Orofacial Granulomatosis Patients Research Articles

Identification of Putative Bacterial Pathogens for Orofacial Granulomatosis Based on 16S rRNA Metagenomic Analysis.

Orofacial granulomatosis (OFG) is a chronic inflammatory disease characterized by nontender swelling of the orofacial tissues, the underlying cause of which remains unknown. Our previous study demonstrated that tooth apical periodontitis (AP) is involved in the development of OFG. To characterize the AP bacterial signatures of OFG patients and identify possible pathogenic bacteria that cause OFG, the compositions of the AP microbiotas in OFG patients and controls were compared using 16S rRNA gene sequencing. Pure cultures of putative bacterial pathogens were established by growing bacteria as colonies followed by purification, identification, and enrichment and then were injected into animal models to determine the causative bacteria contributing to OFG. A specific AP microbiota signature in the OFG patients was shown, characterized by the predominance of phyla Firmicutes and Proteobacteria, notably members of the genera Streptococcus, Lactobacillus, and Neisseria, were found. Streptococcus spp., Lactobacillus casei, Neisseria subflava, Veillonella parvula, and Actinomyces spp. from OFG patients were isolated and successfully cultured in vitro and then injected into mice. Ultimately, footpad injection with N. subflava elicited granulomatous inflammation. IMPORTANCE Infectious agents have long been considered to play a role in the initiation of OFG; however, a direct causal relationship between microbes and OFG has not yet been established. In this study, a unique AP microbiota signature was identified in OFG patients. Moreover, we successfully isolated candidate bacteria from AP lesions of OFG patients and assessed their pathogenicity in laboratory mice. Findings from this study may help provide in-depth insights into the role of microbes in OFG development, providing the basis for targeted therapeutic approaches for OFG.

Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature.

Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data. A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG. Thirty-nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson-Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4years. Histological evaluation was performed in 34/39 patients (87.2%); non-caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti-TNF-α and anti-IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response. OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long-term management.

Characterizing disease manifestations and treatment outcomes among patients with orofacial granulomatosis in China

BackgroundRacial variation exists in the incidence of orofacial granulomatosis (OFG). The epidemiology and clinical characteristics of OFG in Asian countries are poorly described.ObjectiveTo describe the epidemiologic and clinical features of OFG in China from data collected on chronic odontogenic infection and studied in actual practice regarding the long-term outcome of OFG patients receiving different treatments.MethodsData on demographics, medical history, chronic odontogenic infection, and the extent of disease were collected, and long-term outcomes after the end of treatments were evaluated.ResultsOf the 165 OFG patients, 118 (71.5%; 95% CI 64.6%-78.5%) had a chronic odontogenic infection. There was a variety of difference between OFG with and without chronic odontogenic infection. Approximately 98.3% (95% confidence interval 94.8%-100%) of OFG patients with chronic odontogenic infection who received dental treatment showed a marked response, of whom 31 patients (53.4%; 95% confidence interval 40.2%-66.7%) had complete remission.LimitationsEndoscopic investigations were not performed for most of the patients, and more detailed data were not collected, which might have demonstrated additional systemic problems.ConclusionsOFG with chronic odontogenic infection is the major clinical pattern of OFG in China, which may be a subtype of OFG. Dental treatment should necessarily be the preferred first-line therapy for such patients.

A 30-year follow-up study of patients with Melkersson–Rosenthal syndrome shows an association to inflammatory bowel disease

