Although the World Health Organisation has declared the end of the pandemic phase of COVID-19, the situation remains challenging especially for immunocompromised people due to continuous mutations of SARS-CoV-2 that perpetuate the spread of this very contagious virus.1 A major advance in protection from COVID-19 has been the development of effective, constantly updated vaccines which are highly recommended for patients with autoimmune disorders such as immunobullous diseases.2 However, there is a paucity of data on the effect of immunosuppressive drugs on immunological responses to COVID-19 vaccines in this particular patient population. Therefore, similarly to what was previously described in patients with rheumatic diseases,3 we assessed the serological response to COVID-19 vaccination in patients with autoimmune blistering dermatoses. Data were prospectively collected from COVID-19-vaccinated pemphigus and pemphigoid patients who were treated with different immunomodulatory medications including rituximab and recruited in our dermatology department from May 2021 to October 2023. They were serologically screened for antibodies against SARS-CoV-2 using a commercial quantitative anti-SARS-CoV-2 spike protein antibody immunoassay (Roche). In rituximab-treated patients, the time between the most recent administration of the drug and the vaccine was recorded. The primary outcome was the presence of serological responsiveness to COVID-19 vaccination. A total of 25 patients with bullous pemphigoid (n = 10), pemphigus vulgaris (n = 11), and pemphigus foliaceus (n = 4) were included in this study. All subjects were fully vaccinated against COVID-19 (i.e., at least two doses of the Pfizer-BioNTech/Moderna vaccine or one dose of the Johnson & Johnson vaccine) at the time of the immunoassay. 19 patients (76%) were treated with more than one immunomodulatory medication during the assessment (Table 1). Using an antibody threshold level for the applied SARS-CoV-2 immunoassay that was proposed to confer protection in immunocompromised patients,4 we found that 17 of the 25 patients (68%) had a strong (i.e., protective) serological response to vaccination against COVID-19, while the remaining 8 patients (32%) had a negative/weak response to the vaccine. We observed a strong trend towards a higher serological response in association with the number of vaccines (p = 0.052). Although there was generally no significant relationship between the various immunomodulatory therapies and an impaired serological response to SARS-CoV-2 vaccination, among rituximab recipients, we noticed a significant difference in the length of the rituximab-vaccine time interval between those with a strong serological response compared with those with a negative/weak response (Table 1) (Figure 1). Besides the potential risk of a more severe COVID-19 course during B-cell-depleting therapy in patients with immunobullous diseases,5 a major concern is the risk of decreased immunogenicity of vaccination, as already described in other types of autoimmune diseases.3 In our study, a longer time span between the most recent rituximab exposure and last vaccine application was associated with a greater likelihood of a protective serological vaccine response, which may especially apply to patients who received vaccine booster doses. Similar results were obtained in patients with rheumatic diseases on anti-CD20 therapy and correlated with B-cell reconstitution, which usually occurs about 6–12 months post rituximab treatment.3 These data support our previously published and internationally well accepted recommendation to lengthen the time between the last rituximab treatment and the administration of the COVID-19 vaccines in patients with immunobullous diseases.2, 6 Nevertheless, it needs to be noted that, despite the rituximab-induced compromised humoral vaccine antibody response, SARS-CoV-2 vaccine-elicited specific T-cell-mediated responses may be preserved and confer partial protection from COVID-19 during B-cell-depleted states as recently shown in pemphigus vulgaris patients.7 Further studies with larger cohorts are needed to determine the responses to SARS-CoV-2 vaccines and optimisation of vaccination responsiveness in patients with autoimmune bullous diseases. M. Kasperkiewicz (conception/design of the work), B. Levian and D.T. Woodley (data collection), B. Levian and S. Tukaj (data analysis and interpretation), M. Kasperkiewicz (drafting the article), B. Levian, S. Tukaj, and D.T. Woodley (critical revision of the article); all authors discussed the results and contributed to the final manuscript. We thank Claire Stevens (University of Southern California) for her support with the data analysis. The authors declare no conflicts of interest. All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details for publication; this study was approved by the institutional review board of the University of Southern California.