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ORIGINAL STUDY

Clinical Significance of Immunoglobulin Deposition in
Leukocytoclastic Vasculitis: A 5-Year Retrospective Study
of 88 Patients at Cleveland Clinic
Mohamed Alalwani, MD, Steven D. Billings, MD, and Carmen E. Gota, MD
Objective: To study the diagnostic utility and clinical associations
of immunoglobulin deposition, determined by direct immunofluo-
rescence (DIF) in cutaneous leukocytoclastic vasculitis (LCV).
Methods: We performed a retrospective study of all biopsy-proven
LCV cases seen at Cleveland Clinic between 2007 and 2012. All
LCV cases in which DIF was performed were included.
Results: Of the 218 LCV cases, 106 cases had DIF performed and data
from 88 cases were available: median (SD) age 53.3 (19.4), 52% male,
64.1% white, duration of rash 5.5 (20.8) months; follow-up 14 (19.7)
months. DIF results showed any immunoglobulin and/or complement
and/or fibrinogen in 70.5%, immunoglobulin A (IgA) in 36.4%,
immunoglobulin M (IgM) in 21.6%, immunoglobulin G (IgG) in
11.4%. Patients with IgA deposition by DIF, compared with those
without IgA, were younger, 44 (19) versus 56 (17) (P = 0.006),
more likely to be white (P = 0.025) and had more organs affected
by vasculitis (P = 0.002), higher incidence of gastrointestinal tract
involvement (P = 0.0001) and renal disease (P = 0.006). No differ-
ences between rates of infection or malignancy were seen between
DIF IgA, IgM, or IgG–positive versus negative patients.
Conclusions: In patients with cutaneous LCV, IgA is the most
common immunoglobulin found by DIF. IgA deposition, but not
IgM or IgG, is predictive of associated renal and gastrointestinal
organ involvement by vasculitis. No association between the type of
immunoglobulin and preexisting infection or malignancy was found.
DIF results add information that is clinically relevant to the diagnosis
and management of LCV.
Key Words: leukocytoclastic vasculitis, direct immunofluorescence,
IgA vasculitis
(Am J Dermatopathol 2014;36:723–729)
INTRODUCTION
Leukocytoclastic vasculitis (LCV) refers to vasculitis of
small vessels in which the inflammatory infiltrate is pre-
dominantly formed by neutrophils. The conditions associated
with LCV are many and include infections, drugs,
malignancies, as well as autoimmune diseases and primary
vasculitides. The etiology of LCV cannot be guessed from the
mere appearance of the rash or from histopathologic descrip-
tion. Additional information can be obtained by performing
direct immunofluorescence (DIF) from fresh skin biopsy
samples to identify immunoglobulins, complement, and/or
fibrinogen deposited in the vessel wall, but the significance of
the type of the immunoglobulin deposited, including its
diagnostic and clinical correlations are not well known.
Immunoglobulin A (IgA) deposition has been associated with
Henoch Schönlein purpura (HSP), renamed IgA vasculitis.
1,2
IgA vasculitis (IgAV) often involves the skin, gastrointestinal
tract, and kidneys and IgA1-dominant immune deposits affect-
ing small vessels (predominantly capillary, venules, or arterio-
les).
1
A retrospective study from Massachusetts General
Hospital found that the presence of IgA deposition in LCV
biopsies confers an 84% positive predictive value and an
81% negative predictive value for the diagnosis of HSP.
3
Prominent immunoglobulin M (IgM) deposition has been asso-
ciated with cryoglobulinemia and lymphoproliferative dis-
eases.
4–6
IgM has also been reported to adhere
nonspecifically to damaged tissue,
7
thus its presence does not
always represent immune complex deposition.
The triggering factors for IgAV are not known, but
infections and malignancy have been often implicated.
8,9
The
role of infection as a triggering event in IgAV was studied
mostly in children, where 30%–65% of cases were found to
occur after an upper respiratory tract infection, without a con-
sistent causative agent being identified.
9
We performed a retrospective analysis of all consecu-
tive LCV cases identified from the Cleveland Clinic pathol-
ogy database seen within the span of 5 years to investigate the
clinical utility of DIF performed on LCV biopsies.
