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Gliptin-Associated Bullous Pemphigoid: A Valuable Model of the Mechanism of Breakdown of Immune Tolerance against BP180

  • Wataru Nishie
    Affiliations
    Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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  • Kaisa Tasanen
    Correspondence
    Correspondence: Kaisa Tasanen, Department of Dermatology, Medical Research Center Oulu, University of Oulu, Aapistie 5A, FIN-90220 OULU, Finland.
    Affiliations
    Department of Dermatology, PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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      The study by Plaquevent et al. strongly supports the recent discovery that the use of gliptins is a risk factor for bullous pemphigoid (BP). However, regarding the phenotype of gliptin-associated BP and the necessity of gliptin withdrawal, clinical data remain scarce. We predict that future studies of gliptin-associated BP will offer valuable information concerning autoimmunity against BP180 and may also shed light on the pathology of autoimmune diseases in general.
      • Use of dipeptidyl peptidase-4 inhibitors (gliptins), especially vildagliptin, markedly increases the risk for bullous pemphigoid (BP).
      • It is currently unclear whether gliptin-associated BP has specific immunological or phenotypical properties that are distinct from those of BP in individuals who have not received gliptins.
      • Although the effect of cessation of gliptin treatment on the clinical outcome of BP is not known at the moment, it may be prudent to replace gliptins with another diabetes medication.
      Bullous pemphigoid (BP) is a relatively common and well-characterized organ-specific autoimmune disease. Generally seen in elderly patients, BP is caused by a breakdown in immune tolerance of the BP180 protein that is central in epidermal adhesion, but why this happens is still a mystery.
      • Plaquevent M.
      • Tétart F.
      • Fardet L.
      • Ingen-Housz-Oro S.
      • Valleyrie-Allanore L.
      • Bernard P.
      • et al.
      Higher frequency of dipeptidyl peptidase-4 inhibitor intake in bullous pemphigoid patients than in French general population.
      describe the association between dipeptidyl peptidase-4 inhibitor (DPP4i or gliptin) intake and BP onset in a study based on data obtained from the French Study Group on Autoimmune Bullous Skin Diseases and the French reimbursement database. This study confirms that gliptin treatment is a major factor in BP pathogenesis in patients from several ethnic backgrounds, a finding reported in previous studies that were conducted in Finland (
      • Varpuluoma O.
      • Forsti 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.
      ), Switzerland and France (
      • Benzaquen M.
      • Borradori L.
      • Berbis P.
      • Cazzaniga S.
      • Valero R.
      • Richard M.A.
      • et al.
      Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: retrospective multicenter case-control study from France and Switzerland.
      ), Israel (
      • Kridin K.
      • Bergman R.
      Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients.
      ), and Japan (
      • Arai M.
      • Shirakawa J.
      • Konishi H.
      • Sagawa N.
      • Terauchi Y.
      Bullous pemphigoid and dipeptidyl peptidase 4 inhibitors: a disproportionality analysis based on the Japanese Adverse Drug Event Report Database.
      ). We believe that gliptin-associated BP represents a useful model for the investigation of the mechanisms behind BP pathogenesis and propose that studies on gliptin-treated patients with diabetes may offer insight into the breakdown of immune tolerance of BP180.
      Mechanisms by which gliptins induce the immune system to act against BP180 are currently unknown. Their target molecule, DPP4, also known as CD26, is ubiquitously expressed by various cells, including T lymphocytes (
      • Klemann C.
      • Wagner L.
      • Stephan M.
      • von Hörsten S.
      Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP-4) entanglement in the immune system.
      ). It is therefore reasonable to hypothesize that inhibition of CD26 on T cells may affect the immune system. The CD26 protein is known to be involved in the pathophysiology of various autoimmune diseases, including multiple sclerosis and rheumatoid arthritis (
      • Klemann C.
      • Wagner L.
      • Stephan M.
      • von Hörsten S.
      Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP-4) entanglement in the immune system.
      ), and it has been suggested that gliptins could decrease the risk of autoimmune diseases but not increase it. However, there are only limited data regarding the expression of CD26 in inflammatory skin diseases such as psoriasis and atopic dermatitis (
      • Klemann C.
      • Wagner L.
      • Stephan M.
      • von Hörsten S.
      Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP-4) entanglement in the immune system.
      ), and to best of our knowledge, no study has yet examined the possible involvement of CD26 in BP pathogenesis. A previous study reported that inhibition of DPP4 induces the infiltration of eosinophils into the skin of rats (
      • Forssmann U.
      • Stoetzer C.
      • Stephan M.
      • Kruschinski C.
      • Skripuletz T.
      • Schade J.
      • et al.
      Inhibition of CD26/dipeptidyl peptidase IV enhances CCL11/eotaxin-mediated recruitment of eosinophils in vivo.
      ). This is notable because the cutaneous infiltration of eosinophils is a typical histopathologic feature of BP. In addition to various inflammatory cells, DPP4 is also expressed by keratinocytes, and therefore, the effects of DPP4 inhibitors (DPP4is) on the processing, biological activity, or metabolism of BP180 could be involved in the development of gliptin-associated BP. However, gliptins also act on members of the large DPP family other than DPP4, including DPP8 and DPP9. It is thus possible that other substrates may be involved in gliptin-associated BP (
      • Yazbeck R.
      • Howarth G.S.
      • Abbott C.A.
      Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease?.
      ). Current data suggest that vildagliptin is the DPP4i most likely to increase the risk for BP (
