Nickel Allergy and Systemic Nickel Allergy Syndrome in Non Celiac Wheat Sensitivity

April 20, 2016 updated by: Pasquale Mansueto, University of Palermo
In the last few years, a new clinical entity has emerged which includes patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy. This clinical condition has been named non-celiac gluten sensitivity (NCGS), although in a recent article, the investigators suggested the term "non-celiac wheat sensitivity" (NCWS), because it is not known to date what component of wheat actually causes the symptoms. Nickel is the fourth most used metal and the most frequent cause of contact allergy in the industrialized world. As a natural element of the earth's crust small amounts are found in water, soil, and natural foods, especially plant ones. Nickel allergy not only affects the skin but also results in systemic manifestations. Systemic nickel allergy syndrome can have cutaneous (urticaria/angioedema, flares, itching), and/or gastrointestinal (meteorism, colic, diarrhoea) signs and symptoms. In this study, the investigators evaluated 1) the frequency of Nickel allergy and Systemic Nickel allergy syndrome in NCWS patients, and 2) the clinical, serological, and histological characteristics of NCWS patients with contact dermatitis Nickel positive in comparison to NCWS patients without contact dermatitis.

Study Overview

Status

Completed

Conditions

Detailed Description

In the last few years, a new clinical entity has emerged which includes patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy. This clinical condition has been named non-celiac gluten sensitivity (NCGS), although in a recent article, the investigators suggested the term "non-celiac wheat sensitivity" (NCWS), because it is not known to date what component of wheat actually causes the symptoms. Other areas of doubt in NCWS regard its pathogenesis, while some papers reported intestinal immunologic activation, others linked NCWS to the dietary short chain carbohydrate (fermentable oligo-di-monosaccharides and polyols, FODMAPs) load. The investigators recently demonstrated that higher proportions of patients with NCWS develop autoimmune disorders, are antinuclear antibodies (ANA) positive, and show DQ2/DQ8 haplotypes compared with patients with irritable bowel syndrome (IBS), supporting an immunologic involvement in NCWS. Furthermore, some papers reported also a high frequency, ranging from 22% and 35%, of coexistent atopic diseases in NCWS patients, and the investigators suggested that a percentage of NCWS patients could really suffer from non-IgE-mediated wheat allergy.

Nickel is the fourth most used metal and the most frequent cause of contact allergy in the industrialized world. As a natural element of the earth's crust small amounts are found in water, soil, and natural foods, especially plant ones. Nickel allergy not only affects the skin but also results in systemic manifestations. Systemic nickel allergy syndrome can have cutaneous (urticaria/angioedema, flares, itching), and/or gastrointestinal (meteorism, colic, diarrhoea) signs and symptoms.

Volta et al. reported that 15% of NCWS patients suffered from allergy to nickel, but they did not further characterize this subgroup of patients, neither posed the NCWS diagnosis by means the double-blind placebo controlled challenge (DBPCC), as recommended. In this study, the investigators evaluated 1) the frequency of Nickel allergy and Systemic Nickel allergy syndrome in NCWS patients, and 2) the clinical, serological, and histological characteristics of NCWS patients with contact dermatitis Nickel positive in comparison to NCWS patients without contact dermatitis.

Study Type

Observational

Enrollment (Actual)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Palermo, Italy, 90127
        • Pasquale Mansueto
    • Agrigento
      • Sciacca, Agrigento, Italy
        • Antonio Carroccio

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

The study was divided into 2 different parts. In the first, the clinical charts of NCWS patients were retrospectively reviewed, comparing the characteristics of the ones suffering from nickel allergy with those who did not suffer from nickel allergy, using, as control group, 70 IBS patients. In the second, the investigators prospectively surveyed adult patients with functional gastroenterological symptoms (Rome III criteria) and a definitive diagnosis of NCWS, comparing the characteristics of the ones suffering from nickel allergy were compared with those who did not suffer from nickel allergy, using, as control group, 70 patients with functional gastroenterological symptoms.

Description

Inclusion Criteria:

All the patients met the recently proposed criteria:

  • negative serum anti-tissue transglutaminase and antiendomysium (EmA) IgA and IgG antibodies;
  • absence of intestinal villous atrophy;
  • IgE-mediated immunoallergy tests negative to wheat (skin prick tests and/or serum specific IgE detection).

Adjunctive criteria adopted in our patients were:

  • resolution of the gastrointestinal symptoms on a standard elimination diet, without wheat, cow's milk, egg, tomato, chocolate, or other food(s) causing self-reported symptoms;
  • symptom reappearance on double-blind placebo-controlled (DBPC) wheat challenge, performed as described previously. As in previous studies, DBPC cow's milk protein challenge and other "open" food challenges were also performed.

