Oral Graft-Versus-Host Disease

Dent Clin N Am 52 (2008) 79–109

Oral Graft-Versus-Host Disease Mark M. Schubert, DDS, MSDa,b,*, Maria Elvira Pizzigatti Correa, DDS, MSD, PhDc a

Oral Medicine Service, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Seattle, WA 98109, USA b Department of Oral Medicine, Box 356350, School of Dentistry, University of Washington, Seattle, WA 98195, USA c Oral Medicine Ambulatory, Bone Marrow Transplantation Unit, Hematology and Blood Transfusion Center, State University of Campinas (UNICAMP), Centro de Hematologia e Hemoterapia, Rua Carlos Chagas 480, 13083-970 Campinas, SP, Brazil

Hematopoietic cell transplantation (HCT) began in the late 1950s and has seen a steady increase in the overall success and applicability to treat a wide range of malignancies, hematologic and immune deficiency states, and autoimmune diseases [1]. Animal studies in the late 1940s and early 1950s laid the ground work for HCT, and human HCT was first attempted in the late 1950s. However, early HCT attempts were complicated by significant and often lethal complications including infection, graft failure, relapse, hemorrhage, and, in the case of allogeneic HCT (alloHCT), graftversus-host disease (GVHD) [2]. GVHD is a clinical syndrome where donor-derived immunocompetent T cells react against patient tissues directly or through exaggerated inflammatory responses following alloHCT [3–5]. The primary target organs of GVHD classically have been those of skin, liver, and the gastrointestinal (GI) tract. However, the oral cavity is also frequently involved, possibly only second to cutaneous involvement [6–9]. Despite significant advances, GVHD remains a major cause of morbidity and mortality with chronic GVHD being the leading cause of nonmalignant fatality post alloHCT [3,4,6]. Given the impact of GVHD on the allogeneic patient’s post HCT course, timely and accurate diagnosis of oral GVHD, ongoing assessment of responses to therapy, and the appropriate management of oral GVHD can

* Corresponding author. Oral Medicine Service, Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Seattle, Washington 98109. E-mail address: [email protected] (M.M. Schubert). 0011-8532/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cden.2007.10.004 dental.theclinics.com

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contribute to not only improved patient comfort, oral health, and function, but possibly long-term survival [8–13]. Since the oral cavity is frequently involved and is easily assessed for GVHD, recognition of oral GVHD changes can contribute to improved post-HCT medical management. Finally, appropriate therapy for symptomatic oral GVHD can significantly improve the patient’s quality of life and overall oral function. Pathobiology, epidemiology, and clinical manifestations of graft-versus-host disease In 1966 Billingham [14] formulated the three fundamental elements required for the occurrence of GVHD. First, the transplanted graft must contain immunologically competent cells; second, the recipient must be incapable of rejecting the transplanted cells; and third, the recipient must express tissue antigens that are not present in the donor [3,4,14]. In the most simplistic terms, based on these fundamental principles, GVHD is a clinicopathologic syndrome that occurs following alloHCT when transplanted immunologically competent donor (graft) T cells recognize and react against histocompatability antigens on the patient’s cells (host) and induce immune responses resulting in host tissue damage [4,15,16]. These processes are triggered by the recognition of host human leukocyte antigens (HLAs) by donor lymphocytes as being ‘‘foreign’’ antigens; the ensuing complex set of both autoimmune and alloimmune responses and severe inflammatory manifestations are recognized clinically as GVHD [3]. The most important risk factor for GVHD is the degree of HLA match of donor to patient. Mismatching in HLA-A, -B, -C, or -DRB1 will increase the risk of GVHD [3,4,17]. Sibling HLA-matched (ie, related) donor grafts have less risk for GVHD than HLA-matched unrelated donor grafts, possibly because of mismatched minor histocompatibility antigens (mHA) that have been shown to influence GVHD incidence. Further immune-based differences that influence the risk for GVHD are being studied [18]. Additional risk factors for GVHD include increasing patient age, donor parity and sex mismatch, choice of graft source (ie, peripheral blood stem cells, bone marrow, or umbilical cord), and pre-infusion graft modulations/manipulations, most notably T-cell depletion [3,4,16]. Finally, the toxicity of high-intensity conditioning regimens, especially those that use total body irradiation, can increase GVHD risk because they cause more host tissue damage that results in enhanced recognition of host antigens by donor antigen-presenting cells (APCs) leading to increased activation of donor T cells. GVHD was initially classified as either acute GVHD (aGVHD) or chronic GVHD (cGVHD) based on an arbitrary time point with aGVHD occurring within 100 days of transplantation and cGVHD occurring over 100 days after transplantation. Recently, there has been a shift toward separation of acute and chronic forms of GVHD based on clinical and pathological characteristics [19]. While both forms represent the consequence of

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damage to host tissues by activated donor-derived T lymphocytes in response to the major histocompatibility complex (MHC) disparities between the donor and the host, elucidation of the immunopathobiology of GVHD has made it apparent that the specific pathophysiological mechanisms are distinctly different [16]. Acute GVHD can occur as early as 1 week postHCT or following donor lymphocyte infusion (DLI, see next paragraph). In contrast cGVHD can have an onset of 70 days or later post-HCT or DLI and continue for many years. There are four patterns of onset for cGVHD: (1) a de novo onset (without prior aGVHD), (2) quiescent onset (onset is after a period of no apparent aGVHD activity between the resolution of aGVHD and the onset of cGVHD), (3) progressive onset (cGVHD evolves directly from aGVHD), and (4) explosive onset (manifesting with an abrupt onset of severe multisystem involvement with manifestations of both acute and chronic GVHD) [4]. While both forms of GVHD contribute to significant post-HCT morbidity and mortality, for patients transplanted for malignancies, GVHD has also been associated with lower relapse rates because of a graft-versusleukemia (GVL or graft-versus-tumor, GVT) effect [6,20–22]. Chronic GVHD in particular has been shown to be associated with lower relapse rates, especially for patients who are transplanted in relapse [21]. The GVL effect is thought to be mediated, at least in part, by donor T cells; however, the precise mechanisms that result in GVHD and GVL remain to be elucidated. Recognition of this beneficial effect has led to the use of a technique for patients who relapse post-HCT in which lymphocytes are collected from the donor and infused into the patient (referred to as a DLI). The goal of this treatment is to induce a T-cell–mediated GVL effect and has proven to be successful in many instances [22]. Unfortunately, DLIs will also induce GVHD with its associated morbidity and mortality. Acute graft-versus-host disease Acute GVHD has an incidence rate of approximately 20% to 48% for matched related-donor HCTs, up to 70% for matched unrelated-donor HCTs, and MHC-mismatched (HLA haploidentical) patients have rates as high as 80% to 90% [16,23,24]. If related donors are mismatched for 1-, 2-, or 3- HLA antigens, the risk of GVHD ranges from 75% to 80% [16]. Acute GVHD generally occurs within 14 to 35 days of stem cell infusion but can be seen as early as within 1 week of transplant [25]. As noted above, the incidence and severity of aGVHD is related to several immunologically based factors, such as donor-recipient HLA disparity, donor-recipient gender differences, source of stem cells, number of T cells in donor stem cell infusion, and effectiveness of GVHD prophylaxis regime [3,26,27]. In patients receiving conventional GVHD prophylaxis, such as a combination of cyclosporine and methotrexate, the median onset of GVHD is 21 to 25 days after HCT, however onset may be delayed in T-cell depleted grafts

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[28]. Reduced intensity conditioning regimens (previously referred to as nonmyeloablative conditioning regimes) may further decrease the incidence of aGVHD [17,29]. A hyperacute form of GVHD may occur in patients with severe HLA mismatches and in patients who receive inadequate GVHD prophylaxis [30]. Hyperacute GVHD is a severe form of aGVHD that can occur in the first 1 to 2 weeks after HCT and can be rapidly fatal [25]. The pathobiology of aGVHD has been described as a three-step process in which the innate and adaptive immune systems interact: (1) tissue damage to the recipient occurs from the radiation/chemotherapy conditioning regimen; (2) donor T cells recognize host antigens from the damaged tissues as foreign and become activated and stimulated, and then clonally expand; and (3) an effector stage ensues that is characterized by damage to host tissues induced either directly by immune cells or through a series of complex immune and inflammatory responses. In step one, conditioning regimens directly damage host tissues releasing alloantigens and inflammatory cytokines that promote activation of host APCs [3]. In step two, host APCs present the host’s alloantigens to the resting donor T cells, thus activating them. Donor T-cell activation is characterized by cellular proliferation and the production of inflammatory cytokines, including interleukin (IL)-2, tumor necrosis factor alpha (TNF-a), and interferon gamma (INF-g). Step three is characterized by multiple cytotoxic effectors including inflammatory cytokines, cytotoxic T cells, natural killer cells, other cells (mononuclear phagocytes and neutrophils), and nitric oxide production, producing direct target tissue damage or through intense inflammation associated with intense cytokine production, the so-called ‘‘GVHD cytokine storm’’ [3]. The initial inflammation results in the further recruitment of effectors cells into target organs, amplifying local tissue injury with further secretion of inflammatory cytokines, which, together with cytotoxic T lymphocytes, lead to target tissue destruction [31,32]. Additionally, specific proliferating marrow cells (eg, NK1.1þ T-cells and NK1.1- T cells) are capable of suppressing or promoting T-cell responses and thus modulate the incidence and severity of aGVHD [3,33]. Interestingly enough, donor-host histocompatibility differences may not always be needed to produce GVHD. A GVHD-like syndrome, seen rarely following autologous HCT, appears to arise through the inappropriate recognition of selfantigens [5,25]. This is usually a mild self-limiting condition that readily responds to treatment with steroids. The classically reported target organs for clinical manifestation of aGVHD are skin, liver, and the GI tract, but oral manifestations have clearly been documented [34,35]. In the skin, a pruritic skin rash is noted with generalized erythoderma and in severe cases bullae formation and desquamation. Damage to the GI tract from conditioning regimen toxicity increases the translocation of inflammatory stimuli such as endotoxins, which promotes further inflammation and additional damage. Signs and symptoms of GI aGVHD include nausea, vomiting, diarrhea, and pain. Hepatic aGVHD is characterized as a cholestatic jaundice with a marked rise in

