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Association Between Pemphigus and Neurologic Diseases

Educational Objective
To learn about the increased incidence of serious neurologic problems in a cohort of patients with pemphigus and to speculate on common pathologic pathways.
1 Credit CME
Key Points

Question  Is there an association between pemphigus and neurologic diseases?

Findings  This population-based cross-sectional study of 1985 patients with pemphigus revealed a statistically significant comorbidity between pemphigus and epilepsy, dementia, and Parkinson disease. This association retained its statistical significance after multivariable and sensitivity analyses.

Meaning  Clinicians should be aware of this association; further research is warranted to elucidate the mechanism of this link.

Abstract

Importance  The association between pemphigus and neurologic diseases was not evaluated systematically in the past. In a recent uncontrolled cross-sectional study, Parkinson disease was found to be significantly associated with pemphigus; in the same study, epilepsy had a nonsignificant association with pemphigus. Several case reports have suggested that pemphigus coexists with multiple sclerosis and dementia.

Objective  To estimate the association between pemphigus and 4 neurologic conditions (dementia, epilepsy, Parkinson disease, and multiple sclerosis), using one of the largest cohorts of patients with pemphigus.

Design, Setting, and Participants  A retrospective population-based cross-sectional study was performed between January 1, 2004, and December 31, 2014, using the database of Clalit Health Services, the largest public health care organization in Israel, in the setting of general community clinics, primary care and referral centers, and ambulatory and hospitalized care. A total of 1985 patients with a new diagnosis of pemphigus and 9874 controls were included in the study.

Main Outcomes and Measures  The proportion of dementia, epilepsy, Parkinson disease, and multiple sclerosis was compared between patients diagnosed with pemphigus and age-, sex-, and ethnicity-matched control participants. Logistic regression was used to calculate odds ratios (ORs) for dementia, epilepsy, Parkinson disease, and multiple sclerosis. The association was examined after a sensitivity analysis that included only patients treated with long-term, pemphigus-specific medications (corticosteroids, immunosuppressants, or rituximab) and after adjustment for several confounding factors.

Results  When comparing the 1985 cases (1188 women and 797 men; mean [SD] age, 72.1 [18.5] years) with the 9874 controls (5912 women and 3962 men; mean [SD] age, 72.1 [18.5] years), dementia was seen in 622 cases (31.3%) vs 1856 controls (18.8%), with an OR of 1.97 (95% CI, 1.77-2.20). Epilepsy was present in 74 cases (3.7%) vs 210 controls (2.1%), with an OR of 1.78 (95% CI, 1.36-2.33). Parkinson disease was seen in 175 cases (8.8%) vs 437 controls (4.4%), with an OR of 2.09 (95% CI, 1.74-2.51). Multiple sclerosis was present in 2 cases (0.1%) vs 6 controls (0.01%), with an OR of 1.65 (95% CI, 0.34-8.22). Study findings were robust to sensitivity analysis that included patients receiving pemphigus-specific treatments. Estimates were not altered significantly after controlling for comorbidities and overuse of health care.

Conclusions and Relevance  An association was observed between pemphigus and specific neurologic diseases, including dementia, Parkinson disease, and epilepsy. Physicians treating patients with pemphigus should be aware of this possible association. Patients with pemphigus should be carefully assessed for comorbid neurologic disorders and receive appropriate treatment.

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Article Information

Accepted for Publication: October 20, 2017.

Corresponding Author: Khalaf Kridin, MD, Department of Dermatology, Rambam Health Care Campus, PO Box 9602, Haifa 31096, Israel (dr_kridin@hotmail.com).

Published Online: February 16, 2018. doi:10.1001/jamadermatol.2017.5799

Author Contributions: Drs Kridin and Cohen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kridin, Zelber-Sagi, Cohen.

Acquisition, analysis, or interpretation of data: Kridin, Comaneshter, Cohen.

Drafting of the manuscript: Kridin.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kridin, Comaneshter, Cohen.

