Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Influence of Stimulation Location and Posture on the Reliability and Comfort of the Nociceptive Flexion Reflex

BACKGROUND: The lower limb nociceptive flexion reflex (NFR) is commonly used to assess the function of the nociceptive system. Currently, there is a lack of standardized stimulation procedures to determine the NFR threshold, making comparisons of thresholds across studies difficult

The autonomic and nociceptive response to acute exercise is impaired in people with knee osteoarthritis

Objectives: An acute bout of exercise typically leads to short term exercise induced hypoalgesia (EIH), but this response is more variable in many chronic pain populations, including knee osteoarthritis (OA) and fibromyalgia (FM). There is evidence of autonomic nervous system (ANS) dysfunction in some chronic pain populations that may contribute to impaired EIH, but this has not been investigated in people with knee OA. The aim of this study was to assess the acute effects of isometric exercise on the nociceptive and autonomic nervous systems in people with knee OA and FM, compared to pain-free controls. Methods: A cross-sectional study was undertaken with 14 people with knee OA, 13 people with FM, and 15 pain free controls. Across two experimental sessions, baseline recordings and the response of the nociceptive and autonomic nervous systems to a 5-min submaximal isometric contraction of the quadriceps muscle was assessed. The nociceptive system was assessed using pressure pain thresholds at the knee and forearm. The ANS was assessed using high frequency heart rate variability, cardiac pre-ejection period, and electrodermal activity. Outcome measures were obtained before and during (ANS) or immediately after (nociceptive) the acute bout of exercise. Results: Submaximal isometric exercise led to EIH in the control group. EIH was absent in both chronic pain groups. Both chronic pain groups showed lower vagal activity at rest. Furthermore, people with knee OA demonstrated reduced vagal withdrawal in response to acute isometric exercise compared to controls. Sympathetic reactivity was similar across groups. Discussion: The findings of reduced tonic vagal activity and reduced autonomic modulation in response to isometric exercise raise the potential of a blunted ability to adapt to acute exercise stress and modulate nociception in people with knee OA. The impairment of EIH in knee OA may, in part, be due to ANS dysfunction

Reliability of the Conditioned Pain Modulation Paradigm to Assess Endogenous Inhibitory Pain Pathways

BACKGROUND: Conditioned pain modulation paradigms are often used to assess the diffuse noxious inhibitory control (DNIC) system. DNICs provide one of the main supraspinal pain inhibitory pathways and are impaired in several chronic pain populations. Only one previous study has examined the psychometric properties of the conditioned pain modulation technique and this study did not evaluate intersession reliability