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Two types of inflammatory vascular disease in Sjgren's syndrome. Differential association with seroreactivity to rheumatoid factor and antibodies to Ro SS-A and with hypocomplementemia

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125 1
TWO TYPES OF INFLAMMATORY VASCULAR
DISEASE IN SJOGREN’S SYNDROME
Differential Association with Seroreactivity to Rheumatoid Factor and
Antibodies to Ro (SS-A) and with Hypocomplementemia
RODOLFO MOLINA, THOMAS T. PROVOST, and ELAINE L. ALEXANDER
Two types of inflammatory vascular disease
(IVD) occur in Sjogren’s syndrome: neutrophilic IVD
(NIVD) and mononuclear IVD (MIVD). In 45 patients
with Sjogren’s syndrome, we examined the 2 types of
IVD with respect to serologic associations. NIVD, unlike
MIVD, was significantly associated with seroreactivity
reflected by hyperglobulinemia (P = 0.01), rheumatoid
factor (P = 0.002), antinuclear antibodies ( P = 0.02),
and antibodies to Ro (SS-A) (P = 0.00006), and with
hypocomplementemia (P = 0.03). The differential association of the 2 types of IVD with serologic reactivity and
hypocomplementemia suggests that there may be basic
differences in the immunopathogenesis of these 2 forms
of IVD in Sjogren’s syndrome.
Inflammatory vascular disease (IVD) is increasingly being recognized as a complication of Sjogren’s
syndrome (SS) (1,2). Two distinct types of IVD have
been observed (2): neutrophilic IVD (NIVD) and
mononuclear IVD (MIVD). We previously reported a
Publication #570 of the O’Neill Research Laboratories,
Good Samaritan Hospital, Baltimore, Maryland.
Presented in part at the 48th Annual Meeting of the American Rheumatism Association, Minneapolis, MN, June 1984.
From the Department of Internal Medicine, Division of
Clinical Immunology and the Department of Dermatology, the Johns
Hopkins Medical Institutions, Baltimore, Maryland.
Supported in part by NIH grants HL-30748, AM-25650.
AM-28412, and AM-07324, a grant from the Kroc Foundation, and a
gift from the Estee Lauder Corporation.
Rodolfo Molina, MD; Thomas T. Provost, MD; Elaine L.
Alexander, MD, PhD.
Address reprint requests to Elaine L. Alexander, MD, PhD,
The Johns Hopkins Medical Institutions, Division of Clinical Immunology, c/o Good Samaritan Hospital, 5601 Loch Raven Blvd.,
Baltimore, MD 21239.
Submitted for publication September 14, 1984; accepted in
revised form April 22, 1985.
Arthritis and Rheumatism, Vol. 28, No. 11 (November 1985)
striking association between the presence of autoantibodies to the small molecular weight ribonucleoprotein, Ro (SS-A), and rheumatoid factor and the occurrence of vasculitis (1). In that study we also observed a
subgroup of SS patients with IVD who were seronegative. Our preliminary observations suggested that
IVD, as expressed in each of these 2 groups of SS
patients, was histopathologically distinct.
This study further examines the histopathologic
and serologic correlations of a group of 45 patients
with SS who have biopsy-documented IVD. There
was a statistically significant association of NIVD with
seropositivity for Ro (SS-A), rheumatoid factor, and
antinuclear antibodies. Conversely, MIVD was associated with seronegativity with respect to these autoantibodies. Hypocomplementemia occurred in the NIVD
group, while patients with MIVD had normal complement levels. These observations suggest that the 2
histopathologic types of IVD in SS may be mediated
by different immunopathogenetic mechanisms.
PATIENTS AND METHODS
Patient selection. Over a 5-year period (from January
1, 1979 to December 31, 1983) at the Johns Hopkins Medical
Institutions, 45 patients were selected for study from all
patients with Sjogren’s syndrome, on the basis of having
cutaneous lesions, biopsy-documented IVD, and sera available for serologic study during active cutaneous disease. All
patients were evaluated by at least 1 of the authors. Nineteen
of the patients have been included in previous studies (1,2).