Administrative, technical, or material support: Cohen.

Study supervision: Kridin, Zelber-Sagi, Cohen.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This paper was presented at the Annual Meeting of the American Academy of Dermatology; February 16, 2018; San Diego, California.

References
1.
Stanley  JR, Amagai  M.  Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome.  N Engl J Med. 2006;355(17):1800-1810.PubMedGoogle ScholarCrossref
2.
Sitaru  C, Zillikens  D.  Mechanisms of blister induction by autoantibodies.  Exp Dermatol. 2005;14(12):861-875.PubMedGoogle ScholarCrossref
3.
Hsu  DY, Brieva  J, Sinha  AA, Langan  SM, Silverberg  JI.  Comorbidities and inpatient mortality for pemphigus in the USA.  Br J Dermatol. 2016;174(6):1290-1298.PubMedGoogle ScholarCrossref
4.
Friedel  J, Jeandel  C, Abensour  M, Heid  E.  Multiple sclerosis and autoimmune skin bullae: a case of pemphigus vulgaris.  Dermatologica. 1987;175(3):159-160.PubMedGoogle ScholarCrossref
5.
Belniak  E, Stelmasiak  Z, Papuć  E.  Multiple sclerosis and other autoimmune diseases  [in Polish].  Neurol Neurochir Pol. 2007;41(3):259-266.PubMedGoogle Scholar
6.
Estruch  BC.  Comorbilidad en esclerosis múltiple y su abordaje asistencial.  Med Clin (Barc). 2014;143(suppl 3):13-18.PubMedGoogle ScholarCrossref
7.
Siqueira-Neto  JI, Sales  PMG, Sobreira  EST,  et al.  Vascular cognitive impairment in Pemphigus vulgaris Dement Neuropsychol. 2012;6(3):192-195. doi:10.1590/S1980-57642012DN06030014PubMedGoogle ScholarCrossref
8.
Langan  SM, Groves  RW, West  J.  The relationship between neurological disease and bullous pemphigoid: a population-based case-control study.  J Invest Dermatol. 2011;131(3):631-636.PubMedGoogle ScholarCrossref
9.
Cordel  N, Chosidow  O, Hellot  M-F,  et al; French Study Group of Bullous Diseases.  Neurological disorders in patients with bullous pemphigoid.  Dermatology. 2007;215(3):187-191.PubMedGoogle ScholarCrossref
10.
Nielsen  NM, Frisch  M, Rostgaard  K,  et al.  Autoimmune diseases in patients with multiple sclerosis and their first-degree relatives.  Mult Scler. 2008;14(6):823-829.PubMedGoogle ScholarCrossref
11.
Jedlickova  H, Hlubinka  M, Pavlik  T, Semradova  V, Budinska  E, Vlasin  Z.  Bullous pemphigoid and internal diseases—a case-control study.  Eur J Dermatol. 2010;20(1):96-101.PubMedGoogle Scholar
12.
Gambichler  T, Segert  H, Höxtermann  S, Schmitz  L, Altmeyer  P, Teegen  B.  Neurological disorders in patients with bullous pemphigoid.  J Eur Acad Dermatol Venereol. 2015;29(9):1758-1762.PubMedGoogle ScholarCrossref
13.
Rennert  G, Peterburg  Y.  Prevalence of selected chronic diseases in Israel.  Isr Med Assoc J. 2001;3(6):404-408.PubMedGoogle Scholar
14.
Charlson  ME, Pompei  P, Ales  KL, MacKenzie  CR.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.  J Chronic Dis. 1987;40(5):373-383.PubMedGoogle ScholarCrossref
15.
Pearce  N.  Analysis of matched case-control studies.  BMJ. 2016;352:i969.PubMedGoogle ScholarCrossref
16.
