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Bullous pemphigoid associated with linagliptin treatment in diabetic patients with chronic kidney disease
Penfigoide ampolloso asociado al tratamiento con linagliptina en pacientes con diabetes y enfermedad renal crónica
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It primarily affects the elderly, and clinically manifests as subepidermal blisters.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> While there is a long list of both physical agents and drugs related to the pathogenesis of bullous pemphigoid, in many cases the causal agent cannot be identified. However, the diagnosis should be suspected when bullous lesions appear in a patient who has recently started to receive a new drug.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In recent years, cases of bullous pemphigoid have been reported in association with the administration of DPP4 inhibitors in diabetic patients, mainly vildagliptin and sitagliptin,<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">2–5</span></a> with the implication of linagliptin in exceptional cases.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">3–6</span></a> A recent article by Kridin and Bergman found treatment with vildagliptin to increase the risk of bullous pemphigoid (odds ratio [OR]: 9.28; 95% confidence interval [95%CI]: 4.54–18.99) versus linagliptin (OR: 6.61; 95%CI: 2.28–19.17).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present three cases of bullous pemphigoid associated with the use of linagliptin in patients with type 2 diabetes (DM2) and chronic kidney disease (CKD) secondary to diabetic nephropathy (expressed in glomerular filtration [G] and albuminuria stages [A]) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 1</span>. An 84-year-old male presented with a history of arterial hypertension (AHT), DM2, mixed dyslipidemia, hyperuricemia with gout, and left nephrectomy secondary to renal carcinoma. There was no evidence of diabetic retinopathy or neuropathy, and no macrovascular complications. The latest recorded HbA<span class="elsevierStyleInf">1c</span> value was 6.7%. The patient was receiving antidiabetic treatment with metformin 1000<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h and repaglinide 0.5<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h. After the diagnosis of chronic kidney disease (G4A3), metformin was discontinued and linagliptin was started at a dose of 5<span class="elsevierStyleHsp" style=""></span>mg/day. Six months later, the patient developed bullous lesions on the upper extremities and trunk, and after evaluation two weeks later by Dermatology, a clinical diagnosis of bullous pemphigoid was established. Prednisone 30<span class="elsevierStyleHsp" style=""></span>mg was administered and linagliptin was discontinued, with complete resolution after three weeks.</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 2</span>. An 83-year-old woman presented with a history of AHT, DM2, obesity, mixed dyslipidemia, hyperuricemia without gout, and no other known disease. There was no evidence of diabetic retinopathy or neuropathy, and no macrovascular complications; HbA<span class="elsevierStyleInf">1c</span> 7.2%. The patient had been receiving antidiabetic treatment with metformin 850<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h and vildagliptin 50<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h over the previous two years. After establishing a diagnosis of chronic kidney disease (G4A2), metformin was discontinued and vildagliptin was replaced by linagliptin 5<span class="elsevierStyleHsp" style=""></span>mg/24<span class="elsevierStyleHsp" style=""></span>h. One month later she reported to the emergency room due to blister lesions on her limbs. With a clinical diagnosis of possible bullous pemphigoid, oral prednisone was started at a dose of 30<span class="elsevierStyleHsp" style=""></span>mg/day. One month later she was evaluated by Dermatology, with confirmation of the diagnosis of bullous pemphigoid; treatment with prednisone was maintained at a dose of 15<span class="elsevierStyleHsp" style=""></span>mg/day, with the addition of a topical corticosteroid and a cycle of oral doxycycline. At examination two months later, the pemphigoid outbreak was seen to persist, and linagliptin was consequently discontinued, with the introduction of repaglinide. One month later, following considerable clinical improvement, prednisone was discontinued. The clinical condition was seen to have resolved at evaluation two months later.</p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 3</span>. A 78-year-old woman presented with a history of AHT, DM2, chronic kidney disease (G4A2) and non-obstructive hypertrophic cardiomyopathy. There was no evidence of diabetic retinopathy or neuropathy, and no macrovascular complications. The patient consulted due to poor metabolic control, with persistent HbA<span class="elsevierStyleInf">1c</span> >8.5%. Linagliptin was therefore added to her antidiabetic therapy (insulin glargine 72<span class="elsevierStyleHsp" style=""></span>IU/24<span class="elsevierStyleHsp" style=""></span>h and repaglinide 1<span class="elsevierStyleHsp" style=""></span>mg/8<span class="elsevierStyleHsp" style=""></span>h). After four months she consulted her primary care physician due to the development of pruritic bullous lesions over an erythematous base distributed over her entire body surface, starting two weeks before. She was referred to Dermatology, with confirmation of the diagnosis of bullous pemphigoid probably triggered by linagliptin. No biopsy was obtained. Linagliptin was discontinued after one month and a short cycle of topical and systemic corticosteroids (prednisone 10<span class="elsevierStyleHsp" style=""></span>mg via the oral route in a tapered dosing regimen) was added, followed by the disappearance of the lesions in one month.