Patients who met the above criteria and who also met
the American Rheumatism Association criteria for another
connective tissue disorder (CTD), such as rheumatoid arthritis (RA) (3), systemic lupus erythematosus (SLE) (4), or
progressive systemic sclerosis (9,or had dermatomyositis
(DM) or overlap syndromes, were classified as having secondary SS. Patients with classic skin lesions of SLE (i.e.,
1252
Figure 1. Neutrophilic inflammatory vascular disease involving
vessels of superficial and deep dermis. Venules and arterioles are
affected, and there is extensive necrosis of vessel walls with fibrin
deposition and extravasation of erythrocytes (hematoxylin and
eosin stained, original magnification X 180).
malar rash, discoid, subacute cutaneous, or solar-induced)
were not included in this study. In addition, no patient had
the characteristic histopathologic features of SLE: hyperkeratosis, follicular plugging, o r liquefaction degeneration of
the basal cell layer (6).
Forty-five patients with SS and IVD were studied.
The mean age was 47 years (range 13-73. Thirty-eight
patients were women, 7 were men; 35 individuals were white
and 10 were black. Thirty-five had primary SS, while 10 had
SS associated with another CTD (SLE, 5 patients; RA, 3
patients; DM, 1 patient; and overlap syndrome, 1 patient).
Forty-one patients had biopsies of cutaneous lesions,
while 4 patients had biopsies of other tissue (3 biopsies of
muscle tissue; 3 biopsies of peripheral nerve tissue). Two
patients had both nerve and muscle biopsies. Only 2 patients
had received low-dose corticosteroid therapy prior to biopsv.
All patients were symptomatic for the sicca complex
(i.e., xerophthalmia, xerostomia, o r recurrent salivary gland
enlargement). The sicca symptoms were unrelated to drug
therapy. In addition, at least 2 of the 3 following features
were required: 1) an abnormal Schirmer test result (less than
5 mm of filter paper moistening within 5 minutes), 2)
keratoconjunctivitis sicca (KCS) type A or B , defined by a
MOLINA ET AL
positive rose bengal dye test as used by Holm (7), o r 3) grade
3 o r 4 positive minor salivary gland biopsy using the scale of
Greenspan et al (8).
Histopathologic findings. Trephine biopsy specimens
of involved skin lesions, 4 mm2, were obtained following
injection with I % lidocaine without epinephrine. These
specimens and tissue from other sources were submitted for
routine pathologic examination, i.e., fixed in 10% buffered
formalin o r Bouin’s solution, embedded in paraffin, cut into
sections 6 p thick, stained with hematoxylin and eosin, and
examined with a light microscope.
All biopsy specimens were coded and examined for
the presence of IVD, without knowledge of the clinical
diagnosis o r serologic profile, by 2 of the authors (RM and
ELA) and were reviewed by another author (TTP). A
minimum of 20 blood vessels per cutaneous biopsy specimen
were examined. There was uniform interobserver agreement. Direct vessel wall invasion was required for the
diagnosis of IVD. IVD was classified as neutrophilic o r
mononuclear, as previously described ( 2 ) . NIVD was defined
as vascular disease associated with infiltration of the vessel
wall by neutrophilic inflammatory cells. For inclusion into
this category, it was required that neutrophils constitute
>S% of the total inflammatory cell population within the
vessel wall and, in addition, that at least 1 of the following
features be present: fibrinoid necrosis, lumen occlusion,
leukocytoclasis (nuclear debris o r dust), o r extravasation of
erythrocytes. This type of IVD was indistinguishable from
leukocytoclastic vasculitis (9). MIVD was defined as frank
invasion and disruption of mural integrity by mononuclear
cells (lymphocytes, plasma cells, and monocytes) with <S%
neutrophils and with at least I other accompanying feature
listed above. Vessels with perivascular cuffing alone were
not classified as showing IVD. The biopsy specimens were
scored as follows: NIVD only, MIVD only, o r both NIVD
and MIVD.
Figure 2. Early neutrophilic inflammatory vascular disease in a
dermal arteriole. Endothelial cells are swollen and distorted, with
lumen compromise. The integrity of the vessel wall architecture is
disrupted with inflammatory infiltrates containing mononuclear cells
and neutrophils. Nuclear dust is present (hematoxylin and eosin
stained, original magnification x 800).
