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J S Smolen

Publications and source records attributed to J S Smolen.

At least 19 recordsLinked to original sources
PubMed2006

Consensus statement on the use of rituximab in patients with rheumatoid arthritis.

A large number of experts experienced in the treatment of rheumatoid arthritis were involved in formulating a consensus statement on the use of B cell-targeted treatment with rituximab in patients with rheumatoid arthritis. The statement was supported by data from randomised controlled clinical trials and the substantial literature on oncology. The statement underwent three rounds of discussions until its ultimate formulation. It should guide clinicians in the use of this newly approved biological agent in treating patients with rheumatoid arthritis.

Antibodies, Monoclonal↗
PubMed2006

Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease.

OBJECTIVES: Despite early recognition and disease modifying anti-rheumatic drug (DMARD) treatment, a sizable proportion of early rheumatoid arthritis (RA) patients show radiological progression. This study was performed to determine the frequency of erosive arthritis and the pace of radiological progression in an inception cohort of patients with very early RA (<or=3 months after onset of symptoms). METHODS: In order to determine possible prognostic factors for development of erosive disease, we linked the clinical features of these patients to radiological progression in a regression model. About 55 patients with RA and follow-up of at least 3 yrs were analysed. All had complete series of clinical, serological and radiographic assessments. Radiographs were scored according to the Larsen method. RESULTS: Erosive disease developed in 63.6% of the patients over 3 yrs, with the majority (74.3%) appearing already in the first and 97.2% by the end of the second year. Among all variables available, rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) first presentation were the most predictive for both development of erosions and the degree of radiological progression. None of the clinical variables at the onset was useful to discriminate between erosive and non-erosive patients. In the final regression model, however, cumulative clinical activity substantially contributed to explaining radiological progression. CONCLUSION: Despite early treatment, substantial damage occurred in some patients and was associated with presence of strong 'constitutive' predictors such as anti-CCP and RF as well as presence of high long-term clinical disease activity as indicated by C-reactive protein (CRP), swollen joint counts and the absence of a good clinical response (assessed by the failure to achieve lasting low disease activity).

Adult↗
PubMed2006

Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison.

OBJECTIVE: To compare the efficacy and safety of etanercept and sulfasalazine, alone and in combination, in patients with active rheumatoid arthritis despite sulfasalazine treatment. METHODS: A double-blind, randomised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine (2-3 g/day) treatment. The primary end point was a 20% response by the American College of Rheumatology (ACR) criteria at 24 weeks. RESULTS: At baseline, the three treatment groups (sulfasalazine, n = 50; etanercept, n = 103; etanercept and sulfasalazine, n = 101) were comparable for demographic variables and disease activity. Lack of efficacy was the primary reason for discontinuation (sulfasalazine, n = 12; etanercept, n = 1; etanercept and sulfasalazine, n = 4; p<0.001). Significantly more patients receiving etanercept, alone or in combination (74% for each), achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine (28%; p<0.01). Similarly, more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group (p<0.01). In the groups receiving etanercept, significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone (p<0.01). The incidences of several common adverse events (headache, nausea, asthenia) were lower with etanercept alone than with the combination (p<0.05), but infections and injection site reactions were higher with etanercept alone (p<0.05). The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept. CONCLUSIONS: For all efficacy variables assessed, etanercept alone or in combination with sulfasalazine resulted in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment. All three treatments were generally well tolerated.

Adult↗
PubMed2006

The perception of rheumatoid arthritis core set measures by rheumatologists. Results of a survey.

OBJECTIVE: To investigate the perception of values of individual core set measures by rheumatologists, and how it differs across measures and across physicians. METHODS: We designed a survey in which 44 international expert rheumatologists explicitly marked positions on the scales of seven core-set measures that in their opinion corresponded to cut-points between remission, low, moderate and high disease activity. The measures comprised swollen and tender joint counts (SJC, TJC), CRP, ESR, patient and evaluator global assessments of activity (PGA, EGA), and the Health Assessment Questionnaire Disability Index (HAQ). RESULTS: The interpretation of measures across physicians was most consistent for ESR and PGA, while for CRP and joint counts there was most variation. Joint counts and CRP implied active disease at lower relative values (using normalized scales) than did PGA, EGA or ESR (P < 0.01 for most comparisons; Bonferroni-adjusted Wilcoxon signed rank test), and most physicians tended to tolerate higher numbers of tender joints than swollen joints to define similar levels of disease activity. Given these cut-points, more RA patients in a typical cross-sectional cohort would be regarded as being in remission according to joint counts (SJC, 35%; TJC, 55%) than to global scores (PGA, 18%; EGA, 9%), and fewer patients would be regarded as being in remission by physician-derived or laboratory measures than by patient-derived ones. CONCLUSION: These data give insights into the integrative process of activity evaluation and will be informative for future survey designs, studies using physician opinion as the gold standard for criterion validity of disease activity, and allow 'activity mapping' of values on different scales based on expert opinion.

