Oral Health Effects of Immunosuppressive Medications

PART 2 of a two-part series: Appearing in December 2021 (and available here), the first article in this series, “Clinical Signs and Risk Factors for Autoimmune Diseases,” explored the signs and symptoms of autoimmune diseases. This concluding installment focuses on the oral health effects of medications used to treat these conditions.

The number of individuals diagnosed with autoimmune-related conditions has significantly increased in recent decades due to advances in immune system research and improved diagnostics.¹ Additionally, knowledge of potential causes and risk factors has expanded beyond known genetic components to encompass environmental factors, hormones and lifestyle choices.² Autoimmune conditions are heterogeneous, affecting individuals differently, thereby complicating treatment.³ Effective medications for one type of autoimmune condition, or group of individuals, can be less effective for others.⁴ Research has greatly expanded the number of immunosuppressive medications to control autoimmune diseases (ADs) and protect organ or tissue transplants, but there are numerous adverse effects.⁴ Immunosuppression increases the risk for oral and systemic complications; therefore, there is a delicate balance between immune system suppression and protection from side effects. Due to the immune system’s complexity, patients may be on a combination pharmacotherapy to manage their condition.⁴

Immunosuppression is a reduction in the action or efficacy of the immune response. When treated with pharmacotherapy, the goal is to reduce the immune response involved with organ or tissue transplants, ADs, or inflammatory conditions.⁵ The focus is to suppress the immune effectors and control inflammation in the induction phase, and prevent relapse and reduce complications in the maintenance phase. Pharmacotherapy can target specific tissues and cells or have a more systemic approach; importantly, less specific medications can increase adverse effects.⁶

With expanded knowledge of immune system intricacies, immunosuppressive medications have increased in number and application.⁷ Each condition and immune response provides a unique challenge, so a tailored combination of medications is often used to improve efficacy while minimizing adverse effects. To determine the dosage and duration, physicians assess the severity and impact of the disease, as well as the patient’s ability to withstand the course of treatment.⁵ 

Corticosteroids are a common initial immunosuppressive therapy for many rheumatologic autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus (SLE), and pemphigus.^7,8 High doses are toxic to lymphocytes, while lower doses reduce inflammation by limiting cytokines and reproduction of T-cells and B-cells; the dosage is disease dependent. While first-generation medications are effective, newer alternatives are sought to avoid the variety of known long-term side effects, including osteoporosis, hypertension and diabetes.^6,7

Calcineurin inhibitors — cyclosporine and tacrolimus — are T-cell directed therapies and are a mainstay in transplantation cases. They are also used for severe SLE and cutaneous lesions — but to minimize adverse effects on the heart and kidneys, newer medications are now is use.^5,7,9

BIOLOGIC AGENTS

Research on biologic agents, including antibodies, has highlighted various pathogenicity pathways and efficacy in AD treatment.^4,10–12 Biologic agents target T-cell and B-cell interaction, naïve T-cells, specific pro-inflammatory cells, and antibody responses to treat inflammatory ADs.^4,10,11,13 Monoclonal antibodies are part of the next generation of pharmaceuticals that may reduce side effects via their ability to focus on specific targets. The tumor necrosis factor alpha (TNF-α)-inhibiting medications target the TNF-α cytokines that cause the bone and joint pain and destruction seen with rheumatoid arthritis, SLE and psoriatic arthritis.^3,7 TNF-α inhibitors also reduce damage in patients with Crohn’s disease and ulcerative colitis, and can be used to treat multiple sclerosis, pemphigus and psoriasis.^6–8 Another biological agent, the IL17 antagonist, can nearly eliminate psoriasis plaques, but is ineffective at reducing the joint, bone and cartilage damage caused by psoriatic arthritis. While these newer generation medications show promise, the subset of cells initiating disease in one patient may differ from those activated in another with the same condition.¹²

