Richard Lehman’s journal review, 4 October 2010

Richard LehmanNEJM 30 Sep 2010 Vol 363

1303 Spleen tyrosine kinase is an important inflammatory mediator, which for some reason has the abbreviation Syk rather than Stk. The editorial for this paper about fostamatinib therefore bears the title “Healing the Syk through Kinase Inhibitors” – bad enough to be one of mine. You can find Syk in the synovium of people with rheumatoid arthritis, where it promotes the release of metalloproteinases and cytokines and other bad things. Fostamatinib is an oral prodrug which is rapidly converted to a potent and relatively selective inhibitor of Syk, called R406. For reasons that baffle me, fostanimib is referred to throughout this paper as R788. In RA patients already receiving all standard modes of treatment, except TNF blockers, fostamatinib produced a clinically useful effect compared with placebo at 6 months. Depending on its pricing by Rigel, who funded the trial, this might prove a useful alternative to the very expensive “biological” agents currently available, though it tends to elevate blood pressure and cause diarrhoea. Michael E Weinblatt, the chief investigator, is certainly hedging his bets: besides earning from Rigel, he declares financial ties with another 48 drug companies. P.S. Rigel (Arabic for foot) is the name of a bright star in ß Orion, magnitude 0.1, a mere 900 light years away from Earth. But does it rhyme with eagle, or niggle, or Nigel?

1341 Like about 40% of adults of my age in Western countries, I have a fatty liver, though I don’t qualify for having nonalcoholic fatty liver disease because I drink too much. If I wanted to know what is really happening to my liver I would have to have serial biopsies, as would several million people in the UK. This non-disease correlates with a number of other non-diseases such as asymptomatic reduced left systolic ejection fraction and pre-diabetes, and some real risk factors such as actual diabetes and high blood pressure. So I might die of vascular disease; or liver failure if I really overdo the wine; or else from cancer or general crumble or whatever else awaits me and everyone else. This paper on the risk of cardiovascular disease in patients with nonalcoholic fatty liver disease goes through the data and leaves me none the wiser: and by the way, these people are not patients and they don’t have a disease.

Lancet 2 Oct 2010 Vol 376

1147 Once chemical castration has ceased to be effective, treatment for advanced prostate cancer usually proceeds to chemotherapy involving docetaxel, which belongs to the yew-derived taxane group of tubulin-binders. After that comes mitoxantrone, which improves symptoms but does not prolong life. But now there is another taxane on the market, promoted by Sanofi-Aventis in this comparative trial with mitoxantrone for this group of patients. It is called cabazitaxel and the patients randomised to it in this trial lived 2.4 months longer than those who got mitoxantrone. Not a breakthrough, then; perhaps not even an advance: time will tell.

1155 In this cancer-dominated Lancet, here’s an MRC-funded study which casts doubt on the widespread strategy of following up patients with ovarian cancer in remission using serial measurements of serum CA125. The point is to treat them early but in this randomised trial this strategy produced a non-significantly worse survival time than treating once disease recurrence becomes clinically apparent.

1164 So much of cancer progress is a matter of a tweak here and a tweak there, or what to tweak when. Most doctors don’t even bother to keep up. The Great British Public, on the other hand, is fed a constant diet of Great British Cancer Breakthroughs by the Daily Mail and the Daily Express; while Dr Stuttaford in the Times assures his readers of what a jolly good job the drug companies are doing for Times readers unfortunate enough to develop cancer. I’ve no doubt he will have warm words for the achievement of F Hoffmann-La Roche who have proved in this study that rituximab should be a first-line treatment for chronic lymphocytic leukemia: added to fludarabine and cyclophosphamide, it may even offer the prospect of a cure. But the Mail and the Express may be less keen: this Cancer Breakthrough is not British, but – horrors – German and Italian.

BMJ 2 Oct 2010
A large part of general practice consists of seeing people with painful joints due to osteoarthritis and trying to think of something to give them. Glucosamine with or without chondroitin is cheap and harmless. Unfortunately it has no clinically meaningful effect, as this well-conducted and well-written meta-analysis of the placebo-controlled randomised trials makes clear. The trials show a consistent pattern of overall pain reduction of less than 1 on a ten-point visual analogue scale. I’m surprised by this consistency – does it hide a subgroup of patients who have a much larger effect, and is that sustained? Maybe, contrary to the advice of the authors, we should encourage people with OA to try glucosamine for three months and continue if they think it may be of benefit. Ideally, we’d do a blinded n-of-1 trial. The point is, if they get any benefit, placebo or otherwise, we may be able to spare them an early death from the adverse effects of NSAIDs.

The drug we would least want to be without is paracetamol. We feed it to our babies to the extent that 97% of them have been exposed by the age of 2. Could this be the cause of the great increase in asthma and atopy over the last three decades? According to this prospective cohort study from Australia, the answer is no, unless the effect is entirely dose-independent. There was no correlation between the amount of paracetamol given and the later development of asthma in childhood. An important study.

Arch Int Med 27 Sep 2010 Vol 170
1548 I am entirely agnostic about the benefits of exercise in people of normal weight before the age of 50, but I am forced by the evidence to concede that from then on, it becomes increasingly important. Who knows, one day I may do some, if time permits. Meanwhile, osteopenic ladies of 70 take note: 160 Finnish women of this kind were randomised to receive an intensive, mainly home-based exercise programme for a year ending in 2001. In five years of follow-up, one of those randomised to the exercise died, and none had hip fractures: in the control group 8 died and 5 had hip fractures. This was a small trial which has taken a long time to report its findings: but the message is pretty clear.

And so it is for all women and men who Look AHEAD to old age, specifically if they have type 2 diabetes. The Look AHEAD trial proves that it is possible to achieve real changes in individuals using an intensive programme of diet and exercise. You could argue over the detail but the fact is that after 4 years, the intervention group showed a marked improvement in weight, fitness, and lipid profile, with lesser benefits in blood pressure and glycaemic control. I like the way the triallists, rather than claiming that these changes are bound to be beneficial, tell us to wait another ten years to know if there is a real impact on cardiovascular end-points. Would that drug companies were made to do likewise when touting drugs that lower blood sugar.

Plant of the Week: Kerria japonica

I never imagined I would ever say anything favourable about this deeply annoying mess of stems and coarse leaves that appears over our fence from the neighbour’s garden and puts forth innumerable suckers into our ground. In spring it adds insult to this injury by waving about tufts of orange-yellow flower that clash with the soft pinks and whites of magnolias and Clematis montana. My favourite writer on shrubs, Brigadier C E Lucas-Phillips, describes it but briefly in his Ornamental Shrubs (1981), as “a very hardy, kindergarten shrub that almost anyone can grow. Very jolly in April…”

Much too jolly in April, and a year-round nuisance: but I’m prepared to give it just a little leeway in October. By some freak, it is flowering madly as the rest of the garden declines: not on our territory, I hasten to add, but over the top of that fence. A welcome note of exuberance, and a foretaste of spring amongst the slow progression of gloom and rot that leads to November.