Recurrent aphthous stomatitis

Recurrent aphthous stomatitis

1. Introduction Classification Immunopathogenesis Underlying Conditions & Etiology Clinical features Diagnosis Management Conclusions Recurrent Aphthous Stomatitis Attilio Boner University of Verona, Italy [email protected]

2. Recurrent Aphthous Stomatitis Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Recurrent aphthous stomatitis (RAS) is the most common inflammatory and ulcerative condition of the oral cavity . The term aphthous is derived from a Greek word aphtha , which means ulceration . It is estimated that at least 1 in 5 individuals have been affected by aphthous stomatitis . The disorder most commonly affects young adults (with some studies reporting a prevalence as high as 60% in students), decreasing in frequency and severity after 50 years of age.

3. Recurrent Aphthous Stomatitis Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The cause is unknown in most patients, although in some the disease manifests secondary to: underlying infectious, inflammatory, immunologic, nutritional disorder, genetic diseases .

4. Introduction Classification Immunopathogenesis Underlying Conditions & Etiology Clinical features Diagnosis Management Conclusions Recurrent Aphthous Stomatitis Attilio Boner University of Verona, Italy [email protected]

5. Recurrent aphthous stomatitis has 2 presentation forms and 3 morphological types. The 2 forms are simple and complex aphthosis , and the 3 morphological types are: minor, major and herpetiform aphthous ulcers . Baccaglini L. Oral Dis . 2011;17:755e770. Recurrent Aphthous Stomatitis : Classification

6. Recurrent aphthous stomatitis has 2 presentation forms and 3 morphological types. The 2 forms are simple and complex aphthosis , and the 3 morphological types are: minor, major and herpetiform aphthous ulcers . Baccaglini L. Oral Dis . 2011;17:755e770. Recurrent Aphthous Stomatitis : Classification Complex aphthosis refers to the persistent presence of ≥ 3 ulcers, associated genital lesions , and resultant serious disability, in the absence of Behçet disease . Keogan MT. Clin Exp Immunol . 2009;156:1e11.

7. Recurrent aphthous stomatitis has 2 presentation forms and 3 morphological types. The 2 forms are simple and complex aphthosis , and the 3 morphological types are: minor, major and herpetiform aphthous ulcers . Baccaglini L. Oral Dis . 2011;17:755e770. Recurrent Aphthous Stomatitis : Classification Ocular lesions ( uveitis ), erythema nodosum , pustular lesions, cutaneous pathergy (nodule formation after intradermal injection of saline), and bizarre neurologic findings also occur in Behcet Disease , setting this condition apart. Mat MC. Clin Dermatol . 2014;32:435e442 .

8. Recurrent Aphthous Stomatitis : Classification Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 RAS has been classified based on the size and evolution of lesions into 3 types: minor aphthae ( Mikulicz aphthae ), major aphthae (Sutton disease, also referred to as periadenitis mucosa necrotica recurrens ), herpetiform ulcerations . The superficial lesions are rounded, with a yellow-colored slough ( pantano ) and surrounding erythema , and may result in scarring and, rarely , tissue destruction . Morphological Types

9. Recurrent Aphthous Stomatitis Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Table 1: Classification of Recurrent Aphthous Stomatitis (RAS)

10. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Patients presenting with recurrent orogenital ulcers may have Behçet's syndrome is a multi-system vasculitis of unknown aetiology for which there is no diagnostic test. Diagnosis is based on agreed clinical criteria that require recurrent oral ulcers and 2 of the following: recurrent genital ulcers, ocular inflammation, defined skin lesions ( erythema nodosum , papulo-pustular lesions) pathergy . complex aphthosis , Behçet's disease, secondary complex aphthosis (e.g. Reiter's syndrome, Crohn's disease, cyclical neutropenia ) or non- aphthous disease (including bullous disorders, erythema multiforme , erosive lichen planus ).

11. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11.

12. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Patients presenting with recurrent orogenital ulcers may have Behçet's syndrome is a multi-system vasculitis of unknown aetiology for which there is no diagnostic test. Diagnosis is based on agreed clinical criteria that require recurrent oral ulcers and 2 of the following: recurrent genital ulcers, ocular inflammation, defined skin lesions pathergy . complex aphthosis , Behçet's disease, secondary complex aphthosis (e.g. Reiter's syndrome, Crohn's disease, cyclical neutropenia ) or non- aphthous disease (including bullous disorders, erythema multiforme , erosive lichen planus ). The pathergy test is a simple procedure in which a small, sterile needle, is inserted into the skin of the forearm. Occurrence of a small red bump or pustule at the site of needle insertion one to two days following the pathergy test constitutes a positive result. A positive result indicates the immune system is overreacting to a minor injury.

13. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Patients presenting with recurrent orogenital ulcers may have Behçet's syndrome is a multi-system vasculitis of unknown aetiology for which there is no diagnostic test. Diagnosis is based on agreed clinical criteria that require recurrent oral ulcers and 2 of the following: recurrent genital ulcers, ocular inflammation, defined skin lesions pathergy . complex aphthosis , Behçet's disease, secondary complex aphthosis (e.g. Reiter's syndrome, Crohn's disease, cyclical neutropenia ) or non- aphthous disease (including bullous disorders, erythema multiforme , erosive lichen planus ).  Although a positive pathergy test is helpful in the diagnosis of Behcet's Disease, only a minority of Behcet's patients demonstrate the pathergy phenomenon by having a positive test. Patients from the Mediterranean region are more likely to demonstrate a positive response to a pathergy test.

14. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Behçet’s syndrome can present with a variety of symptoms, hence a high index of suspicion is necessary. The most common presentation is with recurrent mouth ulcers, often with genital ulcers; however, it may take some years before diagnostic criteria are met. All patients with idiopathic orogenital ulcers should be kept under review, with periodic focused assessment to detect evolution into Behçet's disease. There is often a delay of several years between patients fulfilling diagnostic criteria and a diagnosis being made, which may contribute to the morbidity of this condition.

15. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11.

16. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Oral ulcers in Behçet ’s syndrome

17. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Pathergy describes cutaneous hyperresponsiveness to trauma which, when elicited correctly, is quite specific for Behcet ’s Disease . After skin-cleansing with alcohol swabs , two or more large (20 G) needles are inserted subcutaneously (minimum depth 3 mm), a few centimetres apart, and read at 48 h. (+) (-) Development of a papule or pustule at the site of insertion is considered positive , while erythema or a residual pin-prick mark is negative.

18. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Pulmonary artery aneurysms in Behçet’s disease. Chest X-ray with multiple pulmonary masses. Computed tomographychest scan confirming pulmonary artery aneurysms. Right pulmonary artery angiography demonstrating an upper lobe pulomonary artery aneurysm and selective segmental pulmonary artery angiography showing the pulmonary artery aneurysm

19. Behçet’s disease as a systemic disease. Mat MC. Clin Dermatol . 2014;32:435e442.

20. Is complex aphthosis a mild form of Behçet’s Disease? Baccaglini L. Oral Dis . 2011;17:755-770. To address this question, one must understand the difference between simple and complex aphthosis . Recurrent aphthous stomatitis has: 2 presentation forms and 3 morphological types : the 2 forms are simple and complex aphthosis . the 3 morphological types are minor , major and herpetiform aphthous ulcers . In contradistinction to patients with Complex aphthosis , patients with Behçet’s disease have a multisystem disease affecting: oral, ocular , and anogenital mucosal surfaces as well as vascular, neurological and rheumatological systems.

21. Complex aphthosis can be divided into primary and secondary groups. Primary complex aphthosis has no identifiable underlying cause and remains idiopathic. Causes of secondary complex aphthosis include: hematinic deficiencies ( iron , vitamins B1, B2, B6, B12, folic acid and zinc), cyclic neutropenia , benign familial neutropenia , primary and secondary immunodeficiencies including HIV disease, MAGIC syndrome, Sweet’s syndrome , PFAPA, gluten-sensitive enteropathy , inflammatory bowel disease including ulcerative colitis and Crohn’s disease, drug reactions to nonsteroidal anti-inflammatory agents (NSAIDs) and nicorandil , Behcet Disease . Is complex aphthosis a mild form of Behçet’s Disease? Baccaglini L. Oral Dis . 2011;17:755-770.