We asked the following questions: (1) Which is the
most common immunoglobulin present by DIF? (2) Is there
an association between the type of immunoglobulin found by
DIF and the clinical presentation? (3) Is there a relationship
between the type of the immunoglobulin found by DIF and
preceding/concomitant infection? and (4) Is there a relation-
ship between the type of the immunoglobulin found by DIF
and preexisting malignancy?
MATERIALS AND METHODS
This study was approved by the Cleveland Clinic
Internal Review Board. We retrospectively searched the
Cleveland Clinic pathology database using the term
From the Department of Orthopedic and Rheumatologic Institute, Cleveland
Clinic, Cleveland, OH.
The authors declare no conflicts of interest.
Reprints: Carmen E. Gota, MD, Desk A50, Orthopedic and Rheumatologic
Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195
(e-mail: gotac@ccf.org).
© 2014 Lippincott Williams & Wilkins
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“leukocytoclastic vasculitis.” All cases of LCV over a period of
5 years, from October 1, 2007 until September 30, 2012 were
reviewed. Included were patients having purpuric rash clini-
cally consistent with LCV, biopsy findings consistent with
LCV, and those who had DIF performed. LCV was considered
present if the pathology report indicated: evidence of vessel
wall and perivascular neutrophilic inflammation, leukocytocla-
sia, extravasated red blood cells, evidence for damage of endo-
thelial cells, and fibrinoid necrosis.
For the patients who met the inclusion criteria, patient
demographic (age, race, and gender) information, duration of
rash, extracutaneous manifestations, and follow-up were
obtained based on chart review. Renal involvement was
considered present in cases with hematuria, proteinuria, red
blood cell (RBC) casts, and/or the presence of glomerulone-
phritis by biopsy. Gastrointestinal involvement was consid-
ered in cases presenting with abdominal pain, nausea,
vomiting, diarrhea, blood in the stool without alternative
explanation, and/or evidence suggestive of mesenteric ische-
mia by imaging studies, and/or evidence of vasculitis
involving the gastrointestinal tract by pathology. All patients
with neurological involvement presented with peripheral
neuropathy. Articular complaints were attributed to vasculitis
if the onset was recent, suggestive of inflammatory arthritis,
and in the absence of an alternative explanation.
The type and number of clinical manifestations attrib-
uted to vasculitis, including skin, joints, gastrointestinal,
renal, neurological, and other manifestations were recorded.
Only manifestations compatible with vasculitis and for which
no alternative explanation was found in the patient record
were included. Any history or evidence of infection in the
month preceding the rash was recorded, as well as antibiotic
use in the same period.
Laboratory results were recorded. The type of immu-
noreactants from the DIF studies was reported. Westergren
sedimentation rate, C reactive protein, white blood cell count,
hemoglobin, platelet count, urine blood, urine protein, urine
red blood cell casts, presence/absence of monoclonal proteins
in blood or urine, cryoglobulin titer, complement C3, C4,
antinuclear antibodies (ANA), SSA/SSB antibodies, rheuma-
toid factor, and presence/absence of hepatitis C antibodies
were also recorded.
The possible clinical outcomes were defined as follows:
improved/resolved, intermittent/persistent, and death/resolved
with damage.
Statistical Analysis
Continuous measures were described by mean and SDs.
Categorical measures were summarized using percentages.
Spearman correlation coefficients were estimated to study
associations between variables. Comparisons between inde-
pendent samples were performed using Fisher exact test and
1-way analysis of variance. Statistical analysis was performed
using IBM SPSS Statistics version 21.
RESULTS
Over a period of 5 years, 218 consecutive cases have
been diagnosed with LCV by skin biopsy. DIF was performed
in 106 cases, and data for 88 patients were available for
analysis.
Table 1 presents the characteristics of LCV cases who
had DIF performed (106) and those who did not have DIF
performed (112). We found no difference in outcome between
the 2 groups. The group of LCV patients who did not have
DIF performed had significantly less organ involvement due
to vasculitis.
The demographic and clinical characteristics of the 88
patients are presented in Table 2. The median duration of rash
from the reported onset to the time of biopsy was 5.5 (20.8)
months, and the duration of follow-up was 14 (19.7) months.
