CLINICAL AND LABORATORY STUDIES Eosinophilic myositis

CLINICAL AND LABORATORY STUDIES
Eosinophilic myositis/perimyositis: Frequency and
spectrum of cutaneous manifestations
Ralph M. Trtieb, MD, Marcus Pericin, MD, Brigitte Winzeler, Brunello Wtithrich, MD, and
Gtinter Burg, MD Zurich, Switzerland
Background: Eosinophilic myositis/perimyositis (EM/P) are a group of rare idiopathic
muscle disorders associated with eosinophilia.
Objective: We describe the frequency and spectrum of cutaneous manifestations in EM/P
and compare them with the idiopathic hypereosinophilic syndrome (HES).
Methods: We review the literature on EM/P and describe an additional case associated
with angioedema.
Results: Of a total of 26 reported patients with EM/P, cutaneous manifestations were
observed in 10. These were, in order of frequency, deep subcutaneous induration, erythema, angioedema, urticaria, and papular lesions.
Conclusion: Skin lesions occur less frequently in EM/P than in HES. Although erythematous papulonodular lesions and urticaria/angioedema are most commonly observed in
HES, the most frequent skin manifestations of EM/P are subcutaneous induration and erythema. In HES, angioedema has been correlated with a favorable prognosis. At least some
of these patients apparently have an idiopathic eosinophilic disorder distinct from HES,
including EM/P. In contrast to HES, the overall prognosis of EM/P is good, particularly
when muscle lesions are focal, and the principal histopathologic finding is perimysial
infiltrates.
(J Am Acad Dermatol 1997;37:385-91.)
Significant elevations in the number (> 0.7 x 109
cells]L) and percentage (> 5%) of peripheral blood
eosinophils are associated with a group of idiopathic inflammatory disorders. These include both local
and multisystem diseases with variable expression
of either direct eosinophilotoxic or vasculitic tissue
damage and end-stage fibrosis. 1 Since the introduction of the term "hypereosinophilic syndrome"
(HES) by Hardy and Anderson2 and diagnostic criteria for HES by Chusid et al. 3 (persistent
eosinophilia > 1.5 x 109 cells/L for at least 6
months, with signs of organ system involvement,
without evidence of other apparent causes for
eosinophilia), it has become apparent that there are
patients with eosinophilic disorders that are clinically distinct from HES, whether the cause is
From the Department of Dermatology, University Hospital of
Zurich.
Accepted for publication April 3, 1997.
Reprint requests: Ralph M. Triieb, MD, Department of Dermatology,
University Hospital of Zurich, Gloriastr. 31, 8091 Zurich,
Switzerland.
Copyright © 1997 by the American Academy of Dermatology, Inc.
0190-9622/97/$5.00 + 0 16/1/82575
known, such as in L-tryptophan-associated
eosinophilia-myalgia and toxic oil syndrome,4 or
unknown, such as in eosinophilic fasciitis,4 episodic angioedema with eosinophilia, 5 and eosinophilic
myositis/perimyositis (EM/P). 6 EM/P encompasses
a clinically and pathologically diverse group of rare,
idiopathic, inflammatory muscle diseases associated with peripheral or tissue eosinophilia. 6 As with
the other idiopathic eosinophilic disorders, the diagnosis of EM/P is one of exclusion, and requires
exclusion of an underlying infectious process (in
particular, parasitic infestation), noneosinophilic
myopathies, and other eosinophilic disorders (such
as eosinophilia-myalgia syndrome). Although
eosinophilic myositis (EM) is well described in the
veterinary literature (it primarily affects the masticator muscles of dogsT), it has only recently been
discussed in the rheumatologic6 and dermatologic
literature. 8,9 We describe an additional patient with
EM associated with angioedema, review the literature on patients with EM/P with respect to the frequency and spectrum of cutaneous manifestations,
and compare these with the skin manifestations of
HES.
386
Journal of the American Academy of Dermatology
September 1997
Triieb et al.
T a b l e I. Characteristics o f the 10 patients with eosinophilic m y o s i t i s / p e r i m y o s i t i s and r e p o r t e d cutaneous
manifestations
Muscle manifestations
Case
No. (Ref.)
Age (yr)
Eosinophilic myositis
117
Sex
Localization
Pain
Swelling
Weakness
47
M
Lower extremities
+
+
217
55
M
Lower extremities
+
+
318
70
F
Unilateral epicondylus
+
+
49
44
F
Proximal upper/lower
extremities
+
+
5 (present report)
39
F
Upper/lower
extremities
+
+
47
M
Lower extremities
+
+
NR
715
35
M
Lower extremities
-
NR
NR
86
55
M
Lower extremities
-
+
NR
916
55
M
Proximal extremities
+
NR
NR
48
M
Upper/lower
extremities
+
+
-
Eosinophilic perimyositis
614
108
N, Normal; NR, not reported.
