Clinicopathologic study of 43 patients with sural nerve vasculitis

Vasculitis is a relatively uncommon finding in sural nerve biopsy specimens and is associated with significant morbidity. This study retrospectively reviewed the clinicopathologic features of 43 patients (44 sural nerve biopsy specimens) with sural nerve vasculitis, defined as infiltration of vessel walls by inflammatory cells. These biopsy specimens were obtained over a 19-year period, during which 1503 nerve specimens were reviewed. The study group comprised 29 females and 14 males, ranging in age from 19 to 94 years (mean, 72.5 years) at the time of biopsy. The most frequent clinical presentations included paresthesias in 19 patients (61%), pain in 17 patients (57%), weakness in 10 patients (32%), and weight loss in 9 patients (29%). Histologically, 26 of 44 biopsy specimens (59%) demonstrated necrotizing vasculitis. The remaining 18 biopsy specimens demonstrated a nonnecrotizing lymphocytic vasculitis. Eosinophils were identified in 4 biopsy specimens, intravascular thrombi in 10 (22%) specimens, and granulomatous inflammation in 1 specimen. In 39 biopsy specimens (89%), multiple vessels were involved by vasculitis. Epineurial vessels were the most common target of vasculitis, (n = 42; 95%). Evidence of vascular wall scarring, indicative of healed vasculitis, was observed in 13 biopsy specimens (30%). All biopsy specimens showed evidence of axonopathy, with mild axonal loss noted in 14 specimens (32%), moderate loss in 18 specimens (41%), and severe loss in 12 specimens (27%). Concomitant muscle biopsy was performed in 31 patients. Fifteen muscle biopsy specimens demonstrated evidence of vasculitis (48%), which was necrotizing in 11 cases. All muscle biopsy specimens demonstrated features of neurogenic atrophy. Twenty-five out of 32 patients were known to have been treated with steroids and demonstrated some degree of clinical improvement. In conclusion, sural nerve vasculitis is a relatively uncommon pathological finding (prevalence of 2.9% in this study). In most cases, multiple vessels were involved. Concomitant vasculitis was also identified in about half of the muscle biopsy specimens obtained at the time of nerve biopsy. In most patients, the vasculitis appeared to be at least partially responsive to immunosuppressive therapy.     

The histological assessment of cutaneous vasculitis

Carlson J A
(2010) Histopathology 56, 3–23
The histological assessment of cutaneous vasculitis Vasculitis is defined as inflammation directed at vessels, which compromises or destroys the vessel wall leading to haemorrhagic and/or ischaemic events. Skin biopsy is the gold standard for the diagnosis of cutaneous vasculitis, whose manifestations include urticaria, infiltrative erythema, petechiae, purpura, purpuric papules, haemorrhagic vesicles and bullae, nodules, livedo racemosa, deep (punched out) ulcers and digital gangrene. These varied morphologies are a direct reflection of size of the vessels and extent of the vascular bed affected, ranging from a vasculitis affecting few superficial, small vessels in petechial eruptions to extensive pan‐dermal small vessel vasculitis in haemorrhagic bullae to muscular vessel vasculitis in lower extremity nodules with livedo racemosa. Skin biopsy, extending to subcutis and taken from the earliest, most symptomatic, reddish or purpuric lesion is crucial for obtaining a high‐yielding diagnostic sample. Based on histology, vasculitis can be classified on the size of vessels affected and the dominant immune cell mediating the inflammation (e.g. neutrophilic, granulomatous, lymphocytic, or eosinophilic). Disruption of small vessels by inflammatory cells, deposition of fibrin within the lumen and/or vessel wall coupled with nuclear debris allows for the confident recognition of small vessel, mostly neutrophilic vasculitis (also known as leukocytoclastic vasculitis). In contrast, muscular vessel vasculitis can be identified solely by infiltration of its wall by inflammatory cells. Extravasation of red blood cells (purpura) and necrosis are supportive, but not diagnostic of vasculitis as they are also seen in haemorrhagic and/or vaso‐occlusive disorders (pseudovasculitis). Vasculitic foci associated with extravascular granulomas (palisaded neutrophilic and granulomatous dermatitis), tissue eosinophilia, or tissue neutrophilia signal the risk for, or co‐existence of systemic disease. This essential histological information coupled with direct immunofluorescence and anti‐neutrophil cytoplasmic data and clinical findings enables more precise and accurate diagnosis of localized and systemic vasculitis syndromes.     

