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Dermatitis Herpetiformis and Celiac Disease Increase the Risk of Bullous Pemphigoid

Open ArchivePublished:October 26, 2018DOI:https://doi.org/10.1016/j.jid.2018.10.010
      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.

      Abbreviations:

      BP (bullous pemphigoid), BCC (basal cell carcinoma), CD (celiac disease), DH (dermatitis herpetiformis), DIF (direct immunofluorescence analysis), ICD (International Classification of Diseases)

      Introduction

      Bullous pemphigoid (BP) and dermatitis herpetiformis (DH) are subepidermal blistering skin diseases of autoimmune origin. Pruritus is intense in both diseases, but in BP, tense bullae are also typically present, while in DH excoriations and erosions secondary to scratching are mainly seen (
      • Bağcı I.S.
      • Horváth O.N.
      • Ruzicka T.
      • Sárdy M.
      Bullous pemphigoid.
      ,
      • Bolotin D.
      • Petronic-Rosic V.
      Dermatitis herpetiformis: part I. epidemiology, pathogenesis, and clinical presentation.
      ). BP is relatively rare, with incidence varying from 2.5 to 43 individuals per million, and it mostly affects older people, typically first appearing at around 80 years of age (
      • Baican A.
      • Baican C.
      • Chiriac G.
      • Chiriac M.T.
      • Macovei V.
      • Zillikens D.
      • et al.
      Pemphigus vulgaris is the most common autoimmune bullous disease in northwestern Romania.
      ,
      • Brick K.E.
      • Weaver C.H.
      • Lohse C.M.
      • Pittelkow M.R.
      • Lehman J.S.
      • Camilleri M.J.
      • et al.
      Incidence of bullous pemphigoid and mortality of patients with bullous pemphigoid in Olmsted County, Minnesota, 1960 through 2009.
      ,
      • Försti A.
      • Jokelainen J.
      • Timonen M.
      • Tasanen K.
      Increasing incidence of bullous pemphigoid in northern Finland: a retrospective database study in Oulu University Hospital.
      ,
      • Joly P.
      • Baricault S.
      • Sparsa A.
      • Bernard P.
      • Bedane C.
      • Duvert-Lehembre S.
      • et al.
      Incidence and mortality of bullous pemphigoid in france.
      ,
      • Langan S.M.
      • Smeeth L.
      • Hubbard R.
      • Fleming K.M.
      • Smith C.J.P.
      • West J.
      Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study.
      ,
      • Marazza G.
      • Pham H.C.
      • Scharer L.
      • Pedrazzetti P.P.
      • Hunziker T.
      • Trueb R.M.
      • et al.
      Incidence of bullous pemphigoid and pemphigus in switzerland: a 2-year prospective study.
      ). By contrast, DH is generally a disease of younger people; a Finnish cohort study reported a mean age of 43 years at diagnosis (
      • Salmi T.T.
      • Hervonen K.
      • Kautiainen H.
      • Collin P.
      • Reunala T.
      Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from finland.
      ), but in a study of 264 DH patients from the United States, the mean age at diagnosis was 49 years (
      • Alonso-Llamazares J.
      • Gibson L.E.
      • Rogers R.S.
      Clinical, pathologic, and immunopathologic features of dermatitis herpetiformis: review of the Mayo Clinic experience.
      ). In the last few decades, studies from different parts of the world have estimated the incidence of DH to be between 11.2 and 75.3 per 100,000 (
      • Collin P.
      • Salmi T.T.
      • Hervonen K.
      • Kaukinen K.
      • Reunala T.
      Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
      ,
      • Salmi T.T.
      • Hervonen K.
      • Kautiainen H.
      • Collin P.
      • Reunala T.
      Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from finland.
      ,
      • West J.
      • Fleming K.M.
      • Tata L.J.
      • Card T.R.
      • Crooks C.J.
      Incidence and prevalence of celiac disease and dermatitis herpetiformis in the UK over two decades: population-based study.
      ). Interestingly, the incidence of DH has decreased over time (
      • Salmi T.T.
      • Hervonen K.
      • Kautiainen H.
      • Collin P.
      • Reunala T.
      Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from finland.
      ) while the incidence of BP is increasing (
      • Langan S.M.
      • Smeeth L.
      • Hubbard R.
      • Fleming K.M.
      • Smith C.J.P.
      • West J.
      Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study.
      ,
      • Joly P.
      • Baricault S.
      • Sparsa A.
      • Bernard P.
      • Bedane C.
      • Duvert-Lehembre S.
      • et al.
      Incidence and mortality of bullous pemphigoid in france.
      ,
      • Försti A.
      • Jokelainen J.
      • Timonen M.
      • Tasanen K.
      Increasing incidence of bullous pemphigoid in northern Finland: a retrospective database study in Oulu University Hospital.
      ).
      Autoantibodies against collagen XVII (BP180) in the cutaneous basement membrane zone are central in the pathogenesis of BP, however, the factors leading to autoantibody production and disease onset still need to be elucidated (
      • Bağcı I.S.
      • Horváth O.N.
      • Ruzicka T.
      • Sárdy M.
      Bullous pemphigoid.
      ,
      • Schmidt E.
      • Zillikens D.
      Pemphigoid diseases.
      ). DH is considered to be a cutaneous form of celiac disease (CD), in which ingestion of gluten leads to the production of autoantibodies against the epidermal enzyme transglutaminase-3 (
      • Collin P.
      • Salmi T.T.
      • Hervonen K.
      • Kaukinen K.
      • Reunala T.
      Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
      ). Direct immunofluorescence microscopy (DIF) is used as a diagnostic tool in both diseases: in BP, DIF reveals linear deposits of IgG and/or complement C3 in the dermo-epidermal junction (
      • Bağcı I.S.
      • Horváth O.N.
      • Ruzicka T.
      • Sárdy M.
      Bullous pemphigoid.
      ), whereas in DH, DIF shows granular IgA deposits in the papillary dermis (
      • Reunala T.
      • Salmi T.T.
