ORIGINAL STUDY
Spectrum of Cutaneous Vasculitis in Eosinophilic Granulomatosis With Polyangiitis (Churg–Strauss): A Case Series Masafumi Ishibashi, MD,*† Yoshie Kawahara, MD, PhD,‡ and Ko-Ron Chen, MD, PhD*
Background: The diverse histopathologic spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (EGPA, Churg–Strauss syndrome) has not been well described. Methods: Fifteen skin biopsy specimens from 9 EGPA patients with histopathologically proven necrotizing vasculitis were reviewed clinicopathologically. Results: Among 8 patients with dermal small vessel vasculitis, neutrophilic vasculitis was observed in 2 myeloperoxidase (MPO)antineutrophil cytoplasmic antibodies (ANCA)–positive patients, whereas the remaining 6 MPO-ANCA–negative patients showed eosinophilic vasculitis in 3 and a mixed infiltrate of neutrophils and eosinophils in another 3 patients. Five patients with muscular vessel vasculitis showed vasculitis at different inflammatory stages in separate or coexisting at the same biopsied skin lesions: acute stage (eosinophilic vasculitis), granulomatous stage (granulomatous vasculitis), and healed stage. Coexistent small vessel and muscular vessel vasculitis was found in 4 patients.
Conclusions: The histopathologic spectrum of dermal small vessel vasculitis in EGPA ranges from eosinophilic vasculitis with negative MPO-ANCA at one end to neutrophilic vasculitis with positive MPO-ANCA at the other end. The affected vessels ranging from dermal small vessels to subcutaneous muscular vessels in addition to the MPO-ANCA phenotype may account for the many facets of vasculitis in EGPA. Key Words: eosinophilic vasculitis, neutrophilic vasculitis, granulomatous arteritis, phlebitis, leukocytoclastic vasculitis, myeloperoxidase antineutrophil cytoplasmic antibody (Am J Dermatopathol 2015;37:214–221)
INTRODUCTION Churg–Strauss syndrome, now renamed eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that occurs most often in patients with preexisting From the *Department of Dermatology, Saiseikai Central Hospital, Tokyo, Japan; †Department of Dermatology, Nippon Kokan Hospital, Kawasaki, Japan; and ‡Department of Dermatology, Keiyu Hospital, Yokohama, Japan. The authors declare no conflicts of interest. Reprints: Ko-Ron Chen, MD, PhD, Department of Dermatology, Saiseikai Central Hospital, 1-4-17, Mita, Minato-ku, Tokyo 108-0073, Japan (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
214
| www.amjdermatopathology.com
asthma and blood and tissue eosinophilia.1 Vessels involved in cutaneous vasculitis in EGPA like vessels of vasculitis in extracutaneous lesions1 are predominantly small vessels such as arterioles and venules. However, deep dermal vessels to subcutaneous muscular vessels of small-sized arteries and veins may be involved.2,3 In 39%–59% of patients, EGPA is associated with antineutrophil cytoplasmic antibodies (ANCAs).4,5 Proteinase 3-ANCA (PR3-ANCA) is identified primarily in patients with granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis), whereas myeloperoxidase (MPO)-ANCA is predominantly detected in patients with microscopic polyangiitis and EGPA. In EGPA, ANCA-negative patients usually present with eosinophilic infiltration in tissues such as the lungs, heart, and gastrointestinal tract; by contrast, ANCA-positive patients tend to present with a vasculitic disease pattern such as glomerulonephritis, pulmonary hemorrhage, and mononeuritis multiplex.6,7 However, many points remain unclear concerning the role of ANCA in the development of EGPA. Cutaneous lesions have been observed in approximately two-thirds of EGPA patients.3,8 Palpable purpura is the most common lesion. Other cutaneous manifestations include infiltrated erythema, erythematous papules, cutaneous or subcutaneous nodules, urticaria, livedo reticularis, digital gangrene, and bullous lesions.2,3,8 Because the skin is the most easily accessible organ for obtaining biopsy samples, skin lesions may frequently contribute to an early diagnosis of EGPA. However, in a few reports,8–10 the cutaneous histopathology of EGPA has roughly been described as dermal leukocytoclastic vasculitis, tissue eosinophilia, and granuloma formation. To date, the histopathologic spectrum of cutaneous vasculitis such as different types of predominant cellular infiltrate and different levels of vessels affected in EGPA has not been noted. The purpose of this study was to focus on the histopathologic variations of cutaneous vasculitis and its correlation with MPO-ANCA and extracutaneous organ involvement in EGPA. This study also provides an excellent model for determining the histopathology of cutaneous vasculitis by understanding the wide spectrum of cutaneous vasculitis in EGPA.
MATERIALS AND METHODS We analyzed the clinical and histopathologic features of EGPA patients who met both the American College of Rheumatology 1990 criteria for diagnosis of EGPA11 and the Chapel Hill Consensus Conference 2012 definition for EGPA.1 Skin biopsy specimens were obtained from 14 Am J Dermatopathol Volume 37, Number 3, March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Cutaneous Vasculitis in EGPA
patients fulfilling these criteria and definition: 10 from Saiseikai Central Hospital, Tokyo, 3 from Keiyu Hospital, Yokohama, and 1 from Nippon Kokan Hospital, Kawasaki. Among 14 patients, 15 skin biopsy specimens with histopathologically proven vasculitis from 9 patients (64%) were included in the study. The remaining 5 patients without histopathologic evidence of vasculitis showed mild to severe perivascular infiltration of eosinophils, however without evidence of vessel wall fibrinoid necrosis. We examined the medical records of all patients with biopsy-proven cutaneous vasculitis. Full blood cell counts, renal and liver function tests, urine analysis, immunoserological tests for ANCA, antinuclear antibodies, rheumatoid factors and immunoglobulins, stool for occult blood, electrocardiogram, chest radiograph, and a nerve conduction velocity study for patients with suspected peripheral nerve neuropathy were performed. Echocardiography or gastrointestinal endoscopy was also performed, depending on the clinical indications. To obtain adequate lesional tissue for identifying vasculitis in dermal or subcutaneous lesions, one or more biopsy specimens from skin lesions
were obtained by the appropriate biopsy procedure (eg, punch biopsy or incisional biopsy for palpable purpura and deep incisional biopsy for lesions with livedo reticularis and for nodular lesions). Histopathologic diagnosis of dermal small vessel vasculitis required angiocentric inflammatory infiltrates with fibrinoid necrosis of the affected vessel walls.12,13 The diagnostic criteria for muscular vessel vasculitis required both (1) perivascular and intravascular infiltration of muscular vessel wall by inflammatory cells and (2) intramural fibrin deposition and/or intramural muscular layer destruction.13 Diagnosis for healed stage of arteritis with internal elastic lamina destruction was confirmed by elastic fiber staining.12 Recuts of serial sections from tissue blocks were stained with elastic tissue staining (elastica van Gieson, elastica hematoxylin and eosin) to confirm the type of affected vessels, respectively. Assessments of the involved dermal small vessels were based on the presence of the internal elastic lamina (ie, arterioles) or the absence of the internal elastic lamina (ie, venules), as confirmed by elastic tissue staining.12 The distinction between muscular vessels of arteries or veins from the deep dermis to
TABLE 1. Demographic, Clinical, and Laboratory Features in EGPA Patients With Cutaneous Vasculitis
Case 1 2 3 4 5 6 7 8 9 All
Sex
Age at Diagnosis (yr)
Eosinophils (cells/mL)
F 79 2040 F 50 20,800 M 38 7000 M 46 11,650 F 50 6120 M 49 23,700 F 67 2840 F 50 13,500 M 67 7710 M/F: 4/5 55.1 6 13.0 10,600 6 7580
Blood Eosinophils Eosinophilia (%) .10% MPO-ANCA Asthma 13.5 73 47 61 46 65.5 33 62 47 49.8 6 18.3
+ + + + + + + + + 9 (100%)
+ (74) 2 + (151) 2 2 2 2 2 + (592) 3 (33%)
Proteinuria Peripheral Renal and Palpable Erythematous Case Neuropathy Involvement Hematuria Eruptions Purpura Vesicle Bullae 1
+
2
2
+
2
3
+
+
+ (LE, UE) + (LE)
4 5
+ +
2 2
+ (LE) + (LE)
6
+
2
+ (LE, UE)
+ + + 9 (100%)
2 2 2 1 (11%)
7 8 9 All
2 + 2 + + + 2 + + 6 (67%) Nodular Erythema/ Subcutaneous Nodules
Lung Involvement: Transient Pulmonary Infiltrates
Ear–Nose–Throat Symptoms
+ + + + 2 + 2 2 + 6 (67%)
2 + 2 + + 2 + + 2 5 (56%)
Other Skin Lesions Livedo reticularis (LE)
+ (LE, UE) + (LE, UE)
+ (LE)
Hemorrhagic blister (LE)
+ (LE) + (LE) + (LE) 7 (78%)
2 (22%)
EM-like eruptions (LE)
2 (22%)
Treatment
Outcome
GC
CR
GC
CR
GC
CR
GC GC
CR CR
GC
CR
GC GC GC GC; 9 (100%) CR;
CR CR CR 9 (100%)
These patients fulfilled the American College of Rheumatology 1990 criteria for EGPA and the Chapel Hill Consensus Conference 2012 definition of EGPA. CR, clinical remission; EM, erythema multiforme; GC, glucocorticoid; LE, lower extremities; UE, upper extremities.
