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Biomedical subjects

J Smolen

Publications and source records attributed to J Smolen.

At least 37 records · Page 2Linked to original sources
PubMed2002

Serum thrombopoietin levels and anti-thrombopoietin antibodies in systemic lupus erythematosus.

Thrombocytopenia is a common phenomenon in patients suffering from systemic lupus erythematosus (SLE). The cause of thrombocytopenia in SLE, however, is poorly understood. In this study, 100 patients with SLE were evaluated for serum thrombopoietin levels, anti-thrombopoietin antibodies and routine laboratory parameters such as peripheral blood counts, parameters of blood chemistry and immunologic parameters of SLE. The median platelet count of SLE patients was 230 g/l and 19 were thrombocytopenic (range 8-148 g/l). Thrombopoietin levels in SLE patients were found to be significantly higher than in healthy controls (n = 96; median, 117 pg/ml vs 64 pg/ml, P < 0.01). When excluding thrombocytopenic SLE patients, thrombopoietin levels in SLE were still above controls (111 pg/ml, P < 0.01). The thrombopoietin levels were correlated to erythrocyte sedimentation rate and ECLAM score of disease activity, and inversely correlated to complement factor C4, but not to the platelet count. Anti-thrombopoietin antibody reactivity was found in 23% of SLE patients. Interestingly, these patients had lower platelet counts than SLE patients without anti-thrombopoietin antibodies (median 174 g/l and 253 g/l, respectively, P < 0.01), but thrombopoietin levels were not significantly different. Taken together, thrombopoietin levels are significantly higher in the sera of SLE patients than in healthy controls and anti-thrombopoietin antibodies are frequently found.

Adolescent↗
PubMed2002

Lessons from the "Euro-Lupus Cohort".

The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium - the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Adolescent↗
PubMed2001

Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion.

BACKGROUND: A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases (MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils. METHODS AND RESULTS: Cardiac lymph and tissue were assayed for atent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation. CONCLUSIONS: Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.

Animals↗
PubMed2001

The stressed synovium.

This review focuses on the mechanisms of stress response in the synovial tissue of rheumatoid arthritis. The major stress factors, such as heat stress, shear stress, proinflammatory cytokines and oxidative stress, are discussed and reviewed, focusing on their potential to induce a stress response in the synovial tissue. Several pathways of stress signalling molecules are found to be activated in the synovial membrane of rheumatoid arthritis; of these the most important examples are heat shock proteins, mitogen-activated protein kinases, stress-activated protein kinases and molecules involved in the oxidative stress pathways. The expression of these pathways in vitro and in vivo as well as the consequences of stress signalling in the rheumatoid synovium are discussed. Stress signalling is part of a cellular response to potentially harmful stimuli and thus is essentially involved in the process of synovitis. Stress signalling pathways are therefore new and promising targets of future anti-rheumatic therapies.

Animals↗
PubMed2001

Adenovirus-based overexpression of tissue inhibitor of metalloproteinases 1 reduces tissue damage in the joints of tumor necrosis factor alpha transgenic mice.

OBJECTIVE: Rheumatoid arthritis is a prototype of a destructive inflammatory disease. Inflammation triggered by the overexpression of tumor necrosis factor alpha (TNFalpha) is a driving force of this disorder and mediates tissue destruction. Since matrix metalloproteinases (MMPs) are among the molecules activated by TNFalpha, we hypothesized that overexpression of their natural inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP-1), in TNFalpha transgenic mice could inhibit the development of destructive arthritis. METHODS: Systemic treatment was carried out by replication-defective adenoviral vectors for TIMP-1, beta-galactosidase, or phosphate buffered saline (PBS), which were applied once at the onset of arthritis. Clinical, serologic, radiologic, and histologic outcomes were assessed 18 days after the treatment. RESULTS: The AdTIMP-1 group showed significantly reduced paw swelling and increased grip strength compared with the 2 control groups, whereas total body weight, TNFalpha, and interleukin-6 levels were similar in all 3 groups. Radiographic assessment revealed a significant reduction of joint destruction in the AdTIMP-1 group; this was confirmed by histologic analyses showing reduced formation of pannus and erosions in the AdTIMP-1 group compared with the AdLacZ and PBS control groups. The formation of arthritis-specific autoantibodies to heterogeneous nuclear RNP A2 was not observed in the AdTIMP-1 group but was present in the 2 control groups. CONCLUSION: These results indicate a central role of MMPs in TNFalpha-mediated tissue damage in vivo and a promising therapeutic role for TIMP-1.

