Drugs, dermatitis herpetiformis and celiac disease as risk factors for bullous pemphigoid in Finland

Abstract Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It mostly affects elderly patients and is characterized by intense pruritus and blistering or bullae. Treatment options include topical and systemic corticosteroids, other immunosuppressive drugs and doxycycline. Disease course may be chronic and relapses are common. The incidence of BP has been reported to have increased in the last few decades, but the reason for this trend is not known. The aim of this thesis was to study the risk factors of BP. Firstly, the influence of the use of dipeptidyl peptidase (DPP-4) inhibitors was analyzed as a risk factor, and then those of other oral diabetes medications. This study also aimed to determine whether drugs used for psychiatric and neurologic conditions are risk factors for BP. Finally, previously diagnosed dermatitis herpetiformis (DH) and celiac disease (CD) were examined as potential risk factors for subsequent BP. For this retrospective, matched case-control study, patient data were obtained from the Finnish Care Register for Health Care database, and data on reimbursed drugs from the Social Insurance Institution of Finland. In the present study, prior use of DPP-4 inhibitors was found to increase the risk of BP twofold and in particular, vildagliptin increased the risk tenfold. The mean time between the initiation of vildagliptin and diagnosis of BP was 449 days. Metformin and other conventional diabetes drugs were not risk factors for BP. Several drugs used for neurological and psychiatric diseases were associated with an elevated risk for BP, but no pharmacological or chemical properties of these drugs emerged as candidates to explain the increased risk. A prior diagnosis of DH increased the risk of BP 22-fold and a diagnosis of CD doubled it. Dapsone had been used in the two years before BP diagnosis by 44% of patients whose BP was preceded by DH. The mean time between the diagnoses of DH and BP was 3.3 years. This study confirms the view that DPP-4 inhibitors increase the risk for BP. No such association was found with other classes of diabetes drugs and therefore their use can be continued following a diagnosis of BP. Doctors treating patients with DH should be aware of the association between DH and BP, and be particularly vigilant if a DH patient’s skin symptoms change or become unresponsive to a gluten-free diet and/or dapsone.Tiivistelmä Rakkulainen pemfigoidi (pemfigoidi) on yleisin ihon autoimmuunirakkulatauti. Pemfigoidi on pääasiassa ikääntyneiden sairaus, ja sen tyypillisiä oireita ovat kova kutina ja rakkulat iholla. Pemfigoidin hoitoon käytetään paikallisia ja systeemisiä kortikosteroideja, muita immunosuppressiivisia lääkkeitä sekä doksisykliiniä. Taudinkulku on usein krooninen ja uusiutumiset ovat yleisiä. Rakkulaisen pemfigoidin ilmaantuvuuden on raportoitu lisääntyneen, mutta syitä tähän muutokseen ei täysin ymmärretä. Tämän tutkimuksen tavoite oli tutkia pemfigoidin riskitekijöitä Suomessa. Retrospektiivisessä tapaus-verrokkitutkimuksessa käytettiin aineistona Terveyden ja hyvinvoinnin laitoksen hoitoilmoitusrekisteristä poimittuja pemfigoidipotilaita (N=3397) ja verrokkeina ihon tyvisolusyöpäpotilaita (N=12941). Tiedot korvatuista lääkeostoista saatiin Kelan lääkekorvausrekisteristä. Tutkimuksessa todettiin DPP-4:n salpaajien kaksinkertaistavan pemfigoidin riskin ja DPP-4:n salpaaja vildagliptiini lisäsi riskiä jopa kymmenkertaiseksi. Vildagliptiinin aloituksen ja pemfigoidin toteamisen välillä kului keskimäärin 449 vuorokautta. Metformiini ja muut tutkitut suun kautta otettavat diabeteslääkkeet eivät lisänneet pemfigoidin riskiä. Useiden psykiatrisiin ja neurologisiin sairauksiin käytettävien lääkkeiden todettiin lisäävän pemfigoidin riskiä. Pemfigoidin on kuvattu voivan puhjeta ihokeliakian jälkeen, mutta laajempia tutkimuksia näiden sairauksien yhteydestä ei oltu aiemmin tehty. Tämän vuoksi samassa potilasaineistossa tutkittiin ihokeliakiaa ja keliakiaa pemfigoidin riskitekijöinä. Edeltävä ihokeliakia lisäsi pemfigoidin toteamisen riskiä selvästi, jopa 22-kertaiseksi ja keliakia kaksikertaiseksi. Huomattava osa potilaista oli ostanut ihokeliakian hoitoon käytettävää dapsonia edeltävän 2 vuoden aikana ennen pemfigoidin toteamista, mikä voi kertoa ihokeliakian oireiden aktiivisuudesta. Tämä tutkimus vahvistaa näkemystä siitä, että DPP-4:n salpaajat ovat pemfigoidin riskitekijä. Muut tutkitut diabeteslääkkeet eivät lisänneet riskiä ja voidaan ajatella, että ne eivät edelleen hankaloita aiemmin todetun pemfigoidin oireita. Koska ihokeliakian todettiin olevan pemfigoidin riskitekijä, tulee näitä potilaita hoitavan lääkärin muistaa pemfigoidin mahdollisuus, jos ihokeliakian oireet muuttuvat tai hoitovaste menetetään