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bilirubin levels. Acute GVHD may also affect hematopoiesis resulting in a reduction in peripheral blood counts, particularly platelets [36]. Chronic graft-versus-host disease cGVHD is the most common late complication after alloHCT and is the leading cause of late HCT non–relapse-related mortality [37,38]. cGVHD prevalence varies from 25% to 80% in long-term survivors after alloHCT with 5-year survival rates as low as 40% for patients with severe multisystem cGVHD [39,40]. The incidence and severity of cGVHD are correlated to immunologically related factors including HLA disparity, donor/host age and sex, donor type, source of progenitor cells, graft manipulations (especially T cell depletion), previous aGVHD, and use of post-HCT DLIs [17,41–43]. Often, cGVHD will present during tapering of or soon after stopping aGVHD prophylaxis or treatment [4,9,17]. The pathophysiology of cGVHD is not well understood. There are two theories regarding the mechanism of cGVHD: the first is simply end-stage alloreactivity and the second is that cGVHD is caused by poor/dysfunctional immunologic recovery with the evolution of autoreactive T lymphocytes because of lack of thymic control [4]. cGVHD is a multisystem alloimmune and autoimmune disorder characterized by immune dysregulation, immunodeficiency, and impaired organ function, all of which negatively impact survival [4,39]. The pathobiology of cGVHD starts with the expansion of donor T cells in response to alloantigens or autoantigens that is unchecked by normal thymic or peripheral mechanisms of deletion. T cells promote target organ damage either directly through inflammatory cytokines, cytolytic attack and fibrosis, and/or by promoting B-cell activation and production of autoantibodies [17]. While there can be widespread organ damage, the leading cause of death for patients with cGVHD is infection [4,6,21]. The most common sites of cGVHD involvement are the skin, oral cavity, eyes, GI tract, liver, and lungs (Fig. 1); however, the spectrum of clinical involvement is remarkably variable [4]. Clinical features are similar to those of collagen vascular diseases, lichen planus (LP), Sjo¨gren syndrome, polyserositis, esophagitis and stricture, vaginal ulcerations and stricture, intrahepatic obstructive liver disease, obstructive pulmonary disease, progressive systemic sclerosis, fasciitis, and myositis [44]. Oral graft-versus-host disease Oral acute graft-versus-host disease Epidemiological studies of oral aGVHD are lacking, but anecdotally we estimate that probably between 35% and 60% of patients with aGVHD will have oral manifestations. Oral aGVHD can occur as early 1 to 2 weeks post-HCT but more often between 18 and 100 days post-HCT; however, early onset of oral aGVHD is usually obscured by (or mistaken for)

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Sites Involved with Chronic GVHD Fig. 1. Frequency of site involvement by cGVHD based on donor stem cell source. Graph shows the proportions of patients who have organs affected by cGVHD at any time following either bone marrow transplantation (BMT, cross hatches) or peripheral blood stem-cell transplantation (PBSCT, solid black). Oral involvement is noted as the most frequent site of involvement for BMT and second most frequently involved site for PBSCT for the five most frequently versus-involved sites. (Adapted from Flowers MED, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood 2002;(100):415–9; with permission. Copyright Ó 2002, American Society of Hematology.)

conditioning regimen–related mucositis [7,25,45]. Oral mucosal involvement has not been part of the classic description of aGVHD. However, if infection is excluded with appropriate cultures, ulcerative lesions that fail to heal with hematologic recovery 21 to 28 days post-HCT may well represent oral aGVHD, although this does not become clinically distinct from oral mucositis until almost 3–4 weeks post-HCT [7]. Clinically, acute and chronic oral GVHD are characterized by mucosal hyperkeratotic responses, erythema and inflammation, atrophy, pseudomembranous ulcerations, fibrosis, and salivary gland dysfunction and taste disorders in patterns reminiscent of autoimmune disorders such as LP, lupus, systemic sclerosis, and Sjo¨gren syndrome [7,44,46–50] (Figs. 2–6). The clinical manifestations and histopathology of oral aGVHD and cGVHD also are very similar, although aGVHD changes tend to be less pronounced and distinct, and tends to be predominated more by erythema and atrophy, especially before day 50 post-HCT; however, LP-like hyperkeratotic changes can be noted but are less prominent than what is generally noted for cGVHD [38] (see Fig. 2). Pseudomembranous ulcerations are noted across the spectrum of aGVHD and cGVHD and are an indicator of severity (see Fig. 4). Whether these variations are due specifically to different pathologic mechanisms or a result of the effect of chronicity and severity of attack is not known.

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Fig. 2. (A) Oral acute GVHD occurring 48 days after transplantation with general buccal mucosal thinning, erythme due to vascular inflammation, and mild lichenoid hyperkeratotic striae. (B) Oral acute GVHD involving the lateral tongue with patchy erythema and hyperkeratotic plaque-like changes with occasional hyperkeratotic striae and inflammation of the fungiform papilla.

Oral chronic graft-versus-host disease In contrast to oral aGVHD, the presence of oral cGVHD is a frequent, prominent, and useful component of cGVHD diagnosis and staging. The frequency of oral cGVHD has been well documented with 72% to 83% of patients with cGVHD showing oral involvement, making this one of the most common manifestations of cGVHD (see Fig. 1) [6,51,52]. Clinical changes include mucosal inflammation and atrophy, lichenoid-hyperkeratotic changes (striae, plaques, papules, and patches), pseudomembranous ulcerations, mucoceles, and perioral fibrosis [7,44,46] (see Figs. 3–6). Clinically, cGVHD oral mucosal inflammation tends to produce a vasculitis-like or even a telangiectatic appearance, especially with longer standing involvement. Chronic GVHD involvement of the maxillary anterior attached gingival is characterized by atrophy with loss of stippling and moderate or worse inflammation of the entire attached gingiva; LP-like changes

Fig. 3. (A) Oral cGVHD with generalized mucosal atrophy and distinct lichenoid hyperkeratotic striae with adjacent erythema. (B) Oral cGVHD with irregular patches of lichenoid hyperkeratosis and patchy erythema.

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Fig. 4. (A) Oral cGVHD involving the buccal mucosa and palatal attached gingiva manifesting as pseudomembranous ulcerations (arrows) and intense erythema of surrounding tissues. (B) Oral cGVHD with extensive pseudomembranous ulceration (arrows) of the left buccal mucosa with moderate erythema and mild LP-like hyperkeratotic changes.

also can be noted. Sclerotic changes in the perioral tissues may result in decreased oral opening [50] (Fig. 6). The symptoms most often reported are pain (usually associated with ulcerative changes), sensitivity to normally tolerated items (hard crunchy foods, spices, acidic and carbonated beverages, and mint and cinnamon flavoring), xerostomia, and occasionally taste dysfunction [7,44,46,53]. Based on the characteristic oral changes and symptoms, the National Institutes of Health (NIH) Consensus Development Project for Clinical Trials in Chronic GVHD has developed a scoring system for following established oral cGVHD (http://www.asbmt.org/ GvHDForms) [12,13]. Salivary gland chronic graft-versus-host disease Saliva plays a major role in maintaining oral health and oral function [54]. When salivary function is compromised there is a significant increase in oral complications including increased risk for dental caries; mucosal infections; mucosal pain and friability; and difficulties with speaking, chewing,

Fig. 5. (A) Severe gingival atrophy and erythema in patient with long-standing oral cGVHD. (B) Multiple superficial mucoceles of the soft palate.

