O r a l G r a f t - Ver s u s - H o s t D i s e a s e Michal Kuten-Shorrer, DMDa, Sook-Bin Woo, Nathaniel S. Treister, DMD, DMScb,*

DMD, MMSc

b

,

KEYWORDS  Graft-versus-host disease  GVHD  Allogeneic  Hematopoietic cell transplantation  Oral mucosal disease KEY POINTS  Allogeneic hematopoietic cell transplantation (allo-HCT) is used for the treatment of a variety of disorders, primarily hematologic malignancies.  Graft-versus-host disease (GVHD) is a significant complication following allo-HCT and a major cause of morbidity and mortality.  The oral cavity is frequently involved in GVHD, leading to pain, functional impairment, and reduced quality of life.  Early diagnosis, management, and long-term follow-up of oral GVHD are important components of overall patient care.

INTRODUCTION

Allogeneic hematopoietic cell transplantation (allo-HCT) is considered to be a curative treatment of many hematologic malignancies as well as for a wide range of hematologic and immune deficiency states and immune diseases.1 Graft-versus-host disease (GVHD, Box 1), an immunologically mediated disease, is a major cause of morbidity and mortality after allo-HCT and the most significant barrier to treatment success.2 In 1966, Billingham3 outlined the 3 fundamental requirements for GVHD. First, the graft must contain immunologically competent cells; second, the host must express tissue antigens that seem foreign to the graft; and finally, the host must be incapable of rejecting the donor graft.3,4 As stipulated in the third precondition, recipients undergo myelosuppressive and immunosuppressive regimens before allo-HCT, reducing the risk of graft rejection.1,5 After transplantation, donor-derived immunocompetent T lymphocytes may react against histocompatibility antigens on the recipient cells and induce immune responses, resulting in recipient tissue damage.5,6

Disclosure: None. a Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA; b Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, 1620 Tremont Street, 3rd Floor, Boston, MA 02115, USA * Corresponding author. E-mail address: [email protected] Dent Clin N Am 58 (2014) 351–368 http://dx.doi.org/10.1016/j.cden.2013.12.007 dental.theclinics.com 0011-8532/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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Box 1 What is GVHD? A clinical syndrome that results from an immunologic attack by donor immunocompetent T cells on patient tissues, directly or through exaggerated inflammatory responses, following allogeneic HCT

The major risk factor for GVHD development is human leukocyte antigens (HLA) disparity.4,5 HLAs are expressed on the cell surfaces of all nucleated cells in the body and are encoded by the major histocompatibility complex (MHC) located on the short arm of chromosome 6. If incompatible with the recipient, the donor’s immune cells mount an alloimmune response against antigens on the recipient cells leading to GVHD. Careful matching of donor and recipient HLA reduces the risk for GVHD (as in sibling HLA-matched grafts). The current guidelines recommend high-resolution DNA-matching (ie, indicating that the donor and recipient express identical alleles) for the following 4 HLA loci in order to maximize post-HCT survival: HLA-A, -B, -C, and -DRB1 (8/8 match).7,8 Ideally, unrelated donors should be genotypically identical to the recipients at all HLA loci; however, finding the ideal match is often extremely challenging in light of the millions of potential haplotypes existing.4 Furthermore, despite selection of an HLA-matched donor, T lymphocyte reaction may still be elicited by minor histocompatibility antigens encoded by non-MHC loci, contributing to GVHD development.4,9 Other important factors determining GVHD development and severity are listed in Box 2.2 Along with the increase in morbidity and mortality, GVHD is also associated with a reduced incidence of malignancy relapse due to the graft-versus-tumor (GVT) effect.1,10 It is thought that this is mediated by donor T lymphocytes that recognize tumor antigens and elicit antitumor responses.1 Successful transplantation results from carefully balancing GVT effects against chronic GVHD (cGVHD). Overtreatment of cGVHD may adversely impact malignancy relapse rates, whereas too robust a GVT effect, such as that achieved by donor lymphocyte infusion (DLI) for patients who relapse after HCT, may induce severe GVHD with its attendant morbidities.6,11 PATHOBIOLOGY AND INCIDENCE OF GVHD

