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Biomedical subjects

Josef Smolen

Publications and source records attributed to Josef Smolen.

17 recordsLinked to original sources
PubMed2007

Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis.

OBJECTIVE: To determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis. METHODS: Human tumor necrosis factor (TNF)-transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease. RESULTS: Initial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus-like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up-regulation of interleukin-1 (IL-1) and IL-6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis. CONCLUSION: Structural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.

Animals↗
PubMed2006

Measuring functioning in patients with hand osteoarthritis--content comparison of questionnaires based on the International Classification of Functioning, Disability and Health (ICF).

OBJECTIVE: When selecting a questionnaire, researchers and clinicians need to know whether or not a questionnaire covers the relevant outcomes. The aim of this study was to analyse and compare the content of questionnaires that have been used to assess functioning in patients with hand osteoarthritis (OA) based on the International Classification of Functioning, Disability and Health (ICF). METHOD: Questionnaires were identified in a structured literature search. All concepts included in the items of the questionnaires were linked to the ICF categories according to the 10 established linking rules by two health professionals. The degree of agreement between the two health professionals was determined by means of kappa statistic. On the basis of the linking, the content of the instruments was compared. For each concept, it was examined whether functioning is measured on the level of activity or participation or both activity and participation. Indicators for content density, content diversity and the percentage of linked ICF categories addressing participation were calculated. RESULTS: Health Assessment Questionnaire, AUSCAN, Cochin scale, FIHOA, SACRAH and AIMS2-SF were analysed. The result of the kappa statistic for agreement between the two investigators was 0.74. 163 concepts were identified in the 113 items of all instruments, which were then linked to seven ICF categories of the component body functions, 45 categories of the component activities and participation and six categories of the component environmental factors. AUSCAN and SACRAH had the lowest and AIMS2-SF showed the highest diversity ratio and the highest percentage of linked ICF categories that addressed participation. CONCLUSION: When selecting instruments for comprehensive measurements of functioning in hand OA, researchers and clinicians are advised to include both one instrument with a low diversity ratio (for disease-specific aspects) and another instrument with a high diversity ratio (for broader aspects of functioning including some aspects of participation).

Activities of Daily Living↗
PubMed2006

Measuring function in rheumatoid arthritis: Identifying reversible and irreversible components.

OBJECTIVE: Measurement of physical function at one point in time cannot distinguish impairment caused by the active disease process from chronic irreversible impairment. We aimed to dissect these two components of functional limitation in rheumatoid arthritis (RA) by using the disability index of the Health Assessment Questionnaire (HAQ) as the measure of function. METHODS: We performed a secondary analysis of data from 6 contemporary clinical trials of RA (2,763 patients). Patients in whom remission was achieved in the trials, based on a simplified disease activity index, were identified. In an individual patient, HAQ scores at trial entry represented both reversible and irreversible impairments, while HAQ scores at the time of RA remission represented the mostly irreversible component, and the difference between these corresponded to the component related to disease activity. We tested the concept that the HAQ has a reversible and an irreversible component by associating the HAQ score during remission with 2 measures associated with the degree of accrued damage: duration of RA and radiographic severity. RESULTS: Among patients in whom clinical remission was achieved (n = 295), average HAQ scores despite clinical remission increased progressively with the duration of RA, from 0.19 (<2 years of RA) to 0.36 (2-<5 years) to 0.38 (5-<10 years) to 0.55 (>/=10 years) (P < 0.001). The reversibility of HAQ scores decreased with the duration of RA (median 100%, 83.3%, 81.9%, and 66.7%, respectively; P < 0.001). Findings were similar in patients subgrouped by quartile of radiographic scores. CONCLUSION: Differences in the sources of functional limitations should be considered in the interpretation of functional measures, and in their use for prediction and in cost analyses.

Adult↗
PubMed2006

IgG and IgM anticardiolipin antibodies following treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis.