Of the 88 patients in whom DIF was performed, 70.5%
were positive for immunoglobulin and/or complement and/or
fibrinogen deposition. The most common immunoglobulin
found by DIF was IgA (36.4%), followed by IgM (21.6%), and
IgG (11.4%) (Table 3). Of the 32 patients with IgA deposition,
53.9% had IgA only, without other immunoglobulins, 25%
with IgM, 3% with IgG, and 9.3% with both IgM and IgG.
To determine the significance of immunoglobulin and/
or complement and/or fibrinogen deposition in LCV, we
compared demographic, clinical, and laboratory data in the
following groups: DIF positive versus DIF negative, DIF
IgA
+
versus DIF IgA
2
, DIF IgM
+
versus DIF IgM
2
, and DIF
IgG
+
versus DIF IgG
2
.
Patients with LCV and negative immunofluorescence
were older and more likely to have objective evidence for
infection than patients with positive immunofluorescence
(likelyhood ratio, 7.4; P = 0.006). We did not find a higher
incidence of Antineutrphil cytoplasmic antibody positivity in
patients with negative DIF, and none of the cases that were
reviewed met the clinical presentation of an ANCA-associated
vasculitis. Negative immunofluorescence correlated with
a shorter duration of the rash (rho = 0.322, P = 0.002), and
weakly correlated with the number of organs affected by vas-
culitis (rho = 0.265, P = 0.006) (Table 4).
Of the 9 DIF-positive, ANCA-positive cases, 5 also
showed deposition of IgG, IgM, or both along with comple-
ment and/or fibrinogen.
Significant differences were observed between the DIF
IgA
+
and DIF IgA
2
groups (Table 5). Patients with DIF IgA
+
were younger, more likely to be white, and had significantly
more organs affected, including renal and gastrointestinal
involvement. Patients who were DIF IgA
+
also had higher
white blood cell levels compared with those who were neg-
ative. Finding of IgA deposition (but not IgG or IgM) corre-
lated with the number of organ affected by vasculitis (rho =
0.307, P = 0.0003), the presence of gastrointestinal involve-
ment (rho = 0.483, P = 0.00007), and renal involvement (rho
= 0.351, P = 0.004). We found an inverse correlation between
IgA deposition and age (rho = 0.373, P = 0.002), low C4 levels
(rho = 0.371, P = 0.009), positive ANCA (rho = 0.464, P =
0.001), or positive ANA (rho = 0.386, P = 0.004). No differ-
ences in the rates of reported infection, antibiotic therapy, and
objective evidence for infection were noted between the DIF
IgA
+
and DIF IgA
2
cases. Also, no differences in the rates of
previous or current malignancies were found between the 2
groups (Table 5). The presence of both IgA and IgM deposition
by DIF, compared with IgA
+
and IgM
2
cases, was associated
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with the presence of RBC casts in the urine (P = 0.024) (data
not shown).
Patients who were DIF IgM
+
, when compared with
patients who were DIF IgM
2
, were more likely to be ANA
positive (50% versus 20%; P = 0.024) and have RBC casts in
the urine (53.8% versus 5%; P = 0.032). No differences were
noted between groups when separated by the presence or
absence of IgG deposition.
DISCUSSION
We designed this retrospective study to understand the
significance and clinical utility of immunoglobulin deposition
in LCV. Slightly less than half of the LCV cases had DIF
performed. Although the outcomes were similar, patients with
LCV and DIF had more severe vasculitis, as indicated by
a longer duration of the rash, mean (SD) 12 (19.6) versus 5.3
(16.09) months, and higher number of organs involved,
compared with LCV patients who did not have DIF
performed. It is possible that the choice of performing
immunofluorescence in LCV patients is determined at least
in part by the suspected extent/severity of disease.
TABLE 1. Demographic and Clinical Characteristics of the LCV Cases With DIF and Those Without DIF Performed
DIF Performed DIF Not Performed P
Demographics
n 106 112
Gender (male) 49.1% 46.4% NS
Age 54.04 (18.6) 53.59 (18.97) NS
Duration of rash (mo) 12.05 (19.6) 5.3 (16.09) 0.012
Organ involvement
Joints 34.9% 10.7% 0.0001
Gastrointestinal 15.1% 1.8% 0.0001
Renal 21.7% 10.7% 0.027
Neuro 2.8% 0.9% NS
No. organs involved 0.0001
1 (skin only) 49.1% 76.8%
2 (skin and one of renal, gastrointestinal tract, neurologic, or articular) 31.1% 22.3%
3 (skin and 2 other) 14.2% 0.9%
4 (skin and 3 other organs) 4.7% 0%
Duration of follow-up 18.47 (18.75) 12.02 (17.4) 0.001
Outcome NS
Improved/resolved 80.02% 82%
Persistent/recurred 7.5% 6.3%
Deceased due to vasculitis 0.9% 0%
NS, not statistically significant.