Other medications include disease modifying anti-rheumatic drugs (DMARDs), such as cyclophosphamide, chemotherapeutic methotrexate and others. Use of DMARDs is the treatment of choice for many ADs, including rheumatoid arthritis, juvenile idiopathic arthritis, SLE, myopathies and systemic sclerosis.^{3,10,11,14,15} Low doses can effectively reduce inflammation, in part by increasing the anti-inflammatory mediator adenosine.¹⁵ 

ADVERSE DRUG EFFECTS

Immunosuppressive medications are associated with increased risk for infection, tissue changes and cancer; they also elevate the risk for caries and possible periodontal changes.¹⁶ As patients navigate treatment modalities, oral health professionals should be diligent in recognizing related changes and maintaining interprofessional communication with patients’ medical teams. Without intervention, outcomes for immunocompromised patients may rapidly deteriorate.

Increased Risk of Infection — An increased risk of infection or reactivation of latent infections — such as hepatitis B, hepatitis C or tuberculosis — is a concern when taking immunosuppressive medications.^3,7,17 While infections are typically mild, opportunistic or severe infections can occur.^3,16 The most vulnerable patients, including children, older adults with comorbidities, pregnant women, and those taking higher immunosuppressive doses, are at greatest risk. Due to an altered immunological response during pregnancy, the risk for new or severe infection is particularly high in the third trimester.^16,17

Reactivation of tuberculosis infections has been associated with some TNF-α inhibitors.^3,17,18 A complete medical history can identify if the patient has had tuberculosis in the past. If tuberculosis infection is recurring, clinicians may recognize redness and irritation in the back of the throat from the chronic, persistent cough. While uncommon, a single, pale, painful ulceration on the tongue is also possible; presenting with irregular borders, inverted margins and exudates, these lesions are often misdiagnosed as potential malignancies.¹⁹

Viral, bacterial, or fungal opportunistic infections are typically only seen in immunocompromised individuals, commonly those older than 65.^3,7,20 The fungal infections candidiasis, cryptococcus, histoplasmosis, blastomycosis and aspergillosis may all cause oral manifestations.^3,7,19,21,22 Oral candidiasis is the most common fungal infection in humans and is most frequently seen with immunosuppression.^19,22 Candidiasis penetrates tissues, causing one of three types of infection: pseudomembranous, erythematous atrophic or hyperplastic. Pseudomembranous candidiasis can present on any oral soft tissues as thrush — a thick, white, plaque-like membrane that exposes erythematous tissue when removed.¹⁹ Erythematous atrophic candidiasis primarily affects the tongue and is bright red, sometimes accompanied by a burning sensation. It can also appear as angular cheilitis, or present on the palate in denture wearers.¹⁹ Hyperplasic candidiasis, also called candidal leukoplakia due to its elevated, white, keratinized appearance and inability to be wiped off, is seen on the lateral tongue or buccal mucosa, more frequently in smokers. Candidiasis can penetrate into blood vessels and become a deep fungal infection that resists treatment and leads to potential clotting issues.^19,22

Less common opportunistic fungal infections create various oral manifestations that can be misdiagnosed as malignancies. Cryptococcus infection affects the gingiva, palate or recent extraction sites as nodules of granulation tissue, indurated ulceration and swelling.^19,22 Blastomycosis manifests as ulcerating lesions or granular, flat or warty projections, and can cause bone or soft tissue necrosis.^14,16 Histoplasmosis causes ulcerations with pseudomembrane or plaque-like lesions on the tongue, buccal mucosa, gingiva or lips. Aspergillosis infections create painful, necrotic lesions on the gingiva, palate or posterior tongue that are yellow, grey or black, with an ulcerated base.^19,22

