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The current knowledge on the associations between coeliac disease and different skin diseases is contradictory and the patient’s perspective on the burden of these is lacking. This study aimed to investigate patient-reported frequency, severity and quality of life effects of skin disorders in coeliac disease patients compared to controls and moreover to study the impacts of gluten-free diet on these skin diseases. A study questionnaire designed for the purposes of this study and a validated Dermatology Life Quality Index (DLQI) questionnaire were posted to 600 adult members of the Finnish Coeliac Society and 1173 matched controls. Responses from 327 coeliac disease patients and 382 non-coeliac controls were compared. Coeliac disease patients were shown to be at no increased risk of atopic dermatitis, acne, rosacea, psoriasis, alopecia areata, vitiligo or chronic urticaria. The severity of these skin diseases did not differ between study groups, but the risk for at least moderate effects on quality of life caused by dermatological diseases was increased among those with coeliac disease. Positive response from gluten-free diet was most commonly experienced by coeliac disease patients with atopic dermatitis. Even though the risk for skin diseases was shown not to be increased among coeliac disease patients, there is still an increased burden related to experienced skin symptoms among these patients, which non-dermatologists treating coeliac disease patients should acknowledge.

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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. publishedVersion

BackgroundDeep immune receptor sequencing, RepSeq, provides unprecedented opportunities for identifying and studying condition-associated T-cell clonotypes, represented by T-cell receptor (TCR) CDR3 sequences. However, due to the immense diversity of the immune repertoire, identification of condition relevant TCR CDR3s from total repertoires has mostly been limited to either "public" CDR3 sequences or to comparisons of CDR3 frequencies observed in a single individual. A methodology for the identification of condition-associated TCR CDR3s by direct population level comparison of RepSeq samples is currently lacking.ResultsWe present a method for direct population level comparison of RepSeq samples using immune repertoire sub-units (or sub-repertoires) that are shared across individuals. The method first performs unsupervised clustering of CDR3s within each sample. It then finds matching clusters across samples, called immune sub-repertoires, and performs statistical differential abundance testing at the level of the identified sub-repertoires. It finally ranks CDR3s in differentially abundant sub-repertoires for relevance to the condition. We applied the method on total TCR CDR3 beta RepSeq datasets of celiac disease patients, as well as on public datasets of yellow fever vaccination. The method successfully identified celiac disease associated CDR3 beta sequences, as evidenced by considerable agreement of TRBV-gene and positional amino acid usage patterns in the detected CDR3 beta sequences with previously known CDR3 beta s specific to gluten in celiac disease. It also successfully recovered significantly high numbers of previously known CDR3 beta sequences relevant to each condition than would be expected by chance.ConclusionWe conclude that immune sub-repertoires of similar immuno-genomic features shared across unrelated individuals can serve as viable units of immune repertoire comparison, serving as proxy for identification of condition-associated CDR3s.

Introduction: Celiac disease is characterized by an abnormal immune activation driven by the ingestion of gluten from wheat, barley, and rye. Gluten-specific CD4+ T cells play an important role in disease pathogenesis and are detectable among peripheral blood mononuclear cells (PBMCs). Areas covered: This review summarizes the use of celiac disease patient PBMCs in clinical applications focusing on their exploitation in the development of diagnostic approaches and novel drugs to replace or complement gluten-free diet. Expert opinion: The most used PBMC-based methods applied in celiac disease research include ELISpot and HLA-DQ:gluten tetramer technology. ELISpot has been utilized particularly in research aiming to develop a celiac disease vaccine and in studies addressing the toxicity of different grains in celiac disease. HLA-DQ:gluten tetramer technology on the other hand initially focused on improving current diagnostics but in combination with additional markers it is also a useful outcome measure in clinical trials to monitor the efficacy of drug candidates. In addition, the technology serves well in the more detailed characterization of celiac disease-specific T cells, thereby possibly revealing novel therapeutic targets. Future studies may also reveal clinical applications for PBMC microRNAs and/or dendritic cells or monocytes present among PBMCs. acceptedVersion

Anemia is a frequent finding in children with celiac disease but the detailed pathophysiological mechanisms in the intestine remain obscure. One possible explanation could be an abnormal expression of duodenal iron transport proteins. However, the results have so far been inconsistent. We investigated this issue by comparing immunohistochemical stainings of duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin, hephaestin and transferrin receptor 1 (TfR1) in duodenal biopsies between 27 children with celiac disease and duodenal atrophy, 10 celiac autoantibody-positive children with potential celiac disease and six autoantibody-negative control children. Twenty out of these 43 subjects had anemia. The expressions of the iron proteins were investigated with regard to saturation and the percentage of the stained area or stained membrane length of the enterocytes. The results showed the stained area of ferroportin to be increased and the saturation of hephaestin to be decreased in celiac disease patients compared with controls. There were no differences in the transporter protein expressions between anemic and non-anemic patients. The present results suggest an iron status-independent alteration of ferroportin and hephaestin proteins in children with histologically confirmed celiac disease. publishedVersion

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Additional file 1. Supplementary Information, Tables and Figures.

The clinical phenotype of celiac disease varies considerably among patients and the dosage of HLA-DQ2.5 alleles has been suggested to be a contributing factor. We investigated whether HLA-DQ2.5 allele dosage is associated with distinct clinical parameters at the time of diagnosis and with patients&rsquo, response to a gluten-free diet. The final cohort included 605 carefully phenotyped non-related Finnish celiac disease patients grouped as having 0, 1 or 2 copies of HLA-DQ2.5. Clinical data at the time of diagnosis and during gluten-free diet were collected systematically from medical records and supplementary interviews. An increasing HLA-DQ2.5 dose effect was detected for celiac disease antibody positivity at diagnosis (p = 0.021) and for the presence of any first-degree relatives with celiac disease (p = 0.011 and p = 0.031, respectively). Instead, DQ2.5-negative patients were suffering most often from classical symptoms at diagnosis (p = 0.007 between HLA groups). In addition, during follow-up they were most often symptomatic despite a gluten-free diet (p = 0.002 between groups). Our results thus suggest that increasing HLA-DQ2.5 dose only has a minor effect on the clinical picture of celiac disease. However, HLA-DQ2.5-negative patients should not be overlooked in clinical practice and particular attention should be paid to this patient group during gluten-free diet.

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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.