      • Arai M.
      • Shirakawa J.
      • Konishi H.
      • Sagawa N.
      • Terauchi Y.
      Bullous pemphigoid and dipeptidyl peptidase 4 inhibitors: a disproportionality analysis based on the Japanese Adverse Drug Event Report Database.
      ,
      • Benzaquen M.
      • Borradori L.
      • Berbis P.
      • Cazzaniga S.
      • Valero R.
      • Richard M.A.
      • et al.
      Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: retrospective multicenter case-control study from France and Switzerland.
      ,
      • Kridin K.
      • Bergman R.
      Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients.
      ,
      • Varpuluoma O.
      • Forsti 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.
      ), but again, the reason for this is not known. Taken together, there are many interesting questions concerning the pathomechanism that causes the association between gliptins and BP. Future studies must address these questions.
      Although this French (
      • Plaquevent M.
      • Tétart F.
      • Fardet L.
      • Ingen-Housz-Oro S.
      • Valleyrie-Allanore L.
      • Bernard P.
      • et al.
      Higher frequency of dipeptidyl peptidase-4 inhibitor intake in bullous pemphigoid patients than in French general population.
      ) study and a previous Israeli (
      • Kridin K.
      • Bergman R.
      Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients.
      ) study found no clinical or immunological characteristics that distinguish gliptin-associated BP from “regular” BP, this finding cannot be generalized to all ethnic backgrounds. Recent Japanese studies have reported that, compared with “regular” BP, gliptin-associated BP tends to show a less erythematous, noninflammatory phenotype, with autoantibodies targeting the non-NC16A domains of BP180 (
      • Izumi K.
      • Nishie W.
      • Mai Y.
      • Wada M.
      • Natsuga K.
      • Ujiie H.
      • et al.
      Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.
      ). Of interest, 86% (18/21) of the noninflammatory gliptin-associated Japanese BP patients had the HLA-DQB1*03:01 haplotype, but this allele was present in only 31% (19/61) of the gliptin-treated, non-BP control individuals (
      • Ujiie H.
      • Muramatsu K.
      • Mushiroda T.
      • Ozeki T.
      • Miyoshi H.
      • Iwata H.
      • et al.
      HLA-DQB1*03:01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP-4 inhibitors.
      ). These results suggest that HLA-DQB1*03:01 is strongly associated with drug-related autoimmune disease, and it will be particularly important for future studies to investigate whether this finding extends to other ethnic groups.
      Whatever the mechanism behind gliptin-associated BP may be, the long latency time between the beginning of gliptin treatment and the initiation of BP symptoms supports the hypothesis that it is a drug-aggravated condition rather than a drug-induced cutaneous reaction. Therefore, gliptin-associated BP may persist after gliptin cessation. Once a definite diagnosis of BP has been made in a patient who is receiving gliptin therapy, it is important for the dermatologist to decide whether to recommend that the gliptin should be withdrawn or replaced. In contrast to the
      • Plaquevent M.
      • Tétart F.
      • Fardet L.
      • Ingen-Housz-Oro S.
      • Valleyrie-Allanore L.
      • Bernard P.
      • et al.
      Higher frequency of dipeptidyl peptidase-4 inhibitor intake in bullous pemphigoid patients than in French general population.
      study, a recent study from Israel (
      • Kridin K.
      • Bergman R.
      Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients.
      ) found that discontinuation of gliptins improved clinical outcomes. However, limited sizes of study populations and variation in the treatment of BP patients limits the conclusions that may be drawn from current studies. Because this issue remains unclear, a safe option at the moment is to replace gliptins with another diabetes medication. Combinations of gliptins with metformin are also associated with increased risk of BP, but no such risk has been proven with metformin alone (
      • Kridin K.
      • Bergman R.
      Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients.
      ,
      • Varpuluoma O.
      • Forsti 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.
      ). This implies that when BP is diagnosed in patients receiving both a gliptin and metformin, the metformin could be safely continued while the gliptin is withdrawn.
      During recent years, more epidemiological data have become available regarding factors associated with the onset of BP. Now it is time for research projects that will examine predisposing factors, comorbidities, and disease processes at the level of autoantigen modification and inflammatory pathways to understand the complex immunopathogenesis of BP. For example, a great deal of valuable information on autoimmunity against BP180, and on triggers of autoimmunity in general, could be obtained were it possible to follow BP patients from the preclinical through to the blistering stages of disease. Moreover, characterization of gliptin-associated BP may be an important character in a story that leads to further revelations in other autoimmune diseases.

      Conflict of Interest

      The authors state no conflict of interest.

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      Linked Article

      • Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population
        Journal of Investigative DermatologyVol. 139Issue 4
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          Dipeptidyl peptidase-4 inhibitors have been suspected to induce bullous pemphigoid (BP). The objective of this study was to compare the observed frequency of gliptin intake in a large sample of 1,787 BP patients diagnosed between 2012 and 2015 in France, with the expected frequency after indirect age standardization on 225,412 individuals extracted from the database of the National Healthcare Insurance Agency. The secondary objective was to assess the clinical characteristics and the course of gliptin-associated BP, depending on whether gliptin was continued or stopped.
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