Traditionally, GVHD has been classified as either acute (aGVHD) or chronic according to the time of clinical onset after transplantation.6,12 Any GVHD manifestations before day 1100 after transplantation were defined as aGVHD, and any manifestations present after day 1100 were defined as cGVHD.12,13 Recently, however, it has been accepted that acute and chronic GVHD represent a clinical continuum with distinct clinical features and underlying pathophysiologic mechanisms.6 aGVHD is Box 2 Factors influencing the risk of GVHD  Donor/recipient sex mismatch (especially female donors to male recipients)  Increasing recipient age  Choice of progenitor cells source  Pretransplantation manipulations and graft composition  Intensity of conditioning regimen

Oral Graft-Versus-Host Disease

characterized by strong inflammatory features, whereas cGVHD displays more autoimmune and fibrotic characteristics (Table 1).1 The current consensus, therefore, is that aGVHD and cGVHD should be differentiated according to clinical manifestations and pathologic features rather than merely the time of onset after transplantation.6,12 The National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGVHD has further defined 2 subcategories for both aGVHD and cGVHD.12 Acute GVHD can be classic, occurring within 100 days after HCT, or persistent, recurrent, or late when occurring beyond day 1100 after HCT (for example, in cases of nonmyeloablative conditioning).14 Similarly, cGVHD can be either classic (ie, without concomitant features or characteristics of aGVHD) or can manifest in an overlap syndrome with features of both cGVHD and aGVHD occurring simultaneously as can be seen in patients receiving DLI.12 aGVHD

The pathobiology of aGVHD is considered to be a 3-step process, starting with tissue damage induced by the pretransplantation conditioning regimen, followed by donorderived T lymphocyte activation and clonal expansion, and ultimately tissue destruction induced by immune and inflammatory responses in the effector step.5 In the first

Table 1 Classic features of aGVHD and cGVHD Organ or Site

aGVHDa

cGVHDb

Skin

Erythema Maculopapular rash Pruritus

Poikiloderma Lichen planus–like features Sclerotic and morphealike features

Oral

Gingivitis Mucositis Erythema Pain

Lichen planus features Hyperkeratotic plaques Restriction of mouth opening from sclerosis

GI tract

Anorexia Nausea Vomiting Diarrhea Weight loss

Esophageal web Strictures or stenosis in the upper to mid third of the esophagus

Genitalia Liver

Lichen planus–like features Vaginal scarring or stenosis Total bilirubin, alkaline phosphatase >2 times upper limit of normal ALT or AST >2 times upper limit of normal

Lung

Bronchiolitis obliterans

Muscles, joints

Fasciitis Joint stiffness or contractures secondary to sclerosis

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GI, gastrointestinal. a Manifestations that can also be found in cGVHD. b Diagnostic features. These features are sufficient to establish the diagnosis of cGVHD. Data from Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11(12):945–56.

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step, the conditioning regimen, comprised of chemotherapy, radiation therapy, and/or immunosuppressive medications, induces tissue damage and subsequent activation of patient antigen presenting cells (APCs). In the second step, APCs present the patients’ alloantigens to donor-derived T lymphocytes, leading to their activation characterized by a primarily T-helper 1 (Th1) response. In step 3, the effector T lymphocytes, along with natural killer cells, macrophages, and proinflammatory cytokines, inflict direct tissue damage, as well as indirect damage, through intense inflammatory responses associated with the massive cytokine production, known as the cytokine storm.1,4,5 The incidence of aGVHD varies with relation to several immunologically based factors, primarily the degree of donor-recipient histocompatibility (Table 2).15 The primary target organs of aGVHD are the skin, the liver, and the gastrointestinal (GI) tract. Other organs may also be involved, including the oral cavity.16,17 The severity of overall aGVHD is graded from I to IV by combining each of the 3 target organs’ clinical stage of involvement.18 The grade of aGVHD has long been known to correlate with overall survival, with the best survival for patients with grade I disease.19 This correlation was demonstrated by the Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation, who reported transplant-related mortality rates for grades I to IV aGVHD to be 27%, 43%, 68%, and 92%, respectively, in 1294 patients after allo-HCT for chronic myeloid leukemia.20 cGVHD