The factors determining the presentation of celiac disease are unclear. We investigated the phenotypic concordance and the distribution of human leukocyte antigen (HLA) risk haplotypes in affected siblings. One hundred sibling pairs were included. Clinical and histological parameters and HLA haplotypes were compared between the first diagnosed indexes and their siblings. The phenotype was categorized into gastrointestinal, extra-intestinal, malabsorption/anemia, and asymptomatic. The phenotype was fully concordant in 21 pairs. The most common concordant phenotype was gastrointestinal (14 pairs). Indexes had more anemia/malabsorption and extra-intestinal symptoms than siblings (45% vs. 20%, p &lt, 0.001 and 33% vs. 12%, p &lt, 0.001, respectively). Twenty siblings and none of the indexes were asymptomatic. The indexes were more often women (81% vs. 63%, p = 0.008). They were also more often seronegative (11% vs. 0%, p = 0.03) and younger (37 vs. 43 year, p &lt, 0.001), and had more severe histopathology (total/subtotal atrophy 79% vs. 58%, p = 0.047) at diagnosis. The indexes and siblings were comparable in other disease features. Pairs with discordant presentation had similar HLA haplotypes more often than the concordant pairs. The phenotype was observed to vary markedly between siblings, with the indexes generally having a more severe presentation. HLA did not explain the differences, suggesting that non-HLA genes and environmental factors play significant roles.

Käypä hoito -suositus. Päivitystiivistelmä

Supplemental material for Long-term health and treatment outcomes in adult coeliac disease patients diagnosed by screening in childhood by Laura Kivelä, Alina Popp, Taina Arvola, Heini Huhtala, Katri Kaukinen and Kalle Kurppa in United European Gastroenterology Journal

Table S1. Correlations between the percentage of TG2-specific plasma cells and other study parameters. (DOCX 15 kb)

In celiac disease, complete histological normalization of the small-intestinal mucosa occurs in only 8-20% of adult patients after commencing a gluten-free diet. Intraepithelial lymphocytosis may persist for years while villous morphology normalizes. Factors contributing to this and the clinical relevance of persistent intraepithelial lymphocytosis were here investigated.Altogether 177 adult celiac disease patients adhering to a long-term strict gluten-free diet were enrolled. Co-morbidities, ongoing medications, and consumption of oats and wheat-starch were recorded. Small-bowel morphology and intraepithelial lymphocyte count as well as laboratory parameters of malabsorption were evaluated. Gastrointestinal symptoms and psychological well-being were measured by structured questionnaires.In all, 170 (96%) out of the 177 patients evinced normal villous architecture and 7 (4%) villous atrophy. Among patients with normal villous structure, 96 (56%) had persistent intraepithelial lymphocytosis and 74 (44%) completely normal small-intestinal mucosa. Consumption of oats was the only factor contributing to the persistent intraepithelial lymphocytosis. Co-morbidities, Helicobacter pylori gastritis, drugs, or wheat-starch in the diet had no effect. The clinical outcome of the patients with persistent intraepithelial lymphocytosis was good, since no signs of malabsorption, excess malignancies, increase in gastrointestinal symptoms, or impaired quality of life were associated with it when compared to subjects with completely normal mucosa. The only outcome found in this study was a significantly lower, although normal villous height-crypt depth ratio among the patients with persistent intraepithelial lymphocytosis as compared to those with completely normal mucosa.Despite excellent villous recovery in this study, persistent intraepithelial lymphocytosis was still common among celiac disease patients on a long-term strict gluten-free diet. Consumption of oats was associated with persistent duodenal lymphocytosis and this calls for further investigations. The prognosis of patients with persistent intraepithelial lymphocytosis seems to be good while adhering to a gluten-free diet for a mean of 11 years.

Autoimmuunienteropatia (AIE) on harvinainen sairaus, jolle on tyypillistä pitkittynyt ripuli, imeytymishäiriö, immuunivälitteinen suolen limakalvovaurio ja reagoimattomuus ruokavaliomuutoksiin. Sairaus ilmenee ennen kaikkea ohutsuolessa. Limakalvolla on kuvattu lymfosyyttikertymiä, ja valtaosalla sairastuneista on kuvattu enterosyytti- tai pikarisoluvasta-aineita. AIE esiintyy ensisijaisesti imeväisillä, mutta myös aikuisiässä alkavaa sairautta on kuvattu. Jälkimmäisen diagnosointi voi olla haastavaa, koska mitään yksittäistä diagnostista testiä ei ole käytettävissä ja biopsialöydökset ovat viitteelliset. Kyseessä on ainakin osittain hoitokokeiluihin perustuva poissulkudiagnoosi. Monia immunosuppressiivisia lääkeaineita on käytetty vaihtelevalla menestyksellä. AIE:n ennuste riippuu suolen limakalvovaurion vaikeusasteesta ja siihen liittyvistä suoliston ulkopuolisista oireista ja sairauksista.

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications. BioMed Central open access

Background Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient. We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration. Methods Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined. Results Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients. Conclusions Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis. BioMed Central open access

Mitä uutta päivityksessä? Hoitamatonta keliakiaa esiintyy runsaasti iäkkäilläkin. Keliakia voi esiintyä ilman villuskatoa. Transglutaminaasispesifiset IgA-kertymät suolen limakalvolla ovat herkin menetelmä tällaisen alkavan keliakian toteamiseksi. Hoitoon reagoimattomassa refraktaarikeliakiassa erotetaan histologisesti tyypit I ja II. Viimeksi mainitussa ennuste on huonompi. EU-asetuksen mukaisesti gluteenittomat tuotteet jaotellaan kahteen ryhmään. "Gluteenittomat" sisältävät gluteenia alle 20 mg/kg ja "erittäin vähän gluteenia sisältävät" alle 100 mg/kg.