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Fig. 6. Severe perioral dermal fibrosis resulting in marked decrease in range of motion. Additional dermal changes include hypo- and hyper-pigmentation.

and swallowing [55]. The effects of HCT, and especially cGVHD, on salivary gland secretions have been extensively studied in both animal models and clinically. Early post-alloHCT salivary gland dysfunction is primarily attributed to conditioning regimen toxicity, especially when total body irradiation is used, and can persist for many months; however, late changes, especially in the context of systemic involvement (eg, skin) can be attributed to cGVHD [56,57]. Sialochemical and sialometric changes associated with cGVHD have been extensively reported [56,58–65]. Severe involvement results in the total destruction of secretory units and thus permanent and profound oral dryness [56]. Taste dysfunction While conditioning regimen–related ageusia or dysgeusia is a multifactorial phenomenon that typically resolves 1 to 2 months following HCT [66], late and selective taste disorders can persist for over 100 days post-HCT [67]. Patients may report a rapid decrease in their sense of taste that is temporally associated with the onset (or flare) of cGVHD, which suggests that the epithelial-derived taste receptor cell may be an immune-based target [67]. It is important to note, however, that calcineurin inhibitors (cyclosporine, tacrolimus) used to prevent and treat GVHD also can induce neurological changes that result in dysgeusia or ageusia, and this can confound the interpretation of this symptom relative to GVHD. Histopathological findings The diagnosis of oral cGVHD can frequently be made based on clinical presentation. When oral changes are less distinct, biopsy of the oral mucosa and minor salivary glands can provide important supportive diagnostic information [37].Oral mucosal and salivary gland biopsy changes are initially dominated by conditioning regimen–related toxicity, but by 50 to 60 days

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post-alloHCT, changes attributable to GVHD are more apparent [45]. In general, histologically there is little distinction between acute and chronic GVHD and, given the possibility for nonspecific inflammation, early postHCT biopsy findings need to be correlated with clinical changes to confirm the diagnosis [38]. Features include lichenoid interface inflammation, exocytosis, and keratinocyte apoptosis [7,45,68] (Fig. 7). Immunohistopathological studies demonstrate the presence of CD8-positive T cells, CD68-positive macrophages, and Langerhans cells, although B cells may also play a role [51,68–72]. Salivary gland changes are characterized by the presence of lymphocytic infiltration (CD8þ over CD4þ) of the glandular parenchyma and periductal tissue with or without plasma cells and exocytosis of lymphocytes (without neutrophils) into intralobular ducts and acini (see Fig. 7) [38,45,57,68,73,74]. The damage to salivary acini ultimately leads to acinar destruction with

Fig. 7. Histopathology of cGVHD. (A) Medium power photomicrograph demonstrating cGVHD induced histopathologic changes with lichenoid interface inflammatory changes, exocytosis, and apoptosis of keratinocytes along the basal cell layer. (B) cGVHD involvement of minor salivary gland with nearly complete loss of acini, dilated ducts, and interstitial fibrosis without inflammation.

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fibrosis. Superficial mucoceles are likely a result of GVHD-induced inflammation and damage to the minor salivary gland ducts with initial duct obstruction and later destruction while the acini are still functional. Impact of graft-versus-host disease The impact of GVHD on patients depends on the severity of the disease and the effectiveness of treatment protocols [75]. When severe, both acute and chronic extensive GVHD have to be considered a potentially life-threatening condition. Because infection is the leading cause of nonrelapse mortality in patients with cGVHD, infectious disease prophylaxis is critical, as is ensuring rapid diagnosis and treatment of infectious complications that develop. Supportive care must be directed toward managing the deleterious effects of cGVHD involvement (eg, hepatic, pulmonary, dermal, ocular, hematopoietic, nervous, and musculoskeletal) and the side effects of therapies, while maintaining an adequate quality of life [9]. Additionally, it is important to educate patients; refer for nutritional counseling; and to use active interventions to manage the financial, physical, emotional, and psychological complications of cGVHD [11,14,76,77]. The impact of oral involvement depends on its severity and duration and ranges from inconsequential to devastating [7,44,78,79]. Oral and dental supportive care measures aimed at managing mucosal and salivary gland disease play a major role in post-alloHCT patient care (see the following section) [44,78,80]. When symptomatic, oral GVHD can affect the patient’s quality of life because of associated pain, sensitivity, and dryness, and can significantly interfere with oral function. Interestingly, however, while cGVHD oral pain and sensitivity is reported to interfere with eating, these symptoms are not significantly associated with weight loss and malnutrition, possibly because patients will either tolerate the pain and discomfort or modify their diet to minimize discomfort and maintain caloric intake [15,81]. Patients with sclerotic involvement of the perioral tissues may report difficulty with oral function and hygiene and the ability to receive dental treatment [50]. Prevention and management of graft-versus-host disease Systemic therapy for graft-versus-host disease In general, the primary strategies to prevent/manage oral GVHD are centered on the strategies for the overall prevention and management of GVHD. Without prophylaxis, the incidence of aGVHD approaches 100%, and while GVHD prophylaxis protocols can reduce the risk, no specific prophylactic protocols have shown efficacy in preventing cGVHD [30]. While it may initially seem desirable to entirely prevent GVHD, this potentially reduces the GVL effect and increases the risk of relapse-related

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mortality, whereas ineffective prophylaxis increases the incidence of GVHD with its associated significant morbidity and mortality. Prevention of GVHD involves trying to control the immune reactivity of the grafted cells against host tissues [4,16,18,82–84]. The primary approach for the prevention of GVHD is minimizing risk factors whenever possible; however, prophylactic regimens are necessary and are effective in reducing the incidence of aGVHD [3,16,83] and include the use of low-dose methotrexate (MTX) alone or MTX plus steroids or a calcineurin inhibitor (cyclosporin or tacrolimum-506), with protocols using MTX with CSP being the most commonly used [16,83]. The schedules for these regimens usually involve administration of MTX early post-alloHCT (eg, days 1, 3, 6, and 11 post-HCT) and CSP administration starting just before transplantation and extending as long as 6 months post-HCT. Additional studies are under way to determine the effectiveness of other combinations of immunosuppressive agents for the prevention of GVHD including FK-506, sirolimus, or mycophenolate mofetil (MMF). If aGVHD is very mild (ie, grade I), prophylaxis will be continued and no additional treatment may be given, or possibly only topical treatments will be administered [18]. For example, topical steroids can be used to manage mild localized aGVHD rashes. Oral beclomethasone is a highly potent steroid that is active locally for GI mucosal surfaces and has been shown to effectively manage GI aGVHD and thus reduce the need for systemic therapy [85,86]. The use of psoralen plus ultraviolet A (PUVA) light has also been successfully used to treat ‘‘skin only’’ aGVHD. The treatment of established Grade II or worse aGVHD varies from center to center and at times even between subsets of patients [82,87]. High-dose systemic steroid therapy (2 mg/kg/d) is the mainstay of management, with a 20% to 70% response rate resulting in complete resolution without recurrence in 20% to 40% of patients [88]. Calcineurin inhibitors, antithymocyte globulin (ATG), PUVA, or oral beclomethasone (possibly in combination with oral budesonide) will often be added in steroid-refractory cases [16,83], although the effectiveness of adding these agents to systemic steroid therapy has not been confirmed by large, randomized clinical trials. Novel approaches to manage steroid-resistant aGVHD are looking at the efficacy of combining steroids with newer agents such as sirolimus, anticytokine antibodies (anti–IL-2 receptor and etanercept, an anti–TNF-a antibody), pentostatin, denileukin diftitox, and monoclonal antibodies (visilizumab, alemtuzumab, infliximab, daclizumab, and ABX-CBL) [3,16,18,82,83]. The prevention of cGVHD primarily is hampered by an incomplete understanding of the pathophysiology of the disease. The most prominent risk factor for developing cGVHD has long been considered to be aGVHD, therefore prevention is organized around the same strategies used to prevent aGVHD, though the effect of these strategies is usually less clear or dramatic. Protocols have examined the effects of stem cell source and composition, graft manipulation, reduced intensity conditioning use of ATG,

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and duration of prophylactic immunosuppression on GVHD and have met with variable success [39,49,76,89]. Pharmacologic approaches to prevent cGVHD have been not been encouraging. Limited cGVHD, like limited aGVHD can often be managed locally with topical corticosteroids, topical tacrolimus, or PUVA [90–93]. For instance, oral beclomethasone with or without budesonide can be very effective in managing limited GI GVHD. The initial treatment of extensive cGVHD depends on systemic corticosteroids (eg, prednisone 1.0 mg/kg/d) [88,89]. Studies comparing prednisone alone or in combination with of CSP or FK-506 have generally been difficult to evaluate and have demonstrated variable benefit from the combined agent protocols, although this approach may reduce long-term complications of corticosteroid therapy [88,94]. Patients at high-risk for cGVHD have shown modest benefit from combined steroid-CSP regimens, but for patients who had standard-risk CGVHD there was no benefit. Additionally, patients treated with prednisone plus CSP are at higher risk for fatal infections. The treatment of extensive cGVHD is subject to high failure and complication rates. Second-line therapies for steroid-refractory cGVHD include azathioprine (AZA), MMF, sirolimus, cyclophosphamide, thalidomide, rituximab, halofuginone and etretinate, daclizumab and etanercept, hydroxychloroquine, and extracorporeal photopheresis (ECP) [39,76,89]. Chronic GVHD tends to resolve slowly. Data from the Fred Hutchinson Cancer Research Center (FHCRC) has shown that for a cohort of 330 patients treated for cGVHD, approximately 33% required secondary systemic treatment in addition to steroids [94]. Within the first 3 years during initial treatment, an additional 10% of the patients died from causes other than recurrent malignancy. Only 5% of patients were off of immunosuppressive therapy within the first year of diagnosis, and only 27% were able to discontinue primary treatment 3 years after diagnosis without the need for secondary treatment. Treatment results for steroid-resistant cGVHD are much less successful than situations where only steroid treatment is necessary. In a group of 104 FHCRC patients, therapies needed to be continued longer and with higher rates of nonrecurrent malignancy-associated mortality (19%), increased rate of development of second malignances (12%), and 13% of patients required continuation on treatment for steroid-resistant beyond 2 years; 48% required subsequent treatment with a variety of other immunosuppressive agents after HCT. It has been reported that 15% of HCT patients diagnosed with cGVHD were still on immunosuppressive therapy as long as 7 years after transplantation [95]. Management of oral graft-versus-host disease Basic oral health Maintaining oral and dental health and preventing oral infections is critical for patients with oral GVHD [28,78,96]. Components of basic oral care