      • Hervonen K.
      Dermatitis herpetiformis: pathognomonic transglutaminase IgA deposits in the skin and excellent prognosis on a gluten-free diet.
      ). In both BD and DH, a diagnosis is based on the combination of DIF findings, clinical appearance, and histopathologic and serologic measures, including BP180-NC16A ELISA and indirect immunofluorescence assay on salt split skin (
      • Baum S.
      • Sakka N.
      • Artsi O.
      • Trau H.
      • Barzilai A.
      Diagnosis and classification of autoimmune blistering diseases.
      ). In BP, typical clinical findings are pruritus and bullae. Eczematous and/or urticarial lesions may also be seen and sometimes these are the only manifestation of the disease (
      • Bağcı I.S.
      • Horváth O.N.
      • Ruzicka T.
      • Sárdy M.
      Bullous pemphigoid.
      ,
      • Schmidt E.
      • Zillikens D.
      Pemphigoid diseases.
      ). The clinical appearance of DH often includes pruritic papules and vesicles, but sometimes consists of only symmetrical patterns of excoriations on the extensor surfaces of the extremities, buttocks, scalp, knees, and elbows, due to scratching (
      • Bolotin D.
      • Petronic-Rosic V.
      Dermatitis herpetiformis: part I. epidemiology, pathogenesis, and clinical presentation.
      ,
      • Collin P.
      • Salmi T.T.
      • Hervonen K.
      • Kaukinen K.
      • Reunala T.
      Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
      ).
      Treatment of BP tends to include oral and topical corticosteroids, and other immunosuppressive agents (e.g., methotrexate, dapsone, azathioprine, and mycophenolate mofetil) and doxycycline are often used, either as adjuvant therapy alongside corticosteroids or alone as monotherapy (
      • Bağcı I.S.
      • Horváth O.N.
      • Ruzicka T.
      • Sárdy M.
      Bullous pemphigoid.
      ,
      • Schmidt E.
      • Zillikens D.
      Pemphigoid diseases.
      ). The management of DH is centered upon a lifelong gluten-free diet. However, due to its rapid effect on pruritus, dapsone is frequently used in the initiation of therapy and in patients whose symptoms persist despite the gluten-free diet (
      • Bolotin D.
      • Petronic-Rosic V.
      Dermatitis herpetiformis: part II. diagnosis, management, and prognosis.
      ,
      • Reunala T.
      • Salmi T.T.
      • Hervonen K.
      Dermatitis herpetiformis: pathognomonic transglutaminase IgA deposits in the skin and excellent prognosis on a gluten-free diet.
      ,
      • Collin P.
      • Salmi T.T.
      • Hervonen K.
      • Kaukinen K.
      • Reunala T.
      Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
      ).
      Neurologic conditions are well known to be associated with BP, and psychiatric diseases, psoriasis, hypertension, hematologic malignancies, and diabetes have also been reported as comorbidities of BP (
      • Atzmony L.
      • Mimouni I.
      • Reiter O.
      • Leshem Y.A.
      • Taha O.
      • Gdalevich M.
      • et al.
      Association of bullous pemphigoid with malignancy: a systematic review and meta-analysis.
      ,
      • Chen Y.J.
      • Wu C.Y.
      • Lin M.W.
      • Chen T.J.
      • Liao K.K.
      • Chen Y.C.
      • et al.
      Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study.
      ,
      • Kibsgaard L.
      • Rasmussen M.
      • Lamberg A.
      • Deleuran M.
      • Olesen A.B.
      • Vestergaard C.
      Increased frequency of multiple sclerosis among patients with bullous pemphigoid: a population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid.
      ,
      • Kridin K.
      • Bergman R.
      Association between bullous pemphigoid and psoriasis: a case-control study.
      ,
      • Schulze F.
      • Neumann K.
      • Recke A.
      • Zillikens D.
      • Linder R.
      • Schmidt E.
      Malignancies in pemphigus and pemphigoid diseases.
      ,
      • Sim B.
      • Fook-Chong S.
      • Phoon Y.W.
      • Koh H.Y.
      • Thirumoorthy T.
      • Pang S.M.
      • et al.
      Multimorbidity in bullous pemphigoid: a case-control analysis of bullous pemphigoid patients with age- and gender-matched controls.
      ). DH is associated with type I diabetes, thyroid diseases, and other autoimmune diseases (
      • Bolotin D.
      • Petronic-Rosic V.
      Dermatitis herpetiformis: part I. epidemiology, pathogenesis, and clinical presentation.
      ,
      • Collin P.
      • Salmi T.T.
      • Hervonen K.
      • Kaukinen K.
      • Reunala T.
      Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
      ). Furthermore, patients with DH who do not adhere to a gluten-free diet appear to carry an elevated risk of developing lymphomas (
      • Hervonen K.
      • Vornanen M.
      • Kautiainen H.
      • Collin P.
      • Reunala T.
      Lymphoma in patients with dermatitis herpetiformis and their first-degree relatives.
      ,
      • Lewis H.M.
      • Renaula T.L.
      • Garioch J.J.
      • Leonard J.N.
      • Fry J.S.
      • Collin P.
      • et al.
      Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis.
      ).
      Case reports of DH evolving into BP have been published (
      • Ameen M.
      • Bhogal B.S.
      • Black M.M.
      Dermatitis herpetiformis evolving into bullous pemphigoid: a probable example of ‘epitope spreading.’.
      ,
      • Didona D.
      • Di Zenzo G.
      Humoral epitope spreading in autoimmune bullous diseases.
      ,
      • Honeyman J.F.
      • Honeyman A.
      • Lobitz W.C.
      • Storrs F.J.
      The enigma of bullous pemphigoid and dermatitis herpetiformis.
      ,
      • Murphy L.A.
      • Bhogal B.S.
      • Banerjee P.
      • Black M.M.
      Dermatitis herpetiformis converting into bullous pemphigoid: a study of three cases.
      ), but larger studies of this probable association are currently lacking. The aim of the present study was to evaluate DH as a risk factor for BP in the setting of a Finnish nationwide registry-based case-control study.