Background Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases. Methods We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease. Results Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples. Conclusion Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated. BioMed Central Open access

Keliakiassa viljatuotteiden valkuaisaine gluteeni aihettaa ohutsuolen limakalvovaurion, jonka paranemiseen tarvitaan elinikäinen gluteeniton ruokavaliohoito. Tyypillisiä oireita ovat ripuli ja vatsavaivat sekä laihtuminen, mutta usein keliakia on vähäoireinen, oireet voivat olla epätyypillisiä ja osa potilaista on täysin oireettomia. On arveltu, että jopa 1%:lla väestössä esiintyy tätä tautia. Keliakiaan on todettu olevan vahva perinnöllinen alttius ja tietyt HLA-tyypit todetaan yli 95%:lla suomalaisista keliaakikoista. Nykyisin tiedetään, että gluteenin aiheuttama ohutsuolen limakalvovaurio kehittyy vähitellen limakalvotulehduksesta suolinukan madaltumiseen ja aina nukan katoon asti. Diagnoosin asettaminen on perustunut vasta tämän selvän suolinukan kadon osittamiseen. Kuitenkin keliakian varhaiseen diagnoosiin ja hoitoon pyritään koska hoitamattomaan tautiin liittyy vaikeita komplikaatioita, kuten riski sairastua luukatoon ja pahanlaatuisiin kasvaimiin. Tutkimukssa selvittiin keliakiaan sopivan ohutsuolen limakalvon nukankadon ja erityisesti tätä ennakoivien varhaismuutosten esiintymistä eräissä keliakian riskiryhmissä. Tällaisiä riskiryhmiä olivat potilaat, joilla oli epäilty kliinisesti keliakiaa ja todettu seerumissa keliakiavasta-aineita, potilaat, jotka saivat suolisto-oireita viljatuotteista, sekä potilaat, joilla oli useampi kuin yksi umpieritysrauhasten autoimmuunisairaus kuten insuliinidiabetes tai kilpirauhasen liikatoiminta. Näiden potilaiden ohutsuolen limakalvomuutoksia verrattiin todettujen uusien keliakikkojen ohutsuolilöydöksiin ennen hoitoa ja gluteenittoman ruokavaliohoidon jälkeen. Lisäksi selvitettiin tälläisten limakalvon rakenne ja tulehdusmuutoksten esiintymistä keliakian paranemisvaiheessa, ja erityisesti miten pienet gluteenimäärät vaikuttavata limakalvon kuntoon. Keliakiaan sopiva ohutsuolen limakalvon nukankato todettiin 30%:lla potilaista, joilla oli epäilty keliakiaa ja todettu keliakiavasta-aineita, 9%:lla viljaoireisista potilaista ja 11%:lla potilaista, joilla oli useita umpierityssairauksia. Tyypillisesti näillä todetuilla keliakiapotilailla ohutsuolen limakalvon intraepiteliaaliset tulehdussolut, ja erityisesti gd+ T-solutiheydet, olivat koholla. Nykyisten keliakian diagnostisten kriteerien perusteella keliakia poissuljettiin kahdella kolmasosalla potilaista, koska heidän ohutsuolen limakalvon nukka oli normaali. Näistä 9%:lla kuitenkin todettiin lieviä alkavaan keliakiaan sopivia rakennemuutoksia. Lisäksi 28%:lla intraepiteliaaliset gd+-solutiheydet olivat koholla; näistä potilaista kymmeneltä otettiin myöhemmin kontrolliohutsuolinäyte ja tuolloin viidelle oli kehittynyt selvä keliakiaan sopiva nukankato kun gluteenin käyttöä oli jatkettu. Vaikka ohutsuolen limakalvon koholla olevat gd+-solut näyttivät ennustuvan alkavaa keliakiaa, näiden solujen esiintyminen ei liittynyt aina keliakialle tyypilliseen perimään (HLA-tyyppiin). Seerumin keliakiavasta-aineiden, retikuliini-, endomysium- ja transglutaminaasvasta-aineiden, tarkuus keliakialle nähtiin myös tässä tutkimuksessä. Koholla olevat keliakiavasta-aineet eivät kuitenkaan aina liittyneet keliakiaan tai alkavaan keliakiaan; 64%:lla gliadiinivasta-aine-positiivisista potilaista ohutsuolen limakalvo oli täysin normaali, eikä tämä vasta-aine-positiivisuus liittynyt aina keliakian perimään. Ohutsuolen limakalvovaurio näytti korjaantuvan täysin pitkäkestoisen gluteenittoman ruokavaliohoidon aikana, jos dieetti oli tiukka. Pienet gluteenijäämät gluteenittomissa vehnätärkkelystuotteissa ei vaikuttanut limakalvon tilanteeseen. Limakalvon paraneminen oli vaillinainen, jos dieetin oli kestänyt alle kaksi vuotta tai jos potilailla oli selviä dieettipoikkeamia. Tutkimuksessa ohutsuolen limakalvon nukankorkeuden ja kuopakkeiden syvyyden-suhteen määrittäminen osottautui herkimmäksi mittariksi osoittamaan limakalvovauriota gluteenittoman dieetin aikana; limakalvon tulehdussolujen mittaaminen ja seerumin keliakiavasta-aineiden määrittäminen eivät olleet yhtä herkkiä osoittamaan vaillinaista dieettiä ja limakalvovauriota. Aiemmin gd+-solujen koholla oloa on pidetty pysyvänä muutoksena jopa keliakian hoidon aikana; tutkimuksessa myös näiden solujen tiheys väheni selvästi dieetin myötä. Suurimmalla osalla kuitenkin keskimäärin kymmenen hoitovuoden jälkeen nämä gd+-solut olivat vielä koholla. Tätä tietoa voidaan käyttä hyväksi keliakian diagnostiikassa tilanteissa, joissa diagnostinen ohutsuolikoepala otetaan vasta, kun potilas on jo gluteenittomalla ruokavaliohoidolla. Tuolloin limakalvon nukan rakenne on voinut jo täysin korjaantua; jos dieetti ei ole kestänyt hyvin pitkään ja jos gd+ solujen tiheys on normaali, puhuvat löydökset keliakian olemassaoloa vastaan. Nykyisten diagnostisten kriteerien perusteella osa oireisistakin keliaakikoista jää toteamatta. Jos keliakian diagnostisia kriteerejä laajennetaan koskemaan myös ohutsuolen limakalvon lievempiä muutoksia, ylidiagnosoinnin vaara on olemassa. Kaikilla potilailla, joilla oli lieviä viiteitä alkavaan keliakian ei ollut keliakialle tyypillisiä HLA-tyypejä; tänä päivänä ei tiedetä mikä tälläisten henkilöiden, joilla ei ole keliakialle tyypillistä perimää, löydösten merkitys tai ennuste on ja tarvitseeko tällaisia potilaita hoitaa elinikäisellä gluteenittomalla ruokavaliohoidolla. Tutkimalla yhdessä ohutsuolen limakalvon tarkkaa rakenneanalyysia, määrittämällä limakalvon kokonais- ja gd+-tulehdussolut ja mittaamalla seerumista retikuliini-, endomysium- tai trasglutmainaasivasta-aineita sekä määrittämällä keliakialle tyypilliset HLA-tyypit voidaan keliakiapotilaat löytää jo ennen selvän suolinukan kadon toteamista. The current diagnostic criteria for coeliac disease require small bowel mucosal villous atrophy with crypt hyperplasia although the damage develops gradually. The disease is strongly associated with HLA DQ2, less commonly with DQ8 haplotype. Untreated coeliac patients are prone to complications such as small bowel lymphoma and osteoporosis; early detection and treatment of the condition is thus warranted. Small bowel mucosal structural and inflammatory changes suggestive of coeliac disease were studied in 96 consecutive patients suspected of coeliac disease and found to have IgA-class antireticulin (ARA) or antigliadin antibodies (AGA), in 93 adults with a history of cereal intolerance, and in 62 adults with multiple autoimmune endocrinological disorders. The focus of interest was on minor small bowel mucosal changes indicative of coeliac disease in patients excluded for coeliac disease on the basis of current diagnostic criteria. Small bowel mucosal changes were compared to those in untreated and treated coeliac patients and in 30 non-coeliac controls. In patients on gluten-free diet, the focus was to investigate how small amounts of ingested gluten affect small bowel mucosal integrity. Small bowel villous atrophy and crypt hyperplasia compatible with coeliac disease were found in 29 (30%) patients suspected of coeliac disease, and positive for ARA or AGA, in eight (9%) with a history of cereal intolerance and in seven (11%) with multiple autoimmune endocrinological disorders. The densities of intraepithelial lymphocytes (IELs), especially gd+ cells, were increased in untreated coeliac patients when compared to non-coeliac controls, and HLA DQ2 was found in all new coeliac patients tested. The small bowel mucosa recovered fully in all patients on a long-term strict gluten-free diet, and mucosal integrity was not dependent on trace amounts of gluten coming from daily ingestion of gluten-free wheat starch. The mucosal recovery was not complete and the villous height and crypt depth ratio (VH/ CrD) was lower than in non-coeliac controls when the duration of the diet was less than 24 months or when patients had dietary lapses. Measurements of small bowel mucosal enterocyte height, IELs, enhanced HLA DR expression or serum coeliac antibodies were not as sensitive indicators of mucosal damage as the VH/CrD ratio during treatment. Even the density of gd+ IELs decreased, but in most patients these cells remained high throughout gluten-free diet; this finding can be applied in cases where the diagnostic small bowel biopsy is taken after the patient is already on a gluten-free diet and if the villous architecture has fully recovered. In all, 179 patients were excluded for coeliac disease. Seventeen (9%) of them were found to have minor mucosal structural abnormalities (mucosal inflammation and/or crypt hyperplasia), and in 50 (28%) patients the densities of gd+ IELs were increased. Five out of 10 patients having initially normal small bowel mucosal villous architecture but an increased density of gd+ IELs had villous atrophy compatible with coeliac disease in the second follow-up biopsy; two of the five were ARA positive and three had only AGA present at the beginning of the study. Even though an increased density of gd+ IELs seemed to predict the forthcoming villous atrophy, the increase in gd+ cells was not restricted to coeliac-type HLA (DQ2 or DQ8). Similarly, these HLA types were not detected in all patients having a high count of total IELs, enhanced mucosal HLA DR expression or positive coeliac serology. A history of abdominal symptoms related to ingestion of cereals turned out to be an unspecific sign of overt or potential coeliac disease. Altogether, a detailed small bowel mucosal morphological examination, determination of total and gd+ IELs, serum coeliac antibodies, and HLA DQ alleles were not alone sufficient for a diagnosis of coeliac disease. With a combination of these tests gluten-intolerant patients may be identified even before the development of overt small bowel mucosal villous atrophy.

