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 Table of Contents  
LETTER TO EDITOR
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 159-161

Secondary diabetes mellitus in pemphigus vulgaris and management issues


1 Department of Dermatology and Venereology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of General Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 Department of Dermatology and Venereology, Government Medical College, Ratlam, Madhya Pradesh, India

Date of Web Publication15-Jul-2019

Correspondence Address:
Naveen Kumar Kansal
Department of Dermatology and Venereology, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_36_18

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How to cite this article:
Divyalakshmi C, Kant R, Hazarika N, Upadhyaya A, Kansal NK, Taneja G. Secondary diabetes mellitus in pemphigus vulgaris and management issues. Clin Dermatol Rev 2019;3:159-61

How to cite this URL:
Divyalakshmi C, Kant R, Hazarika N, Upadhyaya A, Kansal NK, Taneja G. Secondary diabetes mellitus in pemphigus vulgaris and management issues. Clin Dermatol Rev [serial online] 2019 [cited 2019 Aug 23];3:159-61. Available from: http://www.cdriadvlkn.org/text.asp?2019/3/2/159/262778



Sir,

A 45-year-old nondiabetic, normotensive female presented 4 years before to the dermatology outpatient department (OPD) with a history of oral ulcers, pain, and difficulty in ingesting food [Figure 1]. In the ensuing weeks, fluid-filled vesicular lesions developed all over the body progressing to involve almost the entire trunk [Figure 2] and extremities with a body surface area involvement of about 35%–40%. The lesions used to rupture spontaneously forming erosions and were associated with itching and pain. The Nikolsky sign was positive. The patient's history was significant for similar complaints about 15 years back, at which time a skin biopsy was performed at another hospital and the patient was diagnosed as a case of pemphigus vulgaris. As per her records, she was treated with dexamethasone-cyclophosphamide pulse (DCP) therapy, following which there was a complete remission of the lesions until this presentation.
Figure 1: Oral erosions in the buccal mucosa

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Figure 2: Lesions of pemphigus on the abdomen

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As the patient did not agree for DCP again, she was started on oral prednisolone daily with oral cyclophosphamide (100 mg/day). Due to lack of adequate response, the prednisolone dose was gradually increased until no new lesions appeared. However, on an attempt to taper the dose, new lesions evolved again. Later, the patient was found to have raised blood glucose levels (fasting blood sugar = 264 mg/dL). Therefore, she was referred to the general medicine OPD, and a diagnosis of corticosteroid-induced secondary diabetes mellitus (DM) was made. The patient was started on oral hypoglycemic agents (a combination of oral metformin and glimepiride). Although pemphigus was brought under control, her diabetic status remained uncontrolled, following which oral prednisolone was changed to oral deflazacort and oral hypoglycemics with increased dose were continued. Adequate advice on lifestyle and dietary modifications was also given. Injectable insulin preparation was also prescribed; however, due to the presence of lesions on her abdomen, the patient did not administer insulin. At a follow-up visit 2 weeks later, the blood glucose levels were under control along with good clinical response in pemphigus lesions [Figure 3]. The patient is on regular follow-up.
Figure 3: Lesions on the abdomen at a follow-up visit. Significant improvement is seen

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The term “pemphigus,” derived from the Greek pemphix, means a “blister” or “bubble.” Pemphigus vulgaris, the most common (70%–75%) of the pemphigus subtypes, is a potentially fatal, immunobullous mucocutaneous disease characterized by the formation of intraepidermal blisters. It usually begins with oral mucosal lesions followed by the appearance of extensive cutaneous blistering, which rupture to form erosions. Pemphigus vulgaris has the propensity to involve almost all of skin surface, leading to acute skin failure.[1],[2]

Systemic corticosteroids brought down the very high mortality rate (about 75%–90% to <30%)[3],[4] due to pemphigus vulgaris. In recent times, although a few new effective treatment options, e.g., rituximab,[5],[6] have emerged, corticosteroids with an immunosuppressant adjuvant remain the mainstay of therapy, primarily in resource-poor settings and if a patient cannot afford as was the case of our patient. Systemic corticosteroids used in high dosages usually end up in various metabolic complications and associated comorbidities such as secondary DM, hypertension, Cushing's syndrome, and osteoporosis leading to fractures, therefore the critical need for a multidisciplinary clinical approach.

An abnormal increase in blood glucose levels, i.e., fasting blood glucose ≥126 mg/dL and random blood glucose of ≥200 mg/dL associated with the use of glucocorticoids in a patient with or without a prior history of DM, is defined as corticosteroid-induced secondary DM.[7] Mechanisms of systemic corticosteroid-induced secondary DM include (i) impaired glucose metabolism by corticosteroids, (ii) increased insulin resistance in tissues, (iii) increased glucose production in the liver, and (iv) impaired glucose consumption in muscles and adipose tissue cells. Systemic corticosteroids can also exacerbate existing diabetes or cause impairment of blood glucose levels in well-controlled diabetics. Corticosteroids are known primarily to cause postprandial hyperglycemia which is considered more sensitive indicator of corticosteroid-induced diabetes.[7],[8] In a study in the pemphigus patients conducted by Darjani et al., the incidence of corticosteroid-induced DM was found to be 22.2%. In this study, they found no significant differences between the oral therapy and pulse (DCP) therapy of systemic corticosteroids. Usual incidence of the corticosteroid-induced hyperglycemia has been about 30%–40%.[9]

