Nickel oral hyposensitization in patients with systemic nickel allergy syndrome

Abstract

Background: This is the first randomized, double-blind, placebo-controlled trial (EUDRACT No. 2009-013923-43) evaluating nickel oral hyposensitizing treatment (NiOHT) in patients with "systemic nickel allergy syndrome" (SNAS), characterized by Ni-allergic contact dermatitis and systemic reactions after eating Ni-rich food.

Methods: Adults with positive Ni-patch test, who reported symptoms suggesting SNAS, which improved after Ni-poor diet, and were positive to Ni-oral challenge were eligible. Patients were randomly assigned to three treatments (1.5 μg, 0.3 μg, or 30 ng Ni/week) or placebo for a year, with progressive reintroduction of Ni-rich foods form the 5(th) month. Out of 141 patients randomized, 113 completed the trial. Endpoints were efficacy and tolerability of treatment.

Results: During Ni-rich food re-introduction, the 1.5 μg Ni/week group had a mean VAS score significantly higher than placebo (p = 0.044), with significant improvement of gastrointestinal symptoms (p = 0.016;) and significantly fewer rescue medications. Cutaneous manifestations also improved but without reaching statistical significance. After the treatment, oral challenge with higher Ni doses than at baseline were needed to cause symptoms to flare-up in significantly more patients given 1.5 μg Ni/week than placebo (p = 0.05). Patients reported no side-effects.

Conclusions: NiOHT is effective in SNAS, in particular on gastrointestinal manifestations, with trend toward improvement of cutaneous symptoms.

Figure 1.

Enrolment, randomization and follow-up of the study.

Figure 2.

Percent changes of VAS from baseline during the study. (A) No significant differences were found at T1, T2 and T3 visits, whereas at T4, when Ni-rich foods were re-introduced, the mean VAS score of group 1 (receiving the highest Ni dose) was significantly higher than the placebo group *p < 0.048, t-test. (B) Combining group 3 and group 4 raised this significance (groups 3 and 4 had similar results and group 3 dose can be considered a placebo).*p < 0.038, t-test.

Figure 3.

Percent of patients (respect to those included in the intention to treat analysis) with higher or lower/equal NOC doses at the end of the study respect to T1. The nickel oral challenge (NOC) was compared on the basis of the nickel dose required to induce flare-up of SNAS symptoms. After the treatment, oral challenge with higher Ni doses than at baseline were needed to cause symptoms to flare-up in significantly more patients given 1.5 μg Ni/week than placebo: Risk difference (95% CI): 27.6 (0.8 to 49.3); p = 0.05. Comparing Group 1 to Group 3 + 4 the significance increased: Risk difference (95% CI):38.1 (14.5 to 55.7); p = 0.002.

Figure 4.

Positive and negative patch tests in the four groups at the end of the study; as per inclusion criteria, all patients were patch test-positive at baseline. Values are expressed as percentage of patients evaluated in the intention to treat analysis. There were significantly more patch test-negatives in group 1 (Risk difference (95% CI): 32.9 (9.0 to 54.8); p = 0.008). Pos: positive patch test; Neg: negative patch tests; ND: not done.