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Clinical and pathological differences between Mikulicz's disease and

Sjogren's syndrome

Article in British Journal of Rheumatology · March 2005

DOI: 10.1093/rheumatology/keh447 · Source: PubMed

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 Rheumatology Advance Access published October 27, 2004

Rheumatology 2004; 1 of 8 doi:10.1093/rheumatology/keh447

Clinical and pathological differences between

Mikulicz’s disease and Sjögren’s syndrome
M. Yamamoto, S. Harada, M. Ohara, C. Suzuki, Y. Naishiro,
H. Yamamoto, H. Takahashi and K. Imai

Objective. Mikulicz’s disease (MD) has been included within the diagnosis of primary Sjögren’s syndrome (SS), but represents
a unique condition involving enlargement of the lachrymal and salivary glands and characterized by few autoimmune reactions
and good responsiveness to glucocorticoids. We have previously described elevated immunoglobulin (Ig) G4 in the serum of
four patients with MD. In this paper, we accumulated more MD cases and undertook clinical and histopathological analysis of
these patients to clarify differences between MD and SS.
Methods. We diagnosed seven patients with MD according to the following criteria: (i) visual confirmation of symmetrical and
persistent swelling in more than two lachrymal and major salivary glands; (ii) prominent mononuclear infiltration of lachrymal

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and salivary glands; and (iii) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and
lymphoproliferative disease. We summarized the clinical and serological characteristics (IgG subclasses and IFN-c/IL-4 ratio)
of seven patients with MD, compared with SS with glandular swelling (SSw) and without glandular swelling (SSo). After
steroid administration, we analysed changes in IgG subclasses in MD. Labial salivary gland specimens in MD, SSw and SSo
were stained with anti-IgG4 antibodies.
Results. The concentration (
S.D.) of IgG4 was 1169.7
892.2 mg/dl in MD, 24.4
7.0 mg/dl in SSw (P<0.005) and
82.6
189.7 mg/dl in SSo (P<0.005). The IFN-c/IL-4 ratio was 0.392
0.083 (0.78
0.23/2.14
0.31 IU/pg) in MD,
0.004
0.002 (0.20
0.07/57.02
14.05 IU/pg) in SSw (P<0.05) and 0.012
0.009 (0.58
0.86/116.24
207.65 IU/pg) in
SSo (P<0.05). The concentration (
S.D.) of IgG4 in MD decreased to 254.0
50.3 mg/dl (P<0.05) after glucocorticoid
treatment. Histopathologically, only MD was associated with prominent infiltration of IgG4-positive plasmacytes into
lachrymal and salivary glands.
Conclusion. Mikulicz’s disease is quite different from SS clinically and histopathologically. MD is suggested to be an
IgG4-related systemic disease.
KEY WORDS: Immunoglobulin 4, Interferon , Interleukin 4, Mikulicz’s disease, Sjögren’s syndrome.

