Antineutrophil cytoplasmic antibodies in 2 patients with Wegener's granulomatosis

We describe two patients with diffuse alveolar hemorrhage and Wegener s Granulomatosis. In both cases, ANCA were demonstrated. We discuss the profit about ANCA s in the diagnosis and management the systemic vasculitis.     

Cell-mediated autoimmunity in patients with Wegener's granulomatosis (WG)

Despite the well described infiltration of cells of the cellular immune system in vasculitic lesions and the granuloma formation in patients with WG, the role of T cell-mediated autoimmunity in WG is not clear. Reports of T cell proliferation in response to neutrophil azurophilic granule proteins are contradictory. In this study we have assessed the proliferation of T cells of WG patients to purified proteinase 3 (PR3) and to total azurophilic granule proteins in two different assays. In addition to the classical proliferation assay with isolated peripheral blood mononuclear cells, we have used a whole blood proliferation assay. In both assays we found proliferative responses to PR3 in patients with WG. The number of patients reacting to the azurophilic granule extract was higher than the patients reacting to the purified PR3, suggesting that other autoantigens may also be involved. We have identified epitopes of PR3 that may be potential targets of class I-restricted T cell responses in the context of HLA-A*0201, the most common MHC class I molecule. These epitopes were determined by the binding of synthetic PR3 peptides to HLA-A*0201 on the antigen-processing defective cell line, T2. In addition, T cell lines were established from tissue biopsies, obtained from WG patients, and assessed for cytolytic reactivity against T2 cells, preloaded with synthetic PR3 peptides. We conclude that T lymphocytes of WG patients have increased proliferative responses to purified PR3 and to a larger extent to non-fractionated proteins of azurophilic granules of polymorphonuclear neutrophilic leucocytes (PMN).     

Antineutrophil cytoplasmic antibody (ANCA)-positive cutaneous leucocytoclastic vasculitis associated with antithyroid therapy in Graves'' disease

This paper reviews studies of photodynamic therapy for the treatment of lung cancer in Japan, carried out since 1978. Photodynamic therapy has been applied clinically to both early and advanced stages of lung cancer and in combination with surgery. It can preserve pulmonary function, is well tolerated and is cost-effective in comparison with other treatments.     

Serum levels of vascular endothelial growth factor (VEGF) are markedly elevated in patients with Wegener's granulomatosis

OBJECTIVES: Necrotizing vasculitis and granuloma formation are the predominant features of Wegener's granulomatosis (WG). We have investigated the importance of vascular endothelial growth factor (VEGF) in monitoring disease activity in WG. METHODS: Serum VEGF levels were determined in 23 patients with active WG, 21 healthy controls and 25 patients with urinary infection, by ELISA using commercially available antibodies to VEGF. RESULTS: VEGF levels were enormously elevated in patients with WG compared to both controls and patients with urinary infection (P < 0.0001). Of the 23 patients, 21 (91.3%) had VEGF levels above the cut-off value (3.3 ng/ml, calculated as the mean of the controls + 2 S.D.). Further analysis of the data showed that VEGF levels did not correlate with age, sex, incidence of classic antineutrophil cytoplasmic antibodies (c-ANCA) or duration of the disease (P > 0.05), but there was correlation with disease activity (r = 0.51, P < 0.01). VEGF levels were higher in patients with major compared to those with minor disease activity (P < 0.01). However, there was no significant correlation between VEGF levels and the Birmingham scores for vascular activity and damage. CONCLUSION: VEGF levels are raised in WG patients compared to normal controls and may be a marker of disease activity. Further studies on serial blood samples from a large cohort of patients with WG and other systemic vasculitides are needed to evaluate the specificity and usefulness of VEGF levels in monitoring disease activity.     