IVD IN SS
1253
between the mean values for CH50, C3, and C4 were
determined by 2-tailed t-test.
RESULTS
Figure 3. Mononuclear inflammatory vascular disease affecting
venules and arterioles within superficial and deep dermis (hematoxylin and eosin stained, original magnification x 57)
Histopathologic findings. Two types of inflammatory cell infiltrates involving the blood vessels were
observed: NIVD (Figures 1 and 2 ) and MIVD (Figures
3 and 4). Of the total group, 23 patients (51%) had
NIVD alone, while 18 (40%) had MIVD. Four subjects
(9%) had biopsy specimens which demonstrated
individual vessels with either NIVD or MIVD, i.e.,
these patients had both types, Twenty-five patients
had more than 1 biopsy, and from 23 (92%) of these
patients, biopsies remained within the same histopathologic type. Two patients, however, demonstrated a
transition from MIVD to NIVD, while none showed
the converse.
Between 50% and 75% of the total blood vessels
per biopsy specimen were involved. All sizes of blood
vessels were involved, i.e., capillaries, venules, arterioles, and small arteries. Venules and capillaries were
uniformly involved, but in each case, at least I affected
small arteriole or artery was identified by the presence
of both thick wall and smooth muscle. In both types of
IVD, affected vessels demonstrated inflammatory
cells around the entire circumference extending from
the lumen to the periphery.
In NIVD, neutrophils were the predominant
cell type in the inflammatory infiltrate. Mononuclear
cells, however, were always present in significant
Serologic analysis. All sera were stored at -70" C
until testing. Serologic determinations were made without
knowledge of the clinical diagnosis. Rheumatoid factor was
assayed by the latex fixation method (lo), and titers >1:80
were considered positive. Cryoglobulins were determined by
the method of Gough et a1 ( l l ) , and values >2% were
considered abnormal. Antinuclear antibodies were detected
by indirect immunofluorescence using mouse liver as a
substrate (12). Sera that stained at a dilution 21:20 were
considered positive. Precipitating antibodies were determinedl by Ouchterlony double-diffusion in 0.6% agarose gel
against extracts of human spleen (Ro [SS-A]) and calf
thymus (La [SS-B], nRNP, Sm). The total hemolytic complement (CH50) assay was performed according to the
method described by Mayer (13) and was considered abnormal if <25 units. Serum C3 (70-176 mg/dl) and C4 (16-45 mg/
dl) were measured by radial immunodiffusion (14). Hepatitis
B surFace antigen (15) and surface and core antibody (16)
determinations were performed on sera from all patients and
on the cryoprecipitates from 2 patients.
Statistical analysis. Clinical, histopathologic, and serologic correlations were made only after independent assessment of each variable. Differences between the 2 types
of IVI) in the expression of clinical and serologic parameters
were analyzed using Fisher's exact 2-tailed test. Differences
Figure 4. Mononuclear inflammatory vascular disease involving a
small arteriole. Mononuclear cells surround and invade vessel which
shows lumen occlusion and erythrocyte extravasation. Lymphocytes and plasma cells are the predominant cell type (hematoxylin
and eosin stained, original magnification x 730).
MOLINA ET AL
1254
Irrespective of clinical appearance of the cutaneous
lesion, the histopathologic findings did not correlate
with the clinical expression of IVD, i.e., both histopathologic types occurred in all clinical subcategories
of skin lesions (Table 1).
Serologic correlates. The association of the 2
types of IVD with serologic parameters is presented in
Table 2. The most striking serologic correlations with
IVD involved the presence of antibodies to Ro (SS-A),
La (SS-B), and serum rheumatoid factor (RF). Twenty
of 27 patients (74%) with NIVD had anti-Ro (SS-A)
antibodies, in contrast with 2 (11%) of those with
MIVD (P = 0.00006). A similar, but less significant,
association ( P = 0.036) was seen between NIVD and
the presence of the closely related antibodies to La
(SS-B). Serum R F was present in 18 (67%) of patients
with NIVD, but in only 3 (17%) of those with MIVD ( P
= 0.002).
