IgA pemphigus: A systematic review

Journal Pre-proof IgA Pemphigus: A Systematic Review Khalaf Kridin, M.D., PhD, Payal M. Patel, M.D., Virginia A. Jones, M.S., Adriana Cordova, M.S., Kyle T. Amber, M.D. PII:

S0190-9622(19)33151-2

DOI:

https://doi.org/10.1016/j.jaad.2019.11.059

Reference:

YMJD 14042

To appear in:

Journal of the American Academy of Dermatology

Received Date: 26 August 2019 Revised Date:

29 October 2019

Accepted Date: 25 November 2019

Please cite this article as: Kridin K, Patel PM, Jones VA, Cordova A, Amber KT, IgA Pemphigus: A Systematic Review, Journal of the American Academy of Dermatology (2020), doi: https:// doi.org/10.1016/j.jaad.2019.11.059. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.

IgA Pemphigus: A Systematic Review Khalaf Kridin, M.D., PhD1*, Payal M. Patel M.D.2*, Virginia A. Jones M.S.2, Adriana Cordova M.S.2, Kyle T. Amber2 M.D. *both authors contributed equally as first-author 1. Department of Dermatology, Rambam Health Care Campus, Haifa, Israel 2. Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States

The authors declare no conflict of interests. Funding sources: none IRB has exempted this study from review. Keywords: IgA pemphigus, systematic review, immunoreactivity Word count: Abstract= 199; Capsule Summary= 44; Manuscript= 2425 Number of references: 23; Number of tables: 4; Number of figures: 0; Number of supplementary tables: 1 (available at http://dx.doi.org/10.17632/pt9mg6twsy.3); Number of supplementary figures: 0 Correspondence: Dr. Kyle T. Amber Department of Dermatology, University of Illinois at Chicago 808 S Wood St, RM377 Chicago, IL 60612 Telephone and Fax: (312) 996-8666, 312-413-7767 E-mail: [email protected]

Abstract Background: The clinical, histologic, and immunopathologic features of IgA pemphigus have not been studied on a large scale. Objective: To synthesize existing data on the epidemiological, clinical, histological, and immunological features of IgA pemphigus. Methods: We performed a systematic review using Medline, Embase and Web of Science databases. Case reports and series of patents with IgA pemphigus were included. Results: 119 eligible studies comprising 137 patients with IgA pemphigus were included with a mean age of 51.5 ± 21.0 years. Most patients presented with vesicles (80.8%), pustules (75.0%), and circinate plaques (63.6%). Pruritus was present in 65.6% of reported patients. Intercellular deposition of IgA was noted in almost all patients (97.0%) and the remaining 3.0% patients had IgA positivity on indirect immunofluorescence (IIF), or ELISA confirming the diagnosis. IgA circulating intercellular antibodies were detected in only 66.7% patients. IgA gammopathy and ulcerative colitis were associated with IgA pemphigus in 9.5% and 6.6% patients, respectively. Oral dapsone and corticosteroids were the mostly commonly used treatments. Limitations: Results are mainly grounded on case reports and small case series. Conclusions: The diagnosis of IgA pemphigus may be considered in patients presenting with vesiculopustular eruption and circinate plaques with truncal and extremity involvement.

Capsule summary •

The clinical characteristics of IgA pemphigus have not been well-characterized, and most information is drawn from individual observations or case reports.

•

Our study synthesizes clinical variables such as age, sex ratio, an expected clinical presentation, histologic characteristics, immunopathologic criteria for diagnosis, and management information.

Introduction IgA pemphigus, also known as intercellular IgA dermatosis among other names, is a rare and poorly understood epidermal autoimmune blistering disease (AIBD).1 The defining feature of this disease is the presence of IgA anti-keratinocyte cell surface autoantibodies, labeling the epidermal human skin by direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) microscopy. The etiology behind the disease remains elusive but it has been reported concomitantly with inflammatory conditions and internal malignancies.2-4 Data from small case series suggests that IgA pemphigus can be differentiated into 2 subtypes based on clinical presentation and immunoreactivity: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic dermatosis (IEN). However, several case reports note overlapping features and a variety of autoantigens have been implicated in the pathogenesis of the two phenotypes.5-9 Discrepancies between clinical, histopathological and immunological features make it difficult to finally establish the subtype of IgA pemphigus. Data on the clinical course of these patients is limited, mainly due to the lack of large-scale observational studies and the rarity of IgA pemphigus. The aim of the current study is to perform a systematic review aiming to summarize the epidemiological, clinical, histological, and immunopathological characteristics, as well as major comorbidities and treatment options used for patients with IgA pemphigus. Materials and Methods Literature review The literature review was conducted using Ovid-Medline (1946-present), Embase (1947present) and Web of Science (1900-present) to identify eligible articles. Publications up to July 1, 2019 were searched independently and cross-checked by the two researchers. Reference lists