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include brushing, flossing, rinsing with bland agents (eg, normal saline), and xerostomia management with the primary goal being prevention of infections (eg, gingivitis, periodontitis, dental decay, and dental abscesses) [80] (Table 1). Therapy for oral mucosal graft-versus-host disease The overall effectiveness of systemic therapies on oral GVHD has not been specifically studied, but it is likely that a large percentage of patients with oral involvement respond to systemic therapy and do not require specific intensified local treatment. However, many patients will need additional ancillary treatment to heal ulcerative lesions and reduce oral pain and sensitivity. An additional advantage of topical/local treatment of oral GVHD is that it allows for intensifying treatment without having to increase systemic immunosuppression with its associated complications and toxicities. The management strategies for both oral acute and chronic GVHD are essentially the same. Even though aGVHD is self-limiting, this does not diminish Table 1 Basic oral care Basic oral hygiene Brushing Toothpaste

Flossing Xerostomia management Increased fluid intake Bland rinses Saliva substitutes/oral lubricating agents Taste stimulation Sialogogues Xerostomia decay prevention Fluorides

Remineralizing solutions Antibacterials Diet modification Lip care Chapped lips UV protection

Soft toothbrush twice a day using a Bass-sulcular scrub technique Fluoride-containing products Consider nonmint or children’s flavored toothpastes if mint flavors cause sensitivity For thermal dentinal sensitivity use ‘‘desensitizing’’ toothpastes containing potassium nitrate Floss between teeth and under bridges daily Frequent sips of water or flavored sugar-free beverages or ice chips Normal (0.9%) saline rinses, sodium bicarbonate rinses Artificial saliva products, water-soluble lubricants Sugar-free candies/chewing gum (eg, lemon-flavored, mints) Pilocarpine, cevimeline, or bethanechol Prescription strength 1.1% neutral sodium fluoride or 0.4% stannous fluoride Available as gels, dental creams, or rinses Application techniques: brushing, trays, or rinses Calcium phosphate solutions Chlorhexidine rinses Reduce frequency of exposure to refined carbohydrates (sugars) Commercial lip-coating/moisturizers and lip-care products, lanolin cream Lip-coating agents with SPF ratings R 30

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the need to provide timely and appropriate care. In contrast, because cGVHD can potentially require prolonged, specific oral management may be required for many years post HCT. The goals of oral GVHD management center primarily on ameliorating symptoms (eg, pain, sensitivity, and oral dryness), maintaining oral function, and treatment of ulcerative lesions, even when minimally symptomatic in order to restore mucosal integrity. Recently published cGVHD management guidelines specifically address oral cGVHD management as well as the importance of oral health as part of overall patient management [81,97]. Topical and local oral GVHD treatment strategies are essentially the same as those used to treat oral manifestations of autoimmune and immune-mediated disorders (eg, LP ! lupus, pemphigoid). Unfortunately, few oral GVHD clinical treatment trials have been reported and none can be considered to have been designed or adequately powered in order to evaluate and compare the efficacy of the various agents [98]. Often the choice of treatments will be determined by the availability of specific agents and formulations, patient acceptance of the products, and cost. Furthermore, the effectiveness of topical and local treatment for oral GVHD is variable, often requiring successive trials of various agents, and treatment schedules are typically protracted. Oral GVHD treatments can be divided into several basic categories including (1) corticosteroids, (2) nonsteroidal immunomodulatory agents, (3) light-based therapies, and (4) others (Table 2). When choosing an agent, it is important to consider the substantivity and bioavailability of the drug when applied to oral mucosal surfaces, taste and acceptability, and cost. Agents used to topically treat oral GVHD have not been formulated specifically for oral use and specific strategies for use in the mouth must be considered (Table 3). Patients should be given careful instructions with respect to dosage, application technique, and frequency of therapy. Many of the agents used to topically treat oral GVHD can be compounded by a pharmacist to produce a more acceptable taste and/or consistency if necessary. Corticosteroids. Topical oral steroid preparations are the most commonly used agents for oral GVHD and are formulated in a variety of ways including rinses, creams, gels, and ointments (see Table 2) [98,99]. Rinses are convenient to use and effective in managing extensive oral involvement or areas otherwise difficult to treat because of location or poor adherence (eg, soft palate, ventral tongue). Topical corticosteroids have a wide range in potencies and formulations, which will influence how they should be applied, how much is to be used, and whether there is a risk for systemic uptake. The specific agents, formulations, and instructions for use are listed in Table 2. The risk for oral candidiasis with topical steroids is well known and appears to be moderate with oral dexamethasone rinses and much higher with steroid inhalers. Atrophic and erythematous oral candidiasis can cause an acute flare of oral pain and sensitivity that is often inappropriately attributed to

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Table 2 Topical and local treatments for oral GVHD Treatment category

Instructions for use

Dexamethasone Budesonide Betamethasone Prednisolone Triamcinolone

0.1–0.4-mg/mL rinse; 5–10 mL swish/hold 3–5 minutes. Spit out. Repeat 3–6 /d. 0.3–0.6 mg/mL-rinse; 10 mL swished/held for 15 minutes. Spit out. Repeat 2–4 /d. 0.5-mg tablet dissolved in 10 mL, held for 3 minutes. Spit out. Repeat 3–4 /d. 3 mg/mL; rinse 5 mL for 4–6 minutes. Spit out. Repeat 3–6 /d. 1% aqueous solution; 5 mL for 4–6 minutes. Spit out. Repeat 3–6 /d.

Beclamethasone Fluticasone Betamethasone Triamcinalone

1–2 1–2 1–2 1–2

0.05% clobetasol cream, ointment, gel, solution 0.05% halobetasol cream, ointment 0.05% fluocinonide cream, ointment, gel 0.1–0.5% triamcinalone cream 0.05–0.1% betamethasone cream, ointment

Apply Apply Apply Apply Apply

Sprays/ inhalers puffs puffs puffs puffs

in in in in

mouth. mouth. mouth. mouth.

Repeat Repeat Repeat Repeat

2–4 2–4 2–4 2–4

/d. Hold in mouth, do not swallow. Spit out.b /d.b /d.b /d.b

Gels, creams, and ointmentsc to to to to to

lesions lesions lesions lesions lesions

2 2 2 2 2

/d. /d. /d. /d. /d (one formulation includes 1% clotrimazole).

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Corticosteroids Rinses

Treatment a

Nonsteroidal immunosuppressives Rinses Cyclosporined Azathioprine/6-mercaptopurine

Rinse: 100 mg/mL 5 mL swished/held for several minutes, spit out repeat 3 /d. 1.5% gel applied to lesions 2 /d. 5–10 mg/mL, 5–10 mL swished and held for 3–5 minutes, spit out. Repeat 2–6 /d.

Gels/other 0.5 mg/dL in bioadherent base 5 mg/mL in 3% methylcellulose gel base, 1–2 mL applied to lesion 3–4 /d. Apply 0.5 inch to gauze, hold over lesion for 15–20 minutes 2 /d. Monitor plasma levels.

PUVA

0.3 mg/kg psoralen followed by 0.5–6.0 J/cm2 UVA radiation (dose increased as tolerated), 3–4 /wk. 0.02 mJ/cm2 with escalating 0.02 mJ/cm2 every 4th treatment 632–660 nM, 2–3 J/cm2 per treatments, treat 2–3 times a week until healed. Defocused 1 W held 1 cm from surface, 2–3 seconds (surface kept moist).

Phototherapy

UVB Low-level laser therapy CO2 laser

Topical treatments should be easily applied and to have an agreeable taste and consistency. Rinses usually represent the most easily applied formulations for treating oral mucosal GVHD. Gels are most easily applied to discrete oral lesions such as pseudomembranous ulcerations (creams can often be difficult to apply and keep localized to lesions, and patients often find bioadhesive pastes to have a disagreeable consistency). Consideration for custom compounding should be considered for situations where standard products are not acceptable for patients. Abbreviation: PUVA, psoralen plus ultraviolet A. a Anti-Candida prophylaxis may be needed, especially with inhalers. b Consider rinsing mouth after 15–20 minutes to reduce the risk of oral candidiasis. c Ointments can be applied to a sterile gauze and placed over the lesion for 10–15 minutes, then removed. d Cyclosporine is expensive and reduced volumes of rinses (1–3 mL) may be appropriate.

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Cyclosporine Azathiooprine 0.1% tacrolimus

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Table 3 Instructions for use of topical treatments for oral GVHD Topical oral therapy

Creams

Ointments

(1) Rinse mouth with plain water; avoid normal saline. (2) Try not to eat or drink or brush teeth with toothpaste for 15–20 minutes before use of topical agent. (1) Use enough volume to comfortably coat oral tissues; 5–10 mL usually works well. (2) Hold the solution in mouth for generally 3–5 minutes before expectorating. Rinses can be held longer if (a) oral lesions are severe and/or (b) the patient is not able to use rinse the prescribed number of times a day. Note: A flavored rinse may stimulate salivary function and thus the volume in the mouth may increase while held. Small amounts can be expectorated until the rinse is spit out. (3) Avoid eating or drinking for 20–30 minutes after use when possible. (1) Try to dry lesion before application. (2) Warm a metal spoon under hot water, then dry and place medication to be used in the spoon to semi-liquefy the cream. This will improve the ability to apply the drug to the lesion. (3) Apply softened/liquefied cream to the lesion with a cotton swab or a clean finger tip. The key is to apply like ‘‘icing a cake’’ not by trying to rub into the tissue (4) Avoid eating or drinking for 20–30 minutes after use when possible.a (1) Try to dry lesion before application as this will improve adhesion to the lesion. (2) Ointments can be warmed slightly as noted above for creams. (3) Gently apply warmed ointment to the lesion with a cotton swab or a clean finger tip. The key is to apply like ‘‘icing a cake’’ not by trying to rub into the tissue. (4) Avoid eating or drinking for 20–30 minutes after use when possible.a Alternatively: Apply ointment to a 2  2 sterile gauze and place on top of lesion, keeping in place for 10–15a minutes. Remove gauze and avoid eating or drinking for 20–30 minutes after use when possible. Note: Ointments are especially useful for treating vermillion lip GVHD (chapping, cracking, etc.).