Analysis of Variance↗
PubMed2006

Effect of pulsed electromagnetic fields on proteoglycan biosynthesis of articular cartilage is age dependent.

OBJECTIVE: To investigate the effects of a pulsed electromagnetic field (EMF) on articular cartilage matrix biosynthesis with regard to age and cartilage damage using a matrix depleted cartilage explant model. METHODS: Cartilage explants were obtained from metacarpophalangeal joints of calves and adult cows. After depletion of the extracellular matrix by trypsin digestion, samples were maintained in serum-free basal medium with and without the addition of interleukin 1beta (IL1beta). Half the samples were subjected to an EMF for 24 minutes daily; the other half were left untreated. Undigested and untreated explants served as negative controls. After 7 days, biosynthesis of matrix macromolecules was assessed by [35S]sulphate incorporation and values were normalised to hydroxyproline content. RESULTS: The EMF increased matrix macromolecule synthesis in undigested, untreated explants (p<0.009). In matrix depleted samples the EMF had no stimulatory effect on proteoglycan biosynthesis. IL1beta significantly decreased the de novo synthesis of matrix macromolecules (p<0.00004) in young and adult samples, but an EMF partly counteracted this inhibitory effect in cartilage samples from young, but not old animals. CONCLUSION: EMF promoted matrix macromolecule biosynthesis in intact tissue explants but had no stimulatory effect on damaged articular cartilage. The supressive effects of IL1beta were partially counteracted by EMF exposure, exclusively in cartilage derived from young animals. An EMF has age dependent chondroprotective but not structure modifying properties when cartilage integrity is compromised.

Aging↗
PubMed2006

ICF core sets: how to specify impairment and function in systemic lupus erythematosus.

The World Health Organization's International Classification of Function (ICF) is a tool to characterize and illuminate better the full of array of problems a patient faces when affected by disease. Specifying these problems is a particular challenge in a disease like systemic lupus erythematosus (SLE) because of the wide variety in organ systems involved, its variable activity and severity, and considerable ethnic and local differences. The authors of this manuscript believe, however, that a broader understanding will prove essential for optimal patient care, and that there is sufficient experience now in defining ICF Core Sets to successfully complete core sets for SLE. Therefore, we will embark on an international project for developing ICF Core Sets for SLE, which we here delineate. This development will include two versions: 1) The Brief ICF Core Set for SLE will be a very focused list of categories essential for SLE clinical trials; and 2) The Comprehensive ICF Core Set will be much broader and useful for guiding multidisciplinary assessment in patients with SLE. Both Core Sets will be developed in a formal decision-making and consensus process of health professionals integrating evidence gathered from preliminary studies. The final definition of the Core Sets will occur at a consensus conference which will integrate: i) a systematic review of the literature regarding the outcome measures used in clinical trials and selected observational studies; ii) focus groups or semi-structured interviews with SLE patients; iii) a Delphi exercise with world wide involvement of experts; and iv) the evidence from empirical studies. The development of these SLE ICF Core Sets is designed to be an inclusive, open, worldwide process. We therefore invite both SLE clinical experts and SLE patients to participate actively.

Consensus Statements as Topic↗
PubMed2005

Stimulatory effects of distinct members of the bone morphogenetic protein family on ligament fibroblasts.

OBJECTIVE: To investigate effects of cartilage derived morphogenetic protein-1 and -2 (CDMP-1, CDMP-2), bone morphogenetic protein (BMP)-7 and BMP-6 on metabolism of ligament fibroblasts and their osteogenic or chondrogenic differentiation potential. METHODS: Ligament fibroblasts were obtained from 3 month old calves, plated as monolayers or micromass cultures, and incubated with or without CDMP-1, CDMP-2, BMP-7, and BMP-6. Expression of the indicated growth factors was assessed by RT-PCR and western immunoblotting. The presence of their respective type I and II receptors, and lineage related markers, was investigated in stimulated and unstimulated cells by RT-PCR and northern blotting. Biosynthesis of matrix proteoglycans was assessed by [(35)S]sulphate incorporation in monolayers. Alcian blue and toluidine blue staining was done in micromass cultures. RESULTS: CDMP-1, CDMP-2, BMP-7, and BMP-6 were detected on mRNA and on the protein level. Type I and II receptors were endogenously expressed in unstimulated ligament fibroblasts. The growth factors significantly stimulated total proteoglycan synthesis as assessed by [(35)S]sulphate incorporation. Toluidine blue staining showed cartilage-specific metachromasia in the growth factor treated micromass cultures. Transcription analysis of stimulated ligament fibroblasts demonstrated coexpression of chondrocyte markers but no up regulation of osteogenic markers. CONCLUSION: CDMP-1, CDMP-2, BMP-7, and BMP-6 and their receptors were expressed in ligament tissue. These growth factors induced matrix synthesis in fibroblasts derived from bovine ligament. The preferential expression of cartilage markers in vitro suggests that CDMP-1, CDMP-2, BMP-7, and BMP-6 have the potential to induce differentiation towards a chondrogenic phenotype in ligament fibroblasts. Thus, fibroblasts from ligaments may serve as a source for chondrogenesis and tissue repair.

