Vitiligo and the incidence of CD
Four studies, including two case-control and two cross-sectional studies, investigated the incidence of CD in patients with vitiligo. One cross-sectional study investigated the incidence of CD in 176 patients with vitiligo; five (2.8%) of these patients were diagnosed with CD. Further, in a case-control study, Seyhan et al assessed serum anti-endomysial IgA antibody in 61 patients with vitiligo (21 children) and 60 controls. Eleven patients with vitiligo and one control were positive, and among these seropositive patients, five were younger than 18 years of age. The seroprevalence rates for children and adults were 23.8% and 15%, respectively. Seropositive patients underwent endoscopic duodenal biopsy of the upper gastrointestinal tract, and the prevalence of CD confirmed by biopsy was 3.2%. The second case-control study by Shahmoradi et al assessed EMA and anti-tTG IgA in 64 patients with vitiligo and 64 controls; each group included 41 (64.1%) women and 23 (35.9%) men. Among the patients with vitiligo, autoantibody tests were positive in two (3.1%) women. No one in the control group has positive results for autoantibodies. However, the other cross-sectional study investigated the incidence of CD in 198 patients with vitiligo and found no positive CD serology in any of the participants.
CD and incidence of vitiligo
The incidence of vitiligo among CD patients was examined in six cross-sectional studies and one population-based cohort study. Ertekin et al reported on 140 children with CD, of whom 3 (2.1%) had vitiligo, while Lancaster-Smith et al found that 1 (1.8%) out of 57 patients with CD had vitiligo. Further, Seyhan et al studied 55 cases of children and adolescents with CD and found that 45 children (81.8%) had gastrointestinal symptoms; 5 of them were subsequently diagnosed with vitiligo, with an incidence rate of 9.1%. A Swedish population-based cohort study, in which each CD patient was matched with five control patients, demonstrated that among 43300 patients with CD, 106 cases (0.2%) were affected by vitiligo. Moreover, in a population of 198532 patients, vitiligo was diagnosed in 261 cases (0.1%), and the incidence of vitiligo was statistically significant. In a study in Italy, 1 of 82 patients with CD had vitiligo (incidence rate of 1.2%); another report including 1010 patients with CD in Spain found that only 4 children (0.4%) had vitiligo. However, surprisingly, Reunala et al did not report the onset of vitiligo in 383 patients with CD who received GFD. GFD may reduce the risk of vitiligo.
GFD and vitiligo
Only a few cases of GFD and vitiligo have been reported in the literature. Our literature review identified two case reports describing the recoloring of vitiligo lesions after the onset of a GFD. One case reported a 9-year-old child with both CD and vitiligo who developed extensive repigmentation after following a GFD for 1 year. The second report describes a 22-year-old female patient with vitiligo, who received a 2-year treatment including dapsone with no significant response but began to recover after 1 mo of GFD. These cases suggest that elimination of gluten in the early stages of disease may have the potential to encourage and improve the disease.
Additionally, there are some reports on the coexistence of DH and vitiligo. Two case reports describe this relationship; in both, the DH lesions were significantly improved after the patients began a GFD; however, the vitiligo lesions remained unchanged or further aggravated. One report described a 53-year-old woman with vitiligo and DH. The patient begun a GFD, and DH was completely relieved after 5 mo, but vitiligo did not subside and further increased; she did not undergo a CD-related examination. The second case report described a 21-year-old patient with vitiligo and DH who was diagnosed with CD after gastrointestinal endoscopy. He was prescribed strict GFD and topical steroids, after which DH significantly improved, although his vitiligo remained unchanged.
Discussion of CD
CD is a chronic autoimmune disease caused by improper absorption of wheat gluten and related cereal peptides by the small intestine, and this causes the human body to lose its ability to absorb nutrients through the villi. The disease may affect patients of any age, with a peak in early childhood and the 4th and 5th decade. The gastrointestinal symptoms of CD include abdominal distension, abdominal pain, chronic diarrhea, steatosis, anorexia, weight loss, and nutritional deficiency. Further, an increasing number of related diseases and parenteral manifestations have been reported. Vitiligo is also associated with a variety of gastrointestinal comorbidities, including autoimmune liver disease, autoimmune atrophic gastritis, inflammatory bowel disease, and intestinal flora dysfunction[13,36-38]. Furthermore, the incidence of some autoimmune diseases (pernicious anemia, inflammatory bowel disease, systemic lupus erythematosus, Addison's disease, and autoimmune thyroid disease) in patients with vitiligo is significantly increased. These associations indicate that vitiligo has a common genetic etiology with other autoimmune diseases. Studies have found that patients with multiple autoimmune syndromes may have CD and/or vitiligo. In addition to well-defined polygenic syndromes, there may be a positive correlation between CD and vitiligo.
There is no published research explaining the pathophysiological relationship between CD and vitiligo; both are T cell-mediated disorders in which gamma-delta T cells, T-helper 1, and T-helper 17 play important roles[41-44]. CD has been found to be highly correlated with interleukin (IL)-2, IL-6, IL-17, and IL-21[45-47] which have been proven to play important roles in the pathogenesis of vitiligo[48,49]. The shared immunogenic mechanisms between the two conditions could explain their association. The incidence rate of autoimmune diseases is increased in patients with prolonged gluten exposure, due to the intestinal barrier dysfunction associated with CD and increased permeability to immunogenic triggers. CD patients exposed to gliadin can show triggering of the CD4 + T cell responses, causing the production of high levels of interferon-gamma; this has been related to the severity of psoriasis[51,52]. A similar mechanism may be involved in the pathogenesis of vitiligo. On the other hand, in vitiligo, nuclear factor-erythroid 2-related factor 2 activation decreased in keratinocytes with impaired phosphoinositide 3-kinase phosphorylation, increasing the susceptibility to reactive oxygen species (ROS), leading to chemically induced apoptosis. Moreover, IL-15 and CD4 + T cytokines (TNF, IL-2, IL-21) increased the phosphorylation of activators of transcription (STAT) 5 and protein kinase b, as well as the transcription of B-cell lymphoma-extra large (BCL-xL) protein. Further, TNF, IL-2, and IL-21 synergistically trigger the proliferation of Lin(-) intraepithelial lymphocytes (IELs) and CD3-CD56 + IELs in duodenal biopsy specimens of refractory CD type II (RCDII), while CD4 + T cytokines are involved in its pathogenesis. Additionally, another possible mechanism linking vitiligo and CD is vitamin D deficiency in CD patients due to intestinal malabsorption. Vitamin D deficiency can make susceptible individuals develop vitiligo. However, this mechanism may not be important as it has been previously reported that patients with vitiligo have significant recoloring after a GFD. Large population-based studies in the future may provide better insight into the role of GFD in vitiligo.
Furthermore, CD is closely related to DH. Sulfasalazine, a commonly used treatment for DH, may induce vitiligo in patients with CD and DH as it can consume glutathione, leading to a large amount of ROS accumulation, resulting in melanocyte damage[58,59]. Further, sulfasalazine is an inhibitor of the thioredoxin pathway, and reduced thioredoxin participates in the inhibition of tyrosinase, which is the rate-limiting enzyme in melanin biosynthesis and inhibits melanogenesis[61,62]. Moreover, sulfasalazine may reduce the level of cofactor tetrahydrobiopterin (BH4) by inhibiting the squid reductase that plays a crucial role in melanin production; BH4 can also lead to the production of ROS, leading to the disruption of melanin biosynthesis.