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.amjdermatopathology.com |
215
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Ishibashi et al
the subcutis layer was based on the amount and distribution of elastic fibers in the medial muscular layer of the vessel wall and on the smooth muscular pattern and the presence or absence of the internal elastic lamina.12,14 The intensity of the inflammatory infiltrate was evaluated in and around the affected vessel wall, as follows: “absent,” “mild,” “moderate,” or “severe.” Fisher tests were used to compare clinical symptoms and histopathologic findings of cutaneous vasculitis in ANCA-positive patients and ANCA-negative patients. A Pvalue of ,0.05 (by 2-tailed testing) was considered to indicate statistical significance.
RESULTS Nine patients (4 men and 5 women) with an age of onset between 38–79 years (mean age of 55.1 years) were enrolled. Table 1 summarizes the clinical characteristics of the patients. Three patients have been described previously.15–17
Extracutaneous Manifestations and Laboratory Findings
microliter with a mean value of 10,600 cells per microliter. Three of the 9 patients (33%) were MPO-ANCA–positive. There was a trend toward higher levels of peripheral eosinophils count in MPO-ANCA–negative patients in comparison with those in MPO-ANCA–positive patients [mean (SD) eosinophils (cells/mL): 13,100 (8100) vs. 5580 (3090); P = 0.09], although there was no statistically significant difference (Table 2).
Cutaneous Manifestations Table 1 shows the cutaneous manifestations of each patient. Palpable purpura was the most common type of cutaneous lesion in 7 patients (78%) (Fig. 1A). There were a variety of other cutaneous lesions such as erythematous vesicles or bullae (2 patients) (Fig. 1B), nodular erythema or subcutaneous nodules (2 patients), hemorrhagic bullae (1 patient), livedo reticularis (1 patient) (Fig. 1C), and erythema multiforme-like eruption (1 patient). All patients had skin eruptions on the lower extremities. Three patients had cutaneous lesions on the upper extremities.
Histopathologic Analysis
Asthma was present in 6 (67%) of the 9 patients (Table 1). Six patients had lung involvement, which was characterized by transient pulmonary infiltrates without evidence of pleural effusion. Ear, nose, and throat involvements, which manifested as chronic sinusitis or allergic rhinitis were seen in 5 patients (none of MPO-ANCA–positive patients and 5 MPO-ANCA–negative patients, 0% vs. 83%, respectively; P = 0.048) (Table 2). Peripheral neuropathy (most often mononeuritis multiplex) was present in all 9 patients. No patient had cardiac involvement such as impaired wall motion. Gastrointestinal hemorrhage was not present in any patient. One MPO-ANCA– positive patient had renal disease with persistent proteinuria (.1 g per 24 hours) and macrohematuria; however, renal disease was not present in any MPO-ANCA–negative patients. All patients had leukocytosis with eosinophilia (.10%). The absolute eosinophil count ranged from 2040 to 23,700 cells per
The following 2 patterns of cutaneous vasculitis were identified: (1) dermal small vessel vasculitis in 11 specimens from 8 patients (2 specimens from 2 MPO-ANCA–positive patients and 9 specimens from 6 MPO-ANCA–negative patients) and (2) muscular vessel vasculitis in 7 specimens from 5 patients (3 specimens from 2 MPO-ANCA–positive patients and 4 specimens from 3 MPO-ANCA–negative patients) (Table 3). Different levels of vasculitis presenting as dermal small vessel vasculitis or subcutaneous muscular vessel vasculitis were seen in separate lesions, respectively (1 patient, case 3) or even coexisting in the same skin lesion (3 patients).
Dermal Small Vessel Vasculitis Fibrinoid necrosis of the vessel wall occurred more often in venules lacking an internal elastic lamina (Figs. 2A–C) than in arterioles with a disrupted internal elastic lamina (Fig. 2D). The predominant cellular infiltrates ranged from eosinophils to
TABLE 2. Correlation of Clinical Symptoms With MPO-ANCA Status in 9 EGPA Patients With Cutaneous Vasculitis Mean (SD) age at onset [range], yr Mean (SD) eosinophils (cells/mL) Ear–nose–throat symptoms, n (%) Lung involvement, n (%) Asthma Transient pulmonary infiltrate Peripheral neuropathy, n (%) Renal involvement, n (%) Skin conditions, n (%) Palpable purpura Erythematous vesicles/bullae Nodular erythema/subcutaneous nodules Livedo
MPO-ANCA–Positive (n = 3)
MPO-ANCA–Negative (n = 6)
61 (21) [38–79] 5580 (3090) 0
52 (8) [46–67] 13,100 (8100) 5 (83)
1 (33) 3 (100) 3 (100) 1 (33) 3 (100) 2 (67) 0 1 (33)
5 (83) 3 (50) 6 (100) 0 6 (100) 5 (83) 2 (33) 1 (17)
1 (33)
0
P 0.53 0.09 0.048* 0.23 0.46 .0.99 0.33 .0.99 .0.99 0.5 .0.99 0.33
*P , 0.05.
216
| www.amjdermatopathology.com
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Cutaneous Vasculitis in EGPA
FIGURE 1. Skin lesions in cutaneous vasculitis in EGPA. A, Palpable purpura on the lower extremities in case 9. B, Palpable purpura mixed with hemorrhagic bullae and tense bullae on the lower extremities in case 5. C, Livedo reticularis on the lower extremities in case 1.
neutrophils. Neutrophilic vasculitis characterized by a prominent infiltrate of neutrophils with marked nuclear debris were seen in 2 ANCA-positive patients but in none of the ANCAnegative patients (100% vs. 0%, respectively; P = 0.04) (Fig. 2A) (Table 4). Eosinophilic vasculitis of dermal small vessels (primarily of venules) characterized by an exclusively eosinophilic infiltrate without nuclear debris was present in 3 of 6 ANCA-negative patients (50%) (Fig. 2B) but in none of the ANCA-positive patients. Mixed infiltrate of neutrophils and eosinophils was present in the remaining 3 ANCA-negative patients (Figs. 2C, D).
Muscular Vessel Vasculitis Muscular vessel vasculitis was found at dermosubcutaneous junction to subcutis (Figs. 3A, B). Two patients (1 ANCA-positive patient and 1 ANCA-negative patient) had inflammatory cells with a predominant infiltrate of eosinophils in and around the muscular vessel wall with destruction of muscular layers in the arteries or veins (Fig. 3A). The involved arteries showed disruption of the internal elastic lamina. Granulomatous arteritis with a predominant infiltrate of histiocytes mixed with multinucleated giant cells was present in 1 MPO-ANCA–positive patient (Fig. 3B), and granulomatous phlebitis was present in 2 MPO-ANCA–negative patients. Healed arteritis characterized by scant inflammation with marked intimal fibrosis and disruption of internal elastic lamina was found in 2 patients (Table 3).
Inflammatory Stages of Muscular Vessel Vasculitis The morphological evolution of muscular vessel vasculitis in EGPA has been classified into acute, granulomatous, and healed stages. Coexistence of different stages of muscular vessel vasculitis could be found in different or in the same skin lesion (Table 3). Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Acute stage: a predominant infiltrate of eosinophils in and around the affected muscular vessel walls (Fig. 3A). Granulomatous stage: a predominant infiltrate of histiocytes and multinucleated giant cells in and around the vessel walls (Fig. 3B). Healed (scar) stage: there is absent or scant inflammation with intimal fibrous thickening resulting in luminal occlusion.
Renal Involvement and Relationship to Cellular Infiltration and ANCA Serological Phenotype Renal involvement (eg, persistent proteinuria and macrohematuria) was only present in 1 MPO-ANCA–positive patient who had a predominant infiltrate of neutrophils and marked leukocytoclasis in and around the affected dermal small vessels (ie, neutrophilic vasculitis) (case 3, Tables 1 and 3). By contrast, 8 patients without renal failure had dermal small vessel vasculitis (7 patients) or subcutaneous granulomatous arteritis (1 MPO-ANCA– positive patient). Among 7 patients with dermal small vessel vasculitis without renal involvement, a predominant infiltrate of neutrophils was significantly found in 1 ANCA-positive patient; however, a predominance of eosinophilic infiltration was seen in 3 of 6 ANCAnegative patients and a mixed infiltrate of eosinophils and neutrophils was seen in the remaining 3 ANCAnegative patients.
