Diagnostic delay, small bowel villous atrophy, and gluten challenge in dermatitis herpetiformis

Ihokeliakia on keliakian suoliston ulkopuolinen manifestaatio, joka aiheuttaa kutisevan ja pienirakkulaisen ihottuman. Ihottumaa esiintyy tyypillisesti kyynärpäissä, polvissa ja pakara-alueella. Ihokeliakian diagnoosi perustuu terveeltä iholta otettavaan koepalaan ja siitä tehtävään immunofluoresenssitutkimukseen, jossa havaitaan rakeiset IgA kertymät verinahassa. Sairauden aiheuttaa gluteeni eli vehnän, rukiin tai ohran proteiini, joka käynnistää immuunireaktion geneettisesti alttiilla henkilöllä. Immuunivälitteisen reaktion seurauksena suolistoon tulee keliakialle tyypillinen nukkavaurio tai tulehdus ja osalla ihmisistä iholle kehittyy lisäksi ihokeliakialle tyypillisiä rakkuloita. Nykyisin Suomessa 13%:lla aikuisista keliakiapotilaista on ihokeliakia. Ihokeliakian ilmaantuvuus on laskussa, kun taas keliakian ilmaantuvuus päinvastoin lisääntyy. Ihokeliakian ja keliakian hoitona on elinikäinen gluteeniton ruokavalio, joka parantaa suoliston vaurion sekä ihokeliakiassa myös ihottuman. Tämän väitöskirjatyön tutkimuskohorttina olivat vuosina 1970-2014 Tampereen Yliopistollisessa sairaalassa diagnosoidut ihokeliakiapotilaat. Ensimmäisenä tavoitteena oli tutkia ihokeliakian diagnostista viivettä. Toisena tavoitteena oli selvittää ihokeliakiapotilaiden suolivaurion vaikeusasteessa tapahtuneita muutoksia ja sitä, kuinka seerumin transglutaminaasi (TG) 2 vasta-aineet liittyvät suolivaurioasteeseen. Kolmantena tavoitteena oli selvittää, vaikuttaako diagnoosivaiheen suolivaurion olemassaolo hoidettujen ihokeliakiapotilaiden pitkäaikaisennusteeseen. Neljäntenä osatyönä oli gluteenialtistus, jossa tutkittiin, pitkään gluteenittomalla ruokavaliohoidolla olleiden ihokeliakiapotilaiden gluteenin sietokyvyn palautumisen mahdollisuutta, kuten muutamissa aiemmissa tutkimuksissa oli esitetty. Väitöskirja koostuu neljästä erillisestä osatyöstä. Osatyössä I tutkittiin 446 ihokeliakiapotilaalla diagnostista viivettä eli iho-oireiden alkamisesta diagnoosiin kestänyttä aikaa sairaskertomuksista kerätyllä aineistolla. Diagnoosia pidettiin viivästyneenä, jos oireiden alkamisesta diagnoosiin kesti kaksi vuotta tai enemmän. Viivästyneeseen diagnoosiin liittyviä tietoja täydennettiin kyselytutkimustiedolla (n=217). Diagnostisen viiveen mediaaniaika lyhentyi sekä viivästynyt diagnoosi muuttui harvinaisemmaksi seurantajakson aikana. Viivästyneeseen diagnoosiin yhdistyi naissukupuoli sekä vaikeampiasteinen suolen nukkavaurio, mutta ei diagnoosi-ikä tai iho-oireiden vaikeusaste. Potilailla joiden diagnoosi oli viivästynyt, ei kuitenkaan todettu useammin luunmurtumia tai lisääntynyttä syöpäriskiä verrattuna potilaisiin, joilla diagnoosiin päästiin nopeammin. Osatyössä II tutkittiin suolen nukkavaurion olemassaoloa 393 ihokeliakiapotilaalla 45 vuoden tarkastelujakson aikana. Vaikea suolivaurio