Autoimmune encephalitis associated with autoimmune blistering diseases: A case series and retrospective review

Abstract

Autoimmune blistering skin diseases (AIBDs) comprise a group of immune-mediated disorders characterized by the presence of autoantibodies directed against cutaneous epitopes resulting in frequent blister formation. Associations between the most common AIBDs, pemphigus, and pemphigoid and other inflammatory or autoimmune diseases have been described, so-called autoimmune diathesis.1Karakioulaki M. Murrell D.F. Kyriakou A. Patsatsi A. Investigation of comorbid autoimmune diseases in women with autoimmune bullous diseases: an interplay of autoimmunity and practical implications.Int J Womens Dermatol. 2022; 8: e053PubMed Google Scholar This diathesis has been well described with regard to pemphigoid and concomitant neurologic inflammatory or autoimmune diseases such as Alzheimer’ disease, Parkinson’ disease, and multiple sclerosis.2Haitao R. Huiqin L. Tao Q. et al.Autoimmune encephalitis associated with vitiligo?.J Neuroimmunol. 2017; 310: 14-16Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,3Ljubojevic S. Lipozenčić J. Autoimmune bullous diseases associations.Clin Dermatol. 2012; 30: 17-33Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar These neurocutaneous associations are hypothesized to be, at least in part, caused by autoantibodies directed at both cutaneous and neurologic tissues. Due to their shared embryologic origin, several receptor binding domains are co-expressed across both dermatologic and neurologic tissues (eg, BP180, BP230). Cross-reactive antibodies are believed to play a role in mediating the clinical sequelae related to the skin; although the role in various neurological diseases is still unclear, with circulating anti-BP180, 230 autoantibodies reported in patients with Alzheimer disease and Parkinson disease.4Brick K.E. Weaver C.H. Savica R. et al.A population-based study of the association between bullous pemphigoid and neurologic disorders.J Am Acad Dermatol. 2014; 71: 1191-1197Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar,5Kokkonen N. Herukka S.K. Huilaja L. et al.Increased levels of the bullous pemphigoid BP180 autoantibody are associated with more severe dementia in Alzheimer's disease.J Invest Dermatol. 2017; 137: 71-76Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Autoimmune encephalitis (AE) encompasses a group of diseases characterized by autoantibodies targeting various epitopes of the central nervous system.6Fukata M. Yokoi N. Fukata Y. Neurobiology of autoimmune encephalitis.Curr Opin Neurobiol. 2018; 48: 1-8Crossref PubMed Scopus (23) Google Scholar Patients with AE often experience neuropsychiatric symptoms, leading to significant medical morbidity. An autoimmune diathesis has also been reported in patients with AE, including concurrent Hashimoto’s thyroiditis and systemic lupus erythematosus.7Zhao J. Wang C. Xu X. et al.Coexistence of autoimmune encephalitis and other systemic autoimmune diseases.Front Neurol. 2019; 10: 1142Crossref PubMed Scopus (26) Google Scholar Interestingly, some studies have shown cutaneous findings prior to the diagnosis of antibody-positive autoimmune encephalitis further suggesting an association with dermatologic diseases.8Siddiqui Z. Thien V. Patel M. SLE and anti-NMDA receptor encephalitis in an 18 year-old presenting with a skin rash.J Anesth Crit Care Open Access. 2017; 800311Google Scholar In this report, we highlight 3 cases of patients with AIBD who subsequently developed AE. We also further broadened this search to explore a potential association of inflammatory and autoimmune skin diseases with AE. For the case series, clinical data were collected from all 3 patients seen by the same dermatologist and diagnosed based on confirmative clinical, histological, and serological criteria. All 3 cases were co-managed with a neuroimmunologist who confirmed the diagnosis of AE. A 20-year retrospective review of patients in the Emory Healthcare System with autoimmune or inflammatory skin diseases (alopecia areata, AIBD, psoriasis, atopic dermatitis, and vitiligo) and AE was conducted following approval by the institutional review board of Emory University (IRB00114505). Confirmation of a dermatologic diagnosis for AIBD, psoriasis, atopic dermatitis, vitiligo, alopecia areata, vitiligo, or nonmelanoma skin cancer (NMSC) was based on a combination of clinical, laboratory, and pathologic data. Clinical diagnosis was based on several factors including presentation (eg, symptoms, visual appearance/description