Adenoviridae↗
PubMed2001

Decreased serum erythropoietin and its relation to anti-erythropoietin antibodies in anaemia of systemic lupus erythematosus.

OBJECTIVE: This study was performed to assess erythropoietin levels and anti-erythropoietin antibodies in patients with systemic lupus erythematosus (SLE). METHODS: The sera of 100 patients with SLE were investigated for serum erythropoietin levels and the presence of anti-erythropoietin antibodies by ELISA. Routine laboratory parameters such as peripheral blood count, relevant parameters of blood chemistry, and immunological parameters of SLE were recorded. RESULTS: Erythropoietin levels were significantly decreased in SLE patients when related to individual haemoglobin and haematocrit values (P<0.001), suggesting an inadequate erythropoietin response in SLE. Anti-erythropoietin antibodies were found in 46% of SLE patients, and erythropoietin levels (but not haemoglobin or haematocrit values) were significantly decreased in these patients compared with patients without anti-erythropoietin antibodies. Serum erythropoietin concentration as determined by ELISA was reduced in the presence of anti-erythropoietin antibodies. Furthermore, anti-erythropoietin antibodies also correlated with younger age, decreased serum levels of complement factors C3 and C4 and elevated anti-double-stranded DNA antibodies. CONCLUSIONS: We conclude that the anaemia of SLE is characterized by an inadequate erythropoietin response. Anti-erythropoietin antibodies are frequently present in SLE and interfere with the measurement of serum erythropoietin level. However, these antibodies are not associated with increased severity of SLE-associated anaemia.

Adolescent↗
PubMed2000

The lupus erythematosus cell phenomenon: comparative analysis of antichromatin antibody specificity in lupus erythematosus cell-positive and -negative sera.

OBJECTIVE: To compare and investigate antihistone and antichromatin antibody responses as well as clinical variables in patients with systemic lupus erythematosus (SLE) who were either positive (LEC+) or negative (LEC-) for the lupus erythematosus (LE) cell phenomenon. METHODS: The binding properties of LEC+ and LEC- SLE sera to chromatin-associated nuclear antigens (histones H1, H2A, H2B, H3, H4; complexes of H2A-H2B, [H2A-H2B]-DNA, H1-DNA; total and H1-stripped chromatin; native and denatured DNA) were investigated. In addition, sera from patients with drug-induced lupus (by procainamide, hydralazine, or quinidine), as well as from patients with rheumatoid arthritis and osteoarthritis, were assessed. Enzyme-linked immunosorbent assay was used to detect specific antibody binding. RESULTS: Mirroring the important role of histone H1 in the formation of LE cells, anti-histone H1 reactivity was 8-fold higher in LEC+ sera than in LEC- sera. In addition, reactivities to most of the other antigens tested, i.e., other histones and histone-DNA complexes as well as chromatin and DNA, were significantly higher in LEC+ sera than in LEC- sera. All but 1 serum sample from the patients with drug-induced lupus were negative for LE cell formation as well as for anti-histone H1 reactivity, but displayed high antibody reactivities to histone-DNA complexes, including chromatin. Sera from patients with rheumatoid arthritis and osteoarthritis did not show significant binding to these antigens. When comparing the clinical features of LEC+ and LEC- SLE patients, severe organ involvement, including nephritis and central nervous system involvement, was common in the LEC+ group, but rare in the LEC- group. CONCLUSION: A positive LE cell phenomenon not only correlated with the presence of high anti-histone H1 antibody levels in SLE, but also indicated serologically and clinically active disease with major organ involvement.

Antibody Specificity↗
PubMed2000

Rheumatoid arthritis of the craniocervical region: assessment and characterization of inflammatory soft tissue proliferations with unenhanced and contrast-enhanced CT.