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Journal of the European Academy of Dermatology and VenereologyVolume 36, Issue 9 p. e664-e665 Letter to the Editor Role of the International Pemphigus and Pemphigoid Foundation during the COVID-19 pandemic M. Kasperkiewicz, Corresponding Author M. Kasperkiewicz [email protected] orcid.org/0000-0003-0146-1661 Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USACorrespondence: M. Kasperkiewicz. E-mail: [email protected]Search for more papers by this authorR. Strong, R. Strong International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorM. Yale, M. Yale International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorP. Dunn, P. Dunn International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorD.T. Woodley, D.T. Woodley Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USASearch for more papers by this author M. Kasperkiewicz, Corresponding Author M. Kasperkiewicz [email protected] orcid.org/0000-0003-0146-1661 Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USACorrespondence: M. Kasperkiewicz. E-mail: [email protected]Search for more papers by this authorR. Strong, R. Strong International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorM. Yale, M. Yale International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorP. Dunn, P. Dunn International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorD.T. Woodley, D.T. Woodley Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USASearch for more papers by this author First published: 25 April 2022 https://doi.org/10.1111/jdv.18180Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Kasperkiewicz M, Schmidt E, Fairley JA et al. Expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic. J Eur Acad Dermatol Venereol 2020; 34: e302–e303. 10.1111/jdv.16525 CASPubMedWeb of Science®Google Scholar 2Kasperkiewicz M, Schmidt E, Amagai M et al. Updated international expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic. J Eur Acad Dermatol Venereol 2021; 35: e412–e414. 10.1111/jdv.17207 CASPubMedWeb of Science®Google Scholar 3Kneiber D, Kowalski EH, Kridin K, Yale ML, Grando SA, Amber KT. Gastrointestinal symptoms, gastrointestinal bleeding and the role of diet in patients with autoimmune blistering disease: a survey of the international pemphigus and pemphigoid foundation. J Eur Acad Dermatol Venereol 2019; 33: 1935–1940. 10.1111/jdv.15731 CASPubMedWeb of Science®Google Scholar 4Lee J, Seiffert-Sinha K, Attwood K, Sinha AA. A retrospective study of patient-reported data of bullous pemphigoid and mucous membrane pemphigoid from a US-based registry. Front Immunol 2019; 10: 2219. 10.3389/fimmu.2019.02219 CASPubMedWeb of Science®Google Scholar 5Kasperkiewicz M, Yale M, Strong R, Zillikens D, Woodley DT, Recke A. COVID-19 pandemic and autoimmune bullous diseases: a cross-sectional study of the international pemphigus and pemphigoid foundation. J Eur Acad Dermatol Venereol 2021; 35: e418–e421. 10.1111/jdv.17228 CASPubMedWeb of Science®Google Scholar 6Patel PM, Jones VA, Kridin K, Strong RA, Yale M, Amber KT. Assessing the risk factors for anxiety, depression and post-traumatic stress disorder through the international pemphigus and pemphigoid foundation. J Eur Acad Dermatol Venereol 2022; 36: e139–e141. 10.1111/jdv.17700 CASPubMedWeb of Science®Google Scholar 7Kasperkiewicz M, Strong R, Mead K et al. COVID-19 vaccine acceptance and hesitancy in patients with immunobullous diseases: a cross-sectional study of the international pemphigus and pemphigoid foundation. Br J Dermatol 2021; 186: 737–739. https://doi.org/10.1111/bjd.20906 10.1111/bjd.20906 Google Scholar Citing Literature Volume36, Issue9September 2022Pages e664-e665 This article also appears in:JEADV COVID-19 articles ReferencesRelatedInformation

Editor, Autoimmune bullous diseases (AIBDs), including the heterogeneous groups pemphigus and pemphigoid, are rare and potentially life-threatening chronic inflammatory blistering disorders characterized by autoantibodies against desmosomal adhesion proteins and structural proteins of the dermal–epidermal junction, respectively. We have previously provided an overview of different vaccines against bacterial and viral infections possibly associated with the development of AIBDs, but information specifically pertaining to COVID-19 vaccines was lacking at the time of publication. Given the accumulating evidence of a possible association between COVID-19 vaccines and AIBDs since then, a rapid, updated systematic review focusing on this potential link was performed. The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature from the inception of the database until 09 February 2022 was explored using PubMed. Keywords were ‘pemphigus’ or ‘pemphigoid’ or ‘bullous’ or ‘blistering’ combined with ‘COVID-19 vaccination’ or ‘COVID19 vaccine’ or ‘SARS-CoV-2 vaccination’ or ‘SARS-CoV-2 vaccine’. Additional author searches, including screening of bibliographies, were done to find further relevant publications.

