Forum for Nordic Dermato-Venereology Nr 4, 2019 | Page 24

Dissertation
Erika Katariina Mansikka – Diagnostic Delay, Small Bowel Villous Atrophy, and Gluten Challenge in Dermatitis Herpetiformis
Diagnostic Delay, Small Bowel Villous Atrophy, and Gluten Challenge in
Dermatitis Herpetiformis
E riika K atariina M ansikka
Tampere University, Faculty of Medicine and Health Technology, Tampere University, Celiac Research Center, Tampere University
Hospital, Department of Dermatology and Venereology, Finland. E-mail: [e-mail]
Eriika Mansikka, MD, conducted her PhD studies at Department of Dermatology and Venereology, Tampere
University Hospital, Finland during the period 2015-2019. Her dissertation was held on October 25, 2019 at
Tampere University. Supervisors: Professor Timo Reunala, Docent Teea Salmi, and Docent Kaisa Hervonen. Op-
ponent: Professor Kaisa Tasanen-Määttä from the University of Oulu, Finland. Link to complete thesis: https://
trepo.tuni.fi/bitstream/handle/10024/116843/978-952-03-1217-6.pdf?sequence=2&isAllowed=y
Dermatitis herpetiformis (DH) is an extraintestinal manifesta-
tion of coeliac disease presenting with an intensely itchy and
blistering rash mainly on the elbows, knees, and buttocks.
Diagnosis is based on the demonstration of granular IgA
deposits in the papillary dermis by examination with direct
immunofluorescence (IF). The disease is caused by gluten, a
protein found in wheat, rye, and barley, which initiates an
autoimmune response in genetically predisposed individuals.
This leads to small bowel mucosal damage typical of coeliac
disease and, in some individuals, to a blistering rash typical
of DH. At present, 13% of adults with coeliac disease have DH
in Finland. The incidence of DH is decreasing, whereas the
reverse is true for coeliac disease. The mainstay of treatment
for DH and coeliac disease is a life-long gluten-free diet (GFD),
which in DH also heals the rash. 
In the research presented in the present dissertation, a cohort
of patients with DH diagnosed between 1970 and 2014 at
Tampere University Hospital, Finland were investigated. The
first aim was to evaluate diagnostic delay in DH. The second
aim was to study whether small bowel histological findings
have changed over the 45-year period and to determine how
mucosal damage correlates to serum transglutaminase 2 (TG2)
antibody levels. The third aim was to examine if the presence
or absence of small bowel villous atrophy at diagnosis affects
the long-term prognosis of DH patients on a GFD. The fourth
aim was to examine, by gluten challenge, whether DH patients
on a long-term GFD treatment could have developed gluten
tolerance, as suggested by a few earlier studies. 
The dissertation consists of 4 separate studies. In Study I, the
duration of the rash before diagnosis was examined from
hospital records in 446 DH patients. The diagnosis was con-
sidered delayed when the duration of the rash before diagnosis
was two years or longer. Factors associated with the delayed
diagnosis were analysed in more detail using follow-up ques-
tionnaires obtained from 217 patients. Over the study period,
the median duration of the rash before diagnosis decreased
and the number of patients with delayed diagnosis decreased.
Female gender and the presence of villous atrophy correlated
with the delayed diagnosis, whereas age at diagnosis and the
activity of the rash did not. According to the follow-up ques-
tionnaire, bone fractures or malignancies were shown not to
occur more often in those patients with a delayed diagnosis
compared to those with a non-delayed diagnosis.
In Study II, the severity of small bowel villous atrophy was
examined in 393 DH patients over the 45-year study period.
The prevalence of severe (subtotal/total) villous atrophy
(SVA) was shown to decrease over time. At the same time, an
increase was seen in both partial villous atrophy (PVA) and
normal villous architecture. Patients with villous atrophy had
higher TG2 antibody levels than those with normal villous
architecture. However, several patients with villous atrophy
had normal TG2 antibody levels, indicating that a negative
test result does not always exclude villous damage in DH. 
In Study III, long-term prognoses were compared between
DH patients with and without small bowel villous atrophy at
diagnosis (n = 352) and 128 coeliac disease controls. Initial data
was gathered from the patient records and follow-up data was
collected via questionnaires from 181 DH patients on a GFD.
At the DH diagnosis, 98 (28%) patients had normal villous
architecture and 254 (72%) had villous atrophy. Clinical re-
covery did not differ significantly between the DH groups, nor
did the presence of long-term illnesses, coeliac disease-related
complications or quality of life (QoL). By contrast, the coeliac
disease controls had osteopenia/osteoporosis, thyroid diseases
and malignancies more often compared to the DH patients. 
In Study IV, 19 asymptomatic DH patients who had adhered to
a GFD for a mean of 23 years were challenged with gluten for
up to 12 months. Before the challenge skin biopsies showed
negative IgA and transglutaminase 3 (TG3) deposits in 84%
of the patients and normal villous mucosa in all of them. The
gluten challenge caused a relapse of the rash and/or villous
atrophy in 18 (95%) DH patients; 15 (79%) patients showed
a rash within a mean of 5.6 months and 3 (16%) had only
small bowel villous atrophy. 
The results of the present dissertation show that diagnostic
delay in DH has decreased over time. Further, the prevalence
of SVA decreased during the 45-year study period and high
serum TG2 antibody levels reveals rather well whether the
patients have villous atrophy. However, the presence of villous
atrophy at the time of diagnosis was shown not to effect GFD
treatment response or long-term morbidity and QoL and hence
has no effect on the prognosis of DH. Importantly, the gluten
challenge showed that a life-long GFD treatment remains
justified in all DH patients.
L ist
of original publications
This thesis is based on the following original publications,
which are referred to in the text by their Roman numerals:
I.
Mansikka E, Salmi T, Kaukinen K, Collin P, Huhtala H, Reunala
T, Hervonen K. Diagnostic delay in dermatitis herpetiformis in
a high-prevalence area. Acta Derm Venereol 2018; 98: 195–199.
II. Mansikka E, Hervonen K, Salmi TT, Kautiainen H, Kaukinen K,
Collin P, Reunala T. The decreasing prevalence of severe villous
atrophy in dermatitis herpetiformis: a 45-year experience in 393
patients. J Clin Gastroenterol 2017; 51: 235–239.
III. Mansikka E, Hervonen K, Kaukinen K, Collin P, Huhtala H, Reunala
T, Salmi T. Prognosis of dermatitis herpetiformis patients with and
without villous atrophy at diagnosis. Nutrients 2018; 10: 641.
IV. Mansikka E, Hervonen K, Kaukinen K, Ilus T, Oksanen P, Lindfors
K, et al. Gluten challenge induces skin and small bowel relapse in
long-term gluten-free diet treated dermatitis herpetiformis. J Invest
Dermatol 2019, Apr 15 Epub ahead of print.
Fig. 1. From left to right:
Professor Timo Reunala, Pro-
fessor Kaisa Tasanen-Määttä,
Docent Teea Salmi, MD Eriika
Mansikka and Associate Pro-
fessor Kaisa Hervonen.
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Forum for Nord Derm Ven 2019, Vol. 24, No. 4
Forum for Nord Derm Ven 2019, Vol. 24, No. 4
D issertation
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