Calcitonin Gene-Related Peptide and Migraine: Implications for Therapy

It is clearly evident from the literature that headache has troubled mankind from the dawn of civilization (Rapoport & Edmeads, 2000). A variety of methods have been used throughout the ages in an attempt to alleviate or cure this pain; these may have been the most appropriate at that time, and were probably seen as “cutting edge”. Today they seem at best amusing, and at worst cruel and barbaric. The earliest concepts in migraine were those of the supernatural, with migraine believed to be due to malevolent beings within the head; treatment based on this idea included incantations and application to the head of substances intended to drive out the demons and spirits (Edmeads, 1991). These were also driven out physically, as in the Neolithic period (8500-7000 BC). The people living in this time used the method of trepanation, a kind of neurosurgery, which involved removing circular chunks of skull so that the spirits causing the headache could escape. Over 50% of the trepanned skulls have shown evidence of healing, indicating a high survival rate for this operation. Although the scientific rationale behind trepanation is not understood, it is surprising that this procedure was performed as a treatment for migraine as late as the mid 17th century (Edmeads, 1991; Rapoport & Edmeads, 2000)

Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study

Objective This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1 beta monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment.Methods In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4 x 4-weekly doses of canakinumab (50 + 50 + 25 + 25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks.Results A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses >= 50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28-0.38, p <= 0.0083), and the percentage of patients experiencing >= 1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing >= 1 flare for canakinumab doses >= 50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28-0.36, p <= 0.05). The incidence of adverse events was similar across treatment groups.Conclusions Single canakinumab doses >= 50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg

Metabolic and Crystal Arthropathies [70-72]: 70. Single Intramuscular Depot Methylprednisolone Injection: A Convenient, Efficacious and Safe Treatment for Gouty Arthritis in an Inpatient Setting

Background: Various modalities of treatment have been used and recommended in the treatment of acute gout. These include drugs such as colchicine, NSAIDs and oral prednisolone. Intramuscular depot methylprednisolone (im MP) is currently used in the treatment of rheumatoid arthritis as well as polymyalgia. However the response to im MP in acute gouty arthritis in an inpatient setting (where there are usually contraindications to NSAIDs) has not been previously described in literature. Methods: Eighteen case records of patients presenting with acute gouty arthritis and referred to Rheumatology, between October 2008 and October 2009, were reviewed. Results: Fourteen men and four women, with a mean age of 60 years (range 55-88 years) were seen. Of the 18, 14 patients had a previous history of chronic gout and 4 patients were newly diagnosed. Sixteen patients had polyarticular gout (mainly bilateral wrists and knees) and the remaining 2 had monoarticular gout (1 knee, 1 wrist). Seventeen patients had synovial fluid analysis, which revealed negatively birefringent urate crystals, and 1 patient refused joint aspiration. All patients had predisposing co-morbidities such as diabetes (10), hypertension (15), CCF (5), chronic kidney disease (8) and 2 patients had a history of chronic alcohol excess. Five patients initially received NSAIDs and 3 had concomitant colchicine with all 5 showing a delayed response. All patients were given im MP 120 mg in the gluteal region as a deep injection. All responded completely to im yMP within 2 days with resolution of pain and swelling of inflamed joints. All patients felt much improved and rated the treatment highly. Conclusions: The latest BSR guidelines recommends the use of steroids in the management of refractory cases of gout, i.e. patients intolerant of or having contraindications to NSAIDS or colchicine. This restricted indication is based mainly on the side effects to oral steroids or lack of expertise with intra-articular injections. We have shown that a single intramuscular methyl prednisolone injection is highly effective, very convenient, patient acceptable and safe treatment for gout particularly in elderly patients with multiple co-morbidities. As most cases of inpatient gout have comorbidities such as in our series with contraindications to NSAIDs, we recommend the use of im methyl prednisolone as the first-line treatment in such patients. It may be a less painful alternative to intra-articular steroid injections and safer than bigger doses of oral steroids (especially in diabetes). Disclosure statement: All authors have declared no conflicts of interes

Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study

<p>Abstract</p> <p>Background</p> <p>Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate.</p> <p>Methods</p> <p>Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks.</p> <p>Results</p> <p>Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred.</p> <p>Conclusion</p> <p>The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate.</p> <p>Trial Registration</p> <p>(ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00784628">NCT00784628</a>)</p

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study

INTRODUCTION: We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. METHODS: In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to--or had contraindications for--non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). RESULTS: At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P &lt; 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. CONCLUSIONS: Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. TRIAL REGISTRATION: clinicaltrials.gov: NCT00798369