TABLE 2. Demographic and Clinical Characteristics of 88
Patients With LCV and Positive DIF
Demographics
Age 53.3 (19.4)
Gender (male) 52%
Race 64.1% white
7.6% African
American
3.3% other
No. organs affected
1 (skin only) 43.5%
2 (skin and one of renal, gastrointestinal tract,
neurologic, or articular)
30.4%
3 (skin and 2 others) 15.2%
4 (skin and 3 other organs) 5.4%
Type of the organ affected
Skin 100%
Renal 22.8%
Gastrointestinal tract 17.4%
Neurologic 2.2%
Joints 35.9%
TABLE 3. Immunofluorescence Results in 88 Patients With
LCV
DIF Results (Positive DIF Cases) %
Negative (nonspecific immunofluorescence) 29.5
Any immunoglobulin, complement, fibrinogen 70.5
Any immunoglobulin deposition 47.7
IgM 21.6
IgM only* 4.5
IgM + IgG 3.4
IgG 11.4
IgG only 3.4
IgA 36.4
IgA only 21.6
IgA + IgM 9.1
IgA + IgG 1.1
IgA + IgM + IgG 3.4
*Only refers to no other immunoglobulins present on DIF.
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Of the 88 LCV cases with positive DIF, 70.5% were
positive for immunoglobulin deposition and/or complement
and/or fibrinogen, comparable with previous studies.
3
Differ-
ent from our data, other authors reported that in patients pre-
senting with cutaneous vasculitis, up to 100% of cases can be
found to have vascular immunoglobulin, complement and/or
fibrinogen immunofluorescence.
2
IgA was the most common type of immunoglobulin
deposited in the vessel walls, being found in 34.5% of 88
cases. The predominance of IgA deposition by DIF was
reported before; Sais and Vidaller
10
in a study of 160 patients
with histologically documented LCV, reported IgA deposi-
tion in 64.7% of cases, IgM in 49%, and IgG in 42.2% of
cases, whereas C3 was the most common immunoreactant in
TABLE 4. Comparison DIF-Negative and DIF-Positive LCV Cases
DIF Negative DIF Positive P
Age 61.2 (16.9) 50 (19.6) 0.013*
Gender (male) 13/26 (50%) 31/62 (50%) NS†
Race n = 16 n = 53 NS†
White, 14 White, 45
AA, 1 AA, 6
Other, 1 Other, 2
Outcome n = 23 n = 62 NS‡
Improved/resolved, 18 Improved/resolved, 44
Intermittent/recurrent, 5 Intermittent/recurrent, 8
Deceased/resolved with organ damage, 0 Deceased/resolved with organ damage, 6
No. organs involved n = 26 n = 61 NS‡
1 17 23
2 7 21
3 2 12
4 0 5
Organ involvement n = 26 n = 61
Joints 6 27 NS†
Renal 3 18 NS†
Gastrointestinal 2 14 NS†
Neurological 0 2 NS†
Infection history of infection in the month before skin biopsy 11/26 (42.3%) 30/62 (48.3%) NS†
Objective evidence of infection in the month before biopsy 8/11 (72.7%) 18/62 (29%) 0.008†
Antibiotic therapy in the month before skin biopsy 11/26 (41.9%) 31/62 (50%) NS‡
History of malignancy 3/26 (11.5%) 7/62 (11.29%) NS‡
Laboratory data
WSR 41.8 (35.7) 36 (34.2) NS*
CRP 5.6 (6.4) 7.1 (7.9) NS*
WBC 10.3 (6) 9.2 (4.5) NS*
Hemoglobin 12.2 (2.3) 11.8 (2.2) NS*
Platelets 241.1 (96.3) 276 (109.4) NS*
Blood-urine 12/23 (52.1%) 30/53 (56.6%) NS†
Protein-urine 11/23 (47.8%) 41/57 (71.9%) NS†
RBC casts-urine 1/23 (0.4%) 6/51 (11.7%) NS†
Monoclonal protein blood or urine 0/14 (0%) 4/24 (16.6%) NS†
ANCA positive 0/19 (0%) 9/41 (21.9%) NS†
ANA positive 3/20 (15%) 13/47 (27.6%) NS†
SSA or SSB positive 2/8 (25%) 6/28 (21.4%) NS†
Low C3 2/14 (14.2%) 8/43 (18.6%) NS†
Low C4 2/14 (14.2%) 14/44 (13.6%) NS†
Cryoglobulin positive ($51) 3/14 (21.4%) 16/34 (47%) NS‡
Cryoglobulin 188.6 (425.1) 95.9 (167.2) NS*
Hepatitis C antibody
+
1/18 (0.05%) 2/14 (5.5%) NS‡
RF
+
4/11 (36.3%) 4/26 (15.3%) NS‡
*One-way analysis of variance.