In 1888, Johann von Mikulicz-Radecki reported a case with
bilateral, painless and symmetrical swelling of the lachrymal,
parotid and submandibular glands [1]. Schaffer linked the case
with obvious diseases, such as sarcoidosis and lymphoma,
presenting these symptoms as Mikulicz’s syndrome and idiopathic
cases as Mikulicz’s disease (MD) in 1927 [2]. In 1933, Sjögren
summarized 19 cases with keratoconjunctivitis sicca, two of which
displayed swelling of major salivary glands [3]. The concept of
Sjögren’s syndrome (SS) was established after this report. In 1953,
Morgan and Castleman examined specimens from 18 cases
diagnosed with MD. Finding that both MD and SS were histo-
logically similar, they announced that most cases reported as MD
could be considered as SS [4]. Since then, the recognition of MD as
a subtype of SS has taken root, and there have been no more case
reports of MD. However, many studies of the relationship between
MD and SS have been undertaken in Japan. In SS, minor salivary
glands display infiltration by mononuclear cells and resolve
with corticosteroid administration, but salivary function does not
recover [5]. This is attributed histopathologically to the presence of
numerous apoptotic cells in minor salivary glands in SS. However,
Tsubota et al. recently reported that the frequency of gland
cell apoptosis is significantly decreased in MD [6, 7]. We have
also encountered some cases with severe and persistent swelling
of the lachrymal and salivary glands that were diagnosed as
SS following biopsy of the labial salivary glands. However,
sialography did not show the apple-tree sign typically seen in SS.
Salivary function was either normal or improved on glucocor-
ticoid administration. We therefore considered that these cases
represent MD. We have previously described elevated IgG4 levels
in the serum of these patients [8]. We therefore undertook further
clinical and histopathological analysis of the differences between
MD and SS.
Materials and methods
We first summarized the clinical characteristics of our MD patients
and measured serum IgG subclasses and cytokines of patients
with MD, SS with glandular swelling (SSw) and without glan-
dular swelling (SSo), and patients with only a dry mouth who
were not diagnosed as having SS (DY). Next, we examined the
changes in IgG subclasses in the MD group according to
steroid therapy. Finally, we analysed gland specimens immuno-
histologically.

First Department of Internal Medicine, Sapporo Medical University School of Medicine, Hokkaido, Japan.

Submitted 11 July 2004; revised version accepted 21 September 2004.