OBJECTIVE: To assess the occurrence of anticardiolipin antibodies (aCL) in patients with early rheumatoid arthritis (RA) receiving treatment with infliximab plus methotrexate (MTX) versus MTX alone. METHODS: The first 299 patients enrolled in the randomized, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial who had baseline (week 0) samples available for aCL testing were included in this study. Sera were collected at weeks 0, 30, and 54 from 110 patients taking infliximab 3 mg/kg plus MTX, 98 patients taking infliximab 6 mg/kg plus MTX, and 91 patients taking placebo plus MTX. IgG and IgM aCL were measured using an anticardiolipin assay. RESULTS: IgG and IgM aCL positivity at baseline was similar in all treatment groups. Most patients were negative for IgG aCL at baseline and remained so at the last followup evaluation. One percent (2 of 208) of patients who received infliximab plus MTX and were negative for IgG aCL at baseline were positive for IgG aCL at weeks 30 and 54. A slightly higher proportion of patients who received infliximab plus MTX and were negative for IgM aCL at baseline were positive for IgM aCL at weeks 30 and 54 (4.8% [10 of 208]) as compared with patients who received placebo plus MTX (1.1% [1 of 91]), but the difference was not significant. CONCLUSION: There was a low incidence of the development of aCL in patients with early RA who received infliximab in combination with MTX, and the difference was not significant compared with patients who received placebo plus MTX.

Adult↗
PubMed2006

Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis.

OBJECTIVE: Activation of p38 MAPK is a key signaling step in chronic inflammation. Inhibition of p38 MAPK is considered to be a promising future strategy to control inflammatory diseases, but studies of compounds to inhibit this kinase have so far been limited to investigation of their side effects. We undertook the present study to investigate which specific molecule, among 4 different isoforms of p38 MAPK (alpha, beta, gamma, and delta), is predominantly expressed and activated in inflammation. Such knowledge could allow more specific targeting of p38 MAPK in inflammatory disease. METHODS: Studies were performed on inflamed tissue from patients with rheumatoid arthritis, as a prototype of inflammatory disease. The expression and activation of the alpha, beta, gamma, and delta isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry. RESULTS: Immunoblot analysis revealed that alpha and gamma were the predominantly expressed p38 MAPK isoforms, whereas the other 2 isoforms were less frequently present. By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels. Colabeling with cell-specific markers revealed that macrophages expressed the alpha and gamma isoforms, synovial fibroblasts the beta and gamma isoforms, and granulocytes the delta isoform, whereas T lymphocytes were rarely positive for any p38 MAPK isoform. Double-labeling with isoform-specific antibody and pan-p38 antibody against the phosphorylated form of p38 MAPK showed activation of the alpha and gamma isoforms. Occasional activation of the beta isoform was also noted in the synovial lining and the endothelium, whereas the delta isoform, although expressed in pericytes around blood vessels, was not phosphorylated. This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPKalpha and -gamma but not p38 MAPKbeta or -delta. CONCLUSION: These data show that the alpha and gamma isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms.

Adult↗
PubMed2005

Aberrant expression of the autoantigen heterogeneous nuclear ribonucleoprotein-A2 (RA33) and spontaneous formation of rheumatoid arthritis-associated anti-RA33 autoantibodies in TNF-alpha transgenic mice.

Human TNF-alpha transgenic (hTNFtg) mice develop erosive arthritis closely resembling rheumatoid arthritis (RA). To investigate mechanisms leading to pathological autoimmune reactions in RA, we examined hTNFtg animals for the presence of RA-associated autoantibodies including Abs to citrullinated epitopes (anti-cyclic citrullinated peptide), heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (anti-RA33), and heat shock proteins (hsp) (anti-hsp). Although IgM anti-hsp Abs were detected in 40% of hTNFtg and control mice, IgG anti-hsp Abs were rarely seen, and anti-cyclic citrullinated peptide Abs were not seen at all. In contrast, >50% of hTNFtg mice showed IgG anti-RA33 autoantibodies, which became detectable shortly after the onset of arthritis. These Abs were predominantly directed to a short epitope, which was identical with an epitope previously described in MRL/lpr mice. Incidence of anti-RA33 was significantly decreased in mice treated with the osteoclast inhibitor osteoprotegerin and also in c-fos-deficient mice lacking osteoclasts. Pronounced expression of hnRNP-A2 and a smaller splice variant was seen in joints of hTNFtg mice, whereas expression was low in control animals. Although the closely related hnRNP-A1 was also overexpressed, autoantibodies to this protein were infrequently detected. Because expression of hnRNP-A2 in thymus, spleen, brain, and lung was similar in hTNFtg and control mice, aberrant expression appeared to be restricted to the inflamed joint. Finally, immunization of hTNFtg mice with recombinant hnRNP-A2 or a peptide harboring the major B cell epitope aggravated arthritis. These findings suggest that overproduction of TNF-alpha leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.

