DIAGNOSIS AND MANAGEMENT OF ORAL CHRONIC GVHD

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1 Background Department of Clinical Haematology DIAGNOSIS AND MANAGEMENT OF ORAL CHRONIC GVHD The oral cavity is one of the most frequently affected sites in chronic graft versus host disease (cgvhd). Oral symptoms can have a significant effect on quality of life post-hsct. Inability to maintain a normal diet due to oral discomfort is a risk factor for poor nutrition in these patients. In addition there is a risk of second malignancy in the oral cavity and appropriate education and screening is necessary. Oral cgvhd may present as lichenoid-appearing hyperkeratotic lesions, hyperkeratotic plaques, erythema and ulceration, atrophy of the oral mucosa, fibrosis and sclerodermoid changes of the oral mucosa and perioral region, salivary gland dysfunction and taste dysfunction. Patients may report generalised or localised oral mucosal sensitivity and pain, dry mouth symptoms, taste disturbance and difficulty eating. Superficial mucoceles are often described by patients as bubbles developing on the lower lip or palate prior to or during mealtimes. Patients who experienced long periods of mucositis during their transplant or who have severe ulcerative cgvhd may have difficulties maintaining good oral hygiene. This can lead to the development of periodontal disease and dental caries. Hyposalivation also increases the risk of dental decay. Whilst immunosuppressed patients are at greater risk of oral infections, including bacterial, viral and fungal infections. Topical therapy for oral cgvhd may be complicated by infection, usually fungal, and appropriate prophylaxis is usually required. Assessment of severity. Mucosal disease a. Patient reported B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

2 i. Lee symptom scale (mouth subset) ii. Chronic oral mucosal diseases questionnaire (Appendix ) iii. Chronic cgvhd Activity Assessment Patient Self Report () b. Clinical assessment i. NIH modified oral mucosa score (-) () ii. NIH organ scoring (-) (). Salivary gland disease a. Patient reported i. Xerostomia questionnaire may be used ii. Ask regarding modification of diet and symptoms during daytime B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

3 iii. Nocturnal dryness and dryness of the mouth on awakening is normal however it may be more severe in these patients b. Clinical assessment i. Dry oral mucosa mirror or gloved finger sticks to buccal mucosa ii. No saliva pooling in floor of mouth iii. Formal sialometry less than.ml/min resting salivary flow rate. Ask patient to expectorate saliva into a cup for 5 minutes without stimulating flow, measure volume and calculate rate in ml/min. Investigations. Diagnosis of oral cgvhd (,) a. This is primarily a clinical diagnosis, based on the presence of diagnostic features: i. Lichen-planus like changes (hyperkeratotic white lines and lacy appearance) b. Distinctive features include: i. Xerostomia ii. Mucoceles iii. Mucosal atrophy iv. Ulcers v. Pseudomembranes c. Biopsy is not usually necessary, but if performed the pathology is as follows: i. Mucosa lichenoid interface reaction, with lymphocyte exocytosis and apoptosis ii. Minor salivary glands lymphocytic inflammation (periductal or interlobular) with lymphocyte exocytosis and commonly periductal fibrosis. Diagnosis of common infections a. The majority of oral infections may be diagnosed clinically. i. Dental infection pain localised to a tooth, sensitivity to hot and cold or biting, presence of a draining sinus, gingival abscess or swelling. Dental radiographs may demonstrate bone loss around the apex or root of the tooth due to infection. ii. Candidal infection presence of pseudomembranous deposits which wipe off, erythematous areas associated with removable dentures, erythematous areas on the dorsal tongue and hard palate. Swabs are useful for assessing drug resistance but correlate poorly with active infection (organism is a commensal). iii. Viral infection recrudescent herpetic infection presents with small vesicles or ulcers clustered together or coalescing, unilateral and limited to a nerve distribution. Primary herpetic gingivostomatitis B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