22. The answer to this question in much of Asia and the Middle East would be a qualified YES because many patients who present with recurrent oral ulcerations develop Be ç het DiseaSE . In western Europe and North America the answer would be generally NO because even if some patients with complex aphthosis do arguably have a forme fruste of BD, perhaps 10%, the vast majority have a condition which merits a careful evaluation, seeking “correctable causes” ( secondary complex aphthosis ) and is responsive to treatment with an excellent prognosis for control or remission. Is complex aphthosis a mild form of Behçet’s Disease? Baccaglini L. Oral Dis . 2011;17:755-770.

23. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Patients presenting with recurrent orogenital ulcers may have Behçet's syndrome is a multi-system vasculitis of unknown aetiology for which there is no diagnostic test. Diagnosis is based on agreed clinical criteria that require recurrent oral ulcers and 2 of the following: recurrent genital ulcers, ocular inflammation, defined skin lesions pathergy . complex aphthosis , Behçet's disease, secondary complex aphthosis (e.g. Reiter's syndrome , Crohn's disease, cyclical neutropenia ) or non- aphthous disease (including bullous disorders, erythema multiforme , erosive lichen planus ). . Reiter syndrome is a type of reactive arthritis that happens as a reaction to a bacterial infection in the body. The infection usually happens in the intestines, genitals, or urinary tract. Reiter syndrome includes redness, joint swelling and pain, often in knees, ankles, and feet, along with inflammation of the eyes and urinary tract. It is not contagious. But the bacteria that trigger it can be passed from one person to another. There is no cure for Reiter syndrome, but you can control the symptoms. For most people, symptoms go away in 2 to 6 months.

24. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Keogan MT. Clin Exp Immunol . 2009;156:1e11. Patients presenting with recurrent orogenital ulcers may have Behçet's syndrome is a multi-system vasculitis of unknown aetiology for which there is no diagnostic test. Diagnosis is based on agreed clinical criteria that require recurrent oral ulcers and 2 of the following: recurrent genital ulcers, ocular inflammation, defined skin lesions pathergy . complex aphthosis , Behçet's disease, secondary complex aphthosis (e.g. Reiter's syndrome , Crohn's disease, cyclical neutropenia ) or non- aphthous disease (including bullous disorders, erythema multiforme , erosive lichen planus ). . Signs and Symptoms Arthritis. Includes pain, swelling, stiffness, and redness of joints, usually the hips, knees, ankles, spine, and feet. Conjunctivitis , inflammation of the eye. Usually brief and mild. Iritis , inflammation of the iris of the eye Uveitis , inflammation of the inner eye. Less common but needs immediate medical treatment to avoid eye damage. Urinary tract infection. Pain or burning during urination and frequent urge to urinate. May include inflammation of the prostate or cervix. Men may have pus drainage from penis. Painless, shallow ulcers on the penis. Pus-filled sores on soles, palms, and penis. May also include mouth sores. Rashes of small nodules on the soles of the feet, and, less often, on the palms of the hands or elsewhere. Heart problems, affecting about 10% of people who have Reiter syndrome.

25. Introduction Classification Immunopathogenesis Underlying Conditions & Etiology Clinical features Diagnosis Management Conclusions Recurrent Aphthous Stomatitis Attilio Boner University of Verona, Italy [email protected]

26. Recurrent Aphthous Stomatitis : Pathogenesis Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The pathogenesis of aphthous stomatitis is largely unknown, although an abnormal T-cell-mediated immune reaction appears to be involved in patients with RAS. TH2 -related genes are not overexpressed in RAS tissues. A role for oral microbiota in disease pathogenesis also been proposed . Bankvall M . J Oral Microbiol . 2014;6: 25739. IFN- γ , IL-2, IL-4, IL-5, but not for IL-10, suggesting defective tissue healing responses . tumor necrosis factor a ( TNF-a ) and interleukin 15 (IL-15), lesion are infiltrated X