      Results

      Characteristics of patients and controls

      The database search from the Finnish Care Register for Health Care returned data for 4,524 patients who received a diagnosis of BP between 1987 and 2013. The present analysis employed data from a subgroup of 3,397 of these patients who were diagnosed with BP between the years 1997 and 2013. A total of 66,138 basal cell carcinoma (BCC) patients were identified and 12,941 of these were selected randomly to be matched to the BP population by age, sex, and year of diagnosis in a 4:1 ratio. Due to the incomplete availability of drug reimbursement data for some of the BCC controls, 579 of the BP patients had fewer than the intended four matched controls. The characteristics of the BP and control groups are shown in Table 1.
      Table 1Subject characteristics at the time of the diagnosis of bullous pemphigoid or basal cell carcinoma
      CharacteristicsCases (n = 3,397)Controls (n = 12,941)
      Age, sex, and year of the diagnosis matched in 1:4 ratio. Due to availability of drug reimbursement data, 579 patients had fewer than four basocellular carcinoma controls.
      Female, n (%)2,028 (59.7)7,766 (60.0)
      Male, n (%)1,369 (40.3)5,175 (40.0)
      Age, years, mean (range)76.6 (40–102)76.7 (40 –101)
      Neurologic or psychiatric disease,
      Alzheimer’s disease, vascular dementia, other/unspecified dementia, Parkinson’s disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, epilepsy, schizotypal and delusional disorder, schizophrenia, bipolar affective disorder, major depressive disorder, neurotic, stress-related and somatoform disorders, and personality disorders.
      n (%)
      1,612 (47.5)4,367 (33.8)
      1 Age, sex, and year of the diagnosis matched in 1:4 ratio. Due to availability of drug reimbursement data, 579 patients had fewer than four basocellular carcinoma controls.
      2 Alzheimer’s disease, vascular dementia, other/unspecified dementia, Parkinson’s disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, epilepsy, schizotypal and delusional disorder, schizophrenia, bipolar affective disorder, major depressive disorder, neurotic, stress-related and somatoform disorders, and personality disorders.