Due to the increasing number of patients with inflammatory bowel disease (IBD), self-monitoring is being implemented for the treatment and follow-up of the patients. Faecal calprotectin (FC) has replaced repeated colonoscopies in evaluating the inflammatory activity, and also other faecal markers as faecal lactoferrin (FLf) are studied. An enzyme-linked immunosorbent assay (ELISA) test for FC is time-consuming, and several rapid point-of-care -tests have been developed. Long-standing mucosal inflammation of the colon predisposes to colonic dysplasia and colorectal carcinoma (CRC). The aims of this thesis were to evaluate the FC and FLf rapid tests in assessing the activity of colonic IBD, to develop a simple activity index for colonic IBD, to evaluate a new home-monitoring strategy in the follow-up and treatment of patients with colonic IBD, and to study the role of sequential FC measurements and the long-term inflammatory burden in predicting colonic dysplasia or CRC in UC patients. All patients were recruited from Helsinki University Hospital Clinic of gastroenterology. The inflammatory activity was assessed with clinical and endoscopic indices. The point-of-care faecal tests used were CerTest Calprotectin and Prevent ID CalDetect for FC, and CerTest Lactoferrin for FLf. For evaluatingand validating the FC and FLf rapid tests against the clinical, endoscopic, and histological inflammatory activity of colonic IBD, and for developing a combination activity index of FC and a symptom score, consecutive patients with colonic IBD referred to ileocolonoscopy from January 2013 to September 2013 were recruited. The final cohort comprised 72 patients. All patients provided a stool sample for FC and FLf. For the home-monitoring study, consecutive patients with colonic IBD between April 2015 and December 2016 were recruited and randomized into the home-monitoring and control patients. The final cohort constituted of 63 patients in the home-monitoring group and 60 patients in the control group, and the study period was 12 months for each patient. The clinical IBD activity and the health-related quality of life were assessed. The home-monitoring group performed a rapid FC test at home once in two months. For evaluating the role of FC in predicting dysplasia and IBD-related CRC, all the faecal samples and patients with a diagnosis of UC from January 2007 to December 2017 were collected from the databases. The final cohort was 4649 FC results from 982 UC patients. The histological grade of inflammation, detected dysplasias, sporadic adenomas, UC-associated colonic carcinomas, and colectomies related to UC were analyzed. In all studies, the inflammatory activity of IBD was low. The overall correlation with ELISA FC and rapid FC and FLf tests was statistically significant, but the tests yielded same results in only 53-76 % of samples. The patient-reported symptoms correlated significantly with FC, the histological inflammation activity in both CD and UC, and the clinical and endoscopic activity in UC but not in CD. The influence of IBD in the daily life of patients did not correlate with the IBD activity measured with more objective parameters. The combination index consisting of IBD symptom index and CalDetect test detected histological remission or mild disease slightly better than CalDetect test or patient-reported symptoms alone. In the home-monitoring study the drop-out rate was 71 % in total, 62 % in the home-monitoring group and 80 % in the control patients. Older patients and patients with higher disease burden were more compliant to the study. There were no differences in the IBD activity in the home-monitoring group between the baseline and the end of the study, or between the groups. 4 % of patients had IBD-associated dysplasia and 0.7 % developed CRC during a median follow up of 8 years. The colonic dysplasia or CRC was significantly more common in patients with constant severe inflammation and long-term histological inflammation than in patients with constant remission. FC or time-weighted FC did not predict dysplasia in the whole cohort. Both FC rapid tests and FLf test could identify patients with inactive IBD or non-inflammatory symptoms, and thus they can be used in screening for gastrointestinal inflammation. The patient-reported symptoms correlated well with the objective markers of IBD activity, while the quality of life did not. The self-monitoring of IBD activity provides an option for individualized care for IBD patients, but the adherence to the self-monitoring program remains a challenge. UC-patients with long-term severe inflammation are at higher risk for developing colonic dysplasia or IBD-related CRC than patients with long-term remission or mildly active disease. FC does not, however, predict the risk of dysplasia in unselected UC patients. Lisääntyneen tulehduksellisia suolistosairauksia (IBD) sairastavien potilaiden määrän takia tarvitaan uusia keinoja potilaiden seurantaan ja hoitoon, ja kotiseurantaan perustuvia ohjelmia on otettu käyttöön. Aiemmin ainoa objektiivinen keino seurata suolitulehduksen aktiivisuutta olivat toistuvat kolonoskopiat, mutta viimeisten vuosikymmenien aikana ulosteen kalprotektiini on lähes syrjäyttänyt kolonoskopiat tulehduksen seurannassa. Myös muita ulosteen tulehdusmerkkiaineita, kuten laktoferriiniä, on tutkittu. Ulosteen kalprotektiinitaso kuvastaa hyvin suolitulehduksen vaikeusastetta. Kalprotektiini voidaan määrittää laboratoriossa entsyymi-immunologisella menetelmällä (ELISA), mutta testi on aikaa vievä. Tämän vuoksi on kehitetty useita kalprotektiinia