Rishi Goel

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.

Optimizing the use of thiopurines in inflammatory bowel disease

Immunomodulator drugs, of which thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of thiopurine therapy are also discussed.

Thiopurines Dosed to a Therapeutic 6-Thioguanine Level in Combination with Adalimumab Are More Effective Than Subtherapeutic Thiopurine-based Combination Therapy or Adalimumab Monotherapy During Induction and Maintenance in Patients with Long-standing Crohnʼs Disease

Background: The benefit of concomitant immunomodulation with adalimumab (ADA) in Crohns disease is poorly understood. We aimed to compare ADA monotherapy with combination therapy with thiopurines, stratified by thioguanine nucleotides (TGNs). Methods: Retrospective observational study of ADA induction and maintenance. Thiopurines were classified according to TGNs (>235 pmol/8 × 108 red blood cell therapeutic). Results: At induction, response was more frequent in combination than ADA monotherapy (83% versus 61%, P = 0.02) and with therapeutic compared with subtherapeutic TGNs (87% versus 70% P = 0.011). Among 280 maintenance semesters in 91 patients, remission was higher with combination than monotherapy (81% versus 60%, P < 0.0001) and therapeutic versus subtherapeutic TGNs (85% versus 58%, P = 0.004). Therapeutic TGN (odds ratio [OR] 4.32, 95% CI, 1.41–13.29, P = 0.01) and albumin (OR 1.09, 95% CI, 1.01–1.18, P = 0.03) were predictors of response to induction. Therapeutic TGN (OR 3.71, 95% CI, 1.87–7.34, P < 0.0001) and ileal disease (OR 0.21, 95% CI, 0.08–0.57, P = 0.002) were predictors of remission semesters. Concomitant immunomodulation at induction was associated with longer time to failure (69 versus 36 months, P = 0.009). Therapeutic TGN at induction (P = 0.03) and male sex (P = 0.026) were associated with time to failure. Conclusions: Combination therapy was superior to ADA monotherapy for induction and during maintenance. This benefit was increased further when thiopurines resulted in therapeutic TGNs. Early use of adequately dosed thiopurines (≥3 months before starting ADA) was associated with improved clinical outcomes.

Orofacial Fistulae Associated with Crohn’s Disease

A 28-year-old man presented with facial lesions with discharge that had developed 6 years after a diagnosis of Crohns disease. MRI and radiography revealed three orocutaneous fistulae arising from inflamed oral mucosa associated with dental disease.

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.

Thioguanine in inflammatory bowel disease: Long-term efficacy and safety

Background Thioguanine (TG) is efficacious in inflammatory bowel disease (IBD), but its toxicity, particularly nodular regenerative hyperplasia (NRH) of the liver, has limited its use. We assessed the long-term clinical outcomes and safety of TG in patients whom were intolerant or refractory to conventional immunomodulators. Methods This is a retrospective, single-centre study of IBD patients treated with TG from 2001–2013. Response was defined as clinical remission (Harvey–Bradshaw Index < 5 for Crohn’s disease (CD), Simple Clinical Colitis Activity Index < 4 for ulcerative colitis (UC)) without corticosteroids or, if receiving anti-tumour-necrosis-factor (anti-TNF) therapy, absence of dose escalation. We recorded TG failure, withdrawal and adverse events. Patients were monitored with biochemistry, liver biopsy and/or magnetic resonance imaging (MRI). Results 54 patients (47 CD and 7 UC) whom received TG (mean dose: 27 mg/d (range: 20–40 mg/d)) as monotherapy (n = 36) or concomitantly with anti-TNF (n = 18) for a median inter-quartile range of 16 (5–37) months (126 patient-years of follow-up). 32 (59%) patients responded to TG at 6 months and 23 (43%) at 12 months. Pancreatitis did not recur amongst the 19 patients with prior thiopurine-induced pancreatitis. 16 (30%) patients ceased TG due to intolerance or toxicity (four serious); NRH was not observed. 6-thioguanine nucleotide concentrations did not correlate with efficacy nor with toxicity. Conclusions TG was efficacious and well tolerated in one out of two patients who had previously failed conventional immunomodulators. NRH did not occur.