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Rinses

Pre use oral care: considerations for use of specific agents

Gels

Inhalers

Few of the topical treatments for oral GVHD have been formulated for easy use and ‘‘special’’ instructions may be necessary to allow for maximum effectiveness of the therapy. Potentially useful instructions are provided. (1) Systemic uptake can occur from absorption through tissues or swallowingdpatients may require monitoring of for absorbed drug. (2) Monitor mouth for emergence of oral candidiasis. Note: Atrophic and erythematous candidiasis can occur and be difficult to differentiate from oral GVHD. Candida cultures may be important. Some clinicians will use prophylactic antifungals with topical steroids. (3) For products with disagreeable tastes or consistencies, consider having pharmacist recompound to make product more desirable to use. a Unless specifically instructed to do so, patients should avoid swallowing topical drugs for at least 20–30 minutes after using. Strategies (spitting into a cup, facial tissue, and so forth) should be discussed.

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(1) Try to dry lesion before application as this will improve adhesion to the lesion. (2) Gels will generally melt at mouth temperature, but can be warmed slightly as noted above for creams if it helps with application. (3) Gently apply gel to the lesion with a cotton swab or a clean finger tip. The key is to apply like ‘‘icing a cake’’ not by trying to rub into the tissue. (4) Avoid eating or drinking for 20–30 minutes after use when possible. Alternatively: Apply ointment to a 2  2 sterile gauze and place on top of lesion, keeping in place for 10–15a minutes. Remove gauze and avoid eating or drinking for 20–30 minutes after use when possible. (1) Dry oral tissues slightly. (2) Use one or two ‘‘puffs’’ without inhalingdcan be directed specifically toward lesions. (3) For general oral GVHD, gently coat the mouth with the medication. (4) If problems occur with oral candidiasis, in addition to prescribing antifungals, consider having the patient rinse mouth 10–15 minutes after use.

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a flare of oral GVHD, and oral smears and cultures may be necessary to demonstrate Candida colonization. Topical or systemic antifungal agents are effective. However, in cases of frequent recurrences, prophylactic strategies may be necessary. The various corticosteroid rinses are swished for 5 minutes and expectorated and can be compounded in many different flavored bases to improve patient acceptance, however comparative studies are lacking. Dexamethasone elixir (0.1 mg/mL), which is widely available and does not require compounding, used 3 to 6 times a day will provide predictable results [100]. Patients may complain of oral burning when concentrations are compounded above 0.4 mg/mL. Budesonide rinses (0.3 to 0.6 mg/mL) have been studied for the treatment of oral cGVHD by two different groups [101,102] and shown to be most effective for mild-moderate disease. It is recommended that 5 to 10 mL (1.5 to 6.0 mg per dose) be rinsed (held in the mouth) for 4 to 5 minutes and then spit out. No problems with taste were reported, although some complaints of burning were noted. Franca and colleagues [79] reported on the effective use of a betamethasone rinse (0.6 mg/5 ml) for managing a case of steroid-refractory oral GVHD. The use of budesonide and beclamethasone inhalers or nasal sprays for the management of oral aphthous ulcerations has been described and we have anecdotally noted that this is a convenient and effective treatment strategy for oral cGVHD lesions. Oral applications can be carried out by positioning over a lesion and dispensing into the mouth without inhaling. Patients are instructed to rinse their mouths for at least 5 to 10 minutes after application to reduce the risk of oral candidiasis that is frequently noted with the oral use of these products. For distinct lesions that are easily accessible, gels, creams, and ointments can be effective alone or in combination with rinses/inhalers. Gels are generally easier to apply than the creams and ointments because they are hydrophilic and ‘‘melt’’ quickly, providing easier application and possibly improved absorption. The very high potency steroids (eg, clobetasol and halobetasol) are particularly useful for managing localized areas of oral GVHD pseudomembranous ulcerations, since they only need to be applied twice a day; however, it is unclear to what extent these high-potency agents are absorbed systemically. Therefore, it is recommended that these agents be used for direct application to distinct lesions and be discontinued once lesions have resolved are controlled. Nonsteroidal immunomodulatory agents. A number of topical immunosuppressive agents have been used to manage oral GVHD including CSP, AZA or it’s active metabolite 6-mercaptopurine (MP), and tacrolimus. The specific formulations and dosing guidelines are provided in Table 2. Cyclosporine oral rinses and gel (in a bio-adherent base) have been reported in the literature for managing oral GVHD [103–105]. However, many clinicians have reported poor results with topical CSP similar to what has been reported with CSP use for oral LP [106,107]. Additionally, CSP rinse

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(100 mg/ml) is relatively expensive and some have recommended reducing volumes for rinsing from 5 mL to 2 to 3 mL. AZA is the prodrug of 6-MP, the biologically active metabolite, and is one of the original drugs used for GVHD prophylaxis and management; however, calcineurin inhibitors and MMF have replaced AZA as first-line steroid-sparing agents. Both AZA 6-MP have been demonstrated to directly affect lymphocyte function and can be compounded into a rinse or a gel. AZA rinses have been reported to be effective in managing oral GVHD in a small open-label trial with concomitant systemic therapy [107], however no dose-finding studies have been carried out. 6-MP can be compounded into a rinse. AZA and 6-MP have been linked to increased risk of malignancies in a number of transplant settings (as have CSP, FK-506, and MMF), and without definitive risk data for oral malignancies following topical use, it is recommended that, as soon as possible, patients should discontinue their topical use and be transitioned to topical corticosteroids for maintenance therapy. Tacrolimus ointment has been reported in three small case series or reports to be effective in managing oral GVHD [108–110]. Reported protocols use small amounts (1.0 cm) of 0.1% ointment either applied directly or placed on a 2  2 gauze pad and then applied over lesions for 15 to 20 minutes before removal. There can be systemic uptake with this technique and plasma levels should be measured to determine the systemic impact and acceptability of this treatment [111]. The ointment is especially useful for managing cGVHD of the lips. Tacrolimus can additionally be compounded as a gel or rinse, although cost of these preparations may be high. Tacrolimus ointment has been given a ‘‘black box’’ warning by the Food and Drug Administration because it may cause rare malignancies and lymphoma. The relevance of this to the HCT setting where significant extended systemic dosing with this and other immunosuppressive agents linked to increased risk of malignancies is not clear, but it may be prudent to avoid extended topical use. The use of systemic thalidomide as an immunosuppressive agent to treat cGVHD, while initially showing encouraging results in small trials, has demonstrated low response rates and a high incidence of toxicity [112]. Topical thalidomide has been used for the treatment of a number of oral inflammatory conditions (eg, aphthous stomatitis, oral LP) and its use to manage ulcerative oral cGVHD lesions is currently being studied in clinical trials at NIH (www.clinicaltrials.gov). The topical oral use of thalidomide will hopefully allow for good response rates without significant toxicity. Phototherapy. Several phototherapies that have been reported to be effective in treating oral cGVHD include (1) PUVA therapy, (2) ultraviolet B therapy, (3) extracorporeal photopheresis (ECP), (4) CO2 laser therapy, and (5) low-level laser therapy. PUVA therapy is used at some centers to manage skin GVHD, and several anecdotal reports and cases series have reported on the potential benefit of local intraoral PUVA therapy to manage steroid-refractory ulcerative oral cGVHD [100,113–115]. Using protocols

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consistent with skin treatment protocols, psoralen (0.3 mg/kg of body weight) is given orally 1 hour before UVA treatment. UVA dental composite curing lights or medical UVA light sources with fiber-optic delivery systems can be used to expose oral lesions at doses starting at 0.5 J/cm2 and escalating by 0.5 J/cm2 to a maximum of 6.0 J/cm2 over successive treatments as tolerated. Treatments are usually given three times a week over many weeks until there is lesion resolution. Although PUVA therapy has been associated with an increased risk of skin cancer, there are insufficient data available to determine the actual risk for oral malignancy. There is increasing interest in medical phototherapy settings to use UVB, and in particular narrow-band UVB, instead of UVA radiation to treat skin conditions [116,117]. UVB does not require a photosensitizing agent and has not been associated with an increased risk of cancer. Elad and colleagues [118] reported on two cases of steroid-refractory oral cGVHD that responded to direct exposure to UVB radiation (without psoralen). Delivery systems described can be cumbersome and further work is needed to determine whether PUVA and UVB strategies are truly useful for managing severe refractory oral cGVHD. ECP, while not a topical or local therapy, deserves noting as a treatment technique that has shown good activity against severe steroid-refractory oral GVHD. ECP is an immunomodulatory therapy where a proportion of the buffy coat cells are pheresed and then exposed to UVA and psoralen, and then reinfused into the patient. This therapy is thought to possibly inhibit T-cell clones responsible for GVHD attack of tissues. Several studies have demonstrated encouraging clinical response rates for patients with otherwise resistant oral lesions [15,119,120]. Although reports are extremely limited, both low-level laser therapy (LLLT) and high-energy lasers have been used to manage oral cGVHD lesions based on their apparent ‘‘wound healing’’ properties. Two case reports have described the use of LLLT (660 nm 50 mW laser at 2 J/cm2 per spot) in conjunction with systemic therapy that resulted in significant clinical improvement in oral lesions and symptoms [121,122]. The mechanism of action of LLT on GVHD lesions is not clear, and there is growing evidence to suggest that immunomodulatory, anti-inflammatory, and wound healing effects may be involved. In a pilot study, Elad and colleagues [123] noted that a CO2 laser treatment with an energy setting of 1 W and delivered with a defocused technique was able to reduce pain levels and improve function for patients with painful oral cGVHD lesions. While clinical benefits for both LLLT and CO2 laser have been noted, the mechanism for these benefits is not known and further studies are needed. Therapy for salivary gland graft-versus-host disease The most common strategy for managing oral GVHD–related xerostomia is through frequent sipping of fluids (Table 1). Normal saline (0.9%) rinses can directly moisturize mucosal surfaces and stimulate salivary