      Risk for BP after diagnosis of DH or CD, time intervals between diagnoses and medication use

      We identified 41 (1.2%) individuals in the BP group with preceding DH, whereas in the BCC group there were only 7 (0.1%). Preceding CD was found in 34 (1.0%) BP patients and 53 (0.4%) in the control group. In our study population, 12 (29%) of the BP patients with DH also had CD.
      Patients with CD had a twofold greater risk for BP than those without. Remarkably, patients with DH had a 22-fold elevated risk for BP (Table 2). Differences between sexes were not statistically significant, although there was a trend toward a greater risk for BP after DH in males than in females (Table 3).
      Table 2Odds ratios for the development of bullous pemphigoid following a diagnosis of dermatitis herpetiformis or celiac disease
      Preceding DiseaseGroupTotal, nn (%)OR (95% CI)
      Dermatitis herpetiformisBP3,39741 (1.2)22.30 (9.99–49.70)
      BCC12,9417 (0.1)ref
      Celiac diseaseBP3,39734 (1.0)2.54 (1.64–3.92)
      BCC12,94153 (0.4)ref
      Abbreviations: BCC, basal cell carcinoma; BP, bullous pemphigoid; CI, confidence interval; OR, odds ratio; ref, reference.
      Table 3Odds ratios for the development of bullous pemphigoid following a diagnosis of dermatitis herpetiformis or celiac disease by sex
      Preceding Disease/SexGroupTotal, nn (%)OR (95% CI)
      Dermatitis herpetiformis/menBP1,36920 (1.5)73.30 (9.82–546)
      BCC5,1751 (0.0)ref
      Dermatitis herpetiformis/womenBP2,02821 (1.0)13.70 (5.54–34.00)
      BCC7,7666 (0.1)ref
      Celiac disease/menBP1,36912 (0.9)2.61 (1.24–5.49)
      BCC5,17518 (0.3)ref
      Celiac disease/womenBP2,02822 (1.1)2.50 (1.46 –4.28)
      BCC7,76635 (0.5)ref
      Abbreviations: BCC, basal cell carcinoma; BP, bullous pemphigoid; CI, confidence interval; OR, odds ratio; ref, reference.
      Mean age at the time of the BP diagnosis was 68.8 (range 44–89) years in those with preceding DH, and 76.7 (range 40–102) years in the group of BP patients with no preceding DH. Mean age at the time of diagnosis of DH was 64.9 years (median 64.0 years, first quartile 54.0 years, third quartile 78.0 years) in the BP group and 65.6 years (median 73.0 years, first quartile 56.0, years third quartile 76.5 years) in the BCC group. The mean time intervals between the diagnosis of DH and that of BP or BCC were 3.3 years and 10.0 years, respectively, while the mean times between the diagnosis of CD and BP or BCC were 4.9 years and 7.2 years, respectively.
      Using data on reimbursed drugs from the Social Insurance Institution of Finland, we identified all of the DH patients that had used dapsone. Eighteen of the patients with DH had used dapsone in the 2 years preceding the diagnosis of BP and, of those, 14 had received dapsone during the 6 months prior to the diagnosis.
      Use of diabetes medication of the dipeptidyl peptidase-4 inhibitors class, particularly vildagliptin, has been described recently as a risk factor for BP (
      • Benzaquen M.
      • Borradori L.
      • Berbis P.
      • Cazzaniga S.
      • Valero R.
      • Richard M.
      • et al.
      Dipeptidyl peptidase-IV inhibitors, a risk factor for bullous pemphigoid. retrospective multicenter case-control study in France and Switzerland.
      ,
      • Varpuluoma O.
      • Försti A.K.
      • Jokelainen J.
      • Turpeinen M.
      • Timonen M.
      • Huilaja L.
      • et al.
      Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.
      ). To exclude the possibility that use of such medications could have confounded the association we found between DH and BP, we investigated the use of these drugs by examining the aforementioned data set regarding reimbursed drugs. None of the DH patients in either the BP or BCC group had received a dipeptidyl peptidase-4 inhibitor in the 2 years preceding their BP or BCC diagnosis, and only one patient in the BP group with preceding CD had used a dipeptidyl peptidase-4 inhibitor in the previous 2 years.