The mechanisms underlying cGVHD are not well understood. Two basic theories for the pathobiology of cGVHD have been proposed.4,21 According to the first theory, cGVHD is simply an end-stage alloreactivity in which donor T lymphocytes have differentiated toward a Th2 phenotype, associated with B-cell activation and autoantibody production.22 The second theory suggests that cGVHD is the outcome of poor/ dysfunctional immunologic recovery after HCT, involving altered peripheral mechanisms of tolerance and decreased negative selection related to impaired thymic function, resulting in an increase in peripheral autoreactive T lymphocytes that generate further activation of effector functions (cytokine secretion, cytolytic activity, and antibody production).1,2,4 Although the association of cGVHD with altered B-cell homeostasis is well established, the exact role of B lymphocytes in the pathogenesis of GVHD remains unknown.1,23,24 In the clinical setting, reduction of alloreactive B lymphocytes responses using rituximab, a CD20-specific monoclonal antibody, can be effective in the treatment of cGVHD.23,25 Three patterns of cGVHD onset have been identified: (1) de novo onset, without prior aGVHD; (2) quiescent onset, following a recovery period without any GVHD manifestations (postresolution of aGVHD); and (3) progressive onset, with cGVHD directly following aGVHD.26,27 The manifestations of cGVHD may be limited to one organ or widespread and most frequently involve the skin, eyes, oral cavity, GI tract, liver,

Table 2 Incidence of aGVHD according to histocompatibility Matched (%)

Mismatched (%)

Related

20–50

75–80

Unrelated

70

80–90

Data from Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management. Exp Hematol 2001;29(3):259–77.

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and lungs.12,28 With reported incidence rates ranging from 25% to 80% in long-term survivors, cGVHD is the most common late complication following allo-HCT and the leading cause of nonrelapse mortality.2,28,29 The incidence and severity of cGVHD are correlated with multiple factors, including HLA disparity, increasing recipient age, sex mismatch, and source of progenitor cells (see Box 2).12,28 However, the most important risk factor for cGVHD development is the diagnosis of previous aGVHD.30 ORAL GVHD Incidence

Although not a classic target organ of aGVHD, oral manifestations may be encountered, clinically presenting as mucosal erythema, ulcerations, and painful desquamative lesions.17 Because these manifestations are nonspecific, oral aGVHD may be mistaken for or obscured by several other conditions, including conditioninginduced mucositis and herpes simplex virus (HSV) infection.11,17 However, because aGVHD typically develops well after engraftment and resolution of mucositis, and acyclovir prophylaxis is highly effective in preventing reactivation of HSV, these entities can be readily differentiated.31 The incidence of oral aGVHD is unknown but is thought to be exceedingly rare. In contrast, the oral cavity is one of the most frequently affected sites in cGVHD, with more than 70% of patients who develop cGVHD demonstrating oral involvement.32,33 Clinical Findings

As mentioned earlier, oral manifestations of aGVHD are predominated by erythema and ulcerations but can also present as lichen planus–like hyperkeratotic lesions, likely in the context of overlap syndrome.11 Lip involvement with crusting is also a common feature, similar to that seen in patients with erythema multiforme (Fig. 1). The diverse spectrum of oral cGVHD manifestations can be classified into 3 distinct groups, according to the main sites and anatomic structures involved: oral mucosal disease, salivary gland disease, and sclerotic disease.17,33,34 Oral mucosal cGVHD is characterized by lichenoid inflammation that frequently involves the tongue and buccal mucosa but can affect any site in the oral cavity and can range from limited disease with only mild changes to more extensive and symptomatic disease. Clinical changes include white papules, plaques, and hyperkeratotic

Fig. 1. Oral aGVHD with prominent crusting of lips.

