[Misleading systemic manifestations of rheumatoid arthritis].
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Arthritis, Infectious↗
Biomedical subjects
A Schnabel
Publications and source records attributed to A Schnabel.
Elevated monocytic IL-12 and TNF-alpha production in Wegener's granulomatosis is normalized by cyclophosphamide and corticosteroid therapy.
Wegener's granulomatosis (WG) is characterized by a predominance of the type 1 T-helper cell (Th1) response. We have studied monocytic cytokine expression in untreated patients and in patients who did not respond to prior methotrexate or trimethoprim-sulphamethoxazole therapy, i.e. patients with active disease. Intracytoplasmic IL-12 and TNF-alpha expression was significantly increased in WG compared with healthy controls. IL-8 expression was not increased. Two and 12 weeks of daily standard oral cyclophosphamide and corticosteroid (CYC + GC) treatment induced a stable remission of the disease. Elevated IL-12 and TNF-alpha expression of monocytes was normalized. The active metabolite of CYC was shown to down-regulate IL-12 mRNA in vitro. Monocytic cytokines, especially IL-12, may have a role in the early determination and skewing of the immunoregulatory response towards a Th1 profile. It appears that CYC + GC exerts its effect by normalizing the Th1-driving cytokine pattern, and CYC may maintain this mode of action. Normalization of the skewed cytokine pattern may be a prerequisite and an indicator of inducing a remission in WG.
Adrenal Cortex Hormones↗
Gene polymorphisms of immunoregulatory cytokines and angiotensin-converting enzyme in Wegener's granulomatosis.
Wegener's granulomatosis is a granulomatous and vasculitic disease of unknown origin. Gene polymorphisms are known to affect phenotypes of numerous diseases. Polymorphisms within the angiotensin-converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), and interleukin-10 (IL-10) genes are suspected to modify the course of granulomatous disorders. We examined whether the genotype frequencies of the named polymorphisms differ in Wegener's granulomatosis from those in healthy controls. Thirty-nine patients with Wegener's granulomatosis were genotyped for the deletion/insertion polymorphism in intron 16 of the ACE gene, a biallelic polymorphism in codon 25 of the TGF-beta1 gene and a biallelic polymorphism at position -1082 of the IL-10 gene and compared with healthy blood donors. For the ACE polymorphism no significant differences were detected neither in the allele frequencies nor in the genotype frequencies. For TGF-beta1 a trend to genotype CG was found. The most interesting result was the observed, significant shift to genotype AA of the IL-10 polymorphism in Wegener's granulomatosis. IL-10 and TGF-beta1, immunoregulatory cytokines capable of down-regulating T helper cell type 1 response, showed a significant shift or a trend, respectively towards genotypes associated with reduced cytokine release, leading to the hypothesis that different immunoregulatory cytokine patterns dependent on gene polymorphisms might be involved in the pathogenesis of Wegener's granulomatosis.
Adult↗
Lack of association between antiphospholipid antibodies and thrombocytopenia in patients with Wegener's granulomatosis.
BACKGROUND AND OBJECTIVE: In patients with Wegener's granulomatosis (WG), thrombocytopenia is less common than thrombocytosis. An increased prevalence of antiphospholipid antibodies (aPL), which is associated with thrombocytopenia, has been noted in patients with WG. The aim of this study was to examine the relationship between thrombocytopenia and aPL in patients with WG. METHODS: Thrombocytopenic episodes were searched for in a random sample of 83 patients with WG. Stored sera obtained during thrombocytopenia, which was defined as platelet count below 130 x 10(9)/L, were examined by 2 different enzyme-linked immunosorbent assays (ELISA) for IgG and IgM anticardiolipin antibodies (aCL) and for IgG antiphosphatidylserine antibodies (aPS). Screening for lupus anticoagulant was performed by use of activated partial thromboplastin time (aPTT). Results were compared with the prevalence of aPL in 20 consecutive nonthrombocytopenic patients with WG. RESULTS: Six cases with thrombocytopenic episodes were found in the group of 83 patients with WG. Increased IgG and IgM aCL were detected in 1 patient, who also had elevated IgG aPS. A positive test result solely for IgM aCL was found in another patient. These findings were consistent in both ELISA for aPL. Five patients were being treated with cyclophosphamide when thrombocytopenia occurred. In the group of nonthrombocytopenic patients with WG, elevated IgG aCL and IgG aPS were consistently detected in 1 patient in both ELISA. Three other patients had positive results in single tests, which were not confirmed by the second assay. In all patients, aPTT was normal. CONCLUSIONS: Thrombocytopenia is a rare finding in patients with WG. A similar prevalence of aPL in thrombocytopenic and nonthrombocytopenic patients with WG provides no evidence that aPL play a major role in the pathogenesis of these events. Thrombocytopenia in WG is more likely caused by the myelotoxic effect of preceding cyclophosphamide treatment. We found a frequency of aPL in WG that exceeds frequencies seen in the general population but does not approximate those detected in systemic lupus erythematosus and closely related disorders. Semin Arthritis Rheum 31:4-11.