Background Melkersson–Rosenthal syndrome (MRS) is often classified under the term orofacial granulomatosis (OFG). A part of OFG patients eventually develop Crohn’s disease (CD), but the relationship between MRS and CD is unknown. Goals To evaluate the long-term outcomes of MRS patients, with specific interest in bowel-related symptoms. Study This follow-up study consisted of adult patients with MRS – including the monosymptomatic form, cheilitis granulomatosa (CG) – who had participated in our earlier MRS study (diagnosed after 1995 in Helsinki University Hospital). A phone interview was conducted with 27 patients (77.1% of the patients from the earlier study) and included questions about orofacial symptoms, facial palsy, intestinal symptoms, concomitant illnesses, medications, possible food avoidances and family history. Stool samples were collected to measure faecal calprotectin, a surrogate marker for intestinal inflammation. Results The median follow-up time from symptom onset was 30 years. Three (11.1%) patients had developed inflammatory bowel disease (IBD); one CG patient developed CD, and two MRS patients with facial palsy developed ulcerative colitis. In addition, several other patients reported intestinal symptoms, but the examination of faecal calprotectin did not indicate intestinal inflammation. Conclusions There was a connection between MRS and IBD – not only CD but ulcerative colitis as well. Key message Melkersson–Rosenthal syndrome (MRS) is a chronic condition often classified as a subtype of orofacial granulomatosis. Oral manifestations are common in MRS. We found a connection between MRS and inflammatory bowel disease, not only Crohn’s disease but ulcerative colitis as well.

PTH-068 The presence of perianal disease in patients with orofacial granulomatosis increases the risk of developing intestinal crohn’s disease

Introduction Orofacial Granulomatosis (OFG) is a rare chronic inflammatory condition of unknown aetiology, characterised by lip swelling, orofacial erythema and ulceration. A proportion of OFG patients present with perianal disease in conjunction with their oral disease (‘top and tail’ disease). Perianal disease occurs in approximately one-third of Crohn’s Disease (CD) patients and is associated with significant morbidity and a more severe disease course. 1 Perianal disease has been shown to occur in 12% of patients with ileal CD (L1), 41–92% of colonic CD (L2) and 15% of ileocolonic disease (L3). 2 Method We retrospectively analysed a database of OFG patients. Patients with perianal disease were identified and compared to patients without perianal disease. The Montreal classification was used to classify the sites of patient’s CD. We set out to determine how many of our OFG patients had concurrent perianal disease and how many of them developed intestinal CD. Results 263 patients with OFG were identified, of which 208 patients (79.09%) had OFG only and 55 patients (20.91%) had concurrent intestinal CD. 36 patients (13.69%) had intestinal CD and no perianal disease. 19 patients ((7.22%) 13 male, median age 38 (IQR 25–49)) had intestinal CD and concurrent perianal disease. Within the perianal group, all patients had concurrent intestinal CD. The commonest sites were colonic (L2)(8/19; 42.11%) and ileocolonic (L3)(8/19; 42.11%). The ileum (L1) was affected in 1 patient (1/19; 5.26%) and 2 patients had concomitant upper gastrointestinal CD with ileocolonic disease (L3+L4)(2/19; 10.53%). The presence of OFG and perianal disease significantly increased the chances of developing intestinal CD (OR = 222, p = 0.0002, 2-tail Fisher Test). In the perianal group, 11/19 patients (11/19; 57.89%) were diagnosed with CD prior to developing OFG. The median time to diagnosis of OFG was 10 years after the diagnosis of intestinal CD. Conclusion Perianal disease in Crohn’s disease is common and is associated with a more severe disease course. 1 Perianal disease in OFG patients is less common, however, where it does occur it is always associated with intestinal CD in our cohort. Therefore, these patients should be investigated accordingly. The diagnosis of OFG was usually made later in the course of intestinal Crohn’s suggesting it is a later development. Disclosure of interest None Declared. References Ardizzone S, Porro GB. Perianal Crohn’s disease: overview. Dig Liver Dis . 2007; 39 :957–958 Schwartz D, Loftus EV, Tremaine WJ, et al . The natural history of fistulising Crohn’s disease in Olmsted County, Minnesota. Gastroenterology 2002;122:875–880

A rare case of primary orofacial granulomatosis of gingiva during pregnancy

Orofacial granulomatosis (OFG) comprises a group of diseases characterized by noncaseating granulomatous inflammation affecting the soft tissues of the oral and maxillofacial region. It is important to establish the diagnosis accurately because this condition is sometimes a manifestation of many systemic conditions like Crohn's disease or sarcoidosis. The clinical outcome of OFG patients continues to be unpredictable. Current therapies remain unsatisfactory. This article reports a rare case of isolated OFG with langhans type giant cells and inflammatory infiltrate without any systemic involvement, in which the condition was a manifestation of pregnancy. The diagnostic approach to and the treatment of OFG are reviewed.

