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"Weisman, Michael H."
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New therapies for treatment of rheumatoid arthritis
Rheumatoid arthritis is characterised by pain, swelling, and destruction of joints, with resultant disability. Only disease-modifying antirheumatic drugs can interfere with the disease process. In the past few years, biological agents, especially inhibitors of tumour necrosis factor, have allowed for hitherto unseen therapeutic benefit, although even with these drugs the frequency and degree of responses are restricted. Therefore, new agents are needed, and three novel biological compounds for treatment of rheumatoid arthritis have already been used in practice or are on the horizon: rituximab (anti-CD20), abatacept (cytotoxic T-lymphocyte antigen 4 immunoglobulin), and tocilizumab (anti-interleukin 6 receptor). We discuss the targets of these drugs, the roles of these targets in the pathogenesis of rheumatoid arthritis, and the efficacy and adverse effects of these agents from clinical trial data. Novel therapeutic strategies in conjunction with optimised disease assessment for better treatment of rheumatoid arthritis and an outlook into potential future targets are also presented.
Journal Article
Population-based estimates of humoral autoimmunity from the U.S. National Health and Nutrition Examination Surveys, 1960–2014
Based on US National Health and Nutrition Examination Survey (NHANES) data, we attempted to provide an unbiased, population-based estimate of autoantibody prevalence overall and by age and sex.
US autoantibody prevalence estimates for detectable rheumatoid factor, anti-thyroglobulin, anti-thyroperoxidase, anti-transglutaminase, anti-endomysial, anti-GAD65, antinuclear autoantibodies, and autoantibodies to extractable nuclear antigens were estimated from the 1960-1962 National Health Examination Survey, NHANES III (1988-1994), and the NHANES 1999-2014 cross-sectional surveys. Survey design variables and sample weights were used to account for differential probabilities of selection within the complex survey design. Data analysis used SASTM and SUDAAN™ software. US Census Bureau data were used to estimate the absolute numbers of persons with autoantibodies.
NHANES III data show that the overall US prevalence of having a detectable serum autoantibody is substantial in adults, in both women and men. Thyroid autoantibodies were present in 18% of US adults (31 million persons) including 10% of younger adults and 25% of older persons. Overall autoantibody prevalences increased significantly with age: 32% of US adults 60+ years of age (12.8 million persons) had at least one of the four autoantibodies rheumatoid factor, anti-thyroglobulin, anti-thyroperoxidase, or anti-tissue transglutaminase. Older women had higher levels of autoantibodies, but this was a relative difference. Autoantibody prevalence in both sexes was substantial (women 39%; men 22%). Fourteen percent of adults 60+ years of age have multiple autoantibodies.
Autoantibodies are present in a significant fraction of the general population, especially in older adults and women relative to men. Although all known clinically significant autoantibodies were not analyzed, these data provide an important population perspective on the scope and magnitude of humoral autoimmunity in the US. This is vital for prevention efforts to reduce autoimmune disease and helps clarify the potential impact of autoimmunity on the general population.
Journal Article
A promising approach to targeting type 1 IFN in systemic lupus erythematosus
Despite advances in understanding systemic lupus erythematosus (SLE) pathogenesis, most clinical trials of new targeted therapies have been met with disappointment. The type I IFN pathway is believed to play an important role in SLE, and the proposed involvement of this pathway helps explain the frustration behind the failure at targeting either IFN-α or the type 1 IFN receptor itself. In this issue of the JCI, Furie et al. report on an intriguing phase 1b study that demonstrates an approach for inhibiting this pathway in the skin using an mAB (BIIB059) that targets the blood DC antigen 2 (BDCA-2) receptor on plasmacytoid DCs (pDCs). BIIB059 decreased IFN expression and improved cutaneous lupus disease activity, with a favorable safety profile. Whether or not this strategy will be effective in managing SLE in other organs remains unanswered. However, these results suggest that closing the door on targeting the type 1 IFN pathway in SLE may be premature and highlight the emerging question of whether an organ-specific approach toward lupus trials and treatment should be the wave of the future.
