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Alimentary Pharmacology and Therapeutics Review article: cinnamon- and benzoate-free diet as a primary treatment for orofacial granulomatosis H. E. Campbell*, ,à, M. P. Escudier§, P. Patel–, S. J. Challacombe§, J. D. Sanderson*,– & M. C. E. Lomer*, ,– *Diabetes and Nutritional Sciences Division, King’s College London (KCL), London, UK. Department of Nutrition and Dietetics, Guy’s and St Thomas’ NHS Foundation Trust (GSTFT), London, UK. à NIHR Comprehensive Biomedical Research Centre at GSTFT and KCL, London, UK. § Department of Oral Medicine, King’s College London Dental Institute, London, UK. – Department of Gastroenterology, GSTFT, London, UK. Correspondence to: Dr M. C. E. Lomer, Kings College London, Diabetes and Nutritional Sciences Division, Room 4.103 Franklin Wilkins Building, Waterloo Campus, 150 Stamford Street, London, SE1 9NH, UK. E-mail: [email protected] Publication data Submitted 4 November 2010 First decision 28 November 2010 Resubmitted 6 July 2011 Accepted 7 July 2011 EV Pub Online 4 August 2011 This uncommissioned review article was subject to full peer-review. SUMMARY Background Orofacial granulomatosis is a rare chronic granulomatous inflammatory disease of the lips, face and mouth. The aetiology remains unclear but may involve an allergic component. Improvements have been reported with cinnamon- and benzoate-free diets. Aims To explore the prevalence of compound and food sensitivity and examine the dietary treatments used in orofacial granulomatosis. Methods A comprehensive literature search was carried out and relevant studies from January 1933 to January 2010 were identified using the electronic database search engines; AGRIS 1991–2008, AMED 1985–2008, British Nursing and Index archive 1985–2008, EMBASE 1980–2008, evidence based medicine review databases (e.g. Cochrane DSR), International Pharmaceutical and Medline 1950–2008. Results Common sensitivities identified, predominantly through patch testing, were to benzoic acid (36%) food additives (33%), perfumes and flavourings (28%), cinnamaldehyde (27%), cinnamon (17%), benzoates (17%) and chocolate (11%). The cinnamon- and benzoate-free diet has been shown to provide benefit in 54–78% of patients with 23% requiring no adjunctive therapies. A negative or positive patch test result to cinnamaldehyde, and benzoates did not predict dietary outcome. The most concentrated source of benzoate exposure is from food preservatives. Use of liquid enteral formulas can offer a further dietary therapy, particularly in children with orofacial granulomatosis. Conclusion Management of orofacial granulomatosis is challenging but cinnamon- and benzoate-free diets appear to have a definite role to play. Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2011.04792.x 687 H. E. Campbell et al. INTRODUCTION Orofacial granulomatosis (OFG) is a chronic granulomatous condition characterised by disfiguring lip swelling and oral involvement affecting all aspects of the oral mucosa, but most often the buccal mucosa, gingivae and sulcus.1, 2 Swelling and erythema are the most commonly seen features but fissuring, ulceration, nodules, tags and occasionally oral scarring from penetrating or prolonged disease can also be present. OFG frequently exists as a separate entity but is also commonly associated with Crohn’s disease. The aetiology is unknown and no epidemiological studies have been carried out. However, the largest reported population appears to exist in Glasgow.3 Historically, treatments often involved surgery4 but more recently immunosuppressive medicines have been used with success often seen with topical, intra-lesional and systemic corticosteroids, thiopurines and occasionally others such as clofazimine, thalidomide and anti TNF a therapies.5–7 The experience of a combined oral medicine and gastroenterology clinic at a large teaching hospital in London, UK, exceeds over 200 patients for whom the cinnamon- and benzoate-free diet has been used first line in 86%.1 This diet requires avoidance of cinnamon, a spice added to foods and hygiene products, benzoates (which are salts and esters of benzoic acid) used as food additives (E210–E219) and naturally occurring benzoic acid sourced from some fruits and vegetables particularly berries. The cinnamon- and benzoate-free diet is initially used in isolation but some patients do not always benefit from the dietary treatment and sometimes require additional therapies. Symptom recurrence is common and often unexplained. Moreover, the cinnamon- and benzoate-free diet is complex requiring both dietetic expertise and careful patient education and follow-up. Practical information available to most practitioners treating cases of OFG regarding the diet is scarce. The objectives of this study were to explore (i) the prevalence of compound and food sensitivity in OFG, (ii) the dietary treatments used in OFG, (iii) dietary sources of cinnamon and benzoates, (iv) other contributing factors in the dietary management of OFG and (v) the current experience of the cinnamon- and benzoatefree diet in clinical practice. METHODS An extensive literature review was carried out. The search strategy used the following databases; AGRIS 1991–2008, AMED 1985–2008, British Nursing and Index archive 1985–2008, EMBASE 1980–2008, Evidence 688 based medicine review databases (e.g. Cochrane DSR), International Pharmaceutical and Medline 1950–2008. The search criteria included full journals as well as abstracts from conference proceedings. Due to the rarity of OFG, case studies were also accepted. Search terms used included OFG, cheilitis granulomatosa, oral Crohn’s disease, sarcoidosis, Melkersson-Rosenthal syndrome, diet, atopy, allergy, sensitivity, cinnamon and benzoate. Publications were excluded if there was insufficient detail or if the results were not presented in English or could not be translated sufficiently. References of