Animals↗
PubMed2005

Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis.

BACKGROUND: Early treatment prevents progression of joint damage in rheumatoid arthritis (RA), but diagnosis in early disease is impeded by lack of appropriate diagnostic criteria. OBJECTIVE: To study the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide autoantibodies (anti-CCP), and anti-RA33 autoantibodies for diagnosis of RA and prediction of outcome in patients with very early arthritis. METHODS: The prospective follow up inception cohort included 200 patients with very early (<3 months) inflammatory joint disease. Autoantibodies were measured at baseline and analysed in a tree based model which aimed at determining the added diagnostic value of testing for anti-CCP and anti-RA33 as compared with RF alone. RESULTS: RA was diagnosed in 102 patients, while 98 developed other inflammatory arthropathies. Receiver operator curve analysis showed an optimum cut off level for RF at 50 U/ml, above which anti-CCP and anti-RA33 had no additional diagnostic value. Remarkably, RF >or=50 U/ml and anti-CCP showed similar sensitivity and high specificity for RA, but overlapped considerably. Anti-RA33 was less specific and did not correlate with RF or anti-CCP. Among patients with RA, 72% showed at least one of these three autoantibodies, compared with 15% of non-RA patients. RF >or=50 U/ml and anti-CCP were predictors of erosive disease, whereas anti-RA33 was associated with mild disease. CONCLUSIONS: Stepwise autoantibody testing in early inflammatory joint disease, starting with RF, followed by anti-CCP (in patients with RF <50 U/ml), and finally anti-RA33, should be used as a sensitive and effective strategy for distinguishing patients with RA at high risk for poor outcome.

Adolescent↗
PubMed2005

IgG immunoadsorption reduces systemic lupus erythematosus activity and proteinuria: a long term observational study.

OBJECTIVE: To analyse the effects of rigorous immunoglobulin removal by immunoadsorption (IAS) on proteinuria (primary outcome variable), disease activity (SIS, SLEDAI, ECLAM), and autoantibodies to double stranded DNA (anti-dsDNA) in active systemic lupus erythematosus (SLE). METHODS: 16 patients with severe SLE and renal disease, in whom cyclophosphamide was contraindicated or failed to halt disease progression, were treated with IAS for 3 months. Patients achieving at least 20% improvement in two or more of the outcome measures were considered responders and offered a 9 months' extension period. RESULTS: Within 3 months, 14 patients responded and 11 opted for an extension. Proteinuria decreased from 6.7 (4.6) g/day (mean (SD)) at baseline to 4.3 (3.5) g/day at 3 months and 2.9 (2.4) g/day at 12 months (p<0.001). From baseline to 3 and 12 months, disease activity improved independently of scoring by SIS (15 (5) to 5 (2) and to 5 (2), p<0.0001), SLEDAI (21 (7) to 5 (4) and to 5 (4), p<0.0001), or ECLAM (7 (2) to 2 (1) and to 3 (1), p<0.0001). Anti-dsDNA fell from 391 (647) IU/ml to 146 (218) and to 53 (50) IU/ml at 3 and 12 months, respectively. Steroids could be tapered from 117 (159) mg/day at baseline to 29 (17) mg/day at 3 months and 9 (2) mg/day at 12 months. IAS was not associated with an excess of infections. However, one patient died of septicaemia after 1 month of treatment. CONCLUSION: In this negatively selected cohort of patients with SLE, IAS was associated with a significant response shown by reduced proteinuria, improved global disease activity, decreased anti-dsDNA, and lower glucocorticoid dosages, suggesting therapeutic benefit.

Adult↗
PubMed2005

Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study.