†Fisher exact test.
‡Pearson x
2
.
CRP, C reactive protein; WSR, Westergren sedimentation rate; NS, not statistically signficant.
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TABLE 5. Comparison of DIF IgA
+
Patients With DIF IgA
2
Cases
DIF IgA
2
DIF IgA
+
P
Age 56.6 (17) 44 (19.9) 0.006*
Gender (male) 13/37 (35.2%) 19/32 (59.3%) NS†
Race n = 28 n = 31 0.025‡
White, 21 White, 28
AA, 7 AA, 1
Asian, 0 Asian, 2
Outcome n = 37 n = 28 NS‡
Improved/resolved, 30 Improved/resolved, 20
Intermittent/recurrent, 5 Intermittent/recurrent, 5
Deceased, 2 Deceased, 2
Resolved with organ damage, 0 Resolved with organ damage, 1
No. organs involved n = 37 n = 31 0.002‡
1 21 (56.7%) 5 (16.1%)
2 12 (32.4%) 12 (38.7%)
3 3 (8.1%) 4 (12.9%)
Organ involvement n = 37 n = 31
Renal 11 (29.7%) 14 (45.1%) 0.006†
Gastrointestinal 1 (2.7%) 13 (41.9%) 0.0001†
Neurological 3 (8.1%) 0 (0%) 0.243†
Joints 12 (32.4%) 17 (54.8%) NS‡
Infection n = 37 n = 32
History of infection in the month before skin biopsy 16 (43.2%) 20 (62.5%) NS†
Objective evidence of infection in the month before biopsy n = 35, 10 (28.5%) n = 32, 10 (31.2%) NS‡
Antibiotic therapy in the month prior to skin biopsy n = 37, 19 (51.3%) n = 32, 16 (50%) NS‡
History of malignancy n = 37, 5 (13.5%) n = 32, 3 (9.3%) NS‡
Laboratory data
WSR 40.4 (33.2) 31.2 (33.6) NS*
CRP 7 (7.5) 7.3 (8) NS*
WBC 7.9 (3.3) 12.3 (7.3) 0.002*
Hemoglobin 11.5 (2.4) 11.8 (2.2) NS*
Platelets 254 (105.4) 286 (114) NS*
Blood-urine 15/31 (48.3%) 17/27 (69.9%) NS†
Protein-urine 20/33 (60.6%) 23/29 (79.3%) NS†
RBC casts-urine 1/29 (3.4%) 5/27 (18.5%) NS†
Monoclonal protein blood or urine 2/16 (1%) 3/10 (3%) NS†
ANCA positive 11/27 (40.7%) 0/18 (0%) 0.001†
ANA positive 14/31 (45.1%) 2/22 (9%) 0.006†
SSA or SSB positive 7/23 (30.4%) 0/8 (0%) 0.005†
Low C3 6/25 (24%) 4/23 (17.3%) NS†
Low C4 13/25 (52%) 4/24 (16.6%) 0.016†
Cryoglobulin positive ($51) 11/22 (50%) 8/16 (50%) NS‡
Cryoglobulin 135.3 (188.8) 76.9 (147.11) NS*
Cryoglobulin levels n = 22 n = 17 NS‡
0–50 (11) 0–50 (9)
51–100 (3) 51–100 (5)
101–150 (0) 101–150 (2)
151–200 (4) 151–200 (0)
$201 (4) $201 (1)
Hepatitis C antibody+ 4/29 (13.7%) 1/18 (5.5%) NS‡
RF+ 4/18 2/13 NS‡
*One-way analysis of variance.
