Richard Lehman’s journal review—10 November 2014

richard_lehmanNEJM 6 November 2014 Vol 371
1771 The first paper in the New England Journal this week describes a French trial of rituximab versus azathioprine for maintenance in ANCA associated vasculitis. “At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio, 6.61; 95% confidence interval [CI], 1.56 to 27.96; P=0.002). Hence, to avoid one major relapse, 4 patients (95% CI, 3 to 9) had to be treated with systematic rituximab infusions rather than with azathioprine.” Now that’s good reporting, but why so few patients? It’s because ANCA associated vasculitis, first described by Friedrich Wegener in 1936, is quite rare. I went on a miserable detour to find out why Wegener’s name became detached from his granulomatosis. He spent the years 1939-44 as an SS pathologist adjacent to the ghetto at Łódź, where 250 000 Jews were crammed in to die from hunger, disease, overwork, or maltreatment, or sent to nearby Chełmno or more distant Auschwitz to be gassed. One thousand survived. So few records remain that it is impossible to prove that Wegener was guilty. Or innocent. Outside the ghetto at Łódź, 120 000 of the city’s Polish inhabitants are also thought to have died. Plenty of work for a pathologist, then.

1781 Compared with ANCA associated vasculitis, early rheumatoid arthritis is quite common. I remember the sleepy days of rheumatology, when diagnosis and treatment proceeded slowly and nihilistically; whereas now we realise that joint damage frequently begins within weeks or months after the onset of symptoms, and that some of it at least can be prevented by early treatment. In this trial, patients with newly diagnosed RA were given methotrexate plus 50 mg etanercept weekly for 52 weeks. Etanercept is a tumour necrosis factor inhibitor made by Pfizer and its basic cost for this dose is over £700 per week. The question addressed by this Pfizer funded trial is whether to keep giving half that dose to prevent relapses of RA. “Representatives of Pfizer designed the study, collected the data from the study centers, and performed the data analyses.” But the numbers remaining in the important bit of the trial were small, and so was any effect size. By radiological criteria, all showed similar progression. By clinical criteria, 28 patients out of 63 in the combination group had sustained remission, compared with 19 out of 65 in the methotrexate only group and 15 out of 65 in the placebo group. You will need to calculate the number need to treat with its confidence intervals for yourselves. Unlike the French triallists, Pfizer’s representatives have not seen fit to do this for us.

1793 After the US National Lung Screening Trial, there has been great interest in detecting early lung cancers by CT scanning of high risk individuals, since this is one form of screening that has actually been shown to reduce all cause mortality in the group selected. But trying to calculate the cost effectiveness of CT screening from that trial proves difficult. “We estimated that screening for lung cancer with low dose CT would cost $81 000 per QALY gained, but we also determined that modest changes in our assumptions would greatly alter this figure. The determination of whether screening outside the trial will be cost effective will depend on how screening is implemented.”

1813 And reading the clinical practice article that follows makes me wonder if there is really any place for this kind of “preventive” programme. Always remember that detection is not prevention. “A systematic review of eight randomized, controlled trials and 13 uncontrolled cohort studies of screening with low dose CT showed that the average frequency of positive screening results was 20% per round of screening.” That’s a pretty horrific rate of overdiagnosis. Nobody seems to know if there is any net mortality benefit for people over the age of 65 or to people with chronic obstructive pulmonary disease. And most lung cancer could of course be prevented by making it impossible for people to harm themselves by inhaling tobacco smoke. Nobody who is addicted to nicotine needs to get it by this route. But in the UK, a ban would deprive the government of £13bn in tobacco revenue. And people would live longer and so cost more, which is always bad from the point of view of governments.

JAMA 5 November 2014 Vol 312
1744 Metastatic melanoma remains just over the border of curability. As we wait and hope for some breakthrough in an agonisingly incremental process, there will be more trials like this one, and more paragraphs like this to chew through: “Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade.” The trial was disappointing. As for ipilimumab and sargramostim, they sound like something Edward Lear made up on a bad nonsense day.