Characterisation of a Swedish cohort with orofacial granulomatosis with or without Crohn's disease

To compare oral manifestations in a Swedish cohort of patients with orofacial granulomatosis with or without Crohn's disease and to assess NOD2 polymorphisms in the two groups. Twenty-nine patients with orofacial granulomatosis were included. Demographics, disease history, clinical features and concurrent Crohn's disease were recorded. DNA was extracted from buccal swabs and examined for NOD2 variants Arg702Trp, Gly908Arg and Leu1007fsinsC, all previously linked to gastrointestinal Crohn's disease. Twelve of 29 patients were diagnosed with coexisting gastrointestinal Crohn's disease, and of whom 21 were males. Symptom duration was significantly longer for the orofacial granulomatosis group com-pared to the group with coexisting Crohn's disease (P < 0.0001). The orofacial granulomatosis patients also perceived their overall discomfort, aesthetic problems and social discomfort as more severe. No significant differences in the clinical presentation of oral lesions between the two groups were found. None of the patients with orofacial granulomatosis carried any of the NOD2 variations, whereas four of the 12 patients with coexisting Crohn's disease had a NOD2 variant (Arg702Trp). The two patient groups had similar phenotypic characteristics but seemed to have genotypic differences regarding NOD2. The Swedish cohort differed in their clinical characteristics from patients reported in other geographical regions.

Clinical behaviour and long‐term therapeutic response in orofacial granulomatosis patients treated with intralesional triamcinolone acetonide injections alone or in combination with topical pimecrolimus 1%

Orofacial granulomatosis (OFG) is a relapsing inflammatory disorder of unknown aetiology and non-standardized treatment protocols. The aim of this study was to assess the clinical behaviour and long-term therapeutic response in OFG patients treated with intralesional triamcinolone acetonide (TA) injections alone or in combination with topical pimecrolimus 1%, as adjuvant, in those patients partially responders to TA. We analysed data from 19 OFG patients followed-up for 7 years. Demographic characteristics, clinical behaviour and long-term therapeutic response were investigated. Eleven (57.9%) OFG patients treated with intralesional TA injections therapy reached first complete clinical remission in a mean time of 10 ± 2.2 (95% CI, 8.5-11.5) weeks, while eight (42.1%) patients, partially responders to intralesional TA injections, were treated with TA injections plus topical pimecrolimus 1%, as adjuvant, achieving complete clinical remission in a mean time of 29.8 ± 7.8 (95% CI, 23.2-36.3) weeks. Relapses occurred in four TA responder patients with a disease-free time of 35.8 ± 8.7 (95% CI, 21.9-46.4) weeks and in five patients treated with TA and topical pimecrolimus 1% with a disease-free time of 55.8 ± 18.5 (95% CI, 32.8-78.8) weeks. Patients were followed-up for a mean time of 56.3 ± 18.2 (95% CI, 47.6-65.1) months. At last control, all 19 patients were in complete clinical remission. These preliminary data suggest that intralesional TA injections still represent a mainstay in the treatment of OFG. It is unclear the role of topical pimecrolimus, as adjuvant, in leading OFG patients, partly responders to intralesional TA injections, to a complete clinical remission.

Clinical evidence for allergy in orofacial granulomatosis and inflammatory bowel disease