4 presents with generalised ulceration and inflammation of the gingivae and labial mucosae.. Swabs for PCR and viral culture may be useful in identifying the virus and any drug resistance... Diagnosis of abnormal mucosal lesions a. Some lesions may be easily diagnosed clinically (e.g. aphthous ulceration) however the majority of abnormal mucosa lesions which are not consistent with oral cgvhd will require biopsy for diagnosis, in view of the risk of second malignancy/recurrence, post-transplant lymphoproliferative disease and unusual infective or neoplastic processes in this patient population. b. Patients with oral lesions requiring biopsy should be referred to an oral medicine or oral surgery unit. Important differentials It is important to recognise that not all oral symptoms in this patient cohort are due to cgvhd. Patients may have significant oral mucosal sensitivity and pain in the absence of any clinical evidence of GVHD, and this is often due to a small fibre neuropathy of the oral cavity (post-inflammatory hyperalgesia or oral dysaesthesia). This may occur following significant mucosal inflammatory disease or may be idiopathic. The symptoms are worsened by haematinic deficiency, psychological stress/mood disorders and ongoing medical illness. Immunosuppressive treatment is unlikely to change these symptoms.. Infection a. Bacterial infection i. This is usually related to dental or periodontal structures and will require appropriate broad spectrum coverage, including anaerobic coverage. It is important that the source of the infection is also treated ie. teeth are treated by root canal therapy or extracted, and abscesses are drained. Antibiotics will control dental infection but it will recur if the source is not eliminated. b. Fungal infection i. Candidal infection of the oral cavity is a significant problem in the immunosuppressed patient. Candida is a normal commensal organism in the majority of the population. Active infection should be diagnosed clinically swabs are not useful due to the organism being a commensal. Positive swabs do not correlate well with active infection. ii. Systemic antifungal treatment with fluconazole is usually recommended, and the addition of a topical agent such as miconazole or nystatin can be helpful in maintaining long term control. iii. Some patients are particularly susceptible to recurrent fungal infection and will require prophylactic treatment. This may range from second B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

5 daily chlorhexidine mouthwash to a course of nystatin or miconazole for the first week of every month. c. Viral infection i. HSV reactivation is a possibility in these patients although the majority are on prophylactic antiviral treatment. ii. Viral ulceration has a distinct clinical appearance and should be distinguished from cgvhd. iii. Viral ulceration of the oral mucosa is extremely painful and should be managed aggressively with topical anaesthesia and/or prescription of drugs for neuropathic pain (such as amitriptyline or nortriptyline) if symptoms persist after resolution of the ulceration.. Inflammatory a. Oral cgvhd is virtually indistinguishable from oral lichen planus (OLP). The principles of treatment are similar.. Neurological a. Neuropathic pain due to chemotherapy effects, post-inflammatory hyperalgesia or idiopathic oral dysaesthesia is a common cause of persistent oral sensitivity and pain in the absence of clinical signs of active cgvhd or infection. b. Symptoms reported include pain, burning, excessive sensitivity to food and drinks (particularly spicy/hot temperatures), sensation of dryness in the presence of good salivary flow, abnormal taste (often metallic) or loss of taste, perception of abnormal sensations (e.g. pressure, pushing) or size of oral cavity structures (e.g. tongue, teeth). Neoplastic a. Oral epithelial dysplasia is a potentially malignant disorder of the oral mucosa. It is a histological diagnosis. The clinical appearance of dysplastic areas may range from thick homogeneous white plaques, to mixed red and white speckled lesions, to erythroplakia (deep red areas). If the mucosal appearance is not consistent with lichenoid changes of cgvhd then biopsy is required to rule out other pathologies, including dysplasia and malignancy. 5. Other a. Calcineurin-inhibitor associated fibrovascular polyps i. Well-defined, ulcerative, exophytic masses, often associated with trauma ii. Require excision due to interference with function and to rule out other pathology b. Verruciform xanthoma i. Yellow-white to red papillary surface, requires biopsy to rule out carcinoma ii. Managed by surgical excision B..7d Page 5 of February 7 V. Diagnosis And Management of Oral Chronic GVHD