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function. Taste stimulation of saliva above resting flow rates can be achieved with flavored sugar-free gums, lozenges, candies, or mints, and can help palliate mild to moderate xerostomia [55]. Artificial salivas (rinses and gels) and flavored mouthwashes can provide transient mucosal comfort [55]. Sialogogues including pilocarpine, cevimeline, and bethanechol directly stimulate salivary glands to increase resting saliva output and thus increase comfort [124–132]. While generally effective for stimulating saliva production, there are possible side effects (sweating, flushing, postural hypotension, diarrhea, and urinary frequency) that can influence patient acceptance [126]. Medical contraindications for these agents include uncontrolled asthma, narrow-angle glaucoma, acute iritis, and cardiac arrhythmias [126]. Pilocarpine is a parasympathomimetic agent with mild b-adrenergic stimulating properties used to treat patients with salivary gland hypofunction [124,125]. The use of pilocarpine has been shown to be effective for managing xerostomia and hyposalivation in patients with cGVHD [127,128]. Cevimeline is another parasympathomimetic agent that can improve symptoms of dry mouth and increase salivary output and has been recommended for the symptomatic management of cGVHD-associated xerostomia [129,130]. The time from administration of cevimeline to onset of salivation is somewhat longer than pilocarpine, but the duration of action is longer [55]. Bethanachol has been reported to be effective for radiation therapy–induced salivary gland hypofunction and has shown effectiveness in managing cGVHD-related xerostomia [131,132]. Superficial mucoceles are typically considered more of a ‘‘nuisance’’ or ‘‘annoying’’ than painful and do not require specific treatment. Occasionally, deeper mucoceles may develop and become symptomatic requiring surgical excision. Systemic and topical therapy, especially the more potent topical agents, can help to control the frequency and severity of these lesions. In addition to managing xerostomia, patients need to be placed on appropriate decay prevention protocols including topical fluorides, remineralizing solutions, antibacterial rinses, and diet modification along with effective dental plaque removal techniques (see Table 1). Additional considerations in patients with oral graft-versus-host disease Decreased oral opening Decreased oral range of motion can be noted in patients with sclerotic features of skin cGVHD with restriction caused by perioral cutaneous involvement and mucosal fibrosis [13,49]. With successful management of cGVHD, these changes may soften and range of motion may improve; however, these changes are often chronic and progressive and stretching programs will usually be necessary. When severe, there can be significant limitations in oral function, the ability to maintain oral hygiene, and ability to receive routine dental care.

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Oral infections and graft-versus-host disease Because of the profound and persistent immune dysfunction post-alloHCT, secondary oral infections can complicate and exacerbate oral lesions, increase oral pain and dysfunction, and confound the diagnosis. Oral GVHD will often have a distinct enough clinical presentation that oral examinations are adequate for diagnosis and monitoring; however, if there is uncertainty with interpretation of clinical oral findings, oral mucosal biopsies and additional laboratory studies to rule out infection, such as oral candidiasis, herpes simplex virus, and cytomegalovirus, since these infections in the presence of oral GVHD can have unusual clinical presentations [38,97,133,134]. Distinct bacterial infections complicating oral GVHD appear to be uncommon per se, however dental plaque may aggravate gingival GVHD and should be minimized through comprehensive oral hygiene practices. Infections (local or systemic) may induce immune responses and subsequently systemic responses that promote cGVHD activity [135]. Therefore, preventing and managing dental (eg, gingivitis, periodontitis and dental abscesses) as well as other oral infections may be an important aspect of management of alloHCT patients. Second malignancies The occurrence of new or second malignant neoplasms (SMNs) and lymphoproliferative disorders following HCT have long been recognized as a significant complication for long-term survivors [136–142]. Risk factors include the use of total body irradiation, underlying diagnosis, pre-HCT therapy, use of immunosuppressive agents (especially AZA alone or in combination with other immunosuppressive agents), cGVHD, age at HCT, and male sex. In general, the longer the patient survives post-HCT, the higher the risk of developing an SMN. Oral cancers, especially squamous cell carcinomas and salivary gland tumors, have been especially prominent in both adult and pediatric long-term survivors [138–142]. Oral dysplasia and malignancies can often be obscured by oral cGVHD or even mimic cGVHD and only biopsy can discriminate between the two. Consequently, consistent and comprehensive oral soft tissue examinations as well as patient education become critical components of long-term follow-up for all post-HCT survivors. Patients routinely need to monitor their own mouths and to report any suspicious oral tissues immediately for assessment. Summary HCT is increasingly being used to treat a wide range of malignancies, hematologic and immune deficiency states, and autoimmune diseases. GVHD is a significant complication of allogeneic transplantation that increases morbidity and mortality. Despite significant advances in our understanding of the pathobiology of acute and chronic GVHD and improved techniques

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for its prevention and management, it remains as a significant barrier to expand the clinical utilization and application of allogeneic HCT. The oral cavity is one of the most frequent sites of involvement with changes resembling a number of autoimmune collagen vascular diseases such as LP, systemic sclerosis, and Sjo¨gren syndrome. Recognition, diagnosis, and monitoring of oral GVHD changes are an important component of overall patient management. Topical and local management of symptomatic oral GVHD can not only improve patient comfort and oral function, but can additionally reduce the need for more intensive systemic immunosuppressive therapies. References [1] Thomas ED. Bone marrow transplantation from the personal viewpoint. Int J Hematol 2005;81:89–93. [2] Thomas ED, Storb R, Clift RA, et al. Bone-marrow transplantation (second of two parts). N Engl J Med 1975;292:895–902. [3] Ferrara JL, Reddy P. Pathophysiology of graft-versus-host disease. Semin Hematol 2006; 43:3–10. [4] Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis and treatment of graft-versushost disease after bone marrow transplant. Annu Rev Med 2003;54:29–52. [5] Martin RW 3rd, Farmer ER, Altomonte VL, et al. Lichenoid graft-vs-host disease in an autologous bone marrow transplant recipient. Arch Dermatol 1995;131:333–5. [6] Lee SJ, Klein JP, Barrett AJ, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood 2002;100:406–14. [7] Woo SB, Lee SJ, Schubert MM. Graft-vs.-host disease. Crit Rev Oral Biol Med 1997;8: 201–16. [8] Arora M, Burns LJ, Davies SM, et al. Chronic graft-versus-host disease: a prospective cohort study. Biol Blood Marrow Transplant 2003;9:38–45. [9] Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003;9:215–33. [10] Jacobsohn DA, Montross S, Anders V, et al. Clinical importance of confirming or excluding the diagnosis of chronic graft-versus-host disease. Bone Marrow Transplant 2001;28: 1047–51. [11] Lee SJ, Kim HT, Ho VT, et al. Quality of life associated with acute and chronic graftversus-host disease. Bone Marrow Transplant 2006;38:305–10. [12] Pavletic SZ, Lee SJ, Socie G, et al. Chronic graft-versus-host disease: implications of the National Institutes of Health consensus development project on criteria for clinical trials. Bone Marrow Transplant 2006;38:645–51. [13] 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;11:945–56. [14] Billingham RE. The biology of graft-vs-host reaction. Harvey Lecture 1966–1967;62:21–78. [15] Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 2006;107:3074–80. [16] Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management. Exp Hematol 2001;29:259–77. [17] Perez-Simon JA, Sanchez-Abarca I, Diez-Campelo M, et al. Chronic graft-versus-host disease: pathogenesis and clinical management. Drugs 2006;66:1041–57. [18] Bolanos-Meade J, Vogelsang GB. Acute graft-versus-host disease. Clin Adv Hematol Oncol 2004;2:672–82.

