The development of GVHD occurs under three conditions: the graft must contain immunologically competent cells; the recipient must express tissue antigens that are sufficiently different from those of the donor; and the recipient must be incapable of rejecting the graft owing to tolerance, lack of recognition or immunosuppression.^3,8

The acute and chronic forms of GVHD have been thoroughly described in the literature and differ in both onset and clinical features. Acute GVHD appears within 100 days after undergoing BMT and is characterized by erythematous dermatitis, diarrhea and elevation of hepatocellular enzymes.^3,4,6,9

cGVHD affects 25 to 40 percent of long-term BMT survivors and occurs 100 days or more after the transplantation procedure is performed. It occurs after the onset of acute GVHD (a progressive disease) or the previous resolution of acute GVHD (inactive).^6,9 cGVHD is characterized by sclerodematous skin changes, malabsorption and obstructive hepatitis. The pathophysiology of the disease still is unknown and may be related to the increased production of interferon- and cytokines such as interleukin-, or IL-, 4 and IL-6.^6,10,11

cGVHD may be classified further as being limited or extensive, according to the degree of organ involvement. Limited cGVHD manifests as localized skin involvement, liver dysfunction or both, while extensive cGVHD affects multiple organs such as the skin, liver, eyes, salivary glands, oral mucosa and other target organs.^2,3,6,9,12 The condition often shares the features of a variety of autoimmune diseases, such as lichen planus, Sjögren’s syndrome, systemic lupus erythematosus or primary biliary cirrhosis.^6,13

The earlier and more precisely the cGVHD diagnosis can be made, the greater the success will be in predicting the outcome of the disease and in defining an optimum treatment at an early stage.¹⁴

Oral manifestations are observed in about 80 percent of patients who have extensive forms of cGVHD. Lichenoid lesions commonly affect all mucosal surfaces with predominant reticular and papular forms; tongue lesions usually are plaque-like. Ulcerative lesions are not common, but when they appear, they usually are covered by a gray or yellow pseudomembrane surrounded by erythema and are localized mainly in the buccal mucosa, palate and dorsal part of the tongue. Atrophy of the oral mucosa also may be present, interspersed with areas of hyperkeratosis.^4,9,13 Salivary gland involvement in cGVHD manifests as increased xerostomia, accompanied by decreased levels of salivary immunoglobulins and an increased incidence of oral infections.⁵

In this article, we present a case of severe cGVHD with extensive oral involvement refractory to therapeutic protocols. We also discuss the role of the dentist in the management of oral manifestations of cGVHD.

	CASE REPORT

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A 23-year-old black woman diagnosed with severe aplastic anemia received an allogeneic bone marrow transplant through the Bone Marrow Transplantation Program of the Fundação Pró-Sangue Hemocentro de São Paulo, Discipline of Hematology, University of São Paulo medical school in Brazil.

We performed a conditioning regimen, using busulfan (4 milligrams per kilogram of body weight on the fifth day before BMT) and cyclophosphamide (50 mg/kg/day from the fourth day to the day before BMT). The patient underwent BMT with bone marrow from her sister, who was a match in terms of both ABO blood group system and histocompatibility leukocyte antigen.

GVHD prophylaxis was performed with cyclosporin A (3 mg/kg/day from the day before BMT), methotrexate (15 mg per square meter of body height on the day after BMT and 10 mg/m² on the third and sixth days after BMT) and corticosteroid (2 mg/kg/day from the eighth to the 20th day after BMT, 1 mg/kg/day from the 21st to the 40th day after BMT and 0.5 mg/kg/day from the 41st to the 50th day after BMT), according to Mookerjee and colleagues’¹⁴ protocol. Transplant prognosis was uneventful until the patient developed extensive cGVHD (in the skin, liver, gut and oral mucosa) around the 140th day after BMT. We immediately started treatment with cyclosporin A (12 mg/kg/day) and prednisone (1 mg/kg/day), according to the Seattle protocol.¹⁵

There was a good clinical response at all of the sites affected by GVHD except for the oral cavity. These lesions were refractory even to recovery protocols that used thalidomide and later azathioprine.

On the 300th day after BMT, the patient still had symptoms of cGVHD, including xerostomia and severe pain. Lichenoid hyperkeratotic plaques involving the gingiva were present (Figure 1), and the buccal mucosa displayed lichenoid and papular lesions with some atrophic areas (Figure 2). The dorsal surface of the tongue had ulcers delimited by erythema and covered by a yellow pseudomembrane. We found hyperkeratotic plaquelike lesions surrounding the ulcerative lesions in these areas (Figure 3).