Reactivation of human herpesviruses 1–8 during immunosuppression includes a variety of identifiable oral manifestations. Herpes simplex 1 and 2, varicella zoster, hairy leukoplakia, cytomegalovirus, mononucleosis and Kaposi sarcoma are all associated with herpesviruses. The most common reactivation is herpes labialis appearing as small, painful, fluid-filled vesicles that may form one large blister. These vesicles can appear on the lip vermillion border, face, or intraorally on the tongue, palate or buccal mucosa. Gingivostomatitis can also occur with herpes type 1 and type 2 as mucosal ulcerations, erythematous tissues or acute gingivitis. With varicella zoster, the effects on the facial nerve can cause painful lesions and paresthesia or paralysis unilaterally on the face and oral tissues.¹⁹ 

Oral hairy leukoplakia manifests as white plaques with elongated fibers along the lateral border of the tongue or floor of the mouth.²¹ Cytomegalovirus occurs frequently in renal and pancreas transplant patients, especially with high doses of immunosuppressive medications, and includes medium-sized ulcerations on the palate and salivary gland infections. This virus also causes nausea, vomiting and diarrhea, which can lead to enamel erosion and xerostomia.²³ Mononucleosis infection can be identified through palatal petechiae, tonsillitis and cervical lymphadenopathy. Kaposi sarcoma is a malignancy that appears as elevated purple lesions on the skin or oral mucosa.¹⁹

Tissue Changes and Elevated Cancer Risk — Immunosuppressive medications are a first-line treatment for a variety of skin and mucosal lesions, but adverse skin and mucosal effects can occur.³ Long-term use increases cancer risk; specifically, lymphoma and skin, lip and viral-related malignancies. Increased lip dysplasia, lip cancers, squamous cell carcinomas, and progression of leukoplakia to squamous cell carcinoma have been reported among liver and kidney transplant patients.²¹

Despite the fact refractory cases of oral lichen planus can be effectively treated with immunosuppressive medications, these drugs can also initiate oral lesions. Within three to eight weeks of TNF-α inhibitor use, oral lichenoid lesions resembling lichen planus can develop.^3,18,24 Other mucosal reactions to TNF-α inhibitors include erythema mulitforme, which manifests as diffuse redness, irregular oral ulcerations, or crusting and bleeding of the lips.^18,24 In patients taking calcineurin inhibitors, fibrous polyps, sometimes large and multilobulated, on the lateral border of the tongue, lip or buccal mucosa may develop.^9,18

Caries Risk — The gastrointestinal effects of many immunosuppressive medications, such as taste alteration, nausea, vomiting and diarrhea, may increase caries risk.^3,5,7,23 Chronic diarrhea, vomiting, or limiting food and drink intake to avoid nausea can lead to dehydration and decreased salivary flow. Combining xerostomia with an increased number of acidic exposures during the day can result in enamel demineralization and caries. 

Periodontal Changes — Immunosuppressive medications can negatively impact periodontal health by impairing organ function and inducing bone or gingival changes. An increased risk of cardiovascular, kidney and liver disease, pancreatitis, and diabetes are all associated with immunosuppressive medications.^3,5,7 The inflammation associated with periodontitis impacts the cardiovascular system, kidneys and pancreas. As such, this disease process is bidirectional.²⁵

Oral health professionals may detect clinical and radiographic indicators of kidney dysfunction, including hypertension, gingival bleeding, aphthous ulcers, skin hyperpigmentation and bone changes. As function decreases, the prevalence of taste alteration, candidiasis, periodontitis and bone loss increases.²⁵ 

Long-term corticosteroid use increases the risk of developing osteopenia, osteoporosis and osteonecrosis, even among children. The first three to six months of gluticosteroid use is associated with accelerated bone loss and, subsequently, decreased bone formation.¹⁷ 

Fibrous and granulation tissue masses resulting in gingival inflammation, swelling, pyogenic granuloma or gingival hyperplasia are associated with cyclosporine and corticosteroids.^3,5,9,21,25 Gingival hyperplasia in the anterior labial papilla is common, especially among men and children, or with concurrent use of calcium channel blockers within the first six months of cyclosporine A treatment.^26,27 The enlargements are exacerbated by biofilm and calculus accumulation, genetic susceptibility to inflammation, and localized irritation, such as with prosthetic use. On occasion, Kaposi sarcoma or squamous cell carcinoma develop within these enlargements.^9,21,27

REDUCING ORAL SIDE EFFECTS

Prior to immunosuppressive therapy, communication between dental and medical professionals should be established to promote complete patient care. A comprehensive oral examination with periodontal charting, current radiographs, and intraoral photography can document the oral condition at baseline. 