Chillag-Talmor  O, Giladi  N, Linn  S,  et al.  Use of a refined drug tracer algorithm to estimate prevalence and incidence of Parkinson’s disease in a large israeli population.  J Parkinsons Dis. 2011;1(1):35-47.PubMedGoogle Scholar
17.
Caproni  M, Torchia  D, Parigi  L, Fabbri  P.  Brugada syndrome, epilepsy and pemphigus vulgaris.  South Med J. 2008;101(11):1183.PubMedGoogle ScholarCrossref
18.
Labidi  A, Serghini  M, Karoui  S, Ben Mustapha  N, Boubaker  J, Filali  A.  Epilepsy, pemphigus and celiac disease.  Tunis Med. 2014;92(8-9):585-586.PubMedGoogle Scholar
19.
Phuan  ZYC, Yew  YW, Tey  HL.  Pemphigus and nonassociation with antecedent neurological diseases.  Int J Dermatol. 2017;56(5):e96-e97.PubMedGoogle ScholarCrossref
20.
Huijbers  MG, Querol  LA, Niks  EH,  et al.  The expanding field of IgG4-mediated neurological autoimmune disorders.  Eur J Neurol. 2015;22(8):1151-1161.PubMedGoogle ScholarCrossref
21.
Miyata  S, Yoshikawa  K, Taniguchi  M,  et al.  Sgk1 regulates desmoglein 1 expression levels in oligodendrocytes in the mouse corpus callosum after chronic stress exposure.  Biochem Biophys Res Commun. 2015;464(1):76-82.PubMedGoogle ScholarCrossref
22.
Kljuic  A, Christiano  AM.  A novel mouse desmosomal cadherin family member, desmoglein 1γ.  Exp Dermatol. 2003;12(1):20-29.PubMedGoogle ScholarCrossref
23.
Li  L, Chen  J, Wang  B, Yao  Y, Zuo  Y.  Sera from patients with bullous pemphigoid (BP) associated with neurological diseases recognized BP antigen 1 in the skin and brain.  Br J Dermatol. 2009;160(6):1343-1345.PubMedGoogle ScholarCrossref
24.
Brown  A, Bernier  G, Mathieu  M, Rossant  J, Kothary  R.  The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1.  Nat Genet. 1995;10(3):301-306.PubMedGoogle ScholarCrossref
25.
Borradori  L, Sonnenberg  A.  Structure and function of hemidesmosomes: more than simple adhesion complexes.  J Invest Dermatol. 1999;112(4):411-418.PubMedGoogle ScholarCrossref
26.
Liu  X, Cheng  R, Verbitsky  M,  et al.  Genome-wide association study identifies candidate genes for Parkinson’s disease in an Ashkenazi Jewish population.  BMC Med Genet. 2011;12(1):104.PubMedGoogle ScholarCrossref
27.
Kridin  K, Zelber-Sagi  S, Khamaisi  M, Cohen  AD, Bergman  R.  Remarkable differences in the epidemiology of pemphigus among two ethnic populations in the same geographic region.  J Am Acad Dermatol. 2016;75(5):925-930.PubMedGoogle ScholarCrossref
28.
Mimouni  D, Bar  H, Gdalevich  M, Katzenelson  V, David  M.  Pemphigus—analysis of epidemiological factors in 155 patients.  J Eur Acad Dermatol Venereol. 2008;22(10):1232-1235.PubMedGoogle ScholarCrossref
29.
Pisanti  S, Sharav  Y, Kaufman  E, Posner  LN.  Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion.  Oral Surg Oral Med Oral Pathol. 1974;38(3):382-387.PubMedGoogle ScholarCrossref
30.
Baum  S, Astman  N, Berco  E, Solomon  M, Trau  H, Barzilai  A.  Epidemiological data of 290 pemphigus vulgaris patients.  Eur J Dermatol. 2016;26(4):382-387.PubMedGoogle Scholar
31.
Höfler  M.  The Bradford Hill considerations on causality: a counterfactual perspective.  Emerg Themes Epidemiol. 2005;2:11.PubMedGoogle ScholarCrossref
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