retrieved manuscripts were reviewed to identify further publications that may have been missed during the original search. RESULTS Food and compound sensitivity in OFG Since the 1980s, sensitivity to food in OFG has been observed in almost a fifth of patients as a potential aggravating factor.8, 9 The most frequently cited agents include cocoa, cinnamaldehyde, cinnamon, toothpaste with a range of foods including carrot, pork, apple juice, orange juice, egg, cheese and tomato causing recurrence of symptoms with a re-introduction programme following elimination of these foods.8 Patch testing is a commonly used method of identifying sensitivities in oral mucosal disorders and contact dermatitis in oral medicine and allergy clinics. Patch testing typically involves use of a standard battery of patches containing individual compounds which are placed on the skin, normally on the backs of patients with suspected sensitivities. Contact urticaria is diagnosed when a reaction can be seen at 20 min after the patches are placed. Delayed responses are seen at 24, 48 and 72 h following placement of the patches. Two key studies initiated the concept of cinnamon and benzoate sensitivity in OFG. In Belfast, in 1997, Armstrong et al. 10 carried out cutaneous patch test studies in 48 patients with OFG. Twenty demonstrated sensitivity to one or more compounds, the most common (18 ⁄ 20) being benzoic acid. This study also demonstrated sensitivities to cinnamaldehyde, sorbic acid (a common food preservative), fragrance mix, nickel sulphate and a range of other compounds. In Glasgow, in 2000, a retrospective study on 264 patients with OFG assessed 48 different allergens using cutaneous patch tests which included a modified standard European series, food additives, perfumes and flavourings and chocolate.11 Sixtytwo per cent were patch test positive to one or more Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd Review: dietary treatment for orofacial granulomatosis compounds with 122 (51%) and 97 (38%) demonstrating sensitivity to benzoic acid and cinnamaldehyde respectively. A high incidence of patch test positive results to other compounds such as fragrance mix, food additives, perfumes and flavourings was also observed. Twenty patients (8.2%) patch tested positive to chocolate which, anecdotally, patients often cite as aggravating disease symptoms. The authors reported an immediate response (contact urticaria) at 20 min and a delayed response at 48 and 96 h. Contact urticaria to cinnamaldehyde (36%) and benzoic acid (46%) were common but delayed responses were less common [benzoic acid (7%) and cinnamaldehyde (4%)]. Delayed sensitivity to chocolate (7%) was comparable to benzoic acid. Overall, 23 publications on food and compound sensitivity were identified in this literature review, most of which were from the UK or Ireland. The age of subjects ranged from 3 years to 72 years. Table 1 summarises the data on sensitivity testing in OFG. The primary methodologies used were patch tests, often undertaken against a background of Table 1 | Publications identified Country of publication Methodology for identification of sensitivity Number of patients Number of patients with identified sensitivities 2008 England Patch tests 1 1 Armstrong (10) 1997 N Ireland Patch tests 48 20 Booth (104) 1997 England Patch and blind oral challenge 1 1 Cameron (18) 2003 England Dietary exclusion 1 1 Chiu (105) 2008 Taiwan Patch tests 1 1 Downs (106) 1998 England Patch tests 1 0 Endo (107) 2007 Japan Patch tests and dietary assessment 12 12 Fitzpatrick (108) 2011 Ireland Reference (1st author surname) Publication year Alexandroff (103) Patch tests 41 17 Urticarial patch tests 97 63 Gibson (109) 1996 Scotland Patch tests 100 93 Guttman – Yassky (12) 2003 Israel Patch tests 1 1 Khamaysi (110) 2006 Israel Patch tests 13 6 Kiparissi (19) 2006 England RAST and allergen specific IgE tests 15 14 Lazarov (111) 2003 Israel Patch tests 2 2 Mehta (112) 2003 England Patch tests 1 1 Oliver (113) 1991 Australia RAST and skin prick 1 1 Patton (9) 1985 Scotland Patch tests and dietary assessment 80 14 Pryce (13) 1990 England Patch tests 1 1 Reed (114) 1993 Australian Dietary exclusion 1 1 Sweatman (20) 1981 England Allergen specific IgE, diet assessment and skin prick tests 1 1 Taibjee (88) 2004 England Patch tests 1 1 Torgerson (115) 2007 US Patch tests 13 4 White (17) 2006 England Dietary exclusion 25 18 Wray (11) 1999 Scotland Patch tests 264 192 RAST, radioallergosorbent test. Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd 689 H. E. Campbell et al. clinical suspicion. Combining data for 386 patients with OFG (Table 2) where specific sensitivities to one or more compounds could be identified, 140 ⁄ 386 (36%) were sensitive to benzoic acid, 129 ⁄ 386 (33%) to food additives, 108 ⁄ 386 (28%) to perfumes and flavourings and 105 ⁄ 386 (27%) to cinnamaldehyde. Avoidance of oral mucosal contact with many of these compounds through dietary exclusion,8 removal of dental appliances,12 and even removal of cobalt based ink pens in a boy with cobalt sensitivity13 improved symptoms in OFG. It would therefore seem that where a compound sensitivity can be readily identified, and regular contact with the lips and oral mucosa is clear, removal or avoidance improves symptoms in OFG. In contrast, a recent clinical review of patch testing to the standard European series showed only a small trend to increased response from a cinnamon- and benzoate-free diet in those that patch tested positive.14 Furthermore 40% of patients who tested negative still responded to the diet (23 ⁄ 38 patch test positive responded versus 20 ⁄ 50 patch test negative, P = 0.056). Patch test results to benzoates, cinnamon and other Table 2 | Identified sensitivities in orofacial granulomatosis n Compounds 140 Benzoic acid 129 Food additives 108 Perfumes and flavourings 105 Cinnamaldehyde 68 Cinnamon 64 Benzoates 42 Chocolate 21 Nickel 12 Cow’s milk 7 Scorbic acid 6 Cinnamic alcohol 5 Gold sodium thiosulphate 4 Colbalt chloride, mercury 3 Fragrance mix, oak moss absolute, wheat, toothpaste 2 Monosodium glutamate, salicylic acid, dairy, colphony, formaldehyde 1 Piperitone, carvone, betal nut, peanut, potassium dicanaurate, benzyl peroxide, dodecyl gallate, sodium metabisulphate, glutamic acid, butylated hydroxyanisole, eugenol, isoeugenol, kathon GC, neomycin quaternium, balsam of Peru n = number of patients with identified sensitivities. 