Special article
Bullous pemphigoid and DPP4 inhibitors
Penfigoide ampolloso e inhibidores de la DPP4
Rubén García Castro
, Elena Godoy Gijón, Ana María González Pérez, Concepción Román Curto
Corresponding author
Servicio de Dermatología, Hospital Clínico Universitario de Salamanca, Salamanca, Spain
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Tres meses y medio tras el inicio del tratamiento comienza con lesiones ampollosas y erosivas (izquierda). Confirmado el diagnóstico de penfigoide ampolloso, se presenta refractario a dosis de prednisona de hasta 2<span class="elsevierStyleHsp" style=""></span>mg/kg/día y curas tópicas intensificadas (fomentos con sulfato de cinc y betametasona valerato-sulfato de gentamicina cada 6<span class="elsevierStyleHsp" style=""></span>h). Ante la sospecha de PA asociado a IDPP4, se retira la linagliptina, sustituyéndola por insulina. Tras 8 días (centro) experimenta una importante mejoría clínica, con epitelización parcial de las lesiones, sin haberse realizado modificaciones en el tratamiento del PA. Se decide reducir la dosis de prednisona a 1<span class="elsevierStyleHsp" style=""></span>mg/kg/día. En menos de 30 días las lesiones de mediano tamaño han epitelizado por completo y las de gran tamaño presentan una evolución muy favorable (derecha). Se realiza un descenso gradual de la pauta del glucocorticoide con curación completa un mes y medio tras la retirada del IDPP4.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rubén García Castro, Elena Godoy Gijón, Ana María González Pérez, Concepción Román Curto" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Rubén" "apellidos" => "García Castro" ] 1 => array:2 [ "nombre" => "Elena" "apellidos" => "Godoy Gijón" ] 2 => array:2 [ "nombre" => "Ana María" "apellidos" => "González Pérez" ] 3 => array:2 [ "nombre" => "Concepción" "apellidos" => "Román Curto" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020619304371" "doi" => "10.1016/j.medcle.2019.04.022" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020619304371?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775319304075?idApp=UINPBA00004N" "url" => "/00257753/0000015300000009/v1_201910300628/S0025775319304075/v1_201910300628/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020619304280" "issn" => "23870206" "doi" => "10.1016/j.medcle.2018.07.024" "estado" => "S300" "fechaPublicacion" => "2019-11-15" "aid" => "4606" "copyright" => "Elsevier España, S.L.U." 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The presence of a lipooligosaccharide structure of bacterial membrane in <span class="elsevierStyleItalic">Campylobacter</span> which is similar to the GM1, GD1a or GQ1b gangliosides can determine a cross-reaction by antibodies against the peripheral nerve.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Lorena Martín-Aguilar, Elba Pascual-Goñi, Luis Querol" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Lorena" "apellidos" => "Martín-Aguilar" ] 1 => array:2 [ "nombre" => "Elba" "apellidos" => "Pascual-Goñi" ] 2 => array:2 [ "nombre" => "Luis" "apellidos" => "Querol" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775319304488" "doi" => "10.1016/j.medcli.2019.06.007" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775319304488?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020619304395?idApp=UINPBA00004N" "url" => "/23870206/0000015300000009/v1_201911071124/S2387020619304395/v1_201911071124/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Bullous pemphigoid and DPP4 inhibitors" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "368" "paginaFinal" => "371" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Rubén García Castro, Elena Godoy Gijón, Ana María González Pérez, Concepción Román Curto" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Rubén" "apellidos" => "García Castro" "email" => array:1 [ 0 => "rgarciacastro@saludcastillayleon.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Elena" "apellidos" => "Godoy Gijón" ] 2 => array:2 [ "nombre" => "Ana María" "apellidos" => "González Pérez" ] 3 => array:2 [ "nombre" => "Concepción" "apellidos" => "Román Curto" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital Clínico Universitario de Salamanca, Salamanca, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Penfigoide ampolloso e inhibidores de la DPP4" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1937 "Ancho" => 4445 "Tamanyo" => 1106149 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">82-year-old female patient with type 2 diabetes mellitus in therapy with linagliptin. Three and a half months after the start of treatment, blistering and erosive lesions begin to appear (left). Confirmed diagnosis of bullous pemphigoid; refractory to doses of prednisone of up to 2 mg/kg/day and intensified topical cures (applied poultice using zinc sulfate and betamethasone valerate gentamicin sulfate every 6 h). On suspicion of BP associated with iDPP-4, linagliptin is withdrawn and replaced with insulin. After eight days (centre), the patient undergoes a significant clinical improvement, with partial epithelialization of the lesions, without modifications in the treatment of BP. We decided to reduce the doses of prednisone to 1 mg/kg/day. In fewer than 30 days, medium-sized lesions completely epithelized and large lesions had a very favourable evolution (right). The glucocorticoid regime is gradually decreased with complete healing one and a half months after withdrawal of iDPP-4.