BDS10036 Oral ulceration RAS and related diseases.pdf

BDS10036 Oral ulceration: RAS and related diseases Oral ulceration – RAS and related diseases Aim The aim of this lecture is to detail the clinical, diagnostic and therapeutic aspects of recurrent aphthous stomatitis and related disease Objectives: On completion of this lecture, the student shoul...

BDS10036 Oral ulceration: RAS and related diseases Oral ulceration – RAS and related diseases Aim The aim of this lecture is to detail the clinical, diagnostic and therapeutic aspects of recurrent aphthous stomatitis and related disease Objectives: On completion of this lecture, the student should be able to: • • • Understand the clinical presentation of recurrent aphthous stomatitis Understand the differential diagnosis of aphthous-like ulceration Understand the principles of management of recurrent aphthous stomatitis Classification of Oral Ulceration 1) Trauma Typically physical; Radiotherapy and chemotherapy-associated disease more common than before; chemical is uncommon. 2) Infection Typically viral (HSV, VZV; T. pallidum; short term, well defined features) 3) Immunologically-mediated Typically autoimmune; also autoinflammatory (e.g. Behcet’s; FAPA) Can be a feature of vasculitic or granulomatous disease 4) Haematological/gastroenterological reflects an anaemia or neutropenia 5) Malignancy Typically OSCC (but many others can occur) 6) Iatrogenic Mechanisms of above 7) Recurrent aphthous stomatitis Probably the most common of all causes of mouth ulcers 8) Others Connective tissue disease (e.g. epidermolysis bullosa; Ehler Danlos syndrome etc) Trends relevant to oral ulceration 1. Changing patterns of infectious disease. 2. Lifestyle influences oral disease (e.g. trauma can be a reflection of psychological upset, recreational drug use etc) 3. Lifespan is increasing. 4. Oral malignancy remains a significant problem. 5. Widening spectrum of iatrogenic disease. 6. Effective treatment remains challenging. 7. Easy access patient information is lacking. Outline on RAS 1.Definition 2.Epidemiology 3.Clinical features 4.Aetiopathogenesis 5.Associated factors & disease 6.Diagnosis 7.Therapy 8.Conclusions for health care providers 9.RAU-related diseases Recurrent aphthous stomatitis (RAS) Recurrent aphthous ulcer (RAU) 1) Definition: • The most common of all causes of mouth ulcers. • After caries and periodontal disease RAS represents the most common lesions of the mouth. • Recurrent oral mucosal ulceration in healthy persons. • Usually a small number of superficial round ulcers on the non-keratinized mucosa (labial, buccal or floor of mouth). • Recur every few weeks without an obvious precipitating factor. • Pain interferes with oral function and lessen quality of life. 2) Epidemiology • Accurate data lacking but probably global disease. • Suggested to affect 5-50% of individuals. • Recent US population study (NHANES III) suggested a prevalence of 1.03%. • Females are more commonly affected than males. • May arise in childhood/teenage, frequency increases in 2nd and 3rd decades; possibly burns out in middle age. • Rate of recurrence: 1. Frequent as every month or every few months . 2. Infrequent once to twice every year or several years. 3. Sometimes there is no ulcer free period between the attacks i.e. new set of ulcers overlaps a previous group. 3) Clinical Features: •It is presented in three forms: 1. Minor RAU (most common) 50%. 2. Major RAU (uncommon) 25%. 3. Herpetiform RAU 25 %. Minor recurrent aphthous ulcers • Pre-ulcerative stage: Begin by prodromal features (2-48 hours) tingling & burning sensation at site where lesion will develop with localized erythema. • Ulcerative stage: 1. The center of the erythematous area becomes blanched due to necrosis of epithelium. 2. Followed by sloughing of the necrotic epithelium & oral ulcerations. 3. This stage is very painful due to increased tissue destruction, increasing the ulcer size. • Healing stage: 1. After 4-6 days, it starts to heal. 2. Discomfort due to decreased tissue destruction, as it has reached the maximum size. 3. No inflammatory halo is detected. 