OBJECTIVE: To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment. METHODS: Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial. RESULTS: At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28-joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C-reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo-treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX-treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001). CONCLUSION: Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.

Antibodies, Monoclonal↗
PubMed2005

Cytokine expression in lupus kidneys.

Although far from complete, the picture of cytokines present in systemic lupus erythematosus (SLE) glomerulonephritis is already complex. Proinflammatory cytokines, such as TNF, IL-6, IL-1, and IL-18 are upregulated, as are both Th1 and Th2 cytokines, with different implications. In many instances, the local effects may be different from the systemic immunoregulatory ones. For some proinflammatory cytokines, and TNF in particular, the local proinflammatory ones may be more relevant to the disease. This may help solve discrepancies between different murine models of the disease and provide a better rationale for targeting certain cytokines in human SLE.

Animals↗
PubMed2005

Anti-cytokine therapy in systemic lupus erythematosus.

In the course of the disease, a wide variety of cytokines is dysregulated, many of which likely influence systemic lupus erythematosus (SLE) autoimmunity and/or lupus tissue inflammation. Proinflammatory cytokines in particular, such as TNF, IL-6, IL-18 or IFN-gamma, may play a major role in propagating the inflammatory processes responsible for tissue damage. These cytokines are overexpressed both systemically and locally, and preliminary results from open-label trials and/or animal studies suggest potential benefits of blocking either of these inflammatory mediators. Since new therapeutic agents may soon offer many ways to influence the process, controlled clinical trials following open-label safety studies are of central importance to arrive at optimized therapies for SLE patients.

Cytokines↗
PubMed2004

Expression of resistance markers to methotrexate predicts clinical improvement in patients with rheumatoid arthritis.

BACKGROUND: Methotrexate is transported into the cell by the reduced folate carrier (RFC) and out of the cell by members of the multidrug resistance protein family (MRP). Transport proteins may affect the therapeutic efficacy of this drug in patients with rheumatoid arthritis. OBJECTIVE: To investigate the potential benefit of the presence of RFC and the absence of functional MRP for the efficacy of methotrexate treatment. METHODS: The study involved 163 patients (116 female, 47 male; mean age 59.5 years) on methotrexate (mean weekly dose 12.2 mg). RFC was determined using reverse transcriptase polymerase chain reaction, and MRP function by flow cytometry, using a calcein acetoxymethylesther/probenecid assay. Clinical response to methotrexate was evaluated by the EULAR response criteria and the ACR 20% improvement criteria. The clinical data were obtained at the beginning of methotrexate treatment and at the time of blood sampling during ongoing therapy. Patients were divided into four groups according to the presence (+) or absence (-) of RFC and functional (f) MRP. RESULTS: fMRP+/RFC+ and fMRP-/RFC- patients more often had good EULAR response rates (60%, p = 0.014, and 53%, p = 0.035, respectively) in comparison with the fMRP-/RFC+ group (29%); fMRP+/RFC- patients had a low frequency of good disease activity responses. CONCLUSIONS: Absence of fMRP plus presence of RFC did not prove to be related to beneficial effects of methotrexate, but the lack or the presence of both fMRP and RFC led to a significantly better therapeutic outcome. Determination of these markers may predict responsiveness to methotrexate.

Antirheumatic Agents↗
PubMed2004

Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis.

OBJECTIVE: Delay of disease-modifying anti-rheumatic drug (DMARD) therapy is a major contributing factor for poor outcome in rheumatoid arthritis (RA). Although early therapy has been shown to be particularly effective, there is still uncertainty about the optimal time point of DMARD introduction. We wanted to test if a therapeutic window of opportunity may exist within the first few months of the disease. METHODS: In this case-control parallel-group study, 20 very early RA (VERA) patients with median disease duration of 3 months were age and gender matched to a group of 20 late early RA (LERA) patients with median disease duration of 12 months until first DMARD initiation. Follow-up time was 36 months. Primary outcome measures were the disease activity score (DAS28) and radiological joint destruction using the Larsen method. RESULTS: Already after 3 months of DMARD therapy we found a significant difference of improvement in favour of the VERA patients in the DAS28. This trend continued over the study period. At study end the DAS28 showed an improvement of 2.8+/-1.5 in the VERA vs 1.7+/-1.2 in the LERA group (P(c)<0.05). The Larsen scores showed a statistically significant retardation of progression in the VERA compared with the LERA. CONCLUSION: Our results indicate that there is a window of opportunity for highly successful treatment of RA in the first year, and especially within the first 3 months of therapy. Thus, early diagnosis and therapy may be the crucial step in achieving optimal control of disease progression and prognosis in RA.

Acute Disease↗