</p>" ] ] ] "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 (BP) is the most frequent autoimmune blistering disease,<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a> despite having a low annual incidence (one in 1–2 million inhabitants/year).<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It appears mainly in pluripathological<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,5</span></a> elderly (aged > 70)<span class="elsevierStyleSup">4</span> patients and is associated with diabetes mellitus (especially type 2) in 25% of cases.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It predominantly affects the trunk and lower limbs, 20–30% of lesions appear in mucous membranes.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5</span></a> It clinically manifests as pruritus with a long-term evolution, and urticariform plaques,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and the classic solid blisters that erode and heal without scarring subsequently appear.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> There is a variant that predominantly affects mucous membranes, called Mucous Membrane Pemphigoid (MMP); this variant is more frequent in younger patients (aged approximately 60) and manifests in head and neck lesions (ocular, oral, pharyngeal mucous membranes) and has a tendency to heal.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The disease is caused by autoantibodies (primarily IgG type) circulating against hemidesmosomal proteins (BP180 and BP230) present in keratinocytes in contact with the epidermal basement membrane. Most of the antibodies are directed against BP180, either in the NC16a region (80–90%) in BP,<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> or the C-terminal region in MMP.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The antigen-antibody binding activates an inflammatory cascade (complement activation, migration of inflammatory cells and release of proteolytic enzymes) that damages the dermoepidermal junction and results in blistering.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,4,7</span></a> It is common to find eosinophilia in peripheral blood. Pathological studies show a subepidermal bleb with eosinophils, neutrophils and fibrin.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,8</span></a> In the upper dermis a mixed inflammatory infiltrate can be found, mainly due to eosinophils. Direct immunofluorescence of the perilesional skin shows linear deposits of C3 and IgG in the basement membrane.<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. Topical treatment (high-potency glucocorticotherapy associated or not with antibiotic treatment) is very useful in most mild-moderate cases. In refractory cases, other drugs such as azathioprine, methotrexate, cyclosporine, mycophenolate mofetil or dapsone can be used.</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, such as radiotherapy, burns, exposure to ultraviolet radiation, trauma or surgical procedures. It is believed that the alteration these factors provoke in proteins such as BP180 could trigger an immunogenicity against certain HLA alleles (autoantigens).<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,10</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, amiodarone, sulfasalazine, allopurinol, furosemide, chloroquine and penicillin derivatives,<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,11</span></a> and only statistical significance has been demonstrated in the case of aldosterone antagonists and some neuroleptics.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,5</span></a> Recently, its association with inhibitors of dipeptidyl peptidase 4 (iDPP-4)<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–5,10–13</span></a> has also been described, without having been associated with other antidiabetics.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3,14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">To date, no cases of BP associated with taking metformin alone have been described, despite being a widely used drug that have been on the market for more than 20 years.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Furthermore, Varpuluoma et al. showed that there was no association between taking metformin and BP lesions.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> And in the majority of cases of BP associated with iDPP-4, metformin has continued to be taken (alone or associated with other antidiabetics other than an iDPP-4), with improvement of the lesions.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,14</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.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,11</span></a> DPP-4 or CD26 is a membrane protein also expressed in T lymphocytes, keratinocytes, fibroblasts and endothelial cells. It is responsible for degrading incretins, whose function is to promote insulin secretion. Since iDDP-4 blocks the degrading action on incretins (GLP-1 and GIP), they secondarily promote insulin secretion, thereby lowering blood glucose. Their use is becoming more popular because they have a lower risk of hypoglycaemia and, also for this reason, are the drugs of choice for elderly patients.