BackgroundOrofacial granulomatosis (OFG) causes chronic, disfiguring, granulomatous inflammation of the lips and oral mucosa. A proportion of cases have co-existing intestinal Crohn’s disease (CD). The pathogenesis is unknown but has recently been linked to dietary sensitivity. Although allergy has been suggested as an aetiological factor in OFG there are few published data to support this link. In this study, we sought clinical evidence of allergy in a series of patients with OFG and compared this to a series of patients with inflammatory bowel disease (IBD) without oral involvement and to population control estimates.MethodsPrevalence rates of allergy and oral allergy syndrome (OAS) were determined in 88 patients with OFG using questionnaires, skin prick tests, total and specific serum IgE levels. Allergy was also determined in 117 patients with IBD without evidence of oral involvement (79 with CD and 38 with ulcerative colitis (UC)).ResultsPrevalence rates of allergy in patients with OFG were significantly greater than general population estimates (82% versus 22% respectively p = <0.0005). Rates of allergy were also greater in those with CD (39%) and, interestingly, highest in those with OFG and concurrent CD (87%). Conversely, whist OAS was common in allergic OFG patients (35%) rates of OAS were significantly less in patients with concomitant CD (10% vs 44% with and without CD respectively p = 0.006). Amongst CD patients, allergy was associated with perianal disease (p = 0.042) but not with ileal, ileocolonic or colonic disease location. Allergy in UC (18%) was comparable to population estimates.ConclusionWe provide compelling clinical evidence for the association of allergy with OFG whether occurring alone or in association with CD. The presence of gut CD increases this association but, conversely, reduces the expression of OAS in those with atopy. Interestingly, there is no evidence of increased allergy in UC.

Experience with anti-TNF-α therapy for orofacial granulomatosis

Orofacial granulomatosis (OFG) can be challenging to treat and experience with anti-TNF-α therapy is limited. We report our experience with infliximab (IFX) and adalimumab (ADA) for OFG in 14 patients, the largest reported series to date. A review of patients receiving induction and maintenance IFX for OFG +/- Crohn's disease (CD) for active oral disease failing other therapies was performed. Clinical response defined by global physician assessment, aided by oral disease activity scores, was assessed at 2 months, 1 and 2 years. ADA was considered for patients failing IFX. Adverse events were recorded. Predictors of need for anti-TNF-α therapy were determined by comparison with OFG patients not requiring anti-TNF-α from our overall OFG database (n = 207). Fourteen patients (9 men) were treated with IFX [OFG only (n = 7), OFG with CD (n = 7)]. Nine patients received concomitant immunosuppression. Median duration of treatment was 18 months. Shortterm response was achieved in 10/14 (71%) patients. Eight of 14 (57%) and 4/12 (33%) patients remained responsive at 1 and 2 years, respectively. Two patients who failed IFX responded to ADA. Factors predicting need for anti-TNF-α therapy were oral sulcal involvement, intestinal CD and a raised C-reactive protein (CRP). Oral sulcal involvement predicted response at 1 and 2 years. Intestinal CD did not predict response. The only significant adverse event was an IFX infusion reaction. IFX provided good short-term response for most OFG patients; however, a significant proportion lost response long term. Adverse events were uncommon. Patients failing IFX may respond to ADA.

PWE-031 Orofacial granulomatosis and anti-tumour necrosis factor therapy: a case series

<h3>Introduction</h3> Anti-tumour necrosis factor (TNF) therapy (infliximab (IFX) or adalimumab (ADA)) has been used as an alternative treatment in patients with Orofacial granulomatosis (OFG) failing conventional therapies, with evidence of promising clinical efficacy. However, concerns regarding safety have been raised and experience is limited. We report on the short and long-term efficacy and safety of anti-TNF therapy for OFG in this case series of 15 patients, the largest reported series to date. <h3>Methods</h3> A retrospective study of all patients who received anti-TNF therapy for OFG±Crohn9s disease (CD) was performed. Diagnoses of OFG and CD were made on conventional clinical and histological grounds. Demographics, clinical details, oral disease activity scores (ODAS) and laboratory results were obtained from patient records. Patients were considered for induction and maintenance anti-TNF therapy after failing other recognised OFG therapies. Clinical response was assessed at 4 months, 1 and 2 years after anti-TNF initiation. Regular monitoring for adverse effects was performed. <h3>Results</h3> Of 207 patients in our OFG clinic database, 15 (9 males) were treated with anti-TNF therapy between 2001 and 2009 (OFG only (n=7), OFG with CD (n=7), OFG with perianal disease (n=1)). Median age at OFG onset and at anti-TNF initiation were 26 years and 36 years. Median time between OFG onset and presentation to clinic was greater for the anti-TNF treated OFG patients than those not requiring anti-TNF (5 vs 2 years, p=0.001). Mean rank ODAS at initial presentation to clinic was higher in anti-TNF treated group than those not requiring anti-TNF (p&lt;0.05). First line anti-TNF therapy was IFX (n=14) and ADA (n=1). Ten patients received concomitant immunosuppression. Median duration of anti-TNF therapy was 12 months (range; 1 dose to 84 months). Short-term response was achieved in 9/15 (60%) patients. Eight of 15 (53%) and 4/13 (31%) patients remained responders at 1 and 2 years follow-up. Two patients failed IFX therapy and were treated with ADA; one remains responsive at 18 months, the other lost response at 12 months. Oral sulcal involvement was the only predictor for response at 1 and 2 years (p&lt;0.05). Concurrent CD did not predict response. The only adverse event leading to cessation of anti-TNF therapy was a patient with an IFX infusion reaction. <h3>Conclusion</h3> Anti TNF therapy has good short and reasonable long-term clinical efficacy (60% and 31%) for patients with OFG failing other therapies. It appears to be safe with a good side effect profile. OFG patients who fail IFX may respond to ADA.