The aim of this study was to depict and characterize inflammatory soft tissue proliferations caused by rheumatoid arthritis (RA) in the craniocervical region by unenhanced and contrast-enhanced CT. Computed tomography of the craniocervical region was performed in 35 patients in the axial plane before and after the i.v. administration of contrast material. According to the densities and contrast enhancement of the inflammatory soft tissue proliferations, four groups were classified. Ancillary findings, such as a compression of the dural sac or spinal cord, erosions of the bony structures, and atlantoaxial subluxation, were also evaluated. Inflammatory soft tissue proliferations were depicted in 28 of 35 patients and could be differentiated by unenhanced and contrast-enhanced CT according to the above defined criteria: effusion in 6 patients (17%); hypervascular pannus in 8 (23%); hypovascular pannus in 5 (14%); and fibrous tissue in 9 patients (26%). A compression of the dural sac was seen in 11 (31%) patients; 3 of these had neurological symptoms. Erosions of the odontoid process were found in 20 (57%) patients; 16 (80%) of these also showed erosions of the atlas. Atlantoaxial subluxation was seen in 11 (31%) patients. Inflammatory soft tissue proliferations in the craniocervical region caused by RA can be reliably demonstrated and classified by unenhanced and contrast-enhanced CT, which can differentiate between joint effusion and various forms of pannus and depict ancillary findings. Computed tomography is an alternative method for patients unable to undergo an MRI examination.

Arthritis, Rheumatoid↗
PubMed2000

Autoantibody reactivity in a case of Schnitzler's syndrome: evidence for a Th1-like response and detection of IgG2 anti-FcepsilonRIalpha antibodies.

Schnitzler's syndrome is a rare disease characterized by chronic urticaria, monoclonal IgM, and clinical and laboratory signs of inflammation. In a subset of patients, the urticarial lesions cause pruritus. However, the pathophysiology of the disease and the biochemical basis of urticaria are not known. We describe a female patient with Schnitzler's syndrome suffering from chronic urticaria associated with pruritus. The patient's serum was found to contain IgG antibodies recognizing cellular components of the microvasculature. In particular, IgG3 antibodies directed against proteins (14-100 kD) expressed in cultured dermal microvascular endothelial cells and mast cells, were found by immunoblotting. Moreover, IgG2 antibodies specific for the alpha-chain of the FcepsilonRI were detectable. However, the autoantibodies did not mediate histamine release in mast cells or basophils. In patients with IgM paraproteinemia who did not have Schnitzler's syndrome, antibodies against endothelial/mast cells or FcepsilonRI were not detectable. In summary, we describe subclass-specific IgG reactivity against microvascular endothelial cells and mast cells indicating Th1 autoimmunity in a patient with Schnitzler's syndrome. Whether such autoantibodies are recurrently produced in patients with Schnitzler's syndrome and play a role in the pathophysiology of the disease remains to be determined.

Adult↗
PubMed2000

HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus.

The objective of this study was to determine the HLA class II associations of the anticardiolipin (aCL) and anti-beta2GPI (abeta2GPI) antibodies in a large series of European patients with systemic lupus erythematosus (SLE). A cohort of 577 European SLE patients was enrolled. aCL and abeta2GPI were measured by ELISA methods. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 loci was performed by the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. aCL of IgG, IgM and IgA isotypes were detected in 22.8%, 14% and 13.9% of patients, respectively. IgG and IgM abeta2GPI were detected in 20% of patients. aCL showed positive association with HLA DRB1*04, DRB1*0402, DRB1*0403, DRB1*07, DRB3*0301, DQA1*0201, DQA1*0301, DQB1*0302, and negative association with DQA1*0501, DRB3*0202. abeta2GPI showed positive association with DRB1*0402, DRB1*0403, DQB1*0302. DRB1*0402 carried the highest relative risk for the presence of both aCL (RR=8. 1) and abeta2GPI (RR=4.6). Our results confirm the already described associations of aCL with HLA DR4 and DR7, but also demonstrate that, among the alleles at the DRB1*04 locus, the *0402 was most represented both in aCL and in abeta2GPI positive patients. In addition, HLA class II associations of abeta2GPI are for the first time extensively examined in a large cohort of European SLE patients.

Adolescent↗
PubMed2000

Endpoints: consensus recommendations from OMERACT IV. Outcome Measures in Rheumatology.