harvinaistui tarkastelujakson aikana, kun taas lievempi suolivaurio ja normaali suolirakenne yleistyivät. Seerumista tutkittavat TG2 vasta-aineet olivat useammin koholla silloin, kun suolistossa todettiin vaurio, verrattuna tilanteeseen, jossa nukkavauriota ei todettu. Osalla tutkittavista vasta-aineet olivat kuitenkin negatiiviset ohutsuolen nukkavauriosta huolimatta. Vasta-aineita tutkimalla ei täten löydetä kaikkia ihokeliakiapotilaita, joilla on suolivaurio. Osatyössä III tutkittiin, vaikuttaako suolivaurion olemassaolo ihokeliakiapotilaan pitkäaikaisennusteeseen. Sairaskertomustieto kerättiin 352 ihokeliakiapotilaalta, joista diagnoosivaiheessa 98:lla (28%) oli todettu normaali suolirakenne ja 254 (72%) potilasta, joilla oli todettu suolivaurio sekä kontrollina olleilta 128 keliakiapotilaalta. Tietoja täydennettiin kyselytutkimuksen avulla 181 ihokeliakiapotilaalta. Ihokeliakiapotilaiden välillä ei havaittu eroa iho-oireiden keston, keliakiaan yhdistettyjen komplikaatioiden, pitkäaikaissairauksien tai elämänlaadun välillä. Keliakiakontrolleilla todettiin kuitenkin useammin osteopeniaa tai osteoporoosia, kilpirauhassairauksia ja syöpiä verrattuna ihokeliakiapotilaisiin. Osatyössä IV toteutettiin 12 kuukauden gluteenialtistus oireettomille, keskimäärin 23 vuotta gluteenittomalla dieetillä olleille, ihokeliakiapotilaille. Ennen altistusta potilailla ei todettu nukkavauriota suolistossa ja 84%:lla ei todettu ihokoepalassa IgA/TG3 kertymiä. Altistus johti 18 (95%) potilaalla iho-oireiden ja/tai suolivaurion uusiutumiseen eli relapsiin. Iho-oireita tuli keskimäärin 5.6 kuukauden kuluttua 15 (79%) potilaalle ja kolmella (16%) todettiin vain suolivaurio relapsin yhteydessä. Väitöskirjatyön tulokset osoittavat, että ihokeliakian diagnostinen viive on lyhentynyt. Ohutsuolivaurioaste on ihokeliakiassa lieventynyt 45 vuoden aikana, ja seerumin korkeat TG2 vasta-aineet liittyvät usein ohutsuolivaurion olemassaoloon. Diagnoosivaiheen suolivaurion olemassaolo ei kuitenkaan vaikuta gluteenittoman ruokavaliohoidon vasteeseen eikä sairastumisriskiin tai elämänlaatuun ihokeliakiassa. Gluteenialtistus tuki aiempaa tietoa siitä, että tiukka gluteeniton ruokavalio on edelleen välttämätön kaikilla ihokeliakiapotilailla.Dermatitis herpetiformis (DH) is an extraintestinal manifestation 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 four separate studies. In Study I, the duration of the rash before diagnosis was examined from hospital records in 446 DH patients. The diagnosis was considered 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 questionnaires 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 questionnaire, 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 recovery 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 three (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 years 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