of included articles were further screened for additional eligible publications. The search strategies are detailed in the Supplementary Table 1. Article selection Articles published in any language, whether online, in print, or in press from all years were considered for eligibility. Articles were excluded based on the title, abstract, or both if there was no clear indication that they were investigating IgA pemphigus. Editorials and reviews were excluded as well. All articles reporting on 1 or multiple cases of IgA pemphigus were included. The diagnostic inclusion criteria for IgA pemphigus are as follows: (i) clinical picture suggestive of IgA pemphigus, (ii) histological image of intraepidermal clefts and pustules located in a subcorneal location or in the entire or mid-epidermis, and (iii) DIF showing intercellular IgA deposition, and/or (iv) IIF confirmation demonstrating intercellular IgA deposition or IgA desmocollin/desmoglein autoantibodies identified on immunoblotting/ELISA. Patients with concomitant deposition of other immune components were included as long as IgA composed the predominant/equivalent subtype. Data extraction Each eligible paper was critically reviewed, and the following variables were extracted: age, sex, ethnicity, location, clinical subtype, morphological features of the physical manifestation,

histopathologic

findings,

immunopathological

findings,

and

associated

comorbidities. We assigned the clinical subtype of SPD or IEN based on how it was reported in the original case report or series by the author. When no classification was explicitly stated, we reviewed histologic manifestations to assign a classification. When this information was not

reported, we did not assign a subtype. All statistical analysis was performed using SPSS software, version 25 (SPSS, Chicago, IL, USA). Results Systematic review results The literature search yielded 908 manuscripts. Five additional articles were identified from other article references. Overall, 278 manuscripts were duplicates, and 450 manuscripts were not related to IgA pemphigus. Eventually, 119 articles fulfilled the eligibility criteria and were included in the qualitative synthesis. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram is shown in Figure 1. The eligible case reports and case series comprised a total of 137 patients with IgA pemphigus from 26 different countries. Thirty-one cases (22.6%) had been reported from Japan and 18 (13.1%) from the USA, and published years of eligible articles ranged from 1983 to 2019 (Table 1). Clinical characteristics The age distribution of reported cases ranged between 1 month and 94 years, with a mean of 51.5 ± 21.0 years. A slight female preponderance was observed among reported cases with a female-to-male ratio of 1.1 (Table 1). Due to the lack of data on ethnicity of our case reports, we cannot reliably provide the ethnic distribution in IgA pemphigus. The clinical presentation was described by the authors of 103 (75.2%) cases. Of those cases, the leading encountered subtype was the subcorneal pustular dermatoses type (n=46; 44.7%), followed by intraepidermal neutrophilic type (n=41; 39.8%), and IgA/IgG overlap pemphigus (n=12; 11.7%). Two patients (1.9%) developed IgA pemphigus in conjunction with linear IgA bullous dermatosis, whereas the clinical presentation resembled paraneoplastic

pemphigus, pemphigus herpetiformis, and pemphigus erythematosus in one patient (1.0%) each (Table 2). The majority of reported patients presented with frank vesicles (80.8%), pustules (75.0%), and circinate plaques (63.6%), while only 2.5% and 1.6% of patients manifested with urticarial plaques and scars or milia, respectively. Pruritis was reported in 65.6% of patients (Table 2). The anatomical distribution of cutaneous lesions was reported for 121 (88.3%) patients. The trunk was the most frequently involved region (83.5%), whereas the extremities were involved in 80.2% of patients. Intertriginous and cephalic involvement was less frequent and appeared in 39.3% and 29.8% of patients, respectively. Generalized eruption was reported in 9.9% and palmoplantar involvement was observed in 3.3% of patients. Mucosal involvement was present in 13.2 % of cases, none of whom had the mucosa exclusively or predominantly affected (Table 2). Among patients presenting with mucosal lesions, the most frequently affected mucosal surface was the oral mucosa (100%), whereas the genital (n=2), nasal (n=1), and conjunctival (n=1) mucosae were rarely involved. Histological characteristics The histology of biopsy specimens was described for 116 (84.7%) patients. The inflammatory dermal infiltrate predominantly composed of neutrophils in 74 (63.8%) patients. A mixed infiltrate of neutrophils and eosinophils was seen in 35 (30.2%) other patients. In six (5.2%) patients the dermal infiltrate was predominantly lymphocytic, whereas it was predominantly eosinophilic in one (0.9%) patient. Intraepidermal clefting (82.2%) and acantholysis (61.1%) were present in the majority of patients, whereas subcorneal pustulosis was observed in 53.0% of patients (Table 3).

