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John Sibley

Bio: John Sibley is an academic researcher from University of Saskatchewan. The author has contributed to research in topics: Rheumatoid arthritis & Prospective cohort study. The author has an hindex of 15, co-authored 21 publications receiving 2906 citations. Previous affiliations of John Sibley include University of British Columbia & Royal University Hospital.

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Journal ArticleDOI
TL;DR: Mortality rates are increased at least 2-fold in RA, and are linked to clinical severity, with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases.
Abstract: Objective. To determine the risk and causes of death and to quantify mortality predictors in patients with rheumatoid arthritis (RA). Methods. RA patients (n = 3,501) from 4 centers (Saskatoon n = 905, Wichita n = 1,405, Stanford n = 886, and Santa Clara n = 305) were followed for up to 35 years; 922 patients died. Results. The overall standardized mortality ratio (SMR) was 2.26 (Saskatoon 2.24, Wichita 1.98, Stanford 3.08, Santa Clara 2.18) and increased with time. Mortality was strikingly increased for specific causes: infection, lymphoproliferative malignancy, gastroenterologic, and RA. In addition, as an effect of the SMR of 2.26, the expected number of deaths was increased nonspecifically across all causes (except cancer), with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases. Independent predictors of mortality included age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate, joint count, and prednisone use.

1,303 citations

Journal ArticleDOI
TL;DR: An association between consistent DMARD use and improvement in long-term functional outcomes in RA is supported, which suggest up to a 30 percent reduction in long term disability with consistentDMARD use.
Abstract: Objective. Therapeutic strategies for rheumatoid arthritis (RA) have been evolving from the traditional “pyramid” approach toward one based upon early and sustained use of disease-modifying antirheumatic drugs (DMARDs), in the hope of improving long-term health outcomes. However, few data to have been presented to document the effects of this approach. We sought to directly assess associations between consistent DMARD use and long-term functional outcomes. Methods. We studied 2,888 RA patients who were followed up prospectively for up to 20 years (average 9 years) at 8 databank centers. The independent variable was the proportion of patient encounters that resulted in treatment with ⩾1 DMARD (hydroxychloroquine, sulfasalazine, auranofin, intramuscular gold, D-penicillamine, methotrexate, and/or azathioprine). The dependent variable was each patient's last recorded Disability Index value from the Health Assessment Questionnaire (HAQ). Results. Increased DMARD use was strongly associated with better long-term Disability Index values (P < 0.0001). The association was strengthened when restricted to more seriously affected (rheumatoid factor (RF)–positive) patients. The magnitude of the effect, unadjusted, was a difference of 0.53 HAQ Disability units (scale 0–3) between 100% DMARD use and 0%. Correlation coefficients ranged up to 0.26. Effects were similar for all disease duration periods (0–4, 5–9, 10–14, 15–19, and 20+ years). “Control” correlations, with variables computed to represent the proportion of time in which patients were taking either nonsteroidal antiinflammatory drugs or prednisone, failed to show positive associations. A multiple linear regression model, which controlled for age, disease duration, sex, RF positivity, proportion of visits under a prednisone regimen, and initial disability level, included the proportion of time in which patients were taking DMARDs (P < 0.0001), with a model R2 of 0.54. These results were obtained despite an adverse selection bias in which more severely affected individuals were given DMARDs more frequently, and despite absence of data on drug use early in the disease course of many patients. Thus, these results, which suggest up to a 30% reduction in longterm disability with consistent DMARD use, are most likely conservative. Conclusion. An association between consistent DMARD use and improvement in long-term functional outcomes in RA is supported by these data.

208 citations

Journal Article
TL;DR: Most CNS events were self-limited, reversible and not associated with poor outcome unless accompanied by multisystem disease activity, and therapy with corticosteroids did not appear to offer substantial benefit.
Abstract: In a review of our experience with systemic lupus erythematosus (SLE) since 1975, we found 48 of 266 patients with major central nervous system (CNS) manifestations for which a non-SLE explanation could not be identified. Eleven patients developed more than one type of CNS event. The commonest symptom was seizure (18 patients), followed by brainstem dysfunction (12 patients), psychosis (11 patients), organic brain syndrome (11 patients) and stroke (7 patients). In 19% of cases, CNS manifestations were accompanied by a flare of multisystem SLE disease activity. Anticonvulsants were able to be discontinued safely in the majority of patients with seizures. Most CNS events were self-limited, reversible and not associated with poor outcome unless accompanied by multisystem disease activity. Therapy with corticosteroids did not appear to offer substantial benefit.

195 citations

Journal ArticleDOI
01 Jun 2001-Lupus
TL;DR: Increased risk of malignancy, notably non-Hodgkin's lymphoma and perhaps cervical cancer, should be regarded as a complication of SLE.
Abstract: The objective of this study was to determine the relative risks of malignancy and of site-specific malignancies in patients with systemic lupus erythematosus (SLE)A cohort of 297 patients (91% Caucasian) with SLE were seen between 1975 and 1994 and followed for a mean of 12 years at the University of Saskatchewan Rheumatic Disease Unit Expected cancer incidence rates were determined based on Province of Saskatchewan population statistics matched to each study patient for age, sex and calendar year of follow-up Standardized incidence ratios (SIRs) of observed to expected cancers and 95% confidence intervals (95% CI) were calculatedA total of 27 cases of cancer were observed, whereas only 169 were expected (SIR 159 (95% CI 105–232)) For site-specific malignancies, an excess of cancer of the cervix (SIR 815 (95% CI 163–2381)) as well as hemopoietic malignancy (SIR 49 (95% CI 157–1143)) was found The hemopoietic cancers were predominantly non-Hodgkin's lymphoma (SIR 701 (95% CI 188–1796))

175 citations


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TL;DR: By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

4,319 citations

Journal ArticleDOI
TL;DR: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
Abstract: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.

3,975 citations

Journal ArticleDOI
TL;DR: In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotRexate provided clinical benefit and halted the progression of joint damage.
Abstract: Background Neutralization of tumor necrosis factor α (TNF-α) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known. Methods We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-α, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically. Results The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alo...

3,060 citations

Journal ArticleDOI
TL;DR: Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.
Abstract: Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.

2,485 citations