      Discussion

      This study of Finnish BP patients reveals a strong association between DH and BP. Neither DH nor CD were analyzed in previous studies of BP comorbidities (
      • Bastuji-Garin S.
      • Joly P.
      • Lemordant P.
      • et al.
      Risk factors for bullous pemphigoid in the elderly: a prospective case-control study.
      ,
      • Chen Y.J.
      • Wu C.Y.
      • Lin M.W.
      • Chen T.J.
      • Liao K.K.
      • Chen Y.C.
      • et al.
      Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study.
      ,
      • Jedlickova H.
      • Hlubinka M.
      • Pavlik T.
      • Semradova V.
      • Budinska E.
      • Vlasin Z.
      Bullous pemphigoid and internal diseases—a case-control study.
      ,
      • Jeon H.W.
      • Yun S.J.
      • Lee S.
      • Won Y.H.
      • Lee J.
      Mortality and comorbidity profiles of patients with bullous pemphigoid in korea.
      ,
      • Kibsgaard L.
      • Rasmussen M.
      • Lamberg A.
      • Deleuran M.
      • Olesen A.B.
      • Vestergaard C.
      Increased frequency of multiple sclerosis among patients with bullous pemphigoid: a population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid.
      ,
      • Sim B.
      • Fook-Chong S.
      • Phoon Y.W.
      • Koh H.Y.
      • Thirumoorthy T.
      • Pang S.M.
      • et al.
      Multimorbidity in bullous pemphigoid: a case-control analysis of bullous pemphigoid patients with age- and gender-matched controls.
      ,
      • Teixeira V.B.
      • Cabral R.
      • Brites M.M.
      • Vieira R.
      • Figueiredo A.
      Bullous pemphigoid and comorbidities: a case-control study in portuguese patients.
      ). In a British interview-based study of BP and other autoimmune disorders, neither DH nor CD were among the diseases about which the participants (n = 108) were asked (
      • Taylor G.
      • Venning V.
      • Wojnarowska F.
      • Welch K.
      Bullous pemphigoid and autoimmunity.
      ). Dermatitis herpetiformis and BP are both relatively rare diseases, so a large study population is required to discover any association between the two. Moreover, both DH and CD are more common in Finland than almost anywhere else in the world (
      • Salmi T.T.
      • Hervonen K.
      • Kautiainen H.
      • Collin P.
      • Reunala T.
      Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from finland.
      ), which may have allowed the present study’s discovery of these associations. Additional studies of the risk for developing BP in a cohort of DH patients would help us to further confirm this association.
      The clinical appearance and DIF findings of DH are usually easily distinguishable from those of BP, but case reports with overlapping clinical presentation and immunofluorescence microscopy findings have been described (
      • Honeyman J.F.
      • Honeyman A.
      • Lobitz W.C.
      • Storrs F.J.
      The enigma of bullous pemphigoid and dermatitis herpetiformis.
      ,
      • Jablonska S.
      • Chorzelski T.P.
      • Beutner E.H.
      • Maciejowska E.
      • Rzęsa G.
      Dermatitis herpetiformis and bullous pemphigoid: Intermediate and mixed forms.
      ,
      • Sander H.M.
      • Utz M.
      • Peters M.S.
      Bullous pemphigoid and dermatitis herpetiformis: mixed bullous disease or coexistence of two separate entities?.
      ,
      • Schulze F.
      • van Beek N.
      • Terheyden P.
      • Zillikens D.
      • Schmidt E.
      Concomitant bullous pemphigoid and dermatitis herpetiformis.
      ,
      • Setterfield J.
      • Bhogal B.
      • Black M.M.
      • McGibbon D.H.
      Dermatitis herpetiformis and bullous pemphigoid: a developing association confirmed by immunoelectronmicroscopy.
      ,
      • Vaira F.
      • Della Valle V.
      • Fanoni D.
      • Pontini P.
      • Muratori S.
      Bullous pemphigoid and dermatitis herpetiformis association: a genetic predisposition.
      ). For example,
      • Ameen M.
      • Bhogal B.S.
      • Black M.M.
      Dermatitis herpetiformis evolving into bullous pemphigoid: a probable example of ‘epitope spreading.’.
      described a patient who had pruritic papulovesicular eruptions and whose DIF findings showed deposition of IgA and C3 within the papillary dermis. The patient responded well to a gluten-free diet and dapsone treatment, but 11 years later developed an apparently different blistering eruption, and DIF showed IgG and C3 in the basement membrane zone as well as fibrillar IgA staining in the dermal papillae (
      • Ameen M.
      • Bhogal B.S.
      • Black M.M.
      Dermatitis herpetiformis evolving into bullous pemphigoid: a probable example of ‘epitope spreading.’.
      ). Epitope spreading was suggested as an explanation for the disease evolution seen in this case. Epitope spreading is a phenomenon in which an immune response is developed to one or more other epitopes in addition to the dominant epitope. It is known to exist in autoimmune bullous diseases, including BP (