690 related compounds were even less predictive of dietary response. Unpublished data from our clinic in 38 patients with OFG also suggested that routine skin prick testing (SPT) to cinnamon and benzoic acid was not predictive for dietary response. Nine of 13 patients who were SPT positive for cinnamon responded to the diet versus 12 ⁄ 25 who were SPT negative (P = 0.212). Five of eight patients who were SPT positive for sodium benzoate responded to the diet versus 16 ⁄ 30 who were SPT negative (P = 0.643). In summary, a high rate of cinnamon and benzoate sensitivity has been reported in patients with OFG but the response to exclusion of cinnamon and benzoates is not necessarily related. However, other compounds may also cause sensitivity. Furthermore, in clinical practice, identifying the aggravating compounds and determining their clinical relevance is challenging and often inconclusive. Review of dietary management of OFG Table 3 outlines the dietary intervention studies carried out in patients with OFG. Two dietary therapies have been assessed in the management of OFG comprising a cinnamon- and benzoate-free diet14–17 or liquid enteral nutrition.16, 18–20 The latter focused on using elemental formula in preference to whole protein formula. These studies were limited by their small sample sizes and retrospective nature which reflects the rarity of this disease. Nevertheless, both treatments appear to offer beneficial outcomes in OFG. Dietary benefit was not always clearly defined but in most of the studies is measured through improvement of signs and symptoms recorded on a disease severity scoring tool21 adapted specifically for patients with OFG.17 This tool is available at http:// www.kcl.ac.uk/ofg. With respect to the cinnamon- and benzoate-free diet, benefit is seen in 54–78% of patients with OFG.14–17 Differences in these figures possibly relate to differences in study methodologies. One used prospective methods 17 and the previously mentioned oral scoring tools to assess disease severity and activity.15–17 In contrast, the largest study (n = 199) was a retrospective notes review that used a more subjective assessment, and the benefit observed was by clinical impression and could not realistically take into account patient compliance.14 Despite the lower rate of benefit seen (54%), the strength of this study was that it was more reflective of clinical practice and demonstrated that nearly one quarter of patients required no additional therapy, which was not considered in the other studies. The diet appeared marginally more beneficial to those without concurrent Crohn’s disease but overall, there were no significant difAliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd Review: dietary treatment for orofacial granulomatosis Table 3 | Publications investigating the dietary management of OFG Study Year n Study methods Results White (17) 2006 32 Prospective dietary intervention study using the cinnamon- and benzoatefree diet in the treatment of OFG. 18 ⁄ 25 (72%) of patients demonstrated benefit. 7 ⁄ 32 were excluded from the data analysis for issues of non compliance and incomplete data. Nunes (16) 2008 57 (part 1) 12 (part 2) Part 1; Retrospective review of dietary management with a cinnamon- and benzoate-free diet followed by part 2; A dietary intervention study using liquid enteral nutrition. 39 ⁄ 57 (68%) of patients benefited from a cinnamon- and benzoate-free diet with further improvement seen in 8 ⁄ 12 (67%) patients receiving liquid enteral nutrition. Kiparissi (19) 2006 14 Prospective intervention study using elemental enteral nutrition in the treatment of OFG in children. 10 ⁄ 14 (71%) complete remission. The remainder benefited but required additional treatments to induce full remission. Bogner (15) 2009 40 Retrospective assessment of the use of the cinnamon- and benzoate-free diet on disease sites. 31 ⁄ 40 (78%) demonstrated improvement on the diet. The lips, buccal mucosa and all other oral sites improved significantly except the tongue. Campbell (14) 2010 199 Retrospective analysis of use of the cinnamon- and benzoate-free diet in clinical practice 172 ⁄ 199 (86%) used the cinnamon- and benzoate-free diet as the initial treatment. 86 ⁄ 157 (55%) demonstrated some benefit. 45 ⁄ 199 (23%) required no adjunct therapies. OFG, orofacial granulomatosis. ferences between those with and without Crohn’s disease.14, 15, 17 Liquid enteral nutrition has been used to gain symptomatic relief in patients with OFG. One study (n = 12) carried out over 6 weeks demonstrated benefit in eight patients. Of these, six received an elemental formula (Elemental 028 Extra; SHS International Ltd, Liverpool, Meryside, UK) and two, a whole protein formula (Modulen IBD; Nestlé Nutrition, Croydon, Surrey, UK). Out of the remaining 4 patients, 1 did not improve (Modulen IBD; Nestlé UK) and three were unable to comply. A paediatric study (n = 14) found similar success using an elemental formula (Elemental 028 Extra; SHS) with 10 improving and four demonstrating some benefit but requiring adjunct therapies.19, 22 Encouragingly, enteral formula does appear to result in more rapid remission with two case reports of improvement being seen in as little as 2 days.18, 20 Immunological response to the cinnamon- and benzoate-free diet The mechanism for the observed dietary response to cinnamon and benzoate avoidance is not clear. Extrapolating from other reports of hypersensitivity