Bullous pemphigoid and DPP4 inhibitors

García Castro, Rubén; Godoy Gijón, Elena; González Pérez, Ana María; Román Curto, Concepción
doi:10.1016/j.medcle.2019.04.022
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">82-year-old female patient with type 2 diabetes mellitus in therapy with linagliptin&#46; Three and a half months after the start of treatment&#44; blistering and erosive lesions begin to appear &#40;left&#41;&#46; Confirmed diagnosis of bullous pemphigoid&#59; refractory to doses of prednisone of up to 2&#8239;mg&#47;kg&#47;day and intensified topical cures &#40;applied poultice using zinc sulfate and betamethasone valerate gentamicin sulfate every 6&#8239;h&#41;&#46; On suspicion of BP associated with iDPP-4&#44; linagliptin is withdrawn and replaced with insulin&#46; After eight days &#40;centre&#41;&#44; the patient undergoes a significant clinical improvement&#44; with partial epithelialization of the lesions&#44; without modifications in the treatment of BP&#46; We decided to reduce the doses of prednisone to 1&#8239;mg&#47;kg&#47;day&#46; In fewer than 30 days&#44; medium-sized lesions completely epithelized and large lesions had a very favourable evolution &#40;right&#41;&#46; The glucocorticoid regime is gradually decreased with complete healing one and a half months after withdrawal of iDPP-4&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Bullous pemphigoid &#40;BP&#41; is the most frequent autoimmune blistering disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> despite having a low annual incidence &#40;one in 1&#8211;2 million inhabitants&#47;year&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It appears mainly in pluripathological<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5</span></a> elderly &#40;aged&#8239;&#62;&#8239;70&#41;<span class="elsevierStyleSup">4</span> patients and is associated with diabetes mellitus &#40;especially type 2&#41; in 25&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It predominantly affects the trunk and lower limbs&#44; 20&#8211;30&#37; of lesions appear in mucous membranes&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;5</span></a> It clinically manifests as pruritus with a long-term evolution&#44; and urticariform plaques&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and the classic solid blisters that erode and heal without scarring subsequently appear&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> There is a variant that predominantly affects mucous membranes&#44; called Mucous Membrane Pemphigoid &#40;MMP&#41;&#59; this variant is more frequent in younger patients &#40;aged approximately 60&#41; and manifests in head and neck lesions &#40;ocular&#44; oral&#44; pharyngeal mucous membranes&#41; and has a tendency to heal&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The disease is caused by autoantibodies &#40;primarily IgG type&#41; circulating against hemidesmosomal proteins &#40;BP180 and BP230&#41; present in keratinocytes in contact with the epidermal basement membrane&#46; Most of the antibodies are directed against BP180&#44; either in the NC16a region &#40;80&#8211;90&#37;&#41; in BP&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> or the C-terminal region in MMP&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The antigen-antibody binding activates an inflammatory cascade &#40;complement activation&#44; migration of inflammatory cells and release of proteolytic enzymes&#41; that damages the dermoepidermal junction and results in blistering&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;7</span></a> It is common to find eosinophilia in peripheral blood&#46; Pathological studies show a subepidermal bleb with eosinophils&#44; neutrophils and fibrin&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;8</span></a> In the upper dermis a mixed inflammatory infiltrate can be found&#44; mainly due to eosinophils&#46; Direct immunofluorescence of the perilesional skin shows linear deposits of C3 and IgG in the basement membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Systemic treatment is based on the use of glucocorticoids or immunosuppressants&#46; Topical treatment &#40;high-potency glucocorticotherapy associated or not with antibiotic treatment&#41; is very useful in most mild-moderate cases&#46; In refractory cases&#44; other drugs such as azathioprine&#44; methotrexate&#44; cyclosporine&#44; mycophenolate mofetil or dapsone can be used&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Related factors</span><p id="par0020" class="elsevierStylePara elsevierViewall">Multiple factors have been implicated in the appearance of BP&#44; such as radiotherapy&#44; burns&#44; exposure to ultraviolet radiation&#44; trauma or surgical procedures&#46; It is believed that the alteration these factors provoke in proteins such as BP180 could trigger an immunogenicity against certain HLA alleles &#40;autoantigens&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The appearance of BP lesions of pharmacological origin has traditionally been described in the medical literature as associated with spironolactone&#44; amiodarone&#44; sulfasalazine&#44; allopurinol&#44; furosemide&#44; chloroquine and penicillin derivatives&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;11</span></a> and