Tissue Eosinophilia and Extravascular Granuloma Tissue eosinophilia was seen in all of 9 patients [3 ANCA-positive patients and 6 ANCA-negative patients (Table 3)]. Extravascular palisading granuloma with central www.amjdermatopathology.com |
217
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Ishibashi et al
TABLE 3. Correlations of Skin Lesions and Histopathologic Features in EGPA With Cutaneous Vasculitis Type of Vasculitis (Location of Vasculitis) Dermal Small Vessel 11 Specimens (8 Patients) Case
Neu
Eos
Muscular Vessel 7 Specimens (5 Patients)
Mixed (Neu and Eos)
Eosinophilic
Granulomatous
Scarred Vessels
1 A B
Arteritis (SC) Arteritis (SC)
Healed arteritis (SC)
2 A
Venulitis/arteriolitis (D)
B C
Venulitis (D) Venulitis (D)
Phlebitis (DSJ)
3 A B
Venulitis (D) Arteritis (DSJ)
4 5
Venulitis (D) A B
Venulitis (D) Venulitis (D) Phlebitis (DSJ)
6 7
Venulitis (D, SC) A
Venulitis (D) Arteritis/phlebitis (SC) Phlebitis (DSJ)
B 8 9 All specimens (patients)
Healed arteritis/ phlebitis (SC)
Venulitis (D) Venulitis (D) ANCA+: 2 (2) ANCA2: 0 (0)
ANCA+: 0 (0) ANCA2: 4 (3)
ANCA+: 0 (0) ANCA2: 5 (3)
ANCA+: 1 (1) ANCA2: 2 (1)
ANCA+: 2 (1) ANCA2: 2 (2)
ANCA+: 1 (1) ANCA2: 1 (1)
Cellular Composition of the Infiltrate Case
Neu
Eos
His
Tissue Eosinophilia
Palisading Granuloma
Biopsied Skin Lesion
A B
2 2
+ 2
++ ++
+ +
Livedo (LE; R) Livedo (LE; L)
A
++ + ++ +++
++ ++ ++ +++
+ ++ + +
++
Purpura (LE)
++ +++
Purpura (LE) Erythematous vesicle (UE)
A B
+++ 2 +
+ +++ +
2 + 2
+ +++ +
Purpura (LE) Nodule (palm) Purpura (LE)
A B
2 2 2 ++
++ +++ + ++
+ + ++ 2
++ +++
Purpura (LE) Hemorrhagic bullae (LE)
++
Purpura (LE)
2 2 2
++ ++ ++
+ + +
++
Subcutaneous Nodule (LE; L)
1
2
B C 3
4 5
6 7 A B
218
| www.amjdermatopathology.com
++
Eosinophilic degeneration
Subcutaneous nodule (LE; R)
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Cutaneous Vasculitis in EGPA
TABLE 3. (Continued ) Correlations of Skin Lesions and Histopathologic Features in EGPA With Cutaneous Vasculitis Cellular Composition of the Infiltrate Case
Neu
Eos
His
8 9 All specimens (patients)
2 +++
++ +
2 2
Tissue Eosinophilia
Palisading Granuloma
Biopsied Skin Lesion
++ Purpura (LE) + Purpura (LE) ANCA+: 5 (3); ANCA2: 10 (6) ANCA+: 0 (0); ANCA2: 1 (1)
D, dermis; DSJ, dermo-subcutaneous junction; Eos, eosinophils; L, left; LE, lower extremities; His, histiocytes; Neu, neutrophils; R, right; SC, subcutis; UE, upper extremities. Intensity of the inflammatory infiltrate: “2” = absent, “+” = mild, “++” = moderate, “+++” = severe.
infiltration of degenerated eosinophils surrounded by histiocytes was seen in 1 of 9 patients (Table 3) (case 7).
DISCUSSION EGPA usually presents in 3 phases: the prodromal phase characterized by asthma with or without allergic rhinitis, the eosinophilic phase characterized by eosinophilia in the blood and tissue, and the vasculitic phase. The vasculitic phase may occur in multiple organs, including the nerves, lungs, heart, gastrointestinal tract, kidneys, and skin. The prevalence of ANCAs in EGPA is less consistent than in GPA or microscopic polyangiitis and is reported in approximately 40% of patients.3,18 It was recently demonstrated that different clinical phenotypes could be observed based on the presence or absence of ANCA; this suggests that there are various disease mechanisms in the pathogenesis of EGPA.6,18 Compared with ANCA-negative patients, ANCA-positive patients more frequently have peripheral neuropathy, pulmonary
hemorrhage, and renal involvement with necrotizing crescentic glomerulonephritis and less frequently have myocarditis, pleural effusion, and pulmonary infiltrates.7 Patients with EGPA with renal involvement seem to have a significantly higher frequency of MPO-ANCA positivity,10 as seen in the patient with MPO-ANCA positivity with renal involvement in our study (case 3). From these findings, it has been hypothesized that a primarily vasculitic disease pattern in EGPA is strongly associated with MPO-ANCA, whereas a predominant pathological feature of tissue eosinophilia with the resultant tissue deposition of extracellular eosinophilic cytotoxic granular proteins is generally ANCA negative, although vasculitis may be observed less often.7 ANCA seem to have a pathogenic role in vasculitic lesions, possibly through the interaction of activated neutrophils with endothelial cells. As an alternative, activated eosinophils are able to interact with vascular endothelial cell and result in eosinophil-induced small vessel vasculitis, especially in ANCA-negative patients with EGPA (Fig. 2B).
FIGURE 2. Dermal small vessel vasculitis in EGPA. A, Histopathologic findings of palpable purpura on the leg of case 9 shows dermal neutrophilic vasculitis, which is characterized by a predominant infiltrate of neutrophils with marked nuclear debris. B, Fully developed dermal eosinophilic vasculitis, characterized by an infiltrate, is composed almost exclusively of eosinophils without nuclear debris from palpable purpura lesion in case 8. C, A biopsy specimen from palpable purpura on the leg of case 6 shows venulitis with a mixed infiltrate of neutrophils and eosinophils. D, A biopsy specimen from palpable purpura on the leg of case 2 shows arteriolitis with a mixed infiltrate of neutrophils and eosinophils. Elastic tissue staining shows disrupted internal elastic lamina. Hematoxylin–eosin stain (A, B, and C); original magnification: A and C, ·100; B, ·400. Elastica hematoxylin–eosin stain (D); original magnification: ·200. Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.amjdermatopathology.com |
219
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Ishibashi et al
TABLE 4. Correlation of Predominant Cellular Infiltrates With MPO-ANCA Status in EGPA Patients With Cutaneous Vasculitis Dermal Small Vessel Vasculitis Inflammatory Infiltrates Neutrophil-dominant Eosinophil-dominant Mixed infiltrates (neutrophils and eosinophils) Granulomatous
Muscular Vessel Vasculitis (Arteritis/Phlebitis)
MPO-ANCA–Positive MPO-ANCA–Negative (n = 2) (n = 6) 2 (100) 0 0
0 3 (50) 3 (50)
0
0
P 0.04* 0.46 0.46 .0.99
MPO-ANCA–Positive MPO-ANCA–Negative (n = 2) (n = 3)
P
0 1 (50) 0
0 1 (33) 0
.0.99 .0.99 .0.99
1 (50)
2 (66)
.0.99
*P , 0.05.