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3,10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">However, iDPP-4 also blocks the DPP-4/CD26 of the T lymphocytes, involved in signalling pathways for their activation and in the interaction between T cells and antigen presenting cells. It is expressed in multiple tissues, but especially in memory T lymphocytes (CD4+ CD45RO+ phenotype). A high expression of CD26+ correlates with the polarisation of the immune response to Th-1, with cytokine production such as IFN-γ. In addition, these T-CD26+ lymphocytes stimulate the production of antibodies by B lymphocytes and activate cytotoxic T cells. T-CD26+ lymphocytes have an important migratory capacity, as has been shown in synovial fluids. The in vitro inhibition of DPP-4 decreases the production of inflammatory cytokines and promotes the production of other inhibitory immune response, such as TGF-β.<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. Thus, animal studies concluded that DPP-4 inhibition might possibly be beneficial in rheumatoid arthritis, multiple sclerosis, autoimmune diabetes, inflammatory bowel disease (IBD) and graft versus host disease, among others. This has been published by certain studies.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17–19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">However, we also found contrary medical literature, with cases of worsening IBD. Despite confirming an overexpression of CD26 in T lymphocytes in patients with IBD, 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. Attaway et al. found an association not only in IBD, but also in rheumatoid arthritis and systemic lupus erythematosus, with decreased levels of the DPP-4 enzyme.<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.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Similarly, DPP-4 acts as a plasminogen receptor, activating its conversion to plasmin. Plasmin is a serum protease capable of partially cleaving BP180, forming new antigens (LABD-97 and ectodomain 120-kDa)<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> modifying its antigenicity.<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, although these described effects could justify their association.</p><p id="par0065" class="elsevierStylePara elsevierViewall">It has been shown that DPP-4/CD26 inhibition in animal models promotes the migration of eosinophils to the skin<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,11,20</span></a> and in monkeys the appearance of erosions and blisters (dose-dependent effect) has been described with vildagliptin.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,10,14</span></a> In fact, the FDA did not initially approve the sale of vildagliptin due to the appearance of such blistering lesions in monkeys in preclinical studies.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Similar lesions have also been found in animal models with sitagliptin.<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.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In a French study based on pharmacovigilance data, an association was observed between patients using iDPP-4 and BP (OR 67.5 [47.1–96.9]), with vildagliptin having the highest risk (OR 85.98 [70, 98–104.15]).<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,21</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, being higher for vildagliptin. In this study, Benzaquen et al. found an OR of 3.45 for the association iDPP-4 + PA (p < 0.001) and 7.23 for vildagliptin (p < 0.001), although when adjusting for confounding factors the results were: OR 2.64 (p = 0.02) and OR 3.57 (p = 0.04), respectively.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Gravani et al. collected 130 cases of BP in the period from 2005 to 2016. Until 2011 (when iDPP-4 began to be prescribed) they had collected only 28 cases of BP, and the expected figure of new BP cases from 2011 until 2016 was 40. Conversely during in those years, the number of new BP cases was 102: 62 more cases than expected. Of those 62 cases, 53 (81.5%) were taking iDPP-4. These data show that these drugs must have some role in the pathogenesis of BP, even though exactly what role is still unknown.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</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">3,4,11,21</span></a> and aged older than 70–80.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In contrast, patients with MMP are younger.<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.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–5,10,21</span></a> According to one study,<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 (no statistically significant difference). Conversely, they presented IgG antibodies against other regions of BP180 (LAD-1, ectodomain 120-kDa and LABD-97)<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a> and less inflammatory lesions (valued for erythema).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This shows that these drugs could cause BP by a different mechanism.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,24,25</span></a> The formation of IgE and IgA antibodies has also been described.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Horikawa et al. analysed 35 patients with a diagnosis of BP between 2014 and 2016, 12 of whom were taking iDPP-4. They found that among those taking iDPP-4, non-inflammatory lesions were relatively more frequent (50%) than the group who did not take them (13%) (p = 0.038). In the same way, positivity for anti-BP180-NC16a antibodies was relatively less frequent (58%) compared to the group who did not take them (91%) (p = 0.033). In both cases, the differences were statistically significant.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">On the contrary, Mai et al. 