27. Introduction Classification Immunopathogenesis Underlying Conditions & Etiology Clinical features Diagnosis Management Conclusions Recurrent Aphthous Stomatitis Attilio Boner University of Verona, Italy [email protected]

28. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Although most patients with RAS have a primary form of the disease , certain inflammatory, nutritional, toxic, and metabolic factors may contribute to disease pathogenesis. Predisposing factors for aphthous stomatitis include: trauma; tobacco use; use of certain medications; deficiencies of vitamin B12, iron, zinc, and folic acid ; gluten sensitivity (and enteropathy ); chemical irritants, including sodium lauryl sulfate (found in certain brands of toothpaste); hormonal changes; and microbial factors Recurrent Aphthous Stomatitis : predisposing factors

29. Recurrent Aphthous Stomatitis : underlying conditions Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Conditions associated with complex aphthae that may be seen by an allergist immunologist . CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MAGIC, Mouth and genital ulcers, inflamed cartilage; PFAPA, periodic fever , aphthous stomatitis , pharyngitis , adenopathy .

30. Recurrent Aphthous Stomatitis : underlying conditions Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Conditions associated with complex aphthae that may be seen by an allergist immunologist . CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MAGIC, Mouth and genital ulcers, inflamed cartilage; PFAPA, periodic fever , aphthous stomatitis , pharyngitis , adenopathy . simple aphthosis may be associated with celiac disease and gluten sensitivity

31. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Conditions associated with complex aphthae that may be seen by an allergist immunologist . CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MAGIC, Mouth and genital ulcers, inflamed cartilage; PFAPA, periodic fever , aphthous stomatitis , pharyngitis , adenopathy . MAGIC syndrome" ( M outh A nd G enital ulcers with I nflamed C artilage) has been proposed to describe patients with clinical features of both relapsing polychondritis and Behcet disease .  Recurrent Aphthous Stomatitis : underlying conditions

32. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Conditions associated with complex aphthae that may be seen by an allergist immunologist . CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MAGIC, Mouth and genital ulcers, inflamed cartilage; PFAPA, periodic fever , aphthous stomatitis , pharyngitis , adenopathy . Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of severe congenital neutropenia (SCN) and cyclic neutropenia (CN), Recurrent Aphthous Stomatitis : underlying conditions

33. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 Conditions associated with complex aphthae that may be seen by an allergist immunologist . CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MAGIC, Mouth and genital ulcers, inflamed cartilage; PFAPA, periodic fever , aphthous stomatitis , pharyngitis , adenopathy . La sindrome di Sweet si manifesta normalmente con lesioni dure e dolenti papulo-nodulari di colore violaceo; esse si formano su entrambe le metà del corpo. Le parti più colpite sono il viso, il collo e gli arti (superiori ed inferiori). La  dermatosi  è spesso accompagnata o preceduta da sensazioni di malessere,  leucocitosi neutrofile , dolori articolari, febbre elevata, e  congiuntivite . La sindrome di Sweet viene normalmente preceduta da infezioni delle vie aeree e viene associata molte volte a tumori o malattie autoimmuni. Recurrent Aphthous Stomatitis : underlying conditions

34. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The actual role of vitamin deficiencies is uncertain. RAS may be a marker of an underlying systemic illness: celiac disease ; Behçet syndrome ; periodic fever; aphthous stomatitis , pharyngitis , and adenitis (PFAPA); cyclic neutropenia ; mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome; Reiter’s syndrome; Sweet syndrome /acute neutrophilic dermatosis . Recurrent Aphthous Stomatitis : underlying conditions

35. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The actual role of vitamin deficiencies is uncertain. RAS may be a marker of an underlying systemic illness: celiac disease ; Behçet syndrome ; periodic fever; aphthous stomatitis , pharyngitis , and adenitis (PFAPA); cyclic neutropenia ; mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome; Reiter’s syndrome; Sweet syndrome /acute neutrophilic dermatosis ; HIV (AIDS) . Recurrent Aphthous Stomatitis : underlying conditions

36. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The actual role of vitamin deficiencies is uncertain. RAS may be a marker of an underlying systemic illness: celiac disease ; Behçet syndrome ; periodic fever; aphthous stomatitis , pharyngitis , and adenitis (PFAPA); cyclic neutropenia ; mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome; Reiter’s syndrome; Sweet syndrome /acute neutrophilic dermatosis ; HIV (AIDS) . Recurrent Aphthous Stomatitis : underlying conditions However, it is controversial whether the oral ulcerations associated with these systemic conditions are truly RAS or just oral ulcers similar to RAS.

37. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The actual role of vitamin deficiencies is uncertain. RAS may be a marker of an underlying systemic illness: celiac disease ; Behçet syndrome ; periodic fever; aphthous stomatitis , pharyngitis , and adenitis (PFAPA); cyclic neutropenia ; mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome; Reiter’s syndrome; Sweet syndrome /acute neutrophilic dermatosis ; HIV (AIDS) . Recurrent Aphthous Stomatitis : underlying conditions A type of reactive arthritis that happens as a reaction to a bacterial infection in the body. The infection usually happens in the intestines, genitals, or urinary tract.

38. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The actual role of vitamin deficiencies is uncertain. RAS may be a marker of an underlying systemic illness: celiac disease ; Behçet syndrome ; periodic fever; aphthous stomatitis , pharyngitis , and adenitis (PFAPA); cyclic neutropenia ; mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome; Reiter’s syndrome; Sweet syndrome /acute neutrophilic dermatosis ; HIV (AIDS) . Recurrent Aphthous Stomatitis : underlying conditions the prevalence of recurrent aphthous ulcerations in CD has been reported between 4% and 40% of cases

39. Shah K, Ann Allergy Asthma Immunol . 2016;117(4):341-343 The actual role of vitamin deficiencies is uncertain. RAS may be a marker of an underlying systemic illness: celiac disease ; Behçet syndrome ; periodic fever; aphthous stomatitis , pharyngitis , and adenitis (PFAPA); cyclic neutropenia ; mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome; Reiter’s syndrome; Sweet syndrome /acute neutrophilic dermatosis ; HIV (AIDS) . Recurrent Aphthous Stomatitis : underlying conditions Challenge with small amounts of gluten has led to recurrence of oral ulcerations in celiac disease

40. Recurrent aphthous stomatitis as a marker of celiac disease in children. Marty M, Pediatr Dermatol . 2016;33:241. In children, the association of symmetric enamel defects with recurrent oral ulcerations has been considered a presentation of silent celiac disease . Thus, children with a documented history of RAS should undergo a dental examination and, if positive, be referred to a gastroenterologist who will confirm the diagnosis. + ≈

41. The prevalence of CD in pateints with RAS has been reported between 4% and 40% of cases Celiac disease (CD) Is RAS associated with Celiac Disease? Baccaglini L. Oral Dis . 2011;17:755-770.

42. the number of CD patients who have RAS ranges from 3–61% compared against an approximately 37% lifetime prevalence of RAS in the general population Celiac disease (CD) Is RAS associated with Celiac Disease? Baccaglini L. Oral Dis . 2011;17:755-770.

43. Celiac disease (CD) In some cases, oral ulcers can be the first sign of CD. Most of the studies reporting associations between RAS and CD did not report any well-defined criteria for RAS diagnosis, while the diagnosis of CD was usually well-supported by biopsy and/or antibody tests. Thus, the literature reviewed does support an association between oral ulcers and CD; however, these oral ulcers may not be RAS . The oral ulcers that are a manifestation of CD would respond to a gluten-free diet , while classical RAS would not . Is RAS associated with Celiac Disease? Baccaglini L. Oral Dis . 2011;17:755-770.

44. Is RAS associated with Vitamin B12 deficiency? Baccaglini L. Oral Dis . 2011;17:755-770. studies indicate that 0–42% of RAS patients may have a vitamin B12 deficiency This variation may be attributable to geographical and temporal variations in diet and food supplementation. Vitamin B12 deficiency

45. Vitamin B12 deficiency Case reports indicate that some cases of RAS in patients with vitamin B12 deficiency are successfully treated with vitamin B12 supplementation. Treatment with vitamin B12 may be of benefit even in the absence of vitamin B12 deficiency . although RAS may only rarely be associated with low blood levels of vitamin B12; treatment with vitamin B12 may nevertheless be of benefit in RAS, via mechanisms that warrant further study. Is RAS associated with Vitamin B12 deficiency? Baccaglini L. Oral Dis . 2011;17:755-770.