mittaavia ulostepikatestejä. Pitkäkestoinen paksusuolen limakalvon tulehdus altistaa suolen limakalvon solumuutoksille (dysplasia) ja paksusuolisyövälle. Kolonoskopiaseurannan kohdentaminen entistä paremmin vain suuren syöpäriskin potilaille on tärkeää kasvavan potilasmäärän vuoksi. Väitöskirja koostui neljästä osatyöstä. Ulostepikatestien arvioimiseksi ja yhdistelmäindeksin kehittämiseksi analysoitiin 72 IBD-potilaan kolonoskopialöydökset sekä IBD:n kliininen aktiivisuus, ja määritettiin ulosteen kalprotektiini sekä ELISA-menetelmällä että kahdella tutkimuskäytössä olleella kalprotektiinipikatestillä. Lisäksi määritettiin ulosteen laktoferriini tutkimuskäytössä olleella pikatestillä. Oirekyselyllä selvitettiin potilaan oireet ja taudin vaikutus elämänlaatuun edellisen viikon ajalta. Tulehduksen arvioimisen tehostamiseksi luotiin yhdistelmäindeksi yhdistämällä potilaan raportoimat oireet ja kalprotektiinipikatestin tulos. Kotiseurantatutkimukseen osallistui 123 potilasta (63 kotiseurantapotilasta ja 60 kontrollipotilasta). Potilaiden IBD:n aktiivisuutta, elämänlaatua ja ulosteen kalprotektiinia mitattiin vuoden kestävässä seurannassa kotiseurantapotilailla 2 kuukauden välein. Dysplasiaseulonnan kohdentamiseksi suuren dysplasia- tai syöpäriskin IBD-potilaille selvitettiin kalprotektiiniseurannan käyttöä suuren riskin potilaiden tunnistamisessa ja dysplasian kehittymisen ennustamisessa. Tätä varten analysoitiin takautuvasti 982 potilaan 4649 kalprotektiininäytettä vuosien 2007–2017 väliseltä ajalta. Myös kolonoskopioiden histologiset löydökset, adenoomien, dysplasioiden ja paksusuolisyöpien sekä paksusuolen poistoleikkausten määrä selvitettiin. Kaikkien ulostepikatestien tulokset olivat verrannollisia potilaan oireisiin ja kolonoskopialöydöksiin. Yhdistelmäindeksin herkkyys todeta aktiivinen suolitulehdus oli jonkin verran parempi kuin pelkän kalprotektiinin tai oirekyselyn. Potilaiden koettu elämänlaatu ei ollut verrannollinen oireisiin tai objektiivisiin suolitulehduksen mittareihin. Kotiseurantatutkimuksessa 71 % potilaista lopetti tutkimuksen ennen seuranta-ajan päättymistä. Tutkimusta jatkaneet potilaat olivat vanhempia kuin tutkimuksen lopettaneet potilaat, ja he kokivat suolistotulehduksen vaikutuksen elämäänsä suuremmaksi kuin tutkimuksen lopettaneet. 4 %:lla potilaista todettiin solumuutoksia ja 0,7 %:lle kehittyi paksusuolisyöpä tutkimusajanjakson aikana. Solumuutokset tai syöpä olivat tavallisempia niillä potilailla, joiden ulosteen kalprotektiini oli jokaisessa mittauksessa koholla, tai joilla todettiin vaikeita tulehdusmuutoksia jokaisen kolonoskopian kudosnäytteissä, kuin niillä potilailla, joiden tauti oli jatkuvasti rauhallinen. Sekä kalprotektiini- että laktoferriinipikatestit erottivat aktiivisen suolistotulehduksen ei-aktiivisesta tulehduksesta, mutta matalan herkkyytensä takia ne sopivat parhaiten seulontatesteiksi ja erotusdiagnostiikkaan. Yhdistelmäindeksin herkkyys erottaa aktiivinen suolitulehdus oli jonkin verran parempi kuin pelkän kalprotektiinin. Jatkuva vaikea suolitulehdus sekä kalprotektiinilla että kudosnäytteiden tarkastelulla arvioituna altistaa paksusuolisyövälle verrattuna niihin potilaisiin, joiden tauti on jatkuvasti rauhallinen. Kalprotektiini ei kuitenkaan ennustanut solumuutosten tai syövän kehittymistä koko potilasryhmässä. Potilaiden huono sitoutuminen kotiseurantaan heikentää kotiseurannan vaikuttavuutta. Parempaa sitoutumista ennustivat korkeampi ikä ja taudin suurempi vaikutus jokapäiväiseen elämään.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. \ud \ud \ud \ud Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). \ud \ud \ud \ud Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. \ud \ud \ud \ud Results: The median VH in NCGS was significantly shorter (600, IQR: 400–705) than controls (900, IQR: 667–1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390–620) vs. 427 µm (IQR: 348–569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. \ud \ud \ud \ud Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Coeliac disease is hallmarked by an abnormal immune reaction against ingested wheat-, rye- and barley-derived gluten and the presence of transglutaminase 2 (TG2)-targeted autoantibodies. The small-bowel mucosal damage characteristic of the disorder develops gradually from normal villus morphology to inflammation and finally to villus atrophy with crypt hyperplasia. Patients with early-stage coeliac disease have TG2-autoantibodies present in serum and small-intestinal mucosa and they may already suffer from abdominal symptoms before the development of villus atrophy. Previously, we have shown that intraperitoneal injections of coeliac patient-derived sera or purified immunoglobulin fraction into mice induce a condition mimicking early-stage coeliac disease. In the current study, we sought to establish whether recombinantly produced patient-derived TG2-targeted autoantibodies are by themselves sufficient for the development of such an experimentally induced condition in immune-compromised mice. Interestingly, mice injected with coeliac patient TG2-antibodies had altered small-intestinal mucosal morphology, increased lamina propria cellular infiltration and disease-specific autoantibodies deposited in the small bowel, but did not evince clinical features of the disease. Thus, coeliac patient-derived TG2-specific autoantibodies seem to be sufficient for the induction of subtle small-bowel mucosal alterations in mice, but the development of clinical features probably requires additional factors such as other antibody populations relevant in coeliac disease.

