Immunosuppressants

• Immunosuppressants are drugs which differentially block or suppress various aspects of the body's immune system.
• Uses of immunosuppressants:

  • Suppress rejection of transplanted organs (kidney, heart, liver, lungs)
  • Suppress graft versus host disease in bone marrow transplants
  • Treatment of diseases with a significant autoimmune component in their pathogenesis:
  • Rheumatoid arthritis
  • Psoriasis
  • Ulcerative colitis
• Immunosuppressive drugs:

  • Glucocorticoids
  • Non-glucocorticoid drugs
• Glucocorticoids (corticosteroids):

  • Profound anti-inflammatory and immunosuppressant properties
  • Immunosuppressant properties arise through the suppression of T-lymphocyte activity
  • Also decreases gene transcription for TNFα, interferon and IL-1. Thereby affecting the inflammatory and specific immune response
  • Examples include: hydrocortisone, prednisolone, betamethasone, dexamethasone
• Glucocorticoids (corticosteroids):

  • Potential complications of systemic use
  • Adrenal suppression
  • Reflux
  • Increased thirst and urination
  • Dysrhythmia/tachycardia/hypertension
  • Menstrual period changes
• Glucocorticoids (corticosteroids):

  • Potential complications of systemic use
  • Mental/mood changes
  • Muscle weakness/pain
  • Osteoporosis
  • Persistent weight gain/puffy face
  • Seizures
  • Increased risk of infection
  • Delayed healing
  • Increase risk of duodenal ulcers
• Glucocorticoids (corticosteroids):

  • Potential complications of systemic use
  • Oedema of the feet/ankles
  • Skin atrophy
  • Dyspnoea/shortness of breath (SOB)
  • Unusual hair growth
  • Increased risk of developing cataracts
• Glucocorticoids (corticosteroids):

  • Systemic use
  • Prolonged corticosteroid therapy -> adrenal suppression -> adrenal atrophy
  • Pts potentially affected:
  • Systemic steroids at or above 7.5mg prednisolone equivalent
  • Previous  7.5mg prednisolone long term stopped WITHIN last 3 months
  • Steroid-induced osteoporosis (SIOP)
  • Significant bone loss and increased fracture risk is seen with daily prednisone doses as low as 5mg
  • Alternate-day glucocorticoid therapy can lead to similar bone loss
  • No conclusive evidence exists for a safe minimum dose or duration of glucocorticoid exposure
• Non-glucocorticoids:

  • Calcineurin inhibitors
  • Antimetabolites
  • Antibodies
• Non-glucocorticoids - calcineurin inhibitors:

  • Inhibit IL-2 production or action
  • Examples: ciclosporin and tacrolimus
• Ciclosporin (calcineurin inhibitor - non-glucocorticoid):

  • Originally developed as an antifungal agent
  • Targets T-cell responses via inhibition of IL-2
  • Decreased clonal proliferation of T cells
  • Reduced induction and proliferation of suppressor/cytotoxic T-cells
  • Reduced function of effector/helper T-cells
  • Leaves B-cell response functional
• Azathioprine (antimetabolite - non-glucocorticoid):

  • Intereferes with purine synthesis, essential for DNA synthesis
  • Therefore cytotoxic to dividing cells (both T-cells and B-cells)
  • Depresses bone marrow which can cause oral manifestations
  • Neutropenia
  • Thrombocytopenia
  • Agranulocytosis
• Non-glucocorticoids - antimetabolites:

  • Drugs that interfere with nucleic acid synthesis
  • Inhibit purine or pyrimidine synthesis
  • Eg azathioprine
  • Folic acid analogues
  • Eg methotrexate
• Methotrexate (antimetabolite - non-glucocorticoid):

  • Folid acid analogue
  • Inhibits dihydrofolate reductase which is essential for the synthesis of purines and pyrimidines (thereby inhibiting DNA synthesis)
  • Used in the treatment of autoimmune diseases (e.g. Rheumatoid arthritis) and in transplantations
  • Cautions:
  • Bone marrow suppression
  • Liver toxicity
• Non-glucocorticoids - antibodies:

  • Polyclonal (intravenous immunoglobulin)
  • Monoclonal (infliximab)
• Polyclonal (intravenous immunoglobulin) antibodies (non-glucocorticoids):

  • Polyclonal antibodies are antibodies that are secreted by different B cell lineages
  • A collection of antibodies (multiple cell lines)
  • If antibodies are human in origin = usually termed immunoglobulins
  • Normal immunoglobulin
  • Given as a plasma protein replacement therapy (IgG) for immune deficient patients who have decreased/absent antibody production capabilities
• Monoclonal (infliximab) antibodies (non-glucocorticoids):

  • Derived from a single cell line
  • Clones of a single parent cell
  • Bind to and inhibit cytokines involved in innate immune response
  • eg TNF-α, IL-2
  • Examples include: infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira)
• Monoclonal (infliximab) antibodies (non-glucocorticoids) are used in the treatment of:

  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Crohn's disease
  • Psoriasis
• Monoclonal (infliximab) antibodies (non-glucocorticoids) complications:

  • Raise the risk of contracting infections or inducing a latent infection to become active
  • Increased malignancy risks
  • Other risks including hepatic failure (dental relevance)
• General dental/oral problems with immunosuppressants:

  • Increased risk of opportunistic infections
  • Candida
  • Herpes
  • Increased risk of poor wound healing and wound infection
  • Need for antibiotic cover (only if neutropenic) neutrophils < 3x10⁹/L
  • Increased risk of malignancy
  • Skin and lip cancer
  • Lymphomas
• A specific dental/oral problem with immunosuppressants is ciclosporin-induced gingival overgrowth:

  • Prevalence of 30%
  • Higher frequency in adolescents and males
  • Effects anterior gingiva
  • Target cell is gingival fibroblast
  • Changes occur within 3 months of dosing
  • High recurrence rate
  • Extent and severity related to gingival inflammation (OH, periodontal destruction)
  • Exacerbation by nifedipine (calcium channel blocker)
  • Histopathology = enlargement of connective tissue component in gingival tissues
• A specific dental/oral problem with immunosuppressants is ciclosporin-induced gingival overgrowth. Management involves:

  • Good OH and reducing gingival inflammation prevents recurrence
  • Gingival surgery
  • Scalpel
  • Laser
  • Reducing dosage (physicians only)
• Dental/oral problems with systemic use of glucocorticoids (immunosuppressants):

  • Treatment of SIOP (steroid induced osteoporosis) may include bisphosphonates or denosumab
  • Need to be wary of these drugs if dental extractions are planned - risk MRONJ (medication-related osteonecrosis of the jaw)
  • Local protocol
  • Previously antibiotic cover and chlorhexidine mouthwash
  • Now refer to SCDEP guidelines (March 2017)
  • Categorise into high or low risk
  • Preventative treatment and consent is key