      • Chan L.S.
      • Vanderlugt C.J.
      • Hashimoto T.
      • Nishikawa T.
      • Zone J.J.
      • Black M.M.
      • et al.
      Epitope spreading: lessons from autoimmune skin diseases.
      ,
      • Didona D.
      • Di Zenzo G.
      Humoral epitope spreading in autoimmune bullous diseases.
      ). Epitope spreading has been reported to occur often during the first 3 months after a diagnosis of BP and is associated with disease severity (
      • Di Zenzo G.
      • Thoma-Uszynski S.
      • Calabresi V.
      • Fontao L.
      • Hofmann S.C.
      • Lacour J.
      • et al.
      Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study.
      ). Epitope spreading has also been hypothesized to explain the onset of DH in patients with CD (
      • Kárpáti S.
      • Sárdy M.
      • Németh K.
      • Mayer B.
      • Smyth N.
      • Paulsson M.
      • et al.
      Transglutaminases in autoimmune and inherited skin diseases: the phenomena of epitope spreading and functional compensation.
      ). With regard to the present study, epitope spreading is a possible immunomechanism driving the association between DH and BP, but unfortunately, because this was a registry-based study, we had no access to the DIF findings or serum samples of the DH patients who developed BP subsequently and, therefore, we were unable to confirm or disprove this hypothesis.
      Several physical factors have been reported to trigger BP. Exposure to UV rays or other forms of radiation, surgical wounds and ostomies, photodynamic therapy, burns, and several different types of mechanical trauma, have all been reported to have triggered BP (
      • Dănescu S.
      • Chiorean R.
      • Macovei V.
      • Sitaru C.
      • Baican A.
      Role of physical factors in the pathogenesis of bullous pemphigoid: case report series and a comprehensive review of the published work.
      ,
      • Mai Y.
      • Nishie W.
      • Sato K.
      • Hotta M.
      • Izumi K.
      • Ito K.
      • et al.
      Bullous pemphigoid triggered by thermal burn under medication with a dipeptidyl peptidase-IV inhibitor: a case report and review of the literature.
      ,
      • Rakvit P.
      • Kerr A.C.
      • Ibbotson S.H.
      Localized bullous pemphigoid induced by photodynamic therapy.
      ). Physical factors causing tissue damage may disturb the basement membrane zone or activate the inflammatory processes and thus contribute to BP onset in susceptible individuals. Our finding that DH was associated with distinctly higher risk for BP than was CD leads us to hypothesize that active cutaneous inflammation and scratching in DH could act as triggering factors for BP. In a Finnish study of 311 DH patients, only 8% needed dapsone to control their skin symptoms (
      • Hervonen K.
      • Alakoski A.
      • Salmi T.T.
      • Helakorpi S.
      • Kautiainen H.
      • Kaukinen K.
      • et al.
      Reduced mortality in dermatitis herpetiformis: a population-based study of 476 patients.
      ). In the present study 34% (14 of 41) of the patients with DH and subsequent BP had used dapsone during the 6 months preceding their BP diagnosis. This most likely reflects the activity of the DH skin symptoms and itching, which may in turn contribute to the onset of BP.
      Genetic predisposition for both BP and DH has been linked to certain HLA alleles. HLA-DQB1*0301 is overrepresented among BP patients of various ethnic origins (
      • Amber K.T.
      • Zikry J.
      • Hertl M.
      A multi-hit hypothesis of bullous pemphigoid and associated neurological disease: is HLA-DQB1* 03: 01, a potential link between immune privileged antigen exposure and epitope spreading?.
      ,
      • Sun Y.
      • Liu H.
      • Wang Z.
      • Fu X.
      • Wang C.
      • Mi Z.
      • et al.
      The HLA-DQB1* 03: 01 is associated with bullous pemphigoid in the Han Chinese population.
      ). Susceptibility for DH and CD is known to be associated with the HLA-DQ2 and DQ8 haplotypes (
      • Collin P.
      • Salmi T.T.
      • Hervonen K.
      • Kaukinen K.
      • Reunala T.
      Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
      ,
      • Kaukinen K.
      • Partanen J.
      • Mäki M.
      • Collin P.
      HLA-DQ typing in the diagnosis of celiac disease.
      ,
      • Spurkland A.
      • Ingvarsson G.
      • Falk E.S.
      • Knutsen I.
      • Sollid L.M.
      • Thorsby E.
      Dermatitis herpetiformis and celiac disease are both primarily associated with the HLA-DQ (alpha 1*0501, beta 1*02) or the HLA-DQ (alpha 1*03, beta 1*0302) heterodimers.
      ).
      • Vaira F.
      • Della Valle V.
      • Fanoni D.
      • Pontini P.
      • Muratori S.
      Bullous pemphigoid and dermatitis herpetiformis association: a genetic predisposition.