Antineutrophil cytoplasmic antibodies in sera from colectomised ulcerative colitis patients and its relation to the presence of pouchitis

BACKGROUND: Few studies have evaluated the influence of colectomy on antineutrophil cytoplasmic antibody (ANCA) positivity in ulcerative colitis (UC). In small series of patients it has been suggested that ANCA positivity in UC might be predictive for development of pouchitis after colectomy. AIMS: To assess the prevalence of ANCA in UC patients treated by colectomy and a Brooke's ileostomy (UC-BI) or ileal pouch anal anastomosis (UC-IPAA), and the relation between the presence of ANCA, the type of surgery, and the presence of pouchitis. SUBJECTS: 63 UC patients treated by colectomy (32 with UC-BI and 31 with UC-IPAA), 54 UC, and 24 controls. METHODS: Samples were obtained at least two years after colectomy. ANCA were detected by indirect immunofluorescent assay. RESULTS: There were no differences between patients with (36.3%) or without pouchitis (35.0%) and between patients with UC (55%), UC-BI (40.6%), and UC-IPAA (35.4%). However, ANCA prevalence significantly decreases in the whole group of operated patients (38.0%) compared with non-operated UC (p = 0.044). CONCLUSIONS: The prevalence of ANCA in operated patients was significantly lower than in non-operated UC, suggesting that it might be related either to the presence of inflamed or diseased tissue. ANCA persistence is not related to the surgical procedure and it should not be used as a marker for predicting the development of pouchitis.     

Antineutrophil cytoplasmic autoantibodies (ANCA)--markers in diagnosis and monitoring systemic vasculitides

We present a new class of autoantibodies--ANCA (antineutrophil cytoplasmic autoantibodies) which recognize as target antigen different enzyme constituents of primary granules of neutrophil granulocytes. These autoantibodies are present in a large number of diseases, such as: systemic vasculitides, idiopathic crescentic glomerulonephritis, inflammatory bowel diseases and in some other conditions, including rheumatoid arthritis, SLE, Felty syndrome, acute and chronic infections. ANCA not only facilitate the diagnosis but also have a pathophysiological role for some of the idiopathic vasculitides. In our study, including 110 patients referred to the laboratory for ANCA testing by indirect immunofluorescence technique, only 25 patients were positive with a diffuse cytoplasmic (c ANCA) or perinuclear (p-ANCA) pattern on alcohol fixed slides. Some relevant cases are presented in order to emphasize that ANCA antibodies are a useful marker in the early diagnosis of systemic vasculitides, allowing effective therapeutic handling.     

Antineutrophil cytoplasmic antibodies (ANCA) in rheumatoid arthritis: a prospective study

To investigate a possible relationship between the presence of antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor (RF), antinuclear antibodies (ANA), complement, disease activity and disease severity, 111 clinically well-documented RA patients were studied prospectively for ANCA, RF, ANA, C-reactive protein (CRP), total haemolytic complement (CH50) and complement split product C3d. Disease activity and severity were also assessed clinically, as well as anamnestically, using the Hannover Activity of Daily Living Questionnaire, the functional Steinbrocker grades, and numeric and verbal rating scales. At a serum dilution of 1:50, 20% of the 111 sera showed predominantly an atypical perinuclear staining pattern. There was no correlation between ANCA positivity and serological markers, disease activity and disease severity. Regarding previous therapies with disease-modifying antirheumatic drugs, ANCA+ patients took sulphasalazine significantly more often than ANCA- patients.     

Early experience with intravenous immunoglobulin treatment in Wegener's granulomatosis with ocular involvement

BACKGROUND: Pooled intravenous gammaglobulin (IVIg) was reported to be effective in the treatment of Wegener's granulomatosis (WG). No reports have been made on the effects of this new treatment on ocular manifestations of WG. METHOD: IVIg treatment was given to two patients suffering from WG with ocular involvement after several other treatment regimes had failed. RESULTS: Although the systemic disease was under control, the ocular symptoms of both patients worsened during and after IVIg treatment. In one case an adverse effect consisting of retinal vasculitis was noted on two occasions. CONCLUSION: Although beneficial effects of IVIg treatment on WG have been previously described, the two cases with ocular involvement presented here did not reveal any positive response. Paradoxical and unpredictable reactions cannot be ruled out. Thus, patients treated with IVIg should be closely surveyed by an ophthalmologist.     