Adult↗
CD28 negative T cells are enriched in granulomatous lesions of the respiratory tract in Wegener's granulomatosis.
BACKGROUND: Lack of CD28 expression on peripheral blood CD4+ and CD8+ T cells has been reported in patients with Wegener's granulomatosis (WG), suggesting a pathogenetic role of CD28- T cells in WG. METHODS: Ten patients with WG and six with sarcoidosis (disease control) were analysed. Fluorescence activated cell sorter (FACS) analysis was used to detect CD28 expression on T cells from peripheral venous blood and from bronchoalveolar lavage (BAL) fluid. T cells in biopsy specimens from granulomatous lesions of the upper respiratory tract were analysed for CD28 expression by double immunofluorescence staining. RESULTS: A significantly higher fraction of CD28- T cells was found in the CD4+ and CD8+ T cell compartment in BAL fluid (65.6 (5.4)% and 76.3 (4.1)%, respectively) than in blood (13.4 (6.2)% and 42.9 (6.2)%; p<0.001) in patients with WG but not in those with acute sarcoidosis (6.7 (2.2)% and 53.4 (7.3)% in BAL fluid v 4.1 (2.5)% and 52.0 (9.4)% in blood). The total number of CD4+/CD28- T cells but not of CD8+/CD28- T cells was also significantly higher in BAL fluid than in blood in patients with WG (p<0.05). Patients with WG had a significantly higher fraction of CD28- T cells in the CD4+ and CD8+ T cell compartment in BAL fluid than patients with acute sarcoidosis (65.6 (5.4)% v 6.7 (2.2)%; p<0.001; and 76.3 (4.1)% v 53.4 (7.3)%; p<0.05). The total number of CD4+/CD28- and CD8+/CD28- T cells was also significantly higher in patients with WG than in those with sarcoidosis (p<0.01). An abundance of CD28- T cells was found in granulomatous lesions by double immunofluorescence staining in patients with WG. CONCLUSIONS: Our data indicate enrichment of CD28- T cells in BAL fluid and suggest recruitment of CD28- T cells into granulomatous lesions in WG. Further analysis of the phenotype and function of T cell subsets in WG is needed to better understand leucocyte homing in WG and to find new therapeutic targets.
Aged↗
[Pulmonary vasculitis. Lung support in systemic vascular deterioration].
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Arteritis↗
Anticardiolipin antibodies and antibodies to beta(2)-glycoprotein I in patients with Wegener's granulomatosis.
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Antibodies, Anticardiolipin↗
Activation of neutrophils, eosinophils, and lymphocytes in the lower respiratory tract in Wegener's granulomatosis.