      described a patient with BP who later developed concomitant DH; this patient had an HLA profile that predisposed them to both BP and DH. However, any significance of HLA types in the association between DH and BP is currently unknown because, to the best of our knowledge, HLA genetics in patients with concomitant DH and BP have not yet been studied.
      In the present study, the mean time from the diagnosis of DH to the diagnosis of BP was 3 years and the mean time between CD and BP diagnosis was 4.9 years. In case reports, DH has preceded BP by between 4 months and 25 years (
      • Ameen M.
      • Bhogal B.S.
      • Black M.M.
      Dermatitis herpetiformis evolving into bullous pemphigoid: a probable example of ‘epitope spreading.’.
      ,
      • Murphy L.A.
      • Bhogal B.S.
      • Banerjee P.
      • Black M.M.
      Dermatitis herpetiformis converting into bullous pemphigoid: a study of three cases.
      ,
      • Setterfield J.
      • Bhogal B.
      • Black M.M.
      • McGibbon D.H.
      Dermatitis herpetiformis and bullous pemphigoid: a developing association confirmed by immunoelectronmicroscopy.
      ). Reports of the intervals between the onset of comorbid diseases and subsequent diagnosis of BP vary widely: In our recent study of neurologic and psychiatric comorbidities, a BP diagnosis was preceded by a diagnosis of dementia, multiple sclerosis, or psychiatric diseases by a mean interval of 3, 12, and 7–11 years, respectively (
      • Försti A.
      • Jokelainen J.
      • Ansakorpi H.
      • Seppänen A.
      • Majamaa K.
      • Timonen M.
      • et al.
      Psychiatric and neurological disorders are associated with bullous pemphigoid—a nationwide Finnish care register study.
      ). In a Korean cohort of 3,485 BP patients, dementia, Parkinson’s disease, and epilepsy preceded BP by 3, 4, and 2 years, respectively, and comorbid rheumatoid arthritis occurred 5 years before BP (
      • Chen Y.J.
      • Wu C.Y.
      • Lin M.W.
      • Chen T.J.
      • Liao K.K.
      • Chen Y.C.
      • et al.
      Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study.
      ). In the Korean, study the mean time between psoriasis and BP diagnoses was 3 years (
      • Chen Y.J.
      • Wu C.Y.
      • Lin M.W.
      • Chen T.J.
      • Liao K.K.
      • Chen Y.C.
      • et al.
      Comorbidity profiles among patients with bullous pemphigoid: a nationwide population-based study.
      ), but a recent study from Israel reported a very long mean interval of 25 years between diagnoses of psoriasis and BP (
      • Kridin K.
      • Bergman R.
      Association between bullous pemphigoid and psoriasis: a case-control study.
      ). It is worth noting that, in the present study, mean age at time of DH diagnosis was 64.9 years in patients who later developed BP, whereas the mean age at DH diagnosis was 49 years in Finland during years 2000–2009 (
      • Salmi T.T.
      • Hervonen K.
      • Kautiainen H.
      • Collin P.
      • Reunala T.
      Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from finland.
      ). This suggests that physicians should be wary of the possible development of BP when treating patients with late-onset DH who develop itch or other novel skin symptoms.
      A major strength of our study is that it utilized one of the largest nationwide BP cohorts ever studied (
      • Försti A.
      • Huilaja L.
      • Schmidt E.
      • Tasanen K.
      Neurological and psychiatric associations in bullous pemphigoid—more than skin deep?.
      ) and this cohort was formed using data from the Finnish Care Register for Health Care, which is known to be an accurate database (
      • Sund R.
      Quality of the finnish hospital discharge register: a systematic review.
      ). We also had access to data on all reimbursed drugs received by the patients.
      The limitations in the present study arise from the registry-based study setting. Because the data we used were routinely gathered by the registry, we cannot be certain that all of the reported BP and DH cases were confirmed immunologically. Furthermore, we did not have access to information regarding the actual onset of the diseases, results from the diagnostic tests, or patients’ samples. Therefore, we could not completely rule out the existence of other variants of pemphigoid, such as epidermolysis bullosa acquisita, p200 pemphigoid, and laminin-332 pemphigoid among BP patients. However, in Finland, immunofluorescence microscopy tests are performed in the hospital setting and diagnoses of DH and BP are generally made in hospital dermatology clinics, so the recorded diagnoses can be considered reliable.
      In summary, we report a significant association between DH and BP. In daily practice, it is important for the dermatologist to recognize the risk of DH evolving to BP if the clinical picture of a patient’s disease changes or they become unresponsive to the gluten-free diet. Advancing our knowledge of the comorbidities of BP may help us to understand the process that leads to the breaking of cutaneous immunotolerance in BP.

