Alberto D’Alcamo

Non-Celiac Gluten Sensitivity: Literature Review

Background: A significant percentage of the general population report problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy (WA), because they test negative both for CD-specific serology and histopathology and for immunoglobulin E (IgE)-mediated assays. Most patients report both gastrointestinal and nongastrointestinal symptoms, and all report improvement of symptoms on a gluten-free diet. This clinical condition has been named non-celiac gluten sensitivity (NCGS). Aim: We attempt to define the current pathogenic, clinical, and diagnostic criteria of this “new” disease, to provide a practical view that might be useful to evaluate, diagnose, and manage NCGS patients. Methods: We reviewed the international literature through PubMed and Medline, using the search terms “wheat (hyper)sensitivity,” “wheat allergy,” “wheat intolerance,” “gluten (hyper)sensitivity,” and “gluten intolerance,” and we discuss current knowledge about NCGS. Results: It has been demonstrated that patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. NCGS diagnosis can be reached only by excluding CD and WA. Recent evidence shows that a personal history of food allergy in infancy, coexistent atopy, positive for immunoglobulin G (IgG) antigliadin antibodies and flow cytometric basophil activation test, with wheat and duodenal and/or ileum–colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. Conclusions: Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroups. Key teaching points: • Most patients report both gastrointestinal and nongastrointestinal symptoms, and all agree that there is an improvement of symptoms on a gluten-free diet. • NCGS diagnosis can be reached only by excluding celiac disease and wheat allergy. • Patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. • A personal history of food allergy in infancy, coexistent atopy, positive IgG antigliadin antibodies (AGA) and flow cytometric basophil activation test, with wheat and duodenal and/or ileum–colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. • Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroup.

Differences and Similarities between Allergic and Nonallergic Rhinitis in a Large Sample of Adult Patients with Rhinitis Symptoms

Background: Allergic rhinitis (AR) and nonallergic rhinitis (NAR) may present with different clinical and laboratory characteristics. Methods: A total of 1,511 consecutive patients, aged 18–81 years, diagnosed with rhinitis, 56% females and 44% males, underwent complete allergic evaluation including skin prick test, blood eosinophil counts, nasal eosinophil counts, peak nasal inspiratory flow (PNIF) measurement and evaluation of nasal symptoms using a visual analog scale (VAS). Results: A total of 1,107 patients (73%)had AR, whereas 404 (27%) had NAR. Patients with NAR were older and predominantly female. A higher nasal eosinophils count was associated with AR and a lack of clinical response to antihistamines. AR patients had more sneezing and nasal pruritus, whereas NAR was characterized mainly by nasal obstruction and rhinorrhea. AR patients had more severe symptoms and recurrent conjunctivitis, whereas NAR patients had slightly more frequent episodes of recurring headaches as well as olfactory dysfunction. PNIF, blood eosinophil counts and VAS of nasal symptoms were higher in patients with AR. In a final logistic regression model, 10 variables were statistically different between AR and NAR: age [OR 0.97 (95% CI 0.96–0.98)], sneezing [OR 4.09 (95% CI 2.78–6.00)], nasal pruritus [OR 3.84 (95% CI 2.60–5.67)], mild symptoms [OR 0.21 (95% CI 0.09–0.49)], intermittent/severe nasal symptoms [OR 3.66 (95% CI 2.06–6.50)], VAS [OR 1.06 (95% CI 1.04–1.08)], clinical response to antihistamines [OR 22.59 (95% CI 13.79–37.00)], conjunctivitis [OR 4.49 (95% CI 2.86–7.05)], PNIF [OR 1.01 (95% CI 1.00–1.01)] and nasal eosinophil counts [OR 1.14 (95% CI 1.10–1.18)]. Receiver operating characteristic analysis showed high predictive accuracy for a model including these variables independently of the diagnosis of AR/NAR (cutoff <0.74). Conclusions: We showed that the several clinical and laboratory parameters reported above may help to reinforce or exclude the diagnosis of AR obtained with skin prick test.