Levels of cell products released by neutrophils, eosinophils and lymphocytes were measured in the bronchoalveolar lavage fluid (BALF) of 19 patients with pulmonary active Wegener's granulomatosis (WG) to assess in vivo the magnitude of cellular activation at sites of active disease. Measurements included the BAL cell profile and BALF levels of myeloperoxidase (MPO), free proteinase 3 (fPR3), complexes of PR3 and alpha1-antitrypsin (PR3/alpha1-AT), eosinophil cationic protein (ECP), peroxidase activity (PEROX), and soluble interleukin-2 receptor (sIL-2R). Six patients also underwent a repeat examination after immunosuppressive treatment. Pulmonary active WG was found to be associated with elevated MPO, PEROX, ECP, and sIL-2R levels in BALF. Only trace amounts of fPR3 were detected, the bulk of PR3 being found in PR3/alpha1-AT complexes. Clinically effective treatment depressed BAL neutrophil counts and reversed elevated levels of MPO and PEROX but had an inconsistent effect on the BAL lymphocyte count and the sIL-2R level. In conclusion, the elevated levels of extracellular MPO and PEROX at a site of active disease and the correlation between these and clinical disease activity support the view that neutrophils are indeed an important effector cell population in WG lung disease. The present data also suggest that oxidative injury is an important aspect of neutrophil-mediated lung injury, whereas it remains unresolved whether the low levels of fPR3 in the BALF adequately reflect the situation at inflammatory tissue sites.
Adult↗
New perspectives in pulmonary angiitis. From pulmonary angiitis and granulomatosis to ANCA associated vasculitis.
Traditionally clinical and histopathological features were mainly relied on for classification of vasculitis and granulomatosis of the lung. These can be complemented by immunodiagnostic features which contribute to the classification as well as to the understanding of the pathogenesis of these disorders. Previously five conditions were classified together under the heading "pulmonary angiitis and granulomatosis" (PA & G), mainly on the basis of histological similarities. These conditions have in common a granulomatous histopathology together with necrosis of varying degree, pulmonary vasculitis and occasionally systemic vasculitis. The introduction of novel immunodiagnostic methods led to different approaches of classification, specifically a separation between a group of disorders associated with antinuclear antibodies (ANA), referred to as collagen vascular diseases, and a group of systemic autoimmune diseases unrelated to ANA, referred to as primary systemic vasculitides. Among the latter, Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA) are associated with a group of autoantibodies (antineutrophil cytoplasmic antibodies--ANCA) which separate them from other members of the PA & G group. The granulomatous and vasculitic disorders WG and CSS together with the non-granulomatous small-vessel vasculitis MPA now form a new group of diseases ('ANCA-associated vasculitides') which have many clinical, serological and immunohistochemical features in common. Collagen vascular diseases (CVD) are serologically characterized by distinct subspecificities of antinuclear antibodies (ANA), sometimes pronounced hypergammaglobulinaemia, complement consumption and immune deposits (antigen-antibody-complement complexes) which are common in situ in immune-complex vasculitis. In this article newer aspects of the clinical course, the immunodiagnostic procedure, and the immunopathogenesis of the relatively large group of pulmonary angiitis will be described.
Antibodies, Antineutrophil Cytoplasmic↗
[Angel trumpet: a poisonous garden plant as a new addictive drug?].
BACKGROUND AND OBJECTIVE: Angel's trumpet (Species Brugmansia) is widely used as a garden plant because it is easily kept and the luxuriance of its flowering. Belonging to the Family Solanacea it contains a large amount of alkaloids (parasympatholytics). Because of its hallucinogenic action, its leaves and flowers are increasingly used by young people as a substitute for the hallucinogen LSD (lysergic acid diethylamide). In the summer of 1997, one of a group of youths died after they had ingested its flowers which they had gathered from front gardens. An investigation was undertaken to identify the alkaloids and measure their concentration in the various parts of the plant. METHODS: Four young and one eight-year old plant were kept outdoors from May until October, and its flowers and leaves were removed for analysis weekly. All samples were deep-frozen at -20 degrees C and later, at the same time, thawed out, weighed and extracted in methanol. The alkaloids were identified by high pressure liquid chromatography (HPLC), diode array detector, separated by means of a Hypersil HyPurity cartridge, and measured at a wave-length of 220 nm. RESULTS: All 66 flowers, 32 leaves and 2 speed capsules contained tropane alkaloids, mainly scopolamine. The highest concentrations were found in the seed capsules, lower ones in the flowers, while the leaves contained only small amounts. Total alkaloid content per flower of the younger plants averaged 0.94 mg, of the younger ones 1.81 mg. The flowers of the old plant contained up to 3 mg scopolamine. CONCLUSION: The ingestion of even a few flowers of Angel's trumpet can cause symptoms of poisoning. Easy availability of the plant thus presents a danger. Because of the increasing incidence of deliberate ingestion by young people, poisoning by Angel's trumpet should be included in the differential diagnosis in patients with confusion and hallucinations of uncertain origin, especially during the summer months.