Eosinophils and deposition of eosinophil granule proteins have been observed in and around the affected blood vessel walls in documented cases of cutaneous eosinophilic vasculitis in either idiopathic vasculitis19 or in connective tissue disease-associated vasculitis.20 Activated eosinophils generate the leukotriene C4, which increases vascular permeability. Cytotoxic eosinophilic granule proteins (eg, major basic protein, eosinophil-derived neurotoxin, and eosinophil cationic protein) may moreover be responsible for damaging endothelial cells and the subsequent development of eosinophilinduced vasculitis.19,20 Eosinophils may be associated with the pathogenesis of EGPA by inducing T-helper type 2 (Th2) responses through T-cell activation.21 Peripheral blood mononuclear cells in patients with EGPA secrete Th2 cytokines [eg, interleukin (IL)-4, IL-5, and IL-13] and Th1 cytokine interferon-g, which promotes granulomatous inflammation.21 The existence of 2 clinical phenotypes in ANCA-positive and ANCA-negative patients may reveal that ANCA and eosinophils, respectively, are responsible for different pathogenesis in EGPA. A mosaic of vasculitic or nonvasculitic cutaneous lesions—including hemorrhagic lesions (ranging from purpura to hemorrhagic bullae), papules/nodules, vesicles/bullae, livedo reticularis, erythema multiforme-like eruptions, and urticarial eruptions—can be identified in skin lesions of EGPA.2 Cutaneous vasculitis in EGPA most often presented as purpuric lesions that indicated necrotizing vasculitis of the dermal small vessels. By contrast, nodular lesions or livedo reticularis in EGPA indicate eosinophilic or granulomatous
arteritis/phlebitis of the deep dermal to subcutaneous muscular vessels. A most recent large-scale study regarding skin biopsies from 85 EGPA patients reported from French Vasculitis Study Group showed the main findings of skin biopsies were leukocytoclastic vasculitis of dermal small vessels, with eosinophilic infiltrates and granulomas, in 36% and 10%, respectively, nevertheless histopathologic findings of the subcutaneous muscular vessels was not described in this study.10 In our study, dermal small vessel vasculitis, ranging from neutrophilic vasculitis to eosinophilic vasculitis, was identified in 8 patients and clinically appeared as palpable purpura. Among 5 patients with leukocytoclastic vasculitis characterized by neutrophils and nuclear debris, prominent neutrophilic infiltration almost without eosinophils was seen in 2 patients (40%) (Fig. 2A) and a mixed infiltrate of eosinophils and neutrophils was seen in another 3 patients (60%) (Figs. 2C, D). Granuloma was seen in none of the patients. The remaining 3 patients had the features of eosinophilic vasculitis characterized by almost complete absence of neutrophils and nuclear debris (Fig. 2B). These are the unique diagnostic findings of EGPA. It has been reported that ANCA positivity seems to be correlated with a high frequency of vasculitis in biopsy specimens.7,22 Perivascular and/or tissue eosinophil infiltration may be frequently present in ANCA-negative patients, whereas necrotizing small vessel vasculitis with perivascular predominant neutrophilic infiltration was present primarily in ANCA-positive patients. In this study, neutrophilic vasculitis was present in 2 MPO-ANCA–positive patients, which may
FIGURE 3. Muscular vessel vasculitis in EGPA. A, Histopathologic findings of eosinophilic arteritis from a tender erythematous nodule on the palm of case 3 are characterized by a prominent eosinophilic infiltrate in and around the affected arterial vessel wall. B, Deep excisional biopsy obtained from the livedo reticularis in Fig. 1C reveals subcutaneous granulomatous arteritis in the deep subcutis. It is characterized by a marked angiocentric infiltrate of histiocytes mixed with multinucleated giant cells. Hematoxylin–eosin staining (A and B); original magnification: A, ·200; B, ·100.
220
| www.amjdermatopathology.com
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
suggest the association between neutrophil predominance and MPO-ANCA positivity. By contrast, although there was no statistically significant difference in eosinophilic infiltration between ANCA-positive patients and ANCA-negative patients, exclusively predominant infiltrate of eosinophils in small vessel vasculitis was only found in 3 cases and all revealed serological negative for MPO-ANCA. It may be that eosinophils and neutrophils are both involved in the development of dermal small vessel vasculitis in EGPA.23 As indicated in our study, a spectrum of small vessel vasculitis in EGPA is characterized by neutrophilic vasculitis that commonly occurs in ANCA-positive patients at one end to eosinophilic vasculitis in ANCA-negative patients at the other end, whereas a mixed infiltrate of both eosinophils and neutrophils, an intermediate form between neutrophilic vasculitis and eosinophilic vasculitis, is most often found. MPOANCA positivity and nephritis are often recognized in patients with dermal small vessel vasculitis that is characterized by marked neutrophilic infiltration. The features of eosinophilic vasculitis of muscular vessels (Fig. 3A) identified in 2 patients with nodular lesions were also a diagnostic clue to EGPA. Livedo reticularis (Fig. 1C) was observed in 1 patient with histopathologic findings of granulomatous arteritis with a surrounding infiltrate of eosinophils is also a diagnostic clue to EGPA (Fig. 3B). The coexistence of dermal small vessel vasculitis with underlying muscular vasculitis shown in 3 EGPA patients is a unique histopathologic feature for systemic vasculitis such as ANCA-associated vasculitis,2 collagen disease, and Behçet disease.12 Histopathologic changes of vasculitis in muscular vessels in EGPA was classified into the acute stage (characterized by an eosinophil-dominant infiltrate in and around the affected vessel wall) (Fig. 3A), the granulomatous stage (characterized by angiocentric histiocytes and multinucleated giant cells in and around the vessel walls with a peripheral eosinophilic infiltrate) (Fig. 3B), and the healed stage (characterized by luminal fibrosis with sparse or the complete absence of inflammatory cells).15,16 Subcutaneous muscular vessel vasculitis that clinically presents as livedo reticularis or subcutaneous nodules is rarely observed in EGPA; however, a deep subcutaneous incisional biopsy should be performed to locate arteritis/phlebitis in the deep subcutis (Fig. 3B).16 This study shows, for the first time, many histopathologic facets of cutaneous vasculitis in EGPA in relation to MPO-ANCA positivity or negativity and morphological evolution of subcutaneous arteritis, which will provide valuable information for evaluating the mosaic of cutaneous vasculitis in EGPA. Because of case limitation of this study, further clinical and histopathologic studies not only focusing on skin lesions but also extracutaneous lesions in EGPA patients should be performed to elucidate the significance of clinical and pathological correlation between different serological phenotype of MPO-ANCA.
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Cutaneous Vasculitis in EGPA
REFERENCES 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1–11. 2. Chen KR. Skin involvement in ANCA-associated vasculitis. Clin Exp Nephrol. 2013;17:676–682. 3. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore). 1999;78:26–37. 4. Reid AJ, Harrison BD, Watts RA, et al. Churg-Strauss syndrome in a district hospital. QJM. 1998;91:219–229. 5. Della Rossa A, Baldini C, Tavoni A, et al. Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre. Rheumatology (Oxford). 2002;41:1286–1294. 6. Kallenberg CG. Churg-Strauss syndrome: just one disease entity? Arthritis Rheum. 2005;52:2589–2593. 7. Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum. 2005;52:2926–2935. 8. Davis MD, Daoud MS, McEvoy MT, et al. Cutaneous manifestations of Churg-Strauss syndrome: a clinicopathologic correlation. J Am Acad Dermatol. 1997;37:199–203. 9. Solans R, Bosch JA, Perez-Bocanegra C, et al. Churg–Strauss syndrome: outcome and long-term follow-up of 32 patients. Rheumatology (Oxford). 2001;40:763–771. 10. Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and longterm followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. 2013;65:270–281. 11. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33:1094–1100. 12. Chen KR. Histopathology of cutaneous vasculitis. In: AmezcuaGuerra LM, ed. Advances in the Diagnosis and Treatment of Vasculitis. Rijeka, Croatia: InTech; 2011:19–56. ISBN: 978-953-307-786-4. 13. Carlson JA, Ng BT, Chen KR. Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis. Am J Dermatopathol. 2005;27:504–528. 14. Chen KR. The misdiagnosis of superficial thrombophlebitis as cutaneous polyarteritis nodosa: features of the internal elastic lamina and the compact concentric muscular layer as diagnostic pitfalls. Am J Dermatopathol. 2010;32:688–693. 15. Ishibashi M, Kudo S, Yamamoto K, et al. Churg-Strauss syndrome with coexistence of eosinophilic vasculitis, granulomatous phlebitis and granulomatous dermatitis in bullous pemphigoid-like blisters. J Cutan Pathol. 2011;38:290–294. 16. Chen KR, Sakamoto M, Ikemoto K, et al. Granulomatous arteritis in cutaneous lesions of Churg-Strauss syndrome. J Cutan Pathol. 2007; 34:330–337. 17. Chen KR, Ohata Y, Sakurai M, et al. Churg-Strauss syndrome: report of a case without preexisting asthma. J Dermatol. 1992;19:40–47. 18. Pagnoux C, Guillevin L. Churg–Strauss syndrome: evidence for disease subtypes? Curr Opin Rheumatol. 2010;22:21–28. 19. Chen KR, Pittelkow MR, Su WP, et al. Recurrent cutaneous necrotizing eosinophilic vasculitis: a novel eosinophil-mediated syndrome. Arch Dermatol. 1994;130:1159–1166. 20. Chen KR, Su WP, Pittelkow MR, et al. Eosinophilic vasculitis in connective tissue disease. J Am Acad Dermatol. 1996;35:173–182. 21. Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and autoimmunity in Churg-Strauss syndrome. Ann N Y Acad Sci. 2005;1051: 121–131. 22. Sablé-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg–Strauss syndrome. Ann Intern Med. 2005;143: 632–638. 23. Drage LA, Davis MD, De Castro F, et al. Evidence for pathogenic involvement of eosinophils and neutrophils in Churg-Strauss syndrome. J Am Acad Dermatol. 2002;47:209–216.
www.amjdermatopathology.com |
221
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Spectrum of Cutaneous Vasculitis in Eosinophilic Granulomatosis With Polyangiitis (Churg–Strauss): A Case Series Masafumi Ishibashi, MD,*† Yoshie Kawahara, MD, PhD,‡ and Ko-Ron Chen, MD, PhD*
Background: The diverse histopathologic spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (EGPA, Churg–Strauss syndrome) has not been well described. Methods: Fifteen skin biopsy specimens from 9 EGPA patients with histopathologically proven necrotizing vasculitis were reviewed clinicopathologically. Results: Among 8 patients with dermal small vessel vasculitis, neutrophilic vasculitis was observed in 2 myeloperoxidase (MPO)antineutrophil cytoplasmic antibodies (ANCA)–positive patients, whereas the remaining 6 MPO-ANCA–negative patients showed eosinophilic vasculitis in 3 and a mixed infiltrate of neutrophils and eosinophils in another 3 patients. Five patients with muscular vessel vasculitis showed vasculitis at different inflammatory stages in separate or coexisting at the same biopsied skin lesions: acute stage (eosinophilic vasculitis), granulomatous stage (granulomatous vasculitis), and healed stage. Coexistent small vessel and muscular vessel vasculitis was found in 4 patients.