Correspondence to: M. Yamamoto, First Department of Internal Medicine, Sapporo Medical University School of Medicine, South 1-West 16,
Chuo-ku, Sapporo, Hokkaido 060-8543, Japan. E-mail: mocha@cocoa.plala.or.jp
1 of 8
Rheumatology British Society for Rheumatology 2004; all rights reserved
2 of 8 M. Yamamoto et al.
Patients and materials
Analyses were performed in seven patients with MD (two men,
five women) who consulted doctors at Sapporo Medical University
and its related facilities between April 1997 and October 2003. MD
was diagnosed according to the following criteria: (i) persistent
(longer than 3 months) symmetrical swelling of more than two
lachrymal and major salivary glands; (ii) prominent mononuclear
infiltration of lachrymal and salivary glands; and (iii) exclusion of
other diseases presenting glandular swelling, such as sarcoidosis
and lymphoproliferative disease. Another 14 patients with primary
SS were diagnosed in accordance with the revised European
criteria [9]. The five patients in the SS group presented lateral
lachrymal or salivary gland swelling (SSw), and anti-SS-A anti-
bodies were detected serologically. Serum samples from SSw
patients were collected when the patients presented glandular
swelling. The 12 patients with DY were also used as controls.
Serum samples were obtained before and after therapy, and stored
at –80 C. Formalin-fixed paraffin-embedded blocks of minor sali-
vary gland tissue from the above groups were analysed. Blocks of
the lachrymal and submandibular glands, cervical lymph nodes
and bone marrow from patients with MD were also examined.
Written consent for use of the information from these cases
was obtained from the patients in accordance with the Declaration
of Helsinki.
Nephelometry
Pretherapy serum levels of IgG subclasses from the patients
were measured with a Behring nephelometer (Dade Behring,
Deerfield, IL, USA) using IgG subclasses (BS-NIA IgG1–4; The
Binding Site, Birmingham, UK) as antibodies for 0.4 ml serum
samples. Diluted samples (N-dilution liquid; Oriental Yeast,
Japan, in 1:20–100) of standard and control sera were introduced
into the reaction tubes of the nephelometer. Appropriate anti-IgG
subclass reagents and reaction buffer (N-responsive buffer liquid;
Oriental Yeast, Tokyo, Japan) were added. Dispersion strength,
according to irradiation from a light-emitting diode, was measured
at a wavelength of 840 nm and contrasted with dispersion by
available light after 10 s and 6 min. IgG subclass concentrations in
test samples were calculated relative to calibration curves, obtained
using nephelometric IgG subclass standard sera. A control serum
was assayed to confirm the validity of calibration curves and the
accuracy of IgG subclass determinations. Next, the post-therapy
samples from three patients with MD were used to measure IgG
subclass levels. We examined the changes in IgG subclasses in the
MD patients according to steroid therapy.
Enzyme-linked immunosorbent assay
Interferon (IFN) was determined using sera from five patients
with MD, five patients with SSw, five patients with SSo and 12
patients with DY. IFN- was measured using a Human IFN-
ELISA kit (BioSource, Sunnyvale, CA, USA). Standards, controls
and samples (50 l) were introduced into the appropriate micro-
plate wells and 50 l of biotin conjugate was added, and the wells
were incubated for 1.5 h. Each reacted well was washed to remove
unbound IFN- . We added 100 l of streptavidin–horseradish
peroxidase working solution to each well, and incubated for
45 min. Each well was washed. Stabilized chromogen (100 l) was
added, and the wells were incubated for 30 min. Then 100 l of stop
solution was introduced into the wells and coloured reaction