of skin morphology, and response to therapy). Supporting laboratory information included pathologic confirmation as assessed and recorded within the electronic health record. Confirmation of NMSC was assessed by pathologic confirmation and response to excisional therapy. Diagnosis was recorded as the date in which an International Classification of Diseases (ICD) code was first used to identify the skin disease (Table I).Table IA retrospective review was conducted within a 20-year period based on ICD codes for dermatologic disease and AEIndicationICD9ICD10Autoimmune encephalitis323.9, 323.81G.04.9, G04.81Alopecia areata704.01L63.9Atopic dermatitis691.8L20-L30Psoriasis696.1L40.9Pemphigus, pemphigoid, and other bullous skin diseases694-694.9L10-L14Vitiligo709.01L80Nonmelanoma skin cancer173.0-173.9C44ICD codes identified for patients with AE, alopecia areata, atopic dermatitis, psoriasis, pemphigus, pemphigoid and other bullous disorders, vitiligo, and NMSC. Open table in a new tab ICD codes identified for patients with AE, alopecia areata, atopic dermatitis, psoriasis, pemphigus, pemphigoid and other bullous disorders, vitiligo, and NMSC. To identify patients within the full database query with confirmed or probable AE, we utilized clinical standards for diagnosis of AE. Patients must have satisfied the following 3 criteria for inclusion as confirmed AE: (1) subacute onset of neuropsychiatric symptoms (less than 3 months), (2) at least 1 of the following: new focal central nervous system findings, seizures not explained by a seizure disorder, CSF pleocytosis (white blood cell count >5 cells/mm3), or magnetic resonance imaging suggestive of encephalitis, and (3) a reasonable exclusion of alternative causes (eg, infectious, trauma, neoplasm, toxic/metabolic).9Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Google Scholar To further interrogate the patients we manually identified, all cases of interest were reviewed by a neurologist to adjudicate the final diagnosis, according to information available within the electronic health record. Date of diagnosis was recorded as the first date the ICD code diagnosis appeared within the electronic health record. Patients who were identified through the database query were manually reviewed for clinical symptoms and temporal pattern of disease onset, and CSF analysis from lumbar puncture. If no CSF findings were found, a diagnosis of exclusion was utilized to assess for probable AE. The diagnosis of exclusion includes the above listed 3 criteria with the modification of having at least 2 of the following 3 criteria: (1) MRI findings suggestive of AE, (2) CSF pleocytosis, CSF-specific oligoclonal bands or elevated CSF IgG index, or both, or (3) brain biopsy confirming inflammatory infiltrates and excluding other disorders.9Graus F. Titulaer M.J. Balu R. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Google Scholar Herein, we summarize the clinical characteristics of 3 patients with concurrent AIBD and AE (Table II). All patients developed AIBD prior to AE with AIBD diagnoses including pemphigus vulgaris and mucous membrane pemphigoid. The patient with PV developed anti-LGI1 encephalitis while the MMP patients developed clinical manifestations of AE absent detectable autoantibodies. The mean age was 70 ± 8.8 years and AE developed mean 13.3 ± 5.0 months after a diagnosis of AIBD. Two of the patients had previously received rituximab therapy for AIBD when they developed AE. All 3 patients presented with subacute onset of confusion with 2 patients having tremors and muscle spasms, and 1 patient experiencing agitation. Patients were admitted for treatments including high dose intravenous steroids, intravenous immunoglobulin, and plasma exchange with variable response as assessed clinically at the time of discharge per electronic medical record documentation.Table IIPatients identified in case series with AIBD and subsequent development of AEPatient initialsPatient 1Patient 2Patient 3Age656580GenderMaleFemaleFemaleRaceWhiteWhiteWhiteType of AIBDPemphigus vulgarisOCPMMPDiagnosis of AIBDClinical + ELISAClinical + DIFClinical + DIFPast medical historyHashimoto thyroiditisNone notedBladder transitional cell carcinomaDate of AIBD diagnosisMay-2018Jan-2018Oct-2018Date of AE diagnosisNov-2019Mar-2019Jun-2019Time between AIBD and AE diagnosis18 mo14 mo8 moPresenting symptoms of AEConfusion, migraine with visual aura, tremor, abdominal muscle spasmsConfusion, weakness, tremors, dizziness, weight lossConfusion, memory loss, combative behaviorTreatment used for AIBD at the time of