Antineutrophil cytoplasmic autoantibodies (ANCA) and their target antigens in Chinese patients with lupus nephritis

BACKGROUND: ANCA have been found in patients with systemic lupus erythematosus (SLE); however, the prevalence of ANCA and their target antigens is still not certain. This study is to investigate the prevalence of ANCA and their target antigens in Chinese patients with lupus nephritis. METHODS: Ninety-five serum samples were collected from 95 renal-biopsy-proven lupus nephritis patients. Indirect immunofluorescence using ethanol-fixed leukocytes as substrate and ELISA using six highly purified known ANCA antigens as solid-phase ligands were performed. The specific ANCA antigens included proteinase 3, myeloperoxidase, bactericidal/permeability-increasing protein, human leukocyte elastase, cathepsin G, and lactoferrin. The prevalence of ANCA in patients with (n=65) and without (n=30) active renal pathological lesions was also compared to reveal whether ANCA correlates with disease activity. RESULTS: (i) None of the sera recognized proteinase 3, myeloperoxidase, and human leukocyte elastase, and only one serum recognized bactericidal/permeability-increasing protein. The striking finding was that 59/95 (62.1%) sera recognized cathepsin G and the titres of some sera reached 1/3200. Eight of 95 sera (8.4%) recognized lactoferrin. (ii) The percentage of anti-cathepsin G antibody positive samples in patients with active renal lesions was significantly higher than in patients without active lesions (73.4 vs 36.7%, P<0.0001), whereas, anti-lactoferrin antibodies had no correlation with active renal lesions. (iii) By indirect immunofluorescence, only 22% of the 95 sera were ANCA positive. CONCLUSIONS: Our results suggest that the majority of lupus nephritis patients have ANCA and that the major target antigens is cathepsin G. Anti-cathepsin G antibodies seem to be correlated with renal disease activity.     

A case of Wegener's granulomatosis with necrosis of the penis

A 31-year-old male had a sudden onset of painful swelling in the penile root region. He then developed necrosis of the penis and further a progressive, chemotherapy-resistant ulcer which involved the perineal region also. Histologically there was evidence of neither malignancy nor specific inflammation, but there were granulomatous tissues with cellular infiltration and scattered vascular necrosis. Examination of the nose suggested gangrenous rhinitis with perforation of the nasal septum. X-ray examination revealed that the nasal septum and conchae had disappeared. Chest roentgenogram also revealed increased hilar shadows in both fields of the chest. Routine laboratory examinations showed slight albuminuria and a normal BUN level. Positive findings included leucocytosis, hyper-gamma-globulinemia, accelerated ESR, positive RA and CRP tests. The patient's death was caused by bleeding from gastric ulcer and pulmonary failure.     

Wegener's granulomatosis: case report and review of the literature

The clinical manifestations of Wegener's granulomatosis (WG) may be varied and easily overlooked. Awareness of distinguishing signs and symptoms allows early recognition and appropriate management. The body of literature dealing with the various facets of this disorder has grown in the past few years. Development of new diagnostic markers and successful therapies has rekindled interest in this disease. To assure early diagnosis and optimal prognosis the physician must maintain a high index of suspicion for WG. Although introduction of immunosuppressive therapy has dramatically improved the course of this disorder, treatment-related morbidity is often profound.     

Successful treatment of Wegener's granulomatosis during pregnancy: a case report and review of the medical literature

During the 18th week of a first pregnancy, a 20-year-old woman visits her physician complaining of cough, sore throat, and hemoptysis of 4 days in duration. A chest radiograph, laboratory study findings including a cytoplasmic antineutrophil cytoplasmic autoantibody titer, and lung biopsy results were consistent with a limited form of Wegener's granulomatosis. She was treated successfully with prednisone and cyclophosphamide. The remainder of her pregnancy was otherwise uneventful and resulted in a normal labor and delivery of a healthy male infant.     