Conclusions: The histopathologic spectrum of dermal small vessel vasculitis in EGPA ranges from eosinophilic vasculitis with negative MPO-ANCA at one end to neutrophilic vasculitis with positive MPO-ANCA at the other end. The affected vessels ranging from dermal small vessels to subcutaneous muscular vessels in addition to the MPO-ANCA phenotype may account for the many facets of vasculitis in EGPA. Key Words: eosinophilic vasculitis, neutrophilic vasculitis, granulomatous arteritis, phlebitis, leukocytoclastic vasculitis, myeloperoxidase antineutrophil cytoplasmic antibody (Am J Dermatopathol 2015;37:214–221)
INTRODUCTION Churg–Strauss syndrome, now renamed eosinophilic granulomatosis with polyangiitis (EGPA), is a systemic vasculitis that occurs most often in patients with preexisting From the *Department of Dermatology, Saiseikai Central Hospital, Tokyo, Japan; †Department of Dermatology, Nippon Kokan Hospital, Kawasaki, Japan; and ‡Department of Dermatology, Keiyu Hospital, Yokohama, Japan. The authors declare no conflicts of interest. Reprints: Ko-Ron Chen, MD, PhD, Department of Dermatology, Saiseikai Central Hospital, 1-4-17, Mita, Minato-ku, Tokyo 108-0073, Japan (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
214
| www.amjdermatopathology.com
asthma and blood and tissue eosinophilia.1 Vessels involved in cutaneous vasculitis in EGPA like vessels of vasculitis in extracutaneous lesions1 are predominantly small vessels such as arterioles and venules. However, deep dermal vessels to subcutaneous muscular vessels of small-sized arteries and veins may be involved.2,3 In 39%–59% of patients, EGPA is associated with antineutrophil cytoplasmic antibodies (ANCAs).4,5 Proteinase 3-ANCA (PR3-ANCA) is identified primarily in patients with granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis), whereas myeloperoxidase (MPO)-ANCA is predominantly detected in patients with microscopic polyangiitis and EGPA. In EGPA, ANCA-negative patients usually present with eosinophilic infiltration in tissues such as the lungs, heart, and gastrointestinal tract; by contrast, ANCA-positive patients tend to present with a vasculitic disease pattern such as glomerulonephritis, pulmonary hemorrhage, and mononeuritis multiplex.6,7 However, many points remain unclear concerning the role of ANCA in the development of EGPA. Cutaneous lesions have been observed in approximately two-thirds of EGPA patients.3,8 Palpable purpura is the most common lesion. Other cutaneous manifestations include infiltrated erythema, erythematous papules, cutaneous or subcutaneous nodules, urticaria, livedo reticularis, digital gangrene, and bullous lesions.2,3,8 Because the skin is the most easily accessible organ for obtaining biopsy samples, skin lesions may frequently contribute to an early diagnosis of EGPA. However, in a few reports,8–10 the cutaneous histopathology of EGPA has roughly been described as dermal leukocytoclastic vasculitis, tissue eosinophilia, and granuloma formation. To date, the histopathologic spectrum of cutaneous vasculitis such as different types of predominant cellular infiltrate and different levels of vessels affected in EGPA has not been noted. The purpose of this study was to focus on the histopathologic variations of cutaneous vasculitis and its correlation with MPO-ANCA and extracutaneous organ involvement in EGPA. This study also provides an excellent model for determining the histopathology of cutaneous vasculitis by understanding the wide spectrum of cutaneous vasculitis in EGPA.
MATERIALS AND METHODS We analyzed the clinical and histopathologic features of EGPA patients who met both the American College of Rheumatology 1990 criteria for diagnosis of EGPA11 and the Chapel Hill Consensus Conference 2012 definition for EGPA.1 Skin biopsy specimens were obtained from 14 Am J Dermatopathol Volume 37, Number 3, March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Cutaneous Vasculitis in EGPA
patients fulfilling these criteria and definition: 10 from Saiseikai Central Hospital, Tokyo, 3 from Keiyu Hospital, Yokohama, and 1 from Nippon Kokan Hospital, Kawasaki. Among 14 patients, 15 skin biopsy specimens with histopathologically proven vasculitis from 9 patients (64%) were included in the study. The remaining 5 patients without histopathologic evidence of vasculitis showed mild to severe perivascular infiltration of eosinophils, however without evidence of vessel wall fibrinoid necrosis. We examined the medical records of all patients with biopsy-proven cutaneous vasculitis. Full blood cell counts, renal and liver function tests, urine analysis, immunoserological tests for ANCA, antinuclear antibodies, rheumatoid factors and immunoglobulins, stool for occult blood, electrocardiogram, chest radiograph, and a nerve conduction velocity study for patients with suspected peripheral nerve neuropathy were performed. Echocardiography or gastrointestinal endoscopy was also performed, depending on the clinical indications. To obtain adequate lesional tissue for identifying vasculitis in dermal or subcutaneous lesions, one or more biopsy specimens from skin lesions
were obtained by the appropriate biopsy procedure (eg, punch biopsy or incisional biopsy for palpable purpura and deep incisional biopsy for lesions with livedo reticularis and for nodular lesions). Histopathologic diagnosis of dermal small vessel vasculitis required angiocentric inflammatory infiltrates with fibrinoid necrosis of the affected vessel walls.12,13 The diagnostic criteria for muscular vessel vasculitis required both (1) perivascular and intravascular infiltration of muscular vessel wall by inflammatory cells and (2) intramural fibrin deposition and/or intramural muscular layer destruction.13 Diagnosis for healed stage of arteritis with internal elastic lamina destruction was confirmed by elastic fiber staining.12 Recuts of serial sections from tissue blocks were stained with elastic tissue staining (elastica van Gieson, elastica hematoxylin and eosin) to confirm the type of affected vessels, respectively. Assessments of the involved dermal small vessels were based on the presence of the internal elastic lamina (ie, arterioles) or the absence of the internal elastic lamina (ie, venules), as confirmed by elastic tissue staining.12 The distinction between muscular vessels of arteries or veins from the deep dermis to
TABLE 1. Demographic, Clinical, and Laboratory Features in EGPA Patients With Cutaneous Vasculitis
Case 1 2 3 4 5 6 7 8 9 All
Sex
Age at Diagnosis (yr)
Eosinophils (cells/mL)
F 79 2040 F 50 20,800 M 38 7000 M 46 11,650 F 50 6120 M 49 23,700 F 67 2840 F 50 13,500 M 67 7710 M/F: 4/5 55.1 6 13.0 10,600 6 7580
Blood Eosinophils Eosinophilia (%) .10% MPO-ANCA Asthma 13.5 73 47 61 46 65.5 33 62 47 49.8 6 18.3
+ + + + + + + + + 9 (100%)
+ (74) 2 + (151) 2 2 2 2 2 + (592) 3 (33%)
Proteinuria Peripheral Renal and Palpable Erythematous Case Neuropathy Involvement Hematuria Eruptions Purpura Vesicle Bullae 1
+
2
2
+
2
3
+
+
+ (LE, UE) + (LE)
4 5
+ +
2 2
+ (LE) + (LE)
6
+
2
+ (LE, UE)
+ + + 9 (100%)
2 2 2 1 (11%)
7 8 9 All
2 + 2 + + + 2 + + 6 (67%) Nodular Erythema/ Subcutaneous Nodules
Lung Involvement: Transient Pulmonary Infiltrates
Ear–Nose–Throat Symptoms
+ + + + 2 + 2 2 + 6 (67%)
2 + 2 + + 2 + + 2 5 (56%)
Other Skin Lesions Livedo reticularis (LE)
+ (LE, UE) + (LE, UE)
+ (LE)
Hemorrhagic blister (LE)
+ (LE) + (LE) + (LE) 7 (78%)
2 (22%)
EM-like eruptions (LE)
2 (22%)
Treatment
Outcome
GC
CR
GC
CR
GC
CR
GC GC
CR CR
GC
CR
GC GC GC GC; 9 (100%) CR;
CR CR CR 9 (100%)
These patients fulfilled the American College of Rheumatology 1990 criteria for EGPA and the Chapel Hill Consensus Conference 2012 definition of EGPA. CR, clinical remission; EM, erythema multiforme; GC, glucocorticoid; LE, lower extremities; UE, upper extremities.
