Ursula Göbel

15-Deoxyspergualin in Patients with Refractory ANCA-Associated Systemic Vasculitis: A Six-Month Open-Label Trial to Evaluate Safety and Efficacy

The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/ micro l followed by a rest until at least a WBC of 4000/ micro l was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count.

Cardiovascular Magnetic Resonance Imaging Detects Cardiac Involvement in Churg-Strauss Syndrome

BACKGROUND Cardiac involvement in Churg-Strauss vasculitis worsens the prognosis. Early detection is, therefore, warranted. Cardiac magnetic resonance (CMR) can visualize various forms of inflammatory changes in the myocardium. We tested whether CMR could elucidate cardiac damage in patients with biopsy-proven Churg-Strauss syndrome and clinical evidence of cardiac involvement. METHODS AND RESULTS Eleven patients underwent a CMR protocol including cine imaging for left ventricular function in long axes, T2-weighted imaging for edema detection, and contrast-enhanced T1-weighting for early and late gadolinium enhancement. CMR detected various form of myocardial injury in all patients. Systolic left ventricular function was impaired in 6 patients. Mean left ventricular ejection fraction was 45 +/- 15%. Left ventricular size was mildly enlarged (left ventricular end-diastolic volume index 94 +/- 23 mL/m(2)). Edema was present in 4 cases; 7 patients had pericardial effusion. Six patients had increased early contrast uptake. CMR detected late enhancement lesions in 9 of 11 patients, even in those with normal left ventricular size and function. CONCLUSIONS CMR has the potential to detect myocardial injury in Churg-Strauss syndrome even when left ventricular function appears normal.

Disease activity and autoantibodies to endothelial cells in patients with Wegener's granulomatosis

The purpose of this study was to assess the utility of antiendothelial cell antibodies (AECAs) in patients with active and inactive Wegeners granulomatosis. We studied 32 patients with Wegeners disease (clinical criteria and biopsy, as well as titers of antineutrophil cytoplasmic antibodies with a cytoplasmic pattern [cANCA]) over 4 years and compared their AECA values with those of 24 normal subjects similar in age and gender distribution, as well as with those of patients with chronic glomerulonephritis with or without dialysis and of patients with severe arteriosclerosis. We measured AECAs, cANCAs, C-reactive protein, erythrocyte sedimentation rate, proteinuria, and renal function in patients with active disease or in patients reactivating their disease. A time course with repeated AECAs was conducted over 27 months in 24 patients. The AECAs were measured with an enzyme-linked immunosorbent assay. The specificity was verified with immunofluorescent confocal microscopy, which showed the AECA epitopes to be within the cytoplasm of endothelial cells. Elevated AECA titers were found in all patients with active disease, not all of whom had positive cANCAs. Although elevated AECAs were also found in some patients with inactive disease, normal AECA values were seen only in patients with inactive disease. Patients with active disease entering remission showed a decrease in AECA titers, while patients entering a relapse increased their AECA titers. We conclude that AECAs are present in patients with Wegeners granulomatosis. To our knowledge, these are the first serial AECA observations. Our data suggest that AECAs are correlated with disease activity. Antiendothelial cell antibody values in the normal range strongly support remission. These findings may be of clinical utility in distinguishing relapse from concomitant illness.

Cytomegalovirus Colitis during Mycophenolate Mofetil Therapy for Wegener’s Granulomatosis

Cytomegalovirus (CMV) infection of the gastrointestinal tract is an increasingly recognized cause of morbidity and mortality during the course of HIV infection and in association with immunosuppressive pharmacotherapy. Mycophenolate mofetil, a novel immunosuppressive drug, is currently used in renal transplant recipients and is under evaluation for a variety of disorders. There is preliminary evidence to suggest that CMV reactivation may be more common during treatment with mycophenolate than with other immunosuppressive drugs. We present the case of a 59-year-old male with Wegener’s granulomatosis who received mycophenolate and presented with guaiac-positive diarrhea 8 weeks after recovery from Salmonella brandenburg infection. CMV serology and assays for CMV antigens were entirely negative. Colonoscopy demonstrated pancolitis and examination of the specimens disclosed CMV infection. Ganciclovir was administered and the patient made an uneventful recovery. We discuss aspects of gastrointestinal CMV infection with an emphasis on pitfalls in diagnosis and the association with mycophenolate mofetil treatment. We also speculate as to the potential role of previous Salmonella infection and proinflammatory cytokines in CMV reactivation. In summary, when using mycophenolate, clinicians should be more aware of CMV reactivation and disease.

Prognostic factors in Wegener's granulomatosis.

We analysed data from 64 patients with Wegeners granulomatosis to determine predictor variables of outcome. The mean period of observation after the diagnosis had been established was 3.2 (range 0.1-11.2) years. At the time of diagnosis, 15 (23%) patients had only local symptoms. The disease was generalized to multiple organs in 49 (77%) patients. Renal biopsies were obtained in 33 patients; 13 (39%) had extracapillary glomerulonephritis, which was the most common renal lesion. All but three patients received immunosuppressive therapy. At time of follow-up, 17 (27%) patients were in complete, and 26 (40%) in partial remission. We employed a Kaplan Meier analysis to identify predictor variables of outcome. Renal involvement, initial creatinine concentration, serum albumin or total protein concentration, leukocyte count and erythrocyturia proved to be predictor variables. These variables may be of value in guiding the intensity of treatment in patients with Wegeners granulomatosis.

Sudden death and Wegener's granulomatosis of the pituitary.