reactions (normally asthma or allergic contact dermatitis) to benzoates used Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd as food additives, some implicate a type 4 hypersensitivity reaction which is mediated by lymphocytes and involves activated T cells in response to antigens.22 This would occur over a delayed period of 12 h or more as would be illustrated by patch testing. Certainly this would be in keeping with two studies in OFG patients where a T cell response was implicated.23, 24 Delayed hypersensitivity to benzoates has also been proposed in asthma and atopic dermatitis, including possible late phase IgE dependent responses associated with production of leucotrines and other related arachidonic acid based reactions.22 Type III reactions have also been proposed, which initiate the complement system through means of circulating IgE and IgM. An obvious argument is that these compounds are too small to elicit such a response and that they instead act as haptens binding to proteins (in particular mucosal proteins within the mouth) which then trigger a cell mediated response.25, 26 Interestingly, studies have illustrated that sodium benzoate suppresses the Th1 pathway, hence altering the Th1 ⁄ Th2 balance permitting a prominent Th2 response in the presence of a common allergen.27–29 Hence, in OFG, sodium benzoate may not itself be an allergen but in suppressing the Th1 pathway in the oral mucosa it allows a significant Th2 response whilst withdrawal of dietary benzoates re-dresses this 691 H. E. Campbell et al. imbalance. Against this theory are the findings of Freysdottir et al. who identified a Th1 environmental profile in the oral mucosa in OFG in keeping with that seen in Crohn’s disease.30 Remarkably high rates of atopy are an established observation in patients with OFG 31 which is different to other chronic inflammatory disorders, for example, rheumatoid arthritis and multiple sclerosis where atopy rates appear reduced.32 Moreover, Patel et al. recently discovered a novel population of sub- epithelial dendritic B cells in the oral mucosa of which a subset, specifically in patients with OFG, expressed surface IgE implicating a likely IgE mediated response.33 It is not clear if these cells are present as a consequence of local inflammation or are resident prior to disease onset. Benzoates are rarely implicated in IgE mediated reactions although there have been some reports of anaphylaxis in patients without OFG.34, 35 Additionally, in our specialist OFG clinic, some patients (51 ⁄ 88) showed positive SPT to sodium benzoate and cinnamon (54 ⁄ 88) although no clear associations could be made with dietary response. Immediate responses to cinnamaldehyde and benzoates were also common in the Glasgow group.11 The true role of cinnamon and benzoates in the immuno-pathogenesis of OFG remains unclear. However, the prominence of allergic features, the evidence of type I hypersensitivity and the likely abnormal T cell responses suggest an intriguing and perhaps unique, interplay between different immune pathways. STRUCTURE AND PREVALENCE OF CINNAMON AND BENZOATES Cinnamon Cinnamon is harvested from the bark of the cinnamon tree and is naturally high in benzoates.36 True cinnamon (Cinnamomum zeylanium N.) originates from Sri Lanka.37 Many varieties exist and a close relative, Cassia (Cinnamomum cassia Presi), originally sourced from China, Indonesia or Vietnam, is often mistaken for cinnamon. Cinnamon oil makes up 1–8% of cinnamon and provides the characteristic flavour. The pungent taste and smell comes from cinnamaldehyde which has strong antimicrobial activity.38 Cinnamaldehyde also occurs naturally in blueberries and cranberries.37 Other components of cinnamon and cassia include phenolic acids, flavan-3-ols,39 proanthocyanidins,39, 40 cinnamyl alcohol, terpenes, carbohydrates, coumarin and tannins.37 Cassia, however, contains less cinnamaldehyde than cinnamon but is high in coumarin, of which cinnamon contains only a trace.41, 42 692 Both cinnamon and cassia are widely used in the food and cosmetics industries as flavourings, preservatives and perfumes. In a food ingredient label, where a spice makes up <2% by weight of the food, cinnamon can be listed under the generic title ‘spice’, ‘spices’ 43, 44 or mixed spice.45 Cinnamon is often added to medicines, toothpaste and oral hygiene products, chewing gum, sweets, soft drinks, chocolates, cereals, liquors, baked goods, spicy savoury foods and cosmetics including perfumes, creams soaps and balms. Both cassia and cinnamon are predominant spices used in Asian cooking. There are no official safety concerns regarding the use of cinnamon which has been approved as a flavouring and perfuming agent.37, 46, 47 Cinnamaldehyde and cinnamic acid have been cited as irritants and patch test studies demonstrate positive responses particularly in people with atopy and eczema.48 Cross reactions with balsam of Peru, the Myroxylon pereirae tree extract commonly used as a fragrance, have been demonstrated.49 In addition, there have been associated sensitivities between balsam of Peru and tomato, citrus fruits, spices, vanilla and cloves.49, 50 Toothpastes and oral hygiene products with added cinnamon or cinnamon derivatives have been associated with oral intolerance resulting in gingivitis, glossitis, stomatitis and perioral dermatitis.51–53 However, overall, reports of any detrimental effects to health from cinnamon are rare. Nevertheless, dietary studies quantifying cinnamon intakes are limited. There is one study in children aged between 2 and 5 years which demonstrated maximum cinnamon intakes of 220 mg ⁄ kg body weight on peak exposure days normally taken in rice pudding with added cinnamon and sugar.54 These children were having cinnamon at least once every 6 days. This works out at around 2.86 g of cinnamon for a 13 kg child which equates to approximately one teaspoon per day. Longterm exposure of these children