Pritash Patel

Gut-associated lymphoid tissue contains the molecular machinery to support T-cell-dependent and T-cell-independent class switch recombination

A PRoliferation-Inducing Ligand (APRIL) is a secreted cytokine member of the tumor necrosis factor family. It is a B-cell survival factor that also induces class switch recombination (CSR) toward immunoglobulin A (IgA), independent of T cells. It is therefore an important contributor to the maintenance of the mucosal immunological barrier, which has been linked to a putative extrafollicular inductive phase of the IgA response in lamina propria. By immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) on microdissected tissue from normal human gut, we observed APRIL expression, together with TACI (transmembrane activator and CAML interactor) and BCMA (B-cell maturation antigen), in gut-associated lymphoid tissue (GALT), lamina propria, and in the epithelium of stomach, small and large intestine, and rectum. However, no activation-induced cytidine deaminase (AID) expression (an absolute requirement for class switching) was detected in lamina propria by IHC or qRT-PCR. APRIL and its receptors were only observed alongside AID in GALT, showing that GALT contains the apparatus to support both T-independent and T-dependent routes to IgA CSR.

Distinguishing orofacial granulomatosis from crohn's disease: Two separate disease entities?

Background: Orofacial granulomatosis (OFG) is a rare chronic inflammatory disease of unknown etiology sharing histological features with Crohns disease (CD). This study aimed to 1) define the clinical presentation of OFG, 2) establish differentiating features for those with CD, 3) examine if onset of OFG is predictive of CD, and 4) establish differentiating features for children. Methods: Data were extracted from medical notes (n = 207) for demographics, clinical features, blood parameters, diagnosis of CD, and treatments for patients with OFG. Results: Ninety‐seven patients (47%) were female. The lips (184/203; 91%) and buccal mucosa (151/203; 74%) were mainly affected. Forty‐six (22%) had intestinal CD. Ulcers (24/46; 46% versus 29/159; 15%, P = <0.001) were more common in patients with CD as was a raised C‐reactive protein (24/33; 73% versus 60/122; 49%, P = 0.016) and abnormal full blood count (19/41; 46% versus 35/150; 23%). The buccal‐sulcus (12/44; 27% versus 20/158; 13%, P = 0.019) was more often affected in those with CD. Half the patients with CD were diagnosed prior to onset of OFG. The remainder were diagnosed after. The incidence of CD is similar for children (16/69; 23%) and adults (29/132; 22%), although oral onset in childhood is more likely to occur prior to diagnosis of CD. Conclusions: OFG mainly presents in young adults with lip and buccal involvement. Abnormalities in inflammatory markers, hematology and oral features of ulceration, and buccal‐sulcal involvement are factors more commonly associated with CD. Initial presentation of OFG does not necessarily predict development of CD, although this is more likely in childhood. (Inflamm Bowel Dis 2011;)

Review article: cinnamon- and benzoate-free diet as a primary treatment for orofacial granulomatosis.

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.

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.

Subepithelial dendritic B cells in orofacial granulomatosis

Background: Orofacial granulomatosis (OFG) is a chronic, disfiguring, granulomatous inflammation of the lips and oral mucosa. The pathogenesis is unknown, but it has been linked previously to Crohns disease (CD) and more recently to dietary sensitivity. The oral mucosa is an immunologically responsive site associated with the generation of protective mucosal and systemic immune responses to vaccination and also hyperresponsiveness to allergens in some individuals. Classically, immune responses in oral mucosa are considered to be mediated by mucosa‐associated lymphoid tissues (MALT), secondary lymphoid follicles that are intimately associated with epithelia. Methods: Immunohistochemistry was used to investigate the inflammatory infiltrate in OFG and control tissue samples. Polymerase chain reaction (PCR), cloning of PCR products, and sequencing were used to characterize the local immunoglobulin gene profile in OFG. Results: We describe large, active, dendritic B cells in oral mucosa that were not associated with any organized lymphoid tissues in the local subepithelial microenvironment. They express activation induced cytidine deaminase, which is essential for immunoglobulin gene diversification by somatic hypermutation and class switch recombination. IgE is also expressed by these B cells. They do not align with any other previously described B‐cell subset in secondary lymphoid tissues in terms of morphology, proliferative activity, or phenotype. Conclusions: These subepithelial dendritic B cells may contribute to the immune responsiveness of the oral mucosa, including IgE‐mediated allergic responses. In patients with OFG, further understanding of the role these cells play in oral immunity may lead to novel therapeutic possibilities. (Inflamm Bowel Dis 2010)