Adolescent↗
Strontium90 for determination of time since death.
Strontium90 (Sr90) is an artificial nuclear fission product of the atmospheric a-bomb testing between 1945 and 1979. It was spread throughout the atmosphere in the following years. Sr90 is an analogue to calcium and therefore enriched in human bones. Several studies especially in the 1960s and 1970s were undertaken to investigate the Sr90 burden and the resulting incorporated radiation in humans, but present studies are missing. In this study nine bone samples, three from 1931/32 and six from 1989 to 1994 were examined by measuring the Sr90 radiation. The samples from 1931/32 did not show any Sr90 activity. All the samples from 1989 and later showed a Sr90 activity, but the intensity was very variable. Subsequent investigations should be done to determine the cut-off year for measurable Sr90 activity. Furthermore the determination of a specific time since death depending on Sr90 activity should be possible, due to the ranging Sr90 pollution between 1950 and 1980 and different uptake in adolescents and adults.
Adolescent↗
Cytokine profiles in Wegener's granulomatosis: predominance of type 1 (Th1) in the granulomatous inflammation.
OBJECTIVE: To determine whether a specific cytokine pattern (type 1 [Th1] or type 2 [Th2]) predominates in Wegener's granulomatosis (WG), by evaluating interferon-gamma (IFNgamma) and interleukin-4 (IL-4) expression in different compartments of the body (i.e., biopsied nasal mucosal tissue [NBS], bronchoalveolar lavage [BAL] fluid, and peripheral blood [PB]) and comparing the findings with those in disease and healthy control subjects. METHODS: Competitive reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay were used to assess IFNgamma and IL-4 expression in T cell clones (TCC), T cell lines (TCL), and polyclonal CD4+ and CD8+ cells derived from NBS, BAL, and PB. RESULTS: Patients with WG and chronic rhinitis were found to share in situ production of messenger RNA (mRNA) specific for IFNgamma (Th1). Only 2 patients with WG expressed IL-4, whereas IL-4 mRNA PCR products were found in inflamed tissues of the disease control patients. The granuloma-derived T cells of WG patients produced only IFNgamma, while TCC, TCL, and CD4+ and CD8+ T cells from BAL and PB produced mainly IFNgamma. CONCLUSION: Our data indicate that a Thl cytokine pattern predominates in the granulomatous inflammation in patients with WG.
Adult↗
Granulocyte colony-stimulating factor treatment for cyclophosphamide-induced severe neutropenia in Wegener's granulomatosis.
OBJECTIVE: To examine the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in the treatment of cyclophosphamide (CYC)-induced severe neutropenia (<1,000 neutrophils/microl) in patients with generalized Wegener's granulomatosis (WG). METHODS: Six WG patients with severe neutropenia due to CYC treatment (group A) were given short-term dosages of rHuG-CSF. Treatment response in these 6 patients was compared with that in 6 WG patients who were matched for age, sex, disease status, and prior treatment and who received supportive treatment only (group B). RESULTS: The duration of severe neutropenia was significantly shorter in group A patients (4.0+/-0.8 days) than in group B patients (9.0+/-1.3 days; P = 0.03). This was accompanied by fewer bacterial infections (2 versus 4) and fewer nonbacterial infections (0 versus 3) in group A compared with group B patients. Treatment with rHuG-CSF was well tolerated and, notably, no disease flare occurred during treatment and up to 4-6 months after rHuG-CSF administration. CONCLUSION: Short-term, low-dose rHuG-CSF treatment can substantially shorten the duration of CYC-induced neutropenia and appears to confer significant clinical benefit. Such treatment, aimed at raising the neutrophil count above 1,000/microl, does not appear to carry a high risk of inducing a flare of the vasculitis.