Journal of the European Academy of Dermatology and VenereologyVolume 35, Issue 7 p. e412-e414 Letter to the Editor Updated international expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic M. Kasperkiewicz, Corresponding Author M. Kasperkiewicz [email protected] orcid.org/0000-0003-0146-1661 Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Correspondence: M. Kasperkiewicz. E-mail: [email protected]Search for more papers by this authorE. Schmidt, E. Schmidt orcid.org/0000-0002-1206-8913 Department of Dermatology, University of Lübeck, Lübeck, Germany Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, GermanySearch for more papers by this authorM. Amagai, M. Amagai Department of Dermatology, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorJ.A. Fairley, J.A. Fairley Department of Dermatology, University of Iowa, Iowa City, IA, USASearch for more papers by this authorP. Joly, P. Joly orcid.org/0000-0002-5734-0255 Department of Dermatology, Rouen University Hospital, Rouen, FranceSearch for more papers by this authorD.F. Murrell, D.F. Murrell Department of Dermatology, St George Hospital, Faculty of Medicine, University of New South Wales, Sydney, NSW, AustraliaSearch for more papers by this authorA.S. Payne, A.S. Payne Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USASearch for more papers by this authorM.L. Yale, M.L. Yale International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorD. Zillikens, D. Zillikens Department of Dermatology, University of Lübeck, Lübeck, GermanySearch for more papers by this authorD.T. Woodley, D.T. Woodley Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USASearch for more papers by this author M. Kasperkiewicz, Corresponding Author M. Kasperkiewicz [email protected] orcid.org/0000-0003-0146-1661 Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Correspondence: M. Kasperkiewicz. E-mail: [email protected]Search for more papers by this authorE. Schmidt, E. Schmidt orcid.org/0000-0002-1206-8913 Department of Dermatology, University of Lübeck, Lübeck, Germany Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, GermanySearch for more papers by this authorM. Amagai, M. Amagai Department of Dermatology, Keio University School of Medicine, Tokyo, JapanSearch for more papers by this authorJ.A. Fairley, J.A. Fairley Department of Dermatology, University of Iowa, Iowa City, IA, USASearch for more papers by this authorP. Joly, P. Joly orcid.org/0000-0002-5734-0255 Department of Dermatology, Rouen University Hospital, Rouen, FranceSearch for more papers by this authorD.F. Murrell, D.F. Murrell Department of Dermatology, St George Hospital, Faculty of Medicine, University of New South Wales, Sydney, NSW, AustraliaSearch for more papers by this authorA.S. Payne, A.S. Payne Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USASearch for more papers by this authorM.L. Yale, M.L. Yale International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorD. Zillikens, D. Zillikens Department of Dermatology, University of Lübeck, Lübeck, GermanySearch for more papers by this authorD.T. Woodley, D.T. Woodley Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USASearch for more papers by this author First published: 02 March 2021 https://doi.org/10.1111/jdv.17207Citations: 24Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Kasperkiewicz M, Schmidt E, Fairley JA et al. Expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic. J Eur Acad Dermatol Venereol 2020; 34: e302–e303. 10.1111/jdv.16525 CASPubMedWeb of Science®Google Scholar 2Schmidt E, Kasperkiewicz M, Joly P. Pemphigus.Lancet 2019; 394: 882–894. 10.1016/S0140-6736(19)31778-7 CASPubMedWeb of Science®Google Scholar 3Schmidt E, Zillikens D. Pemphigoid diseases. Lancet 2013; 381: 320–332. 10.1016/S0140-6736(12)61140-4 PubMedWeb of Science®Google Scholar 4Kasperkiewicz M. COVID-19 outbreak and autoimmune bullous diseases: a systematic review of published cases. J Am Acad Dermatol 2021; 84: 563–568. 10.1016/j.jaad.2020.08.012 CASPubMedWeb of Science®Google Scholar 5Mahmoudi H, Farid AS, Nili A et al. Characteristics and outcomes of COVID-19 in patients with autoimmune bullous diseases: a retrospective cohort study. J Am Acad Dermatol 2020; 84: 1098-1100. 10.1016/j.jaad.2020.12.043 PubMedWeb of Science®Google Scholar 6Santos CS, Férnandez XC, Moriano Morales C et al. Biological agents for rheumatic diseases in the outbreak of COVID-19: friend or foe? RMD Open 2021; 7(1): e001439. 10.1136/rmdopen-2020-001439 PubMedWeb of Science®Google Scholar 7Strangfeld A, Schäfer M, Gianfrancesco MA et al. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 2021. https://doi.org/10.1136/annrheumdis-2020-219498 10.1136/annrheumdis-2020-219498 Web of Science®Google Scholar 8Waldman RA, Creed M, Sharp K et al. Letter in Reply: Toward a COVID-19 vaccine strategy for pemphigus patients on rituximab. J Am Acad Dermatol 2020; 84: E197–E198. 10.1016/j.jaad.2020.10.075 PubMedWeb of Science®Google Scholar Citing Literature Volume35, Issue7July 2021Pages e412-e414 This article also appears in:JEADV COVID-19 articles ReferencesRelatedInformation