product was measured photometrically at 450 nm. The concen-
trations of IFN- in test samples were calculated relative to
calibration curve values.
Chemiluminescent enzyme immunoassay
Interleukin (IL)-4 was measured in the serum of five patients
with MD, five patients with SSw, nine patients with SSo and 12
patients with DY using the methods described by Kricka [10].
Chemiluminescent enzyme immunoassay was performed in micro-
plate wells. Wells were coated with unlabelled monoclonal anti-
IL-4 antibodies (mouse anti-human IL-4 antibody; BD
Biosciences, Pharmingen, San Diego, CA, USA) and washed.
Test samples and standard (recombinant IL-4 protein; R & D
Systems, Minneapolis, MN, USA) and control sera were intro-
duced into the appropriate wells and incubated. Reacted wells were
washed to remove unbound IL-4. Secondary antibodies (biotiny-
lated anti-human IL-4 antibody; BD Pharmingen) were added to
each well and unbound conjugate was removed by washing. Plates
were incubated with substrate solution and luminosity was
measured. The concentrations of IL-4 in test samples were
calculated relative to calibration curve values and the IFN- /IL-
4 ratio was then calculated.
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Immunohistochemistry
For all immunostainings, each monoclonal antibody was reacted
for 24 h at 4 C with steam after endogenous peroxidase activity
had been stopped in each section. Primary antibodies comprised
anti-IgG4 antibodies (mouse anti-human IgG4; The Binding Site)
diluted 1:500. Secondary antibodies (biotinylated anti-mouse IgG
[HþL]; Vector Laboratories, Burlingame, CA, USA) were diluted
1:500. Nuclear staining was performed using haematoxylin after
indirect peroxidase staining in labial salivary gland specimens from
the patients with MD, SSw, SSo and DY. Lachrymal and
submandibular glands, cervical lymph nodes and bone marrow
from the patients with MD were also examined. Next, gland
specimens from patients with MD were stained using anti-CD138
antibodies (CD138; Biogenesis, Poole, UK) diluted 1:250 to
identify IgG4-producing cells.
Statistical analysis
The Mann–Whitney U test was used for comparisons of data
between subject groups, and P values of <0.05 were considered
statistically significant. Statistical processing was performed using
StatView version 5.0 software (SAS Institute, Cary, NC, USA).
Results
Patient profiles
Background characteristics of the patients with MD are shown
in Table 1 . Mean age was 66.71
5.31 years. Their symptoms were
not consistent with the revised European criteria for SS [9],
although specimens of swollen lachrymal and minor salivary
glands displayed severe mononuclear infiltration. Salivary function
was only slightly decreased (Saxon’s test, 1.96
2.14 g/2 min), and
was improved (post-therapy improvement, 535.60
485.70%)
following administration of glucocorticoids. (The mean dose of
prednisolone started at 40 mg/day and decreased to 5–10 mg/day.
The steroid treatment was continued because of recurrent glan-
dular swelling.) Sialography yielded normal results, and the apple-
tree sign, which is typical of SS, was not seen. Half of the MD
patients did not have keratoconjunctivitis sicca. Although cases 2,
4 and 7 displayed the presence of anti-nuclear antibody, and cases 2
and 4 also displayed hypocomplementaemia and they did not
satisfy the criteria for systemic lupus erythematosus [11].
Serologically, mean total IgG level was 3835.9
2702.7 mg/dl in
MD. No case of MD displayed anti-SS-A or anti-SS-B antibodies.
Cases 1 and 4 were complicated with retroperitoneal fibrosis, and
cases 2 and 5 exhibited tubulointerstitial nephritis.
 Differences between Mikulicz’s disease and Sjögren’s syndrome 3 of 8