AE diagnosisRituximab, MMF, topicalsMMF, RituximabDapsone, topicalsRituximab treatment year20152017n/aTreatment used for AEIV steroids, IVIGIV steroids, IVIG, PLEXIVIGResponse to AE treatmentModeratePoorExcellentAE Antibody studiesAnti-LGI-1 positiveNegativeNegativeDIF, Direct immunofluorescence; ELISA, enzyme linked immunosorbent assay; IVIG, intravenous immunoglobulin; MMF, mycophenolate; MMP, mucous membrane pemphigoid; OCP, ocular cicatricial pemphigoid; PLEX, plasma exchange. Open table in a new tab DIF, Direct immunofluorescence; ELISA, enzyme linked immunosorbent assay; IVIG, intravenous immunoglobulin; MMF, mycophenolate; MMP, mucous membrane pemphigoid; OCP, ocular cicatricial pemphigoid; PLEX, plasma exchange. Retrospective review of Emory Healthcare database for associated diagnoses based on ICD codes was completed (Fig 1). In total, 217 patients were identified, with 13 patients meeting criteria for codiagnosis of AE and a dermatologic diagnosis as summarized in Table III. Of the 13 patients with AE, 12 patients had confirmed skin disease (1 patient had an unknown dermatologic diagnosis). Most patients had dermatologic diagnosis preceding AE (8 vs 5). The relative risk ratio (RRR) for each dermatologic indication was calculated and compared to patients with NMSC as a control (Table IV). Patients with AIBD had a significantly increased relative risk ratio (10.93, [2.00, 59.65]) compared to NMSC patients. Patients with psoriasis (5.40, [0.99, 29.48]) and vitiligo (7.78, [0.71, 85.82)] also had increased relative risk ratiorelative to NMSC but did not achieve statistical significance.Table IIIDemographics of retrospective case series for patients with concurrent AE and dermatologic diseaseCategoryAE Confirmed (n = 12)Sex, No. (%) Male4 (33.3) Female8 (66.7)Age of Neuro Dx, mean (SD) in years52.4 (19.2)Age of Derm Dx, mean (SD) in years51.3 (18.7)Race and ethnicity, No. (%) African American or Black3 (25.0) American Indian or Alaskan Native0 (0.0) Asian0 (0.0) Caucasian or White7 (58.3) Multiple0 (0.0) Native Hawaiian or other Pacific Islander0 (0.0) Not recorded1 (8.3) Unknown1 (8.3)Skin disorder prevalence, No. (%) Atopic dermatitis1 (8.3) Pemphigus/pemphigoid/other bullous dermatoses4 (33.3) BCC/SCC/other malignant neoplasm2 (16.7) Psoriasis4 (33.3) Alopecia Areata0 (0.0) Vitiligo1 (8.3)Neuro dx precedes derm dx, No. (%)5 (41.7) Time between neuro and derm dx, mean (SD) in months26.8 (39.6)Derm dx precedes neuro dx, No. (%)7 (58.3) Time between derm and neuro dx, mean (SD) in months40.2 (20.4)A search for patients with a co-diagnosis of NMSC and AE was performed as a control since these is no known association between the 2 conditions. Confirmation of AE diagnosis was made based on clinical standards. Dermatologic diseases were confirmed based on clinical, laboratory and histologic data. Open table in a new tab Table IVSummary table comparing patients identified with each dermatologic indication and those specifically with a codiagnosis of AEIndicationOverall patient count over 20 years (n = 163,333)Patient count in AE dataset over 20 years (n = 12)20-year prevalence per 100,000 ptsRRR95% CIAtopic dermatitis93,14111.070.23(0.02, 2.49)Bullous disorders7702451.9310.93(2.00, 59.65)NMSC42,07924.751.00-Psoriasis15,586425.665.40(0.99, 29.48)Vitiligo2703137.007.78(0.71, 85.82)The relative risk ratio (RRR) and 95% confidence intervals (CI) of each dermatologic indication is calculated relative to NMSC as a control group. The AE patient dataset was found to be statistically different from this overall patient dataset (χ2 = 35.65, P < .0001). There were no patients identified with alopecia areata within this retrospective search – data not shown. Open table in a new tab A search for patients with a co-diagnosis of NMSC and AE was performed as a control since these is no known association between the 2 conditions. Confirmation of AE diagnosis was made based on clinical standards. Dermatologic diseases were confirmed based on clinical, laboratory and histologic data. The relative risk ratio (RRR) and 95% confidence intervals (CI) of each dermatologic indication is calculated relative to NMSC as a control group. The AE patient dataset was found to be statistically different from this overall patient dataset (χ2 = 35.65, P < .0001). There were no patients identified with alopecia areata within this retrospective search – data not shown. This study provides further support for increases in other autoantibody-mediated diseases in patients with AIBD. While our results did not reach significance with other inflammatory skin diseases, prior studies demonstrated anti-NMDAR and anti-LGI1 AE patients with concomitant inflammatory skin diseases (ISDs) such as vitiligo and chronic urticaria. In our cohort, most patients developed ISDs prior to the onset of AE, suggesting possible initial loss of tolerance to cutaneous epitopes. Genetic susceptibilities related to specific HLA class II alleles has been proposed in development of pemphigus and potentially shared in patients with anti-LGI1 encephalitis.10Kim T.J. Lee S.T. Moon J. et al.Anti-LGI1 encephalitis is associated with unique HLA subtypes.Ann Neurol. 