was calculated as 63 mg ⁄ kg body weight per day, assuming a 2 day per week peak exposure of 220 mg ⁄ kg body weight. Benzoates Benzoates are known most commonly for their use as antimicrobial preserving agents.55 Rich natural sources of benzoates can be found in berries, prunes, tea, some herbs and spices such as nutmeg, cinnamon, cassia, cloves and in lower quantities, other foods such as milk, cheese, yoghurts, soya, nuts and pulses.55, 56 The food additives E210–219 are benzoate containing preserving agents used in processed foods, for example soft drinks, jams, sweets, chocolates, ice creams, pickles, baked Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd Review: dietary treatment for orofacial granulomatosis goods.57, 58 E216 and E217 have been banned in the European Union (EU) following studies showing reduced sperm counts in adolescent rats following ingestion of the acceptable daily intake (ADI).59 Other sources include the additive E928 (benzyl peroxide) which is not listed for use in foods in the EU60 but is used in the cosmetics industry.61 E322 (lecithin) is an emulsifier used in foods and medicines which, in some non-EU countries, can be bleached with the use of benzyl peroxide. In the EU however, hydrogen peroxide is now the only permitted bleaching agent for lecithin.60 Lecithin can also be manufactured from soya which is a natural source of benzoates.55 However, the dietary contribution of benzoates from soya lecithin is likely to be comparatively low. Benzoates are added to cosmetics and pharmaceutical products including creams, soaps, gels, oral hygiene products, ointments and tablets.55, 61, 62 In 2003, an EU directive was set up to ensure that ingredients previously listed on labels as ‘parfum’ or ‘aroma’ would comply with the regulations for listing the 26 likely allergens.58 This encompasses many cinnamon and benzoate derivatives. Oral hygiene products, in particular, tartar control toothpastes and mouthwashes are common sources of benzoates 55 and benzoic acid has been found to leach from denture materials.63, 64 Benzoates have also been found in oral dental impression materials used to create moulds of teeth.65 The use of benzoates and quantities permitted in the UK is controlled by EU regulations.57 A comprehensive list of foods in which benzoates can be added is useful to help identify potential benzoate sources but does not necessarily mean that all these foods will contain added benzoates. Furthermore, this legislation includes maximum permitted levels of benzoates often in combination with sorbic acid rather than solely as benzoates. For the general population, daily oral intake of benzoates is thought to be safe up to levels of 5 mg ⁄ kg body weight at a concentration of 0.015–0.5%.55 A number of nationwide population studies have demonstrated significant variation in benzoate intakes.55 These differences have been attributed largely to variations in national legislation policing benzoate as an additive in different countries.66 In the UK, a national survey analysed 250 samples of soft drinks and concluded that estimated benzoate intakes would be below the advised daily intake (ADI) of 5 mg ⁄ kg body weight in line with the EU recommendations.67 This survey also demonstrated relatively low usage of benzoates as preservatives in soft drinks. Of the 250 samples only four had levels above the permitted level of 150 mg ⁄ L. Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd Reports of benzoic acid toxicity are rare. Potential toxic effects of sodium benzoate are thought to be similar to salicylic acid poisoning and generally non-specific causing nausea, vomiting, malaise, irritability and hypoglycinaemia.68 Renal tubular dysfunction has also been suggested secondary to therapeutic use of sodium benzoate in one case of hyperglycinaemia,68 a rare inborn error of metabolism. Despite the body of evidence surrounding the safety of benzoates, public awareness has been raised with substantial negative press relating to a number of studies implicating benzoates as having detrimental effects on health.69, 70 Three key studies have contributed to this. A study investigating the effects of weak organic acid food preservatives (including benzoic acid) on yeast cells found a pro-oxidant and mutagenic effect on the mitochondrial genome when exposed at very low levels.71 The authors extrapolated for the potential implicated oxidative risks and mitochondrial damage these preservatives might be responsible for in humans. Further negative press ensued in 2006 when the soft drinks industry was required by the Food Standards Agency (FSA) to measure benzene levels in 230 soft drinks available in the UK.72 Benzene is a carcinogen formed by the interaction of sodium benzoate and ascorbic acid.73 Only four products were found to contain levels above the limit of 10 lg ⁄ kg and these were subsequently withdrawn from the market. More recently, a study commissioned by the FSA was conducted to investigate the influence of certain food additives (food colourings and sodium benzoate) on behaviour in children with Attention Deficit Hyperactivity disorder.73 The authors concluded that avoidance of the additives used in the study might have some beneficial effects on behaviour. Some companies have consequently attempted to reduce their use of benzoates in food products.74 Quantification of benzoates Five papers were identified on the quantification of benzoates in foods. High performance liquid chromatography was the method used to quantify benzoate levels. Two papers were German,36, 56 one was from Japan,75 one from China76 and one from New Zealand.77 Cinnamon contained the highest level of naturally occurring benzoic acid with a mean of 33.6 mg ⁄ 100 g.36 Preserved salted fish from Japan was very high in benzoic acid with mean levels of 75.4 mg ⁄ 100 g.75 Other notably concentrated sources included soft drinks, mean levels of 14.4 mg ⁄ 100 g,77 