TABLE 1. Background data for patients with MD

Saxon-t (g/2 min)

Case Age (yr), sex Before treatment After treatment KCS IgG (mg/dl) IgG4 (mg/dl) ANA SS-A SS-B Complications
1. 70, F n.d. n.d. (þ) 2011 228 () () () Retroperitoneal fibrosis
2. 72, M 1.23 4.63 (þ) 9470 2940 (þ) () () Tubulointerstitial nephritis
3. 69, F 0.24 2.98 () 1860 409 () () ()
4. 68, F 5.46 4.15 (þ) 2630 1160 (þ) () () Retroperitoneal fibrosis
5. 64, M 2.43 4.18 () 5100 1360 () () () Tubulointerstitial nephritis
6. 68, F 0.42 3.41 (þ) 2960 1280 () () ()
7. 56, F n.d. n.d () 2820 811 () () ()

Saxon-t, Saxon’s test; KCS, keratoconjunctivitis sicca; ANA, antinuclear antibody; SS-A, anti-SS-A antibody; SS-B, anti-SS-B antibody;
n.d., not done.

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FIG. 1. Serum IgG subclasses in MD and SS. Serum IgG4 levels were significantly higher and serum IgG1 levels were significantly
lower in MD than in SS. MD; Mikulicz’s disease, SSw; Sjögren’s syndrome with glandular swelling, SSo; Sjögren’s syndrome without
glandular swelling. Bars represent standard deviations.

IgG subclasses
Serum IgG subclasses of these patients, as measured by nephe-
lometry, are shown in Fig. 1. The IgG4 level was 1169.7

892.2 mg/dl in MD, 24.4
7.0 mg/dl in SSw (P<0.005), 82.6

189.7 mg/dl in SSo (P<0.005) and 41.1
34.4 mg/dl in DY
(P<0.0005). IgG4 as a percentage of total IgG was
29.99
9.68% in MD, 1.28
0.82% in SSw (P<0.005),
2.47
4.71% in SSo (P<0.005) and 3.49
2.85% in DY
(P<0.0005).
Cytokines
Before therapy, IFN- concentration was 0.78
0.23 IU/ml in
MD, 0.20
0.07 IU/ml in SSw (P<0.01), 0.58
0.86 IU/ml in SSo
(P ¼ 0.12) and 0.092
0.090 IU/ml in DY (P<0.005) (normal
value <0.1 IU/ml). The IL-4 level was 2.14
0.31 pg/ml in MD,
57.02
14.05 pg/ml in SSw (P<0.05), 116.24
207.65 pg/ml in
SSo (P<0.005) and 3.00
1.31 pg/ml in DY (P ¼ 0.10) (normal
value <4.0 pg/ml). The IFN- /IL-4 ratio was 0.392
0.083 in MD,
0.004
0.002 in SSw (P<0.05), 0.012
0.009 in SSo (P<0.05)
and 0.040
0.039 in DY (P<0.005).
Changes in IgG subclass levels following
glucocorticoid therapy
Figure 2 shows the changes in IgG subclasses following steroid
therapy in MD. The IgG4 level decreased from 1820.0

975.1 mg/dl to 254.0
50.3 mg/dl (P<0.05) after treatment, and
IgG4/total IgG percentage declined from 37.20
2.78 to 19.39