Pemfigoidien varhainen tunnistaminen on tärkeää

Tiivistelmä Pemfigoidit ovat autoimmuunisairauksia, joissa muodostuu vasta-aineita ihon tyvikalvovyöhykkeen rakenteita kohtaan. Oireina ovat useimmiten ihon kutina ja rakkulointi. Myös limakalvo-oireita voi esiintyä. Pemfigoidien diagnostiikan kulmakivi on iho- tai limakalvokoepalan suora immunofluoresenssitutkimus. Osaan pemfigoideista liittyy merkittävää kuolleisuutta ja tautitaakkaa. Hoidossa ja seurannassa tarvitaan useiden erikoisalojen osaamista

Gliptin-associated bullous pemphigoid and the expression of dipeptidyl peptidase-4/CD26 in bullous pemphigoid

Abstract Dipeptidyl peptidase-4 inhibitors (DPP-4i or gliptins) increase the risk of developing bullous pemphigoid (BP). To clarify, whether gliptin-associated BP has special features, we analyzed the clinical, histopathological and immunological features of 27 BP patients, 10 of which previously used gliptin medication. Compared to those who had not previously received gliptins, subjects who had, showed higher BP180-NC16A ELISA (enzyme-linked immunosorbent assay) values, fewer neurological co-morbidities and shorter time to remission, but differences were not statistically significant. The HLA-DQB1*03:01 allele was more commonly present among the BP patients than the control population, but was not more common in those with gliptin history. To determine the effect of gliptins on the expression of the DPP-4/CD-26 protein we performed immunohistochemistry, which showed that the skin expression of DPP-4/CD-26 was increased in BP patients, but not affected by prior gliptin treatment. We conclude that DPP-4i medication is common among BP patients and prior gliptin treatment may be associated with some specific features

Dermatitis herpetiformis and celiac disease increase the risk of bullous pemphigoid

Abstract Bullous pemphigoid (BP) and dermatitis herpetiformis (DH) are autoimmune bullous skin diseases. DH has been described to evolve into BP and the two diseases can have overlapping clinical appearances and diagnostic findings, but the association between DH and BP has not previously been studied in a large population. To evaluate DH and celiac disease as risk factors for BP, we conducted a retrospective case-control study of patients with BP and matched controls with basal cell carcinoma diagnosed in Finland between 1997 and 2013. A total of 3,397 patients with BP and 12,941 controls were included in the study. Forty-one (1.2%) BP patients and 7 (0.1%) controls had preceding DH. Diagnosed DH increased the risk of BP 22-fold (odds ratio = 22.30; 95% confidence interval = 9.99–49.70) and celiac disease 2-fold (odds ratio = 2.54; 95% confidence interval = 1.64–3.92) compared to controls. Eighteen (43.9%) of the patients who had DH and subsequent BP had bought dapsone during the 2 years prior to their BP diagnosis. Mean time between diagnosed DH and BP was 3 years. We conclude that diagnosis of DH is associated with a striking increase in the risk for BP

Drugs used for neurologic and psychiatric conditions increase the risk for bullous pemphigoid:a case-control study

Abstract To the Editor: The association between neurologic diseases and bullous pemphigoid (BP) is well established.1 However, it has not yet been established whether drugs that affect the nervous system can influence the onset of BP. The aim of this study was to determine if patients who receive drugs to treat neurologic and psychiatric diseases have an altered risk for BP

Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid:a Finnish nationwide case-control study

Abstract Background: Dipeptidyl peptidase 4 inhibitors (DPP4is) used to treat diabetes have been reported to be associated with an increased risk of bullous pemphigoid (BP). There are no previous reports analyzing the risk of BP in patients who are using other diabetes medications. Objective: To evaluate the association between diabetes medications other than DPP4i and development of BP. Methods: We investigated the prevalence of diabetes among patients with BP and the association between the use of diabetes drugs (excluding DPP4i, metformin, and insulin) and BP by analyzing national Finnish registry data for 3397 patients with BP and 12,941 patients with basal cell carcinoma as controls. Results: Our results show that 19.6% of patients with BP have type 2 diabetes. Use of none of the investigated medications was associated with an increased risk of BP. Limitations: Because this was a registry-based study, it was not possible to verify the accuracy of the diagnoses. The risk of BP in users of glucagon-like peptide 1 receptor agonists could not be analyzed. Conclusion: Our study shows that the investigated diabetes drugs are not associated with an increased risk of BP in a Finnish patient database, indicating they can be safely used in this population. Generalization of these results to other populations will require further study