ANCA-Negative Wegener's Granulomatosis with Multiple Lower Cranial Nerve Palsies

Wegener''s granulomatosis (WG) is a systemic vasculitis affecting small and medium-sized vessels with granulomatous formation. Though it is known for respiratory tract and kidney involvement, neurologic manifestation has been also reported. Herein we report a patient who suffered pansinusitis with multiple lower cranial nerve palsies but reached remission by immunosuppressant after the diagnosis of WG. A 54-yr-old female visited with headache, hearing difficulty, and progressive bulbar symptoms. She experienced endoscopic sinus surgeries due to refractory sinusitis. Neurologic examination revealed multiple lower cranial nerve palsies. Vasculitic markers showed no abnormality. Nasal biopsy revealed granulomatous inflammation and vasculitis involving small vessels. Given cyclophosphamide and prednisolone, her symptoms were prominently improved. WG should be considered in the patient with multiple cranial nerve palsies, especially those with paranasal sinus disease. Because WG can be lethal if delayed in treatment, prompt immunosuppressant is warranted after the diagnostic tissue biopsy.     

Skeletal muscle vasculitis exclusive of inflammatory myopathic conditions: a clinicopathologic study of 40 patients

Vasculitis is an infrequently encountered pathology in skeletal muscle biopsy specimens, the diagnosis of which has significant therapeutic implications. This study retrospectively reviewed the clinicopathologic features of 40 patients with vasculitis (infiltration of vessel walls by inflammatory cells) diagnosed via skeletal muscle biopsy during a 27-year period of time. Cases of vasculitis associated with inflammatory myopathic conditions, such as polymyositis or dermatomyositis, were excluded from study. Forty patients, including 21 women and 19 men ranging in age from 19 to 83 years (mean of 52 years), formed the study group. The most common clinical presentations included muscle pain (n = 22, 55%), paresthesias (n = 16, 40%), and weight loss (n = 15, 38%). Westergren erythrocyte sedimentation rate was known in 31 patients and ranged from 12 to >150 mm/h (mean, 61 mm/h). Necrotizing vasculitis was identified in 35 patients (88%). The vasculitic process involved multiple vessels in 30 cases (75%). Vessel wall scarring and/or fibrosis were identified in 11 patients (28%), thrombi in 3 patients (8%), eosinophils in 2 patients (5%), and granulomas in 1 patient (3%). Neurogenic changes were observed in the majority of biopsy specimens as follows: angular atrophic esterase-positive muscle fibers (n = 35, 88%), grouped atrophy (n = 14, 35%), fiber type grouping (n = 17, 43%), and target fibers (n = 6, 15%). Other commonly identified pathologies included scattered degenerating muscle fibers (n = 15, 38%), regenerating muscle fibers (n = 17, 43%), and type II muscle fiber atrophy (n = 10, 25%). Thirty-three patients also underwent sural nerve biopsy. Vasculitis was identified in the nerve in 26 of 33 of these patients (79%). Peripheral nerve vasculitis was classified as necrotizing in 15 cases (57.7%) and as nonnecrotizing in 11 cases (42.5%). Seventeen of 33 patients (52%) with known follow-up showed clinical improvement with steroid/immunosuppressive therapy. The following 2 conclusions were made: the majority of vasculitis cases arising outside the setting of inflammatory myopathy in skeletal muscle are necrotizing, and the predominant muscle pathology in the setting of vasculitis is neurogenic atrophy, likely caused by concomitant involvement of the peripheral nervous system.     

Manifestations mimicking relapsing polychondritis in a patient with microscopic polyangiitis]

Microscopic polyangiitis (MPA) is a systemic disorder characterized by inflammation of small vessels mainly affecting the kidneys and lungs. We describe a 72-year-old woman who developed multiple cartilage involvements as well as major manifestations of MPA. The left ear biopsy demonstrated cartilaginous inflammation and small vessel vasculitis. She also had conjunctivitis, hearing impairment, interstitial lung disease, glomerulonephritis with vasculitis and mononeuritis multiplex. Serological examinations revealed a positive antineutrophil cytoplasmic antibody (PR-3 ANCA). Cyclophosphamide and oral corticosteroid therapy was instituted and remission achieved. Due to lacks of nasal and bronchial involvements, as well as the evidence of auricular vasculitis, we concluded that her findings mimicking relapsing polychondritis developed as systemic manifestations of MPA.     