8.29% (P<0.05). The IgG1 level decreased from 1706.7
854.9 to
656.7
231.3 mg/dl (P<0.05) after therapy, but the ratio increased
from 36.23
0.70% to 45.86
5.44% (P<0.05).
Immunohistochemistry
Anti-IgG4 antibody staining showed that the specimens from the
minor salivary glands in MD revealed numerous IgG4-producing
cells infiltrating around acinar and ductal cells (Fig. 3a). Specimens
from patients with SSw (Fig. 3b), SSo and DY showed no IgG4-
producing cells. In MD patients, numerous infiltrating cells with
IgG4 were recognized in the lachrymal and submandibular
glands (Fig. 4a, b). Large numbers of cells with IgG4 were also
apparent in lymphoid tissue, such as lymph nodes and bone
marrow (Fig. 4c, d). IgG4-producing cells in the glands were
identified as plasma cells on anti-CD138 antibody staining.
Discussion
It is usually the gland of SS that is repeatedly swelling. MD
presents with bilateral and persistent swelling of the lachrymal and
salivary glands, but since the findings of Morgan and Castleman
were published in 1953 it has been considered as being included
under primary SS or as a subtype of primary SS. Our cases of MD
patients displayed a gender ratio of 1:2.5 (M:F). In SS the ratio is
about 1:20 [12]. In the present study, keratoconjunctivitis sicca was
present in only half of all patients with MD, and the symptoms
were very mild. The sialography in patients with MD did not show
the apple-tree sign in any. This apple-tree sign represents contrast
4 of 8 M. Yamamoto et al.
FIG. 2. Changes in serum IgG1 and IgG4 after steroid therapy in
MD. (a) Serum concentrations of both IgG1 and IgG4 from
patients with MD decreased after treatment. (b) The ratio of
serum IgG1 to total IgG was significantly increased and the
IgG4/total IgG ratio was significantly decreased after corticos-
teroid administration.
FIG. 3. Minor salivary glands in MD and SS. Anti-IgG4 antibody stain, 200. (a) Specimens of minor salivary glands in MD
revealed abundant IgG4-bearing mononuclear cells infiltrating around acinar and ductal cells. (b) Specimens of labial salivary
glands in SS showed no infiltrating cell with IgG4. This figure may be viewed in colour as supplementary data at Rheumatology
Online.
medium filling out from salivary acini and ducts of severely
degenerated or destroyed glands in SS [13]. The present results
seem to indicate a lack of glandular destruction in MD. This
suggestion would explain two other clinical and histopathological
observations. First, salivary function in MD improved significantly
after steroid therapy, whereas SS is considered unable to be
improved using corticosteroids [5]. Second, gland cells in MD
display less apoptosis, as noted by Tsubota [6, 7], while SS is
associated with apoptosis due to autoimmune disease. These
findings strongly suggest that MD represents an entity separate
from clinical and histopathological SS.
Serological analyses revealed that no case with MD displayed
anti-SS-A or -SS-B antibodies, instead displaying elevated IgG4
concentrations, which is one of serological characteristics of MD.
Our analysis revealed that IgG4 in the patients with MD
constituted about 30% of total IgG, which was quite an unusual
finding. We could not find this phenomenon in other any
connective tissue disease [8], including SSw. In healthy adults,
relative serum concentrations of the human IgG subclasses are as
follows: IgG1>IgG2>IgG3 ¼ IgG4 [14, 15]. In Japanese popula-
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tions, mean levels for each IgG subclass are as follows: IgG1, 65%;
IgG2, 25%; IgG3, 6%; IgG4, only 4% [16]. The Japanese
population shows almost no differences from other populations
in the percentages of Ig subclasses to total IgG. IgG4 is not
generally associated with differences in sex and age, and both the
IgG4 level and the IgG4/total IgG ratio are basically constant [17].
The physiological role of IgG4 remains unknown, except for
actions as a blocking antibody in allergic reactions, as seen in the
present study. IgG4 usually responds to allergens, especially to
polysaccharides [18]. However, we are still looking for the antigen
responsible for the increased IgG4 in MD. It may only be increased
in some responses.
In the regulation of IgG4 production, Jeannin found that iso-
type switching to IgE or IgG4 in B cells needs two signals, namely
Th2-type cytokines such as IL-4 and IL-13, and interactions
between CD40 on B cells and CD40 ligand on T cells [19].
Production of IgG4 for mononuclear cells in vitro increased with
elevated IFN- /IL-4 ratio and decreased with a low IFN- /IL-4
ratio [20, 21]. Our measurements showed that the IFN- /IL-4 ratio
 Differences between Mikulicz’s disease and Sjögren’s syndrome 5 of 8