Granulomatosis with polyangiitis involves sustained mucosal inflammation that is rich in B-cell survival factors and autoantigen

OBJECTIVE Granulomatosis with polyangiitis (GPA) is a rare chronic autoimmune disease that may be triggered by upper airway infection. ANCAs specific for PR3 that is expressed by activated neutrophils and macrophages are associated with GPA. Our aim was to investigate regional immune mechanisms that might induce or support the autoimmune response in GPA. METHODS Biopsy samples from 77 patients including 8 with GPA were studied by immunohistochemistry. B-cell homing subsets in blood samples from 16 patients with GPA and 11 healthy controls were studied by FACS. The distribution of B-cell clones was searched in paired biopsies and blood samples from one patient by analysing immunoglobulin heavy chain gene (IGH) junctional sequences. RESULTS Activated B cells were located alongside PR3-expressing cells and B-cell survival factors BAFF and APRIL in mucosa from patients with GPA. We detected APRIL production by the granulomas and giant cells. B cells were proliferating in all cases and persistent for 5 years in biopsies obtained from one patient. However, there was no evidence of B-cell clones from the mucosal biopsies circulating in peripheral blood in GPA or any numerical or proportional change in B-cell subsets expressing markers of regional homing in blood in GPA. CONCLUSIONS Our study illustrates chronically activated B cells alongside autoantigens and B-cell survival factors in the mucosa in GPA.

Hyperbaric oxygen as a treatment for malabsorption in a radiation-damaged short bowel.

Radiation enteritis can be challenging to diagnose and treat. We report the case of a 44-year-old woman who was diagnosed with a squamous cell carcinoma of the cervix in 1978 and treated with hysterectomy and post-operative radiotherapy. Over the next 20 years she required multiple intestinal operations resulting in short bowel syndrome. She became symptomatic of severe hypomagnesaemia which could not be corrected with oral supplementation and which required intravenous magnesium sulfate every 5-7 days for an 11-month period. However, following 25 sessions of hyperbaric oxygen therapy, she was able to discontinue intravenous magnesium and maintain her serum magnesium level with oral treatment. Her weight and stoma output improved. For over 4 years subsequent to this therapy she has not required further intravenous magnesium although has needed temporary nutritional support. Her case is complicated by vitamin A, B and D deficiencies.

Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis.

Background:Orofacial granulomatosis (OFG) is a rare, inflammatory disorder of the mouth, in which some patients also have intestinal Crohns disease (CD). The etiology remains largely unknown, although there is a high prevalence of atopy, and oral granulomas are also seen in other immune disorders particularly CD and sarcoidosis. We investigated whether genetic variants associated with an increased risk of CD, sarcoidosis, or atopy were also associated with susceptibility to OFG. Methods:Patients were stratified clinically as isolated oral manifestations (OFG only) or concurrent intestinal CD (OFG+CD). We genotyped 201 patients and 1023 healthy controls for risk variants in NOD2, IRGM, IL23R, ATG16L1 (CD), BTNL2 (sarcoidosis), and FLG (atopy). The coding regions of the NOD2 gene were screened for rare, potentially pathogenic variants in OFG. Results:A combined analysis of 3 CD-risk variants in NOD2 showed no association with any OFG subgroup. NOD2 p.L1007insC was associated with OFG+CD (P = 0.023) and IL23R p.R381Q with all OFG (P = 0.031). The sarcoidosis risk variant rs2076530 in BTNL2 was associated with all OFG (P = 0.013). We identified 7 rare missense NOD2 alleles in 8 individuals with OFG, 4 OFG-only patients and 4 patients with OFG+CD. There was a significant enrichment of NOD2 variants in the OFG+CD group compared to the OFG-only group (P = 0.008, common variants; P = 0.04, all common and rare variants). Conclusions:Our findings suggest that genetic variants in NOD2 are only associated with OFG in patients with concurrent intestinal disease. A genome-wide association scan is needed to fully define the genetic architecture of OFG.