only statistical significance has been demonstrated in the case of aldosterone antagonists and some neuroleptics&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5</span></a> Recently&#44; its association with inhibitors of dipeptidyl peptidase 4 &#40;iDPP-4&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;5&#44;10&#8211;13</span></a> has also been described&#44; without having been associated with other antidiabetics&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3&#44;14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">To date&#44; no cases of BP associated with taking metformin alone have been described&#44; despite being a widely used drug that have been on the market for more than 20 years&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Furthermore&#44; Varpuluoma et al&#46; showed that there was no association between taking metformin and BP lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> And in the majority of cases of BP associated with iDPP-4&#44; metformin has continued to be taken &#40;alone or associated with other antidiabetics other than an iDPP-4&#41;&#44; with improvement of the lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;14</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">iDPP-4 began to be prescribed in Japan for the treatment of type 2 diabetes in 2006&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;11</span></a> DPP-4 or CD26 is a membrane protein also expressed in T lymphocytes&#44; keratinocytes&#44; fibroblasts and endothelial cells&#46; It is responsible for degrading incretins&#44; whose function is to promote insulin secretion&#46; Since iDDP-4 blocks the degrading action on incretins &#40;GLP-1 and GIP&#41;&#44; they secondarily promote insulin secretion&#44; thereby lowering blood glucose&#46; Their use is becoming more popular because they have a lower risk of hypoglycaemia and&#44; also for this reason&#44; are the drugs of choice for elderly patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">However&#44; iDPP-4 also blocks the DPP-4&#47;CD26 of the T lymphocytes&#44; involved in signalling pathways for their activation and in the interaction between T cells and antigen presenting cells&#46; It is expressed in multiple tissues&#44; but especially in memory T lymphocytes &#40;CD4&#43; CD45RO&#43; phenotype&#41;&#46; A high expression of CD26&#43; correlates with the polarisation of the immune response to Th-1&#44; with cytokine production such as IFN-&#947;&#46; In addition&#44; these T-CD26&#43; lymphocytes stimulate the production of antibodies by B lymphocytes and activate cytotoxic T cells&#46; T-CD26&#43; lymphocytes have an important migratory capacity&#44; as has been shown in synovial fluids&#46; The in vitro inhibition of DPP-4 decreases the production of inflammatory cytokines and promotes the production of other inhibitory immune response&#44; such as TGF-&#946;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Overexpression of DPP-4 has been demonstrated in T lymphocytes of inflammatory and autoimmune processes&#46; Thus&#44; animal studies concluded that DPP-4 inhibition might possibly be beneficial in rheumatoid arthritis&#44; multiple sclerosis&#44; autoimmune diabetes&#44; inflammatory bowel disease &#40;IBD&#41; and graft versus host disease&#44; among others&#46; This has been published by certain studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#8211;19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">However&#44; we also found contrary medical literature&#44; with cases of worsening IBD&#46; Despite confirming an overexpression of CD26 in T lymphocytes in patients with IBD&#44; it is believed that their aggravating role in this disorder comes from the lower levels and decreased activity of DPP-4 in blood when compared with controls&#46; Attaway et al&#46; found an association not only in IBD&#44; but also in rheumatoid arthritis and systemic lupus erythematosus&#44; with decreased levels of the DPP-4 enzyme&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The pathophysiological basis of this finding is unknown with certainty&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Similarly&#44; DPP-4 acts as a plasminogen receptor&#44; activating its conversion to plasmin&#46; Plasmin is a serum protease capable of partially cleaving BP180&#44; forming new antigens &#40;LABD-97 and ectodomain 120-kDa&#41;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> modifying its antigenicity&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> How iDPP-4 is able to induce BP lesions through this route is still unknown&#44; although these described effects could justify their association&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">It has been shown that DPP-4&#47;CD26 inhibition in animal models promotes the migration of eosinophils to the skin<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;11&#44;20</span></a> and in monkeys the appearance of erosions and blisters &#40;dose-dependent effect&#41; has been described with vildagliptin&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;10&#44;14</span></a> In fact&#44; the FDA did not initially approve the sale of vildagliptin due to the appearance of such blistering