4. Healing within 1-2 weeks by primary intention with no scar. Clinical picture of RAU minor form: Peak Age 10-20 years old Size Small < 1cm (8 mm) Depth Shallow Margins Regular and erythematous Floor Covered by yellowish white exudate Shape • Round on lip & cheek • Elongated in vestibule/tongue. Site • Common on non keratinized mucosa. • Rare on keratinized mucosa. Number Few in number 1-6 crops of ulcers. Major recurrent aphthous ulcer Peak Age Prodrome Size Shape Depth Margins • 5-20 years • In some cases regional lymphadenopathy, sensation of illness and fever may be recorded. • Larger > 1 cm (5 – 15 mm) • Oval • Deeper in connective tissue • Minor salivary gland • Facial muscle • Raised due to edema • Erythematous Floor Base Site • • • • Number • Solitary mainly • Sometimes 1-5 per crop. Covered by greyish slough Indurated on palpation (D.D. malignant ulcer) Any where both keratinized & non-keratinized mucosa. Specially soft palate, tonsillar areas, oropharynx. •Healing: 1. Slow healing within 4 months. 2. The ulcer destroy the deep tissue and heal with scarring. 3. A cobblestone appearance may be seen on the oral mucosa due to recurring ulcers which heal by scar. 4. Scar formation which may interfere with tongue movement & with mobility of uvula. • DD with malignant ulcer: 1. Long duration last for few months. 2. Heaped-up margin. 3. Single ulcer. 4. Indurated base. Malignant ulcer Major RAS Scarring Herpetiform recurrent aphthous ulcer Extremely painful, interfere with speaking and eating. Peak Age: • 20-35 years Number Size Shape Site Margin • • • • • • Multiple 5-20 per crop (often dozen) Tiny pinhead sized (1-2 mm). May coalesce forming larger irregular ulcer Round and irregular (coalesce) Mainly non-keratinized mucosa. Lateral border of the tongue, lip, Floor of mouth • Widespread bright erythema around the ulcers. •Healing: 1. Healing is much quicker than major or minor forms. 2. The whole cycle may take only 3-4 days, but by the time this happened there are new crops of ulcers develop. 3. Cycling pattern continue for two weeks. 4. Completely heal within 2 months. 5. Heals with no scar. 6. Sometimes recurrence is so frequent that new set of ulcers overlap a previous group with nearly no intervals between remission. • DD with RIH that it is not preceded by vesicles. 4) Aetiopathogenesis for RAU: • Possible Etiological Factors : 1. Genetic predisposition (both parents). 2. Immunological abnormalities. • Associated factors: 1. 2. 3. 4. 5. 6. Food Allergy (chocolate, fruits, cheese) increase Ig E. Response to local trauma following dental procedures. Hormonal disturbances (PMS, decrease in pregnancy). Stress. Infections. Quitting smoking. • Associated disorders: 1. 2. 3. 4. 5. 6. Bechet syndrome. FAPA syndrome. Magic syndrome. Gastrointestinal disorders (Coeliac & Chron’s diseases). Hematological deficiencies. HIV • No definitive answer. • Probably immunologically driven – that’s why systemic corticosteroids are effective • CD8+ T cells dominate in the pre-ulcerative stage. • No distinct HLA haplotype confers risk; but polymorphisms of IL-4, IL-6, Mediterranean Fever Gene (MEFV), E-selectin and Metalloproteinase 9 have been described in small groups of RAS patients. • Antigenic stimulation of keratinocytes of RAS may generate proinflammatory cytokines (e.g. IFN-γ; IL-6, IL-1β, TNF-α) that may drive a local inflammatory process. • Circulating TNF-α levels increased in pre-ulcerative stage (and hence drives a local acute inflammatory response) • A Th1 (i.e. IL-2, IL-12, IFN-γ and TNF-α) response may be at play associated with a deranged TLR gene expression (i.e. TLR2>TLR3, TLR5). • No notable evidence of an antibody-mediated process. • Final cellular damage may be due to oxidative stress. • Infections: No links with viral infections (hence low risk of re-emergence in immunosuppression), association with H. pylori suggested in a SR, an indirect effect • Food allergy; raised Ig E in some RAS patients. Allergy to cow’s milk observed in some patients, with lessening of ulceration following exclusion of cow’s milk. • Sodium Lauryl sulphate sensitivity No good evidence. • Haematinic deficiency, up to 20% of patients may have reduced iron stores; rarely low folate +/- Vit B12. Probably signifies no aetiological link as no evidence that haematinic replacement is therapeutic. • Gluten sensitive enteropathy (coeliac disease) No association. • Psychological distress • Probably has a link, but mechanism of action unknown • Early studies observed RAS in “stressed” US students • Raised circulation cortisol