Azathioprine is effective for oral involvement in Crohn's disease but not for orofacial granulomatosis alone

BACKGROUND There have been no previous reports assessing the effectiveness of azathioprine (AZA) in the treatment of orofacial granulomatosis (OFG). This report is a review of patients receiving AZA for active OFG with or without concomitant gut Crohns disease (CD) in a specialist tertiary referral centre. METHODS Clinical response was defined by Global Physician Assessment at 4-, 12- and 24-month follow-up and a standardised oral disease activity score (ODAS). RESULTS Sixty of 215 patients seen with OFG in our clinic over a 12-year period were treated with AZA. Of these, 22 had concomitant CD. The proportion of patients responding to AZA with a diagnosis of CD/OFG vs. OFG only at 4, 12 and 24 months were 54% vs. 21% (P = 0.03), 59% vs. 21% (P = 0.003) and 41% vs. 24% (P = 0.16), respectively. A statistically significant difference was seen between starting and follow-up ODAS scores at 4 months in the CD/OFG group which was not observed in the OFG only group. Factors predicting a need for AZA included a diagnosis of intestinal CD, sulcal swelling, sulcal ulcers and upper lip involvement. The factor predicting response to treatment was a diagnosis of CD at 12 months of follow-up. No difference in the number of adverse effects was observed between the two groups of patients. CONCLUSIONS AZA is significantly more effective in the treatment of oral disease with a concurrent diagnosis of CD rather than in the treatment of OFG alone.

OC-095 A clinical overview of the presentation and management of orofacial granulomatosis in a combined oral medicine and gastroenterology clinic

Introduction Orofacial granulomatosis (OFG) is a rare chronic inflammatory disease of unknown aetiology sharing histological features with gut Crohns disease (CD). A notes review of 207 patients with OFG aimed to define the common presentation of this condition and establish differentiating features between those with and without concurrent diagnosis of CD. Methods Data were extracted for age of onset, gender, clinical features, blood parameters, concurrent CD and treatments used. Diagnosis of CD was established by standard criteria. Results Ninety-seven out of 207 patients (47%) were female. Median age of disease onset was 23 years (range 2–73 years). Referrals were mainly sourced from maxillo-facial surgeons (31%) and gastroenterologists (19%). The buccal mucosa (74%) and lower lip (68%) were the most common sites involved followed by gingivae (63.5%) and upper lip (61%). Forty-six (22%) had CD. Ulcers (46% vs 15%, p<0.001) and mucosal scarring (20% vs 5%, p<0.001) were more common in patients with CD than in those without as was a raised C reactive protein (73% vs 49%, p=0.016), abnormal full blood counts (46% vs 23%) and low haemoglobin (31% vs 11%). The sulcus (27% vs 13%, p=0.019) and fauces (4% vs 0%, p=0.008) were significantly more likely to be affected in those with CD. Of the patients with concurrent CD, half were diagnosed with this prior to onset of OFG symptoms. Conversely 42.5% had OFG symptoms prior to diagnosis of CD. The remaining patients (7.5%) presented with symptoms and were diagnosed with CD within the same year. The predominant treatment used (86%) was the cinnamon and benzoate free diet. Topical treatments including antifungal and steroidal creams, ointments, mouthwashes and intralesional steroid injections were used in 64% of cases. Azathioprine was used in 39% of patients and anti TNF α therapy in 7.5% of patients. Only 3% of patients required cheiloplasty. Conclusion OFG most commonly presents with buccal and lower lip involvement. Abnormalities in inflammatory markers, haematinic deficiencies and oral presentation of ulceration and scarring are all factors which can increase the likelihood of concurrent CD. Initial presentation of OFG is not necessarily predictive of further development of CD.