BACKGROUND:Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are common autoimmune bullous dermatoses (AIBD) characterized by blisters and erosions. Treatment options are limited and often insufficient. Immune checkpoint receptors play critical roles in immune homoeostasis and self- tolerance. Targeting checkpoint receptors is highly efficient in treatment of various cancers, but often also associated with autoimmune side effects.OBJECTIVES:We therefore aimed to investigate the expression of immune checkpoint receptors in patients with BP and PV.METHODS:We analysed expression of the checkpoint receptors programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain 3 (Tim-3) and lymphocyte activation gene 3 (Lag-3) in lesional skin of patients with BP and PV compared to healthy control skin as well as the expression patterns of PD-1 and Tim-3 on various infiltrating immune cells in skin sections of AIBD by immunohistochemistry and immunofluorescence. We also measured serum levels of soluble PD-1, Tim-3 and Lag-3 in AIBD patients by ELISA.RESULTS:We report on increased expression of PD-1 and Tim-3, but not Lag-3, in lesional skin of patients with BP and PV. Investigating the expression pattern of PD-1 and Tim-3 on different cutaneous immune cells, we observed significant upregulation of PD-1 predominantly on infiltrating CD8 T cells and upregulation of Tim-3 on CD8 T cells as well as macrophages.CONCLUSIONS:Our results suggest exploring immune checkpoint receptors as novel therapeutic targets using an agonistic approach in autoimmune bullous diseases.

Journal of the European Academy of Dermatology and VenereologyVolume 35, Issue 7 p. e418-e421 Letter to the Editor COVID-19 pandemic and autoimmune bullous diseases: a cross-sectional study of the International Pemphigus and Pemphigoid Foundation M. Kasperkiewicz, Corresponding Author M. Kasperkiewicz [email protected] orcid.org/0000-0003-0146-1661 Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Correspondence: M. Kasperkiewicz. E-mail: [email protected]Search for more papers by this authorM. Yale, M. Yale International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorR. Strong, R. Strong International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorD. Zillikens, D. Zillikens Department of Dermatology, University of Lübeck, Lübeck, GermanySearch for more papers by this authorD.T. Woodley, D.T. Woodley Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USASearch for more papers by this authorA. Recke, A. Recke Department of Dermatology, University of Lübeck, Lübeck, GermanySearch for more papers by this author M. Kasperkiewicz, Corresponding Author M. Kasperkiewicz [email protected] orcid.org/0000-0003-0146-1661 Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Correspondence: M. Kasperkiewicz. E-mail: [email protected]Search for more papers by this authorM. Yale, M. Yale International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorR. Strong, R. Strong International Pemphigus and Pemphigoid Foundation, Sacramento, CA, USASearch for more papers by this authorD. Zillikens, D. Zillikens Department of Dermatology, University of Lübeck, Lübeck, GermanySearch for more papers by this authorD.T. Woodley, D.T. Woodley Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USASearch for more papers by this authorA. Recke, A. Recke Department of Dermatology, University of Lübeck, Lübeck, GermanySearch for more papers by this author First published: 16 March 2021 https://doi.org/10.1111/jdv.17228Citations: 9Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1Kasperkiewicz M, Schmidt E, Fairley JA et al. Expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic. J Eur Acad Dermatol Venereol 2020; 34: e302–e303. 10.1111/jdv.16525 CASPubMedWeb of Science®Google Scholar 2Kasperkiewicz M. COVID-19 outbreak and autoimmune bullous diseases: a systematic review of published cases. J Am Acad Dermatol 2021; 84: 563–568. 