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reticulations resembling Wickham striae in oral lichen planus, erythema, and pseudomembranous ulcerations (Fig. 2).11,33,34 The symptom most often associated with oral mucosal cGVHD is sensitivity to otherwise normally tolerated items, such as spicy, acidic, or rough (crunchy) foods and drinks as well as mint and strongly flavored toothpaste and mouthwashes.33 Most patients report little or no oral discomfort at rest, even in the presence of extensive oral ulcerations. Chronic GVHD of the salivary glands results in both quantitative and qualitative alterations in saliva, including altered concentrations of electrolytes, epidermal growth factor, and salivary proteins.35,36 Because of these changes, patients experience increased morbidity from xerostomia, difficulty with speaking, chewing and swallowing, as well as recurrent candidiasis.11,33,37 Patients may present with rampant caries, characterized by cervical and interproximal patterns of decay that develop at a median of less than 2 years after HCT (Fig. 3).38 In addition to the sialochemical and sialometric changes, oral cGVHD is also associated with recurrent superficial mucoceles, presenting primarily as asymptomatic 0.2- to 0.5-cm vesicles on the palatal mucosa (Fig. 4). Their putative etiopathogenesis is damage to excretory salivary ducts secondary to cGVHD.33 Sclerotic disease affecting the oral cavity is rare but can be a potentially serious complication. Sclerosis can present in the orofacial region as an extension of primary sclerotic cutaneous cGVHD or as a sequela of long-standing mucosal cGVHD and is characterized by sclerodermalike manifestations, including fibrosis and limited mouth opening associated with pain and secondary ulcerations (Fig. 5). The decreased mouth opening results in functional impairment (difficulty with speaking, eating, and maintaining oral hygiene), potentially contributing to infection and malnutrition.33,34,37 Diagnosis and Assessment

The diagnosis of oral GVHD can typically be made based on history, clinical findings, and context of onset. For standardization purposes, the NIH has introduced criteria for clinical (see Table 1) and histologic diagnosis of cGVHD, a scoring system to document the extent and severity of clinical involvement (Fig. 6), and a staging system for assessing the functional impact (Table 3).12,37,39,40 The global scoring of cGVHD can be calculated based on the number of organs involved (eg, oral cavity) and the severity of involvement according to a 4-point scale, resulting in a classification of mild, moderate, or severe.12

Fig. 2. Oral cGVHD involving the buccal mucosa with pseudomembranous ulceration and lichenoid hyperkeratosis. Hyperkeratotic changes can also be noted on the lower lip.

Oral Graft-Versus-Host Disease

Fig. 3. (A) Rampant cervical caries affecting nearly all teeth. (B) Bitewing radiograph demonstrating multiple interproximal radiolucent changes (caries, indicated by arrows) involving the crown and root surfaces, in some cases at the margins of restorations.

Fig. 4. Oral cGVHD with multiple superficial mucoceles of the palate.

Fig. 5. Oral sclerotic cGVHD with fibrous band formation of the right buccal mucosa (arrows) secondary to long-standing mucosal cGVHD, resulting in limited opening and impaired oral hygiene.

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Mucosal change Erythema

Mouth Hard Palate Pharynx

Soft Palate Uvula

Lichenoid

Tongue

Ulcers Mucoceles*

Mild

No evidence of cGVHD

Severe

Moderate

0

1

2

3

0 0 0

1 0 1

2 3 2

3 6 3 Total score for all mucosal changes

Fig. 6. The NIH’s oral cGVHD clinical scoring instrument. In this 0- to 15-point system, clinical evidence of erythema, lichenoid changes, ulcerations, and mucoceles is assessed globally as to reflect the severity and extent of involvement. (From Treister NS, Stevenson K, Kim H. Oral chronic graft-versus-host disease scoring using the NIH consensus criteria. Biol Blood Marrow Transplant 2010;16:108–14; with permission. Courtesy of American Society for Blood and Marrow Transplantation, www.asbmt.org.)