Video capsule endoscopy for the investigation of the small bowel: primary care diagnostic technology update

#### Clinical Question How effective is video capsule endoscopy in investigating the small bowel compared to traditional investigations? Video capsule endoscopy (VCE) was first developed in 1999 and has been in widespread use since the late 2000s. It is primarily used for investigation of the small bowel and has the advantage of being able to accurately examine the small bowel which cannot be easily reached by standard endoscopy methods. The major advantages are that it is non-invasive, safe, and convenient for the patient, and involves no ionising radiation. Additionally, VCE can provide some information on the rest of the gastrointestinal (GI) tract as well as basic information on small bowel transit time. Previously the small bowel could only be imaged by contrast small bowel studies (for example, barium/gastrograffin) and more recently by cross-sectional imaging such as computed tomography (CT) and Magnetic resonance imaging (MRI). CT and contrast small bowel meal are relatively insensitive for examining the small bowel. Small bowel ultrasound, CT enterography/enterocolysis and MRI enterography/enterocolysis are readily available and can be performed to visualise the small bowel, but requires a radiologist with specialist experience for interpretation of the results. CT has the limitation of exposure to ionising radiation. Available examinations to investigate the small bowel mucosa are by anterograde, that is, per oral push enteroscopy, single/double balloon enteroscopy, and retrograde, that is, per rectum ileoscopy, however, these are not widely available, invasive, and are technically challenging. However, these investigations do allow therapy such as the treatment of angiodysplasia and small lesion removal where necessary. They are generally reserved for cases where non-invasive investigation has confirmed an abnormality. Disadvantages of VCE are that therapeutic work cannot be performed and biopsies cannot be obtained. New developments in VCE have led to new capsules which can be used …

Cyclist: slightly foxed

Abnormal liver function tests (LFTs) are a common cause for referral to hepatology outpatient departments. Cross-sectional imaging may reveal a liver lesion. We report the case of a 33-year-old man who presented with abdominal pain and deranged LFTs and was found to have a large liver cyst on ultrasound scanning. Specific Echinococcus multilocularis serology testing was positive and he underwent triple phase CT, MRI and positron emission tomography-CT to further characterise the lesion. He was treated with long-term albendazole with subsequent improvement in symptoms, blood results and cyst size on follow-up imaging.

Streptococcus salivarius - a potential salivary biomarker for orofacial granulomatosis and Crohn's disease?

Objective Orofacial granulomatosis (OFG) is a rare disease characterised by chronic, non-caseating, granulomatous inflammation primarily affecting the oral cavity. Histologically, it is similar to Crohn’s disease (CD) and a proportion of patients have both OFG and CD. The cause of OFG remains elusive but it has been suggested that microbial interactions may be involved. The aim of this study was to compare the salivary microbial composition of subjects with OFG and/or CD and healthy controls. Design 261 subjects were recruited, of whom 78 had OFG only, 40 had both OFG and CD, 97 had CD only with no oral symptoms and 46 were healthy controls. Bacterial community profiles were obtained by sequencing the V1-V3 region of the 16S rRNA gene. Results There were no differences in richness or diversity of the salivary bacterial communities between patient groups and controls. The relative abundance of the Streptococcus salivarius-group were raised in patients with OFG or CD only compared to controls while that of the Streptococcus mitis -group was lower in CD compared to both OFG and controls. One S. salivarius oligotype made the major contribution to the increased proportions seen in patients with OFG and CD. Conclusion The salivary microbiome of individuals with OFG and CD was similar to that found in health although the proportions of S. salivarius, a common oral Streptococcus were raised. One specific strain-level oligotype was found to be primarily responsible for the increased levels seen.

A jackhammer in the gullet: high amplitude oesophageal contractions as a cause of atypical chest pain.

Chest pain is a common cause for referral to emergency departments. A proportion of these patients have non-cardiac chest pains with normal investigations. Such patients should be considered for oesophageal studies as these may reveal an underlying dysmotility disorder. We report the case of a 51-year-old man who presented with chest pain and underwent oesophageal studies. He was diagnosed with acid reflux and high amplitude oesophageal contractions, otherwise known as a jackhammer oesophagus. Treatment was successful with omeprazole and glyceryl trinitrate relieving his symptoms.