Clinical and pathological differences between skin‐limited IgM/IgG vasculitis and skin‐limited IgA vasculitis

Cutaneous IgM/IgG vasculitis (IgM/IgG V) is characterized by leukocytoclastic vasculitis histologically and by IgM‐ or IgG‐ perivascular deposition. However, clinical differences between IgM/IgG V and skin‐limited IgA vasculitis (IgA V) have not been fully clarified. In the present study, we assessed the clinical and histopathological differences between IgM/IgG V and IgA V.


| INTRODUC TI ON
The 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012) showed the definition of vasculitis. 1 However, CHCC2012 did not explicitly discuss the presence of skin-limited or skin-dominant forms of vasculitis.
Therefore, cutaneous small-vessel vasculitis was defined as a distinct entity differing from systemic vasculitides in the dermatologic addendum to CHCC2012. 2  IgA vasculitis (IgA V) is the most common small-vessel leukocytoclastic vasculitis(LCV). 2,3 However, the clinical differences between skin-limited IgM/IgG V and skin-limited IgA V have not been fully studied. 4 Thus, in the present study, we assessed the clinical and histopathological differences between IgM/IgG V and IgA V.

| Patients
We examined adult Japanese patients aged > 15 years with skin-

| Methods
We compared the types and localization of skin lesions between the two groups. Laboratory data, including peripheral blood counts, serum levels of IgG, IgA, and IgM, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and complement (C3, C4, and CH50), were compared. In addition, the values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, and antistreptolysin-O (ASO) were measured.
Systemic therapies and the clinical course were compared.
Histologically, cell infiltration of neutrophils, lymphocytes, eosinophils, and histiocytes, and nuclear dusts in the dermis were evaluated in four different high-power fields (HPF) (400×).
Immunohistochemical staining was performed using mono-

| Statistical analyses
Statistical analyses were performed using chi-square and two-tailed Student's t-tests, and Mann-Whitney U test. Statistical significance was defined as a p value of < 0.05.

| Clinical features
Livedo lesions were observed more often in IgM/IgG V than IgA V.
Palpable purpura appeared more often in IgA V than in IgM/IgG V patients. However, there were no differences in induration, nonpalpable purpura, ulcer, blood blisters, and erythema. Localization of the skin lesions was mostly in the lower legs in both groups. Skin eruptions limited to the lower legs were more frequently in IgM/IgG V ( Table 1). The duration from onset to biopsy was not significantly different between the two groups ( Table 1).

| Laboratory data
There were no statistical differences in peripheral blood cell counts between the two groups. IgG levels were higher than normal ranges in six patients of both groups. IgA levels were higher than normal ranges in five out of 24 IgA V (20.8%) and four out of 14 IgM/IgG V (28.6%) patients. IgM levels were higher in three out of 24 IgA V (12.5%) and 2 out of 14 IgM/IgG V (14.3%) patients. There were no differences in IgG, IgA, and IgM levels between the two groups.
Serum ASO levels were slightly elevated in two out of 19 IgA V patients tested (11%). However, no antecedent symptoms of upper respiratory inflammation were noticed in these two patients. Serum ASO levels were not elevated in all 3 IgM/IgG V patients tested.

| Histological findings
Both groups showed damage to the capillaries mainly in the upper dermis ( Figure 1). The association between the depth of affecting vessels and clinical features was not found. The numbers of infiltrated neutrophils and nuclear dusts were lower in the IgM/IgG V (Table 1).
Immunohistochemical analyses showed CD3 + , CD4 + , and CD8 + T cells infiltrated around capillaries in the upper dermis of these two groups ( Figure 1), but few CD20 + B cells and CD56 + cells. The numbers of CD3 + and CD8 + T cells were significantly higher in IgA V.
Of the 14 IgM/IgG group, 2 were positive for IgG only, 10 for IgM only, and two for both IgG and IgM on the vessels in the upper dermis by DIF study. C3 and C1q deposition was observed in the upper dermis of 10 (71.4%) and 1 (7.1%) of 14 IgM/IgG V cases, respectively. C3 and C1q deposition was observed in the upper dermis of 20 (83.3%) and 1 (4.2%) of 24 IgA V cases, respectively (Table 1).

| Treatments and clinical courses
Systemic steroids were given to IgA V patients significantly more often (

| DISCUSS ION
Skin eruptions of IgA V are characterized mainly by palpable purpura 5-8 with a predilection for the lower legs. 3,4 Although skin involvement is the most frequent in IgA V, systemic involvement is observed in 25%-70% of cases. 5,[9][10][11] Immune complex-mediated vasculitis is subdivided to LCV with or without deposition of IgA-containing immune complexes; the latter includes IgM/IgGassociated LCV. 12 IgM/IgG V patients do not show any systemic symptoms according to previous reports. 2,4,12 Thus, IgM/IgG V patients were compared to skin-limited IgA V in our study.
A recent study 4 has shown that blood blisters are significantly more frequent in IgA V than in IgM/IgG V, as well as targetoid lesions that are absent in IgM/IgG V patients. 4 This suggests that these two features may help discriminate the two forms. 4 In our study, livedo lesions appeared more often in IgM/IgG V, and palpable purpura was more common in IgA V (Table 1).
IgM deposition in IgA V lesions is correlated with renal involvement. 13 However, in our study, IgA V with additional IgM or IgG deposition were excluded to compare between pure skin-limited IgA The profiles of infiltrated cells may be related to the different clinical features between the two groups.
IgA V is usually considered as a self-limited disease with remission within 4-6 weeks in children, though adult patients require more aggressive treatment. 5 Systemic steroids were administered in 30.8% of IgA V patients as the first-line treatment. 5 In our study, systemic steroids were administered to more patients with IgA V. According to a previous report, 4 symptoms recur in 24.4% of patients with IgM/ IgG V and 35.7% of those with IgA V, and the time from onset to initial remission is significantly longer in IgA V. In the present study, the IgM/IgG V did not recur, and the time from onset to initial remission did not differ between two groups. As limitations of our study include the small sample size, further studies are required for completely assessing the differences between IgM/IgG and IgA V.

ACK N OWLED G EM ENTS
We thank Mrs. Kayoko Tanaka for technical assistance.

CO N FLI C T O F I NTE R E S T
The authors declares no conflict of interest.

D ECL A R ATI O N S EC TI O N
Approval of the Research Protocol: The study protocol was approved by the ethics committee of Gifu University Graduate School