Diagnosis of cGVHD can be established by the presence of hallmark diagnostic manifestations, including lichen planus–like changes, hyperkeratotic plaques, and decreased oral range of motion from sclerosis (see Table 1). This, however, requires that all other possible diagnoses, such as secondary viral and fungal infections (most frequently, recrudescent HSV, and candidiasis), have been excluded.12,37,41 When the oral changes are not typical, a biopsy of the oral mucosa or minor salivary glands can provide valuable confirmatory information.17,40 According to the NIH’s minimum histologic criteria for cGVHD, histopathologic features of oral mucosal cGVHD include lichenoid interface inflammation, leukocyte exocytosis, and keratinocyte apoptosis (Fig. 7). Salivary gland cGVHD is characterized by intralobular periductal lymphocytic infiltration (often with associated fibrosis) and exocytosis of lymphocytes into intralobular ducts and acini.31,40 Immunohistochemical studies demonstrate a lymphocytic infiltrate of primarily CD41 and CD81 T lymphocytes as well as the presence of Langerhans cells and CD681 macrophages.37,42,43 IMPACT OF GVHD Overall Survival

GVHD, in its acute and chronic forms, is a main cause of nonrelapse mortality and a leading contributing factor for morbidity associated with prolonged immunosuppressive therapy, impaired functional status, and decreased quality of life.27,44,45 The impact of GVHD on patients depends on the severity of the disease and its response to treatment.11,46 Both advanced-grade aGVHD and severe cGVHD constitute a major threat to survival after allo-HCT, with GVHD-related organ failure second only to infection as the leading causes of death.27 The negative effects of cGVHD are balanced by its positive effect on survival, attributed to a reduced incidence of relapse caused by Table 3 The NIH’s organ scoring of cGVHD: mouth Score 0

Score 1

Score 2

No Mild symptoms with Moderate symptoms with disease signs with partial symptoms disease signs but limitation of oral intake not limiting oral intake significantly

Score 3 Severe symptoms with disease signs on examination with major limitation of oral intake

Data from Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11(12):945–56.

Oral Graft-Versus-Host Disease

Fig. 7. Oral mucosal cGVHD biopsy specimen obtained from the tongue dorsum demonstrating acanthosis and hyperkeratosis with a dense bandlike lymphocytic infiltrate at the basement membrane interface (Hematoxylin-eosin, original magnification 100).

the GVT effect. However, with increasing severity of cGVHD there is more treatmentrelated mortality, explaining the negative correlation between severity of cGVHD and survival.47 Quality of Life

Patients who develop aGVHD have been found to report a decrease in their quality of life over the first 6 months after allo-HCT, influenced by infectious complications, intense immunosuppressive regimens, or longer durations of hospitalization.48 This condition improves significantly at 1 year after HCT in the absence of cGVHD onset. In long-term allo-HCT survivors, cGVHD is associated with compromised quality of life, influenced by multiple factors, including a decrease in general health status, side effects of therapies, reduction in sexual activity, and loss of employment.27,46,48 However, patients with successfully resolved cGVHD do not seem to have long-term impairment and, moreover, have a similar health status to that of allo-HCT survivors who never had cGVHD, emphasizing the importance of a timely diagnosis and effective therapy protocols.46 Oral GVHD

The impact of oral GVHD, as that of GVHD in general, depends on its severity and on the extent of tissue involvement. Severe oral cGVHD results in pain, impaired alimentation and speech, diminished social well-being, and difficulty with maintaining oral and dental health.11,49,50 Morbidity is more pronounced in patients with concomitant salivary gland involvement compared with mucosal disease only. Although clinically plausible, the data on the association between oral cGVHD and swallowing difficulty, nutrition, and weight loss are lacking.51–53 PREVENTION AND MANAGEMENT OF GVHD Management Principles

Prevention of GVHD focuses primarily on minimizing risk factors, starting with optimal donor selection. Nevertheless, the use of unrelated or related HLA-mismatched donors accounts for most of the allogeneic grafts, and preventive measures are used accordingly. One approach involves pretransplantation graft manipulation by T-cell