PATIENTS AND METHODS
Review of the literature
A MEDLINE literature search was performed for
reports on EM/P and related conditions since the 1993
review by Kaufman et al. 6 of 29 patients (not 31: cases
8 & 10 and 9 & 12 actually represent the same patients).
Patients with an apparent cause of their EM syndrome
(such as I~-tryptophan-associated eosinophilia-myalgia
syndrome and parasitic infection), as well as other welldelineated, idiopathic eosinophilic disorders, such as
eosinophilic fasciitis, systemic necrotizing vasculitis
with eosinophilia (Churg-Strauss syndrome and periarteritis nodosa), and HES were excluded. Of the cases
included in the review of idiopathic EM by Kaufman et
al., 6 the following were not included in this study:
allegedly drug-associated cases of EM (tranilast, 1° sulfisoxazolell), a single case report with a granulomatous
histology, 12 and eosinophilic polymyositis. The latter
was excluded because it represents a multisystem disease with widespread eosinophilic infiltration of tissues,
blood eosinophilia, poor response to glucocorticoid
therapy, and cardiac and thromboembolic complica-
Journal of the AmericanAcademyof Dermatology
Volume 37, Number 3, Part 1
Cutaneous
manifestations
Triieb et al. 387
Eosinophil count
(109/L)
CPK/Aidolase
Skin
histopathology
2.6
$/NR
N
1.5
$/NR
N
0.3
N/NR
NR
5.9
$/NR
Dermal
infiltrates of
eosinophils
with "flame
figures"
Moderate
perivascular
mononuclear
infiltrate
Deep subcutaneous
induration
Deep subcutaneous
induration
Erythema overlying
swelling
Pruritic urticarial lesions,
erythematous plaques
and trates of morphealike induration
Angioedema
4.6
Tense, hard, nonpitting
edema
Skin induration
2.0
N/N
NR
NR/NR
Erythema
4.5
N/NR
Angioedema
9.2
N/N
Macular erythema
overlying swollen
muscles and on the
dorsa of the hands;
palmar erythematous
papules
1.1
N/~"
tions, 12,13 suggesting--as formerly proposed14--that it
belongs to HES rather than to the variants of EM/P.
Illustrative
e a s e report
A 39-year-old white woman had a 2-year history of
episodic swelling of the face, hands, arms, feet, and
legs associated with pain and weakness of the proximal
muscles of the arms and legs. She also complained of
periarticular joint pain of the hands and knees. She had
no fever or fatigue. She denied use of any drugs,
including L-tryptophan. Alcohol consumption was
NR
Treatment
Course
Indomethacin
(75 mg/day)
Prednisone
(40 rag/day)
Prednisone
(20 mg/day)
Prednisone
(60 mg/day)
Resolution
Prednisone
(50 mg/day)
Improvement,
relapse
Indomethacin
(100 mg/day)
Prednisone
(60 mg/day)
Improvement
relapse
Improvement
Lymphoplasmacellular and
eosinophilic
infiltration of the
dermis and
subcutaneous tissue
with fibrosis
Scant dermal
Prednisone
infiltrates of
(30 mg/day)
eosinophils
NR
Prednisone
(60 mg/day)
Lymphocytic
Prednisoue
small-vessel
(15 rag/day)
vasculitis
Improvement,
relapse
Resolution
Improvement,
relapse
Improvement,
relapse
Improvement,
relapse
Improvement,
relapse
moderate, and there was no recent travel or history of
ingesting poorly cooked meat. Pertinent laboratory
findings were total eosinophil counts greater than 1.5 x
109 cells/L and elevated lactate dehydrogenase (1024
U/L; normal, < 430 U/L) and aldolase (9.2 U/L; normal, < 7.8 U/L). A bone marrow aspirate revealed
eosinophilia without evidence of myeloid dysplasia.
Investigations for parasites were negative. A biopsy
specimen of the biceps brachial muscle was interpreted
as showing eosinophilic small-vessel vasculitis. We
reviewed the specimen and found both perimysial and
388
Triieb et al.