Immunopathological characteristics DIF data was available in 132/137 cases. When data was available, DIF microscopy of perilesional skin biopsy specimens showed intercellular deposition of IgA in 97.0% of patients. Isolated intercellular deposition of IgA was observed in 72.7% of patients. The concurrent deposition of IgA and IgG was observed in 10.6% of patients, whereas the deposition of IgA, IgG, and C3 was observed in 9.8% of patients. Less frequently, a combined deposition of IgA alongside with C3 and IgM was observed in 3.0% and 0.8% of patients, respectively (Table 3). 3% of patients met diagnostic criteria based on IIF confirmation demonstrating intercellular IgA deposition or IgA desmocollin/desmoglein autoantibodies identified on immunoblotting/ELISA. IIF analysis of patient sera on varying skin substrates demonstrated IgA circulating intercellular antibodies in only 66.7% of cases. The most frequently utilized epithelial substrates to detect IgA intercellular antibodies were human skin alone (28.4%) and monkey esophagus alone (13.7%), whereas the immunoassay was positive on both human skin and monkey esophagus simultaneously in 4.9% of patients (Table 3). Immunoblotting and ELISA immunoassays demonstrated lower sensitivity rates with 40% and 55% of patients having IgA reactivity to any autoantigen in immunoblotting and ELISA, respectively. Reactivity to desmoglein 3 (Dsg3) was the most frequently observed positive finding in immunoblotting (17.8%), whereas reactivity to desmoglein 1 (Dsg1) was the leading positive finding on ELISA (37.5%; Table 3). Amongst patients with oral mucosa involvement, 10 out of the 16 (62.5%) had IgA/IgG immunoreactivity against Dsg3 on immunoblotting or ELISA. To elaborate, 8 out of 10 patients showed IgA+ to Dsg3, only 2 patient had isolated IgG+ to Dsg3. Only 28 patients reported as the SPD or IEN subtype provided data regarding immunoreactivity. Eleven out of 16 (68.8%) of those SPD patients reacted to Dsc1, while other

recognized autoantigens include Dsc2 (n=4, 25%), Dsc3 (n=3, 18.8%), Dsg1 (n=2, 12.5%), and Dsg3 (n=1, 6.3%). Five out of the 12 (41.7%) patients of IEN subtype reacted to Dsg1 and other recognized autoantigens include Dsg3 (n=4, 33.3%), Dsc1 (n=2, 16.7%), and Dsc3 (n=1, 8.3%). Associated comorbidities Concomitant lymphoproliferative disorders and solid malignancies were reported in 25 (18.2%) patients (with an individual patient having two coexistent tumors). The leading associated malignancy was IgA monoclonal gammopathy (n=13; 9.5%), with two patients (1.5%) presenting with IgA type multiple myeloma. Eight out of the 13 (61.5%) patients were diagnosed with IgA gammopathy concomitantly while 5 (38.5%) patients were diagnosed with IgA gammopathy after the cutaneous eruption.

Other remarkable coexistent hematologic

malignancies were peripheral T-cell lymphoma (n=2; 1.5%), chronic myeloid leukemia (n=1; 0.7%), and diffuse large B-cell lymphoma (n=1; 0.7%; Table 4). Solid malignancies were less frequent and reported in five patients (3.6%; Table 4). A notable association with ulcerative colitis had been reported in nine (6.6%) patients. Other comorbid autoimmune diseases were Sjögren syndrome (n=2; 1.5%), Crohn`s disease (n=1; 0.7%), myasthenia gravis (n=1; 0.7%), and rheumatoid arthritis (n=1; 0.7%). Of note, three patients (2.2%) showed seropositivity to HIV (Table 4). Treatment Management data was avaialble for 80.3% of patients and oral dapsone was the most frequently utilized treatment (n= 77; 70%), followed by corticosteroids, used concurrently or as the

primary

treatment

(n=60;

54.5%),

vitamin

A

derivatives

(n=7;

0.1%),

and

immunosuppressants, such as cyclophosphamide, mycophenolate mofetil, and azathioprine.