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depletion, aimed not only at reducing the frequency of GVHD but also at reducing the recipient’s immune responses, favoring engraftment.54 All patients receive GVHD prophylaxis, with the most frequently used immunosuppressive regimens consisting of a combination of methotrexate (MTX) and a calcineurin inhibitor (CNI).55 Once GVHD has developed, management is largely dependent on the extent and severity of disease, ranging from topical steroid therapy alone to intensive multiagent systemic immunosuppressive therapy. Patients with mild aGVHD or limited forms of cGVHD can be managed using topical immunosuppressive therapies only; in the case of grade I aGVHD, continuation of prophylactic regimens alone may suffice.11,13 Systemic pharmacologic therapy, including high-dose systemic corticosteroids, is indicated for patients with grade II or worse aGVHD or severe cGVHD, because of their broad immunosuppressive properties.13 Because infection is the leading cause of nonrelapse mortality in patients with cGVHD, antimicrobial prophylaxis and supportive care are critical components of disease management. Supportive care is also directed at symptomatic relief and management of the deleterious cGVHD-related effects in the involved organs, with the aim of ameliorating function and quality of life.56 Prophylaxis

The mainstay of GVHD prophylaxis is the combination therapy for a CNI (cyclosporine [CsA] or tacrolimus [TAC]) and a short course of MTX. The administration of the CNI begins just before transplantation and extends into the post-HCT period for as long as 6 months thereafter, whereas MTX is administered early after transplantation, usually on days 11, 13, 16, and 111 only. Following studies that demonstrated a reduced incidence of aGVHD (but not cGVHD) with combination regimens containing TAC and short-course MTX, TAC has become more frequently used than CsA.6,54 Because of the toxicity associated with MTX, including severe mucositis, delays in neutrophil and platelet engraftment, and pulmonary as well as hepatic toxicity, the effectiveness of other combination regimens is being explored. The use of mycophenolate mofetil (MMF) instead of MTX in a CNI-based regimen seems to provide equivalent rates of GVHD prevention, with the additional benefit of a decrease in the incidence and severity of treatment-related mucositis.6,57 Similarly, the substitution of MTX with the mammalian target of rapamycin (mTOR) inhibitor sirolimus in a TAC-based regimen was found to be advantageous because of the associated lower incidence of aGVHD and a significantly reduced rate of mucositis.6,58,59 Systemic Therapy

Systemic corticosteroids serve as the first-line therapy for GVHD and are indicated for advanced grade aGVHD (grade II or worse) as well as for patients with severe cGVHD involving 3 or more organs or with a score of 2 or greater in any single organ, indicating major disability.12,13 Treatment of aGVHD with high-dose systemic steroid therapy for 1 to 2 mg/kg/d of methylprednisolone or a prednisone equivalent is associated with a 20% to 70% response rate and a durable response in 20% to 40% of patients.6,13 In order to improve durable response rates in steroid-refractory cases and to mitigate the adverse effects associated with long-term systemic steroid therapy, such as osteoporosis and avascular necrosis, other agents have been evaluated as steroid sparing second-line therapies with various successes. These agents include MMF, sirolimus, CNIs, monoclonal antibodies (eg, rituximab, alemtuzumab), and extracorporeal photopheresis (ECP).6,19,60 Because there is currently no standard of care for secondary therapies, these are typically evaluated empirically on an individual basis.6,61,62

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The initial systemic treatment of cGVHD is with prednisone at a starting dosage of 1 mg/kg/d, often in combination with a CNI.6,63 For patients with progressive cGVHD who were already on steroid and CNI therapy during the onset of cGVHD, other strategies are considered, such as adding ECP to the existing regimen or the substitution of the CNI with an mTOR inhibitor.63 Topical therapies based on agents such as corticosteroids or TAC may also be used as an adjunct to systemic therapy for improved local disease control.63 Overall, clinical resolution of cGVHD is a slow process, with more than 50% of patients requiring systemic immunosuppressive therapy for more than 2 years and 15% of HCT survivors requiring continued treatment for more than 7 years.64–66 MANAGEMENT OF ORAL GVHD Pharmacologic Strategies