Health-related quality of life (HRQoL) measurement has become an important outcome in treatment trials and in health policy decisions. HRQoL can be measured by using generic or disease-specific tools. Generic instruments can be used for comparing health status among patients in different health states and conditions but they do not focus specifically on the issues relevant in a particular disease. Disease-specific tools may be more responsive to changes within a specific condition. In earlier studies, impairment of HRQoL has been evident in patients with inflammatory bowel disease (IBD), especially when the disease is active. Data about the impact of comorbidity or demographic characteristics of the patients on HRQoL are partly controversial. This study, which comprised 2913 adult IBD patients, examined HRQoL using the disease-specific IBDQ and the general 15D instruments. The 15D scores of IBD patients were compared with scores of a gender and age matched general population sample. Frequency of IBD symptoms and arrangement of therapy were studied and compared with those of IBD patients in an earlier European study. Furthermore, data of other chronic diseases of the patients were obtained from the Social Insurance Institution s reimbursement register and comorbidity of IBD patients was compared with that of age and gender matched controls. --- Of the respondents, 37% reported that they suffered from disturbing IBD symptoms weekly. In 17% of the patients, the symptoms greatly affected the ability to enjoy leisure activities, and 14% stated that these symptoms greatly affected their capacity to work. Despite that, the great majority (93%) of patients expressed satisfaction with their current treatment, which exceeded the rate observed in the other European patients. The mean IBDQ score was 163, as the possible range is 32-224, and disease activity was strongly correlated with HRQoL. Older age, comorbid diseases, and female gender were also related to impairment of HRQoL. Lower HRQoL scores were seen also in newly-diagnosed patients and in those with a history of surgery, especially after stoma or ileal pouch-anal anastomosis (IPAA) operation. The range of 15D scores was 0.30-1.00, with mean of 0.87. As with the IBDQ, disease activity, older age and history of surgery were correlated with the score. Both the newly-diagnosed patients and patients with a long-lasting disease had lower scores than average even after adjusting for age. The 15D scores of IBD patients were significantly lower than those of the control group. A strong correlation was seen between the 15D and the IBDQ scores. Comorbidity with other chronic diseases was observed in 29% of IBD patients. Connective tissue diseases, chronic obstructive pulmonary diseases, pernicious anaemia, and coronary heart disease (CHD) were significantly increased in patients with IBD. Especially female IBD patients appeared to be at increased risk for CHD, and patients who reported weekly IBD symptoms had a higher risk for having other chronic diseases in addition to IBD. Comorbidity impaired HRQoL, as measured with both generic and disease-specific tools. In conclusion, HRQoL is impaired in IBD patients. An understanding of predictors of HRQoL will help to recognise patients who will need special support. Terveyteen liittyvä elämänlaatu on tärkeä hoidon vaikuttavuuden mittari hoitotutkimuksissa ja terveyspoliittisissa päätöksissä. Terveyteen liittyvää elämänlaatua voidaan tutkia yleisillä tai tautispesifisillä elämänlaatumittareilla. Yleiset mittarit sopivat elämänlaadun vertailuun eri väestö- ja sairausryhmien välillä, mutta niiden antama kokonaiskäsitys tietyn sairauden vaikutuksesta yksilöön on usein rajallinen. Tautispesifiset mittarit on kehitetty antamaan tietoa tilan ja elämänlaadun vaihtelusta tietyssä sairaudessa. Tulehdukselliset suolistosairaudet ovat kroonisia sairauksia, joihin usein liittyy ajoittaisia pahenemisvaiheita. Aiemmissa tutkimuksissa on todettu tulehduksellisten suolistosairauksien huonontavan elämänlaatua etenkin sairauden ollessa aktiivinen. Tutkimustieto muista elämänlaatuun vaikuttavista tekijöistä ja potilaiden muusta sairastavuudesta on osin ristiriitaista ja puutteellista. Tutkimuksen tarkoituksena oli tutkia tulehduksellista suolistosairautta sairastavien potilaiden elämänlaatua sekä yleisellä (15D) että tautispesifisellä (Inflammatory Bowel Disease Questionnaire, IBDQ) elämänlaatumittarilla. Tutkimuspotilaat kerättiin Kelan erityiskorvausrekisteristä ja potilasyhdistyksen jäsenrekisteristä. Potilaiden elämänlaatua verrattiin ikä- ja sukupuolivakioituun verrokkiväestöön ja oireiden yleisyyttä ja hoidon järjestelyä muualta Euroopasta aiemmin saatuihin tuloksiin. Kelan erityiskorvattavuusrekisteristä saatiin tiedot potilaille ja heidän verrokeilleen myönnetyistä erityiskorvausoikeuksista. Tutkimuksen kyselykaavake postitettiin 5342:lle täysi-ikäiselle tulehduksellista suolistosairautta sairastavalle henkilölle. Vastausprosentti oli 57%. Tutkittavista 37% kertoi kärsivänsä viikoittain tulehdukselliseen suolistosairauteen liittyvistä oireista ja 14%:lla oireet vaikuttivat huomattavasti myös työkykyyn. Siitä huolimatta tyytyväisyys nykyiseen hoitoon oli suurempaa kuin aiemmassa eurooppalaisessa tutkimuksessa. Taudin aktiivisuus vaikutti eniten sekä yleisellä että tautispesifisellä mittarilla mitattuun elämänlaatuun, mutta myös lisäsairaudet ja ikääntyminen ennustivat huonompia elämänlaatupistemääriä. Vastikään diagnoosin saaneiden ja leikkauksen läpikäyneiden potilaiden pistemäärät olivat keskimääräistä huonompia ja tautispesifisellä mittarilla mitattu elämänlaatu oli naisilla merkittävästi alhaisempi kuin miehillä. Tulehduksellista suolistosairautta sairastavien elämänlaatu oli verrokkiryhmää huonompi. 15D:n ja IBDQ:n pistemäärät korreloivat toisiinsa voimakkaasti. Sidekudostautien, kroonisten keuhkosairauksien, pernisiöösin anemian ja sepelvaltimotaudin esiintyvyys oli merkittävästi lisääntynyt tulehduksellista suolistosairautta sairastavilla verrattuna ikä- ja sukupuolivakioituun verrokkiryhmään. Sepelvaltimotaudin riski oli suurentunut selvimmin naispuolisilla potilailla. Aktiivia tulehduksellista suolistosairautta sairastavilla oli useammin myös jokin muu erityiskorvausoikeus ja lisäsairaudet huononsivat sekä yleistä että tautispesifistä elämänlaatua. Tulehduksellista suolistosairautta sairastavien elämänlaatu on verrokkiväestöä huonompi. Terveyteen liittyvään elämänlaatuun vaikuttavien tekijöiden tunteminen auttaa tunnistamaan erityistä tukea tarvitsevat potilaat.