High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear Antibodies

BACKGROUND & AIMS There is much interest in wheat sensitivity among people without celiac disease (CD), but little is known about any risks associated with the condition. We evaluated the prevalence of autoimmune diseases (ADs) among patients with nonceliac wheat sensitivity (NCWS), and investigated whether they carry antinuclear antibodies (ANA). METHODS We performed a retrospective study of 131 patients diagnosed with NCWS (121 female; mean age, 29.1 years) at 2 hospitals in Italy from January 2001 through June 2011. Data were also collected from 151 patients with CD or irritable bowel syndrome (IBS) (controls). Patient medical records were reviewed to identify those with ADs. We also performed a prospective study of 42 patients (38 female; mean age, 34 years) diagnosed with NCWS from July 2011 through March 2014 at 3 hospitals in Italy. One hundred age- and sex-matched subjects with CD or IBS served as controls. Serum samples were collected from all subjects and ANA levels were measured by immunofluorescence analysis. Participants completed a questionnaire and their medical records were reviewed to identify those with ADs. RESULTS In the retrospective analysis, similar portions of subjects with NCWS (29%) and CD (29%) developed ADs (mainly Hashimotos thyroiditis, 29 cases), compared with a smaller proportion of subjects with IBS (4%) (P < .001). In the prospective study, 24% of subjects with NCWS, 20% of subjects with CD, and 2% of subjects with IBS developed ADs (P < .001). In the retrospective study, serum samples tested positive for ANA in 46% of subjects with NCWS (median titer, 1:80), 24% of subjects with CD (P < .001), and 2% of subjects IBS (P < .001); in the prospective study, serum samples were positive for ANA in 28% of subjects with NCWS, 7.5% of subjects with CD (P = .02), and 6% of subjects with IBS (P = .005 vs patients with NCWS). ANA positivity was associated with the presence of the HLA DQ2/DQ8 haplotypes (P < .001). CONCLUSIONS Higher proportions of patients with NCWS or CD develop autoimmune disorders, are ANA positive, and showed DQ2/DQ8 haplotypes compared with patients with IBS.

Leukotriene receptor antagonists in monotherapy or in combination with antihistamines in the treatment of chronic urticaria: a systematic review

In vitro and in vivo clinical and experimental data have suggested that leukotrienes play a key role in inflammatory reactions of the skin. Antileukotriene drugs, ie, leukotriene receptor antagonists and synthesis inhibitors, are a class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma and in rhinitis with asthma. We searched MEDLINE database and carried out a manual search on journals specializing in allergy and dermatology for the use of antileukotriene drugs in urticaria. Montelukast might be effective in chronic urticaria associated with aspirin (ASA) or food additive hypersensitivity or with autoreactivity to intradermal serum injection (ASST) when taken with an antihistamine but not in mild or moderate chronic idiopathic urticaria [urticaria without any possible secondary causes (ie, food additive or ASA and other NSAID hypersensitivity, or ASST)]. Evidence for the effectiveness of zafirlukast and the 5-lipoxygenase inhibitor, zileuton, in chronic urticaria is mainly anecdotal. In addition, there is anecdotal evidence of effectiveness of antileukotrienes in primary cold urticaria, delayed pressure urticaria and dermographism. No evidence exists for other physical urticarias, including cholinergic, solar and aquagenic urticarias, vibratory angioedema, and exercise-induced anaphylaxis.

Role of FODMAPs in Patients With Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a condition characterized by abdominal pain, bloating, flatus, and altered bowel habits. The role of dietary components in inducing IBS symptoms is difficult to explore. To date, foods are not considered a cause but rather symptom-triggering factors. Particular interest has been given to the so-called FODMAPs (fermentable oligo-, di-, and monosaccharides and polyols). We aimed to summarize the evidence from the most common approaches to manage suspected food intolerance in IBS, with a particular interest in the role of FODMAPs and the effects of a low FODMAP diet. We reviewed literature, consulting PubMed and Medline by using the search terms FODMAP(s), fructose, lactose, fructans, galactans, polyols (sorbitol, mannitol, maltitol, xylitol, erythritol, polydextrose, and isomalt), irritable bowel syndrome, and functional gastrointestinal symptoms. FODMAP-restricted diets have been used for a long time to manage patients with IBS. The innovation in the so-called FODMAP concept is that a global restriction should have a more consistent effect than a limited one in preventing abdominal distension. Even though all the potential low FODMAP diets provide good relief of symptoms in many patients, there is just a little relief in others. Several studies highlight the role of low FODMAP diets to improve symptoms in patients with IBS. The evidence on this dietary approach supports the hypothesis that a low FODMAP diet should be the first dietary approach. However, many points remain to be clarified, including the evaluation of possibly significant nutrition concerns.