Journal of the American Academy of Dermatology
September 1997
antinuclear antibody, syphilis, hepatitis B and C, and
Lyme disease. Further immunologic studies revealed
an elevated level of serum IgE (310 CAP kU/L; norreal, < 25 kU/L) with specific IgE reactivity (class 3:
3.5 to 17.5 kU/L) on RAST CAP FEIA (fluoroenzyme
immunoassay) testing to grass pollen, house dust mites,
and cat; the soluble interleukin-2 (IL-2) receptor level
was slightly elevated (486 U/ml; normal, < 477.0
U/ml). These were in the normal range: IgA, IgM, IgG
and IgG subclasses; C3, C4, Clq-binding capacity;
serum levels of interferon gamma, IL-1, IL-2, IL-6, and
tumor necrosis factor-c~. Findings of radiographic
chest examination, electrocardiography, and echocardiographic studies were normal.
A lesional skin biopsy specimen demonstrated a
moderate perivascular mononuclear infiltrate devoid of
eosinophils or vasculitic changes. Direct immunofluorescence was negative for fibrinogen, C3, IgG, IgA,
and IgM.
RESULTS
Clinical and laboratory findings
Fig. 1. Eosinophilic myositis with angioedema.
Eosinophilic infiltration of muscle in (A) perimysial
and (B) endomysial distribution. Note perivascular distribution without evidence of vasculitis. (Hematoxylineosin stain; original magnifications: A, X 25; B, ×
62.5.)
endomysial inflammatory infiltrates consisting of histiocytes, lymphocytes, and a large number of eosinophils
in a partly perivascular distribution without overt signs
of vasculitis (Fig. 1). The patient responded promptly
to oral prednisone 50 mg daily. Repeated attempts to
reduce the dosage resulted in recurrence of her symptoms. Further evaluation revealed angioedematous
swelling of the face and neck.
Laboratory studies revealed the following values:
erythrocyte sedimentation rate (Westergren) 4 mm/hr;
white blood cell count 25.86 x 109/L with 17.8% (4.6
x 109/L) eosinophils, 63.4% neutrophils, 16.0% lymphocytes, 1.6% monocytes, and 0.6% basophils; hemoglobin 14.8 gm/dl; hematocrit 43.5%; platelets 321 x
109/L; eosinophilic cationic protein level 270 mg/L
(normal, 1.8 to 18 rag/L); slightly elevated serum
aldolase (8.5 U/L; normal, < 7.6 U/L); and serum creafine kinase in the normal range. The results of these
tests were also normal: C-reactive protein, serum glucose, creatinine, alkaline phosphatase, AST, ALT, basal
thyroid-stimulating hormone, and routine urinalysis.
Results were negative on testing for rheumatoid factor,
The features of the 10 cases of EM/P with
reported cutaneous manifestations 6,8,9,14-18 of a
total of 26 published cases of EM/P are detailed in
Table I. All cases were characterized by eosinophilia in the peripheral circulation, the bone marrow, or
the involved muscle tissue. Depending on the localization of the eosinophilic infiltrate and whether
there was associated myofiber necrosis, EM and
eosinophilic perimyositis (EP) were differentiated;
EM indicates inflammation within the endomysium
with associated myoflber necrosis, whereas in EP
the inflammation is limited to the perimysium in
the absence of myonecrosis. 6 A summary of the
demographic, clinical, and laboratory features associated with EM/P is outlined in Table II.
The mean age at disease onset in the 26 patients
(EM: 13; EP: 13) was 43.5 years (EM: 44 years;
EP: 43 years), and the male/female ratio was 2.6:1
(EM: 2:1; EP: 3.3:1). Muscle swelling or masses
were noted in 77% of the patients (EM: 100%;
EP: 54%), with myalgia or palpable muscle tenderness in 73% (EM: 85%; EP: 62%). However,
muscle weakness was noted in only 15% of the
patients (EM: 15%; EP: 15%).
The most striking laboratory finding was prominent peripheral or tissue eosinophilia. However, in
five patients (24% of the 21 patients in whom the
absolute eosinophil counts were reported; two
patients with EP and three patients with focal
lesions of EM), the peripheral blood eosinophil
count was reported as less than 0.7 x 109 cells/L.