Animals↗
PubMed2005

Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT).

OBJECTIVE: To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA). METHODS: One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score. RESULTS: The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of >/=2.5 at baseline, 68% of infliximab-treated patients achieved improvement of >/=75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups. CONCLUSION: Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.

Adult↗
PubMed2004

Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease.

BACKGROUND: Osteoprotegerin is a novel member of the tumor necrosis factor receptor superfamily and a soluble decoy receptor of the receptor activator of nuclear factor-kappaB ligand. Recent experimental research has implicated osteoprotegerin in atherogenesis, but epidemiological confirmation of this concept is sparse. METHODS AND RESULTS: As part of the prospective, population-based Bruneck Study, severity, initiation, and progression of atherosclerosis were assessed in carotid arteries. Cases of incident cardiovascular disease and vascular mortality were carefully recorded over a 10-year period (1990 to 2000). Osteoprotegerin levels were measured in samples obtained at baseline and during follow-up. Serum osteoprotegerin showed a strong association with numerous vascular risk factors, including age, diabetes, markers of systemic inflammation, chronic infection, and smoking. In multivariate analyses, osteoprotegerin was significantly related to severity and 10-year progression of carotid atherosclerosis. Furthermore, a high level of osteoprotegerin was an independent risk factor for incident cardiovascular disease (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 2.2 [1.3 to 3.8]; P=0.001) and vascular mortality (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 3.1 [1.2 to 8.2]; P=0.010) but not for mortality due to nonvascular causes. CONCLUSIONS: Osteoprotegerin is an independent risk factor for the progression of atherosclerosis and onset of cardiovascular disease.

Aged↗
PubMed2004

Soluble RANKL and risk of nontraumatic fracture.

CONTEXT: The receptor activator of nuclear factor kappaB ligand (RANKL) is essential for osteoclast and, possibly, osteoblast activation and may represent a key link between bone formation and resorption. OBJECTIVE: To determine the relationship between serum level of RANKL and the risk of nontraumatic fracture. DESIGN, SETTING, AND PARTICIPANTS: As part of a prospective population-based study conducted in Bruneck, Italy, we recorded all fractures that occurred between 1990 and 2000 in 906 participants and classified them as traumatic (n = 115) or nontraumatic (n = 31). Serum levels of RANKL and osteoprotegerin and characteristics of bone metabolism and lifestyle were assessed in 1990 and at follow-up in 1995 and 2000. MAIN OUTCOME MEASURE: Incident nontraumatic fracture by levels of RANKL. RESULTS: Levels of RANKL did not differ between sexes and were not related to age, menopausal status, lifestyle characteristics, or data from bone ultrasound at the heel. However, RANKL emerged as a significant predictor of nontraumatic fracture. In pooled logistic regression analysis, the relative risks of nontraumatic fracture in the lowest and middle vs highest tertile for RANKL were 10.0 (95% confidence interval [CI], 2.3-43.1) and 3.9 (95% CI, 0.8-19.0) (P<.001 for trend), respectively. Patients in the highest-tertile group had a low risk of fracture even in the presence of other predisposing factors, whereas women aged 60 years or older in the lowest tertile had a 5-year rate of nontraumatic fracture greater than 7%. CONCLUSIONS: A low level of RANKL is an independent predictor of nontraumatic fracture. This finding is consistent with the hypothesis of an important role of RANKL in human bone turnover and if confirmed in future investigations may gain relevance for assessment of fracture risk.

