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Studies on vasculitis. VI. Antiglobulins or rheumatoid-like factors in cutaneous vasculitis lesions detected by an improved immunofluorescence procedure.

Human cutaneous vasculitis lesions tend to be chronic in contrast to ephemeral experimental Arthus responses. Human lesions were examined for fixed antiglobulin antibodies, as occur in rheumatoid joint synovia, which could bind globulins to form tissue-damaging complexes and perpetuate the inflammation. The immunofluorescence procedure was modified by pretreating sections with 5% bovine serum albumin, and by using fluorescein conjugates of F(ab)2 portions of antibodies to avoid the antigen-nonspecific binding that sometimes occurs in inflamed or necrotic tissue. Previous findings of immunoglobulins in lesions were confirmed by the more discriminating technique. IgG and IgM was present more frequently in lesions with mainly mononuclear cell changes, than in those with mainly neutrophil changes, leucocytoclastic or necrotizing vasculitis. Fab occurred in some lesions without Fc of IgG or IgM. Three lesions containing IgM or IgM and IgG, specifically bound heat-aggregated whole IgG or Fc of IgG. None bound IgM. The results indicate that the immunoglobulin in some cutaneous vasculitis lesions is locally formed or fixed antiglobulin, which will bind aggregated IgG possibly forming complexes perpetuating the lesion.

Antibodies, Anti-Idiotypic

IgA Vasculitis with necrotizing arteritis: a multicenter retrospective study from the French Vasculitis Study Group and systematic review of the literature.

IgA vasculitis (IgAV) primarily affects small vessels, but rare cases with necrotizing arteritis (NA) raise questions about overlap with polyarteritis nodosa (PAN). To characterize IgAV with necrotizing arteritis (IgAV-NA) and compare its phenotype with classical IgAV and PAN. We performed a multicenter retrospective study combined with a systematic literature review (1990-2025). Patients fulfilled EULAR/PRINTO/PRES IgAV criteria, had pathological or imaging evidence of NA in small or medium arteries, and were ANCA-negative. Thirty patients were included (7 from databases, 23 from the literature). NA was confirmed by biopsy (n = 16) or vascular imaging (n = 14). Clinical features, treatments, remission, and mortality were compared with 257 adult IgAV and 196 PAN patients. Median age was 54.5 years. IgAV-NA was characterized by severe manifestations, including gastrointestinal bleeding, perforation, surgical abdomen, neuropathy, pancreatitis, and livedo. Compared with classical IgAV, IgAV-NA showed significantly higher rates of multi-organ involvement and mortality. Compared with PAN, IgAV-NA shared vascular complications but had less fever and neuropathy. Despite arterial involvement, patients did not fulfil PAN criteria. IgAV-NA represents a rare, severe IgAV phenotype with life-threatening complications rather than an IgAV-PAN overlap. Severe or atypical IgAV presentations should prompt vascular imaging and intensified immunosuppression.

Humans

Circulating immune complexes in cutaneous vasculitis. Detection with C1q and monoclonal rheumatoid factor.

To investigate the pathogeneic significance of immune complexes in cutaneous vasculitis, 107 patients with various forms of cutaneous vasculitis, including 59 patients with necrotizing (leukocytoclastic) vasculitis (group 1), and 48 patients with lymphocytic vasculitis, or a predominately lymphocytic perivascular infiltrate (group 2), were studied. Immunoglobulins or complement components in cutaneous blood vessels were detected by direct immunofluorescence in high frequency in both groups (91 and 88%, respectively). Using two radioassays for circulating immune complexes, Clq or monoclonal rheumatoid factor (mRF) reactive material was detected in 68% of the patients with necrotizing vasculitis but only 44% of the patients in the lymphocytic-perivascular group. The mRF radioassay was elevated in 58% of the first group of patients and 41% of the patients in group 2, although Clq binding activity was increased in 54% of the patients with necrotizing vasculitis but only in 9% of the patients with a lymphocytic vasculitis or lymphocytic perivascular infiltrate. By using both sucrose density gradient ultracentrifugation and Sepharose 6B gel filtration, the Clq and mRF reactive material detected in some patients with necrotizing vasculitis eluted in high molecular weight fractions that were also anticomplementary. In one patient with necrotizing vasculitis and hepatitis B antigenemia, these heavy molecular weight Clq and mRF reactive fractions contained a two- to three-fold increase in hepatitis B surface antigen when compared with lighter molecular weight fractions. Heavy and light molecular weight mRF reactive material could be detected in selected patients in the lymphocytic-perivascular group as well as in the necrotizing vasculitis group. These studies suggest that cutaneous vasculitis, including acute necrotizing (leukocytoclastic) vasculitis and some forms of lymphocytic vasculitis, and perhaps some diseases characterized by a lymphocytic perivascular infiltrate, may represent cutaneous expressions of immune complex disease.