Exclusion Criteria:

Exclusion criteria were:

  • age < 18 years;
  • positive EmA in the culture medium of the duodenal biopsies, even if the villi to crypts ratio in the duodenal mucosa was normal;
  • self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study;
  • other organic cutaneous and/or gastrointestinal diseases;
  • concomitant treatment with steroids and/or antihistamines.

Allergic contact dermatitis was diagnosed in patients showing local eczematous lesions on the skin in close contact with nickel-containing objects. Suspected systemic nickel allergy syndrome (SNAS), was defined as a reaction characterized not only by diffused eczematous lesions (systemic contact dermatitis) but also by extracutaneous signs and symptoms, mainly gastrointestinal, after ingestion of nickel-rich foods (i.e. tomato, cocoa, beans, mushrooms, vegetables, wheat flour, etc). In all cases, the diagnosis was confirmed by means of the epicutaneous patch tests which provoked delayed lesions.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only

Cohorts and Interventions

Group / Cohort
Retrospective NCWS patients
The clinical charts of NCWS patients attending the outpatient centers of the Department of Internal Medicine at the University Hospital of Palermo and the Department of Internal Medicine of the Hospital of Sciacca were retrospectively reviewed. Patients had all been diagnosed with NCWS between January 2001 and June 2011, by a DBPCC method, and included in a previously published study. These charts included specific sections for the presence of associated atopic diseases, including nickel allergy. In this way, the characteristics of the NCWS patients suffering from nickel allergy were compared with those of the NCWS patients who did not suffer from nickel allergy. Incomplete clinical charts were excluded.
Prospective NCWS patients
The investigators also prospectively surveyed adult patients with functional gastroenterological symptoms according to the Rome III criteria, and a definitive diagnosis of NCWS. The patients were recruited between December 2014 and March 2016 at 3 centers: the two already mentioned and the Gastroenterology Unit of the ARNAS Civico Hospital of Palermo, Italy. Most of the patients had been referred due to gastrointestinal symptoms, the onset of which, they reported, could be related to wheat ingestion. Again, the characteristics of the NCWS patients suffering from nickel allergy were compared with those of the NCWS patients who did not suffer from nickel allergy.
Retrospective NCWS control patients
To compare the frequency of nickel allergy in NCWS and non-NCWS patients, a control group composed of 70 irritable bowel syndrome (IBS) patients, was selected. These controls were randomly chosen by a computer-generated method from subjects diagnosed during the same period and age- (+/-2 years) and sex-matched (+/-5%) with the NCWS patients. The IBS controls had been receiving the same elimination diet as the NCWS patients and had not shown any clinical improvement; they belonged to the cohort of subjects the investigators had studied previously.
Prospective NCWS control patients
As for the retrospective study, to compare the frequency of nickel allergy in NCWS and non-NCWS patients, a control group composed of 70 patients with functional gastroenterological symptoms, was selected, with the same criteria adopted for the retrospective study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Nickel allergy and Systemic Nickel allergy syndrome in retrospective NCWS patients
Time Frame: Up to 10 years
Frequency of Nickel allergy and Systemic Nickel allergy syndrome in retrospective NCWS patients and controls
Up to 10 years
Nickel allergy and Systemic Nickel allergy syndrome in prospective NCWS patients
Time Frame: Up to 15 months
Frequency of Nickel allergy and Systemic Nickel allergy syndrome in prospective NCWS patients and controls
Up to 15 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Characteristics of retrospective NCWS patients with contact dermatitis Nickel positive in comparison to retrospective NCWS patients without contact dermatitis and controls.
Time Frame: Up to 10 years
Clinical, serological, and histological characteristics of of retrospective NCWS patients with contact dermatitis Nickel positive in comparison to retrospective NCWS patients without contact dermatitis and controls.
Up to 10 years
Characteristics of prospective NCWS patients with contact dermatitis Nickel positive in comparison to prospective NCWS patients without contact dermatitis and controls.
Time Frame: Up to 15 months
Clinical, serological, and histological characteristics of prospective NCWS patients with contact dermatitis Nickel positive in comparison to prospective NCWS patients without contact dermatitis and controls.
Up to 15 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Palermo

Investigators

  • Study Chair: Antonio Carroccio, PhD, University of Palermo

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2001

Primary Completion (Actual)

June 1, 2011

Study Completion (Actual)

March 1, 2016

Study Registration Dates

First Submitted

April 15, 2016

First Submitted That Met QC Criteria

April 20, 2016

First Posted (Estimate)

April 25, 2016

Study Record Updates

Last Update Posted (Estimate)

April 25, 2016

Last Update Submitted That Met QC Criteria

April 20, 2016

Last Verified

April 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACPM10

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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