Evaluation of simultaneous muscle and nerve biopsies for the diagnosis of neuromuscular diseases

Skeletal muscle and peripheral nerve are occasionally simultaneously biopsied with the goal of increasing diagnostic yield in patients with an uncertain clinical diagnosis or in cases where the pathology is known to be focal or multifocal (eg, vasculitis or amyloidosis). The purpose of the present study is to evaluate the diagnostic utility of performing simultaneous muscle and nerve biopsies. A surgical pathology database was searched from 1993 to 2011 to identify patients who had concomitant skeletal muscle and peripheral nerve biopsies. Demographic and pathologic findings were recorded for all cases. Two hundred eighty-seven patients were included for study. There were 161 (56%) males and 126 (44%) females with a mean age at the time of biopsy of 51 years. The most commonly sampled sites were gastrocnemius muscle (n = 186, 65%) and sural nerve (n = 264, 92%). Most cases (n = 166, 58%) were found to have a definitive diagnosis in either muscle or nerve. Of the cases with definitive diagnoses, 44 (27%) were based off the muscle only, 100 (60%) off the nerve only, and 22 (13%) had a definitive diagnosis in both the muscle and nerve. The most common diagnoses made on muscle biopsy alone were denervation atrophy (n = 34) and inflammatory myopathy (n = 7). The most common diagnosis made on nerve biopsy alone was a moderate or greater degree of axonal loss (n = 82). Vasculitis was found in muscle in 2 cases, in the nerve in 14 cases, and both muscle and nerve in 4 cases. Amyloidosis was exclusive to muscle in no cases, was seen in nerve only in 1 case, and was found in both muscle and nerve in 4 cases. Performing simultaneous muscle and nerve biopsies can improve diagnostic yield (from 8% to 58% in the current study).     

Diagnosis and classification of polyarteritis nodosa

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis preferentially targeting medium-sized arteries and not associated with glomerulonephritis or small vessel involvement. Anti-neutrophil cytoplasmic antibodies are typically negative. PAN may be triggered by viral infections, particularly hepatitis B virus, but remains idiopathic in most cases. Clinical manifestations of PAN are multisystemic. Peripheral nerve and skin are the most frequently affected tissues. Involvement of the gastrointestinal tract, kidneys, heart, and central nervous system is associated with higher mortality. Laboratory abnormalities reveal a prominent acute phase response but are non-specific. Histologic confirmation of vasculitis in medium sized arteries is desirable and biopsies must be obtained from symptomatic organs if feasible. Skin or muscle and nerve are preferred because of higher diagnostic yield and safety. If biopsies are negative or cannot be obtained, visceral angiography, may reveal multiple micro-aneurysms supporting the diagnosis of PAN. Current treatment policy includes high-dose corticosteroids, which are combined with immunosuppressive agents when critical organ involvement or life-threatening complications occur. IV pulse cyclophosphamide in the remission induction phase, later switched to a safer immunosuppressant for remission maintenance is a frequently used therapeutic approach. A recent consensus algorithm for the classification of PAN has attempted to overcome some of the caveats of the 1990 American College of Rheumatology (ACR) classification criteria which have proven to be unsatisfactory, and has also confirmed the low prevalence of PAN compared to other systemic necrotizing vasculitides. European league against rheumatic diseases (EULAR)/ACR endorsed international cooperation to establish new diagnostic/classification criteria is currently under way.     

Rectal biopsy in the diagnosis of systemic vasculitis.

Vasculitis has been seen in rectal biopsies from 22 patients over a six year period. The most common finding was a necrotising vasculitis of small arteries, indistinguishable from that seen in polyarteritis nodosa (PAN). Sub-acute, chronic ("burnt out") and leucocytoclastic changes were also seen. Sixteen patients had vasculitis complicating rheumatoid arthritis (RA), 3 PAN and 3 overlap syndromes. Patients with RA and rectal vasculitis had a higher mortality, and a greater incidence of neuropathy than those with negative biopsies. An adequate biopsy is positive in 40% of patients with clinical vasculitis and RA but was only positive in one of a control series of 46 RA patients with no clinical vasculitis. Rectal biopsy in experienced hands is a safe, and repeatable procedure. It is useful as a "blind" biopsy site in the diagnosis of systemic vasculitis, especially that complicating RA. It can also be used for serial studies of the evolution of vasculitis. Serial sections of the entire biopsy may be required to reveal the vasculitis which is often focal in nature.     

