10.5826/dpc.1301a63
text/xml
2160-9381
2637
en
Paulo Filipe
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Treatment Of Diabetes In Bullous Pemphigoid Patients: Where Do We Stand?
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Commentary
2023-01-31
2022-06-06
2023-01-31
2023-02-27
e2023063
Dermatol Pract Concept
Paulo Filipe
2023/01/31
10.5826/dpc.1301a63
e2023063
Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal;  Dermatology Universitary Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal;  Dermatology Research Unit, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal
2160-9381
en
e2023063
Lee H, Chung HJ, Pawar A, Patorno E, Kim DH. Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase-4 Inhibitor vs Second-generation Sulfonylurea. JAMA Dermatol. 2020 Oct 1;156(10):1107-1114.
Treatment Of Diabetes In Bullous Pemphigoid Patients: Where Do We Stand?
https://dpcj.org/index.php/dpc/article/download/2637/1928
         Treatment of Diabetes in Bullous Pemphigoid
                Patients: Where Do We Stand?
                       Maria Inês Alexandre1, Pedro Miguel Garrido2, Paulo Filipe2,3,4


1 Endocrinology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
2 Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
3 University Dermatology Clinic, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
4 Dermatology Research Unit, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal



Citation: Alexandre MI, Garrido PM, Filipe P. Treatment of diabetes in bullous pemphigoid patients: where do we stand? Dermatol Pract
Concept. 2023;13(1):e2023063. DOI: https://doi.org/10.5826/dpc.1301a63
Accepted: April 13, 2022; Published: January 2023
Copyright: ©2023 Alexandre et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Maria Inês Alexandre, Serviço de Endocrinologia, Hospital de Santa Maria, Centro Hospitalar Universitário de
Lisboa Norte, 1649-028 Lisboa, Portugal. Phone: 00351 21 780 5000; E-mail: mariaines.f.alexandre@gmail.com



Bullous pemphigoid (BP) affects predominantly elderly pa-                pathogenesis of how DPP4i might induce BP remains largely
tients, and the disease incidence rises exponentially with age.          unclear and it is not known if the suspension of DPP4i can
A high prevalence of diabetes mellitus (DM) in patients with             revert this immunological process. However, the clinical out-
BP has been noticed, ranging from 20 to 30% [1].                         come appears to be better if DPP4i is discontinued.
    The treatment of BP patients is challenging and should be                 A presumed association between BP and glucagon-like
carefully assessed bearing in mind their multiple comorbid-              peptide-1 (GLP-1) receptor agonists has also been ­reported [5].
ities. Corticosteroids are the mainstay of treatment for BP.             The underlying mechanism is unclear, however since DPP4i
However, their systemic use is limited in diabetic patients by           and GLP-1 receptor agonists both rely on enhancing the activ-
the risk of acute hyperglycemic complications. This is par-              ity of the incretin hormone GLP-1, a common effect between
ticularly concerning given the age group of BP patients and              these two classes of antidiabetic drugs should be sought.
the chronicity of treatment. Adjunctive therapy with immu-               ­Although more robust studies are required, we suggest that
nosuppressants such as azathioprine, mycophenolate mofetil               this association is taken into account when selecting the most
or methotrexate may also be needed [2]. Also, novel targeted             appropriate medication for BP patients.
therapeutic approaches such as omalizumab and dupilumab                       Other    widely     used    antidiabetic     drugs     like
have been reported as effective alternatives, but their use in           second-generation sulfonylureas and metformin seem safer
BP is still off-label [3].                                               options, but their use can be limited by the patient’s comor-
    Several population-based studies supported an increased              bidities [6]. The sodium–glucose cotransporter (SGLT)2 in-
risk of developing BP in diabetic patients treated with dipep-           hibitors also seem like good alternatives. These drugs do not
tidyl peptidase-4 inhibitors (DPP4i). A recent meta-analysis             increase the risk of hypoglycemia, have low rates of adverse
showed that the odds ratio (OR) for BP among patients re-                effects and may be continued in patients with moderate renal
ceiving any DPP4i ranged from 1.27 to 3.45 [4]. The exact                impairment. Overall, they can be used in selected BP patients.