Managing autoimmune conditions requires healthy lifestyle choices, including proper sleep, adequate nutrition, stress reduction, and abstaining from excessive alcohol intake and tobacco use.¹ Health promotion and oral hygiene education to reduce inflammation may help patients minimize adverse drug effects and improve quality of life. 

At each appointment, oral health professionals should identify medical or medication changes and document these within the treatment notes. When recognizing oral or skin changes, use of intraoral photographs and/or radiographs for comparison and patient education are advised. Signs of oral infection, pathology or periodontal conditions should be addressed promptly or referred to a specialist.²² Periodontists, oral pathologists and oral or maxillofacial surgeons are the experts in addressing advanced oral conditions. 

Oral manifestations of systemic disease or reduced organ function should be shared with patients and their medical teams. For patients with taste alteration or chronic oral ulcerations, a loss of appetite may compromise balanced nutrition. When recognizing unintended weight loss or signs of nutritional deficiencies, the patient should be referred to a dietitian.

With immunosuppression, the contributing factors of nutrition, systemic disease, medication use and oral hygiene should be identified before treating a fungal infection with antifungal medications. Oral candidiasis can be managed with topical miconazole, chewable nystatin pastilles, amphotericin lozenges, or one of the latter two medications in suspension. Systemic antifungals are needed to address recurrent, refractory, or deep fungal infections.^19,22

Herpes lesion treatment is typically palliative with topical anesthetics — but, with immunosuppression, antiviral medications may be needed. Antiviral medications are also prescribed for cytomegalovirus infections, but a cocktail of antiviral medications, corticosteroids, analgesics and neurological medications may be required to manage varicella zoster. Defer elective dental care for patients with active oral herpes, shingles lesions or tuberculosis.¹⁹

Biofilm control and antiseptic mouthrinses can reduce gingival hyperplasia and periodontal disease risk.^27,28 Dental professionals should assess the patient’s self-care ability and recommend the appropriate adjuncts for biofilm removal, such as power toothbrushes and interdental aids. Regular periodontal therapy to remove biofilm and calculus, with periodontal debridement as needed, can manage gingival overgrowth and periodontal disease.²⁸ Treating periodontal disease with inflammatory conditions can reduce symptom severity, while untreated periodontal disease may interfere with medication efficacy.¹⁵ Intervention via periodontal flap surgery, laser therapy or gingivectomy can reduce severe periodontal pockets and gingival overgrowth, but recurrence is possible. Changing to a medication such as tacrolimus can reduce cyclosporine-associated gingival hyperplasia, but tacrolimus is associated with oral fibrous growths.^9,28

Prescription fluoride toothpaste or fluoride varnish application may reduce the effects of acidity on tooth structure caused by nausea, vomiting or xerostomia. Treatment for xerostomia includes a variety of over-the-counter products, techniques and prescription options. Dentists or physicians may prescribe medications, including salivary stimulants and muscarinic agonists that promote salivary function, such as pilocarpine and cevimeline.^15,29

SUMMARY

Advances in immunosuppressive pharmacotherapy have improved the management of ADs and reduced tissue and organ transplantation complications, but adverse drug effects are common. Oral health professionals should encourage regular prophylaxes and dental examinations (with additional periodontal therapy, as needed) to mitigate the impact of these medications on oral and systemic health. Treatment success depends on the detection and management of oral changes, appropriate communication with medical teams, and provision of referrals to dental specialists to effectively treat complications that arise. 

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From Decisions in Dentistry. January 2022;8(1):32-35.