Histopathologie systemischer Vaskulitiden

Inflammatory diseases of blood vessels can occur in any part of the vascular system with a variety of clinical and histopathological manifestations. Possible etiologies include primary systemic vasculitis, secondary vasculitis or isolated single organ vasculitis. Key criteria of morphological vasculitis work-up are vessel size, type of inflammation (granulomatous, necrotizing and/or leukocytoclastic) as well as presence or absence of immune complexes and extravascular inflammatory changes. Together with the typical organ involvement and serological data, these criteria constitute the basis of vasculitis classification. A histopathologically confirmed biopsy is the gold standard for a diagnosis of vasculitis, although a definite diagnosis can frequently not be made solely on histopathological grounds. Differential diagnostic overlaps and possible ways of discrimination are presented. In many cases, however, histopathology can only provide a definite diagnosis in combination with clinical and serological data. A conclusive morphological diagnosis depends on the right time of biopsy and selection of appropriate biopsy material.     

Vasculitis in chronic urticaria

We have explored the problem of the histologic basis of chronic urticaria and its relation to vasculitis and immune complex disease. In a prospective study, 42 consecutive patients with chronic urticaria (from twice weekly to daily episodes lasting more than 6 wk) had skin biopsies and were studied for immunologic variables. Twenty-two patients (52%) had vasculitis on biopsy as defined by the presence of cellular infiltrates within the vessel wall. The other 20 patients (48%) had either edema only or perivascular infiltrates with mononuclear cells (perivasculitis). The group with vasculitis could be subdivided into seven patients with neutrophilic venulitis including three with fibrinoid change, seven with mixed-cellular vasculitis, four with lymphol monocytic vasculitis, and four with eosinophilic vasculitis. Vascular deposits of immunoreactants were found in only four (18%) of the vasculitis patients, compared with 65% of concurrently studied patients who had cutaneous venulitis manifested as palpable purpura, i.e., Henoch-Schönlein syndrome. Urticarial patients with vasculitis were more often male and had a longer mean duration of hives compared with the nonvasculitis group. We saw no differences between the vasculitis and nonvasculitis cases of urticaria with regard to the incidence of arthralgia, elevated erythrocyte sedimentation rate (ESR), or hypocomplementemia. The group with vasculitis did not have more generalized disease nor were the hives more resistant to therapy. We have discussed the definition and histologic criteria for the diagnosis of vasculitis when it occurs in very small blood vessels.     

The diagnosis and classification of giant cell arteritis

Giant-cell arteritis (GCA) involves the major branches of the aorta with predilection for the extracranial branches of the carotid artery. It occurs in individuals older than 50 years and the incidence increases with age. The signs and symptoms of giant cell arteritis can be classified into four subsets: cranial arteritis, extracranial arteritis, systemic symptoms and polymyalgia rheumatica. Patients may develop any combination of these manifestations, associated with laboratory evidence of an acute-phase reaction. The only test that confirms GCA diagnosis is a temporal artery biopsy, showing vasculitis with mononuclear cell inflammatory infiltrates, often with giant cells. Due to the focal and segmental nature of the infiltrates, areas of inflammation may be missed by the biopsy and the histological examination is normal in about 15% of the cases. Some imaging modalities may aid in the diagnosis of GCA. Among those, color duplex ultrasonography of the temporal arteries is more commonly used. There are no independent validating criteria to determine whether giant cell arteritis is present when a temporal artery biopsy is negative. The American College of Rheumatology criteria for the classification of giant cell arteritis may assist in the diagnosis. However, meeting classification criteria is not equivalent to making the diagnosis in individual patients, and the final diagnosis should be based on all clinical, laboratory, imaging and histological findings. Glucocorticoids are the treatment of choice for GCA. The initial dose is 40–60 mg/day for most uncomplicated cases. Addition of low-dose aspirin (100 mg/d) has been shown to significantly decrease the rate of vision loss and stroke during the course of the disease.     

