in oral submucous fibrosis, vascular anomalies, and giant cell granuloma
  3. Orofacial granulomatosis
  4. Temporomandibular disorders
  5. Causes of orofacial pain including temporal arteritis, Bell's palsy, post-herpetic neuralgia, and Ramsay–Hunt syndrome
  6. Perioperative use in third molar removal
  7. Salivary gland disorders such as Sjogren's syndrome, sarcoidosis, uveoparotid fever, mucoceles, ranulas, and allergic sialadenitis
  8. Oral hypersensitivity disorders such as plasma cell stomatitis, fixed drug eruption, angioedema, oral allergy syndrome, and lichenoid eruptions.[5]


Side effects

However, long-term use of corticosteroids, as required in these disorders, results in several adverse effects, including gastric ulcer or upper gastrointestinal bleeds, hyperglycemia, hypertension, myopathy, osteoporosis, altered response to physical stress, adrenal insufficiency, opportunistic infections, Cushingoid habitus, cataract, and glaucoma.[8] Search for alternative drugs resulted in the use of steroid sparing drugs that permit partial withdrawal of corticosteroids.[9]

Steroid sparing drugs

Sometimes immunosuppressive medications are given in addition to or instead of steroid therapy to lower the dose of steroids needed, and thus, spare some of the undesirable side effects of steroid therapy. Therefore, these drugs are sometimes called “steroid-sparing” medications or “adjuvant” drugs. Nonsteroid immune-suppressive drugs that permit partial or total withdrawal of corticosteroids is thus known as steroid sparing therapy.[1] These agents can be further subdivided into the following categories based on their specific mechanism of action – alkylating (cyclophosphamide and chlorambucil), antimetabolite (methotrexate, mycophenolate mofetil, and azathioprine), and antibiotic/calcineurin inhibitor (cyclosporine, tacrolimus, and sirolimus).[9]

The success of corticosteroid sparing therapy may be defined as – (1) the ability to reduce systemic corticosteroid to a daily dose of 10 mg of oral prednisone or less; (2) clinically reduced inflammation; (3) stabilization or improvement in symptoms such as pain; and (4) patient tolerance of any drug-related side effects.[10]

Mechanism of action

The mechanism for various groups of steroid sparing drugs is different and is listed in [Table 2].[11],[12]
Table 2: Mechanism of action, monitoring, indications and adverse reactions of steroid sparing drugs

Click here to view


Oral indications

  1. Immunologically mediated disorders such as RAS, Behcet's disease, erythema multiforme, lichen planus, pemphigus, pemphigoid, epidermolysis bullosa, rheumatoid arthritis, Sjogren's syndrome, and Wegener's granulomatosis
  2. Connective tissue disorders such as SLE and scleroderma
  3. In cases of acute or chronic graft rejection.[13],[14],[15],[16],[17]


General side effects

  1. Bone marrow suppression, pancytopenia
  2. Increased risk of opportunistic infections
  3. Increased risk of malignancies
  4. Cardiotoxicity, nephrotoxicity.[13],[14],[15],[16],[17]


Biologics

Definition

Biopharmaceuticals – biologics, biologicals or biological agents (BAs) – are any medicinal product manufactured in or extracted from a biological source. Biologics often target immunocytes or their products, thus targeting specific steps in proinflammatory pathways.[18] Their mode of action is by blocking specific pathways involved in the pathophysiology of immune mediated and neoplastic diseases. These agents promise a more targeted anti-inflammatory or immunosuppressive action in comparison to corticosteroids and classic corticosteroid-sparing immunosuppressants. Hence, probably, they represent a pathogenesis-based treatment and not just palliative therapy, and may consist of a cytokine, antibody, or fusion protein.[19]

Chemically, biologics belong to three main classes:[19],[20]

  1. Biologics: Nearly identical to key signalling proteins, for example, biosynthetic human insulin, erythropoietin, colony stimulating factors, or growth hormone
  2. Monoclonal antibodies (mAbs): “Custom-designed” using hybridoma or other technology; these are antibodies that aim to counteract or block a given biological substance or to target and damage a specific cell type
  3. Receptor constructs or fusion proteins are created through fusion of different genes encoding for the same protein. Chimerization involves replacing segments of the antibody produced in a mouse that distinguish it from a human antibody, to reduce adverse reactions; this is shown by inserting -xi- into the name.