Commentary | Dermatol Pract Concept. 2023;13(1):e2023063                                                                                1
                                                                             Type 2 DM with BP


                                                                    Consider
                                                               discontinuation of
                                                                DPP4i, if present

                                                                             If patient is treated
                                                                                 with systemic
                                                                                corticosteroids

                                                        Inpatient                                       Outpatient
                                                          care               Consider referral to          care
                                                                             an endocrinologist
                                                                                if glycemia is                    Advise to check
                                         Check glycemia                      persistently above                   glycemia before
                                        at admission and                          200 mg/dL                          every meal
                                          every 4 hours

                      Non-insulin-                                             Insulin-
                        treated                                                treated
                       patients                                                patients                              Optimize metformin
                                                                                                                     dose if tolerated and
                                                                                                                      patient’s eGFR>30
 Morning basal                        Pre-prandial rapid/short        Switch to basal morning                          mL/min/1.72m2
  insulin 0,2                        action insulin according to         administration and
 U/kg/day (Ex:                       glycemia (Ex: <140 mg/dL:        consider increase dose in                           Consider adding
 glargin/NPH)                         OU; 140-200mg/dL: 2U;            10-20%. If ambulatory                            SGLT2i (adjustments
                                         201-250mg/dL: 4U;             dose is not known start                           may be needed for
                                         251-300mg/dL: 6U;               at 0,3-0,4 U/kg/day                           renal impairment; see
                                         301-350mg/dL: 8U;                                                               drug information)
       Increase basal insulin           351-400mg/dL: 10U;
        2U every 2-3 days if            401-450mg/dL: 12U;                                                              Sulfonylureas (later
      glycemia before dinner                                            Increase basal insulin
                                          ≥451mg/dL: 14U)                                                               generation) also an
        is above 180 mg/dL                                               2U every 2-3 days if                           option; higher risk
                                                                           glycemia before                               of hypoglycemia
                                                                           dinner is above
                                                                              180 mg/dL
                                     After discharge, return                                                               Avoid DPP4i
                                       to oral antidiabetic                                                             combination/mono
                                      drugs if possible (see                                                                 therapy
                                         outpatient care
                                        scheme); evaluate
                                     need to maintain basal                                                             Caution with GLP1a
                                              insulin

                                                                                                                            Morning basal
                                                                                                                           insulin may be
                                                                                                                         needed if glycemia
                                                                                                                        is above 180 mg/dL
                                                                                                                            before dinner

Figure 1. Proposed treatment algorithm for bullous pemphigoid patients with type 2 diabetes mellitus treated with corticosteroids.
BP, bullous pemphigoid; DM, diabetes mellitus; DPP4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP1a,
glucagon-like peptide 1 receptor agonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor.




    In many cases, insulin is the most suitable choice, partic-          guidelines on this matter. Endocrinologists should be aware of
ularly for inpatients on corticosteroids. Morning basal insu-            BP as a challenging problem in patients with DM and collabo-
lin may closely fit the glucose excursion induced by a single            ration with dermatologists is essential for good outcomes.
dose of morning corticosteroid. The initial dose and titration
should take into account the patient’s weight and dose of
                                                                         References
corticosteroid. Dairy adjustments are frequently necessary
and often difficult to predict.                                           1. Chai ZT, Tan C, MeiQi Liau M, et al. Diabetes mellitus and hy-
    Based on the previous data, a treatment algorithm for BP                 perglycemic complications in bullous pemphigoid. J Am Acad
                                                                             Dermatol. 2020 May;82(5):1234-1237.
patients with type 2 DM is proposed in Fig. 1.
                                                                          2. Di Lernia V, Casanova DM, Goldust M, Ricci C. Pemphigus Vul-
    In conclusion, it is decisive that we view BP patients beyond
                                                                             garis and Bullous Pemphigoid: Update on Diagnosis and Treat-
a single-disease framework and treat them in the context of                  ment. Dermatol Pract Concept. 2020 Jun 29;10(3):e2020050.
multi-morbidities. Diabetes management in these patients can              3. Garrido PM, Alexandre MI, Travassos AR, Filipe P.
be particularly troublesome and, to date, there are no orienting             Dipeptidyl-peptidase IV inhibitor-associated bullous pemphigoid



2                                                                                Commentary | Dermatol Pract Concept. 2023;13(1):e2023063
    efficiently treated with omalizumab. Dermatol Ther. 2020           5. Burruss CP, Jones JM, Burruss JB. Semaglutide-associated bul-
    Nov;33(6):e14160.                                                     lous pemphigoid. JAAD Case Rep. 2021 Aug 5;15:107-109.
 4. Kridin K, Cohen AD. Dipeptidyl-peptidase IV inhibitor-associated   6. Lee H, Chung HJ, Pawar A, Patorno E, Kim DH. Evaluation
    bullous pemphigoid: A systematic review and meta-analysis. J          of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl
    Am Acad Dermatol. 2021 Aug;85(2):501-503.                             Peptidase-4 Inhibitor vs Second-generation Sulfonylurea. JAMA
                                                                          Dermatol. 2020 Oct 1;156(10):1107-1114.




Commentary | Dermatol Pract Concept. 2023;13(1):e2023063                                                                             3