levels in RAS patients from India and Jordan • Raised levels of “anxiety” observed in RAS patients in India and Jordan; raised psychological stress observed in RAS patients in Brazil; correlation between stressful events and onset of RAS noted in Brazilian patients • Psychological profile of Jordanian RAS patients no different to controls – hence perhaps lifestyle is influencing the RAS risk • Recent phone-based study suggests stressful episodes increase likelihood of RAS episode by 3 fold. RAS has been linked with other diseases: Disease Behçet’s disease Presentation Recurrent oral and genital ulcers, and ocular involvement, erythema nodosum and other systemic and haematological abnormalities. Magic syndrome Major aphthae and generalized inflamed cartilage – rare . Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (FAPA syndrome) Acute neutrophilic dermatosis (Sweet’s syndrome) Recurrent episodes oral ulceration, idiopathic pyrexia, pharyngitis and cervical lymphadenopathy. Reflects a bacterially driven over expression of IL-1β. Ulcers mimicking recurrent aphthous stomatitis but with a sudden pyrexia, leucocytosis and cutaneous skin plaques. Neutropenias and phagocytic dysfunction HIV disease Ulcers may be deep and supposedly have no inflammatory halo Inflammatory bowel disease Superficial ulceration probably related to haematinic deficiency. Gluten-sensitive enteropathy (coeliac disease) Superficial ulceration probably related to haematinic deficiency. • Severe HIV disease may occasionally cause large areas of superficial oropharyngeal ulceration. No notable clues to the cause of RAS 5) Diagnosis • History • Recurrent mouth ulcers • No identifiable local precipitant • No fever, mucocutaneous, genital or ocular symptoms • No known gastrointestinal and/or haematological disease • Clinical examination • 1-5 superficial oral ulcers; yellow covering; red halo • Usually no lymphadenopathy • No signs of anaemia • Investigations • Full Blood cell count; serum ferritin and Vitamin B12. • ONLY if these are abnormal should other investigations be done. 6) Therapy: 1-Lessen local factors. 2- Local anaesthetic agents. 3- Topical anti-inflammatory agents. 4- Topical corticosteroids. 5- Topical antimicrobials. 6- Physical agents. 7- Other agents 8- Systemic drugs. N.B. Regimen for all topical agents is: 4 times per day, after meals & before bed time for 10 days 6) Therapy: 1-Lessen local factors • Atraumatic oral hygiene technique. • Protect orthodontic appliances. • Avoid irritating food (e.g. citrus fruits & highly spices). • Protective agents e.g. carboxymethyl cellulose (Orabase). 2-Local anaesthetic agents • There is no substantial evidence that they truly lessen painful symptoms. • They are the only agents that patients readily find helpful. • e.g. : Benzydamine Hydrochloride products Lidocaine gel 3- Topical anti-inflammatory agents: • 5% Amlexanox gel may lessen pain & duration (available in few countries). • Diclofenac with hyaluronidase gel. 4-Topical corticosteroids: • They are the mainstay of therapy. • When used during the prodromal period, it may abort the developing ulcer or may decrease the duration of lesion. • If used at ulcerative stage where tissue destruction has already progressed will be of no value. • e.g. betamethasone, triamcinolone, fluticasone, dexamethasone. • Available as: mouth rinses, sprays, creams, ointments. • Generally safe – low risk of adrenal gland atrophy. • Antifungal drug should be prescribed as a prophylactic therapy at least 1 week out of every 4 weeks of steroid treatment. 5-Topical antimicrobials: • Evidence that they lessen duration & pain of RAS. • Chlorhexidine gluconate mouth wash. • Topical tetracyclines mouth bath: minocycline capsules dissolved in 5 ml of water held in the mouth for 2-3 min/6 hrs. • Doxycline gel, topical penicillin G lozenges. • Berbarine gelatin 6-Physical agents (impractical) • • • • • Surgical removal; debridement. Laser ablation. Low density ultrasound. Chemical cautery. Coagulant agents (Hyben X, commercially available in some countries but is difficult to apply to inaccessible sites). 