Antigen-Antibody Complex

Immunologic mechanisms in systemic vasculitis.

Thirty-four patients with systemic vasculitis were studied to determine the possible type and frequency of associated immunologic abnormalities. The patients were divided into three clinical groups--those with systemic vasculitis without respiratory tract involvement, those with systemic vasculitis with respiratory tract involvement (particularly Churg-Strauss vasculitis and Wegener's granulomatosis), and those with limited vasculitis without visceral involvement. A diminished level of serum complement was found in half the patients with systemic vasculitis without respiratory tract involvement. These patients usually had diffuse skin disease that often was associated with the presence of rheumatoid factor and cryoglobulinemia and most likely represented an immune-complex induced disease. The serum IgE often was elevated in patients who had systemic vasculitis with respiratory tract involvement, particularly those with Churg-Strauss vasculitis and Wegener's granulomatosis, and may be a clue to the pathogenesis in this group of patients.

Adult

Cryoimmunoglobulinemia in rheumatoid arthritis. Significance in serum of patients with rheumatoid vasculitis.

Cryogloculins were examined in a standardized manner in an unselected group of 35 patients with rheumatoid arthritis (RA) and 8 patients with RA complicated by cutaneous vasuclitis and neuropathy. Optimum conditions for detection and characterization of cryoglobulins were established; the proportion of resolubilized to total precipitable protein remained constant in an individual patient under these conditions. All 8 vascultis patients and 9 of 35 other patients with RA exhibited cryoglobulins; total protein and immunoglobin content were significantly higher in the cryoglobulins of patients with vasculitis. Immunoglobulins G and M constituted two-thirds and three-quarters of the total protein in the cryoglobulins from uncomplicated rheumatoid and vasculitis patients, respectively. Serum antiglobulin titers were higher, and serum C3 levels were lower, in vasculitis patients compared to rheumatoid patients without vasclitis. Anti-gamma globulin activity was detected in all cryoglobulins from vasculitis patients. Cryoglobulin IgG and IgM were polyclonal. Density gradient analyses demonstrated the majority of the cryoglobulin activity to reside in the 19S IgM fraction. There was no evidence of a light weight (8S) IgM. A monoclonal rheumatoid factor did not detect 7S-ANTI-7S complexes in the cryoprecipitates, but acid eluates from some cryoglobulins absorbed with insoluble IgG revealed an antiglobulin of the IgG class. Serial studies performed on vasculitis patients treated with cyclophosphamide disclosed a relationship between clinical evidence of vasculitis and the presence of cryoglobulins. The antigen (IgG) and antibody (largely IgM rheumatoid factor) nature of these cryglobulins is presented as evidence that the widespread vascular complications of RA are mediated, at least in part, by circulating immune complexes.

Aged

Management of necrotizing vasculitis with colchicine. Improvement in patients with cutaneous lesions and Behcet's syndrome.

Six patients with necrotizing vasculitis were treated with oral colchicine as part of an open study. Four patients with cutaneous vasculitis and normal levels of serum complement and one patient with vasculitis associated with Behcet's syndrome demonstrated clinical improvement while receiving colchicine. One patient with cryoglobulinemia, hypocomplementemia, and cutaneous vasculitis showed no response to colchicine therapy. In three patients, clinical improvement persisted after its withdrawal. Colchicine may be effective in controlling cutaneous necrotizing vasculitis and Behcet's syndrome through its effect on polymorphnuclear leukocyte function.