Journal of the American Academy of Dermatology
Volume 37, Number 3, Part 1
Triieb et al. 389
Table II. Summary of the demographic, clinical, and laboratory features in 26 patients with eosinophilic
myositis/perimyositis
Eosinophilic myositis
or perimyositis (Total)
(N = 26)
Demographic features
Mean age (yr)
Sex (M:F)
Muscle manifestations: No. (%)
Swelling/mass
Pain/tenderness
Weakness
Cutaneous manifestations: No. (%)
Induration
Erythema
Angioedema
Urticaria
Papules
Laboratory features: No. (%)
Eosinophilia
$CPK
~'Aldolase
Eosinophilic myositis
Eosinophilic perimyositis
(n = 13)
(n = 13)
43.5
2.6:1
24 (92)
20 (77)
19 (73)
4 (15)
10 (38)
5 (19)
4 (15)
2 (8)
1 (4)
1 (4)
44
2:1
13 (100)
13 (100)
11 (85)
2 (15)
5 (38)
3 (23)
2 (15)
1 (8)
1 (8)
0
43
3.3:1
11 (85)
7 (54)
8 (62)
2 (15)
5 (38)
2 (15)
2 (15)
1 (8)
o
1 (8)
16/21 (76)
10/20 (50)
5/9 (56)
8/11 (73)
8/12 (67)
3/4 (75)
8/10 (80)
2/8 (25)
2/5 (40)
CPK, Creatine phosphokinase.
Essentially all patients demonstrated eosinophilic
infiltrates in muscle biopsy specimens. Elevation
of the creatine phosphokinase was found in 50% of
the 20 patients (67% of 12 with EM; 25% of eight
with EP) for whom these measurements were
available. The serum aldolase level was elevated in
56% of the nine patients (75% of four with EM;
40% of five with EP) in whom it was recorded.
Cutaneous manifestations were observed in
38% (10 of 26): These included deep subcutaneous induration/solid edema in 19% (EM: 23%;
EP: 15%), erythemain 15% (EM: 15%; EP: 15%),
angioedema in 8% (EM: 8%; EP: 8%), urticaria in
4% (EM: 8%; EP: 0%), and papular lesions in 4%
(EM: 0%; EP: 8%). Peripheral edema was
observed in four patients.
papular skin changes, a biopsy specimen of an
erythematous lesion revealed perivascular inflammatory infiltrates of lymphocytes devoid of
eosinophils, with associated endothelial swelling
in the superficial dermal vessels, and moderate
erythrocyte extravasation compatible with lymphocytic small vessel vasculitis. 8 In a case of EM
with urticarial and erythematous lesions, later
evolving to indurated morphealike plaques, histologic examination demonstrated a striking infiltration of the dermis with leukocytes, mostly
eosinophils, and "flame figures. ''9 Finally, in our
patient with EM with angioedema, only a moderate perivascular mononuclear infiltrate devoid of
eosinophils and an absence of vasculitic changes
were noted.
Dermatohistopathologic findings
DISCUSSION
Skin biopsies were reportedly performed in 13
patients with EM/P, but positive histopathologic
findings were specified in only five patients with
skin manifestations. 6'8,9 In one case of EP associated with skin induration, a lymphoplasmacellular
and eosinophilic infiltration and fibrosis of the
dermis and subcutaneous tissue were noted15; in a
case of EP associated with erythema, scant infiltrates of eosinophils were observed in the dermis6;
in a case of EP associated with erythematous and
The term eosinophilic perimyositis was first
coined by Serratrice et al. 14 in 1980. They
described two patients with a benign relapsing
myalgia involving the legs, with perimysial
eosinophilic infiltrates, peripheral eosinophilia,
normal creatine phosphokinase levels, and no evidence of systemic involvement. They explicitly
distinguished it from the formerly reported cases of
eosinophilic polymyositis, 12 which they considered
as probably a variant of HES. Subsequently, EP
390
Tr~ieb et al.
was recognized to represent one of a pathologically diverse group of disorders affecting the muscle
or its supporting connective tissue structures with
infiltration of eosinophils. 15 Although there have
been claims of muscle involvement in eosinophilic
fasciitis, 15 EM/P is distinguished by an absence of
fascial infiltrates and prompt response to antiinflammatory therapy.
The pathogenesis of these disorders has
remained elusive. It has been proposed that, after
an undefined triggering event (e.g., trauma, physical exertion, alcohol abuse, or exposure to some
unknown toxin), there is an increase in eosinophil
production and activation, mediated by cytokines
(granulocyte-macrophage colony-stimulating factor, IL-3, IL-5) that possess eosinophilopoietic
activity and enhance eosinophilic cell survival and
function, including leukotriene production and
eosinophil degranulation. 19-22 Activation and
degranulation of eosinophils is accompanied by
the release of cytotoxic granule proteins, in particular major basic protein and eosinophilic cationic
protein, 21,22 both of which have been demonstrated either in immunofluorescence-stained sections
of muscle biopsy specimens 6 or in elevated concentrations in the serum of patients with EM/P, 8,9
respectively. The few examples of allegedly drugassociated disease (tranilast, 1° sulfisoxazole v)
and the L-tryptophan-associated eosinophiliamyalgia syndrome were excluded from this study.