Journal Article
The prevalence of inflammatory back pain: population-based estimates from the US National Health and Nutrition Examination Survey, 2009–10
Objective To estimate the current US inflammatory back pain (IBP) prevalence using four published case definitions. Methods Analysis of an IBP data collection instrument specifically designed for the 2009–10 National Health and Nutrition Examination Survey. Subjects were 5103 US adults ages 20–69 with complete data. IBP prevalence as determined by Calin et al criteria, European Spondylarthropathy Study Group (ESSG) criteria, and Berlin criteria 8a and 7b. Results Age-adjusted US prevalence of IBP by Calin criteria was 5.0% (95% CI 4.2% to 5.8%). Prevalence of IBP was 5.6% (95% CI 4.7% to 6.5%) by ESSG criteria, and 5.8% (95% CI 5.2% to 6.4%) and 6.0% (95% CI 4.9% to 7.1%) by Berlin Criteria 8a and 7b, respectively. IBP prevalence did not differ significantly by age groups or between men and women. IBP prevalence was significantly lower among non-Hispanic black persons compared with non-Hispanic white persons for the Calin and ESSG IBP criteria. For the ESSG and Berlin 7b criteria, non-Hispanic white persons had significantly higher IBP prevalences compared with Mexican Americans. Conclusions IBP is associated with spondyloarthritis. Awareness of the prevalence of IBP may be useful for planning future epidemiological studies as well as development and validation of diagnostic and classification criteria for specific clinically defined diseases.
Journal Article
Longitudinal patterns and predictors of response to standard-of-care therapy in lupus nephritis: data from the Accelerating Medicines Partnership Lupus Network
Background
Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis.
Methods
Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (
n
= 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day.
Results
Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (OR
adj
= 3.71 [95%CI = 1.34–10.24];
p
= 0.012), > 25% decrease in UPCR from baseline to week 12 (OR
adj
= 2.61 [95%CI = 1.07–6.41];
p
= 0.036), lower chronicity index (OR
adj =
1.33 per unit decrease [95%CI = 1.10–1.62];
p
= 0.003), and positive anti-dsDNA antibody (OR
adj
= 2.61 [95%CI = 0.93–7.33];
p
= 0.069).
Conclusions
CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.
Journal Article
Mycophenolate Mofetil or Intravenous Cyclophosphamide for Lupus Nephritis
This 24-week randomized, open-label, noninferiority trial compared oral mycophenolate mofetil with monthly intravenous cyclophosphamide as induction therapy for active lupus nephritis. Mycophenolate mofetil appeared more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, with a more favorable safety profile.
Mycophenolate mofetil appeared to be more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, with a more favorable safety profile.
Intravenous cyclophosphamide has been the standard of care for treating severe lupus glomerulonephritis
1
; however, its use is limited by potentially severe toxic effects including bone marrow suppression, hemorrhagic cystitis, opportunistic infections, malignant diseases, and premature gonadal failure.
2
Clinical trials of treatment with intermittent intravenous cyclophosphamide combined with corticosteroids show greater long-term renal survival but not overall survival, as compared with treatment with corticosteroids alone.
3
–
6
Furthermore, failure to achieve remission, which is associated with an increased rate of progression to renal failure, is reported in 18 to 57 percent of patients who received cyclophosphamide.
7
–
10
Mycophenolate mofetil, an immunosuppressive . . .