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FIG. 3. Continued.

FIG. 4. Other glands and lymphoid tissues in MD. Anti-IgG4 antibody stain. (a) Numerous mononuclear cells with IgG4 are apparent
in the lacrymal glands. Magnification 200. (b) Abundant plasma cells with IgG4 are present around the lymphoid follicles in
the submandibular glands. Magnification 200. (c) IgG4-bearing cells are apparent in the cervical lymph nodes. Magnification 400.
(d) Cells with IgG4 are present in bone marrow. IgG4-producing cells are thus present in both central and peripheral lymphoid tissues.
Magnification 400. This figure may be viewed in colour as supplementary data at Rheumatology Online.
 Downloaded from http://rheumatology.oxfordjournals.org/ by guest on June 3, 2013
M. Yamamoto et al.

FIG. 4. Continued.
6 of 8
 Differences between Mikulicz’s disease and Sjögren’s syndrome
FIG. 4. Continued.
was very high in MD, and raised IgG4 production was considered
dependent on the high IFN- /IL-4 ratio.
Infiltrating cells in the lachrymal and salivary glands of SS are
known to predominantly comprise IgG- and IgA-bearing plasma-
cytes [22]. We revealed that IgG4-bearing plasmacytes were
abundant in the lachrymal and salivary glands in MD, histologi-
cally. Moreover, in the present study we found this phenomenon in
the central and peripheral lymphoid tissues of the patients with
MD. However, our analysis could not detect any plasma cells with
IgG4 in specimens from patients with SSw, SSo or DY. This seems
to confirm that MD represents a quite different entity to SS. This
finding suggests that MD is not a disease that occurs only in
lachrymal and salivary glands, and it is possible that MD is a
systemic disease.
In the present study, we showed that the pathogenesis MD
involves IgG4. Elevated concentrations of IgG4 are known to be
present in pemphigus vulgaris [23], pemphigus foliaceus [24] and
some types of sclerosing pancreatitis [25]. Oliveira found that
IgG4-related immune complexes was involved in the pathogenesis
of some membranous nephropathies [26, 27]. Recent analyses of
antigens for IgG4 have revealed that desmoglein 3 represents the
antigen in pemphigus vulgaris, while desmoglein 1 is the antigen in
pemphigus foliaceus [23, 24]. These antigens are adhesion mole-
cules that help to maintain skin structures. IgG4 can act as a
pathogenic antibody [23, 24]. The amount of IgG4 may be reflected
in the severity of pemphigus vulgaris [28], and also in MD activity.
Autoimmune pancreatitis has recently been the focus of interest in
pancreatology. Abdominal computed tomography shows a diffuse
pancreas or limited swelling of the pancreas, and endoscopic
retrograde cholangio-pancreatography discloses a sclerosing pan-
creatic duct. The condition has good responsiveness to glucocorti-
coids, unlike the usual chronic pancreatitis. Serologically, there is
also hypergammaglobulinaemia, especially elevated IgG4 [25].
7 of 8
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It is known that autoimmune pancreatitis with elevated IgG4 is
sometimes complicated by retroperitoneal fibrosis [29], sclerosing
cholangitis [30], and so on. Kamisawa et al. proposed a new
concept of ‘IgG4-related autoimmune disease’ around autoim-
mune pancreatitis, placing the emphasis on the importance of IgG4
in the pathogenesis [31]; also included here are Riedel’s thyroiditis
[31], tubulointerstitial nephritis [32] and seronegative SS (SS
without anti-SS-A or -SS-B antibodies) [31].
We consider that there are some problems in the concept of
‘IgG4-related autoimmune disease around autoimmune pancrea-
titis’. The cases of seronegative SS reported by Kamisawa et al. may
be equivalent to what we have described as MD. Some of our MD
cases displayed complications of retroperitoneal fibrosis and tubu-
lointerstitial nephritis, but autoimmune pancreatitis was not seen.
In future, we intend to examine the role of the elevated IgG4 in
the pathogenesis of MD, and the relationships between MD and
the IgG4-related autoimmune diseases discussed above.
Our research disclosed that MD represents an IgG4-related
systemic disease that differs substantially from SS. The lachrymal
and salivary secretion in MD can be expected to improve following
adequate treatments. We consider that the administration of MD
must be considered separately from that of SS.
Key messages
Rheumatology
 Mikulicz’s disease is quite different from
Sjögren’s syndrome both clinically and
histopathologically.
 Mikulicz’s disease is suggested to be an
IgG4-related systemic disease.
8 of 8 M. Yamamoto et al.
The authors declare that they have no conflicts of interest with
regard to the publication of this study.
References
1. Mikulicz J. Über eine eigenartige symmetrische Erkrankung der
Tranen und Mundspeicheldrusen. Stuttgart: Beitr Chir Fortsch
Gewidmet Theodor Billroth, 1892:610–30.