PWE-036 Allergy in orofacial granulomatosis and inflammatory bowel disease

<h3>Introduction</h3> Orofacial granulomatosis (OFG), including oral Crohn9s disease (CD) is a chronic inflammatory condition presenting characteristically with lip swelling but also affecting a number of other sites in the oral cavity. Bouts of acute swelling and frequently reported atopy suggest an allergic component. There is evidence for dietary triggers with objective improvement on a cinnamon and benzoate-free diet.1 The Oral Allergy Syndrome (OAS) is a well recognised condition with a clear immunological pathogenesis.2 There are similarities between OAS and OFG in terms of symptoms, triggers and treatment regimes. The role of allergy in inflammatory bowel disease (IBD) remains unclear with conflicting data in the literature. <h3>Methods</h3> We performed skin prick tests to common allergens in a cohort of 88 patients with biopsy proven OFG between August 2007 and July 2009. We measured Specific serum IgE levels to relevant allergens and total serum IgE levels. The prevalence of OAS in patients with OFG was also determined. For comparison, a group of 121 consecutive patients with a confirmed diagnosis of IBD without oral involvement were also studied. <h3>Results</h3> The incidence of clinical allergy of 82% in the OFG cohort was considerably higher than the 4–20% incidence reported in the general population. OAS incidence was 28%, also significantly higher than population estimates. OFG patients with disease onset below 30 years and no concomitant CD had a significantly higher incidence of allergy (95%) and OAS (38%). ImmunCAP and total serum IgE levels also confirmed increased allergy. Allergy in CD (39%) was higher than the general population, especially in the colonic (43%) and ileocolonic (52%) compared to the ileal group (24%). Allergy in Ulcerative colitis was comparable to population estimates (18%). <h3>Conclusion</h3> Patients with OFG have an astonishingly high incidence of allergy. A large proportion of patients have OAS. A novel subepithelial dendritic B cell population demonstrating class switching to IgE, described in oral biopsies from patients with OFG by our group, could provide the link between dietary antigens, chronic oral inflammation and symptoms of hypersensitivity.3 The comparative significance of the differences in allergy in the different IBD groups remains unclear.

Orofacial granulomatosis – a 20‐year review

Orofacial granulomatosis (OFG) is the presence of persistent enlargement of the soft tissues of the oral and maxillofacial region, characterized by non-caseating granulomatous inflammation in the absence of diagnosable systemic Crohn's disease (CD) or sarcoidosis. Over 20 years have passed since OFG was first described and an extensive review of the literature reveals that there is no consensus whether OFG is a distinct clinical disorder or an initial presentation of CD or sarcoidosis. Furthermore, the precise cause of OFG is still unknown although several theories have been suggested including infection, genetic predisposition and allergy. The clinical outcome of OFG patients continues to be unpredictable. Current therapies remain unsatisfactory. Regular clinical review is indicated to identify the development of gastrointestinal or systemic involvement. The aim of this review was to analyse the developments in our understanding of the aetiology, pathogenesis and treatment protocols, with particular emphasis on management and outcomes of OFG since this entity was first described in 1985.