nutmeg 4.41 mg ⁄ 100 g,36 ice cream confectionery 10.7 mg ⁄ 100 g,77 ice cream toppings 693 H. E. Campbell et al. 5.6 mg ⁄ 100 g,77 soya sauce 5.1 mg ⁄ 100 g,75 cranberry 8.9 mg ⁄ 100 g,36 jams 7.1 mg ⁄ 100 g,75 and dried apricots 3.04 mg ⁄ 100 g.77 Comparatively, quantities of benzoates obtained from preservatives are higher than natural sources (Table 4). A recent project set out to assess the levels of benzoates in processed foods, cosmetics and pharmaceuticals by contacting UK manufacturers (n = 174).78, 79 Ninety manufacturers responded but only 14 of these could provide quantitative data. The results demonstrated that benzoates are little used in the UK food industry and are most commonly added to soft drinks. In the cosmetic and pharmaceutical industries, benzoates are added more significantly to a wide range of products, with two analgesics [Paracodal and Co-codamol effervescent (Bayer plc)] containing as much as 120 mg per tablet. In addition, soya flour added to bread is not sufficient (estimated benzoic acid values calculated as 0.0051 mg ⁄ slice) to merit avoidance of breads containing soya flour. Similarly, soya lecithin contains only trace amounts of benzoic acid at 2– 30 ppm and therefore need not be avoided. In addition, rennet typically contains 0.4% sodium benzoate, and 6 mL of rennet are added per 100 L of milk in the production of cheese. Consequently the contribution of benzoates from rennet is minimal although the question of naturally occurring benzoates in cheese and other milk related products remains unclear.36, 80 Consideration of natural sources of benzoic acid therefore remains important in patients with sensitivity to benzoates. In summary, natural benzoate sources do contribute to the overall exposure of patients to benzoic acid and a cinnamon- and benzoate-free diet can be very restrictive irrespective of the use of added benzoates. It is therefore likely that in patients who respond well to dietary avoidance of cinnamon and benzoates, threshold tolerance levels are comparatively higher than those who partially respond or do not respond to dietary treatment. It is also reasonable to consider other sensitivities which may be unrelated in these patients. The relationships between cinnamon and benzoates Cinnamon is a source of benzoic acid (Figure 1),36 cinnamaldehyde (see Figure 2) 81 and other phenolic compounds.37, 40, 41, 81 Cinnamic acid (see Figure 3) is found in cinnamon oil and is also readily oxidised from benzaldehyde which is synthesised by gentle heating of cinnamaldehyde.38 Cinnamic acid and benzoic acid are structurally similar compounds classified as hydroxycinnamic acid and hydroxybenzoic acid respectively.82 Collectively, hydroxycinnamic and hydroxybenzoic acids are known as phenolic acids. Phenolic acids make up approximately one-third of a group of compounds known as phenolics. Phenolic compounds are characterised by a phenol ring which is comprised of an aromatic ring and at least one hydroxyl group (C6OH). There are over 8000 phenolic compounds and there are many complex sub-classifications, the most well known being the flavanoid (C6C3C6) group of which there are over 5000 83 and include mainly flavanols, anthocyanidins, flavones, flavanones and isoflavones all of which can be further sub-categorised. Cinnamon contains many phenolic comOH O Figure 1 | Benzoic acid. O H Table 4 | Comparison of benzoate content of foods Food Quantity (mg ⁄ 100 g) Per portion (mg) Estimated portion Cinnamon 33.6 1.008 1 teaspoon (3 g) Preserved salted fish (Japan) 75.4 37.7 50 g Soft drinks 14.4 28.8 1 glass (200 mL) Nutmeg 4.41 0.1323 1 teaspoon (3 g) Cranberries (fresh) 8.9 1.78 20 g 694 Figure 2 | Cinnamaldehyde. O OH Figure 3 | Cinnamic acid. Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd Review: dietary treatment for orofacial granulomatosis pounds including phenolic acids, phenolic volatile oils, 2hydroxycinnamaldehyde and cinnamaldehyde derivatives, flavon-3-ols, catechin derivatives, 39 and proanthocyanidines.40 Phenolic compounds are recognised antioxidants and cinnamon has a very high oxygen radical absorbance capacity.84 The antioxidant capacity of cinnamic acids is greater than in the homologous benzoic acid counterparts.85 Other contributing factors Chocolate. Patients with OFG often associate symptoms with chocolate consumption and indeed patch test studies have demonstrated positive results to chocolate.11, 86–88 The largest patch test study demonstrated that, unlike benzoic acid and cinnamaldehyde, a delayed response to chocolate is more likely than contact urticaria.11 Furthermore, a case study reported recurrence of OFG symptoms whilst undergoing a patch test study to cocoa, chocolate and chocolate associated ingredients which involved no oral mucosal contact with these compounds.88 In clinical practice, symptom control of OFG can be achieved in some patients with avoidance of only chocolate and few other dietary limitations. Patients will often report a delayed reaction with re-introduction of chocolate. The relationship between chocolate and cinnamon and benzoates and the reason for sensitivity in OFG is not clear. Chocolate can on occasion be flavoured with cinnamon but is not a recognised source specifically of benzoic acid. Cocoa does however contain phenolic acids89 and is a rich source of proanthocyadinis 40, 90 as is cinnamon.91 Proanthocyadinis are degraded in the gut to smaller molecule phenolics and urinary phenolic acid excretion is increased following a ‘chocolate meal’.92 Absorption of some larger molecule phenolics have been demonstrated in oral mucosal epithelium 93 but no studies exist specifically in relation to degradation and absorption of these compounds in the mouth from chocolate. Flavourings. There are approximately 2800 approved flavourings that can be added to foods in the UK.94 However, ‘flavourings’ or ‘natural flavourings’ labelled on foods are not legally required to