Matrix metalloproteinases (MMPs) represent a family of 23 metalloendopeptidases, collectively capable of degrading all components of the extracellular matrix. MMPs have been implicated in several inflammatory processes such as arthritis, atherosclerosis, and even carcinomas. They are also involved in several beneficial activities such as epithelial repair. MMPs are inhibited by endogenous tissue inhibitors of matrix metalloproteinases (TIMP). In this study, MMPs were investigated in intestinal mucosa of inflammatory bowel diseases (IBD), chronic intestinal disorders. The main focus was to characterize mucosal inflammation in the intestine, but also cutaneous pyoderma gangrenosum (PG), to assess similarites with IBD inflammation. MMPs and TIMPs were mainly examined in colonic mucosa, in adult Crohn s disease (CD), and paediatric CD, ulcerative colitis (UC), and indeterminate colitis (IC). Ileal pouch mucosa of proctocolectomized paediatric onset IBD patients was also investigated to characterize pouch mucosa. The focus was on finding specific MMPs that could act as markers to differentiate between different IBD disorders, and MMPs that could be implied as markers for tissue injury, potentially serving as targets for MMP-inhibitors. All examinations were performed using immunohistochemistry. The results show that immunosuppressive agents decrease stromal expression of MMP-9 and -26 that could serve as specific targets for MMP-inhibitors in treating CD. In paediatric colonic inflammation, MMP-10 and TIMP-3 present as molecular markers for IBD inflammation, and MMP-7 for CD. MMP expression in the the pouch mucosa could not be classified as strictly IBD- or non-IBD-like. For the first time, this study describes the expression of MMP-3, -7, -9, -12, and TIMP-2 and -3 in pouch mucosa. The MMP profile in PG bears resemblance to both intestinal IBD inflammation and cutaneous inflammation. Based on the results, MMPs and their inhibitors emerge as promising tools in the differential diagnosis of IBD and characterization of the disease subtype, although further research is necessary. Furthermore, the expression of several MMPs in pouch has been described for the first time. While further research is warranted, the findings contribute to a better understanding of events occurring in IBD mucosa, as well as pyoderma gangrenosum. Matriksin metalloproteinaasit (MMP) muodostavat 23 metalloendopeptidaasin perheen, jotka yhdessä kykenevät hajottamaan kaikkia soluväliaineen rakenneosia. Ne on yhdistetty useisiin tulehduksellisiin tapahtumiin, kuten nivelrikkoon, valtimonrasvoittumistautiin, jopa syöpiin. MMP:t osallistuvat myös suotuisiin tapahtumiin, kuten epiteelirikon korjaamiseen. MMP:iden toimintoja estävät niiden spesifit kudosestäjät, TIMP:t. Tässä tutkimuksessa olemme tarkastelleet suolen limakalvoa kroonisissa tulehduksellisissa suolistosairauksissa (IBD). Tavoitteenamme on ollut luokitella ja kuvata tulehdusta paitsi suolen limakalvolla myös autoimmuunitauteihin yhdistetyssä ihon haavassa, pyoderma gangrenosumissa (PG), jonka samanlaisuutta IBD-tulehduksen kanssa olemme pyrkineet arvioimaan. Olemme tutkineet MMP:itä ja TIMP:itä pääasiallisesti paksusuolen limakalvolla aikuisten Crohnin taudissa (CD), lasten CD:ssa ja haavaisessa paksusuolen tulehduksessa (UC) sekä määrittämättömässä koliitissa (IC). Olemme arvioineet myös nuoruusiässä puhjennutta tautia sairastavia henkilöitä, joilta paksusuoli on poistettu. Heiltä olemme tutkineet ohutsuolesta tehdyn ulostesäiliön limakalvoa ja pyrkineet luonnehtimaan sen MMP-profiilia. Tutkimuksen keskeisenä tavoitteena on ollut löytää tiettyjä MMP:itä, jotka voisivat toimia markkereina tulehduksellisen suolistosairauden erotusdiagnostiikassa, sekä tunnistaa limakalvovaurioon liittyviä MMP:itä, joita vastaan voisi mahdollisesti käyttää MMP-estäjiä. Kaikki tutkimukset on toteutettu immunohistokemiallisin menetelmin. Tuloksista näemme, että immunosuppressoivat lääkkeet vähensivät MMP-9:n ja MMP-26:n ilmentymistä Crohnin tautia sairastavien aikuispotilaiden suolen limakalvolla. Nämä MMP:t voisivat mahdollisesti toimia MMP-estäjien kohteina Crohnin taudin hoidossa. Sen sijaan lasten paksusuolen tulehduksessa MMP-10 ja TIMP-3 näyttäytyvät mahdollisina markkereina IBD-tulehdukselle ja MMP-7 markkerina Crohnin taudille. Paksusuolen poiston läpikäyneiden potilaiden ohutsuolen säiliön limakalvon MMP-profiilin ei voitu näyttää olevan selkeästi IBD- tai ei-IBD-tyyppistä. Tässä tutkimuksessa kuitenkin ensimmäistä kertaa osoitetaan MMP-3:n, MMP-7:n, MMP-9:n, ja MMP-12:n, sekä TIMP-2:n ja TIMP-3:n ilmentyminen ohutsuolisäiliön limakalvolla. PG:n MMP-profiili muistutti osin IBD:n tulehtunutta limakalvoa. PG:n tulehduksessa on kuitenkin piirteitä myös ihon tulehduksesta. Näihin tutkimuksiin pohjautuen, MMP:t ja niiden estäjät vaikuttavat lupaavilta apuvälineiltä tulehduksellisen suolistosairauden erotusdiagnostiikassa ja luokittelussa. Lisäksi useiden MMP:iden ilmentyminen ohutsuolesta rakennetussa säiliössä osoitettiin nyt ensimmäisen kerran. Nämä löydökset lisäävät tietämystä tulehduksellisen suolistosairauden limakalvon ja pyoderma gangrenosumin tapahtumista.