Sex-differences in Gluten-free Dietary Adherence and Clinical Symptoms in Patients with Long-term Treated Dermatitis Herpetiformis

Dermatitis herpetiformis is a blistering autoimmune skin disease, and a cutaneous manifestation of coeli-ac disease. The burden of coeliac disease is increased especially in females, but studies concerning sex differences in patients with long-term treated dermatitis herpetiformis are scarce. This questionnaire study compared adherence to a gluten-free diet, clinical symptoms and well-being between females and males in a cohort of 237 long-term treated (median 24 years) patients with dermatitis herpetiformis. Females had better adherence to a gluten-free diet (p = 0.022) and they used dapsone significantly less often at the time of the study than did males (4% vs 13%, p = 0.017). The occurrence of skin symptoms was equal in both sexes, but dermatological quality of life was lower in females (p = 0.024), and gastrointestinal symptoms were more severe among females with dermatitis her-petiformis than among males (p = 0.027). In conclusi-on, long-term treated female patients with dermatitis herpetiformis have better adherence to a gluten-free diet, but they also experience more severe clinical symptoms compared with males.publishedVersionPeer reviewe

Phenotypic Analysis of Disease-Relevant T Cells in Dermatitis Herpetiformis

publishedVersionNon peer reviewe

Gluten Challenge Induces Skin and Small Bowel Relapse in Long-Term Gluten-Free Diet-Treated Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of celiac disease causing an itchy, blistering rash. Granular IgA deposits in the skin are pathognomonic for DH, and the treatment of choice is a lifelong gluten-free diet (GFD). Preliminary evidence suggests that there are patients with DH who redevelop gluten tolerance after adherence to a GFD treatment. To evaluate this, we performed a 12-month gluten challenge with skin and small-bowel mucosal biopsy samples in 19 patients with DH who had adhered to a GFD for a mean of 23 years. Prechallenge biopsy was negative for skin IgA and transglutaminase 3 deposits in 16 patients (84%) and indicated normal villous height-to-crypt depth ratios in the small bowel mucosa in all 19 patients. The gluten challenge caused a relapse of the rash in 15 patients (79%) in a mean of 5.6 months; of these 15 patients, 13 had skin IgA and transglutaminase 3 deposits, and 12 had small-bowel villous atrophy. In addition, three patients without rash or immune deposits in the skin developed villous atrophy, whereas one patient persisted without any signs of relapse. In conclusion, 95% of the patients with DH were unable to tolerate gluten even after long-term adherence to a GFD. Therefore, lifelong GFD treatment remains justified in all patients with DH.Peer reviewe

Hepatoosipotilaiden synnytykset ja synnytysanalgesia TAYS:ssa vuosina 1997 - 2001

Syventävä työ ei kirjastoss

Hepatoosipotilaiden synnytykset ja synnytysanalgesia TAYS:ssa vuosina 1997 - 2001

Syventävä työ ei kirjastoss

Tunnistatko ihokeliakian?

publishedVersionPeer reviewe

Persistent skin symptoms after diagnosis and on a long-term gluten-free diet in dermatitis herpetiformis

Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease treated with a gluten-free diet. However, the itching and blistering rash alleviates slowly after gluten withdrawal and occasionally persists despite a long-term gluten-free diet. This study investigated the prevalence and factors associated with prolonged (i.e. > 2 years) and ongoing skin symptoms in 237 patients with dermatitis herpetiformis. Data were gathered from medical records and via questionnaires. Among patients with dermatitis herpetiformis, 38% had prolonged symptoms after diagnosis, and 14% had ongoing skin symptoms at follow-up (median duration of gluten-free diet 24 years). A severe rash at diagnosis was associated with both prolonged and ongoing cutaneous symptoms. In addition, patients with dermatitis herpetiformis with ongoing skin symptoms at follow-up had been on the dietary treatment for a shorter time (median duration 16 vs 25 years) and were less often on a strict diet (53% vs 78%) compared with patients with dermatitis herpetiformis without ongoing skin symptoms.publishedVersionPeer reviewe

Prognosis of Dermatitis Herpetiformis Patients with and without Villous Atrophy at Diagnosis

Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. At diagnosis, the majority of patients have villous atrophy in the small bowel mucosa. The objective of this study was to investigate whether the presence or absence of villous atrophy at diagnosis affects the long-term prognosis of DH. Data were gathered from the patient records of 352 DH and 248 coeliac disease patients, and follow-up data via questionnaires from 181 DH and 128 coeliac disease patients on a gluten-free diet (GFD). Of the DH patients, 72% had villous atrophy when DH was diagnosed, and these patients were significantly younger at diagnosis compared to those with normal small bowel mucosa (37 vs. 54 years, p < 0.001). Clinical recovery on a GFD did not differ significantly between the DH groups, nor did current adherence to a GFD, the presence of long-term illnesses, coeliac disease-related complications or gastrointestinal symptoms, or quality of life. By contrast, the coeliac disease controls had more often osteopenia/osteoporosis, thyroid diseases, malignancies and current gastrointestinal symptoms compared to the DH patients. In conclusion, villous atrophy at the time of DH diagnosis does not have an impact on the clinical recovery or long-term general health of DH patients