lesions in monkeys in preclinical studies&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Similar lesions have also been found in animal models with sitagliptin&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The first case of BP associated with the use of iDPP-4 was described in 2011&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In a French study based on pharmacovigilance data&#44; an association was observed between patients using iDPP-4 and BP &#40;OR 67&#46;5 &#91;47&#46;1&#8211;96&#46;9&#93;&#41;&#44; with vildagliptin having the highest risk &#40;OR 85&#46;98 &#91;70&#44; 98&#8211;104&#46;15&#93;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;21</span></a> Another European pharmacovigilance study corroborated that the relative frequency of BP in patients exposed to iDDP-4 was higher compared to other oral antidiabetics&#44; being higher for vildagliptin&#46; In this study&#44; Benzaquen et al&#46; found an OR of 3&#46;45 for the association iDPP-4&#8239;&#43;&#8239;PA &#40;p&#8239;&#60;&#8239;0&#46;001&#41; and 7&#46;23 for vildagliptin &#40;p&#8239;&#60;&#8239;0&#46;001&#41;&#44; although when adjusting for confounding factors the results were&#58; OR 2&#46;64 &#40;p&#8239;&#61;&#8239;0&#46;02&#41; and OR 3&#46;57 &#40;p&#8239;&#61;&#8239;0&#46;04&#41;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Gravani et al&#46; collected 130 cases of BP in the period from 2005 to 2016&#46; Until 2011 &#40;when iDPP-4 began to be prescribed&#41; they had collected only 28 cases of BP&#44; and the expected figure of new BP cases from 2011 until 2016 was 40&#46; Conversely during in those years&#44; the number of new BP cases was 102&#58; 62 more cases than expected&#46; Of those 62 cases&#44; 53 &#40;81&#46;5&#37;&#41; were taking iDPP-4&#46; These data show that these drugs must have some role in the pathogenesis of BP&#44; even though exactly what role is still unknown&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Clinical presentation</span><p id="par0075" class="elsevierStylePara elsevierViewall">Patients with BP associated with taking iDPP-4 have been described as being more often male<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;11&#44;21</span></a> and aged older than 70&#8211;80&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In contrast&#44; patients with MMP are younger&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The time from when the patient starts treatment with the drug until the appearance of the lesions varies between six and 19 months according to the study&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5&#44;10&#44;21</span></a> According to one study&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> patients with BP taking iDPP-4 had lower or absent levels of anti-BP180 IgG antibodies against the NC1a6 region &#40;no statistically significant difference&#41;&#46; Conversely&#44; they presented IgG antibodies against other regions of BP180 &#40;LAD-1&#44; ectodomain 120-kDa and LABD-97&#41;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> and less inflammatory lesions &#40;valued for erythema&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This shows that these drugs could cause BP by a different mechanism&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;24&#44;25</span></a> The formation of IgE and IgA antibodies has also been described&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Horikawa et al&#46; analysed 35 patients with a diagnosis of BP between 2014 and 2016&#44; 12 of whom were taking iDPP-4&#46; They found that among those taking iDPP-4&#44; non-inflammatory lesions were relatively more frequent &#40;50&#37;&#41; than the group who did not take them &#40;13&#37;&#41; &#40;p&#8239;&#61;&#8239;0&#46;038&#41;&#46; In the same way&#44; positivity for anti-BP180-NC16a antibodies was relatively less frequent &#40;58&#37;&#41; compared to the group who did not take them &#40;91&#37;&#41; &#40;p&#8239;&#61;&#8239;0&#46;033&#41;&#46; In both cases&#44; the differences were statistically significant&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">On the contrary&#44; Mai et al&#46; analysed three cases of patients with negative autoimmunity prior to the start of treatment with iDPP-4 for anti-BP180 that showed positive in subsequent controls after the appearance of BP lesions&#44; specifically against the classic NC1a region of BP180&#46; In addition&#44; these authors hypothesised an aggravating role of iDPP-4 in BP lesions with the epitope spreading theory&#46; This theory states that after the cellular damage caused in the basal keratinocytes by the T lymphocyte in the BP lesions&#44; iDPP-4 would favour the recognition and presentation as foreign antigens of other regions&#47;epitopes of the BP180 to the T lymphocytes&#44; thus perpetuating the inflammatory response&#46; Therefore&#44; they suggest that lesions that are not responding to conventional treatment for BP could be perpetuated by taking iDPP-4&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The BP cases collected by Fania et al&#46; associated with iDPP-4 showed a behaviour similar to the usual BP &#40;inflammatory lesions&#44; positive autoimmunity&#41;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Histopathological