When analyzed further, an even stronger statistical association between NIVD and the concomitant
presence of both autoantibodies to Ro (SS-A) and R F
was demonstrated (Figure 5 ) . Sixteen (59%) of the
patients with NIVD had both antibodies to Ro (SS-A)
and RF, while no patient with MIVD had both of these
antibodies ( P = 0.000016). Twenty-two patients (81%)
with NIVD had antibodies to Ro (SS-A) or rheumatoid
factor (or both), in contrast to only 5 patients (28%)
with MIVD ( P = 0.0008).
A similar association between NIVD and hyperglobulinemia ( P = 0.01) and antinuclear antibodies
( P = 0.02) was observed. Two patients, both of whom
demonstrated a temporal transition from MIVD to
NIVD, had cryoglobulinemia. When initially studied,
1 of these patients was seronegative and subsequently
developed R F and cryoglobulins, whereas the other
patient had serum R F and then developed antibodies
to Ro (SS-A) and cryoglobulins. None of the patients
demonstrated hepatitis B virus antigen or antibody
within either their sera or cryoglobulins.
Table 1. Cutaneous manifestations in primary Sjogren’s syndrome
patients with inflammatory vascular disease of 2 histopathologic
types*
Cutaneous
manifestations
NIVD
(n = 25)
Purpura
Urticaria
Erythematous lesions
Subcutaneous nodules
12 (48)t
7 (28)
4 (16)
2 (8)
MIVD
(n = 16)
4
4
7
I
Total
( n = 41)
16 (39)
II (27)
I I (27)
3 (7)
(25)
(25)
(44)
(6)
~
NIVD = neutrophilic inflammatory vascular disease; MIVD
mononuclear inflammatory vascular disease.
+ Numbers in parentheses are percentages.
-+
=
numbers (Figure 2). While the majority of granulocytes were of the neutrophilic series, occasional eosinophils were seen. On the contrary, in MIVD, the cellular
infiltrate was composed of mononuclear cells alone
(Figures 3 and 4). The majority of cells were lymphocytes, with a smaller number of plasma cells (Figure
4). Cells with the morphology of monocytes or macrophages were also observed. Nuclear dust, karyorrhexis, fibrin deposition, and extravasation of erythrocytes
were seen more commonly in NIVD than in MIVD. In
MIVD, as in NIVD, frank occlusion of the vessel
lumen with endothelial cell swelling and proliferation
was observed.
The anatomic location of involved blood vessels in the skin included superficial and deep dermis,
subcutaneous, adipose, and connective tissue. In the 3
patients with subcutaneous nodules, vessels of the
subcutaneous adipose tissue were affected in association with an inflammatory panniculitis.
Cutaneous manifestations of inflammatory vascular disease. The most common cutaneous clinical
lesions were palpable purpura (usually of the lower
extremity), occurring in 16 patients (39%), and chronic
urticaria, occurring in 11 patients (27%). Eleven patients (27%) had erythematous lesions (macules or
papules), and 3 had subcutaneous nodules. The clinical expression of the 2 types of 1VD was similar.
Table 2. Serologic/histopathologic correlates in inflammatory vascular disease in patients with
Sjogren’s syndrome*
NIVD
(n = 27)
MIVD
(n = 18)
P
ANA
Glob.
RF
Anti-Ro (SS-A)
Anti-La (SS-B)
21 (78)t
14 (52)
18 (67)
20 (74)
12 (44)
7 (39)
2 (11)
3 (17)
2 (11)
2 (11)
0.02
0.01
0.002
0.00006
0.036
Antibodies to Ro (SS-A) and La (SS-B) determined by gel double-diffusion. ANA = antinuclear
antibodies on mouse liver substrate >1:40; Glob. = serum globulin concentrations >4 grn/dl; RF =
rheumatoid factor by latex fixation > I:80; NIVD = neutrophilic inflammatory vascular disease;
MIVD = mononuclear inflammatory vascular disease.
t Numbers in parentheses are percentages.
IVD IN SS
1255
n
N E U l R O P H I L I C I.V.D.
F1-
C:+RF & R O
D:-RF & R O
PERCENT
MONONUCLEAR I.V.D.