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.amjdermatopathology.com |
215
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Ishibashi et al
the subcutis layer was based on the amount and distribution of elastic fibers in the medial muscular layer of the vessel wall and on the smooth muscular pattern and the presence or absence of the internal elastic lamina.12,14 The intensity of the inflammatory infiltrate was evaluated in and around the affected vessel wall, as follows: “absent,” “mild,” “moderate,” or “severe.” Fisher tests were used to compare clinical symptoms and histopathologic findings of cutaneous vasculitis in ANCA-positive patients and ANCA-negative patients. A Pvalue of ,0.05 (by 2-tailed testing) was considered to indicate statistical significance.
RESULTS Nine patients (4 men and 5 women) with an age of onset between 38–79 years (mean age of 55.1 years) were enrolled. Table 1 summarizes the clinical characteristics of the patients. Three patients have been described previously.15–17
Extracutaneous Manifestations and Laboratory Findings
microliter with a mean value of 10,600 cells per microliter. Three of the 9 patients (33%) were MPO-ANCA–positive. There was a trend toward higher levels of peripheral eosinophils count in MPO-ANCA–negative patients in comparison with those in MPO-ANCA–positive patients [mean (SD) eosinophils (cells/mL): 13,100 (8100) vs. 5580 (3090); P = 0.09], although there was no statistically significant difference (Table 2).
Cutaneous Manifestations Table 1 shows the cutaneous manifestations of each patient. Palpable purpura was the most common type of cutaneous lesion in 7 patients (78%) (Fig. 1A). There were a variety of other cutaneous lesions such as erythematous vesicles or bullae (2 patients) (Fig. 1B), nodular erythema or subcutaneous nodules (2 patients), hemorrhagic bullae (1 patient), livedo reticularis (1 patient) (Fig. 1C), and erythema multiforme-like eruption (1 patient). All patients had skin eruptions on the lower extremities. Three patients had cutaneous lesions on the upper extremities.
Histopathologic Analysis
Asthma was present in 6 (67%) of the 9 patients (Table 1). Six patients had lung involvement, which was characterized by transient pulmonary infiltrates without evidence of pleural effusion. Ear, nose, and throat involvements, which manifested as chronic sinusitis or allergic rhinitis were seen in 5 patients (none of MPO-ANCA–positive patients and 5 MPO-ANCA–negative patients, 0% vs. 83%, respectively; P = 0.048) (Table 2). Peripheral neuropathy (most often mononeuritis multiplex) was present in all 9 patients. No patient had cardiac involvement such as impaired wall motion. Gastrointestinal hemorrhage was not present in any patient. One MPO-ANCA– positive patient had renal disease with persistent proteinuria (.1 g per 24 hours) and macrohematuria; however, renal disease was not present in any MPO-ANCA–negative patients. All patients had leukocytosis with eosinophilia (.10%). The absolute eosinophil count ranged from 2040 to 23,700 cells per
The following 2 patterns of cutaneous vasculitis were identified: (1) dermal small vessel vasculitis in 11 specimens from 8 patients (2 specimens from 2 MPO-ANCA–positive patients and 9 specimens from 6 MPO-ANCA–negative patients) and (2) muscular vessel vasculitis in 7 specimens from 5 patients (3 specimens from 2 MPO-ANCA–positive patients and 4 specimens from 3 MPO-ANCA–negative patients) (Table 3). Different levels of vasculitis presenting as dermal small vessel vasculitis or subcutaneous muscular vessel vasculitis were seen in separate lesions, respectively (1 patient, case 3) or even coexisting in the same skin lesion (3 patients).
Dermal Small Vessel Vasculitis Fibrinoid necrosis of the vessel wall occurred more often in venules lacking an internal elastic lamina (Figs. 2A–C) than in arterioles with a disrupted internal elastic lamina (Fig. 2D). The predominant cellular infiltrates ranged from eosinophils to
TABLE 2. Correlation of Clinical Symptoms With MPO-ANCA Status in 9 EGPA Patients With Cutaneous Vasculitis Mean (SD) age at onset [range], yr Mean (SD) eosinophils (cells/mL) Ear–nose–throat symptoms, n (%) Lung involvement, n (%) Asthma Transient pulmonary infiltrate Peripheral neuropathy, n (%) Renal involvement, n (%) Skin conditions, n (%) Palpable purpura Erythematous vesicles/bullae Nodular erythema/subcutaneous nodules Livedo
MPO-ANCA–Positive (n = 3)
MPO-ANCA–Negative (n = 6)
61 (21) [38–79] 5580 (3090) 0
52 (8) [46–67] 13,100 (8100) 5 (83)
1 (33) 3 (100) 3 (100) 1 (33) 3 (100) 2 (67) 0 1 (33)
5 (83) 3 (50) 6 (100) 0 6 (100) 5 (83) 2 (33) 1 (17)
1 (33)
0
P 0.53 0.09 0.048* 0.23 0.46 .0.99 0.33 .0.99 .0.99 0.5 .0.99 0.33
*P , 0.05.
216
| www.amjdermatopathology.com
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Cutaneous Vasculitis in EGPA
FIGURE 1. Skin lesions in cutaneous vasculitis in EGPA. A, Palpable purpura on the lower extremities in case 9. B, Palpable purpura mixed with hemorrhagic bullae and tense bullae on the lower extremities in case 5. C, Livedo reticularis on the lower extremities in case 1.
neutrophils. Neutrophilic vasculitis characterized by a prominent infiltrate of neutrophils with marked nuclear debris were seen in 2 ANCA-positive patients but in none of the ANCAnegative patients (100% vs. 0%, respectively; P = 0.04) (Fig. 2A) (Table 4). Eosinophilic vasculitis of dermal small vessels (primarily of venules) characterized by an exclusively eosinophilic infiltrate without nuclear debris was present in 3 of 6 ANCA-negative patients (50%) (Fig. 2B) but in none of the ANCA-positive patients. Mixed infiltrate of neutrophils and eosinophils was present in the remaining 3 ANCA-negative patients (Figs. 2C, D).
Muscular Vessel Vasculitis Muscular vessel vasculitis was found at dermosubcutaneous junction to subcutis (Figs. 3A, B). Two patients (1 ANCA-positive patient and 1 ANCA-negative patient) had inflammatory cells with a predominant infiltrate of eosinophils in and around the muscular vessel wall with destruction of muscular layers in the arteries or veins (Fig. 3A). The involved arteries showed disruption of the internal elastic lamina. Granulomatous arteritis with a predominant infiltrate of histiocytes mixed with multinucleated giant cells was present in 1 MPO-ANCA–positive patient (Fig. 3B), and granulomatous phlebitis was present in 2 MPO-ANCA–negative patients. Healed arteritis characterized by scant inflammation with marked intimal fibrosis and disruption of internal elastic lamina was found in 2 patients (Table 3).
Inflammatory Stages of Muscular Vessel Vasculitis The morphological evolution of muscular vessel vasculitis in EGPA has been classified into acute, granulomatous, and healed stages. Coexistence of different stages of muscular vessel vasculitis could be found in different or in the same skin lesion (Table 3). Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Acute stage: a predominant infiltrate of eosinophils in and around the affected muscular vessel walls (Fig. 3A). Granulomatous stage: a predominant infiltrate of histiocytes and multinucleated giant cells in and around the vessel walls (Fig. 3B). Healed (scar) stage: there is absent or scant inflammation with intimal fibrous thickening resulting in luminal occlusion.
Renal Involvement and Relationship to Cellular Infiltration and ANCA Serological Phenotype Renal involvement (eg, persistent proteinuria and macrohematuria) was only present in 1 MPO-ANCA–positive patient who had a predominant infiltrate of neutrophils and marked leukocytoclasis in and around the affected dermal small vessels (ie, neutrophilic vasculitis) (case 3, Tables 1 and 3). By contrast, 8 patients without renal failure had dermal small vessel vasculitis (7 patients) or subcutaneous granulomatous arteritis (1 MPO-ANCA– positive patient). Among 7 patients with dermal small vessel vasculitis without renal involvement, a predominant infiltrate of neutrophils was significantly found in 1 ANCA-positive patient; however, a predominance of eosinophilic infiltration was seen in 3 of 6 ANCAnegative patients and a mixed infiltrate of eosinophils and neutrophils was seen in the remaining 3 ANCAnegative patients.