Involvement of brain parenchyma or meninges in ANCA-associated small-vessel vasculitis such as Wegeners granulomatosis (WG) is not uncommon. In contrast, involvement of the pituitary is exceedingly rare with only a few cases reported so far. The diagnosis is usually made on the basis of imaging techniques and abnormal pituitary function tests in the setting of active systemic vasculitis. However, histology-proven involvement of the pituitary by WG has not been reported so far. We report a case of WG with histology-proven granulomatous necrotizing inflammation of the pituitary and hypothalamo-pituitary stalk, disclosed at autopsy after the patient had died suddenly and unexpectedly in his sleep. In a setting of histology-proven WG, these findings were regarded as a pituitary manifestation of the disorder. A distinct cause of death could not be found, hence we speculate that hypothalamo-pituitary inflammation due to WG may have caused the sudden death in this patient.Involvement of brain parenchyma or meninges in ANCA-associated small-vessel vasculitis such as Wegeners granulomatosis (WG) is not uncommon. In contrast, involvement of the pituitary is exceedingly rare with only a few cases reported so far. The diagnosis is usually made on the basis of imaging techniques and abnormal pituitary function tests in the setting of active systemic vasculitis. However, histology-proven involvement of the pituitary by WG has not been reported so far. We report a case of WG with histology-proven granulomatous necrotizing inflammation of the pituitary and hypothalamo-pituitary stalk, disclosed at autopsy after the patient had died suddenly and unexpectedly in his sleep. In a setting of histology-proven WG, these findings were regarded as a pituitary manifestation of the disorder. A distinct cause of death could not be found, hence we speculate that hypothalamo-pituitary inflammation due to WG may have caused the sudden death in this patient.

Temporal arteritis with pauci-immune glomerulonephritis: a systemic disease.

Temporal arteritis is easily diagnosed and responds gratifyingly to treatment. Renal complications are unusual, but nevertheless occur. Earlier, an association between pauci-immune glomerulonephritis and temporal arteritis was shown. We present a patient who clearly had temporal arteritis but also developed cerebral hemorrhage, pulmonary infiltrates related to granulomatous pulmonary vasculitis, and pauci-immune glomerulonephritis. We suggest that temporal arteritis is neither always localized nor temporal. Instead, the condition can be a lethal, systemic disease. Renal involvement in patients with temporal arteritis is not common and the presence of glomerulonephritis is rare [Jennette and Falk 1994]. Lenz et al. [1998] described a patient who developed vision loss, optic nerve atrophy, elevated erythrocyte sedimentation rate, a positive rheumatoid factor and terminal glomerulonephritis. The renal biopsy showed focal and segmental necrotizing glomerulonephritis, despite negative antineutrophil cytoplasmatic antibodies (ANCA), antinuclear antibodies and antiglomerular basement membrane antibodies. Giant cells were identified in the necrotic vessel walls within the kidney. Immunofluorescence was negative and a diagnosis of ANCA-negative pauci-immune glomerulonephritis was made. The patient did not respond to immunosuppression and developed end-stage renal disease. Although the clinical attributes were consistent with temporal arteritis, no temporal artery biopsy was done in that patient. We recently treated a patient with temporal arteritis and pauci-immune glomerulonephritis. Our patients course was somewhat different in comparison to the patient described by Lenz et al. [1998].

Spontaneous splenic hemorrhage in a patient with Wegener's granulomatosis

We report the occurrence of spontaneous splenic hemorrhage in a patient with Wegeners granulomatosis. Pulmonary infiltrates, hemoptysis, and crescentic glomerulonephritis were accompanied by a progressive splenic enlargement with minimal abdominal symptoms. Magnetic resonance imaging was particularly helpful. The spleen was removed by minimally invasive endoscopic surgery. Subcapsular hemorrhage had occurred because of splenic vasculitis. Postoperatively, a remission was achieved by a combination of high-dose corticosteroids and cyclophosphamide.

Membrane proteinase 3 and Wegener's granulomatosis.

Proteinase 3 (PR3) is found in neutrophil and monocyte lysosomal granules. Anti-neutrophil cytoplasmatic antibodies (ANCA) with specificity for PR3 are characteristic for patients with Wegeners granulomatosis. The interaction of ANCA with neutrophilic ANCA antigens is necessary for the development of ANCA-associated diseases. ANCA bind to membrane-expressed PR3 and induce full-blown activation in primed neutrophils. We discuss two different aspects of membrane PR3 (mPR3). The first aspect is the amount of PR3 and mechanisms controlling this issue. The second aspect is the presence of two neutrophil subsets that differ in the mPR3 expression phenotype.

Pericardial effusion in the nephrotic syndrome.

Hydropericardium is a known cause of pericardial effusion related to severely expanded extracellular fluid volume. Nephrotic patients have expanded extracellular fluid volume but obviously may have other causes for pericardial effusion. We tested the hypothesis that pericardial effusion is related to inflammation and not to hydropericardium in patients with nephrotic syndrome. Twenty nephrotic patients with systemic lupus erythematosus (SLE) were compared to 20 patients with nephrotic syndrome of other causes. No patient in either group had symptoms or signs of pericardial disease. Pleural effusion and ascites were equally common in SLE-nephrotic patients compared to non-SLE-nephrotic patients. However, 8 SLE patients had pericardial effusion, while none of the non-SLE-nephrotic patients had pericardial effusion. We suggest that hydropericardium is rare in nephrotic patients and that an inflammatory or other secondary cause should be considered when pericardial effusion complicates nephrotic syndrome.