study</span><p id="par0085" class="elsevierStylePara elsevierViewall">Chijiwa et al&#46; demonstrated that eosinophilic infiltration in BP-iDPP-4 biopsies is lower compared to those that are not associated with htaking iDPP-4&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and stated that during the formation of blisters&#44; iDPP-4 inhibit the migration of eosinophils due to a decrease in levels of IL-13 and other cytokines&#44; as found in animal models with sitagliptin in animal asthmatic lung tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> This contradicts the results from previous studies&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">On the other hand&#44; HLA-DQ &#40;B1&#42;03&#58;01&#41; &#40;associated with MMP&#41; has been more frequently associated with non-inflammatory BP and treatment with iDPP-4&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It more often presents with mucosal lesions compared to the usual BP&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;7</span></a> In contrast&#44; the MMP associated with taking iDPP-4 have more frequent skin lesions&#44; less involvement of the oral mucosa&#44; usual negative antibodies and negativity for their characteristic immunofluorescence&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In protein electrotransfer studies&#44; integrin a6b4 has been found to be a possible target in MMP<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">DPP-4 inhibitors and risk of bullous pemphigoid</span><p id="par0095" class="elsevierStylePara elsevierViewall">Within iDPP-4&#44; vildagliptin and linagliptin have been shown to be the most associated with BP&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10&#8211;12&#44;20&#44;27</span></a> this association is statistically significant&#44; unlike others such as sitagliptin&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In a Finnish registry&#44; a significant association was found between taking vildagliptin and BP &#40;OR 10&#46;4 &#91;4&#46;56&#8211;23&#46;80&#93;&#41;&#46; Gaudin et al&#46; suggest that vildagliptin has a greater capacity to induce blistering diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This is corroborated by Benzaquen et al&#46; and B&#233;n&#233; et al&#46;&#44; who agree that&#44; although the most frequently prescribed iDPP-4 in Europe is sitagliptin&#44; the relative frequency of BP&#8239;&#43;&#8239;iDPP-4 is highest with vildagliptin&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;10</span></a> And Benzaquen et al&#46; &#40;n&#8239;&#61;&#8239;183&#41; confirmed a statistically significant increase in the prevalence of BP in diabetic patients treated with iDPP-4 &#40;approximately 46&#37; versus 18&#37; of control&#41;&#44; especially for vildagliptin3&#46; Interestingly&#44; vildagliptin is one of the least specific iDPP-4&#44; since it also inhibits DPP8 and DDP9&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> which possibly explains its immunogenic role &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Prognosis and treatment</span><p id="par0100" class="elsevierStylePara elsevierViewall">Whether iDPP-4 act as an aggravating condition or are the direct cause of BP when BP is associated with taking iDPP-4 is currently unknown&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Abandoning treatment with iDPP-4 has been shown to improve the evolution of BP lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11&#44;21</span></a> Certain published cases have found complete remission after withdrawal of the drug despite systemic treatment<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;26&#44;28</span></a> and yet others have found relapses of BP despite treatment and withdrawal&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The drug was not reintroduced in any of those cases&#44; except one&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In that case&#44; sitagliptin was withdrawn with a partial remission of the condition along with systemic therapy&#44; but the lesions reappeared after the reintroduction of the drug&#46; After suspending again and changing the antidiabetic to another from a different family &#40;in this case&#44; repaglinide&#41;&#44; evolution was favourable&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Benzaquen et al&#46; described a less favourable prognosis of the disease in patients who do not suspended iDPP-4&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The worsening of a case has also been described after replacing sitagliptin with vildagliptin<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Since iDPP-4 can be easily suspended or substituted for another antidiabetic treatment&#44; should an adverse drug reaction occur&#44; withdrawing them or replacing them with another family of antidiabetics in patients with BP is recommended&#46; A pharmacovigilance notification should also be made&#46; Despite being a class effect for all iDPP-4&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> the risk is greater for vildagliptin&#46; Improvement after withdrawal of the iDDP-4 and the start of treatment is fast &#40;average 10&#8211;14 days&#41;&#44; with a complete remission of lesions usually occurring within two months&#44; even