Richard Lehman’s journal review – 12 December 2011

Richard LehmanJAMA  7 Dec 2011  Vol 306
2331   Over the period I have been writing these reviews, rheumatology has moved from being a rather sleepy discipline to being a hotbed of innovation, largely thanks to the arrival of tumour necrosis factor (TNF)-α antagonists. Known rather quaintly as “biologicals,” these drugs inspired fear when first used because of the threat that they might increase the risk of severe infection in their recipients, as well as bankruptcy in the NHS units which prescribed them. In the USA, where this observational study was conducted, usage is less inhibited by financial constraints and has climbed steeply over the last decade. There are four large databases which permitted the investigators to compare 8,000 matched pairs of patients who received TNF-α blockers or conventional treatment. Rates of infection requiring hospital admission were the same in both. Cause for rejoicing? No, just for careful reflection, as in the accompanying editorial: conventional treatment with leflunomide, methotrexate and/or steroids is far from risk-free, and the rates of infection in the RA population of this study were much higher than in the general population, and higher than in many similar comparative studies done elsewhere.

2340   Still, there’s no doubt that these drugs often make a dramatic difference. In the case of Dutch children with juvenile idiopathic arthritis, “often” means one third of children taking etanercept, the standard anti-TNF-α agent in use there. These kids are more likely to be male, to have localized disease, and to have previously received DMARDs. Another third show a moderate response, and the others little or none. This is a national cohort study which includes all children diagnosed with JIA and treated with biologicals since 1999, and the detail of the text contains a wealth of information about infection, relapse after “cure” (happily uncommon) and much else – a gold mine for paediatric rheumatologists and interested parents of children with JIA.

2348   Going right back to the earliest gestational age compatible with survival, this US cohort study examines whether the benefit of antenatal corticosteroids extends as far back as 22 weeks. Yes it does, but the figures are grim: death or neurodevelopmental impairment in 90.5% of babies without steroid exposure, versus 83.4% after antenatal steroids had been given.

2382   A meta-analysis of randomized trials of androgen deprivation therapy in non-metastatic, high-risk prostate cancer brings good news for the increasing number of men who opt for castration (usually by regular injection of GnRH agonists) as a long term treatment of high Gleason index localized prostate cancer. Contrary to expectation, their risk of cardiovascular events is no higher than the comparator group of men with localized prostate cancer: but in fact the presence of the cancer itself confers extra cardiovascular risk. Androgen deprivation certainly reduces prostate cancer specific mortality and all-cause mortality in this group. Since localized prostate cancer is almost ubiquitous in men over 60, perhaps all men who value longevity should undergo castration around the time of retirement, though this might leave them less to do with their spare time.

NEJM  8 Dec 2011  Vol 365
2155    Open any pre-war medical textbook and half of it will be about tuberculosis. Now most primary care doctors in the richer world think they can almost forget about it; but according to this paper, about 2 billion people around the world harbour latent TB, so this insidious old enemy of mankind is unlikely to disappear as long as there are humans on earth. Starting ten years ago, the PREVENT-TB study started recruiting patients from the USA, Canada, Brazil and Spain with evidence of latent TB to see if a regimen of rifapentine with isoniazid given weekly under direct observation for 12 weeks would prove more effective than nine months of self-administered daily isoniazid. The rate of overt TB over 33 months was halved, but the investigators are modestly content to claim no more than equivalence until they have more data.

2167   Oops, it’s happened again. Bristol Myers Squibb and Pfizer funded this study of their new oral anticoagulant apixaban taken for 30 days by hospitalized high risk medical patients to prevent thromboembolism, in a double-dummy trial with daily enoxaparin by injection for 6-14 days as the comparator. But far from creating a vast new market for long courses of their new factor Xa inhibitor, they simply proved that enoxaparin is safer.

2178   Norwalk is a Connecticut coastal town which we visited because it boasts a September Oyster Festival of which we had high gastronomic hopes. We hired a car, paid a high parking fee, an even higher fee to enter the muddy fields in which the festival was being held, and then – no oysters, just a wealth of stalls offering tacky goods for sale. In fact we did eventually find a solitary stall selling oysters at the furthest end of the muddiest field, but not the 23 varieties that greet the molluscophage at the Grand Central Oyster Bar in New York. It would have been much cheaper to enjoy some there. Why am I telling you all this? It has nothing to do with the matter in hand, except for the name Norwalk as in Norwalk virus. Which actually comes not from the Connecticut town but from Norwalk in Ohio, in honour of an outbreak of winter vomiting there in 1968. Now there is an intranasal vaccine against it for the first time, which was tested on 50 volunteers matched with another 48 who received no protection. They were all then infected with Norwalk virus, and the vaccinated group got about half as much gastroenteritis as the control group. It’s wonderful what some people will suffer for the cause of science, or for the sake of eating shellfish in strange locations.

Lancet  10 Dec 2011  Vol 378
1997   Now and again, The Lancet takes us to the cutting edge of some new surgical technique, and this time it’s a “proof-of-concept study” of clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. That’s a rather grand way of describing a lavishly illustrated single case report of a 36 year old male with a tracheal cancer which would have been incurable but for the creation of an artificial trachea using stem cells from his bone marrow laid out on tubular matrix. Wonderful stuff, but don’t try it at home.