Bronchiolitis obliterans-organizing pneumonia (BOOP)-like variant of Wegener's granulomatosis. A clinicopathologic study of 16 cases

The classic histologic features of Wegener's granulomatosis (WG) in lung include necrotizing granulomatous inflammation and necrotizing vasculitis. Recently, several histologic variants have been recognized, including cases characterized by bronchocentric inflammation, a marked eosinophil infiltrate, alveolar hemorrhage, and capillaritis or interstitial fibrosis. We report 16 cases of another variant in which bronchiolitis obliterans-organizing pneumonia (BOOP)-like fibrosis represents the main histologic finding. The extensive geographic necrosis characteristic of Wegener's granulomatosis was absent in all cases, although small suppurative granulomas, minute foci of bland necrosis, and microabscesses were common. All cases showed the typical necrotizing vasculitis of Wegener's granulomatosis. Other frequent findings included darkly staining multinucleated giant cells, prominent acute inflammation, aggregates of epithelioid histiocytes, hemosiderin-filled macrophages, and areas of nonspecific parenchymal fibrosis. The clinical and radiographic features of this variant of Wegener's granulomatosis appear to be indistinguishable from the classic type. Pathologists need to be aware that Wegener's granulomatosis can occasionally manifest histologic changes suggestive of BOOP. The diagnosis will not be overlooked if additional features, especially vasculitis, suppurative granulomas, tiny necrotic zones, microabscesses, and multinucleated giant cells, are appreciated.     

Survival and vasculitis activity in patients with end-stage renal disease due to Wegener's granulomatosis

BACKGROUND: In patients with end-stage renal disease (ESRD) due to Wegener's granulomatosis, a decrease in vasculitis activity after the development of ESRD, as described in other autoimmune diseases, has been postulated. However, up to now no data in a larger group of patients with Wegener's granulomatosis on chronic dialysis have been available. METHODS: We retrospectively analysed the clinical course of 35 patients with Wegener's granulomatosis and ESRD during chronic dialysis treatment. Diagnosis was based on clinical manifestation, antineutrophil cytoplasmic antibodies and/or histology. RESULTS: During a mean follow-up of 43 months (5-113 months), six patients died, three related to treatment toxicity. The patient survival rates (according to Kaplan-Meier calculation) were 93% after 2 years and 79% after 5 years. Twenty-nine relapses of Wegener's granulomatosis occurred in 17 patients (relapse rate 0.24/patient/year); 2/3 of the relapses were seen during treatment with steroids, 1/6 during cyclophosphamide therapy. The relapses were not related to the dialysis membrane used. Remission or partial remission could be achieved in 93% of the relapses. CONCLUSIONS: The survival of patients on chronic dialysis treatment due to Wegener's granulomatosis was comparable to that of other patient groups with ESRD. The relapse rate was not different from that of non-dialysed patients with Wegener's granulomatosis, and this finding underlines the need for a therapeutic strategy to maintain long-term remission in dialysis-dependent patients, too.     

Antineutrophil cytoplasmic antibodies (ANCA) and abnormal angiograms in polyarteritis nodosa and Churg-Strauss syndrome: indications for the diagnosis of microscopic polyangiitis

Microscopic polyangiitis (MPA) is one of the vasculitides previously included in the polyarteritis nodosa (PAN) group. A diagnosis of MPA is usually considered when glomerulonephritis and/or lung hemorrhage are present. Small-sized vessels are involved and this sign is considered, for some authors, to be the main diagnostic criterion. The present study attempted to define clinical, radiological and immunological characteristics of MPA and to separate them from classic PAN (c-PAN) and Churg-Strauss syndrome. We have shown that, in most cases, patients presenting microaneurysms and/or multiple vessel stenoses, which reflect medium-sized vessel involvement, do not have ANCA. Conversely, patients with glomerulonephritis have almost never had abnormal angiograms. Furthermore, the clinical characteristics of ANCA-positive patients also indicate small-sized vessel involvement. Although at present it is not possible to definitively separate MPA from c-PAN, our results show that ANCA should be considered diagnostic for MPA and, in most cases, should be an exclusion criterion for c-PAN.