Scatered reports described refractory cases that were managed with infliximab, adalimumab, IVIG, or plasmapheresis. Discussion We herein synthesize the clinical, histological, immunopathological features for patients with IgA pemphigus. A majority of patients presented with a pruritic vesiculopustular eruption, often organized in a circinate pattern. Most commonly affected areas were the trunk and extremities, followed by intertriginous and cephalic areas. Only a small number of patients had mucosal involvement. Almost all patients had intercellular IgA deposition detected by DIF with 10% cases showing concomitant IgA and IgG deposition, which several authors proposed as the IgA/IgG pemphigus subtype. However, the most commonly encountered subtype of IgA pemphigus was the SPD type followed by the IEN type. Clinically, IgA pemphigus more closely resembles pemphigus foliaceus (PF) than pemphigus vulgaris (PV). Compared to PF, the cutaneous lesions of IgA pemphigus had a similar prevalence of vesicles (68% vs. 80.8%), but a much higher prevalence of pustules (8% vs. 75.0%).10 In addition, IgA pemphigus lesions have a distinctive circinate configuration that exhibit central crusting with peripheral vesiculation. Although 13.2% of IgA pemphigus cases exhibited mucosal involvement, the majority of the disease was limited to the trunk, extremities, and intertriginous areas unlike the classic seborrheic pattern seen in PF. Oral mucosal involvement maybe linked to immunoreactivity against Dsg3 as the oral epithelium has preferential expression of the 130 kDa molecule of Dsg311 and 10 out of the 16 (62.5%) patients with oral mucosa involvement were found to have immunoreactivity against Dsg3 on immunoblotting or ELISA. Despite these similarities, only 25.6% of pemphigus vulgaris

patients10 present with pruritus compared to 65.6% of IgA pemphigus patients, possibly due to the increased infiltration of the epidermis by granulocytes in IgA pemphigus. The epidemiologic information on IgA pemphigus is sparse, but appears to follow that of pemphigus vulgaris and nonendemic pemphigus foliaceous, with an average age on onset of 40 to 60 years.12,13 IgA pemphigus presents at any age, with the average age being 51.5 years. Pemphigus is reported with a slight female preponderance.14 Despite the well described ethnic predispositions in PV, interpretation of ethnic predominance from systematic review is subject to publication bias and therefore not directly comparable. Thus, large-scale cross-sectional studies are needed to confirm these findings. However, no ethnic predilection emerged based on the reported cases so far. Cross-sectional studies considering pemphigus patients have found increased prevalence of hematologic malignancies, solid malignancies, other autoimmune disorders, psoriasis, and neurologic disorders.15-17 Correspondingly, 18% of IgA pemphigus patients had coexistent malignancies, with IgA monoclonal gammopathy being the most frequent association. Two of the reported cases were also diagnosed with IgA type multiple myeloma. IgA gammopathy and IgA pemphigus have long been linked but it is unclear if cutaneous manifestation precedes the gammopathy or vice versa. In our assessment, 8 out of the 13 patients with IgA pemphigus were diagnosed with IgA gammopathy concomitantly while 5 patients were diagnosed with IgA gammopathy after the cutaneous eruption. However, it is unclear if patient recall of when the cutaneous lesions first appeared and the delay in cutaneous manifestation influenced these results. Regardless, it is noteworthy that none of the patients had an established diagnosis of gammopathy prior to their cutaneous symptoms. A French study reported that 6 out of 29 patients (20.6%) were found to have concomitant IgA pemphigus and IgA gammopathy.2

