Chapter 3.1
Orofacial granulomatosis and nutrition
Helen Campbell, Jeremy D. Sanderson and Miranda C. E. Lomer
Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
The term ‘orofacial granulomatosis’ (OFG) is a descriptor for the presentation of granulomatous inflammation which affects, most noticeably, the lips and face but invariably intraoral features are also present and can include swelling, erythema, nodules, tags and ulcers [1]. Orofacial granulomatosis is rare and the incidence is unknown although the highest reported published patient numbers are from Scotland. Approximately one quarter of patients present with a concurrent diagnosis of Crohn’s disease and more rarely a diagnosis of Melkersson Rosenthal syndrome is appropriate when facial palsy and fissured tongue are additional clinical findings [2]. Both children and adults can be affected. The diagnosis is made through oral examination and the gold standard histological diagnostic criteria require the presence of non-casaeating granulomas observed in the biopsies taken from the disease sites.
3.1.1 Aetiology
The aetiology is unknown. Hypotheses have included allergic, infective and genetic causes [3]. However, the majority of studies have been limited by the rarity of the disease. Allergic causes have received most coverage, with oral exposure to foods, dental hygiene products and dental materials being implicated in the disease process for some patients.
3.1.2 Treatments
Treatments have involved exclusion of suspected allergens but where this fails, topical immunosuppression such as topical steroids or tacrolimus is used, often prior to systemic immunosuppression [4,5]. It is not uncommon for patients to also present with accompanying candidiasis or bacterial infections, particularly in fissures, which can exacerbate disease and may require treatment with topical antifungals or antibiotic therapies [6]. Intralesional steroids can offer benefit but are unpleasant and recurrence is common although more recently, a succession of injections with accompanying use of anaesthetic nerve block has been described as inducing long-term remission [7]. Oral steroids often have some initial benefit but recurrence is common [8,9]. Azathioprine has been used but does not tend to have an immediate response. However, it shows some promise, particularly in those with a concurrent diagnosis of Crohn’s disease [10]. Anti-tumour necrosis factor (TNF)-alpha has been used in refractory OFG but reports are rare and again long-term response is not always satisfactory [11].
Dietary treatments have involved exclusion diets and have demonstrated some resolution when the offending food can be readily identified [12]. The most frequently used dietary treatment avoids cinnamon and benzoate [13]. Elemental diets have shown some promise, particularly in children, but this has its limitations in terms of palatability and acceptability [14].
3.1.3 History of the cinnamon- and benzoate-free diet
Sensitivity to cinnamon and benzoates was first observed in patients with OFG in 1997 when patch testing in a small group of patients indicated a higher rate of benzoic acid sensitivity [15]. In 2000, Wray et al. undertook a retrospective review of patch test data in 1252 patients with oral disease, of whom 261 had OFG [16]. A high rate of sensitivity to perfumes and flavourings, and in particular benzoic acid and cinnamaldehyde sensitivity, was illustrated and the authors reported improvement through avoidance of these compounds. They also reported chocolate sensitivity in OFG. In 2006, White et al. demonstrated improvement in 72% of patients who could comply with this diet and subsequently a cinnamon- and benzoate-free diet became the primary therapy employed in the management of OFG [17].
3.1.4 Mechanisms involved in dietary avoidance of cinnamon and benzoates in orofacial granulomatosis
The immunopathological mechanisms for the observed response to dietary avoidance of cinnamon and benzoates are not clear. However, other rare reports of allergic reactions have implicated benzoates, mainly in asthma and allergic contact dermatitis [18]. One postulated but unproven theory includes the potential for a type 4 reaction involving a T-cell response. Another suggests a possible late-phase IgE-dependent response. A further hypothesis suggests that benzoates are too small to act as allergens but they may act as haptens that potentially bind to proteins in the mouth that then trigger a reaction [19,20]. Additionally, sodium benzoate has been shown to suppress a Th1 pathway [21]. The implication is that sodium benzoate is not an allergen itself but aggravates an allergic response by suppressing the Th1 pathway and in doing so, allows a Th2 response to flourish in the presence of an allergen. This too could apply in OFG. However, contradicting this theory is a study in which 10 patients with OFG were predominantly found to have a Th1 profile in keeping with Crohn’s disease. However, more recently, discovery of a novel subepithelial dendritic B-cell which expresses IgE in the lips of patients with OFG has contributed to a hypothesis of a possible contribution of a Th2 pathway and an IgE-mediated response [22].
The mechanisms involving the role of cinnamon and benzoates in OFG are not understood and much work is still required to appreciate the immunological impact this diet might have.
3.1.5 Sources of cinnamon and benzoates
Benzoates
Benzoates are naturally present in plant foods and are also added to foods as preserving agents (Table 3.1.1) [23–27]. Sources of added benzoates can include drinks, chewing gums, biscuits, cakes, yoghurts, pickles, sauces, preserved fish and meat. A maximum dose of 150 mg/kg can be added and the highest likely exposures would be from soft drinks [28,29]. Natural sources of benzoic acid are found in plant foods, most commonly in berry fruits but also in other sources such as spinach, pumpkin and spices (Table 3.1.2) [23–27].
Table 3.1.1 Preservatives to be avoided on the cinnamon- and benzoate-free diet
| aPreservative | E number |
| Benzoic acid | E210 |
| Sodium benzoate | E211 |
| Potassium benzoate | E212 |
| Calcium benzoate | E213 |
| Ethyl 4-hydroxybenzoate or ethyl para-hydroxybenzoate | E214 |
| Ethyl 4-hydroxybenzoate, sodium salt or sodium ethyl para-hydroxybenzoate | E215 |
| bPropyl 4-hydroxybenzoate or propyl para-hydroxybenzoate | E216 |
| bPropyl 4-hydroxybenzoate, sodium salt or sodium para-hydroxybenzoate | E217 |
| Methyl 4-hydroxybenzoate or methyl para-hydroxybenzoate | E218 |
| Methyl 4-hydroxybenzoate, sodium salt or sodium methyl-hydroxybenzoate | E219 |
aAll food labels need to be checked for these preservatives which are most commonly found in soft drinks but can potentially be added to jams, sauces, pickles, yoghurts, salad dressings, ketchups, cakes, biscuits, preserved delicatessen foods and other preserved foods.
bBanned in the European Union but might be available in imported goods.
Table 3.1.2 Main sources of cinnamon and benzoates
| Foods to avoid | Alternatives |
| Herbs and spices | |
| Cinnamon, cloves, nutmeg, sage, curry powder, all spice, mixed spice, garum masala. Check food products (e.g. curries, puddings, sweet and savoury baked goods, cereals with added cinnamon) | Salt, pepper, single herbs and spices (e.g. cumin, coriander, turmeric, chilli, paprika, basil, marjoram, oregano, mint, etc.) |
| Drinks | |
| Any drinks with added flavourings (e.g. most soft drinks, squash, flavoured waters, flavoured spirits and alco-pops), tea including black, rooibos and green tea or any herbal teas with tea leaves, chai tea, chicory drinks, camp coffee or liquid coffees, non-alcoholic grape drinks, mulled wine and fruit juices from ‘not allowed’ fruits (e.g. berry juices, prune juice, peach or papaya juice, tropical juices with these additions) | |