PER C E N f
N=18
11.1
50.2
18.6
A:RO
C:+RF
B:RF
D:-RF
(L
RO
16.6
0.0
(L
RO
72.2
Figure 5. Comparison of autoantibodies to R o (SS-A) and rheumatoid factor (RF) in rreutrophilic inflammatory vascular disease (IVD)
and mononuclear IVD in Sjogren’s syndrome patients.
There were differences in serum complement
levels between the 2 groups of IVD patients. Patients
with NIVD had significantly lower mean total hemolytic complement levels (25.2 5 11.6 units) than did
patients with MIVD (33.4 +- 10.1 units) ( P = 0.03). The
percentage of NIVD patients with abnormal CH5O
values (50%) was also higher than that of MIVD
patients (12.5%) ( P = 0.03). There were no differences
between the 2 groups in the mean C3 concentrations
(NIVD, 110.6 t 51.6 mg/dl; MIVD, 122.8 t 49.1 mg/
dl) or C4 concentrations (NIVD, 22.1 +- 15.7 hg/dl;
MIVDl, 23.6 t 10.2 mg/dl). Nor were there differences
between the 2 groups in the percentage of individuals
with abnormal values (C3 concentrations, NIVD 26%,
MIVD 9%; C4 concentrations, NIVD 53%, MIVD
35%). Of the 13 patients with decreased CH5O levels
who also had C3 and C4 determinations, however, 11
(85%) ,had decreased C4 and 8 (62%) had decreased C3
concentrations.
DISCUSSION
In this series of SS patients, 2 types of inflammatory vasculopathy (NIVD and MIVD) with distinct
serologic associations have been described. NIVD
was characterized by a striking seroreactivity with
respect to antibodies to Ro (SS-A), La (SS-B), rheumatoid factor, and antinuclear antibodies in association with hypocomplementemia. In contrast, MIVD
tended to occur in the setting of seronegativity with
respect to these autoantibodies, with normal complement levels.
NIVD, as defined in this study, was histopathologically indistinguishable from leukocytoclastic vasculitis (9) or hypersensitivity vasculitis (17). Leukocytoclastic vasculitis has previously been observed to
affect predominantly postcapillary venules, although,
less commonly, other vessels may be involved (9). In
our series, the postcapillary venules as well as larger
venules, arterioles, and small- to medium-sized arteries were affected.
The other histopathologic type of IVD observed
in SS (MIVD) is less well recognized. Soter et a1 (18)
described 2 histopathologic forms of necrotizing arteritis (Lee,neutrophilic and lymphocytic) in a series of 14
patients, 4 of whom had Sjogren’s syndrome. Monroe
et a1 (19) similarly have described 2 types of inflammatory cell infiltrates in chronic urticaria1 vasculitis. The
histopathologic findings in the inflammatory vascular
lesions described by these authors closely resemble
the 2 types of IVD described in our series.
Two major pieces of clinical evidence support
the concept that MIVD, as well as NIVD, can produce
significant alterations in blood vessel integrity. First,
both MIVD and NIVD give rise to identical clinical
expressions of cutaneous disease, including purpura,
chronic urticaria, subcutaneous nodules, and in some
cases, not reported here, infarction and ulcers (2).
Second, both types of vascular inflammation
are associated with a high frequency of serious systemic complications. In particular, central nervous
system disease, unattributable to other causes, has
been observed in 20 (44%) of the 45 SS patients in this
series and was present with equal frequency in both
types of IVD (20). Twenty-three patients (51%) had
peripheral nervous system involvement, which was
also seen in both types of IVD. Although the majority
of biopsies performed were of cutaneous lesions, the
coexistence of active nervous system disease and
biopsy-documented peripheral IVD suggests that a
similar immunopathologic process, if present in the
nervous system, may give to rise to nervous system
dysfunction.
There is also histopathologic evidence that
MIVD is a true inflammatory vasculopathy, rather
than the mere presence of mononuclear cells (lymphocytes and plasma cells) in the perivascular space (i.e.,
perivasculitis). In MIVD, there is direct vessel wall
invasion by mononuclear inflammatory cells with alterationldestruction of the normal architecture of the
vessel wall. There are hyperplasia and hypertrophy of
endothelial and smooth muscle cells and, in some
1256
MOLINA ET AL
Table 3. Histopathologic documentation of inflammatory vascular disease in 17 female patients with
Sjogren’s syndrome*
Ref.
no.