Topical management of oral cGVHD may be indicated as complementary therapy to systemic treatment in locally refractory cases or as the sole therapy in cases whereby the oral cavity is the only site involved.11,37,67 The primary goals of oral GVHD management are to reduce symptoms and maintain oral function. The topical management of both oral aGVHD and cGVHD is essentially the same, with the caveat that cGVHD may require treatment for many years after HCT. The first-line therapy for oral mucosal GVHD is intensive topical corticosteroid therapy that can be delivered in various formulations (Table 4). Solutions and gels are most commonly used because of their ease of use and hydrophilic properties.11,33,67 The potency of the agent, as well as the delivery formulation and the duration/ frequency of use, can have a significant impact on the treatment effectiveness. In order to ensure maximal efficacy, patients must be given explicit instructions on use (see Table 4).11,33,37,67 It should be noted that most of these agents are not approved by

Table 4 Topical treatment of oral GVHD Formulation

Treatment (Dosage Per Use)

Instruction for Use

Solutions

Dexamethasone 0.1 mg/mL (5 mL) Budesonide 0.3–0.6 mg/mL (10 mL) Prednisolone 3 mg/mL (5 mL) Triamcinolone 1% (5 mL)

Hold solution and swish in mouth for 4–6 min before expectoration Wait 10–15 min after topical therapy before eating/drinking or brushing teeth Repeat up to 4–6 times per day

Gels, creams, and ointments

Fluocinonide 0.05% gel, cream, ointment Clobetasol 0.05% gel, cream, ointment Betamethasone dipropionate 0.05% gel Triamcinolone 0.1%–0.5% ointment

Apply to lesions 2–4 times per day Gels can be applied with gauze and left in place 10–15 min

Corticosteroids

Nonsteroidal immunosuppressives

a

Solution

Tacrolimus 0.1 mg/mL (5 mL)a

Hold and swish in mouth for 4–6 min before expectoration Repeat up to 4–6 times per day

Ointment

Tacrolimus 0.1% ointment

Apply to lesions 2–4 times per day

Typically used concurrently with steroid therapy.

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the US Food and Drug Administration for intraoral mucosal therapy, and patients should also be made aware of the risks associated with systemic absorption caused by swallowing or transmucosal penetration.34,37 In keeping with the NIH’s guidelines for ancillary therapy in cGVHD, the various corticosteroid solutions should be swished in the mouth for 4 to 6 minutes before expectoration and used up to 4 to 6 times per day (see Table 4). High-potency corticosteroid gels are effective for managing limited areas of involvement and can also be used as an adjunct to topical solutions in patients with extensive oral involvement. In this context, the application of tacrolimus ointment can be considered, although, because of its high viscosity and hydrophobic properties, it is less preferred for intraoral use and is usually the treatment of choice for lip involvement.67 For intraoral use, tacrolimus can be compounded as a solution and used in combination with a corticosteroid solution in patients that do not have an adequate response to topical steroid therapy alone.63,68 Finally, intralesional injections of triamcinolone acetonide (10–40 mg/mL) may be beneficial for resolution of refractory and symptomatic localized ulcerative lesions. Oral moisturizing agents and saliva substitutes help to reduce salivary gland cGVHD-associated xerostomia.11,69 Salivation can be stimulated by gustatory and masticatory means through the use of sugar-free chewing gums and candies.69 More severe hyposalivation is managed by systemic therapy with the cholinergic agonists pilocarpine and cevimeline in the absence of contraindications, such as glaucoma, cardiac arrhythmias, or pulmonary disease.11,33,67,69 Both agents have parasympathomimetic activity and similar safety profiles and are approved for symptomatic treatment of Sjo¨gren syndrome. In salivary gland hypofunction associated with cGVHD, both agents have been reported to improve symptoms of dry mouth and increase salivary output.70,71 The decision to use these agents should be balanced against the potential side effects, most commonly excessive sweating and flushing, and must be avoided in patients with pulmonary disease.72 Topical supportive care and antimicrobial prophylaxis are complementary to definitive treatment. Viscous lidocaine is the most frequently used palliative agent for relief of discomfort and pain and may be mixed with other soothing solutions, such as diphenhydramine and bismuth subsalicylate (Kaopectate) or aluminum hydroxide, magnesium hydroxide, and simethicone (Maalox).31,37,67 Chronic GVHD is associated with a higher rate of oral infections that may exacerbate oral symptoms and dysfunction. Moreover, topical immunosuppressive treatment of oral cGVHD increases the risk of developing secondary oropharyngeal candidiasis. For these reasons, a prophylactic antifungal treatment, in the form of oral solution or troche, is generally recommended for patients receiving topical immunosuppressive therapy.33,34,37 Nonpharmacologic Strategies