The purpose of this study was to evaluate subjective food-related gastrointestinal symptoms and their relation to cow’s milk by determining the genotype of adult-type hypolactasia, measuring antibodies against milk protein, and screening the most common cause for secondary hypolactasia, namely coeliac disease. The whole study group comprised 1900 adults who gave a blood sample for the study when they attended a health care centre laboratory for various reasons. Of these 1885 (99%) completed a questionnaire on food-related gastrointestinal symptoms. Study No. I evaluated the prevalence of adult-type hypolactasia and its correlation to self-reported milk induced gastrointestinal symptoms. The testing for hypolactasia was done by determination of the C/T-13910 genotypes of the study subjects. The results show that patients with the C/C-13910 genotype associated with adult type hypolactasia consume less milk than those with C/T-13910 and T/T-13910 genotypes. Study No. II evaluated the prevalence and clinical characteristics of undiagnosed coeliac disease in the whole study population with transglutaminase and endomysium antibodies and their correlation with gastrointestinal symptoms. The prevalence of coeliac disease was 2 %, which is surprisingly high. Serum transglutaminase and endomysium antibodies are valuable tools for recognising an undiagnosed coeliac disease in outpatient clinics. In the study No. III the evaluation of milk protein IgE related hypersensitivity was carried out by stratifying all 756 study subjects with milk related problems and randomly choosing 100 age and sex matched controls with no such symptoms from the rest of the original study group. In the study No. IV 400 serum samples were randomly selected for analyzing milk protein related IgA and IgG antibodies and their correlation to milk related GI-symptoms. The measurement of milk protein IgA, IgE or IgG (studies No. III and IV) did not correlate clearly to milk induced symptoms and gave no clinically significant information; hence their measurement is not encouraged in outpatient clinics. In conclusion, adult type hypolactasia is often considered the reason for gastrointestinal symptoms in adults and determination of the C/T-13910 genotypes is a practical way of diagnosing adult type hypolactasia in an outpatient setting. Undiagnosed coeliac disease, should be actively screened and diagnosed in order to apply a gluten free diet and avoid the GI-symptoms and nutritional deficiencies. Cow’s milk hypersensitivity in the adult population is difficult to diagnose since the mechanism in which it is mediated is still unclear. Measuring of cow’s milk protein specific antibodies IgE, IgA or IgG do not correlate with subjective milk-related GI-symptoms. Väitöskirjatyössä tarkasteltiin työikäisen väestön maidon käyttöön liitettyjä vatsavaivoja. Tutkimukseen osallistui 1900 pääkaupunkiseudun terveyskeskusten laboratorioissa asioinutta henkilöä, jotka antoivat tutkimustarkoitukseen verinäytteen. Heistä 1885 ( 99%) täytti kyselykaavakkeen ruokaan ja erityisesti maitoon liittyvistä vatsavaivoista. Tutkimuskokonaisuus koostui neljästä osiosta, joista ensimmäisessä tarkasteltiin aikuistyypin hypolaktasian diagnostiikassa käytettävän geenitestin korrelaatiota maidosta koettuihin vatsaoireisiin sekä maidon käyttöön. Toisessa osiossa tarkasteltiin keliakian, tavallisimman sekundaarisen aikuistyypin hypolaktasian aiheuttajan, esiintyvyyttä ja korrelaatiota noninvasiivisiin laboratoriotesteihin. Kolmannessa osiossa tarkasteltiin maitoproteiini IgE:n välittämän yliherkkyyden mahdollista osuutta maidosta koettuihin vatsaoireisiin aikuisilla ja neljännessä osiossa maitoproteiini IgA:n ja IgG:n korrelaatiota maidosta koettuihin vatsaoireisiin. Tutkimustuloksena oli, että ruokaan ja erityisesti maitoon liitetyt vatsaoireet olivat varsin yleisiä aikuisilla. Aikuistyypin hypolaktasiaan liittyvän C/C-13910 genotyypin omaavat käyttivät merkitsevästi vähemmän maitoa kuin C/T-13910 ja T/T-13910 genotyypin omaavat (korkea laktaasi aktiviteetti). Keliakian esiintyvyys oli 2 %, joka oli selkeästi korkea aiemmin todettuihin esiintyvyyksiin verrattuna. Keliakian dignosoimiseen käytetyt endomysium- ja kudostransglutaminaasivasta-ainemääritykset olivat luotettavia menetelmiä ko. taudin selvittämiseksi, jatkotutkimusten ohjelmoimiseksi ja edelleen gluteiinittoman ruokavalion aloittamiseksi. Maitoproteiini IgA, IgE ja IgG eivät korreloineet maidosta koettuihin vatsavaivoihin. Aikuisten maitoon liittyvien vatsaoireiden selvittelyyn ja seulontaan avohoidossa tulisi käyttää aikuistyypin hypolaktasian geenitestiä, kudostransglutaminaasi- tai endomysiumvasta-aineita keliakian poissulkemiseksi sekä maidotonta koedieettiä. Maitoproteiinispesifisistä immunoglobuliini A, E tai G määrityksistä ei sen sijaan ole tutkimuksen mukaan aikuisväestössä hyötyä, eikä niitä tulisi turhaan tehdä.