Age
Race
18
18
18
18
22
22
22
22
22
22
22
22
22
23
24
25
26
46
50
67
37
52
49
48
73
55
69
64
52
41
57
52
54
66
U
U
U
U
B
W
W
W
W
W
W
W
W
W
W
W
W
Skin lesion
Biopsv site
P
P
P
P
P. u
P
P
Skin
Skin
Skin
Skin
Muscle
Skin
Skin
Muscle
Muscle
Muscle
Muscle
Muscle
Muscle
Colon
Parotid, muscle, bowel
Muscle
Gall bladder, spleen
-
P
-
P
P
P
-
P
P
Histopathologic
diagnosis
RF
NIVD
NIVD
NlVD
MIVD
MIVD,
NIVD
MlVD
MIVD,
NIVD,
NIVD
MIVD
NlVD
MIVD
NIVD
NlVD
NIVD
NIVD,
ND
ND
ND
ND
H
L
L
H
H
H
H
H
L
H
H
H
H
NIVDt
NlVDt
MlVD
MlVD
* R F = rheumatoid factor; U = unknown; p = purpura; NIVD = neutrophilic inflammatory vascular
disease; N D = not done; MIVD = mononuclear inflammatory vascular disease; u = urticaria; H =
high-titer R F using bentonite flocculation test o r latex agglutination; L = low-titer RF.
t Transition from MIVD to NIVD.
cases, vessel lumen occlusion. Elastin-containing vessels show disruption of the internal and external
laminae. Fibrin deposition and erythrocyte extravasation, although present in some cases, are not necessarily required for significant alteration of vascular integrity. Furthermore, repeated biopsies of lesions of
varying age in the same individual over time have
consistently revealed the continued presence of MIVD
(except in cases where a transition from MlVD to
NIVD occurred).
Although IVD only recently has been emphasized as a serious and not uncommon complication of
SS (12), there is evidence that both types of IVD have
been observed previously. In 1938, only 5 years after
Sjogren’s original description of the sicca syndrome,
the case of a woman with KCS, lower extremity
purpura, and nervous system abnormalities characterized by seizures and neurotic behavior was reported
(21). A biopsy of the cutaneous lesions showed extensive mononuclear and plasma cell infiltrates of the
dermis; unfortunately, however, the presence of vascular injury was not commented upon.
Subsequently, 17 SS patients, with IVD documented by biopsy, have been described in the literature (18,22-26). The clinical, pathologic, and serologic
features of these patients, which closely resemble
those observed in our patients, are summarized in
Table 3. Purpuric skin lesions were the most frequent
cutaneous manifestation, occurring in 13 patients.
Chronic urticaria, the second most common cutaneous
manifestation in our group, occurred in I patient.
Inflammatory vascular disease was documented histopathologically in skin (5patients), muscle (9 patients),
or other tissue (3 patients). Neutrophilic inflammatory
infiltrates occurred in 13 patients and mononuclear
infiltrates were observed in 8 (4 patients had both
types of IVD). Serious systemic complications were
documented in 13 patients.
Despite the existence of 2 distinct histopathologic types of IVD, which in most cases remain
constant over time, several lines of evidence suggest
that, in some cases, there may be a transition from 1
type to another (i.e., from MIVD to NIVD). Both
types of IVD have been observed to occur in the same
patient, both in our series and in previously reported
cases (Table 3 and ref. 22). In addition, in a subset of
patients, a transition from MIVD to NIVD has been
documented not only in the present series, but also by
others (22). Neither we nor Soter et a1 (ref. 18 and Soter
NA: personal communication) have observed a temporal transition from NIVD to MIVD in patients who
have had multiple biopsies over time. Furthermore,
neutrophilic inflammatory cells always occur in the
setting of mononuclear cell vascular infiltrates (18).
This observation has been recognized, but not emphasized, in descriptions of leukocytoclastic or necrotizing arteritis (NIVD).
