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      Bullous pemphigoid in a patient with a neuropsychological disorder and a possible novel drug trigger: A case report and review of the literature

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          Abstract

          A 59‐year‐old woman with schizoaffective disorder presented with an itchy, blistering generalised rash. One month prior, she had started empagliflozin, a sodium glucose transporter‐2 (SGLT‐2) inhibitor, used in type‐2‐diabetes. She was already established on paliperidone, an atypical antipsychotic, for 1 year. Serology at presentation was positive for anti‐pemphigoid antibodies. Histology demonstrated subepidermal blistering, perivascular inflammation and eosinophils. Direct immunofluorescence was characteristic of bullous pemphigoid (BP), with linear IgG and C3 at the basement membrane. Both empagliflozin and paliperidone were discontinued. However, the blisters persisted. Treatment included: topical Dermovate and Eumovate ointment for the body and face respectively, alongside oral doxycycline 200 mg and prednisolone 40 mg for a week (reducing by 5 mg/week over 8 weeks). Nevertheless, new blisters continued developing, hence dapsone 50 mg was introduced, with significant improvement. Increasingly, several neurological and psychiatric disorders have been linked with BP, complicating aetiology and management. The underlying mechanism for these associations is not fully understood. Bullous pemphigoid autoantigens BP180 and BP230 are expressed in the central nervous system and it is thought that neurodegeneration may expose antigens to the immune system, generating a cross‐reactive immune response. However, there also appears to be bidirectional causality between BP and neuropsychological conditions. Furthermore, as there was an association of empagliflozin initiation and BP onset, this further complicates the aetiology and presents a potential novel drug cause of BP. This case emphasises the neuropsychological issues associated with managing complex BP cases, a possible novel cause of drug‐induced BP and highlights the likelihood of these issues becoming increasingly prevalent for the future.

          Abstract

          This case emphasises the neuropsychological issues associated with managing complex bullous pemphigoid (BP) cases, a possible novel cause of drug‐induced BP and highlights the likelihood of these issues becoming increasingly prevalent in the future.

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          Most cited references20

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          Psychiatric complications of treatment with corticosteroids: review with case report.

          Corticosteroids are widely used in modern medicine but can result in troubling psychiatric side-effects. Physicians and other medical professionals should be aware of the potential for these side-effects, possible means of prevention, and efficacious treatments. Herein, we review adult case report data published during the past quarter-century on adverse corticosteroid-induced psychiatric effects, and present a case of corticosteroid-induced psychotic depression. PubMed and PsychLit databases were searched using the terms 'corticosteroids', 'steroids', and the generic names of corticosteroid medications with terms for psychiatric symptoms or syndromes, including psychosis, mania, hypomania, depression, apathy, anxiety, panic, depersonalization, delirium, confusion, hallucinations, delusions, paranoia, cognitive impairment and dementia. Fifty-five cases and a number of clinical trials investigating the incidence and treatment of these psychiatric symptoms and syndromes were identified. Data on incidence, drug dose, risk factors, course of illness and treatment (when present) were tabulated. We conclude that the cumulative data indicate that psychiatric complications of corticosteroid treatment are not rare and range from clinically significant anxiety and insomnia, to severe mood and psychotic disorders, delirium and dementia. While tapering or discontinuation of the corticosteroid treatment may remedy these adverse side-effects, psychotropic medications are often required because of the medical necessity of the corticosteroid or the severity of the psychiatric symptom. Further studies are needed to better understand the deleterious psychiatric effects associated with corticosteroids. © 2011 The Authors. Psychiatry and Clinical Neurosciences © 2011 Japanese Society of Psychiatry and Neurology.
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            Risk factors for bullous pemphigoid in the elderly: a prospective case-control study.

            A rise in the incidence of bullous pemphigoid (BP) was documented recently in Europe, and the main risk factors for BP remain unknown. We conducted a multicenter case-control study to evaluate risk factors for BP. We identified 201 incident BP cases and 345 controls individually matched for age, gender, center, and place of residence (home, nursing home, or extended-care facility). We used univariate and multivariate logistic regression analyses to compare drugs used for over 3 months, comorbidities, and physical and cognitive impairments between cases and controls. Mean age of BP patients was 84.2 (±8.7) years. Factors independently associated with BP by multivariate analysis were major cognitive impairment (odds ratio (OR), 2.19; 95% confidence interval (95% CI), 1.24-3.87), bedridden condition (OR, 2.19; 95% CI, 1.23-3.89), Parkinson's disease (OR, 2.16; 95% CI, 1.09-4.27), unipolar or bipolar disorder (OR, 5.25; 95% CI, 1.21-22.86), and chronic use of spironolactone (OR, 2.30; 95% CI, 1.20-4.46) or phenothiazines with aliphatic side chains (OR, 3.70; 95% CI, 1.21-11.34). Chronic analgesic use was associated with a lower risk of BP (OR, 0.49; 95% CI, 0.30-0.81). Thus, risk factors for BP include neurological disorders, particularly dementia and Parkinson's disease, psychiatric disorders (unipolar and bipolar disorders), bedridden condition, and chronic use of several drugs.
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              Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial

              Summary Background Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. Methods We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. Findings Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001. Interpretation Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Funding NIHR Health Technology Assessment Programme.
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                Author and article information

                Contributors
                sarah.dyson@nnuh.nhs.uk
                Journal
                Skin Health Dis
                Skin Health Dis
                10.1002/(ISSN)2690-442X
                SKI2
                Skin Health and Disease
                John Wiley and Sons Inc. (Hoboken )
                2690-442X
                21 October 2022
                December 2022
                : 2
                : 4 , Psychodermatology – a special edition of Skin Health and Disease ( doiID: 10.1002/ski2.v2.4 )
                : e176
                Affiliations
                [ 1 ] Dermatology Department Norfolk and Norwich University Hospital Colney UK
                [ 2 ] Norwich Medical School, UEA Norwich UK
                [ 3 ] Cellular Pathology Department Norfolk and Norwich University Hospital Colney UK
                Author notes
                [*] [* ] Correspondence

                Sarah M. Dyson, Dermatology Department, Norfolk and Norwich University Hospital, Colney NR4 7UY, UK.

                Email: sarah.dyson@ 123456nnuh.nhs.uk

                Author information
                https://orcid.org/0000-0002-4235-2085
                Article
                SKI2176
                10.1002/ski2.176
                9720203
                36479274
                058dcc67-0fb9-4c46-979c-a3c9a33529fe
                © 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 September 2022
                : 08 June 2022
                : 26 September 2022
                Page count
                Figures: 6, Tables: 0, Pages: 6, Words: 2985
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                December 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.1 mode:remove_FC converted:05.12.2022

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