Journal Article
Spondyloarthritis in inflammatory bowel disease cohorts: systematic literature review and critical appraisal of study designs
To critically appraise study designs evaluating spondyloarthritis (SpA) phenotypes in patients with inflammatory bowel disease (IBD). A systematic literature review of PubMed, Ovid, Scopus, Cinahl, Medline, Web of Science, and Cochrane databases was performed. Articles published from January 2000 - March 2020 were included if they evaluated the prevalence/incidence of musculoskeletal disease in cohorts of IBD patients. Most of the 69 included studies were clinic based (54/69, 78%), single center (47/69, 68%) and cross-sectional (60/69, 87%). The median prevalence of axial and peripheral SpA in IBD was 5% (range 1 - 46%) and 16% (range 1 - 43%), respectively. In 38 studies that evaluated axial disease in prospectively enrolled patients, inflammatory back pain was analyzed in 53%. SpA classification criteria were used in 68% and imaging was performed in 76%. In 35 studies that evaluated peripheral disease in prospectively enrolled patients, SpA classification criteria were used in 46%. A physical exam was performed in 74%, and it was performed by a rheumatologist in 54% of studies with a physical exam. Sub-phenotypes of peripheral SpA (mono- or oligo-arthritis, polyarthritis, enthesitis, dactylitis) were variably reported. Seventy-four percent of studies did not mention whether osteoarthritis and fibromyalgia had been assessed or excluded. The spectrum of SpA phenotypes in IBD patients remains incompletely characterized. Future studies should focus on standardizing the variables collected in IBD-SpA cohorts and defining musculoskeletal phenotypes in IBD-SpA in order to better characterize this disease entity and advance the field for clinical and research purposes.
Journal Article
The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?
Inflammatory bowel disease (IBD) associated arthritis is a subgroup of spondyloarthritis (SpA) that has suffered from lack of recognition in rheumatology clinical and research circles for over 100 years. Although clinically distinguishable from rheumatoid arthritis and ankylosing spondylitis, it took advances in detection systems in the middle of the last century (rheumatoid factor, HLA-B27) to convincingly make the final separations. We now know that significant numbers of patients with SpA have associated clinical IBD and almost half of them show subclinical gut inflammation, yet the connection between the gut and the musculoskeletal system has remained a vexing problem. Two publications from Nathan Zvaifler (one in 1960, the other in 1975) presciently described the relationship between the gut and the spine/peripheral joints heralding much of the work present today in laboratories around the world trying to examine basic mechanisms for the connections (there are likely to be many) between the gut, the environment (presumably our intestinal flora) and the downstream effect on the musculoskeletal system. The role of dysregulated microbiome along with microbiome-driven T helper 17 cell expansion and immune cell migration to the joints has been recognised, all of which occur in the appropriate context of genetic background inside and outside of the human leucocyte antigen system. Moreover, different adhesion molecules that mediate immune cells homing to the gut and joints have been noted. In this review, we studied the origins and evolution of IBD-arthritis, proposed pathogenic mechanisms and the current gaps that need to be filled for a complete understanding of IBD-arthritis.
Journal Article
HLA-B27 is associated with reduced disease activity in axial spondyloarthritis
HLA-B27 is associated with increased susceptibility and disease activity of ankylosing spondylitis, but the effect of HLA-B27 on the activity of the broader category now called axial spondyloarthritis (AxSpA) is apparently the opposite. A modified Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to assess disease activity among 3435 patients with spondyloarthritis (SpA) who participated in a survey designed to assess the effect of their disease and its treatment on the susceptibility and severity of Covid-19. Chi square testing was used to compare BASDAI scores between HLA-B27 positive and negative subjects. 2836 survey respondents were HLA B27 positive. The average BASDAI for the HLA-B27 negative cohort was 4.92 compared to 4.34 for the HLA-B27 positive subjects. Based on linear regression, a subject’s sex could not fully account for the differing BASDAI score in HLA-B27 negative subjects compared to those who are HLA-B27 positive. The difference between B27 positive and negative subjects was skewed by those with a BASDAI score of one or two. HLA-B27 positive subjects were more than twice as likely to have a BASDAI score of 1 compared to HLA B27 negative subjects and about 60% more likely to have a BASDAI score of 2 (p < 0.0001). HLA-B27 positive subjects have less active spondyloarthritis compared to HLA-B27 negative subjects as measured by a BASDAI score. Our data indicate that patients with mild back pain and a diagnosis of AxSpA are disproportionately HLA-B27 positive. The HLA-B27 test facilitates the diagnosis of axial spondyloarthritis such that patients from a community survey with mild back pain may be disproportionately diagnosed as having AxSpA if they are HLA-B27 positive. The test result likely introduces a cognitive bias into medical decision making and could explain our observations.
Journal Article