be specified on food ingredient labels.43 Foods often contain such flavourings and some derivatives are from cinnamon and benzoate. It is not possible to identify the quantities used or what the flavourings are unless they are stated. Consequently this is another potential source of compounds that are avoided on the cinnamon- and benzoate-free diet. Tomatoes. Patients with OFG often complain of reactions to tomato and in particular cooked tomato. Tomato contains small amounts of benzoic acid (mean levels 0.02 mg ⁄ 100 g, maximum levels 0.04 mg ⁄ 100 g.75 However, this is likely to be markedly increased in tomato puree as much of the water content is removed as part of the cooking process making it more concentrated. Raw tomato contains 97% water compared with less than 1% water in tomato puree.95 Therefore, more concentrated tomato could exacerbate symptoms in sensitive patients or there may be another tomato component that contributes to symptoms. More recently, tomatoes have also been discovered to contain cinnamic alcohol.96 Dermal exposure of benzoates and related compounds Topically applied benzoic acid dissolved in acetone is readily absorbed dermally with 43% subsequently Table 5 | Practical considerations for the dietary management of orofacial granulomatosis • The cinnamon- and benzoate-free diet is considered to be nutritionally adequate and indeed a recent service review in our own clinic demonstrated nutritional adequacy for a selection of patients following this exclusion diet. However, it is not uncommon for patients to have other food allergies ⁄ intolerances, or they may already have suspicions regarding certain foods which they feel are contributing to their symptoms. They may therefore be already avoiding a number of foods and further dietary exclusion can lead to dietary inadequacy which can be avoided with a dietary assessment prior to intervention. • Compliance can be an issue as the diet is challenging and lack of information on the cinnamon and benzoate content of foods has undoubtedly contributed to this. Long-term avoidance is not possible and indeed, many patients will unwittingly eat foods containing cinnamon and benzoates. The problem of symptom recurrence remains an ongoing issue in the clinical setting and controlled re-introduction can be difficult. Non-response and frequent recurrence suggests that there are other factors to be considered. Hence, it is not unusual for patients to complain of associations to other foods or compounds outside the spectrum of the cinnamon and benzoate restricted diet. • As quantitative information of foods in the UK is lacking, a re-introduction programme that does not specify foods but offers guidance on controlled re-exposure and ways to identify and record foods that might induce recurrence is useful. Patients should be advised to continue to avoid soft drinks, obvious sources of cinnamon and any foods they have associated previously with symptoms with a view to these being re-introduced only if symptom resolution is maintained throughout the re-introduction phase. Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd 695 H. E. Campbell et al. Table 6 | Dietary management of orofacial granulomatosis Baseline assessment Document oral lesions and site of presentation (see tool at www.kcl.ac.uk ⁄ ofg). Further assessment to include clinical photography (both portrait and profile), swabs of angles and fissures, inflammatory markers, haematinics (particularly if gastrointestinal signs which might merit further investigation). fl Dietary assessment • Check dietary exposure to cinnamon and benzoates. Rich sources are from preservatives normally in soft drinks ⁄ processed foods and cinnamon used in spiced foods and bakery. • Check for flavourings (mainly processed foods). • Check for intake of chocolate. • Check for intake of tomato, in particular tomato products which may contain tomato concentrate or puree. • Consider other sources of cinnamon and benzoates (e.g. cosmetics, hygiene products and medicines). • Consider potential contributing dietary deficiencies (e.g. anaemia related to iron, vitamin B12 or folic acid deficiency.116, 117 fl Dietary exclusion Commence dietary intervention for 12 weeks (see www.kcl.ac.uk ⁄ ofg for resources). Benefit is often seen within the first few weeks but strict adherence is necessary and it can take much longer. fl Review • Review at 4–6 week intervals and repeat objective oral assessment and dietary assessment. Consider that progression can be slow and check for dietary compliance. • After 12 weeks, if symptom improvement is not satisfactory, medical intervention can be considered. (Many patients use a less strict version of the diet in addition to medicines to control symptoms). fl Dietary re-introduction It is unrealistic to remain on a cinnamon- and benzoate-free diet indefinitely. Dietary re-introduction aims to minimise recurrence and can also help patients identify specific foods they might relate to symptoms irrespective of the cinnamon and benzoate component. A re-introduction tool is available at www.kcl.ac.uk ⁄ ofg (it is common and achievable for patients to maintain their symptoms through avoidance of soft drinks, cinnamon and chocolate). fl Dietary failure Improvement may not be seen from dietary exclusion. Consider other responsible compounds ⁄ foods or use of an elemental or whole protein liquid diet (only with the support of a dietitian). Medical intervention may be required. excreted in urine within 24 h.97 This can be increased to 61% absorption after 96 h when the dose is given in petrolatum.98 The absorption rate is site dependent with the forehead being three times more absorptive than the back.99 Ethnicity has little effect 100 but age does with 22–40 year olds having almost double the dermal absorption of benzoic acid compared to those over 65 years of age.101 Balsam of Peru and fragrance mix sensitivity are often implicated in contact