Adult↗
Treatment of severe neutropenia due to Felty's syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor.
OBJECTIVES: To examine the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for the treatment of severe neutropenia due to Felty's syndrome (FS) or systemic lupus erythematosus (SLE). METHODS: Eight patients with absolute neutrophil counts (ANC) below 1,000/microL attributable to FS (n = 4) or SLE (n = 4) were treated with rhG-CSF. The hematologic and clinical response as well as side effects were recorded. In addition, reports on the use of rhG-CSF/rhGM-CSF in FS and SLE retrieved from the English language literature were analyzed. RESULTS: RhG-CSF effectively corrected neutropenia due to FS and SLE in seven of the current eight patients. In 54 of 55 FS and SLE patients retrieved from the literature, G-CSF or GM-CSF, respectively, proved to be effective at elevating the neutrophil count, which was often associated with improvement of infectious complications. The neutrophil count often declined again when growth factor treatment was stopped but generally stabilized at a level that exceeded the pretreatment count. Side effects included rare cases of thrombocytopenia, arthralgias, and development of cutaneous leukocytoclastic vasculitis. Side effects were dose dependent and resolved when treatment was discontinued. One of our own patients and 17 previously reported patients continued to benefit from long-term administration of rhG-CSF over periods of more than 40 months. CONCLUSIONS: RhG-CSF is an effective and generally well-tolerated treatment for neutropenia due to FS or SLE. Exacerbation of the underlying rheumatic condition due to G-CSF appears to be rare if G-CSF is administered at the lowest dose effective at elevating the ANC above 1,000/microL.
Adult↗
Bronchoalveolar lavage cell profiles in Wegener's granulomatosis.
Pulmonary involvement due to Wegener's granulomatosis (WG) can present radiologically either as diffuse infiltrates or as nodular and linear opacities. Clinical experience suggest that these radiological patterns are associated with different bronchoalveolar lavage (BAL) cell profiles, but this has not been examined formally. We compared the BAL cell profile in eight WG patients with diffuse infiltrates on chest X-ray, indicative of highly active pneumonitis, with corresponding findings in 37 patients with nodular, linear and focal low-attenuation infiltrates on high-resolution computed tomography (HRCT) which reflected low-grade, mainly interstitial disease. A control group was composed of 11 patients with pulmonary sarcoidosis. Diffuse infiltrates occurred in association with high systemic disease activity and featured a neutrophilic BAL profile in the presence of generally normal BAL lymphocytes. HRCT findings suggestive mainly of interstitial disease were associated with either a lymphocytic BAL cell profile or a normal cell pattern. Patients with a lymphocytic cell profile generally had a preferential elevation of CD4+ cells in the BAL in the presence of a normal CD4/CD8 ratio in the blood. This was a common feature of WG and pulmonary sarcoidosis. In conclusion, highly active pneumonitis and pulmonary disease of low or moderate activity in WG are associated with disparate BAL cell profiles. It remains to be examined whether the preferential elevation of CD4+ cells in the latter condition reflects a common pathogenetic role of this subset of cells in WG and pulmonary sarcoidosis.
Aged↗
Subclinical alveolar bleeding in pulmonary vasculitides: correlation with indices of disease activity.