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, specifically against the classic NC1a region of BP180. In addition, these authors hypothesised an aggravating role of iDPP-4 in BP lesions with the epitope spreading theory. This theory states that after the cellular damage caused in the basal keratinocytes by the T lymphocyte in the BP lesions, iDPP-4 would favour the recognition and presentation as foreign antigens of other regions/epitopes of the BP180 to the T lymphocytes, thus perpetuating the inflammatory response. Therefore, they suggest that lesions that are not responding to conventional treatment for BP could be perpetuated by taking iDPP-4.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The BP cases collected by Fania et al. associated with iDPP-4 showed a behaviour similar to the usual BP (inflammatory lesions, positive autoimmunity)<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</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. demonstrated that eosinophilic infiltration in BP-iDPP-4 biopsies is lower compared to those that are not associated with htaking iDPP-4,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and stated that during the formation of blisters, iDPP-4 inhibit the migration of eosinophils due to a decrease in levels of IL-13 and other cytokines, as found in animal models with sitagliptin in animal asthmatic lung tissue.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> This contradicts the results from previous studies.</p><p id="par0090" class="elsevierStylePara elsevierViewall">On the other hand, HLA-DQ (B1*03:01) (associated with MMP) has been more frequently associated with non-inflammatory BP and treatment with iDPP-4.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It more often presents with mucosal lesions compared to the usual BP.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,7</span></a> In contrast, the MMP associated with taking iDPP-4 have more frequent skin lesions, less involvement of the oral mucosa, usual negative antibodies and negativity for their characteristic immunofluorescence.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In protein electrotransfer studies, integrin a6b4 has been found to be a possible target in MMP<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</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, vildagliptin and linagliptin have been shown to be the most associated with BP,<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,10–12,20,27</span></a> this association is statistically significant, unlike others such as sitagliptin.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In a Finnish registry, a significant association was found between taking vildagliptin and BP (OR 10.4 [4.56–23.80]). Gaudin et al. suggest that vildagliptin has a greater capacity to induce blistering diseases.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This is corroborated by Benzaquen et al. and Béné et al., who agree that, although the most frequently prescribed iDPP-4 in Europe is sitagliptin, the relative frequency of BP + iDPP-4 is highest with vildagliptin.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,10</span></a> And Benzaquen et al. (n = 183) confirmed a statistically significant increase in the prevalence of BP in diabetic patients treated with iDPP-4 (approximately 46% versus 18% of control), especially for vildagliptin3. Interestingly, vildagliptin is one of the least specific iDPP-4, since it also inhibits DPP8 and DDP9,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> which possibly explains its immunogenic role (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</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.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> Abandoning treatment with iDPP-4 has been shown to improve the evolution of BP lesions.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11,21</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">5,26,28</span></a> and yet others have found relapses of BP despite treatment and withdrawal.<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, except one.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In that case, sitagliptin was withdrawn with a partial remission of the condition along with systemic therapy, but the lesions reappeared after the reintroduction of the drug. After suspending again and changing the antidiabetic to another from a different family (in this case, repaglinide), evolution was favourable.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Benzaquen et al. described a less favourable prognosis of the disease in patients who do not suspended iDPP-4.<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> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Since iDPP-4 can be easily suspended or substituted for another antidiabetic treatment, should an adverse drug reaction occur, withdrawing them or replacing them with another family of antidiabetics in patients with BP is recommended. A pharmacovigilance notification should also be made. Despite being a class effect for all iDPP-4,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> the risk is greater for vildagliptin. Improvement after withdrawal of the iDDP-4 and the start of treatment is fast (average 10–14 days), with a complete remission of lesions usually occurring within two months, even allowing for a rapid de-escalation of the systemic treatment.