Several types of intraoral phototherapy have been anecdotally reported to be beneficial in the management of oral mucosal cGVHD. These types include psoralen–UV-A (PUVA) using intraoral psoralen sensitizers, UV-B therapy, low-level laser therapy, and carbon dioxide laser therapy.73–77 Although the results are encouraging, specifically in cases of refractory oral cGVHD, available data are limited, and further studies are required for determining safety, efficacy, and understanding the underlying mechanisms of action.11,37 Although not specific treatments for oral cGVHD, basic oral care is critical for eliminating local factors that might aggravate oral symptoms of GVHD and for preventing odontogenic infections. This care includes brushing, flossing, and application of remineralization agents on a regular basis (Box 3).11,33,37 Patients should undergo a dental

Oral Graft-Versus-Host Disease

Box 3 Basic oral care recommendations Basic oral hygiene  Brush at least twice daily, using a soft toothbrush  Consider use of children’s flavored toothpaste to minimize sensitivity associated with mint flavors  Floss daily Lip care  Apply lip-coating agents with UV protection Caries prevention  Minimize intake of refined carbohydrates (sugars)  Increase water intake  Apply prescription fluoride 1.1% gel: brush on teeth or use in custom trays, daily  Apply remineralizing agent in addition to fluoride  Professional fluoride varnish applications

evaluation 6 to 12 months after HCT and subsequent routine follow-ups on an annual basis (once a year or more, as needed) including necessary bitewing radiographs to screen for interproximal caries.38,78 Importantly, patients should be provided with appropriate literature on their condition as part of patient education and empowerment (www.aaom.com, see patient information sheets). LATE COMPLICATIONS OF ORAL GVHD

A history of oral cGVHD is associated with an increased risk for the development of several late complications, in some cases many years after diagnosis and management. Perioral sclerodermatoid changes, resulting from fibrosis of the facial skin and mucosal cGVHD, may lead to restricted oral range of motion and reduced mouth opening. When severe, there can be significant limitation in oral intake of food and the ability to maintain oral hygiene. Additionally, fibrosis may lead to a loss of vestibular depth and attached gingiva, creating periodontal defects resulting in tooth loss. These changes may respond to systemic cGVHD treatment and physical therapy; however, severe cases may necessitate surgical intervention.11,33,37,67 It has long been known that allo-HCT is associated with an increased risk of developing secondary malignancies, including new solid cancers, such as squamous cell carcinoma (SCC) of the skin and oral cavity.44,79–82 The increased risk of developing SCC of the skin and oral cavity has been associated with cGVHD and its therapy, and oral cGVHD specifically seems to be directly related with the occurrence of secondary oral cancer.83,84 With a median time from transplantation to solid tumor diagnosis of 7 years and increasing risk with time since transplantation, annual comprehensive screening for oral malignancies is critical for all allo-HCT survivors.37,80,83 SUMMARY

Despite advances in the understanding of transplant immunology and clinical care, GVHD remains a significant cause of morbidity and mortality for allo-HCT recipients.

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The oral cavity is one of the most frequent sites affected by cGVHD, with mucosal, salivary, and/or sclerotic manifestations that are associated with pain, impaired function and diminished quality of life. Accurate diagnosis and effective management of oral GVHD and its associated complications is a critical component of the overall care of patients with GVHD. REFERENCES

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Oral graft-versus-host disease.

Allogeneic hematopoietic cell transplantation (allo-HCT) is used for the treatment of a variety of disorders, primarily hematologic malignancies. Graf...
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