View larger version (90K): [in this window] [in a new window]   Figure 1. Hyperkeratotic lichenoid plaques involving the gingiva. Sutures indicate the target sites for elliptical biopsies of labial and buccal mucosa.

View larger version (93K): [in this window] [in a new window]   Figure 2. Lichenoid and papular lesions with atrophic areas in the buccal mucosa.

View larger version (115K): [in this window] [in a new window]   Figure 3. Ulcer delimited by erythema and hyperkeratotic areas, covered by a yellow pseudomembrane on the dorsal surface of the tongue. (Lesions refractory to recovery protocols appeared on the 300th day after bone marrow transplantation.)

Based on the patient’s medical history, clinical examination, and appropriate viral and fungal tests, we concluded that the oral lesions were the result of cGVHD, and we initiated a new protocol using mycophenolate mofetil, which led to complete improvement of the oral lesions.¹⁴

In addition to systemic therapy, the patient obtained symptomatic relief through improved oral hygiene, topical medications and a monitored diet. The patient’s oral hygiene regimen included using a soft toothbrush and a toothpaste for people with xerostomia twice a day in place of regular toothpaste. We instructed the patient to rinse her mouth with a mouthwash that contained calcium and antibacterial enzymes. The patient obtained local pain control by rinsing with 5 milliliters of 2 percent viscous lidocaine three times a day and 5 mL of betamethasone mouthwash three to four times a day. At a follow-up appointment 15 months later, the patient had no relapse of intraoral lesions.

	DISCUSSION

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The patient in our case report had cGVHD with severe oral manifestations, which included oral mucosal atrophy, erythema, lichenoid reactions and oral pain associated with other extensive manifestations in the gastric mucosa and skin. She experienced inadvertent weight loss because of poor food intake, as has been described in many other patients.⁵

The presence of oral manifestations in people who have GVHD is not used to diagnose acute or chronic forms, although an increasing number of medical centers are using changes in the oral mucosa and observations of the salivary gland as simple, noninvasive means of monitoring BMT patients’ conditions.^3,4,13 Some studies have reported that the presence of oral lichenoid lesions shows a statistically significant relationship with cGVHD diagnosis.^4,9,14

A lip biopsy specimen frequently is used to diagnose and determine the stage of the GVHD, and it has been noted that lip biopsy specimens need to include both mucosal and salivary gland tissue.⁴ Salivary gland biopsy findings have been correlated with the presence and clinical severity of GVHD, as well as being useful for evaluating the efficacy of therapeutic approaches.^2,16–18

The primary treatment of GVHD usually consists of therapy with systemic steroids and cyclosporin A. If patients fail to respond to initial immunosuppressive therapy, various recovery protocols are available, including thalidomide, psoralen ultraviolet A radiation, low-dose radiation and azathioprine.^2,3,19

When the patient was being treated with systemic immunosuppressive therapy, the lesions in the oral mucosa took a long time to resolve completely. We managed the condition by treating specific oral lesions and providing pain control and oral health maintenance.

When immunosuppressive therapy is used to treat BMT patients, cGVHD lesions may lead to opportunistic infections, which are the major cause of morbidity and mortality in these patients.^2,3 The oral cavity is a primary target for such infections. The qualitative and quantitative changes observed in the salivary secretions of people who have GVHD suggest suppressed local immunity that allows for the development of erosive ulcerative mucosal lesions, which may serve as a portal of entry for Candida species, and of gram-negative anaerobic bacteria.¹⁷

Prophylactic regimens that are used to prevent oral manifestations of GVHD include the removal of traumatic factors and severely diseased teeth, and definitive oral rehabilitation before BMT. After BMT, the main role of the dentist is to follow the patient carefully and to recognize and treat oral complications as early as possible to reduce the disease’s morbidity. To alleviate GVHD oral manifestations’ symptoms, a basic protocol should be used that includes instructions for meticulous oral hygiene, topical steroids (dexamethasone or betamethasone mouthwash), effective analgesia (lidocaine), and artificial saliva or a saliva stimulant.^3,16,18

	CONCLUSION

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GVHD is a complex and dynamic process that requires the skills of a multidisciplinary health care team to treat. Effective intervention by a dentist is necessary for a successful prognosis for the BMT patient and to improve his or her quality of life.