Tissue Eosinophilia and Extravascular Granuloma Tissue eosinophilia was seen in all of 9 patients [3 ANCA-positive patients and 6 ANCA-negative patients (Table 3)]. Extravascular palisading granuloma with central www.amjdermatopathology.com |
217
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Ishibashi et al
TABLE 3. Correlations of Skin Lesions and Histopathologic Features in EGPA With Cutaneous Vasculitis Type of Vasculitis (Location of Vasculitis) Dermal Small Vessel 11 Specimens (8 Patients) Case
Neu
Eos
Muscular Vessel 7 Specimens (5 Patients)
Mixed (Neu and Eos)
Eosinophilic
Granulomatous
Scarred Vessels
1 A B
Arteritis (SC) Arteritis (SC)
Healed arteritis (SC)
2 A
Venulitis/arteriolitis (D)
B C
Venulitis (D) Venulitis (D)
Phlebitis (DSJ)
3 A B
Venulitis (D) Arteritis (DSJ)
4 5
Venulitis (D) A B
Venulitis (D) Venulitis (D) Phlebitis (DSJ)
6 7
Venulitis (D, SC) A
Venulitis (D) Arteritis/phlebitis (SC) Phlebitis (DSJ)
B 8 9 All specimens (patients)
Healed arteritis/ phlebitis (SC)
Venulitis (D) Venulitis (D) ANCA+: 2 (2) ANCA2: 0 (0)
ANCA+: 0 (0) ANCA2: 4 (3)
ANCA+: 0 (0) ANCA2: 5 (3)
ANCA+: 1 (1) ANCA2: 2 (1)
ANCA+: 2 (1) ANCA2: 2 (2)
ANCA+: 1 (1) ANCA2: 1 (1)
Cellular Composition of the Infiltrate Case
Neu
Eos
His
Tissue Eosinophilia
Palisading Granuloma
Biopsied Skin Lesion
A B
2 2
+ 2
++ ++
+ +
Livedo (LE; R) Livedo (LE; L)
A
++ + ++ +++
++ ++ ++ +++
+ ++ + +
++
Purpura (LE)
++ +++
Purpura (LE) Erythematous vesicle (UE)
A B
+++ 2 +
+ +++ +
2 + 2
+ +++ +
Purpura (LE) Nodule (palm) Purpura (LE)
A B
2 2 2 ++
++ +++ + ++
+ + ++ 2
++ +++
Purpura (LE) Hemorrhagic bullae (LE)
++
Purpura (LE)
2 2 2
++ ++ ++
+ + +
++
Subcutaneous Nodule (LE; L)
1
2
B C 3
4 5
6 7 A B
218
| www.amjdermatopathology.com
++
Eosinophilic degeneration
Subcutaneous nodule (LE; R)
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Cutaneous Vasculitis in EGPA
TABLE 3. (Continued ) Correlations of Skin Lesions and Histopathologic Features in EGPA With Cutaneous Vasculitis Cellular Composition of the Infiltrate Case
Neu
Eos
His
8 9 All specimens (patients)
2 +++
++ +
2 2
Tissue Eosinophilia
Palisading Granuloma
Biopsied Skin Lesion
++ Purpura (LE) + Purpura (LE) ANCA+: 5 (3); ANCA2: 10 (6) ANCA+: 0 (0); ANCA2: 1 (1)
D, dermis; DSJ, dermo-subcutaneous junction; Eos, eosinophils; L, left; LE, lower extremities; His, histiocytes; Neu, neutrophils; R, right; SC, subcutis; UE, upper extremities. Intensity of the inflammatory infiltrate: “2” = absent, “+” = mild, “++” = moderate, “+++” = severe.
infiltration of degenerated eosinophils surrounded by histiocytes was seen in 1 of 9 patients (Table 3) (case 7).
DISCUSSION EGPA usually presents in 3 phases: the prodromal phase characterized by asthma with or without allergic rhinitis, the eosinophilic phase characterized by eosinophilia in the blood and tissue, and the vasculitic phase. The vasculitic phase may occur in multiple organs, including the nerves, lungs, heart, gastrointestinal tract, kidneys, and skin. The prevalence of ANCAs in EGPA is less consistent than in GPA or microscopic polyangiitis and is reported in approximately 40% of patients.3,18 It was recently demonstrated that different clinical phenotypes could be observed based on the presence or absence of ANCA; this suggests that there are various disease mechanisms in the pathogenesis of EGPA.6,18 Compared with ANCA-negative patients, ANCA-positive patients more frequently have peripheral neuropathy, pulmonary
hemorrhage, and renal involvement with necrotizing crescentic glomerulonephritis and less frequently have myocarditis, pleural effusion, and pulmonary infiltrates.7 Patients with EGPA with renal involvement seem to have a significantly higher frequency of MPO-ANCA positivity,10 as seen in the patient with MPO-ANCA positivity with renal involvement in our study (case 3). From these findings, it has been hypothesized that a primarily vasculitic disease pattern in EGPA is strongly associated with MPO-ANCA, whereas a predominant pathological feature of tissue eosinophilia with the resultant tissue deposition of extracellular eosinophilic cytotoxic granular proteins is generally ANCA negative, although vasculitis may be observed less often.7 ANCA seem to have a pathogenic role in vasculitic lesions, possibly through the interaction of activated neutrophils with endothelial cells. As an alternative, activated eosinophils are able to interact with vascular endothelial cell and result in eosinophil-induced small vessel vasculitis, especially in ANCA-negative patients with EGPA (Fig. 2B).
FIGURE 2. Dermal small vessel vasculitis in EGPA. A, Histopathologic findings of palpable purpura on the leg of case 9 shows dermal neutrophilic vasculitis, which is characterized by a predominant infiltrate of neutrophils with marked nuclear debris. B, Fully developed dermal eosinophilic vasculitis, characterized by an infiltrate, is composed almost exclusively of eosinophils without nuclear debris from palpable purpura lesion in case 8. C, A biopsy specimen from palpable purpura on the leg of case 6 shows venulitis with a mixed infiltrate of neutrophils and eosinophils. D, A biopsy specimen from palpable purpura on the leg of case 2 shows arteriolitis with a mixed infiltrate of neutrophils and eosinophils. Elastic tissue staining shows disrupted internal elastic lamina. Hematoxylin–eosin stain (A, B, and C); original magnification: A and C, ·100; B, ·400. Elastica hematoxylin–eosin stain (D); original magnification: ·200. Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.amjdermatopathology.com |
219
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Ishibashi et al
TABLE 4. Correlation of Predominant Cellular Infiltrates With MPO-ANCA Status in EGPA Patients With Cutaneous Vasculitis Dermal Small Vessel Vasculitis Inflammatory Infiltrates Neutrophil-dominant Eosinophil-dominant Mixed infiltrates (neutrophils and eosinophils) Granulomatous
Muscular Vessel Vasculitis (Arteritis/Phlebitis)
MPO-ANCA–Positive MPO-ANCA–Negative (n = 2) (n = 6) 2 (100) 0 0
0 3 (50) 3 (50)
0
0
P 0.04* 0.46 0.46 .0.99
MPO-ANCA–Positive MPO-ANCA–Negative (n = 2) (n = 3)
P
0 1 (50) 0
0 1 (33) 0
.0.99 .0.99 .0.99
1 (50)
2 (66)
.0.99
*P , 0.05.