Aged↗
PubMed2004

Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction.

OBJECTIVE: To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (IL-1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF-driven arthritis model. METHODS: Human TNF-transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically. RESULTS: Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL-1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra. CONCLUSION: Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.

Animals↗
PubMed2004

Occupational balance of women with rheumatoid arthritis: a qualitative study.

OBJECTIVE: Occupational balance has been shown to be an important factor in maintaining health. Rheumatoid arthritis (RA) reduces functional ability and quality of life and may thus reduce occupational balance. The aim of this qualitative pilot study was to explore occupational balance in women who have RA. METHODS: Nine women with RA with past, but not current, paid work experience, no other confounding neuro-motor disease and with disease duration of 0.75-31 years were selected from an Austrian rheumatology outpatient clinic. Age range of the participants was 28-68 years. A semi-structured interview was conducted with each participant and transcribed verbatim. Data were analysed by the constant comparative method from an occupational perspective. RESULTS: Three main categories emerged: (1) The participants experienced a process of change that affected their occupational balance. (2) This new state of occupational balance was characterized by changed levels of involvement in physical, mental, social and rest occupations and by a certain level of unpredictability of symptoms. (3) Overall, the new state of occupational balance was valued differently: positively, indifferently or negatively. CONCLUSION: RA was found to have a considerable impact on occupational balance. The experience is not invariably seen as negative as previous literature would suggest. Further research should explore the longitudinal dimension of occupational balance in people with RA.

Journal Article↗
PubMed2003

Moberg picking-up test in patients with inflammatory joint diseases: a survey of suitability in comparison with button test and measures of disease activity.

OBJECTIVE: To assess and compare the suitability of Moberg pickup test (MPUT) and button test (BT) as indicators for functional impairment in patients with inflammatory joint diseases. METHODS: Measurements for 369 patients attending a rheumatology outpatient clinic were collected. In addition to MPUT and BT, measurements collected were grip strength, tender and swollen joint counts, visual analog scales for pain and disease activity, Health Assessment Questionnaire, C-reactive protein levels, and erythrocyte sedimentation rates. RESULTS: We found a significant relationship between MPUT and BT. Both tests show the same pattern of correlations with the other parameters, although all correlations are higher for MPUT. There is a significant sex and learning effect for the BT, which implies a confounding of hand function and motor abilities. A significantly higher proportion of patients was unable to complete BT. CONCLUSION: MPUT and BT measure comparable aspects of hand function. In several theoretical and practical aspects, MPUT seems superior to BT in arthritis. It is necessary to evaluate its value in long-term followup.

Activities of Daily Living↗
PubMed2002

Autoantibodies in rheumatoid arthritis and their clinical significance.

Autoantibodies are proven useful diagnostic tools for a variety of rheumatic and non-rheumatic autoimmune disorders. However, a highly specific marker autoantibody for rheumatoid arthritis (RA) has not yet been determined. The presence of rheumatoid factors is currently used as a marker for RA. However, rheumatoid factors have modest specificity (~70%) for the disease. In recent years, several newly characterized autoantibodies have become promising candidates as diagnostic indicators for RA. Antikeratin, anticitrullinated peptides, anti-RA33, anti-Sa, and anti-p68 autoantibodies have been shown to have >90% specificity for RA. These autoantibodies are reviewed and the potential role of the autoantibodies in the pathogenesis of RA is briefly discussed.

Arthritis, Rheumatoid↗
PubMed2002

Treatment of rheumatoid arthritis by TNF-blocking agents.

Chimeric, humanized and fully human monoclonal antibodies directed against tumor necrosis factor-alpha as well as TNF receptor constructs can be administered relatively safely during long-term use for the treatment of rheumatoid arthritis (RA). Their therapeutic efficacy in patients refractory to treatment with conventional disease-modifying drugs was proven in large clinical trials and their ability to slow the progression of disease was demonstrated radiographically. The insights into the pathophysiology of RA provided by the beneficial effects of blocking proinflammatory cytokines will lead to further drug development for this destructive autoimmune disease.

Animals↗