7-Other approaches (few supportive evidence) • • • • • • • Sodium cromoglycate lozenges Carbenoxolone sodium mouthwash Interferon cream Prostaglandin E2 gel Aspirin mouthwash Sucralfate Deglycirrhizinated liquorace 8-Systemic drugs: (Few supportive data) a. Systemic corticosteroids • Will stop ulceration but not a practical long term therapy b. Clofazimine (anti-leprotic) • May reduce number of episodes of RAS • Side effects; cutaneous pigmentation; hepatitis; GI bleeding risk c. Colchicine • Cause cessation of RAS in one study but not always effective • GI upset often prevents its use d. Pentoxifyline • Suggested to stop ulceration and/or pain, number and duration of ulcers • Side effects are common e. Levamisole (anti-helminthic) • Initial studies demonstrated no benefit. • One recent study suggested some lessening of ulceration f. Thalidomide • Will cause cessation of ulceration • Adverse side effects overwhelmingly suggest it not be routinely used. g. Dapsone • No good evidence • Adverse side effects can be a problem h. Anti-TNF-α biologicals • May be logical to use. • Costs, mode of administration & adverse side effects prevent their use for RAS. The dentist should avoid: (SALIVEX) • Using phenol, sliver nitrate and other caustics in the treatment because it will delay healing or healing may be accompanied by scar formation. • These chemicals provide pain relief though their caustic action on sensory nerves. Summary for treatment of RAS RAU without systemic disease RAU with systemic disease 1. 2. 3. Proper case history. Complete blood count. Treatment of systemic disease. Minor & Major RAS 1. 2. 3. 4. 5. Herptiform RAS Local anesthetic. Tetracycline Topical corticosteroid. mouth bath Tetracycline mouth bath Dentist care Patient care Summary of therapy (Cochrane systematic review 2012) “No well described, safe means of reducing the ulceration. No substantial evidence of long term benefit with local or systemic agents” Conclusions for health care providers • Explanation • • • • • Common Non-infectious Not associated with systemic disease BUT no immediate solution and likely to be long-term Use an atraumatic tooth cleaning technique • Topical analgesic/protectant • Often are useful in lessening the pain • Topical corticosteroids • Often are useful in lessening the pain and duration • Adverse side effects are uncommon (including candidal infection) • Antimicrobial mouthwashes will probably not help • Systemic azathioprine for severe disease • Has well known side effects and monitoring guidelines are available • BUT remember that many patients with RAS may be fertile females or females with IUDs. RAU–related diseases Mucocutaneous-occular syndromes • These syndromes involve the skin, oral mucosa and the eyes : 1. Steven Johnson’s syndrome (a form of EM) 2. Behcet’s Syndrome 3. Reiter’s Syndrome Behcet's Disease • A multisystem inflammatory disorder affecting young males characterized by: 1. Recurrent oral ulcers 2. Recurrent genital ulcers 3. Recurrent eye lesions. 4. Recurrent skin lesion. • RAU of Behcet's disease are similar to common RAU. • Major RAU is more common with multiple scarring. • Greater involvement of soft palate and oropharynx • Ulcers are more resistant to treatment. Dental Implication: Since oral ulceration is frequently the first manifestation, when the dentist suspects Behcet’s disease, dermatologic & ophthalmologic referral is mandatory as it may cause blindness. Diagnosis Pathergy Test: The test is positive if there is an exaggerated response to a sterile needle puncture of the skin, where such puncture is followed by pustule formation. Reiter’s Syndrome A triad of urethritis, arthritis and conjunctivitis. Oral manifestations: 1. Painless circinate lesions that may ulcerate giving aphthous-like ulcers. 2. Geographic tongue like-lesions 3. Purpuric rash in palate Reading material Students are advised to review any relevant teaching provided in the first year. In addition they are advised to read relevant sections of the following text: 1. Scully C. Oral and Maxillofacial Medicine Churchill Livingstone 2008 pp 151-159 Oral ulceration – RAS and related diseases Aim The aim of this lecture is to detail the clinical, diagnostic and therapeutic aspects of recurrent aphthous stomatitis and related disease Objectives: On completion of this lecture, the student should be able to: • Understand the clinical presentation of recurrent aphthous stomatitis • Understand the differential diagnosis of aphthous-like ulceration • Understand the principles of management of recurrent aphthous stomatitis