Eosinophils and deposition of eosinophil granule proteins have been observed in and around the affected blood vessel walls in documented cases of cutaneous eosinophilic vasculitis in either idiopathic vasculitis19 or in connective tissue disease-associated vasculitis.20 Activated eosinophils generate the leukotriene C4, which increases vascular permeability. Cytotoxic eosinophilic granule proteins (eg, major basic protein, eosinophil-derived neurotoxin, and eosinophil cationic protein) may moreover be responsible for damaging endothelial cells and the subsequent development of eosinophilinduced vasculitis.19,20 Eosinophils may be associated with the pathogenesis of EGPA by inducing T-helper type 2 (Th2) responses through T-cell activation.21 Peripheral blood mononuclear cells in patients with EGPA secrete Th2 cytokines [eg, interleukin (IL)-4, IL-5, and IL-13] and Th1 cytokine interferon-g, which promotes granulomatous inflammation.21 The existence of 2 clinical phenotypes in ANCA-positive and ANCA-negative patients may reveal that ANCA and eosinophils, respectively, are responsible for different pathogenesis in EGPA. A mosaic of vasculitic or nonvasculitic cutaneous lesions—including hemorrhagic lesions (ranging from purpura to hemorrhagic bullae), papules/nodules, vesicles/bullae, livedo reticularis, erythema multiforme-like eruptions, and urticarial eruptions—can be identified in skin lesions of EGPA.2 Cutaneous vasculitis in EGPA most often presented as purpuric lesions that indicated necrotizing vasculitis of the dermal small vessels. By contrast, nodular lesions or livedo reticularis in EGPA indicate eosinophilic or granulomatous
arteritis/phlebitis of the deep dermal to subcutaneous muscular vessels. A most recent large-scale study regarding skin biopsies from 85 EGPA patients reported from French Vasculitis Study Group showed the main findings of skin biopsies were leukocytoclastic vasculitis of dermal small vessels, with eosinophilic infiltrates and granulomas, in 36% and 10%, respectively, nevertheless histopathologic findings of the subcutaneous muscular vessels was not described in this study.10 In our study, dermal small vessel vasculitis, ranging from neutrophilic vasculitis to eosinophilic vasculitis, was identified in 8 patients and clinically appeared as palpable purpura. Among 5 patients with leukocytoclastic vasculitis characterized by neutrophils and nuclear debris, prominent neutrophilic infiltration almost without eosinophils was seen in 2 patients (40%) (Fig. 2A) and a mixed infiltrate of eosinophils and neutrophils was seen in another 3 patients (60%) (Figs. 2C, D). Granuloma was seen in none of the patients. The remaining 3 patients had the features of eosinophilic vasculitis characterized by almost complete absence of neutrophils and nuclear debris (Fig. 2B). These are the unique diagnostic findings of EGPA. It has been reported that ANCA positivity seems to be correlated with a high frequency of vasculitis in biopsy specimens.7,22 Perivascular and/or tissue eosinophil infiltration may be frequently present in ANCA-negative patients, whereas necrotizing small vessel vasculitis with perivascular predominant neutrophilic infiltration was present primarily in ANCA-positive patients. In this study, neutrophilic vasculitis was present in 2 MPO-ANCA–positive patients, which may
FIGURE 3. Muscular vessel vasculitis in EGPA. A, Histopathologic findings of eosinophilic arteritis from a tender erythematous nodule on the palm of case 3 are characterized by a prominent eosinophilic infiltrate in and around the affected arterial vessel wall. B, Deep excisional biopsy obtained from the livedo reticularis in Fig. 1C reveals subcutaneous granulomatous arteritis in the deep subcutis. It is characterized by a marked angiocentric infiltrate of histiocytes mixed with multinucleated giant cells. Hematoxylin–eosin staining (A and B); original magnification: A, ·200; B, ·100.
220
| www.amjdermatopathology.com
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
suggest the association between neutrophil predominance and MPO-ANCA positivity. By contrast, although there was no statistically significant difference in eosinophilic infiltration between ANCA-positive patients and ANCA-negative patients, exclusively predominant infiltrate of eosinophils in small vessel vasculitis was only found in 3 cases and all revealed serological negative for MPO-ANCA. It may be that eosinophils and neutrophils are both involved in the development of dermal small vessel vasculitis in EGPA.23 As indicated in our study, a spectrum of small vessel vasculitis in EGPA is characterized by neutrophilic vasculitis that commonly occurs in ANCA-positive patients at one end to eosinophilic vasculitis in ANCA-negative patients at the other end, whereas a mixed infiltrate of both eosinophils and neutrophils, an intermediate form between neutrophilic vasculitis and eosinophilic vasculitis, is most often found. MPOANCA positivity and nephritis are often recognized in patients with dermal small vessel vasculitis that is characterized by marked neutrophilic infiltration. The features of eosinophilic vasculitis of muscular vessels (Fig. 3A) identified in 2 patients with nodular lesions were also a diagnostic clue to EGPA. Livedo reticularis (Fig. 1C) was observed in 1 patient with histopathologic findings of granulomatous arteritis with a surrounding infiltrate of eosinophils is also a diagnostic clue to EGPA (Fig. 3B). The coexistence of dermal small vessel vasculitis with underlying muscular vasculitis shown in 3 EGPA patients is a unique histopathologic feature for systemic vasculitis such as ANCA-associated vasculitis,2 collagen disease, and Behçet disease.12 Histopathologic changes of vasculitis in muscular vessels in EGPA was classified into the acute stage (characterized by an eosinophil-dominant infiltrate in and around the affected vessel wall) (Fig. 3A), the granulomatous stage (characterized by angiocentric histiocytes and multinucleated giant cells in and around the vessel walls with a peripheral eosinophilic infiltrate) (Fig. 3B), and the healed stage (characterized by luminal fibrosis with sparse or the complete absence of inflammatory cells).15,16 Subcutaneous muscular vessel vasculitis that clinically presents as livedo reticularis or subcutaneous nodules is rarely observed in EGPA; however, a deep subcutaneous incisional biopsy should be performed to locate arteritis/phlebitis in the deep subcutis (Fig. 3B).16 This study shows, for the first time, many histopathologic facets of cutaneous vasculitis in EGPA in relation to MPO-ANCA positivity or negativity and morphological evolution of subcutaneous arteritis, which will provide valuable information for evaluating the mosaic of cutaneous vasculitis in EGPA. Because of case limitation of this study, further clinical and histopathologic studies not only focusing on skin lesions but also extracutaneous lesions in EGPA patients should be performed to elucidate the significance of clinical and pathological correlation between different serological phenotype of MPO-ANCA.
Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
Cutaneous Vasculitis in EGPA
REFERENCES 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1–11. 2. Chen KR. Skin involvement in ANCA-associated vasculitis. Clin Exp Nephrol. 2013;17:676–682. 3. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore). 1999;78:26–37. 4. Reid AJ, Harrison BD, Watts RA, et al. Churg-Strauss syndrome in a district hospital. QJM. 1998;91:219–229. 5. Della Rossa A, Baldini C, Tavoni A, et al. Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre. Rheumatology (Oxford). 2002;41:1286–1294. 6. Kallenberg CG. Churg-Strauss syndrome: just one disease entity? Arthritis Rheum. 2005;52:2589–2593. 7. Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum. 2005;52:2926–2935. 8. Davis MD, Daoud MS, McEvoy MT, et al. Cutaneous manifestations of Churg-Strauss syndrome: a clinicopathologic correlation. J Am Acad Dermatol. 1997;37:199–203. 9. Solans R, Bosch JA, Perez-Bocanegra C, et al. Churg–Strauss syndrome: outcome and long-term follow-up of 32 patients. Rheumatology (Oxford). 2001;40:763–771. 10. Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and longterm followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. 2013;65:270–281. 11. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33:1094–1100. 12. Chen KR. Histopathology of cutaneous vasculitis. In: AmezcuaGuerra LM, ed. Advances in the Diagnosis and Treatment of Vasculitis. Rijeka, Croatia: InTech; 2011:19–56. ISBN: 978-953-307-786-4. 13. Carlson JA, Ng BT, Chen KR. Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis. Am J Dermatopathol. 2005;27:504–528. 14. Chen KR. The misdiagnosis of superficial thrombophlebitis as cutaneous polyarteritis nodosa: features of the internal elastic lamina and the compact concentric muscular layer as diagnostic pitfalls. Am J Dermatopathol. 2010;32:688–693. 15. Ishibashi M, Kudo S, Yamamoto K, et al. Churg-Strauss syndrome with coexistence of eosinophilic vasculitis, granulomatous phlebitis and granulomatous dermatitis in bullous pemphigoid-like blisters. J Cutan Pathol. 2011;38:290–294. 16. Chen KR, Sakamoto M, Ikemoto K, et al. Granulomatous arteritis in cutaneous lesions of Churg-Strauss syndrome. J Cutan Pathol. 2007; 34:330–337. 17. Chen KR, Ohata Y, Sakurai M, et al. Churg-Strauss syndrome: report of a case without preexisting asthma. J Dermatol. 1992;19:40–47. 18. Pagnoux C, Guillevin L. Churg–Strauss syndrome: evidence for disease subtypes? Curr Opin Rheumatol. 2010;22:21–28. 19. Chen KR, Pittelkow MR, Su WP, et al. Recurrent cutaneous necrotizing eosinophilic vasculitis: a novel eosinophil-mediated syndrome. Arch Dermatol. 1994;130:1159–1166. 20. Chen KR, Su WP, Pittelkow MR, et al. Eosinophilic vasculitis in connective tissue disease. J Am Acad Dermatol. 1996;35:173–182. 21. Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and autoimmunity in Churg-Strauss syndrome. Ann N Y Acad Sci. 2005;1051: 121–131. 22. Sablé-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg–Strauss syndrome. Ann Intern Med. 2005;143: 632–638. 23. Drage LA, Davis MD, De Castro F, et al. Evidence for pathogenic involvement of eosinophils and neutrophils in Churg-Strauss syndrome. J Am Acad Dermatol. 2002;47:209–216.
www.amjdermatopathology.com |
221
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