2005   I managed to spend 35 years in general practice without seeing a single case of carcinoid syndrome, or at least without managing to diagnose one. But it is not all that rare – as the editorial on this study points out, it is commoner than Hodgkin’s disease, and you can read all about it in our Easily Missed series. In some patients it can get fully as nasty as Hodgkin’s lymphoma, and less treatable. This international randomized controlled trial funded by Novartis managed to recruit 429 patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid) and gave them either just one Novartis-manufactured drug – everolimus – or two Novartis-manufactured drugs, everolimus plus long-acting octreotide. The main finding of this study is that patients loathe taking everolimus – the drop-out rate was 179 patients in both arms, leaving a combined total of just 71 at the completion of the trial. The ones taking the combination showed a five-month improvement in progression-free survival: but with a drop-out rate as high as this, I would beware of this statistic.

2013   A follow-up study of the Heart Protection Study cohort by the Clinical Trials Support Unit at Oxford shows both benefit and safety from the long term use of simvastatin in high-risk patients. “More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards”, they say in their conclusion. But why on earth do they slip in “LDL-lowering” before the word statin? We have no idea whether or not statins work by lowering LDL-C, and we have good evidence that their effectiveness at lowering cardiovascular risk is not related to their degree of LDL-lowering. Nor have any other LDL-lowering agents been shown to lower risk, though the CTSU gets a nice tranche of funding from attempts to prove that they do.

2039    As a seven-year-old I took to collecting spiders of every size and shutting them together in matchboxes: I would then release the very large spider that remained. As punishment for these youthful crimes of investigative biology, I later became somewhat spider-phobic: and the smaller ones have very good reason to single me out for revenge. This article on spider bite is not good bedtime reading for arachnophobes: widow spiders of the genus Lactrodectus are spreading around the world and there might be one here in the Northern USA which has its particular sights on me. Loxosceles species from South America are also on the move. Both lactrodectism and loxoscelism are very painful and sometimes life-threatening conditions, and there is no real evidence that treatment with anti-venom is effective. The huge spiders we now call tarantulas are pretty innocuous; in fact the fatal envenomation attributed to them by the inhabitants of Taranto probably came from a much smaller endemic species of Lactrodectus. The only cure, of course, is to dance the Tarantella: see if you can keep up with Heifetz in this public broadcast from the 1940s.

BMJ  10 Dec 2011  Vol 343
It’s amazing how little evidence you need to have before getting permission to put things into human beings. Artificial hips have been around for fifty years, ever since their inventor John Charnley experimented on himself with some of the components to test their effect on human tissues. But since then manufacturers have played around with new hip prostheses purely for the sake of getting a share in a lucrative market. This systematic review by members of the US Food and Drug Administration looks at the evidence to determine the comparative safety and effectiveness of combinations of bearing surfaces of hip implants. Basically, there isn’t any.

Ann Intern Med  6 Dec 2011  Vol 155
725    Far from the Madding Crowd, Madame Bovary, and a biography of John Adams: what do these miscellaneous works have in common? Well, firstly that I have read them all in the last few weeks, to sweeten my hours of exile; and secondly that the characters in them do a lot of walking. Moving about on two legs is really the intended default setting of humanity when not asleep: and this is what our knees are designed for. This may explain the paradox that as we become more sedentary, we experience more knee pain. Here is a fascinating report of the changing pattern of knee pain in the USA, derived from 6 NHANES (National Health and Nutrition Examination Survey) surveys between 1971 and 2004 and from three similar time-points in the Framingham Osteoarthritis Study. It concludes that “the prevalence of knee pain has increased substantially over 20 years, independent of age and BMI. Obesity accounted for only part of this increase. Symptomatic knee osteoarthritis increased but radiographic knee osteoarthritis did not.” And the cure for all this extra knee pain? Why, knee replacement surgery of course, a wonderful source of income for scores of thousands of American orthopaedic surgeons.

772    Are all second-generation antidepressants the same? Assuredly not, for those doomed to take them, but the evidence base for selecting one of them over another remains pitifully bad. This updated meta-analysis finds that there is no good evidence for any difference in efficacy between them – and this includes agents such as trazodone, bupropion and duloxetine as well as the standard serotonin reuptake inhibitors. There are some differences in known harms and onset of action. About the widespread problem of induced dependency, there is no mention at all.

Plant of the Week: Viburnum farreri

It is always a shock when December comes round and there are almost no plants of any kind worth looking at: and it is even worse here in New England where the Himalayan species brought back by the great British plant-hunters a century or more ago cannot survive the severe winters. Readers will be aware of my fondness for Reginald Farrer, who died alone in the mountains of northern Burma in 1920 while seeking new treasures for our gardens. His name is commemorated in this tousled shrub which looks a mess all year, but then produces white or pink flowers of lovely scent just as Christmas is bringing its hallowed season of unease and expenditure to the population of Great Britain. It is a must for every garden, to be tucked away somewhere to hide its summer ugliness; but never so inaccessible that you cannot get to smell it, and to cut some branches for the house to breathe perfume amongst the holly and the ivy. Most Americans cannot do this, but we can and will on our return to England this week.