6 Treatment Treatment consists of active treatment aimed at reducing the intensity of the inflammatory response in the oral mucosa, and symptom control treatment, which should run in parallel with active therapy. Active treatment The intensity of treatment depends on severity and chronicity of symptoms. The treatment ladder, in order of increasing intensity of treatment, is as follows:. Topical corticosteroids a. Betamethasone mouthwash i. Betamethasone 5mcg soluble tablets dissolve in ml water, rinse and hold in mouth for -5 mins then spit out, - times daily b. Fluticasone propionate mouthwash or spray (mouthwash for widespread disease, spray for localised areas of disease) i. Flixonase mcg nasules open one nasule into -5ml water, rinse and hold in mouth for -5 mins then spit out, up to three times daily ii. Flixonase 5mcg nasal spray puffs to painful area twice daily c. Elocon.% ointment i. Apply a small amount directly to the ulcerated area twice daily d. Budesonide mouthwash (second line therapy) i. Budesonide mg respules (Pulmicort) open one respule into ml water, rinse and hold in mouth for -5 mins then spit out, twice daily. Topical immunomodulators a. Tacrolimus.% ointment i. Apply a small amount directly to the ulcerated area twice daily ii. Use for up - weeks at a time with - week window. Intralesional corticosteroids a. These are indicated for localised persistent areas of ulceration which have not responded to a combination of topical therapies as above b. Up to mg of triamcinolone acetonide injected directly underneath the ulcerated area, may be repeated after a week period (use mg/ml concentration). Systemic therapy a. If topical therapy has failed to control symptoms, systemic therapy including oral prednisolone and/or immunosuppression should be initiated according to local guidelines 5. Extra-corporeal photophoresis a. There is some evidence that ECP can be an effective means of managing severe oral GVHD which is poorly responsive to topical and systemic therapies.() B..7d Page 6 of February 7 V. Diagnosis And Management of Oral Chronic GVHD

7 Symptom control. Pain relief a. Topical anaesthetic i. Difflam (benzydamine hydrochloride). Available as a spray or mouthwash, may be used hourly as required for relief of symptoms. Some patients may experience stinging with this formulation ii. Lidocaine 5% ointment. May be applied up to four times daily to painful or ulcerated lesions in the oral cavity iii. Lidocaine % spray. sprays to oral mucosa every hours as required, maximum sprays per day. Barrier treatment a. Gelclair i. Forms a film over the oral mucosa and can effectively control symptoms in atrophic, erosive or ulcerative disease. Dry mouth symptom control a. Simple measures i. Water sipping and maintaining hydration ii. Stimulation of salivary flow sugar-free sweets or chewing gum, massage of parotid glands (apply firm pressure from pre-auricular area forwards across cheek) iii. Comfort bicarbonate of soda mouthwash ( teaspoon of bicarb soda to litre of water), olive oil applied to the oral mucosa at night b. Salivary replacement i. Bioextra or Biotene (OUH st line) saliva replacement gels ii. Xerotin, Saliva Orthana (OUH st line) or Glandosane saliva replacement sprays (NB Orthana contains porcine products) c. Salivary stimulation i. Pilocarpine. Parasympathomimetic drug avoid in uncontrolled asthma or COPD, decompensated cardiac failure; caution in controlled asthma/copd/cardiac disease, biliary tract disease, urinary obstruction, angle-closure glaucoma. Side effects sweating, visual disturbance (blurring), abdominal upset, urinary frequency. Prescribe Salagen 5mg times daily with meals and at bedtime. Discontinue if side effects not tolerated or ineffective after months. Oral hygiene a. If toothpaste causes pain, switch to Kingfisher toothpaste (SLS free) B..7d Page 7 of February 7 V. Diagnosis And Management of Oral Chronic GVHD

8 b. Recommend liaison with hygienist to ensure that oral hygiene is optimised whilst mouth is painful i. Aim to reduce bacterial flora due to plaque as this can delay resolution of ulcerative cgvhd due to secondary infection c. If toothbrushing is too difficult due to pain, use chlorhexidine-soaked swabs or cotton tips to gently disrupt plaque around gingival margins 5. Prevention of infection a. If patients are not receiving systemic antifungal prophylaxis and are using potent topical corticosteroids in the oral cavity, they should be prescribed chlorhexidine mouthwash to use second daily as antifungal prophylaxis Monitoring and prevention. Review of oral symptoms/clinical appearance a. At each follow-up visit, or at least monthly during systemic immunosuppressive therapy (5). Dental review a. Recommend 6 monthly dental checkup and professional hygiene(5,6) b. More frequently if high caries rate or periodontal disease is present. Oral mucosal soft tissue screening a. Recommend 6 monthly soft tissue examination by general dental practitioner and immediate referral to oral medicine or maxillofacial surgery if any abnormalities noted(6) b. Patients should be educated regarding the risk of oral mucosal malignancy following HSCT. One study reports the median time to diagnosis of oral squamous cell carcinoma after transplant to be 8 years, with a range of - years.(7) It is important that patients are aware of the need to continue screening for this significant late effect. Resources For useful clinical photos and a comprehensive discussion of management, see Treister et al (8) References. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Biology of Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation. Elsevier Inc; 5 Jun ;(6): Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. Biology of Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation. Elsevier Inc; 5 Mar ;():89.e.. Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E, et al. Biology of Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation. Elsevier Inc; 5 Apr ;(): B..7d Page 8 of February 7 V. Diagnosis And Management of Oral Chronic GVHD