      Methods

      Populations and databases

      This was a retrospective database study of patients diagnosed with BP in Finland between January 1, 1997 and December 31, 2013. Patient records were obtained from the Finnish Care Register for Health Care, which contains data on the diagnosis codes of hospitalized inpatients from the year 1994 onwards and of outpatient visits from 1998 onward, but no detailed clinical information. The Finnish Care Register for Health Care contains data collected from all hospitals in Finland that are maintained by local authorities, municipal federations, and central government, and from the largest of the country’s private hospitals. As described previously (
      • Försti A.
      • Jokelainen J.
      • Ansakorpi H.
      • Seppänen A.
      • Majamaa K.
      • Timonen M.
      • et al.
      Psychiatric and neurological disorders are associated with bullous pemphigoid—a nationwide Finnish care register study.
      ), patients in the BP group were selected by their BP diagnoses, defined by the International Classification of Diseases (ICD)-9 codes 6945A and 6945B, and ICD-10 code L12.0. The control population consisted of patients diagnosed with BCC as defined by the ICD-9 codes 1730A–1739A and ICD-10 codes C44.01, C44.11, C44.21, C44.31, C44.41, C44.51, C44.61, C44.71, C44.81, and C44.91 over the same time period described. BCC was selected because, like BP, it affects elderly people but is not an inflammatory skin disease (
      • Diepgen T.L.
      • Mahler V.
      The epidemiology of skin cancer.
      ,
      • Wong C.
      • Strange R.C.
      • Lear J.T.
      Basal cell carcinoma.
      ). The BCC control patients were matched by sex, age, and year of the diagnosis (within 2 years). From the same registry, we also collected data regarding all other diagnoses received by our selected populations. Patients aged younger than 40 years were excluded from the study because BP is extremely rare in younger age groups. Diagnoses of DH and CD in the study populations were identified by searching the same database for ICD-9 and ICD-10 codes 6940A and L13.0 for DH and 5790A and K90.0 for CD.
      Data on drugs received by patients and controls were obtained from the Social Insurance Institution of Finland. This registry includes reliable data on all reimbursed drugs from the year 1995 onwards. In order to obtain complete medication data for the 2 years preceding the first BP diagnosis, only patients diagnosed between the years 1997 and 2013 were included in the present study. The unique personal identification number given to every resident of Finland was used to combine the data from different databases. Data were collected using ATC-code J04BA02 for dapsone, A10BH01-A10BH51 for dipeptidyl peptidase-4 inhibitors, and A10BD07-A10BD13 for combinations of dipeptidyl peptidase-4 inhibitor and other diabetes medications.

      Statistical analyses

      The characteristics of the study population are presented as proportions and means. The associations of BP with DH and CD were evaluated using a conditional logistic regression model. Odds ratios and 95% confidence intervals are presented. Because previous analyses of the same study population showed that psychiatric and neurologic diseases are associated with BP (
      • Försti A.
      • Jokelainen J.
      • Ansakorpi H.
      • Seppänen A.
      • Majamaa K.
      • Timonen M.
      • et al.
      Psychiatric and neurological disorders are associated with bullous pemphigoid—a nationwide Finnish care register study.
      ), the following variables were considered as potential confounding factors: Alzheimer’s disease, vascular dementia, other/unspecified dementia, Parkinson’s disease, multiple sclerosis, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, epilepsy, schizotypal and delusional disorder, schizophrenia, bipolar affective disorder, major depressive disorder, neurotic, stress-related and somatoform disorders, and personality disorders. Because those had no effect on the main outcome, only unadjusted results are shown. All statistical analyses were performed using the SAS software (version 9.4; SAS Institute, Cary NC). Two-sided P values <0.05 were considered statistically significant.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      This study was supported by research grant from the Academy of Finland .

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