dermatitis.50 The main chemical components include benzoic acid, cinnamic acid, benzyl benzoate, benzyl cinnamate, cinnamyl cinnamate, vanillin and nerolidol amongst other related phenolic compounds. Balsam of Peru is used in a wide range of products including cosmetics and per696 fumes, pharmaceuticals, food flavourings, sweets, chocolates, drinks, pastries and cigarettes. Balsam of Peru identifies fragrance sensitivity in 50% of patients with fragrance sensitivity.49 Fragrance mix contains a mix of oak moss cinnamaldehyde, cinnamic alcohol, alpha amyl cinnamic alcohol geraniol, hydroxycitronellal, isoeugenol and eugenol. Fragrance mix and balsam of Peru were number 2 and 3 respectively of the top 10 positive patch test compounds observed in 9948 patients with contact dermatitis.102 Sensitivity to either balsam of Peru or fragrance mix is thought to be indicative of possible systemic contact dermatitis reactions to a range of balsam cross reacting foods.96 These include citrus fruits, certain flavouring agents, spices including cinnamon and cloves, Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd Review: dietary treatment for orofacial granulomatosis Table 7 | Available resources (www.kcl.ac.uk ⁄ ofg) Simple dietary tool • For use in chronic OFG where the disease is not severe. (Some patients may require only minimal restriction). • For clinicians to start a patient with dietary treatment prior to referral to a dietitian. • For maintenance of stable OFG which has previously responded to a cinnamon- and benzoate-free diet. Dietary tool for the management of OFG • For use only after a full dietary assessment has been undertaken by a dietitian. • For use in severe OFG. • For use in OFG which has been unresponsive to simple dietary avoidance (1). Controlled re-introduction programme • For use following symptom improvement. May help identify safe foods and tolerance levels. Oral disease severity scoring tool • Can be used to facilitate oral examination and monitor disease progression. OFG, orofacial granulomatosis. vanilla, ketchups and other sauces ⁄ pickles, perfumed teas, tobacco, chocolate, medicines, ice creams, cola and other soft drinks, spicy foods and tomatoes.50 Many of these foods are avoided on the cinnamon- and benzoatefree diet as are added food flavourings. The implication of dermal absorption of cinnamates and benzoates from cosmetics used on other parts of the body in OFG is unclear. However, it is possible that people use their hands to apply these products and subsequent hand to mouth contact could therefore be a further source of benzoate exposure. Thus avoidance of perfumed cosmetics or other topical products with added cinnamates or benzoates, such as oral hygiene products is currently recommended in clinical practice. DISCUSSION Orofacial granulomatosis is a rare but distressing condition. The rarity of the disease has limited research and consequently the aetiology remains unclear. However, there is repeated and persuasive evidence that an allergic component may be involved and this is further supported by observed success with a cinnamon- and benzoate-free diet. Patch testing is common to try and identify sensitivities in OFG and both contact urticaria and delayed hypersensitivity have demonstrated sensitivity to a range of compounds.11 Patch test sensitivity to cinnamon, benzoates and related compounds feature repeatedly. However, the clinical relevance of these is not always clear and a large proportion of patients have demonstrated benefit to a cinnamon- and benzoate-free diet irrespective of patch test results. Whether this relates to avoidance of cinnamon and benzoates specifically, or other unidentified components of this restrictive diet is not clear. Immunosuppressive treatments are often beneficial but, due to their side effects, are used reluctantly and, not unreasonably, patients often prefer non-medicinal options. The most obvious sources of cinnamon and benzoates tend to be cinnamon added to spiced foods and bakery products and benzoates added as preservatives in soft drinks. Chocolate appears to be a further common trigger and also merits avoidance. The dietary programme of avoidance of cinnamon and benzoates in clinical practice should be undertaken for a period of 12 weeks and is likely to benefit over half of patients with one quarter requiring no further intervention. Table 5 provides guidance on practical considerations for the management of OFG and Table 6 illustrates an algorithm for the dietary management of OFG. Table 7 provides a link for tools which can facilitate this process and Figure 4 illustrates the improvement observed in a patient with OFG who was treated with a cinnamon- and benzoate-free diet. Figure 4 | Photographs of pre and postdietary intervention with a cinnamon- and benzoate-free diet (patient consent was obtained for publication of these photographs). Aliment Pharmacol Ther 2011; 34: 687–701 ª 2011 Blackwell Publishing Ltd 697 H. E. Campbell et al. Future work is required to further quantify cinnamon and benzoates in foods, understand the relationships between these dietary triggers and the potential immunological mechanisms responsible. In the meantime, the cinnamon- and benzoate-free diet offers an appealing non-medicinal treatment which benefits the majority of patients and in a large proportion, may be the only course of management required. ACKNOWLEDGEMENTS Declaration of personal interests: None. Declaration of funding interests: Helen Campbell has received research funding from the National Institute of Health Research Comprehensive Biomedical Research Centre at GSTFT and KCL, and the Foundation for Allergy Information and Research. REFERENCES 1. Campbell H, Escudier M, Patel P, et al. Distinguishing orofacial granulomatosis from crohn’s disease: two separate disease entities? Inflamm Bowel Dis 2011 [Epub ahead of print]. 2. 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