These observations suggest that there is a subset of patients with MlVD whose inflammatory vascular lesions may eventually evolve into a neutrophilic
IVD IN SS
form of IVD. This proposal is contrary to the traditional concept of the temporal appearance of vascular
inflanimatory cellular infiltrates. On the basis of experimental evidence obtained from the local cutaneous
infiltration of histamine (27) and the cutaneous urticarial reaction (28), it is assumed that acute arteritis,
characterized by the presence of polymorphonuclear
cells, usually precedes the development of chronic
(healing) vasculitis, characterized by mononuclear infiltrates. Similar data for the temporal evolution of
spontaneously occurring inflammatory vascular lesions in clinical settings, however, are not available.
The hypothesis that MIVD may antedate the
onset of NIVD and that the former histopathologic
prototype may develop into the latter is supported by
our observations in murine models of IVD. In chronologic (studiesof MRLlMp mice, which develop systemic necrotizing vasculitis accelerated by the lpr gene,
we have observed a similar transition from predominantly MIVD to NIVD (29). The development of
MIVD always precedes NIVD. Subsequently both
types of IVD are seen in the same animal. Ultimately,
NIVD is the predominant form of IVD. Mononuclear
cells are always a prominent component of inflammatory cell infiltrates in NIVD. Thus the evolution of
IVD in the MRL/Mp mice parallels the spectrum of
IVD seen in human patients and supports the proposed
hypothesis.
Previous studies have linked serologic abnormalities with IVD in CTD. The presence of high-titer
IgG- and IgM-RF has been associated with vasculitis
in RA (30,31). Similarly, the presence of RF has been
associated with clinical vasculitis in SLE (32). Antibodies to Ro (SS-A) antigen have been observed in the
setting of necrotizing renal vasculitis in SLE (33). In
addition, SS patients with antibodies to Ro (SS-A)
antigen and R F have been observed to have a high
prevalence of vasculitis (1). Of the SS patients with
biopsy-documented vasculitis described in the literature (Table 3), serologic data on R F were available in
13. Nine of 10 patients with NIVD had high-titer RF,
in contrast to only 1 of 3 patients in the small MIVD
group. Sufficient data were not available on antibodies
to Ro (SS-A) in these patients.
Activation of the complement pathway has
been considered as an important pathophysiologic
mechanism for the development of vasculitis. We have
observed differences in serum total hemolytic complement levels between the 2 forms of IVD. Likewise,
Soter et al (18) found hypocomplementemia more
commonly with the neutrophilic form of vasculitis.
Hypocomplementemia with urticaria1 leukocytoclastic
vasculitis also has been observed (34,35).
1257
One explanation for the association of hypocomplementemia with NIVD is the fixation of complement by immune complexes or R F and their passive
deposition in tissue or in situ fixation by complexes in
the vessel wall. Alternative explanations for hypocomplementemia in NIVD include decreased production of
complement components, increased clearance by the
reticuloendothelial system (36), genetic deficiencies of
complement which have been associated with some
forms of CTD (37,38), or alterations in erythrocyte C3
receptor density as have been reported in SLE (39).
In summary, we have observed 2 histopathologic types of IVD in SS (NIVD and MIVD), both of
which can lead to similar cutaneous manifestations
and can be associated with serious systemic complications such as nervous system disorders. Although we
do not know whether the serologic associations have
any relationship to the pathogenesis of IVD in SS
patients, the striking differences suggest that the 2
forms of IVD may be mediated by different immunopathologic mechanisms.
ACKNOWLEDGMENTS
The authors wish to express their appreciation to
Drs. Evan Farmer, Antoinette Hood, Robert Jordan, Nicholas Soter, and Daniel Synkowski for their helpful suggestions
and stimulating discussions, to Drs. Sheldon Glusman and
Donald Edlow for their generous donation of histopathologic
material, and to Denise Fritter for expert preparation of the
manuscript.
REFERENCES
1 . Alexander EL, Provost TT, Arnett FC, Stevens MB:
Vasculitis in Sjogren’s syndrome: association of antiRo(SS-A) antibodies with vasculitis, hematologic abnormalities, and serologic hyper-reactivity. Ann Intern Med
98:155-159, 1983
2 . Alexander EL, Provost TT: Cutaneous manifestations
of primary Sjogren’s syndrome: a reflection of vasculitis
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