Immunolocalization of protein-bound 3-nitrotyrosine in inflammatory myopathies

3-nitrotyrosine (3NT) is regarded as a "footprint" of nitric oxide generation. The study aimed at documenting the presence and distribution of 3-nitrotyrosine (3NT) in muscle tissue samples from patients with idiopathic inflammatory myopathies (IIM) as well as from those with non-inflammatory myopathies to consider whether polymyositis (PM) and dermatomyositis (DM) could be distinguished based on 3NT immunohistochemistry in muscle biopsy. Cryosections prepared from muscle biopsies of 54 patients with either IIM, i.e., PM and DM, or various non-inflammatory myopathies were immunostained using monoclonal antibody against 3NT. The 3NT immunostaining was localized to endothelial cells and their close surroundings in muscle biopsies of DM and PM patients but only in those areas of tissue sections where inflammatory cell infiltrates were present. No 3NT positivity was found in tissue sections of IIM patients without inflammatory infiltrates in the studied sample as well as in muscle tissue sections of patients with non-inflammatory myopathies. However, the endothelial cells were also positive in cases of confirmed non-inflammatory myopathies with secondary lymphocytic infiltration (myodystrophies, myasthenia gravis). Despite the pathogenetic significance, the 3NT immunohistochemistry is of low diagnostic value for the differential diagnosis of IIM in muscle biopsy.     

The diagnosis and classification of microscopic polyangiitis

Microscopic Polyangiitis (MPA) is a small vessel vasculitis. The disease is defined by the 2012 revised Chapel Hill Consensus Conference Nomenclature of Vasculitides [1] as necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e. capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent. MPA belongs to the ANCA-associated vasculitides (AAV). ANCA in MPA are predominantly directed against myeloperoxidase (MPO-ANCA) but may, in a minority of patients, be directed against proteinase 3 (PR3-ANCA). Not all patients, however, have ANCA. Microscopic polyangiitis (MPA) belongs to the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. MPA is clinically characterized by small-vessel vasculitis primarily affecting the kidneys and the lungs but other organs may be involved as well. Renal involvement, which can be the only manifestation, is clinically apparent as rapidly progressive glomerulonephritis and histopathologically as pauci-immune necrotizing and crescentic glomerulonephritis. ANCA in MPA are mainly directed to myeloperoxidase (MPO-ANCA). Besides their diagnostic significance, MPO-ANCA appear pathogenic in MPA. Rituximab with steroids is at least as effective as cyclophosphamide with steroids for induction of remission.     

Vasculitides: classification,clinical aspects and pathology. A review

The Consensus Conference of Chapel Hill (1994) laid a common base for a standardized classification of vasculitides which, after a pre-existing historical diversity, enabled a comparison of different studies. The criteria for this classification are foremost anatomico-pathological and are based on the caliber of affected blood vessels. In addition the quality of the inflammatory reaction, and the entirety of clinical symptoms, as well as the results of immunological tests are included. Moreover a unified pathogenetic concept is proposed for all types of vasculitis. The diagnosis of vasculitis of large, medium or small vessels is made primarily by biopsies and examination of HE-stained sections. However, overlap of calibers of vessels affected and lack of specificity of inflammatory reaction with individual vasculitis types have to be paid attention to. Immunohistochemical methods are only rarely routinely applied. In contrast the complete clinical picture and the results of immunological laboratory tests (especially AntiNeutrophilCytoplasmicAntibodies, ANCA) play an important role in the differential diagnosis of various vasculitis types. Definitions, clinical findings and pathology of the various types of vasculitis are described. Also mentioned are secondary vasculitides, e.g concurrent to collagen diseases or infections. Not only the diagnosis of vasculitis but also the recognition of the specific type and, last but not least monitoring by histological controls, may be decisive for an optimal therapy.     