9 . Flowers MED, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V, et al. A multicenter prospective phase randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 8 Sep ;(7): Carpenter PA, Kitko CL, Elad S, Flowers MED, Gea-Banacloche JC, Halter JP, et al. Biology of Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation. Elsevier Inc; 5 Jul ;(7): Dignan FL, Scarisbrick JJ, Cornish J, Clark A, Amrolia P, Jackson G, et al. Organspecific management and supportive care in chronic graft-versus-host disease. British Journal of Haematology. Apr 6;58(): Mawardi H, Elad S, Correa ME, Stevenson K, Woo S-B, Almazrooa S, et al. Oral epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation: clinical presentation and treatment outcomes. Bone Marrow Transplantation. Nature Publishing Group; Apr ;6(6): Treister N, Duncan C, Cutler C, Lehmann L. How we treat oral chronic graft-versus-host disease. Blood. Oct 5;(7):7 8. Appendix Chronic Oral Mucosal Disease Questionnaire Author(s) Dr Rubeta Matin, Consultant Dermatologist Dr Martina Shephard, Consultant Oral Physician Audit These processes are subject to the OxBMT audit programme Circulation NSSG Haematology Website Review Name Revision Date Version Review date New document Feb 7. Feb 8 B..7d Page 9 of February 7 V. Diagnosis And Management of Oral Chronic GVHD

10 Appendix - Chronic Oral Mucosal Disease Questionnaire Pain and functional limitation. How much do certain types of food/drink cause you discomfort (spicy food, acidic food)?. How much does your oral condition cause you to limit the types of food/ drinks you consume?. How much do certain food textures cause you discomfort (rough food, crusty food)?. How much does your oral condition cause you to limit the textures of the food you consume? 5. How much does the temperature of certain foods/drinks cause you discomfort? 6. How much does you oral condition cause you to limit the temperature of the foods/drinks you consume? B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

11 7. How much does your oral condition lead to discomfort when carrying out your daily oral hygiene routine (brushing, flossing, mouthwash usage)? 8. How much does your oral condition cause you to limit your daily oral hygiene routine (brushing, flossing, mouthwash usage)? 9. How much does your oral condition lead to discomfort when wearing a denture (false teeth)? Medication and treatment (including mouthwashes, gels, creams, ointments, injections, tablets, infusions). How much do you feel you need medication to help you with activities of daily life (talking, eating etc.)?. How satisfied are you with the medication being used to treat your oral condition?. How concerned are you about the possible side effects of the medications used to treat your oral condition? B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

12 . How much does it frustrate you that there is no single standard medication to be used in your oral condition? 5. How much does the use of the medication limit you in your every day life (routine / the way you apply or take your medications)? 6. How much does it bother you that there is no cure for your oral condition? Social and emotional. How much does your oral condition get you down?. How much does your oral condition cause you anxiety?. How much does your oral condition cause you stress? B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

13 . How much does the unpredictability of your oral condition bother you? 5. How much does your oral condition cause you to worry about the future (spread of the condition, possible cancer risk)? 6. How much does your oral condition make you pessimistic about the future? 7. How much does your oral condition disrupt social activities in your life (social gatherings, eating out parties)? Patient Support. How satisfactory do you consider the information available to you regarding your oral condition?. How satisfied are you with the level of support and B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD

14 understanding shown to you by family regarding this oral condition?. How satisfied are you with the level of support and understanding shown to you by friends/work colleagues regarding your oral condition?. How isolated do you feel as a result of this oral condition? B..7d Page of February 7 V. Diagnosis And Management of Oral Chronic GVHD