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[19] Lee SJ. New approaches for preventing and treating chronic graft-versus-host disease. Blood 2005;105:4200–6. [20] Weiden PL, Sullivan KM, Flournoy N, et al. Antileukemic effect of chronic graft-versushost disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981;304:1529–33. [21] Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989;73:1720–8. [22] Porter D, Levine JE. Graft-versus-host disease and graft-versus-leukemia after donor leukocyte infusion. Semin Hematol 2006;43:53–61. [23] Teshima T, Matsuo K, Matsue K, et al. Impact of human leucocyte antigen mismatch on graft-versus-host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors. Br J Haematol 2005;130: 575–87. [24] Eapen M, Rubinstein P, Zhang MJ, et al. Comparable long-term survival after unrelated and HLA-matched sibling donor hematopoietic stem cell transplantations for acute leukemia in children younger than 18 months. J Clin Oncol 2006;24:145–51. [25] Deeg HJ, Antin JH. The clinical spectrum of acute graft-versus-host disease. Semin Hematol 2006;43:24–31. [26] Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant 1999;5:347–56. [27] Bacigalupo A. Management of acute graft-versus-host disease. Br J Haematol 2007;137: 87–98. [28] Antin JH, Bierer BE, Smith BR, et al. Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies. Blood 1991;78:2139–49. [29] Bonini C, Ferrari G, Verzeletti S, et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997;276:1719–24. [30] Sullivan KM, Deeg HJ, Sanders J, et al. Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation. Blood 1986;67: 1172–5. [31] Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992;80:2964–8. [32] Wang H, Clouthier SG, Galchev V, et al. Intact-protein-based high-resolution three-dimensional quantitative analysis system for proteome profiling of biological fluids. Mol Cell Proteomics 2005;4:618–25. [33] Lowsky R, Takahashi T, Liu YP, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005;353:1321–31. [34] Johnson ML, Farmer ER. Graft-versus-host reactions in dermatology. J Am Acad Dermatol 1998;38:369–92; [quiz: 393–6]. [35] Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000;95:2754–9. [36] Anderson KC, Soiffer R, DeLage R, et al. T-cell-depleted autologous bone marrow transplantation therapy: analysis of immune deficiency and late complications. Blood 1990;76:235–44. [37] Gilman AL, Serody J. Diagnosis and treatment of chronic graft-versus-host disease. Semin Hematol 2006;43:70–80. [38] Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versushost disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 2006;12:31–47. [39] Baird K, Pavletic SZ. Chronic graft versus host disease. Curr Opin Hematol 2006;13: 426–35.

ORAL GRAFT-VERSUS-HOST DISEASE

105

[40] Akpek G. Titrating graft-versus-host disease: is it worth a try? Bone Marrow Transplant 2006;38:653–6. [41] Rocha V, Wagner JE Jr, Sobocinski KA, et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000;342:1846–54. [42] Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991;28:250–9. [43] Atkinson K, Horowitz MM, Gale RP, et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood 1990;75:2459–64. [44] Schubert MM, Sullivan KM, Morton TH, et al. Oral manifestations of chronic graft-v-host disease. Arch Intern Med 1984;144:1591–5. [45] Sale GE, Shulman HM, Schubert MM, et al. Oral and ophthalmic pathology of graft versus host disease in man: predictive value of the lip biopsy. Hum Pathol 1981;12:1022–30. [46] Schubert MM, Sullivan KM. Recognition, incidence, and management of oral graft-versushost disease. NCI Monogr 1990;9:135–43. [47] Seber A, Khan SP, Kersey JH. Unexplained effusions: association with allogeneic bone marrow transplantation and acute or chronic graft-versus-host disease. Bone Marrow Transplant 1996;17:207–11. [48] Lawley TJ, Peck GL, Moutsopoulos HM, et al. Scleroderma, Sjogren-like syndrome, and chronic graft-versus-host disease. Ann Intern Med 1977;87:707–9. [49] Demarosi F, Bez C, Sardella A, et al. Oral involvement in chronic graft-vs-host disease following allogenic bone marrow transplantation. Arch Dermatol 2002;138:842–3. [50] da Fonseca MA, Schubert M, Lloid M. Oral aspects and management of severe graft-vshost disease in a young patient with beta-thalassemia: case report. Pediatr Dent 1998;20: 57–61. [51] Ratanatharathorn V, Ayash L, Lazarus HM, et al. Chronic graft-versus-host disease: clinical manifestation and therapy. Bone Marrow Transplant 2001;28:121–9. [52] Flowers ME, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood 2002;100:415–9. [53] Cunningham BA, Lenssen P, Aker SN, et al. Nutritional considerations during marrow transplantation. Nurs Clin North Am 1983;18:585–96. [54] Mandel ID. The role of saliva in maintaining oral homeostasis. J Am Dent Assoc 1989;119: 298–304. [55] Fox PC. Salivary enhancement therapies. Caries Res 2004;38:241–6. [56] Schubert MM, Izutsu KT. Iatrogenic causes of salivary gland dysfunction. J Dent Res 1987; 66 Spec no:680–8. [57] Coracin FL, Pizzigatti Correa ME, Camargo EE, et al. Major salivary gland damage in allogeneic hematopoietic progenitor cell transplantation assessed by scintigraphic methods. Bone Marrow Transplant 2006;37:955–9. [58] Izutsu KT, Menard TW, Schubert MM, et al. Graft versus host disease-related secretory immunoglobulin A deficiency in bone marrow transplant recipients. Findings in labial saliva. Lab Invest 1985;52:292–7. [59] Nagler RM, Laufer D, Nagler A. Parotid gland dysfunction in an animal model of chronic graft-vs-host disease. Arch Otolaryngol Head Neck Surg 1996;122:1057–60. [60] Nagler RM, Nagler A. The effect of pilocarpine on salivary constituents in patients with chronic graft-versus-host disease. Arch Oral Biol 2001;46:689–95. [61] Nagler RM, Nagler A. Sialometrical and sialochemical analysis of patients with chronic graft-versus-host diseaseda prolonged study. Cancer Invest 2003;21:34–40. [62] Hiroki A, Nakamura S, Shinohara M, et al. A comparison of glandular involvement between chronic graft-versus-host disease and Sjogren’s syndrome. Int J Oral Maxillofac Surg 1996;25:298–307.

106

SCHUBERT & CORREA

[63] Chaushu S, Chaushu G, Garfunkel A, et al. Salivary immunoglobulins in recipients of bone marrow grafts. II. Transient secretion of donor-derived salivary IgA following transplantation of T cell-depleted bone marrow. Bone Marrow Transplant 1994;14:925–8. [64] Chaushu S, Chaushu G, Garfunkel AA, et al. Salivary immunoglobulins in recipients of bone marrow grafts. I. A longitudinal follow-up. Bone Marrow Transplant 1994;14:871–6. [65] Izutsu KT, Sullivan KM, Schubert MM, et al. Disordered salivary immunoglobulin secretion and sodium transport in human chronic graft-versus-host disease. Transplantation 1983;35:441–6. [66] Comeau TB, Epstein JB, Migas C. Taste and smell dysfunction in patients receiving chemotherapy: a review of current knowledge. Support Care Cancer 2001;9:575–80. [67] Marinone MG, Rizzoni D, Ferremi P, et al. Late taste disorders in bone marrow transplantation: clinical evaluation with taste solutions in autologous and allogeneic bone marrow recipients. Haematologica 1991;76:519–22. [68] Soares AB, Faria PR, Magna LA, et al. Chronic GVHD in minor salivary glands and oral mucosa: histopathological and immunohistochemical evaluation of 25 patients. J Oral Pathol Med 2005;34:368–73. [69] Horn TD, Rest EB, Mirenski Y, et al. The significance of oral mucosal and salivary gland pathology after allogeneic bone marrow transplantation. Arch Dermatol 1995; 131:964–5. [70] Hasseus B, Jontell M, Brune M, et al. Langerhans cells and T cells in oral graft versus host disease and oral lichen planus. Scand J Immunol 2001;54:516–24. [71] Sato M, Tokuda N, Fukumoto T, et al. Immunohistopathological study of the oral lichenoid lesions of chronic GVHD. J Oral Pathol Med 2006;35:33–6. [72] Izumi R, Fujimoto M, Yazawa N, et al. Bullous pemphigoid positive for anti-BP180 and anti-laminin 5 antibodies in a patient with graft-vs-host disease. J Am Acad Dermatol 2007;56:S94–7. [73] Alborghetti MR, Correa ME, Adam RL, et al. Late effects of chronic graft-vs.-host disease in minor salivary glands. J Oral Pathol Med 2005;34:486–93. [74] Sale GE, Gallucci BB, Schubert MM, et al. Direct ultrastructural evidence of targetdirected polarization by cytotoxic lymphocytes in lesions of human graft-vs-host disease. Arch Pathol Lab Med 1987;111:333–6. [75] Fraser CJ, Bhatia S, Ness K, et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood 2006;108:2867–73. [76] Shlomchik WD, Lee SJ, Couriel D, et al. Transplantation’s greatest challenges: advances in chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007;13:2–10. [77] Wingard JR, Vogelsang GB, Deeg HJ. Stem cell transplantation: supportive care and longterm complications. Hematology Am Soc Hematol Educ Program 2002;422–44. [78] Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004;100:2026–46. [79] Franca CM, Domingues-Martins M, Volpe A, et al. Severe oral manifestations of chronic graft-vs.-host disease. J Am Dent Assoc 2001;132:1124–7. [80] McGuire DB, Correa ME, Johnson J, et al. The role of basic oral care and good clinical practice principles in the management of oral mucositis. Support Care Cancer 2006;14: 541–7. [81] Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2006;12:138–51. [82] Bolanos-Meade J. Update on the management of acute graft-versus-host disease. Curr Opin Oncol 2006;18:120–5.