2. Schaffer AJ, Jacobsen AW. Mikulicz’s syndrome: a report of ten
cases. Am J Dis Child 1927;34:327–46.
3. Sjögren H. Zur Kenntnis der Keratoconjunctivitis Sicca. Acta
Ophthalmol 1933;Suppl. II:1–151.
4. Morgan WS, Castleman B. A clinicopathologic study of ‘Mikulicz’s
disease’. Am J Pathol 1953;29:471–503.
5. Zandbett MM, van den Hoogen FH, de Wilde PC, van den Berg PJ,
Schneider HG, van de Putte LB. Reversibility of histological and
immunohistological abnormalities in sublabial salivary gland biopsy
specimens following treatment with corticosteroids in Sjögren’s
syndrome. Ann Rheum Dis 2001;60:511–3.
6. Tsubota K, Fujita H, Tsuzaka K, Takeuchi T. Mikulicz’s disease and
Sjögren’s syndrome. Invest Ophthalmol Vis Sci 2000;41:1666–73.
7. Tsubota K, Fujita H, Tadano K, Onoda N, Tsuzaka K, Takeuchi T.
Abnormal expression and function of Fas ligand of lacrimal glands
and peripheral blood in Sjögren’s syndrome patients with enlarged
exocrine glands. Clin Exp Immunol 2002;129:177–82.
8. Yamamoto M, Ohara M, Suzuki C et al. Elevated IgG4 concentra-
tions in serum of patients with Mikulicz’s disease. Scand J Rheumatol,
in press.
9. Vitali C, Bombardieri S, Jonsson R et al. European Study Group on
Classification Criteria for Sjögren’s Syndrome: classification criteria
for Sjögren’s syndrome: a revised version of the European criteria
proposed by the American–European Consensus Group. Ann Rheum
Dis 2002;61:554–8.
10. Kricka LJ. Chemiluminescent and bioluminescent techniques. Clin
Chem 1991;37:1472–81.
11. Hochberg MC. Updating the American College of Rheumatology
revised criteria for the classification of systemic lupus erythematosus.
Arthritis Rheum 1997;40:1725.
12. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol
2001;2:777–80.
13. Rubin P, Holt JF. Secretory sialography in disease of the major
salivary glands. Am J Roentgenol 1957;77:575–98.
14. Shakib F, Stanworth DR. Human IgG subclasses in health and
disease. Ric Clin Lab 1980;10:561–80.
15. French M. Serum IgG subclasses in normal adults. Monogr Allergy
1986;19:100–7.
16. Sakiyama Y. IgG deficiency [in Japanese]. Med Immunol 1989;17:
105–10.
View publication stats
17. Lock RJ, Unsworth DJ. Immunoglobulins and immunoglobulin
subclass in the elderly. Ann Clin Biochem 2003;40:143–8.
18. Aalberse RC, Schuurman J. IgG4 breaking the rules. Immunology
2002;105:9–19.
19. Jeannin P, Delneste Y, Lecoanet-Henchoz S, Gretener D, Bonnefoy JY.
Interleukin-7 (IL-7) enhances class switching to IgE and IgG4 in the
presence of T cells via IL-9 and sCD23. Blood 1998;91:1355–61.
20. Carballido JM, Carballido-Perrig N, Oberli-Schrammli A, Heusser
CH, Blaser K. Regulation of IgE and IgG4 responses by allergen
specific T-cell clones to bee venom phospholipase A2 in vitro. J Allergy
Clin Immunol 1994;93:758–67.
21. Akdis M, Akidis CA, Weigl L, Disch R, Blaser K. Skin-homing
CLAþ memory T cells are activated in atopic dermatitis and regulate
IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation
by CLAþ memory T cells. J Immunol 1997;159:4611–9.
22. Lane HC, Callihan TR, Jaffe ES, Fauci AS, Moutsopoulos HM.
Presence of intracytoplasmic IgG in the lymphocytic infiltrates of the
minor salivary glands of patients with primary Sjögren’s syndrome.
Clin Exp Rheumatol 1983;1:237–9.
23. Parlowsky T, Welzel J, Amagai M, Zillikens D, Wygold T. Neonatal
Downloaded from http://rheumatology.oxfordjournals.org/ by guest on June 3, 2013
pemphigus vulgaris: IgG4 autoantibodies to desmoglein 3 induce skin
blisters in newborns. J Am Acad Dermatol 2003;48:623–5.
24. Warren SJ, Arteaga LA, Rivitti EA et al. The role of subclass
switching in the pathogenesis of endemic pemphigus foliaceus. J Invest
Dermatol 2003;120:104–8.
25. Hamano H, Kawa S, Horiuchi A et al. High serum IgG4 con-
centrations in patients with sclerosing pancreatitis. N Engl J Med
2001;344:732–8.
26. Oliveira DB. Membranous nephropathy: an IgG4-mediated disease.
Lancet 1998;351:670–1.
27. Oliveira DB. The immunopathogenesis of membranous nephropathy.
Minerva Med 2002;93:323–8.
28. Ayatollahi M, Joubeh S, Mortazavi H, Jefferis R, Ghaderi A. IgG4
as the predominant autoantibody in sera from patients with active
state of pemphigus vulgaris. J Eur Acad Dermatol Venereol 2004;18:
241–2.
29. Fukukura Y, Fujiyoshi F, Nakamura F, Hamada H, Nakajo M.
Autoimmune pancreatitis associated with idiopathic retroperitoneal
fibrosis. AJR Am J Roentgenol 2003;181:993–5.
30. Ichimura T, Kondo S, Ambo Y et al. Primary sclerosing cholangitis
associated with autoimmune pancreatitis. Hepatogastroenterology
2002;49:1221–4.
31. Kamisawa T, Funata N, Hayashi Y et al. A new clinicopathological
entity of IgG4-related autoimmune disease. J Gastroenterol 2003;
38:982–4.
32. Takeda S, Haratake J, Kasai T, Takaeda C, Takazakura E. IgG4-
associated idiopathic tubulointerstitial nephritis complicating auto-
immune pancreatitis. Nephrol Dial Transplant 2004;19:474–6.