allowing for a rapid de-escalation of the systemic treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;20&#44;28</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">It is worth noting here that the most frequently prescribed treatment for BP is oral glucocorticoids&#44; which when maintained have hyperglycemic effects&#46; It has been shown that metformin alone is usually not sufficient for glycemic control in patients previously controlled with metformin and an iDDP-4&#46; For this reason&#44; associating an antidiabetic from another different pharmacological family &#40;oral glinides &#8595;&#8595; or injectable &#8595;GLP-1 analogues &#8595;&#41; is recommended&#44; but carrying out glycemic control with insulin is preferable due to the frequent presence of comorbidities in elderly patients &#40;chronic renal failure and cardiovascular disease&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;29</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conflict of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        1 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Related factors"
        ]
        2 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Clinical presentation"
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          "identificador" => "sec0020"
          "titulo" => "Histopathological study"
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        4 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "DPP-4 inhibitors and risk of bullous pemphigoid"
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          "titulo" => "Prognosis and treatment"
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          "titulo" => "References"
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    "fechaRecibido" => "2019-02-18"
    "fechaAceptado" => "2019-04-25"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Garc&#237;a Castro R&#44; Godoy Gij&#243;n E&#44; Gonz&#225;lez P&#233;rez AM&#44; Rom&#225;n Curto C&#46; Penfigoide ampolloso e inhibidores de la DPP4&#46; Med Clin &#40;Barc&#41;&#46; 2019&#59;153&#58;368&#8211;371&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">82-year-old female patient with type 2 diabetes mellitus in therapy with linagliptin&#46; Three and a half months after the start of treatment&#44; blistering and erosive lesions begin to appear &#40;left&#41;&#46; Confirmed diagnosis of bullous pemphigoid&#59; refractory to doses of prednisone of up to 2&#8239;mg&#47;kg&#47;day and intensified topical cures &#40;applied poultice using zinc sulfate and betamethasone valerate gentamicin sulfate every 6&#8239;h&#41;&#46; On suspicion of BP associated with iDPP-4&#44; linagliptin is withdrawn and replaced with insulin&#46; After eight days &#40;centre&#41;&#44; the patient undergoes a significant clinical improvement&#44; with partial epithelialization of the lesions&#44; without modifications in the treatment of BP&#46; We decided to reduce the doses of prednisone to 1&#8239;mg&#47;kg&#47;day&#46; In fewer than 30 days&#44; medium-sized lesions completely epithelized and large lesions had a very favourable evolution &#40;right&#41;&#46; The glucocorticoid regime is gradually decreased with complete healing one and a half months after withdrawal of iDPP-4&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Males&#44; aged &#62;70&#8211;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Time from the start of treatment with iDPP-4 until the appearance of lesions&#58; six-19 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Minor or no levels of anti-BP180 IgG antibodies against NC1a6 region&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Higher levels of anti-BP180 antibodies compared to other regions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Fewer inflammatory lesions &#40;fewer erythematous plaques&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Less eosinophilic infiltration in pathological anatomy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">B&#233;n&#233; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> n &#40;BP&#8239;&#43;&#8239;iDPP-4&#41;&#8239;&#61;&#8239;42&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">23&#46;8&#37; &#40;n&#8239;&#61;&#8239;10&#41;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Series of most relevant cases &#40;by &#34;n&#34; of patients&#41; who presented bullous pemphigoid associated with taking iDPP-4&#46;</p>"
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        0 => array:2 [
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                0 => array:2 [
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                    0 => array:2 [
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                      "titulo" => "Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid&#58; A Finnish nationwide case-control study"
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                      "titulo" => "Dipeptidyl peptidase IV inhibitors&#44; a risk factor for bullous pemphigoid&#58; Retrospective multicenter case-control study from France and Switzerland"
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                            5 => "S&#46; Mignot-Grootenboer"
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