10.1016/j.jaad.2020.08.012 CASPubMedWeb of Science®Google Scholar 3Kuang Y, Shen M, Wang Q et al. Association of outdoor activity restriction and income loss with patient-reported outcomes of psoriasis during the COVID-19 pandemic: a web-based survey. J Am Acad Dermatol 2020; 83: 670–672. 10.1016/j.jaad.2020.05.018 CASPubMedWeb of Science®Google Scholar 4Wang Q, Luo Y, Lv C et al. Nonadherence to treatment and patient-reported outcomes of psoriasis during the COVID-19 epidemic: a web-based survey. Patient Prefer Adherence 2020; 14: 1403–1409. 10.2147/PPA.S263843 PubMedWeb of Science®Google Scholar 5Ruggiero A, Megna M, Annunziata MC et al. Teledermatology for acne during COVID-19: high patients' satisfaction in spite of the emergency. J Eur Acad Dermatol Venereol 2020; 34: e662–e663. 10.1111/jdv.16746 CASPubMedWeb of Science®Google Scholar 6Lesage FX, Berjot S. Validity of occupational stress assessment using a visual analogue scale. Occup Med (Lond) 2011; 61: 434–436. 10.1093/occmed/kqr037 CASPubMedWeb of Science®Google Scholar 7Plummer F, Manea L, Trepel D, McMillan D. Screening for anxiety disorders with the GAD-7 and GAD-2: a systematic review and diagnostic metaanalysis. Gen Hosp Psychiatry 2016; 39: 24–31. 10.1016/j.genhosppsych.2015.11.005 PubMedWeb of Science®Google Scholar 8Kroenke K, Spitzer RL, Williams JBW. The patient health questionnaire-2: validity of a two-item depression screener. Med Care 2003; 41: 1284–1292. 10.1097/01.MLR.0000093487.78664.3C PubMedWeb of Science®Google Scholar 9Salari N, Hosseinian-Far A, Jalali R et al. Prevalence of stress, anxiety, depression among the general population during the COVID-19 pandemic: a systematic review and meta-analysis. Global Health 2020; 16: 57. 10.1186/s12992-020-00589-w PubMedWeb of Science®Google Scholar Citing Literature Volume35, Issue7July 2021Pages e418-e421 This article also appears in:JEADV COVID-19 articles ReferencesRelatedInformation

Healthcare may be influenced by the healthcare system to which the patient is aligned1, as well as the characteristics of the patients within a given healthcare system. The University of Southern California (USC) has two healthcare systems on the same campus - the private system (PS) University Hospital for patients with healthcare insurance and the safety net system (SNS), Los Angeles County Hospital for indigent patients. The same USC physicians provide care in both systems. This article is protected by copyright. All rights reserved.

A 53-year-old man presented with a37-year history of erosive and scarring mucosal lesions of several organs. An initial diagnosis of Stevens-Johnson syndrome was maintained for many years. Due to late correct diagnosis of an anti-laminin 332 mucous membrane pemphigoid and the fact that early, targeted, intensified immunosuppressive therapy was not initiated, the disease led to almost complete loss of vision and obstruction of airways.

Epidemiological evidence suggests that smoking cigarettes may be beneficial in pemphigus, but no systematic evaluation exists to corroborate this assumption. Therefore, a systematic literature review with pooled data analysis of the smoking status in patients with pemphigus was conducted. Electronic searches using PubMed from inception to November 2017 identified 13 reports meeting predetermined inclusion and exclusion criteria. Most were case-control studies partly reporting that pemphigus vulgaris and foliaceus occurred less frequently in current and former smokers. Studies also indicated that duration of smoking and number of cigarettes smoked were lower in patients with pemphigus than controls and that remission may be achieved sooner in those who smoke. However, although a generally low prevalence of smoking was demonstrated in patients with pemphigus, which was lower than in controls by pooled analysis, some investigations found no difference regarding the smoking status compared with non-pemphigus subjects. One study demonstrated more severe mucosal involvement in non-smoking patients with pemphigus, whereas another observed no difference in the rate of cutaneous or mucosal lesions between smokers and non-smokers with pemphigus. This review indicates that smoking may be a possible protective factor in pemphigus, although some compromised study methodologies yet hinder any firm conclusion. Further investigations with a refined quality design are required to resolve the so far partly conflicting results in this area.