Inflammatory muscle involvement in systemic vasculitis: A systematic review

Vasculitis are severe systemic autoimmune diseases which may involve different organs and systems. Conversely, muscles do not represent an organ commonly involved by systemic vasculitis and myositis is not include among any classification or diagnostic criterion of vasculitis.In this regard, we aimed to review the literature in order to report all the available evidence concerning the inflammatory involvement of muscle in patients affected by systemic vasculitis.We collected a total of 108 papers, for a sum of 395 patients affected by muscle vasculitis. Most of them suffered from medium and small vessels vasculitis (mainly polyarteritis nodosa and ANCA-associated vasculitis) or from vasculitis secondary to rheumatoid arthritis. Conversely, muscle involvement in case of large vessel vasculitis occurred seldom, while only few papers reported such occurrence in Kawasaki or Behçet's disease.Histological findings may differ, but the most common ones displayed a necrotizing vasculitis of perimysium vessels, while granulomatous vasculitis was assessed only in case of ANCA-associated vasculitis patients.Creatine kinase were usually within normal range, seldom elevated, while imaging findings were generally undistinguishable from the ones found in idiopathic inflammatory myopathies: magnetic resonance imaging displays signal hyperintensity in T2 and STIR scans, while few data exist for positron emission tomography.The presentation of the disease may be fearsome and severe, sometimes life-threatening, but an overall good response to conventional immunosuppressants and/or glucocorticoids has been reported.     

Necrotizing angiitis of the small intestine related to AA-amyloidosis: a novel association

A 71-year-old man with intestinal pseudo-obstruction was found to have a diffusely thickened adynamic small bowel with AA-amyloid in submucosal vessels and muscularis propria, foreign body giant cell reaction to amyloid, and necrotizing angiitis. The mucosa was unremarkable. Immunostains demonstrated numerous CD68+ monocyte/macrophages and CD8+ T cells associated with the amyloid deposits. The patient had no evidence of systemic vasculitis and no underlying cause for AA-amyloidosis was identified. Necrotizing angiitis coexistent with amyloid angiopathy has been reported in brain and temporal arteries, but not in the gastrointestinal tract and not with AA-amyloid. The inflammatory cell infiltrates in this case are consistent with a foreign-body and/or cell-mediated immunologic reaction to AA-amyloid, although a role for these cells in amyloid formation cannot be excluded.     

HLA-DR in Brazilian Patients with Polyarteritis Nodosa (PAN) and Microscopic Polyangiitis (MPA)

The aim of this study was to evaluate the frequency and clinical associations of HLA-DR alleles in Brazilian Caucasian patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA). We evaluated 29 Caucasian patients with vasculitis classified as PAN or MPA according to the American College of Rheumatology (ACR) 1990 Criteria, Chapel Hill Consensus Conference (CHCC) nomenclature for vasculitis and EULAR recommendations for conducting clinical studies in systemic vasculitis. HLA-DR alleles were typed using polymerase chain reaction-amplified DNA, hybridized with sequence-specific low resolution primers. DNA obtained from 59 Caucasian healthy blood donors were used as control. In order to evaluate if a specific HLA may have influence on the clinical profile of those diseases, we also divided the patients according to Birmingham vasculitis score (BVAS) and Five-Factors Score (FFS) at the time of diagnosis. Increased frequency of HLA-DRB1*16 (p = 0.023) and DRB4*01 (p = 0.048) was found in patients with higher disease activity at the time of diagnosis (BVAS ≥ 22). Patients with less severe disease (FFS = 0) had a higher frequency of HLA-DRB1*03 (p = 0.011). Patients with gastrointestinal tract involvement had significantly increased frequency of HLA-DRB1*11 or B1*12 (p = 0.046), B1*13 (p = 0.021) and B3 (p = 0.008). In contrast, patients with renal disease, had higher frequency of DRB1*15 or DRB1*16 (p = 0.035) and B5 (p = 0.035). In the subgroup of patients with MPA, increased frequency of HLA-DRB1*15 was found in patients with BVAS ≥ 22 (p = 0.038) and FFS ≥ 1 (p = 0.039) suggesting that this allele is associated with more aggressive disease. Antineutrophil cytoplasmic antibodies (ANCA) negative MPA patients had significantly increased frequency of HLA-DRB1*11 or DRB1*12 when compared to ANCA positive patients (p = 0.023). Our results suggest that HLA-DR alleles may influence PAN and MPA clinical expression and outcome and that in MPA they participate in the mechanisms involved in the development to ANCA.     