Haemosiderin-laden alveolar macrophages are a common finding in patients with alveolar bleeding. Iron-positive macrophages, suggestive of subclinical alveolar bleeding, were found to be fairly common in bronchoalveolar lavage (BAL) fluid in primary systemic vasculitis but uncommon in collagen vascular diseases (CVDs) and rheumatoid arthritis (RA). To substantiate the impression that subclinical alveolar bleeding may be a feature distinguishing between these disorders, fibreoptic bronchoscopy and BAL were performed in 49 patients with active Wegener's granulomatosis or Churg-Strauss syndrome and 44 patients with CVDs or RA, all of them without clinically manifest alveolar bleeding. The percentage of iron-positive cells was compared with clinical and radiological findings. Only a minority of the CVD and RA patients had iron-positive alveolar macrophages; the 95th percentile of the median number of such cells was 5%. Fifty-three per cent of the patients in the vasculitis group had >5% iron-positive cells, with individual counts ranging up to 95%. Patients with iron-positive macrophages had more extensive disease, more frequent microhaematuria, a higher antineutrophil cytoplasmic antibody titre, a higher myeloperoxidase concentration in the BAL fluid and somewhat more frequent low-attenuation opacities in pulmonary high-resolution computed tomography than the patients with a low iron-positive cell count. In conclusion, subclinical alveolar bleeding was, indeed, a common finding in antineutrophil cytoplasmic antibody-associated vasculitis, which distinguished these disorders from lung disease due to collagen vascular diseases or rheumatoid arthritis. Its association with indices of disease activity, although weak in this cross-sectional study, merits a longitudinal study of its value for the long-term monitoring of vasculitis patients.
Aged↗
Glomerular and tubular proteinuria as markers of nephropathy in rheumatoid arthritis.
OBJECTIVE: We examined the prevalence of nephropathy in unselected patients with rheumatoid arthritis (RA) by measurement of marker proteins for glomerular and tubular damage in urine. METHODS: A highly sensitive immunoluminometric assay was used to measure albumin, immunoglobulin G and alpha1-microglobulin in 24 h urines of 44 RA patients and a control group of 46 patients with generalized osteoarthritis (OA). RESULTS: Fifty-five per cent of RA patients were found to have proteinuria as a symptom of renal disease. Drug therapy or vasculitis were identified as possible reasons for proteinuria in only 25% of these patients; in most patients (75%), no reason for proteinuria was found. Tubular and mixed proteinuria were more frequent than glomerular proteinuria. Only 15% of the control group exhibited mild proteinuria, which was attributable to nephrotoxic factors. The renal function of RA patients and the control group did not differ significantly. CONCLUSIONS: Proteinuria is a frequent symptom of nephropathy in RA. Screening for renal disease in RA should not only include creatinine measurement and dipstick examination of urine, but also more sensitive methods to detect tubular and glomerular proteinuria as a marker of tubular and early stages of glomerular damage.
Adult↗
Inflammatory cells and cellular activation in the lower respiratory tract in Churg-Strauss syndrome.
BACKGROUND: To obtain insight into the mechanisms of tissue injury in lung disease due to Churg-Strauss syndrome (CSS), the bronchoalveolar lavage (BAL) cell profile and the levels in the BAL fluid of cell products released by activated eosinophils and neutrophils were assessed. METHODS: Thirteen patients with active progressive CSS (n = 7) or CSS in partial remission (n = 6) underwent clinical staging and bronchoalveolar lavage. The levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), and peroxidase activity in the BAL fluid were determined and the results were compared with those of 19 patients with pulmonary active Wegener's granulomatosis (WG) and nine control subjects. RESULTS: In patients with progressive CSS the BAL cell profile was dominated by eosinophils, neutrophil elevation being the exception. The eosinophilia was associated with high ECP levels (4.39 ng/ml and 0. 40 ng/ml in the two CSS groups compared with unmeasurable values in the controls). Individual patients with highly active CSS also had raised MPO levels, comparable to the levels in the most active WG patients. Peroxidase activity in the BAL fluid was 1.26 U/ml and 0. 10 U/ml in the two groups of patients with CSS and 0.20 U/ml in the controls. Pulmonary disease in patients with WG was characterised by an extensive increase in MPO (0.30 ng/ml versus 0.13 ng/ml in the controls) together with high peroxidase activity in the BAL fluid (4. 37 U/ml), but only a small increase in ECP levels was seen. No correlation was found between the ECP and MPO levels in patients with CSS which suggests that eosinophil and neutrophil activation vary independently of each other. CONCLUSIONS: These findings suggest that, in addition to eosinophil activation, neutrophil activation is an important feature in some patients with highly active CSS. The balance of neutrophil and eosinophil involvement appears to be variable and this may be one explanation for the individually variable treatment requirements of patients with CSS.
Adult↗