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,20,28</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, which when maintained have hyperglycemic effects. It has been shown that metformin alone is usually not sufficient for glycemic control in patients previously controlled with metformin and an iDDP-4. For this reason, associating an antidiabetic from another different pharmacological family (oral glinides ↓↓ or injectable ↓GLP-1 analogues ↓) is recommended, but carrying out glycemic control with insulin is preferable due to the frequent presence of comorbidities in elderly patients (chronic renal failure and cardiovascular disease).<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,29</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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Related factors" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Clinical presentation" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "Histopathological study" ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "DPP-4 inhibitors and risk of bullous pemphigoid" ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Prognosis and treatment" ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-02-18" "fechaAceptado" => "2019-04-25" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: García Castro R, Godoy Gijón E, González Pérez AM, Román Curto C. Penfigoide ampolloso e inhibidores de la DPP4. Med Clin (Barc). 2019;153:368–371.</p>" ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1937 "Ancho" => 4445 "Tamanyo" => 1106149 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">82-year-old female patient with type 2 diabetes mellitus in therapy with linagliptin. Three and a half months after the start of treatment, blistering and erosive lesions begin to appear (left). Confirmed diagnosis of bullous pemphigoid; refractory to doses of prednisone of up to 2 mg/kg/day and intensified topical cures (applied poultice using zinc sulfate and betamethasone valerate gentamicin sulfate every 6 h). On suspicion of BP associated with iDPP-4, linagliptin is withdrawn and replaced with insulin. After eight days (centre), the patient undergoes a significant clinical improvement, with partial epithelialization of the lesions, without modifications in the treatment of BP. We decided to reduce the doses of prednisone to 1 mg/kg/day. In fewer than 30 days, medium-sized lesions completely epithelized and large lesions had a very favourable evolution (right). The glucocorticoid regime is gradually decreased with complete healing one and a half months after withdrawal of iDPP-4.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <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, aged >70–80 \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: six-19 months \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">Minor or no levels of anti-BP180 IgG antibodies against NC1a6 region \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">Higher levels of anti-BP180 antibodies compared to other regions \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">Fewer inflammatory lesions (fewer erythematous plaques) \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">Less eosinophilic infiltration in pathological anatomy \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2160541.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Typical clinical and histological characteristics of bullous pemphigoid associated with taking iDPP-4.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Béné et al.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> n (BP + iDPP-4) = 42 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gaudin et al.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> n (BP + iDPP-4) = 40 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Horikawa et al.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> n (BP + iDPP-4) = 12 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">García et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> n (BP + iDPP-4) = 170 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><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">Vildagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">73.8% (n = 31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45% (n = 19) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41.67% (n = 5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66.47% (n = 113) \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">Sitagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.8% (n = 10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24% (n = 10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.3% (n = 1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23.52% (n = 40) \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">Linagliptin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19% (n = 8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33.33% (n = 4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.64% (n = 13) \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">Others \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.38% (n = 1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12% (n = 5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.67% (n = 2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.35% (n = 4) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2160540.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Series of most relevant cases (by "n" of patients) who presented bullous pemphigoid associated with taking iDPP-4.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dipeptidyl peptidase-4 inhibitors-associated bullous pemphigoid: A retrospective study of 168 pemphigoid and 9,304 diabetes mellitus patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. 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