†Fisher exact test.
‡Pearson x
2
.
CRP, C reactive protein; WSR, Westergren sedimentation rate; NS, not statistically significant.
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82.2% of LCV cases. Similarly, in a prospective study of
50 patients with vasculitis, IgA was the most common immu-
noglobulin deposited followed by IgM and IgG.
11
The issue
remains a matter of controversy, as other authors report C3,
IgM, or IgG being the most common immunoreactants.
2,5,12–14
It is possible that DIF is more likely to be performed when
there is a clinical suspicion of IgAV (HSP), and thus, the true
answer can only be found if DIF is consistently performed in
all cases of LCV.
Positive IgA deposition by DIF was found in 32 cases,
mean (SD) age 44 (19.9), 59.3% male; 45.1% had renal
disease, 41.9% had gastrointestinal tract involvement, and
had 54.8% joint involvement. These data are similar to those
of a recent retrospective study of 87 adult IgAV patients from
Mayo clinic (mean (SD) age 46.1, 59% male, 45% with renal
disease, 37% with gastrointestinal involvement, and 45%
with joint involvement).
15
Significant correlations were found between IgA, but not
IgM or IgG deposition, with the number of organs affected,
and with renal and gastrointestinal tract involvement. This, in
accordance with prior studies,
16
indicates that IgA deposition in
LCV should prompt the clinician to consider the patient as
having a systemic vasculitis, and screen for renal and gastro-
intestinal involvement. We were not able to confirm the
increased incidence of renal involvement with age in IgAV,
reported by previous studies
8,15
(data not shown).
Of the 32 IgA
+
cases, 59.3% had IgA alone, 25% had
IgA and IgM, 3% had IgA and IgG, and 9.3% had IgA with
IgM and IgG, findings that are comparable with the DIF
results in 87 HSP patients from Mayo Clinic (37% IgA and
IgM, and 3% IgA and IgG).
15
Previous reports have sug-
gested that finding of IgA deposition in combination with
IgM or IgG is nonspecific, and only cases of IgA deposition
alone are characteristic of HSP.
10
Linskey et al
3
found that of
the 26 IgA-positive HSP cases, only 1 case each had IgA and
IgM or IgA and IgG deposition. In our study, all of the 32
patients with IgA
+
LCV, alone or in combination with other
immunoglobulins, had a clinical presentation compatible with
IgAV. We found no differences between IgA-only cases, and
IgA with IgM cases with regards to renal, gastrointestinal, or
articular involvement (data not shown). Also, none of the
32 IgA
+
cases showed compelling features of other well-
defined small vessel vasculitides, such as alveolar hemorrhage,
cavitary lung lesions, destructive sinusitis, or mononeuritis
multiplex. Only 1 patient, whose initial cutaneous manifesta-
tion was consistent with LCV, and in whom DIF indicated “full
house” IgA + IgG + IgM, in perivascular distribution and in
a granular pattern along the basement membrane, which later
developed discoid lupus and type IV lupus glomerulonephritis.
Eleven of 32 DIF IgA
+
patients (34.3%), were also
positive for IgM by DIF, and although this combination
was not significantly associated with renal involvement,
hematuria, or proteinuria, the presence of IgM along with
IgA in LCV biopsies was associated with the presence of
RBC casts in the urine. In a study of 87 patients with IgAV,
of whom 37% had both IgA and IgM deposition, no associ-
ation was found of the IgM deposition with renal involvement
defined as proteinuria, hematuria, or both, or IgA deposition
on renal biopsy specimens, but the authors did not include
RBC casts in their renal evaluations.
15
In contrast, a study of
25 adult patients with HSP found 60% of patients having both
IgA and IgM deposition by DIF and reported a correlation
between the presence of IgM and renal involvement (defined
as hematuria and/or proteinuria).