Although secondary DM with systemic corticosteroids is a well-known entity, acute hyperglycemia due to use of Class I (super potent) topical fluocinonide 0.1% cream has been described as well for the treatment of a psoriasis flare. It has been hypothesized that topical corticosteroids cause hyperglycemia through increasing alanine transport, thereby facilitating hepatic gluconeogenesis, and therefore causing relative insulin resistance.[10] Another recent pilot study has explored the efficacy and safety potential to prevent corticosteroid-induced DM with linagliptin (dipeptidyl peptidase-4 inhibitor). However, linagliptin was found clinically insufficient to prevent the development of glucocorticoid-induced DM but had the important potential to reduce the requirement for insulin injection therapy in the study.[11] Still, the dermatological significance of the second study is that such therapies with a dipeptidyl peptidase-4 inhibitor may itself induce other important immunobullous disease (i.e., bullous pemphigoid) though exact incidence remains unknown.

Patients with secondary DM need to be managed with appropriate hypoglycemic agents and insulin therapy. Choosing the suitable medications poses a critical clinical challenge to the treating physician. To manage rationally, lifestyle measures, dietary modification, and mild-to-moderate exercise, depending on general condition of the (pemphigus) patient, should always be combined with pharmacotherapy.[8] Corticosteroids may also be timed with a mid-day or an evening meal with concomitant administration of intermediate-acting insulin for better glycemic control. However, selection of appropriate cutaneous site for insulin injections again creates difficulty, especially in cases with generalized blistering and erosions, as was the case in our patient [Figure 2]. Afrezza (inhaled insulin) is a rapid-acting inhaled form of insulin which may also be useful in control of blood glucose levels.[12] In patients with mild hyperglycemia, who are unable or unwilling to be treated with injections of insulin, a trial of oral hypoglycemics with lifestyle measures should be considered.[7] During treatment of the disease, close follow-up and monitoring of patients on systemic corticosteroids are essential, especially with pre-existing type 2 diabetes mellitus, so that further complications of the disease could be prevented.[8]


  What Is New? Top


  • Systemic corticosteroids can worsen existing diabetes as well as induce corticosteroid-induced diabetes
  • Postprandial hyperglycemia is commoner than fasting hyperglycemia with systemic corticosteroid use, and therefore, postprandial testing may be a more sensitive indicator
  • Glycemic targets should be the same in corticosteroid-induced diabetes as in those with preexisting diabetes.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Schmidt E, Groves R. Immunobullous diseases. In: Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D, editors. Rook's Textbook of Dermatology. 9th ed. Oxford, UK: John Wiley & Sons, Ltd.; 2016. p. 50.1-50.57.  Back to cited text no. 1
    
2.
Inamadar AC, Palit A. Acute skin failure: Concept, causes, consequences and care. Indian J Dermatol Venereol Leprol 2005;71:379-85.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Ahmed AR, Moy R. Death in pemphigus. J Am Acad Dermatol 1982;7:221-8.  Back to cited text no. 3
    
4.
Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus. An update. Arch Dermatol 1996;132:203-12.  Back to cited text no. 4
    
5.
Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, et al. British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol 2017;177:1170-201.  Back to cited text no. 5
    
6.
Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): A prospective, multicentre, parallel-group, open-label randomised trial. Lancet 2017;389:2031-40.  Back to cited text no. 6
    
7.
Hwang JL, Weiss RE. Steroid-induced diabetes: A clinical and molecular approach to understanding and treatment. Diabetes Metab Res Rev 2014;30:96-102.  Back to cited text no. 7
    
8.
Caplan A, Fett N, Rosenbach M, Werth VP, Micheletti RG. Prevention and management of glucocorticoid-induced side effects: A comprehensive review: Gastrointestinal and endocrinologic side effects. J Am Acad Dermatol 2017;76:11-6.  Back to cited text no. 8
    
9.
Darjani A, Nickhah N, Hedayati Emami MH, Alizadeh N, Rafiei R, Eftekhari H, et al. Assessment of the prevalence and risk factors associated with glucocorticoid-induced diabetes mellitus in pemphigus vulgaris patients. Acta Med Iran 2017;55:375-80.  Back to cited text no. 9
    
10.
Sue LY, Milanesi A. Acute hyperglycemia due to topical corticosteroid administration. Case Rep Endocrinol 2019;2019:6058076.  Back to cited text no. 10
    
11.
Miyawaki Y, Sada KE, Asano Y, Hayashi K, Yamamura Y, Hiramatsu S, et al. An open-label pilot study on preventing glucocorticoid-induced diabetes mellitus with linagliptin. J Med Case Rep 2018;12:288.  Back to cited text no. 11
    
12.
Afrezza. Available from: https://afrezza.com/pdf/Afrezza_MedGuide.pdf. [Last accessed on 2018 Aug 20].  Back to cited text no. 12
    


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  [Figure 1], [Figure 2], [Figure 3]



 

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