Administration, Oral

Necrotizing vasculitis. Etiologic aspects of immunology and coagulopathy.

Thirty-one patients with cutaneous necrotizing vascultis were studied for immunological and coagulation disturbances. Serum immunoglobulin levels did not correlate with tissue deposition of the corresponding immunoglobulins in the lesions of cutaneous necrotizing vasculitis. In all instances, localization of immunoglobulins, complement, and fibrinogen, when present in the lesions of necrotizing vasculitis, was limited to the vascular wall or perivascular space. Soluble fibrinogen-fibrin complexes (cryoprofibrin) were detected in the blood of four of 17 patients with cutaneous necrotizing vasculitis. Since it represents a product of the limited action of thrombin on fibrinogen, its presence in the blood in some patients with necrotizing vasculitis suggests that intravascular coagulation may play a part in the pathogenesis of the disease. In 12 of the 31 patients studied, a cause of the vasculitis was found or presumed.

Adolescent

Drug related vasculitis. Clinicopathologic correlations in 30 patients.

Drug related vasculitis has variously been described as necrotizing hypersensitivity or allergic angiitis or microscopic panarteritis nodosa. We reviewed tissue sections from 30 patients with validated drug hypersensitivity and vasculitis in order to precisely define this entity. No evidence of necrotizing vascular lesions or of fibrinoid associated with necrosis was found. The vascular lesions in all 30 patients involved small arteries, arterioles, capillaries, and venules. The inflammatory infiltrate consisted primarily of mononuclear cells and prominent numbers of eosinophils and was present in all three layers of the involved vessel walls. Clinically the patients developed either localized or systemic vasculitis, which could not be predicted on the basis of the associated drug. The findings of a skin rash, fever, or eosinophilia and the development of symptoms consistent with a hypersensitivity reaction while medication was being taken were all suggestive of the diagnosis of drug related vasculitis.

Adolescent

The spectrum of vasculitis: clinical, pathologic, immunologic and therapeutic considerations.

Vasculitis is a clinicopathologic process characterized by inflammation and necrosis of blood vessels. Certain disorders have vasculitis as the predominant and most obvious manifestation, whereas others have various degrees of vasculitis in association with other primary disorders. Within the entire spectrum of vasculitis virtually any size or type of blood vessel in any organ system can be involved. Most of the vasculitides can be associated directly or indirectly with immunopathogenic mechanisms. In this regard, immune complex mediation is being increasingly recognized as the underlying mechanism in several of the vasculitides. With clinical, pathologic, and immunologic criteria, certain vasculitic disorders can be clearly recognized and categorized as distinct entities, whereas in others there is an overlap of different diseases within a broader category. In recent years, several of the more serious vasculitides, such as Wegener's granulomatosis and the systemic necrotizing vasculitides of the polyarteritis nodosa group, which formerly had extremely poor prognoses, have been shown to be extraordinarily responsive to chronic low-dose cytotoxic therapy, particularly cyclophosphamide.

Adult

Urticarial vasculitis: report of a case and review of the literature.

A woman with cutaneous vasculitis had a severe bullous eruption that was suggestive of erythema multiforme. The patient also had a history of recurrent urticaria that continued intermittently for over a year of follow-up examination. Skin biopsy specimens of both urticarial and erythema and multiforme lesions showed leukocytoclastic vasculitis. An illness resembling systemic lupus erythematosus (SLE) is suggested by transient, low-titer, positive antinuclear antibody tests, persistent deposits of immunoglobulin and complement in normal skin, arthralgias, circulating immune complexes, and chronic hypocomplementemia. This case is similar to cases previously reported as "hypocomplementemic vasculitis," an "unusual SLE-related syndrome," and "urticaria with vasculitis."

Adult

[Circulating immune complexes and necrotizing vasculitis].