The goal of the 'Outcome Measures in Rheumatology' (OMERACT) process is to select domains and/or outcome measures for clinical trials in each defined disease category according to truth, discrimination and feasibility. OMERACT IV, held in Cancun, Mexico, April 1998, included the module 'Systemic Lupus Erythematosus (SLE)', designed to define a preliminary core set of outcome domains for randomized controlled trials and longitudinal observational studies (LOS). Although specific measures to be used in clinical trials of SLE have yet to be determined, both randomized controlled trials and longitudinal observation studies groups recommended that outcome be assessed in terms of disease activity and damage in all organ systems involved, as well as by health related quality of life, meaningful to patients, and adverse events. These recommendations were ratified by the majority of participants. In a heterogeneous patient population such as SLE, it is recognized that any individual measure of clinical response may reflect only a portion of what might be termed the 'true outcome'. A responder index could integrate such relatively independent measures of outcome into a single assessment, potentially increasing statistical power and decreasing sample size. Results from randomized controlled trials currently underway assessing these outcome domains are eagerly awaited, and are expected to rapidly advance the field.

Clinical Trials as Topic↗
PubMed2000

Anti-ganglioside antibodies in a large cohort of European patients with systemic lupus erythematosus: clinical, serological, and HLA class II gene associations. European Concerted Action on the Immunogenetics of SLE.

OBJECTIVE: To assay anti-ganglioside antibodies (aGM1) in sera of a large cohort of European patients with systemic lupus erythematosus (SLE) to define the prevalence of these autoantibodies in SLE; to evaluate the association of aGM1 with clinical manifestations and other autoantibodies found in SLE; and to search for aGM1 association with HLA class II alleles. METHODS: Four hundred forty-eight patients with SLE were consecutively enrolled in 8 centers from 6 European countries. All sera were tested for antinuclear antibodies by immunofluorescence on HEp-2 cells as substrate, anti-dsDNA, aGM1, aCL, abeta2-glycoprotein I (abeta2-GPI) antibodies by ELISA, and antineutrophil cytoplasmic antibodies (ANCA) by immunofluorescence and by ELISA. Genomic typing for HLA class II loci was performed by polymerase chain reaction-sequence specific oligonucleotide probe method. Clinical assessment was done at the time of enrolment. RESULTS: We found 41.9% of patients with clinical signs of neuropsychiatric involvement; 15.5% of patients were positive for aGM1, 8% of the IgG isotype and 8.6% of the IgM isotype; aGM1-IgG were associated with neuropsychiatric manifestations (NPM) (RR = 3.7), with migraine (RR = 2.4), with OBS (RR = 7.3), and with peripheral neuropathy (RR = 8.5). aGM1-IgM were associated with NPM (RR = 4) and with depression (RR = 3.4). Furthermore, the genetic study showed that aGM1-IgG were associated with HLA-DQB1*0404 (RR = 7.2) while aGM1-IgM were associated with HLA-DQB1*0605 (RR = 33.3). No associations were found between aGM1 and anti-dsDNA, aCL, abeta2GP1, or ANCA. CONCLUSION: Our results show aGM1 can be found in patients with SLE. aGM1 may play a pathogenetic role for some NPM in this condition.

Adolescent↗
PubMed2000

Cardiovascular autonomic function, autoantibodies, and esophageal motor activity in patients with systemic sclerosis and mixed connective tissue disease.

OBJECTIVE: To study cardiovascular autonomic nerve function and presence of autoantibodies in relation to esophageal motor activity in patients with systemic sclerosis (SSc) and mixed connective tissue disease (MCTD). METHODS: Twenty-five patients with SSc (13 limited, 12 diffuse cutaneous disease; disease duration 1-19 yrs) and 6 patients with MCTD (disease duration 1-10 yrs) were studied. Cardiovascular autonomic function was assessed using 5 standard tests and autoantibody status determined. Esophageal motor activity and lower and upper esophageal sphincter pressures were recorded manometrically. RESULTS: Five patients with SSc had definite, 7 borderline, and 13 no autonomic dysfunction; 23 had antinuclear. 9 anti-Sc170, 4 anticentromere, and 1 U1snRNP antibodies. Contraction amplitudes in the smooth muscle as well as the striated muscle esophagus and lower esophageal sphincter pressures were significantly lower and autonomic dysfunction more frequent in patients with than in those without anti-Sc170 (6 of 9 vs 6 of 16 patients); upper esophageal sphincter pressures did not differ. All patients with MCTD had antinuclear antibodies, 5 had definite autonomic dysfunction; their lower esophageal sphincter pressures were significantly lower than in SSc patients without anti-Sc170 and anti-U1snRNP. CONCLUSION: Esophageal motor dysfunction may be associated with the presence of anti-Sc170 and anti-U1snRNP autoantibodies and prevail in patients with cardiovascular autonomic neuropathy.

Adult↗