Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor α

232

193

There are accumulating data describing the association between diabetes and cancer mortality from Westernised populations. There are no data describing the relationship between diabetes and cancer mortality in African or South Asian populations from developing countries. We explored the relationship of abnormal glucose tolerance and diabetes on cancer mortality risk in a large, multi‐ethnic cohort from the developing nation of Mauritius. Population‐based surveys were undertaken in 1987, 1992 and 1998. The 9559 participants comprised 66% of South Asian (Indian), 27% of African (Creole), and 7% of Chinese descent. Cox's proportional hazards model with time varying covariates was used to obtain hazard ratios (HRs) and 95% confidence intervals (95% CI) for risk of cancer mortality, after adjustment for confounding factors. In men, but not women, cancer mortality risk increased with rising 2h‐PG levels with HR for the top versus bottom quintile of 2.77 (95%CI: 1.28 to 5.98). South Asian men with known diabetes had a significantly greater risk of cancer mortality than those with normal glucose tolerance (NGT) HR: 2.74 (95%CI: 1.00‐7.56). Overall, impaired glucose tolerance was associated with an elevated risk of cancer mortality compared to NGT (HR: 1.47, 95% CI: 0.98–2.19), though this was not significant. We have shown that the association between abnormal glucose tolerance and cancer extends to those of African and South Asian descent. These results highlight the importance of understanding this relationship in a global context to direct future health policy given the rapid increase in type 2 diabetes, especially in developing nations.

Section: From Animal Models Toward the Clinicsupporting

confidence: 79%

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

Bevaart¹,

Vervoordeldonk²,

Tak³

2010

232

193

“…In addition, marked variability in the features of synovial inflammation among RA patients has been described (6)(7)(8). The wide variation in responsiveness to different modes of antirheumatic treatment is consistent with this notion (9,10). Hence, the data suggest that distinct pathogenetic mechanisms contribute to disease in RA.…”

mentioning

confidence: 60%

Rheumatoid arthritis is a heterogeneous disease: Evidence for differences in the activation of the STAT‐1 pathway between rheumatoid tissues

Kraan

Gaalen

Kasperkovitz

et al. 2003

236

176

ObjectiveTo generate a molecular description of synovial tissue from rheumatoid arthritis (RA) patients that would allow us to unravel novel aspects of pathogenesis and to identify different forms of disease.MethodsWe applied complementary DNA microarray analysis to profile gene expression, with a focus on immune‐related genes, in affected joint tissues from RA patients and in tissues from osteoarthritis (OA) patients as a control. To validate microarray data, real‐time polymerase chain reaction was performed on genes of interest.ResultsThe gene expression signatures of synovial tissues from RA patients showed considerable variability, resulting in the identification of at least two molecularly distinct forms of RA tissues. One class of tissues revealed abundant expression of clusters of genes indicative of an involvement of the adaptive immune response. Detailed analysis of the expression profile provided evidence for a prominent role of an activated signal transducer and activator of transcription 1 pathway in these tissues. The expression profiles of another group of RA tissues revealed an increased tissue remodeling activity and a low inflammatory gene expression signature. The gene expression pattern in the latter tissues was reminiscent of that observed in the majority of OA tissues.ConclusionThe differences in the gene expression profiles provide a unique perspective for distinguishing different pathogenetic RA subsets based on molecular criteria. These data reflect important aspects of molecular variation that are relevant for understanding the biologic dysregulation underlying these subsets of RA. This approach may also help to define homogeneous groups for clinical studies and evaluation of targeted therapies.

“…Although IL-1 and TNF␣ share many biologic actions that are relevant in RA (4)(5)(6), research in animal models of arthritis suggests that IL-1 is the dominant cartilagedestructive cytokine (7). The biologic effects of both cytokines are modulated in vivo by naturally occurring protein inhibitors (8,9), and both have become prime targets for biologic therapy in RA (10)(11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Long‐term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin‐1 receptor antagonist) in patients with rheumatoid arthritis: Extension phase of a randomized, double‐blind, placebo‐controlled trial

Nuki¹,

Bresnihan²,

Bear³

et al. 2002

200

Objective. To demonstrate the long-term efficacy of anakinra, a human recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long-term safety of anakinra at different daily doses.Methods. The efficacy and safety of anakinra were previously demonstrated in a double-blind, placebocontrolled, 24-week evaluation in 472 patients with active RA. Of 345 patients who completed the placebocontrolled phase of the study, 309 continued in a 52-week, multicenter, double-blind, parallel-group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52-week extension phase (76 weeks total exposure).Results. A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24-week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment-related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy.Conclusion. The clinical benefits of treatment with daily self-administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long-term use of anakinra for the treatment of patients with RA.