55 patients with necrotizing and with various forms of lymphocytic vasculitis were investigated for the presence of vascular deposits of immunoglobulins (Ig) and C3 by immunofluorescence testing of skin biopsies and with a 125I-Clq-binding assay for the presence of circulating immune complexes. Vascular deposits of Ig and C3 were found frequently both in patients with necrotizing and with lymphocytic vasculitis. In contrast, C1q binding activity was found almost exclusively in sera of patients with systemic necrotizing vasculitis. With one exception, all sera with C1q binding activity were from patients with vascular deposits of Ig and C3. The implications of these findings for our understanding of the development of system involvement in necrotizing vasculitis are discussed.

Antigen-Antibody Complex

Vasculitis with hepatitis B antigenemia: long-term observation in nine patients.

The development of generalized necrotizing vasculitis in association with hepatitis B antigenemia is the first example in man of a chronic rheumatic disease presumably caused by a viral infection. This report reviews the experience in nine biopsy-proven cases of hepatitis B-associated necrotizing vasculitis followed for up to six years. The natural history of the disease is emphasized and the manifestations of patients with vasculitis who carry hepatitis B antigen are compared with those of vasculitis patients who are antigen negative.

Adult

Effect of intracerebral vasculitis on regional cerebral blood flow.

Regional cerebral blood flow was measured by the xenon 133-inhalation method in a 40-year-old man during an acute exacerbation of intracranial vasculitis. Neurologic function was quantitated by the Halstead-Reitan Neuropsychological test battery. The patient was also studied during remission that was induced by steroid therapy. Vasculitis produced a diffuse encephalopathy with generalized reduction in cerebral blood flow. During remission, only local symptoms secondary to a small cerebral infarction remained and regional cerebral blood flow returned to the normal range. There seems to be a close correlation between the severity of symptoms in cerebral vasculitis and reduction of flow through diseased vessels.

Adult

Paraneoplastic vasculitis of nerve: a remote effect of cancer.

The development of mononeuritis multiplex brought three men to medical attention weeks to months prior to the diagnosis of a malignancy. In each case, sural nerve biopsy exhibited active wallerian degeneration with vasculitis. Two of the men died and at autopsy were found to have clinically unrecognized oat cell carcinoma and carcinomatous sensory neuropathy with brainstem encephalitis. The third patient is still alive but was found to have a lymphoma and has subsequently developed a liposarcoma. The vasculitis in all 3 cases seems limited mainly to the peripheral nervous system. Mononeuritis multiplex due to vasculitis may represent a new remote effect of cancer on the nervous system.

Brain Stem

Immunoelectronmicroscopic examination of early lesions in histamine induced immune complex vasculitis in man.

In 4 cases of allergic vasculitis circulating immune complexes (IC) were demonstrated. Spontaneous and histamine induced vascular changes were studied by immunofluorescence microscopy. The early events in IC vasculitis were investigated at the ultrastructural level by immunoelectronmicroscopy using the peroxidase-antiperoxidase multistep technique. Our findings support the concept that human IC vasculitis is triggered by the deposition of circulating IC in the walls of postcapillary venules between endothelial cells, pericytes and the layers of the basal lamina. Tissue destruction is only secondary due to local complement activation and the release of lysosomal enzymes from chemotactically attracted leukocytes.

Adult

Immunologic vasculitis in beige mice with deficiency of leukocytic neutral protease.

Immune complex vasculitis has been induced in normal mice and in mice with features of the Chediak-Higashi syndrome ("beige" mice). The accumulation of neutrophils in peritoneal exudates after the injection of C5a is not quantitatively depressed in beige as compared with normal mice. Immune complex-induced vasculitis in these two strains of mice is not quantitatively different, as assessed by vascular damage (vasopermeability changes and histologic criteria). Measurements of leukocyte enzymes confirm the findings of Vassalli et al. that leukocytes of beige mice lack neutral protease activity. The data suggest that the neutral protease of murine leukocytes does not account for the vascular damage of immune complex vasculitis.

Animals