Immunoadsorption (IA) is increasingly used for the initial adjuvant treatment of severe pemphigus. Since the pathogenic effect of anti-BP180 antibodies in bullous pemphigoid (BP) has clearly been shown, IA appears to be rational therapeutic approach also in BP. At present, information on the use of IA in BP is limited to individual case reports and a small case series. Here, we report on 20 patients with severe or relapsed BP (13 female, 7 male, mean age 78.6 years; range 56 to 94 years) treated by adjuvant IA on 3 consecutive days in addition to tapering doses of oral prednisolone, dapsone, and lesional topical clobetasol propionate 0.05% ointment. Fifteen patients had been pretreated with topical and systemic glucocorticosteroids and immunosuppressants without satisfying success. We observed a rapid clinical response (complete remission on therapy) in 8 patients (42%) within 4 weeks after initiation of the IA protocol. Serum anti-BP180 autoantibody levels decreased by 73% and 87% within 1 and 3 months, respectively. Reversible anaemia in 8 patients was the most common adverse event, most likely attributed to concomitant dapsone. Severe adverse events occurred in 3 patients: one patient developed a cardiac decompensation after the 3rd day of IA, one patient an apoplex after the 2nd day of IA and one patient suffered from a sigma perforation several weeks after IA. This case series shows that the application of IA in patients with severe and/or therapy-refractory BP, in addition to a standard therapy regimen, is a feasible treatment option also in this elderly patient population.

BackgroundThe hormonally active vitamin D metabolite calcitriol and its analogues exert potent effects on cellular differentiation and regulation of immune responses. Although topical vitamin D analogues are widely used for treatment of psoriasis and vitamin D has been increasingly implicated in prevention and protection from several autoimmune diseases, experimental and clinical data in autoimmune bullous diseases are generally lacking.ObjectiveHere, we investigated the effects of calcitriol on keratinocytes treated by bullous pemphigoid (BP) autoantibodies.MethodsHuman keratinocyte (HaCaT) cells were treated with purified human BP or normal IgG from one BP patient and healthy subject, respectively, in the absence or presence of calcitriol and effects on (i) cell viability, (ii) IL-6 and IL-8 secretion, (iii) STAT3 and NFB activation, (iv) heat shock protein 70 (Hsp70) level, and (v) vitamin D receptor (VDR) expression were studied.ResultsWe found that BP IgG-induced IL-6 and IL-8 release from HaCaT cells was reduced in the presence of non-toxic doses of calcitriol. Additionally, calcitriol blunted BP IgG-mediated STAT3 phosphorylation and NFB activity, whereas Hsp70 and VDR expression were not affected.ConclusionAlthough the results of this study are based on autoantibodies prepared from a single patient, they show that calcitriol protects from BP IgG-induced inflammatory processes in vitro, thus favouring its potential inclusion into the therapeutic repertoire of BP.

Cell stress-inducible heat shock protein 90 (Hsp90) has been recognized as key player in mediating inflammatory responses. While its systemic blockade was successfully used to treat autoimmune diseases in preclinical models, efficacy of a topical route of Hsp90 inhibitor administration has so far not been evaluated in chronic inflammatory and autoimmune-mediated dermatoses. Here, effects of the Hsp90 blocker 17-allylamino-demethoxygeldanamycin (17AAG) applied topically to the skin were determined in experimental inflammatory epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-induced blistering skin disease. Topical 17AAG ameliorated clinical disease severity when given before or during occurrence of skin lesions without causing cutaneous or systemic toxicity in mice with antibody transfer- and immunization-induced EBA. In both EBA models and in the setting of locally induced inflammation, topical 17AAG treatment was associated with (i) reduced neutrophilic infiltrates, (ii) decreased NFκB activation, (iii) lowered expression of matrix metalloproteinases and Flightless I, and (iv) induction of anti-inflammatory Hsp70 in the skin. Our results suggest that topical delivery of Hsp90 antagonists, offering the benefit of a reduced risk of systemic side effects of Hsp90 inhibition, may be useful for the control of EBA and possibly other related inflammatory skin disorders.