Predominance of type 1 innate lymphoid cells in the rectal mucosa of patients with non-celiac wheat sensitivity: reversal after a wheat-free diet.

OBJECTIVES:Non-celiac wheat sensitivity (NCWS) is defined as a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis is incompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients with well-defined NCWS.METHODS:The prospective study included 22 patients with irritable bowel syndrome (IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. Eight IBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge was performed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughly characterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surface markers.RESULTS:Rectal biopsies from wheat-challenged NCWS patients showed that a significant mucosal CD45+ infiltrate consisted of CD3+ and CD3− lymphocytes, with the latter spontaneously producing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45+ cells were T-bet+, CD56−, NKP44−, and CD117−, defining them as a type-1 innate lymphoid cells (ILC1). IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed a wheat-free diet.CONCLUSIONS:These data indicate that, in patients with active NCWS, IFN-γ-producing ILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in the pathogenesis of NCWS.

Persistence of Nonceliac Wheat Sensitivity, Based on Long-term Follow-up

We investigated how many patients with a diagnosis of nonceliac wheat sensitivity (NCWS) still experienced wheat sensitivity after a median follow-up time of 99 months. We collected data from 200 participants from a previous study of NCWS, performed between July and December 2016 in Italy; 148 of these individuals were still on a strict wheat-free diet. In total, 175 patients (88%) improved (had fewer symptoms) after a diagnosis of NCWS; 145 of 148 patients who adhered strictly to a gluten-free diet (98%) had reduced symptoms, compared with 30 of 52 patients who did not adhere to a gluten-free diet (58%) (P < .0001). Of the 22 patients who repeated the double-blind, placebo-controlled challenge, 20 reacted to wheat. We conclude that NCWS is a persistent condition. Clinicaltrials.gov registration number: NCT02823522.

Malignant tumor-like gastric lesion due to candida albicans in a diabetic patient treated with cyclosporin: a case report and review of the literature

The gastrointestinal tract of healthy individuals is colonized by hundreds of saprophytes and mycetes, especially the Candida species, are habitual ones. Under certain conditions, the fungal flora may overgrow, resulting in lesions of the digestive mucosa which, rarely, can have a local diffusion and/or spread to the lympho-hematogenous system. Mycotic infections of the stomach can sometimes look like benign gastric ulcers. Here, we present the case report of a woman, aged 64, who presented with type II diabetes mellitus and psoriasis, on chronic treatment with cyclosporin A and with endoscopic evidence of an ulcerated, vegetating gastric lesion secondary to Candida albicans infection. Although strongly suggestive of malignancy, it completely healed after cyclosporin withdrawal and the administration of oral antifungal drugs.

Contact dermatitis due to nickel allergy in patients suffering from non-celiac wheat sensitivity

Background: Non-celiac wheat sensitivity (NCWS) is a new clinical entity in the world of gluten-related diseases. Nickel, the most frequent cause of contact allergy, can be found in wheat and results in systemic nickel allergy syndrome and mimics irritable bowel syndrome (IBS). Objective: To evaluate the frequency of contact dermatitis due to nickel allergy in NCWS patients diagnosed by a double-blind placebo-controlled (DBPC) challenge, and to identify the characteristics of NCWS patients with nickel allergy. Methods: We performed a prospective study of 60 patients (54 females, 6 males; mean age 34.1 ± 8.1 years) diagnosed with NCWS from December 2014 to November 2016; 80 age- and sex-matched subjects with functional gastrointestinal symptoms served as controls. Patients reporting contact dermatitis related to nickel-containing objects underwent nickel patch test (Clinicaltrials.gov registration number: NCT02750735). Results: Six out of sixty patients (10%) with NCWS suffered from contact dermatitis and nickel allergy and this frequency was statistically higher (p = 0.04) than observed in the control group (5%). The main clinical characteristic of NCWS patients with nickel allergy was a higher frequency of cutaneous symptoms after wheat ingestion compared to NCWS patients who did not suffer from nickel allergy (p < 0.0001). Conclusions: Contact dermatitis and nickel allergy are more frequent in NCWS patients than in subjects with functional gastrointestinal disorders; furthermore, these patients had a very high frequency of cutaneous manifestations after wheat ingestion. Nickel allergy should be evaluated in NCWS patients who have cutaneous manifestations after wheat ingestion.