Nomenclature

Biologics include a number of human (suffix “mab”), humanized (suffix “zumab”), or chimeric (mouse–human; suffix “ximab”) monoclonal antibodies or variant fusion proteins (suffix “cept”).[21]

Mechanism of action

Biologics are often used to target immunocytes or their products, and thus, specific steps in proinflammatory pathways. Biologics may act in this manner by binding directly to immunocytes [T lymphocytes, B cells, granulocytes, antigen-presenting cells (APCs), dendritic cells (DCs), macrophages or other immunocytes] or immune mediators (cytokines, chemokines, growth factors, and complement components) thereby acting to:

  1. Suppress their function
  2. Prevent their homing to lymphoid organs and inflammatory sites
  3. Induce anergy (immune unresponsiveness)
  4. Deplete the cells.[22],[23],[24],[25]


Oral indications for use of biologics

  1. Ulcerative disorders: RAS, Behcet's disease, pemphigus, pemphigoid, and lichen planus. Patients with refractory ulcerative lesions respond well to TNF alpha inhibitors such as eteranacept and adalimumab
  2. Crohn's disease or Orofacial granulomatosis: Biologics (TNF alpha inhibitors) may also help patients with extraintestinal manifestations of Crohn's disease, including oral Crohn's disease and related disorders, such as orofacial granulomatosis (OFG), and allied conditions such as Melkersson–Rosenthal syndrome (MRS), and a more limited granulomatous cheilitis
  3. Sjogren's syndrome: Rituximab, however, has produced some improved SS symptoms (xerostomia, etc.) and increased salivary gland function and MALT has remitted in some patients. There appears to be a clinical benefit from rituximab in systemic extraglandular complications of SS (fatigue, cryoglobulinemia, pulmonary disease, polysynovitis, arthralgia, and peripheral neuropathy)
  4. Cancer: Biologics against angiogenesis, such as VEGF inhibitors (bevacizumab) and others against epidermal growth factor receptors (anti-EGFR) agents are prime examples now in clinical use. Anti-EGFRs such as cetuximab have significantly improved oral cancer patients survival.[26],[27],[28],[29],[30]


Side effects and precautions

They pose an inherent risk for adverse immune-mediated drug reactions such as infusion reactions, cytokine storms, fatigue, arthralgia, immunosuppression, autoimmunity, infections, potential malignancy, and other disorders. Precautions include screening for coexistent medical disorders; the use of strict eligibility criteria which include (a) severe disease, as measured by objective measurements and (b) use only where patients are refractory to/intolerant of conventional systemic therapy or where such therapy is contraindicated.[31],[32],[33]

Classification

The four main classes of BAs are TNF-α inhibitors, lymphocyte modulators, interleukin inhibitors, and miscellaneous agents.[18]

  1. TNF Inhibitors: TNF-α is a key pro-inflammatory cytokine central in the pathogenesis of immunologically driven disease acting via pathways to promote increased leucocyte activation and recruitment to sites of tissue inflammation. TNF acts by binding to the plasma membrane receptor TNFR, leading to inflammation, or programmed cell death (apoptosis). TNF-receptor 1 is generally expressed in all cell types, whereas TNF-receptor 2 is expressed only on endothelial and immune cells. TNF induces apoptosis by binding to TNF-receptor 1, which activates the caspase 3–8 cascade. TNF may promote inflammation by binding to either receptor 1 or 2 by activating one or more of three pathways:

    JNK (c-Jun N-terminal kinase)-dependent kinase cascade

    MAPK (Mitogen-activated protein kinases) kinase cascade

    NF-κB (Nuclear factor-kappa B) transcription factor.
  2. Lymphocyte modulators: Lymphocyte modulators act on specific lymphocyte antigens [cluster of differentiation (CD) antigens]. They are further divided into:


    1. T-cell modulators
    2. T-cell costimulators
    3. B-cell modulators.


  3. Interleukin inhibitors: Interleukins are a group of cytokines (IL-1 to IL-35 have been identified) synthesised mainly by lymphocytes, monocytes, and macrophages that play a role in the regulation of the immune system. Interleukin inhibitors are immunosuppressive agents that inhibit various interleukins and have a broad spectrum of uses depending on the interleukin they target
  4. Miscellaneous biologic agents: Include a wide range of biologics used for miscellaneous purposes including treatment of cancer


    1. Anticoagulant and neovascularization agents
    2. Antiepidermal growth factor receptor
    3. Receptor activator of nuclear factor kappa B ligand blockers
    4. Antimicrobial agents
    5. Vaccines.


The details of various biologics are given in [Table 3].
Table 3: Mechanism of action, indications, and adverse reactions of biologic agents

Click here to view



   Conclusion Top


There is a new range of therapeutic solutions to steroid resistant or recalcitrant oral lesions available in the form of steroid sparing drugs and biologics. However, more randomized control trials with the use of these newer drugs should be conducted to elaborate the risk–benefit ratio in the management of patients with oral lesions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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