46. Effectiveness of vitamin B12 in treating recurrent aphthous stomatitis : a randomized, double-blind, placebo-controlled trial. Volkov I, J Am Board Fam Med . 2009;22:9–16. 58 patients suffering from RAS: 31 a sublingual dose of 1000 mcg of vitamin B(12), 27 placebo for 6 months % patients free of ulceration after 6 months of treatment 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – vitamin B12 placebo 74.1% 32% p < 0.01

47. Effectiveness of vitamin B12 in treating recurrent aphthous stomatitis : a randomized, double-blind, placebo-controlled trial. Volkov I, J Am Board Fam Med . 2009;22:9–16. 58 patients suffering from RAS: 31 a sublingual dose of 1000 mcg of vitamin B(12), 27 placebo for 6 months % patients free of ulceration after 6 months of treatment 80 – 70 – 60 – 50 – 40 – 30 – 20 – 10 – vitamin B12 placebo 74.1% 32% p < 0.01 This significant response to vitamin B12 was independent of initial blood B12 level.

48. Is Periodic Fever, aphthous stomatitis , pharyngitis , and cervical adenitis (PFAPA) syndrome a distinct medical entity ? Baccaglini L. Oral Dis . 2011;17:755-770 . First described in 1987, PFAPA syndrome is a clinical entity characterized by recurrent episodes of fevers without an identifiable source of infection. Marshall GS, PFAPA syndrome. Pediatr Infect Dis J. 1989 Sep ;8(9):658-9. The diagnosis is established on the basis of clinical criteria that require the presence of: a recurrent fever of early onset (<5 years) with a clockwork periodicity (usual interval <4 weeks) and ≥1 of the 3 associated symptoms: i ) aphthosis , ii) cervical adenitis , iii) pharyngitis , in the absence of upper respiratory tract infections and cyclic neutropenia .

49. Is Periodic Fever, aphthous stomatitis , pharyngitis , and cervical adenitis (PFAPA) syndrome a distinct medical entity ? Baccaglini L. Oral Dis . 2011;17:755-770 . First described in 1987, PFAPA syndrome is a clinical entity characterized by recurrent episodes of fevers without an identifiable source of infection. Marshall GS, PFAPA syndrome. Pediatr Infect Dis J. 1989 Sep ;8(9):658-9. The diagnosis is established on the basis of clinical criteria that require the presence of: a recurrent fever of early onset (<5 years) with a clockwork periodicity (usual interval <4 weeks) and ≥1 of the 3 associated symptoms: i ) aphthosis , ii) cervical adenitis , iii) pharyngitis , in the absence of upper respiratory tract infections and cyclic neutropenia . The primary complaint is the periodic fever rather than the stomatitis .

50. Is Periodic Fever, aphthous stomatitis , pharyngitis , and cervical adenitis (PFAPA) syndrome a distinct medical entity ? Baccaglini L. Oral Dis . 2011;17:755-770 . Different cohorts of patients with PFAPA Distribution of main clinical manifestations associated with fever episodes While fever is always present the presence of aphthae sometimes is reported in a minority of the cases .

51. Is Periodic Fever, aphthous stomatitis , pharyngitis , and cervical adenitis (PFAPA) syndrome a distinct medical entity ? Baccaglini L. Oral Dis . 2011;17:755-770 . Intraoral ulcers in PFAPA are generally described as few to several, non-clustered, small (<5 mm), shallow ulcers that heal over 5 to 10 days . By definition, the diagnosis of PFAPA syndrome requires also exclusion of other monogenic periodic fevers , which are hereditary conditions and include Familial Mediterranean Fever ( FMF ), the spectrum of mevalonate kinase deficiencies ( MKD ) (such as Hyper Ig -D syndrome and mevalonate aciduria ), and tumor necrosis factor-associated periodic syndrome ( TRAPS ) amongst others, each characterized by a specific genetic mutation . Scully C, Oral Dis. 2008;14(8):690-9 .