Screening for associated comorbidities among patients with IgA pemphigus at initial evaluation is thus advisable.18 Another association that requires further investigation is the prevalence of gastrointestinal disorders in IgA pemphigus patients with 9 cases of ulcerative colitis and 1 case of Crohn’s disease noted in our review. The pathomechanism underlying this interaction remains unclear, though inflammatory bowel disease has been well characterized as a predisposing factor to develop epidermolysis bullosa acquisita, also a neutrophil rich AIBD.19 The histopathological features do not help definitely differentiate between IgA pemphigus and other epidermal AIBD. Most prevalent features include intraepidermal clefts, acantholysis, and subcorneal pustules in a descending order. Predominantly neutrophilic infiltration within the epidermis should prompt immunoserologic studies to exclude the diagnosis of IgA pemphigus. However, 35% of patients showed a mixed infiltrate comprising both neutrophils and eosinophils. Definitive diagnosis of IgA pemphigus is made via immunofluorescence, and in our case, almost all cases demonstrated IgA deposits or circulating anti-IgA antibodies, albeit IgG and C3 deposits were also concurrently noted. In 1996, Hashimoto et al.20 found that sera from 17 patients with IgA pemphigus demonstrated a clear distinction between immunoreactivity of SPD and IEN: Dsc-1 was the primary antigen in SPD and heterogeneous antigens were noted in IEN and IgG/IgA pemphigus. The latter observation has been further elucidated by Wang et al.21 who found nonsecretory IgA1 autoantibodies targeting Dsg1 and Dsg3 by Karpati et al.22 Our qualitative synthesis revealed detectable circulating IgA intercellular antibodies in only 66.7% of cases. Out of the 137 cases studied, only 20.5% reported as the SPD or IEN subtype also provided data regarding immunoreactivity. As previously studied, the majority of the SPD patients reacted to Dsc1 (68.8%), and other desmocollins, Dsc2 and Dsc3.23 However, it is

important to recognize that a few cases demonstrated isolated and dual reactivity to members of the desmoglein family. Given that the clinical subtype was reported by authors, we cannot confidently comment on the accuracy of the association of autoantigen reactivity and subtypes. Dsg1 and Dsg3 comprised the main autoantigens noted in IEN patients but as noted above, isolated and dual reactivity was noted with desmocollins. We

herein

characterize

the

epidemiological,

clinical,

histological,

and

immunopathological features of IgA pemphigus. Integrating the data of reported cases may provide more precise information on the characteristics of the disease and contribute to overcoming the lack of data. The main limitation of the review stems from the grounded reliance on case reports and small case series. Consequently, some of the variables were missing for numerous patients. Prospective studies are needed to confirm these findings and would allow further characterization of different subtypes based on immunoreactivity and histology.

Table 1- Demographic characteristics of the reported patients with IgA pemphigus

Sex Male patients, n (%) Female patients, n (%) Not reported, n (%)

62 (45.3%) 67 (48.9%) 8 (5.8%)

Age at diagnosis Mean (±SD)* Median (range) Mean age of male patients (±SD)* Mean age of female patients (±SD)*

51.5 (21.0) 55.5 (0.1-94) 51.3 (20.8) 52.7 (20.3)

Abbreviations: n, number; SD, standard deviation; USA, United States of America; UK, United Kingdom

Table 2- Clinical and morphological characteristics of the reported patients with IgA pemphigus * Number of reported cases ¥ Clinical subtype, n (%)reported in 103 cases Subcorneal pustular 46 (44.7%) 103 dermatoses Intraepidermal neutrophilic 41 (39.8%) 103 IgA/IgG pemphigus 12 (11.7%) 103 IgA pemphigus foliaceus* 4 (3.9%) 103 Simultaneous occurrence of 2 (1.9%) 103 IgA pemphigus and linear IgA bullous dermatosis ** Paraneoplastic pemphigus-like 1 (1.0%) 103 Pemphigus herpetiformis -like 1 (1.0%) 103 Pemphigus erythematosus 1 (1.0%) 103 like Morphology and symptoms of cutaneous lesions, n (%) Vesicles Pustules Circinate plaques Pruritus Urticarial plaques Scars/milia

101 (80.8%) 90 (75%) 75 (63.6%) 80 (65.6%) 3 (2.5%) 2 (1.6%)

125 120 118 122 121 122

Anatomical distribution of cutaneous lesions, n (%) Trunk Extremities Intertriginous Head and neck Mucosal involvement Generalized Palms and soles

101 (83.5%) 97 (80.2%) 48 (39.3%) 36 (29.8%) 16 (13.2%) 12 (9.9%) 4 (3.3%)