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In our three patients we observed a time relationship between linagliptin administration and the development of bullous pemphigoid, as well as the complete clearance of the lesions after drug discontinuation (one week to one month, i.e., similar to previous studies).<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> In addition, in all the cases the absence of disease recurrence was found at re-evaluation months after treatment discontinuation.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The physiopathological mechanism whereby patients treated with DPP4 inhibitors develop pemphigoid is unclear, though gliptins are known to have multiple biological actions. Many types of skin cells, including keratinocytes, express DPP4, which participates in cytokine production, tissue differentiation and collagen metabolism. In addition, DPP4 inhibitors could also increase dermal eosinophil recruitment mediated by the CCL11/eotaxin-2 chemokine.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a> All these properties could favor the appearance of bullous pemphigoid in susceptible individuals, either by modifying the immune response and/or by altering the antigenic properties of the epidermal basal membrane.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">To date, there is no evidence that patients with DM2 and chronic kidney disease due to diabetic nephropathy are more susceptible to developing bullous pemphigoid or producing autoantibodies against BP180.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> It should be noted that in patient 2, who had been treated with vildagliptin for two years, renal functional impairment and a change in DPP4 inhibitor triggered the clinical condition, though it is not discarded that she may have been previously immunized after treatment with vildagliptin. Although we have found no justification in the reviewed literature, we postulate that the worsened renal function may have influenced the appearance of this clinical condition.</p><p id="par0050" class="elsevierStylePara elsevierViewall">These three cases confirm that bullous pemphigoid induced by DPP4 inhibitors should be considered as a class adverse effect, though further studies are needed to establish an unequivocal causal relationship.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Authorship</span><p id="par0055" class="elsevierStylePara elsevierViewall">Belén Sánchez López-Muelas: principal author. Salomé Muray-Cases, Fátima Illán-Gómez, Gloria García-Guzmán, María Elena Arjonilla-Sampedro: participation in study conception, data acquisition and review of the manuscript draft.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Authorship" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Sánchez López-Muelas B, Muray Cases S, Illán Gómez F, García Guzmán G, Arjonilla Sampedro ME. Penfigoide ampolloso asociado al tratamiento con linagliptina en pacientes con diabetes y enfermedad renal crónica. Endocrinol Diabetes Nutr. 2019;66:338–339.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 711 "Ancho" => 900 "Tamanyo" => 92736 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Bullous lesions in different evolutive stages in patients 1–3 (from left to right: upper images, patient 1; lower left corner, patient 2; lower right, patient 3).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib0045" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "E. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 2 | 10 |
| 2024 October | 44 | 5 | 49 |
| 2024 September | 39 | 6 | 45 |
| 2024 August | 42 | 3 | 45 |
| 2024 July | 49 | 9 | 58 |
| 2024 June | 53 | 4 | 57 |
| 2024 May | 57 | 9 | 66 |
| 2024 April | 29 | 5 | 34 |
| 2024 March | 49 | 13 | 62 |
| 2024 February | 48 | 6 | 54 |
| 2024 January | 47 | 12 | 59 |
| 2023 December | 58 | 8 | 66 |
| 2023 November | 66 | 1 | 67 |
| 2023 October | 66 | 11 | 77 |
| 2023 September | 45 | 14 | 59 |
| 2023 August | 46 | 2 | 48 |
| 2023 July | 53 | 21 | 74 |
| 2023 June | 33 | 21 | 54 |
| 2023 May | 67 | 20 | 87 |
| 2023 April | 64 | 16 | 80 |
| 2023 March | 50 | 21 | 71 |
| 2023 February | 52 | 12 | 64 |
| 2023 January | 30 | 31 | 61 |
| 2022 December | 49 | 12 | 61 |
| 2022 November | 37 | 18 | 55 |
| 2022 October | 30 | 21 | 51 |
| 2022 September | 40 | 18 | 58 |
| 2022 August | 44 | 10 | 54 |
| 2022 July | 26 | 8 | 34 |
| 2022 June | 22 | 7 | 29 |
| 2022 May | 34 | 9 | 43 |
| 2022 April | 23 | 15 | 38 |
| 2022 March | 32 | 15 | 47 |
| 2022 February | 57 | 15 | 72 |
| 2022 January | 75 | 9 | 84 |
| 2021 December | 58 | 9 | 67 |
| 2021 November | 50 | 14 | 64 |
| 2021 October | 51 | 8 | 59 |
| 2021 September | 53 | 10 | 63 |
| 2021 August | 75 | 11 | 86 |
| 2021 July | 50 | 7 | 57 |
| 2021 June | 28 | 11 | 39 |
| 2021 May | 41 | 7 | 48 |
| 2021 April | 105 | 30 | 135 |
| 2021 March | 37 | 5 | 42 |
| 2021 February | 37 | 13 | 50 |
| 2021 January | 43 | 15 | 58 |
| 2020 December | 47 | 7 | 54 |
| 2020 November | 24 | 4 | 28 |
| 2020 October | 11 | 10 | 21 |
| 2020 September | 27 | 16 | 43 |
| 2020 August | 28 | 6 | 34 |
| 2020 July | 15 | 10 | 25 |
| 2020 June | 12 | 3 | 15 |
| 2020 May | 19 | 9 | 28 |
| 2020 April | 14 | 3 | 17 |
| 2020 March | 10 | 4 | 14 |
| 2020 February | 15 | 1 | 16 |
| 2020 January | 9 | 5 | 14 |
| 2019 December | 9 | 7 | 16 |
| 2019 November | 3 | 5 | 8 |
| 2019 July | 1 | 2 | 3 |
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