52. Is Periodic Fever, aphthous stomatitis , pharyngitis , and cervical adenitis (PFAPA) syndrome a distinct medical entity ? Baccaglini L. Oral Dis . 2011;17:755-770 . Intraoral ulcers in PFAPA are generally described as few to several, non-clustered, small (<5 mm), shallow ulcers that heal over 5 to 10 days . By definition, the diagnosis of PFAPA syndrome requires also exclusion of other monogenic periodic fevers , which are hereditary conditions and include Familial Mediterranean Fever ( FMF ), the spectrum of mevalonate kinase deficiencies ( MKD ) (such as Hyper Ig -D syndrome and mevalonate aciduria ), and tumor necrosis factor-associated periodic syndrome ( TRAPS ) amongst others, each characterized by a specific genetic mutation . Scully C, Oral Dis. 2008;14(8):690-9 . However, genetic tests have been only sporadically used to support the PFAPA diagnosis despite the fact that current PFAPA syndrome diagnostic criteria have very low specificity.

53. Is Periodic Fever, aphthous stomatitis , pharyngitis , and cervical adenitis (PFAPA) syndrome a distinct medical entity ? Baccaglini L. Oral Dis . 2011;17:755-770 . A relevant number of patients with monogenic periodic fevers also meet the diagnostic criteria for PFAPA syndrome. In a preliminary experience, 83% of patients with mevalonate kinase deficiency ( MKD ) , 57% of patients with (tumor necrosis factor receptor–associated periodic fever syndrome ( TRAPS) , and 8% of patients with Familial Mediterranean fever ( FMF) satisfied the criteria for PFAPA syndrome, which shows that the criteria have limited utility in differentiating PFAPA syndrome from monogenic periodic fevers. Importantly, although oral aphthosis was found less frequently in monogenic periodic fever than in PFAPA there was a high overlap with the other signs and symptoms. Gattorno M. Arthritis Rheum . 2008;58(6):1823-32. Gattorno M, Pediatrics. 2009;124(4):e721-8.

54. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children . Gattorno M. Arthritis Rheum . 2008;58(6):1823-32. Familial Mediterranean fever (FMF ), tumor necrosis factor receptor–associated periodic fever syndrome (TRAPS;), and mevalonate kinase deficiency (MKD ) are hereditary diseases caused by mutations of genes involved in the regulation or activation of the inflammatory response, characterized by recurrent episodes of fever associated with a number of manifestations: rash, serositis , lymphadenopathy , and arthralgias / arthritis . Systemic reactive amyloidosis may be a severe complication of these conditions . FMF is caused by recessive mutations in the MEFV gene, which encodes a protein called pyrin . TRAPS is due to dominant mutations in TNFRSF1A, the TNF receptor superfamily 1A gene. MKD is caused by recessive mutations in MVK, the mevalonate kinase gene.

55. OR for a (+) genetic test 40 – 30 – 20 – 10 – 4.0 – 3.0 – 2.0 – 1.0 – 0. 4.1 (+) FH of periodic fever thoracic pain 4.6 abdominal pain 33.1 diarrhea 3.3 oral aphthosis 0.2 A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children . Gattorno M. Arthritis Rheum . 2008;58(6):1823-32. A total of 228 consecutive patients with a clinical history of periodic fever screened for mutations in the MVK, TNFRSF1A, and MEFV genes. P = 0.039 P = 0.05 P < 0.001 P = 0.028 P = 0.007

56. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children . Gattorno M. Arthritis Rheum . 2008;58(6):1823-32.

57. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children . Gattorno M. Arthritis Rheum . 2008;58(6):1823-32. Patients were classified as high risk if their diagnostic score was 1.32 ; otherwise, they were classified as low risk. * age of onset in months (the greater the age of onset the lower the scor e) *

58. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children . Gattorno M. Arthritis Rheum . 2008;58(6):1823-32. Proposed diagnostic flow chart for use in children with periodic or recurrent fever. This score identified 91% of the genetically positive individuals and those at risk for carrying genes associated with monogenic periodic fevers.