121 121 122 121 121 121 121

Abbreviations: n, number ¥ The right column represents the number of cases where the variable was reported or could be concluded. The ratios represent number of positive cases out of the number of reported cases. *These cases were defined as IgA pemphigus foliaceus without detecting autoantibodies. Histologically, these cases correspond to the diagnosis of subcorneal pustular dermatoses and were considered as such in the analysis. ** One of them presenting with intraepidermal neutrophilic subtype

Table 3- Immunopathological and immunological characteristics of the reported patients with IgA pemphigus *

Number of reported cases

Direct immunofluorescence, n (%) Isolated IgA intercellular deposits Combined IgA, IgG intercellular deposits Combined IgA, IgG, and C3 intercellular deposits Combined IgA and C3 intercellular deposits Combined IgA and IgM intercellular deposits Only C3 deposition** No intercellular deposition** Insufficient Data**

96 (72.7%) 14 (10.6%) 13 (9.8%) 4 (3.0%) 1 (0.8%) 1 (0.8%) 3 (2.3%) 5 (3.6%)

132 132 132 132 132 132 132 137

74 (63.8%) 1 (0.9%) 35 (30.2%) 6 (5.2%)

116 116 116 116

69 (61.1%) 88 (82.2%) 53 (53.0%) 5 (5.7%) 2 (2.3%)

113 107 100 87 87

14 (13.7%) 29 (28.4%) 5 (4.9%)

102 102 102

12 (11.8%) 34 (33.3%)

102 102

27 (60.0%) 3 (6.7%)

45 45

Predominant cells in infiltrates, n (%) Predominantly neutrophils Predominantly eosinophils Mixed neutrophils and eosinophils Predominantly lymphocytes Other histological features, n (%) Acantholysis Intraepidermal cleft Subcorneal pustule Neutrophilic microabscesses Neutrophilic spongiosis Indirect immunofluorescence analysis, n (%) Intercellular IgA autoantibodies against monkey esophagus Intercellular IgA autoantibodies against human skin Intercellular IgA autoantibodies against both monkey esophagus and human skin Intercellular IgA autoantibodies without specifying the substrate No intercellular IgA autoantibodies were detected Immunoblot analysis, n (%) Negative for IgA antibodies Anti- desmocollin 1 IgA antibodies

Anti- desmocollin 3 IgA antibodies Anti- desmocollin 1+2 IgA antibodies Anti- desmoglein 3 IgA antibodies

3 (6.7%) 3 (6.7%) 8 (17.8%)

45 45 45

ELISA, n (%) Negative for IgA antibodies Anti-desmocollin 1 IgA antibodies Anti-desmocollin 2 IgA antibodies Anti-desmocollin 3 IgA antibodies Anti-desmoglein 1 IgA antibodies Anti-desmoglein 3 IgA antibodies

18 (45.0%) 5 (12.5%) 3 (7.5%) 1 (2.5%) 15 (37.5%) 9 (22.5%)

40 40 40 40 40 40

Abbreviations: n, number; Ig; immunoglobulin; ELISA, enzyme-linked immunosorbent assay. *The right column represents the number of cases where the variable was reported or could be concluded. The ratios represent number of positive cases out of the number of reported cases. **Patients meet diagnostic criteria based on IIF confirmation demonstrating intercellular IgA deposition or IgA desmocollin/desmoglein autoantibodies identified on immunoblotting/ELISA.

Table 4- Remarkable comorbidities among the reported patients with IgA pemphigus

Hematologic malignancies/lymphoproliferative disorders, n (%)* IgA monoclonal gammopathy IgA type multiple myeloma Peripheral T cell lymphoma Chronic myeloid leukemia Diffuse large B-cell lymphoma Lymphomatoid papulosis type E Thymoma

13 (9.5%) 2 (1.5%) 2 (1.5%) 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Solid malignancies, n (%)* Lung cancer Adenocarcinoma of pancreas Laryngeal squamous cell carcinoma Ovarian cancer

2 (1.5%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Autoimmune disease, n (%) Ulcerative colitis Sjögren syndrome Crohn's disease Myasthenia gravis Rheumatoid arthritis

9 (6.6%) 2 (1.5%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Other, n (%) Human immunodeficiency viruses infection Wilson's Disease Alpha-1 antitrypsin deficiency

3 (2.2%) 1 (0.7%) 1 (0.7%)

Abbreviations: n, number; IgA; immunoglobulin A *Twenty-six different malignancies were reported among 25 patients (one individual patient had both IgA monoclonal gammmopathy and lung cancer simultaneously)

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