2017; 81: 183-192Crossref PubMed Scopus (104) Google Scholar Emerging data also suggest unique HLA alleles which may also genetically predispose individuals to cutaneous and neurologic injury with the common denominator being IgG4-mediated autoimmunity,11Koneczny I. Yilmaz V. Lazaridis K. et al.Common denominators in the immunobiology of IgG4 autoimmune diseases: what do glomerulonephritis, pemphigus vulgaris, myasthenia gravis, thrombotic thrombocytopenic purpura and autoimmune encephalitis have in common?.Front Immunol. 2021; 11605214Crossref PubMed Scopus (13) Google Scholar and thereby responsive to B cell depletion therapies.12Dalakas M.C. Autoimmune neurological disorders with IgG4 antibodies: a distinct disease spectrum with unique IgG4 functions responding to anti-B cell therapies.Neurotherapeutics. 2022; 19: 741-752Crossref PubMed Scopus (9) Google Scholar This dual development of autoantibody-mediated diseases, autoimmune diathesis, could be explained in the context of epitope spreading in which inappropriate exposure of receptors with cutaneous injury from AIBD could result in autoantibody generation. Indeed, LGI-1 and NMDA receptors are expressed in cutaneous structures, and bullous pemphigoid-related collagen XVII (BP180) proteins are localized in both neuronal and cutaneous structures thought to derive from common ectodermal lineage.3Ljubojevic S. Lipozenčić J. Autoimmune bullous diseases associations.Clin Dermatol. 2012; 30: 17-33Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar One patient with anti-contactin-associated protein-like 2 (CASPR2) AE developed BP also suggesting a role for the neuronal cell adhesion molecule contactin 2/TAG1 although no evidence for cutaneous expression of this protein has been documented.7Zhao J. Wang C. Xu X. et al.Coexistence of autoimmune encephalitis and other systemic autoimmune diseases.Front Neurol. 2019; 10: 1142Crossref PubMed Scopus (26) Google Scholar Interestingly, the delayed timing between both autoimmune diseases and treatment with rituximab lends credence to re-emergence of novel autoreactive B cell clones.13Lee D.S. Rojas O.L. Gommerman J.L. B cell depletion therapies in autoimmune disease: advances and mechanistic insights.Nat Rev Drug Discov. 2021; 20: 179-199Crossref PubMed Scopus (164) Google Scholar This was partially supported by our inability to detect anti-LGI-1 antibodies by ELISA in the pemphigus patient 1 year prior to the diagnosis of AE (data not shown). Of note, 2 of the 3 patients in this case series had previously received rituximab therapy which carries a black box warning for reactivation of JC virus and development of progressive multifocal leukoencephalopathy. Patient 2 did have negative CSF testing for JC virus, and all 3 patients did not demonstrate magnetic resonance imaging findings consistent with progressive multifocal leukoencephalopathy. Other contributing factors may include local and systemic cytokine profiles for which IL17 A has been found to be increased in both skin and blood from patients with AIBD,14Chakievska L. Holtsche M.M. Künstner A. et al.IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid.J Autoimmun. 2019; 96: 104-112Crossref PubMed Scopus (63) Google Scholar and recently in CSF from patients with non-NMDA receptor encephalitis,15Levraut M. Bourg V. Capet N. et al.Cerebrospinal fluid IL-17A could predict acute disease severity in Non-NMDA-receptor autoimmune encephalitis.Front Immunol. 2021; 12: 673021Crossref PubMed Scopus (10) Google Scholar thus representing a potential common therapeutic target. Future studies including a larger patient subset across multiple geographic sites may provide further evidence to support and broaden these potential associations. This study highlights a unique association of AIBD with AE with all our cases of AE occurring subsequent to AIBD. Additionally, these data support the concept of autoimmune diathesis which may result from loss of tolerance to shared neurocutaneous epitopes.