Nonceliac Wheat Sensitivity in the Context of Multiple Food Hypersensitivity: New Data From Confocal Endomicroscopy

Dear Editor: We enjoyed reading the article by Fritscher-Ravens et al who showed, by confocal endomicroscopy, that candidate food antigens caused immediate duodenal mucosa damage in irritable bowel syndrome (IBS) patients with a prolonged clinical history of symptoms after meals. Their in vivo data add evidence to the relationship between IBS and food allergy and seem to reinforce our hypothesis that a percentage of “nonceliac wheat sensitive” (NCWS)–patients with an IBS-like clinical presentation could suffer from non– immunoglobulin E-mediated wheat allergy. However, we would suggest that the very high percentage of positive confocal laser endomicroscopy patients (CLE)—22 out of 36—found in the study of FritscherRavens et al could depend on their inclusion criteria (refractory daily symptoms >1 year, daily shortly after meal symptoms); in our experience, the frequency of food hypersensitivity diagnosed by double-blind, placebocontrolled (DBPC) food challenges in IBS is slightly <30% (276 patients out of 920). Apart from the epidemiologic data, which were not the objectives of this pilot study, we would like to underline some aspects of the study and make some suggestions for future research. It is interesting that a total of 32 reactions were analyzed, with different food antigens, in 22 CLE-positive patients and that the second most frequently offending food, after wheat, was cow’s milk. This is in keeping with our data about the high frequency of multiple food hypersensitivities in patients with NCWS. We showed that 206 of 276 NCWS subjects also became symptomatic after DBPC cow’s milk proteins challenge. These observations should induce the physicians who suspect a relationship between NCWS or food hypersensitivity and IBS to suggest an elimination diet with the exclusion of more food rather than just wheat, and that the reintroduction should be performed singly and with great caution, as described. In fact, a lack of response to a wheat-free diet could depend on hypersensitivity to other food antigens which are still included in the patients’ diet. We found also of great interest that CLE showed significantly higher intraepithelial lymphocyte (IEL) count in CLEpositive than CLE-negative patients and in controls. Furthermore, histology showed that themean values of IEL in CLE-positive patients were 26.4 ± 2.7 per 100 cells. Overall, this could indicate a state of mucosal inflammation owing to food hypersensitivity. A previous NCWS study which excluded patients with >25 IEL per 100 EC in the duodenal mucosa, very probably missed the group of NCWS patients who had an immunologic pathogenesis at the basis of their troubles. However, in our opinion, NCWS is a heterogeneous condition, which includes different subgroups of patients and the “allergic hypothesis” does not exclude that, in other NCWS patients, wheat amylase trypsin inhibitors or fermentable sugars could be the main pathogenetic triggers. Finally, we think that the authors showed that CLE is an excellent instrument to demonstrate food-related reactions in IBS and to separate a subgroup of the NCWS—those with non–immunoglobulin E-mediated wheat hypersensitivity—from the confuse melting pot that NCWS still is. However, awaiting a wider diffusion of this endoscopic means, and taking into account that the economic resources are decreasing in developed countries, it would be very important to correlate the CLE finding with simpler, noninvasive biomarkers. In this respect, it would be interesting to know whether CLE findings correlate with the eosinophil cationic protein concentrations in the stools or with the flow cytometric allergen stimulation assay results, biomarkers that showed a good concordance with the DBPC challenge results in IBS patients.