Expression of protease‐activated receptor‐1 and ‐2 in orofacial granulomatosis

Orofacial granulomatosis (OFG) is a rare condition characterized by non-caseating granulomas in the orofacial region. Protease-Activated Receptors (PARs) play a role in inflammatory diseases in diverse human tissues. The aim of the study was to investigate the expression of PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 in tissues taken from OFG patients. PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 expression was evaluated by immunohistochemistry in biopsies taken from oral Crohn's disease (five cases), Melkersson-Rosenthal syndrome (MRS) (six cases), cheilitis granulomatosa (five cases) and normal oral mucosa (five cases). PAR-1 was observed in mononuclear inflammatory cells in edematous/lichenoid lesions, whereas a strong PAR-2 immunostaining was detected in epithelioid histiocytes and giant cells in granulomatous lesions, irrespective of the clinical features (Crohn vs MRS). MMPs and COX-2 were expressed in the inflammatory component of edematous/lichenoid lesions and markedly overexpressed in granulomatous lesions. COX-1 was weakly and variably expressed in both edematous/lichenoid and granulomatous lesions. Thus, PAR-1 and PAR-2 expressions were related to the intensity and type of inflammatory response but not to the type of clinical lesion. Simultaneous overexpression of PARs, MMPs and COXs suggests synergism among these proinflammatory receptors and enzymes.

Lip impressions: a new method for monitoring morphological changes in orofacial granulomatosis

To develop and evaluate an objective method for assessing lip size and treatment-related morphological changes in orofacial granulomatosis (OFG) patients. Patients with swollen lips because of OFG (n=21) were enrolled. A light-body polyvinylsiloxane material was used to take lip impressions before and after treatment (n=10), or during treatment (n=11). Plaster models were cast from the impressions and the lips were measured using callipers. The intra-examiner and inter-examiner reproducibility of the technique were assessed. OFG patients had significantly larger lips than controls (P<0.0001). The coefficient of variation on repeated measurements of the same impression was 1.6% and for duplicate impressions was 2.6%. Significant reduction in lip size was shown in all 10 patients after diet restriction (P<0.002). Seven of 11 patients whose impressions were taken at least 3 months after the initiation of cinnamon- and benzoate-free diet also showed reduction in lip size during follow up (P<0.002). Serial lip impressions appear to be reliable for routine quantification of morphological changes of the lips in OFG patients. We present a new reproducible and sensitive method for assessing changes in lip size in response to treatment in OFG.

Oral Biopsies from Patients with Orofacial Granulomatosis with Histology Resembling Crohnʼs Disease Have a Prominent Th1 Environment

Orofacial granulomatosis (OFG) is an idiopathic inflammatory disorder of children and young adults whose clinical symptoms include swelling of the lips or face, mucosal nodularity (cobblestoning), mucosal tags, hyperplasia of the gingivae, and aphthous oral ulcers. Whether some OFG patients with clinical and histological characteristics resembling Crohn's disease (CD) are a special group (oral CD) or true CD patients with symptoms reaching all the way to the oral mucosa remains to be determined. In this study oral biopsies from 10 patients with OFG were analyzed for the presence of T cells, T-cell subsets, B cells, and macrophages, as well as cytokines (IL-4, IL-10, IFN-gamma, IL-12, and TNF-alpha), chemokines (RANTES and MIP-1alpha), and chemokine receptors (CCR3, CCR5, and CXCR3). For comparison, oral tissues from 7 patients with other granulomatous diseases were included. Compared with the non-OFG group, the OFG group had raised levels of CD4(+) T cells, IFN-gamma, IL-10, and RANTES but reduced levels of CD68(+) macrophages outside the granulomas, whereas within the granulomas the levels of CD3(+) and CD4(+) T cells and of IFN-gamma were raised, but the levels of IL-4 were decreased. These data are indicative of a Th1 environment within the oral OFG tissues, which resembles that already observed in gut CD tissues. Therefore, it can be concluded that some OFG patients have both histopathological and immunopathological features that resemble those observed in CD patients.