Conversely, we included a report of "episodic
eosinophilia-myalgia-like syndrome in a patient
without L-tryptophan u s e ''16 as a case of EP in our
study.
Skin changes associated with EM/P were, in
order of frequency, deep subcutaneous induration
(solid edema), erythema, urticarial or angioedematous plaques, and erythematous papular
lesions. Biopsy specimens from patients with skin
lesions demonstrated scanty-to-moderate perivascular mononuclear infiltrates with a considerable
variability in the number of admixed eosinophils,
ranging from lymphocytic vasculitis devoid of
eosinophils 8 to eosinophilic cellulitis-like lesions
with widespread dermal infiltration with "flame
figures. ''9 As in HES, the cutaneous manifestations were not diagnostic either clinically or histologically.
Although in HES the skin is affected in 56% of
patients, 23 most commonly with erythematous,
pruritic papules and nodules or angioedematous
Journal of the AmericanAcademy of Dermatology
September t997
and urticarial plaques, 24 skin changes in EM/P
were present in 38% of patients, most frequently
deep subcutaneous induration, erythema, or
angioedema. Angioedema has been correlated
with a favorable prognosis in HES. At least some
of these patients are now recognized to have
benign idiopathic eosinophilic disorders that are
distinct from HES, such as episodic angioedema
and eosinophilia, 5 and EM/P with angioedema.
The overall prognosis of EM/P is excellent,
particularly when focal lesions occur and the principal histopathologic finding is perimysial infiltrates. 6 Glucocorticoids in moderate doses (10 to
60 mg/day prednisone) have been effective in virtually all patients. 6,8,9,16 Indomethacin alone has
been claimed to be effective in all of three patients
in whom it was used, 14, 15, 17 but we have not had
any success treating one patient with EM in this
manner. 9
Although not specified as such in the criteria
for the diagnosis of HES, patients with idiopathic
eosinophilic disorders with distinctive features
(i.e., limitation to specific organs, such as the skin
or muscles, and the lack of secondary eosinophilmediated cardiac damage) should be included in
the differential diagnosis of HES, although it is
unclear whether these might not actually represent
the benign end of a spectrum of HES.
The processes that lead to the accumulation of
eosinophils within specific tissue sites and to
eosinophil-mediated organ damage involve both
the presence of increased eosinophils and other as
yet ill-defined stimuli that enable eosinophils to
adhere to and transmigrate through the endothelia
in preferential organ sites. 22 The pathogenic effect
of eosinophils is evidenced by eosinophil activation and degranulation at sites of tissue injury. 25
IL-5 is an important factor that selectively controls the peripheral eosinophil number as well as
the recruitment, survivability, and function
(including degranulation and cytotoxicity) of
eosinophils at sites of inflammation. 26 Although
massive, life-long eosinophilia has occurred in IL5 transgenic mice, they have remained healthy
without evidence of the organ damage found in
HES, 27 suggesting that more than IL-5-mediated
eosinophil overproduction may be needed to
cause tissue damage (i.e., the migration of
eosinophils from the blood to the sites of the
inflammatory response). This involves the
sequential interaction of specific adhesion mole-
Journal of the American Academy of Dermatology
Volume 37, Number 3, Part 1
cules expressed by both eosinophils and vascular
endothelium. Skin-specific expression of IL-5 in
transgenic m i c e leads to a distinctive phenotype
with peripheral b l o o d eosinophilia, a m a r k e d
increase in cutaneous eosinophil infiltrates, and
eosinophilic infiltrates within the muscle. 28 The
striking similarity to a recently reported observation of E M with eosinophilic dermal infiltrates
and increased serum levels of IL-5, 9 suggests that
the overproduction of IL-5 and its localization in
specific target organs would be a candidate m e c h anism
for
explaining
eosinophilia
with
eosinophil-mediated tissue damage. Progress in
k n o w l e d g e o f the regulatory m e c h a n i s m s governing the eosinophil reaction promise m o r e sophisticated therapeutic approaches in the m a n a g e m e n t
of eosinophil-mediated disease, whether they act
on
IL-5,29-31
immune
cells
elaborating
eosinophilopoietins, or other yet to be identified
factors responsible for the entry and activation of
eosinophils within specific target tissues.
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