17
The significance of IgM
deposition in LCV biopsies of IgAV thus remains unclear, but
we cannot exclude that IgM deposition in skin biopsies of
LCV can be a marker of renal involvement that has extended
beyond the mesangium to the glomerular capillaries, thus
presenting with nephritic urinary sediment. Deposition of
IgM has been associated with cryoglobulinemic vasculitis.
4
We found no association between the presence of cryoglobu-
lins and IgM deposition (data not shown).
Ig Deposition and Infection
The association of LCV with infections is well known; in
a 10-year retrospective review, a recent infection was men-
tioned in 32% IgA-positive and 35% IgA-negative LCV cases.
3
The association of IgAV and infection has been raised
based on the observations in children, where 30%–65% of
IgA vasculitis cases occur after an upper respiratory tract
infection, mostly in autumn and winter, and follows a self-
limited course.
18–20
In our study, infection was reported/sus-
pected in 62.5% of the 32 IgAV cases, half of which had
objective evidence for infection. No consistent causative
agent was identified, in agreement with previous data, which
has linked IgAV to a wide array of pathogens.
9
Despite these
relatively large numbers, we found no statistically significant
difference in reported infection, antibiotic use, and objective
evidence of infection in DIF IgA
+
and DIF IgA
2
cases. Sim-
ilarly, no differences regarding preceding infection were
noted between DIF IgG
+
and IgG
2
, or DIF IgM
+
and IgM
2
patients. In our study, rather surprisingly, objective evidence
for infection as indicated by positive cultures of a pathogen
within the month before the onset of the rash was more likely
to be associated with negative DIF findings in LCV biopsy,
an observation at this time of unclear significance, which
needs to be further investigated.
IgAV and Malignancy
We found not relationship between DIF findings and
a history of previous or present cancer. IgA vasculitis has
been linked to cancer in adults
21–23
; a study of 129 HSP
patients found 4.6% of patients having cancer, a higher per-
centage than in healthy controls.
24
In our study, we found no
significant difference in the rate of cancer between IgA
+
LCV
patients (3 of 32, 9.3%, 1 urothelial cancer, 1 non–small-cell
lung cancer, and 1 case of hepatoma) and IgA
2
LCV cases (5
of the 37, 13.5%, 3 breast cancers, 1 case of lymphocytic
lymphoma, and 1 case of chronic lymphocytic leukemia)
(data not shown).
Our study has several limitations, mainly its retrospec-
tive nature and the fact that less than half (47%) of all LCV
cases had DIF performed. We found it difficult to assign
precise diagnoses of specific types of vasculitides, through
retrospective chart review, and thus, we were not able to
calculate sensitivities and specificities.
For example, 1 patient with DIF IgA
+
LCV had cryo-
globulin levels of 642 tested positive for hepatitis C and SSA
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antibodies, and developed LCV in the setting of methicillin-
sensitive staphylococcal endocarditis.
It has been reported that the extension of the purpuric
rash above the waist to be suggestive of IgAV and predictive
of organ involvement.
15
Variable descriptions of the rash in
this retrospective study did not allow us to collect reliable
data regarding the extent of the rash.
Despite these limitations, our study illustrates that
IgAV in adults is not a rare occurrence, comprising at least
15% of all LCV cases and about one-third of all DIF-positive
cases. The finding of IgA, but not IgG or IgM, deposition by
DIF correlates with extent of organ involvement. It is part of
the initial evaluation of every patient presenting with
cutaneous vasculitis to ensure there is no internal organ
involvement. In IgAV, the initial cutaneous findings can be
followed weeks later by involvement of kidneys or gastroin-
testinal tract, thus the finding of IgA deposition in LCV
biopsies should prompt the clinicians to follow these patients
closely and screen repeatedly for gastrointestinal and renal
involvement.
Patients with LCV and a positive DIF are more likely to
have more internal organs affected than patients with negative
DIF, a finding that needs further investigation. It is possible
that in our case, this was driven by the high percentage of
IgA-positive cases.
We were not able to demonstrate any association
between IgA deposition and infection or malignancy. The
significance of finding IgM along with IgA in the walls of
affected skin vessels needs to be further studied, but may be
associated with a more significant level of renal involvement.
We were not able to find any clinical associations with IgM or
IgG deposition in LCV.
In conclusion, performing DIF on LCV biopsies adds
information that is clinically relevant to diagnosis and
management.
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