L-tryptophan and the eosinophilia-myalgia syndrome: pathologic findings in eight patients

Pathologic findings in eight patients with the eosinophilia-myalgia syndrome, secondary to L-tryptophan ingestion, are reported. Tissue was obtained by biopsy alone in six patients, by biopsy and autopsy in the seventh patient, and by autopsy alone in the eighth patient. Muscle biopsies in five patients demonstrated an inflammatory infiltrate composed predominantly of lymphocytes, histiocytes, plasma cells, and a few eosinophils. The inflammation involved the perimysial and epimysial connective tissue, the walls of some small blood vessels, the perineurium of small nerve twigs, muscle spindles, and fibrous septae of subcutaneous adipose tissue. In two patients with peripheral neuropathy and one patient without overt neuropathy, denervation atrophy of muscle and perimysial and epimysial fibrosis were present. Sural nerve biopsy tissue taken from two patients displayed prominent axonopathy in one, and minimal changes in the second. Pulmonary changes in the two autopsied patients included endothelial cell damage, endovasculitis and fibromyxoid intimal change im arteries and veins, and interstitial pneumonitis with fibrosis.     

Diagnostic features and differential diagnosis of Churg-Strauss syndrome in the lung. A review

Churg-Strauss syndrome is a rare systemic vasculitis occurring in patients with asthma and blood eosinophilia. Lungs, skin, and nervous system are the most common sites of involvement, although many other organs are affected frequently. The diagnosis often is established from clinical findings or biopsy of extrapulmonary sites, and lung biopsy is performed infrequently. The classic pathologic findings in the lung include a combination of eosinophilic pneumonia, granulomatous inflammation, and vasculitis. All 3 features may not be present in every case, however, and diagnosis often requires careful correlation of the clinical and pathologic findings. The differential diagnosis in the lung includes diseases that are associated with eosinophil infiltrates or a combination of eosinophil infiltrates and granulomatous inflammation. Distinguishing these various diseases from Churg-Strauss syndrome is especially important, since many are more common than Churg-Strauss syndrome, and treatment is usually different.     

Systemic injection of products of activated neutrophils and H2O2 in myeloperoxidase-immunized rats leads to necrotizing vasculitis in the lungs and gut.

The strong association of anti-neutrophil cytoplasmic antibodies with various forms of systemic vasculitis suggests a role for these autoantibodies in the pathophysiology of systemic vasculitis. In the present study, we tested the hypothesis that release of neutrophil lysosomal enzymes in the presence of an anti-myeloperoxidase (anti-MPO) immune response may underlie the development of systemic vasculitis. Brown Norway rats were immunized with MPO in complete Freund's adjuvant or complete Freund's adjuvant alone. Two weeks after immunization, rats bad developed antibodies to human and rat MPO as measured by enzyme-linked immunosorbent assay. Next, rats were intravenously infused with 400 micrograms of a human neutrophil lysosomal extract containing 200 micrograms of MPO followed by 0.5 ml of a 1 mmol/L solution of H2O2 through a cannula inserted into the right jugular vein. Rats were sacrificed at 4 hours, 24 hours, 7 days, or 14 days, and several organs (lungs, heart, liver, spleen, gut, and kidneys) were examined for vasculitic lesions and inflammatory cell infiltrates. Macroscopically, patchy hemorrhagic spots were observed in the lungs and gut of MPO-immunized rats at days 7 and 14 after systemic infection of the neutrophil lysosomal extract and H2O2. Such changes were not observed at earlier time points or in control immunized rats. Histologically, the lungs of MPO-immunized rats sacrificed at days 7 and 14 showed patchy inflammatory cell infiltrates associated with vasculitis, granuloma formation, giant cells, and foci of hemorrhage. At 14 days, early signs of fibrosis were found with deposition of collagen and proliferation of fibroblasts. Furthermore, a prominent leukocytoclastic vasculitis was found in the small intestine of these rats characterized by fibrinoid necrosis and an extensive neutrophilic infiltrate. No inflammatory changes were found in the other organs studied (heart, liver, spleen, and kidneys). Control immunized rats, sacrificed at days 7 and 14 showed only some small foci of inflammatory infiltrates in the lungs whereas no inflammatory changes were found in the gastrointestinal tract. These studies show that release of products from activated neutrophils in the presence of anti-MPO autoantibodies may be relevant to the pathogenesis of anti-MPO-associated vasculitides.