ORAL GRAFT-VERSUS-HOST DISEASE

107

[83] Chao NJ, Chen BJ. Prophylaxis and treatment of acute graft-versus-host disease. Semin Hematol 2006;43:32–41. [84] Ferrara JL. Novel strategies for the treatment and diagnosis of graft-versus-host-disease. Best Pract Res Clin Haematol 2007;20:91–7. [85] McDonald GB, Bouvier M, Hockenbery DM, et al. Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology 1998;115:28–35. [86] Castilla C, Perez-Simon JA, Sanchez-Guijo FM, et al. Oral beclomethasone dipropionate for the treatment of gastrointestinal acute graft-versus-host disease (GVHD). Biol Blood Marrow Transplant 2006;12:936–41. [87] Svennilson J. Novel approaches in GVHD therapy. Bone Marrow Transplant 2005; 35(Suppl 1):S65–7. [88] Martin PJ, Carpenter PA, Sanders JE, et al. Diagnosis and clinical management of chronic graft-versus-host disease. Int J Hematol 2004;79:221–8. [89] Cutler C, Antin JH. Chronic graft-versus-host disease. Curr Opin Oncol 2006;18:126–31. [90] Horwitz ME, Sullivan KM. Chronic graft-versus-host disease. Blood Rev 2006;20:15–27. [91] Bertz H, Afting M, Kreisel W, et al. Feasibility and response to budesonide as topical corticosteroid therapy for acute intestinal GVHD. Bone Marrow Transplant 1999;24: 1185–9. [92] Iyer RV, Hahn T, Roy HN, et al. Long-term use of oral beclomethasone dipropionate for the treatment of gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 2005;11:587–92. [93] Hockenbery DM, Cruickshank S, Rodell TC, et al. A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease. Blood 2007;109:4557–63. [94] Koc S, Leisenring W, Flowers ME, et al. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 2002;100:48–51. [95] Stewart BL, Storer B, Storek J, et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood 2004;104:3501–6. [96] Schubert MM, Peterson DE, Lloid ME. Oral complications. In: Appelbaum F, Blume KG, Forman SJ, editors. Thomas’ hematopoietic cell transplantation. Malden (MA): Blackwell Scientific Publishers; 2004. p. 911–23. [97] Couriel D, Carpenter PA, Cutler C, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 2006;12:375–96. [98] Gonzalez-Moles MA, Scully C. Vesiculo-erosive oral mucosal diseasedmanagement with topical corticosteroids: (1) Fundamental principles and specific agents available. J Dent Res 2005;84:294–301. [99] Imanguli MM, Pavletic SZ, Guadagnini JP, et al. Chronic graft versus host disease of oral mucosa: review of available therapies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:175–83. [100] Wolff D, Anders V, Corio R, et al. Oral PUVA and topical steroids for treatment of oral manifestations of chronic graft-vs.-host disease. Photodermatol Photoimmunol Photomed 2004;20:184–90. [101] Elad S, Or R, Garfunkel AA, et al. Budesonide: a novel treatment for oral chronic graft versus host disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:308–11. [102] Sari I, Altuntas F, Kocyigit I, et al. The effect of budesonide mouthwash on oral chronic graft versus host disease. Am J Hematol 2007;82:349–56. [103] Epstein JB, Reece DE. Topical cyclosporin A for treatment of oral chronic graft-versushost disease. Bone Marrow Transplant 1994;13:81–6.

108

SCHUBERT & CORREA

[104] Epstein JB, Truelove EL. Topical cyclosporine in a bioadhesive for treatment of oral lichenoid mucosal reactions: an open label clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:532–6. [105] Parquet N, Reigneau O, Humbert H, et al. New oral formulation of cyclosporin A (Neoral) pharmacokinetics in allogeneic bone marrow transplant recipients. Bone Marrow Transplant 2000;25:965–8. [106] Thongprasom K, Chaimusig M, Korkij W, et al. A randomized-controlled trial to compare topical cyclosporin with triamcinolone acetonide for the treatment of oral lichen planus. J Oral Pathol Med 2007;36:142–6. [107] Epstein JB, Nantel S, Sheoltch SM. Topical azathioprine in the combined treatment of chronic oral graft-versus-host disease. Bone Marrow Transplant 2000;25:683–7. [108] Eckardt A, Starke O, Stadler M, et al. Severe oral chronic graft-versus-host disease following allogeneic bone marrow transplantation: highly effective treatment with topical tacrolimus. Oral Oncol 2004;40:811–4. [109] Sanchez AR, Sheridan PJ, Rogers RS. Successful treatment of oral lichen planus-like chronic graft-versus-host disease with topical tacrolimus: a case report. J Periodontol 2004;75:613–9. [110] Albert MH, Becker B, Schuster FR, et al. Oral graft vs. host disease in childrendtreatment with topical tacrolimus ointment. Pediatr Transplant 2007;11:306–11. [111] Conrotto D, Carrozzo M, Ubertalli AV, et al. Dramatic increase of tacrolimus plasma concentration during topical treatment for oral graft-versus-host disease. Transplantation 2006;82:1113–5. [112] Parker PM, Chao N, Nademanee A, et al. Thalidomide as salvage therapy for chronic graftversus-host disease. Blood 1995;86:3604–9. [113] Vogelsang GB, Wolff D, Altomonte V, et al. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant 1996;17: 1061–7. [114] Redding SW, Callander NS, Haveman CW, et al. Treatment of oral chronic graft-versushost disease with PUVA therapy: case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:183–7. [115] Menillo SA, Goldberg SL, McKiernan P, et al. Intraoral psoralen ultraviolet A irradiation (PUVA) treatment of refractory oral chronic graft-versus-host disease following allogeneic stem cell transplantation. Bone Marrow Transplant 2001;28:807–8. [116] Wackernagel A, Legat FJ, Hofer A, et al. Psoralen plus UVA vs. UVB-311 nm for the treatment of lichen planus. Photodermatol Photoimmunol Photomed 2007;23:15–9. [117] Enk CD, Elad S, Vexler A, et al. Chronic graft-versus-host disease treated with UVB phototherapy. Bone Marrow Transplant 1998;22:1179–83. [118] Elad S, Garfunkel AA, Enk CD, et al. Ultraviolet B irradiation: a new therapeutic concept for the management of oral manifestations of graft-versus-host disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:444–50. [119] Foss FM, DiVenuti GM, Chin K, et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant 2005;35:1187–93. [120] Bisaccia E, Palangio M, Gonzalez J, et al. Treatment of extensive chronic graft-versus-host disease with extracorporeal photochemotherapy. J Clin Apher 2006;21:181–7. [121] Chor A, de Azevedo AM, Maiolino A, et al. Successful treatment of oral lesions of chronic lichenoid graft-vs.-host disease by the addition of low-level laser therapy to systemic immunosuppression. Eur J Haematol 2004;72:222–4. [122] Chor A, Sotero Caio AB, de Azevedo AM. The irreplaceable image: Amelioration of oral mucosal lesions of acute graft-versus-host disease by low-level laser therapy. Haematologica 2001;86:1321.

ORAL GRAFT-VERSUS-HOST DISEASE

109

[123] Elad S, Or R, Shapira MY, et al. CO2 laser in oral graft-versus-host disease: a pilot study. Bone Marrow Transplant 2003;32:1031–4. [124] Fox PC, Atkinson JC, Macynski AA, et al. Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 1991;151:1149–52. [125] Horiot JC, Lipinski F, Schraub S, et al. Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study. Radiother Oncol 2000;55:233–9. [126] Wiseman LR, Faulds D. Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia. Drugs 1995;49:143–55. [127] Singhal S, Powles R, Treleaven J, et al. Pilocarpine hydrochloride for symptomatic relief of xerostomia due to chronic graft-versus-host disease or total-body irradiation after bonemarrow transplantation for hematologic malignancies. Leuk Lymphoma 1997;24:539–43. [128] Nagler RM, Nagler A. Pilocarpine hydrochloride relieves xerostomia in chronic graft-versus-host disease: a sialometrical study. Bone Marrow Transplant 1999;23:1007–11. [129] Petrone D, Condemi JJ, Fife R, et al. A double-blind, randomized, placebo-controlled study of cevimeline in Sjogren’s syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum 2002;46:748–54. [130] Carpenter PA, Schubert MM, Flowers ME. Cevimeline reduced mouth dryness and increased salivary flow in patients with xerostomia complicating chronic graft-versus-host disease. Biol Blood Marrow Transplant 2006;12:792–4. [131] Jham BC, Teixeira IV, Aboud CG, et al. A randomized phase III prospective trial of bethanechol to prevent radiotherapy-induced salivary gland damage in patients with head and neck cancer. Oral Oncol 2007;43:137–42. [132] Chainani-Wu N, Gorsky M, Mayer P, et al. Assessment of the use of sialogogues in the clinical management of patients with xerostomia. Spec Care Dentist 2006;26:164–70. [133] Schubert MM, Epstein JB, Lloid ME, et al. Oral infections due to cytomegalovirus in immunocompromised patients. J Oral Pathol Med 1993;22:268–73. [134] de la Rosa Garcia E, Bologna Molina R, Vega Gonzalez Tde J. Graft-versus-host disease, an eight case report and literature review. Med Oral Patol Oral Cir Bucal 2006;11:E486–92. [135] D’Aiuto F, Parkar M, Brett PM, et al. Gene polymorphisms in pro-inflammatory cytokines are associated with systemic inflammation in patients with severe periodontal infections. Cytokine 2004;28:29–34. [136] Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med 1997;336:897–904. [137] Gallagher G, Forrest DL. Second solid cancers after allogeneic hematopoietic stem cell transplantation. Cancer 2007;109:84–92. [138] Curtis RE, Metayer C, Rizzo JD, et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood 2005;105:3802–11. [139] Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 2000;18:348–57. [140] Hasegawa W, Pond GR, Rifkind JT, et al. Long-term follow-up of secondary malignancies in adults after allogeneic bone marrow transplantation. Bone Marrow Transplant 2005;35: 51–5. [141] Demarosi F, Lodi G, Carrassi A, et al. Oral malignancies following HSCT: graft versus host disease and other risk factors. Oral Oncol 2005;41:865–77. [142] Leisenring W, Friedman DL, Flowers ME, et al. Nonmelanoma skin and mucosal cancers after hematopoietic cell transplantation. J Clin Oncol 2006;24:1119–26.