1772 The preliminary report about frozen poo for C difficile has now appeared in print. Since I mentioned this paper a few weeks ago, I saw a TV programme about Hitler’s doctor Theodor Morell. In the 1930s, he made a preparation from the faeces of German soldiers, gave this the name of Mutaflor, and fed it to the Führer with good effect on his colonic symptoms. Although Morell is a repulsive figure, he was perhaps a pioneer in the therapeutic use of macriobiota. And he can probably take more credit for shortening the war than any other individual, by rendering Hitler completely insane for the last two years of his life with incessant painful injections of opioids and toxic stimulants and imaginary nutrients.

Lancet 8 November 2014 Vol 384
1691 The paper Lancet this week is chiefly of interest for its articles on the Great War. Prior to that conflict, it is quite possible that more soldiers died from diarrhoea than from battle, and during the 1914-18 period, dysentery owing to Shigella flexneri was rife in the trenches. A fascinating insight into the versatility of enterobacteria is provided by a new genomic analysis of the oldest extant Shigella flexneri serotype 2a isolate, taken from a dying British soldier at Wimereux on the Western Front in 1915. Unlike the common respiratory bacterial pathogens, faecal bacteria need to be smart to survive. They live among fungi, which produce antibiotics like penicillin and erythromycin. So we shouldn’t be too amazed that this shigella was already resistant to these antibiotics fourty years before they came into widespread use in humans. They had been in the ground for millions—perhaps billions—of years already.

1708 Another article worth looking at if you can get through the paywall is called “Battle for the mind: World War 1 and the birth of military psychiatry.” It’s interesting that it took about another 50 years for military authorities to realise that all war is mentally traumatic and that everybody has a breaking point. About 200 000 British soldiers reached it during the Great War, of whom probably fewer than 300 were shot for alleged “cowardice” alone. Shell shock outlasted the war for many victims. Read Owen, Sassoon, Blunden, Graves, Rosenberg, Ford, and Paul Fussell’s angry masterpiece of literary scholarship, The Great War and Modern Memory.

The BMJ 8 November 2014 Vol 349
Two papers in The BMJ‘s research section deal with the effect of cervical excision for cervical intraepithelial neoplasia on fertility and early pregnancy outcomes. The first one is a meta-analysis showing that it has no effect on fertility, but does increase the risk of second trimester miscarriage. The second explores the possibility that this risk is proportionate to the depth of excision. This case-control study nested within a record linkage cohort study demonstrates a minimal risk from small excisions, but a doubling of the risk of both preterm and very preterm births if the excision is large (over 15 mm or 2.66 cm3).

Many doctors are good writers and insightful thinkers, but great essays on medicine are rare. It is the most difficult thing to communicate both the importance and the unimportance of our place in the wider scheme of humanity. Somehow Iona Heath does this to perfection in a piece based on her lecture at the recent conference on overdiagnosis. This is something wonderful, simple, and concentrated, like one of those last bagatelles in which Beethoven sums up all that is communicable in a brief dance between themes. Keep it.

Ann Intern Med 4 November 2014 Vol 161

634 Hepatitis C genotype 1 can now be cured, although not many affected people can afford the treatment. There are several effective combinations, one of which is sofosbuvir plus ribavirin, which cures over 70% of people. A small phase 2a trial selected 14 people who had a recurrence of infection despite this regimen, and gave them sofosbuvir plus ledipasvir for 12 weeks. Everybody responded, including those with severe liver disease. So probably every millionaire in the world with hepatitis C genotype 1 can now be cured.

639 Nobody has worked harder on the problems of shared decision making in diabetes than Victor Montori and his team at the Mayo Clinic in distant Rochester, Minnesota. Here they produce an “Umbrella systematic review and comparative effectiveness network meta-analysis of pharmacologic interventions for painful diabetic neuropathy.” Working a session a week at the UK Cochrane Centre has taught me quite a lot about systematic reviews, but I haven’t previously come across one named umbrella. Still, that’s quite a good term if you think of a very large umbrella that shelters all sorts of evidence. Here it is exposed to the sun of inspection and the rain of criticism, and the results are mixed: “Confidence in findings was limited because most evidence came from indirect comparisons of trials with short (≤3 months) follow-up and unclear or high risk of bias. Conclusion: Several medications may be effective for short term management of painful diabetic neuropathy, although their comparative effectiveness is unclear.” Alas, this applies pretty well to all the wide ranging systematic reviews on symptom relief I have ever encountered. As a basis for shared decision making, most of the evidence available is scarcely fit for purpose. It is a case of try this, and then try that. But please remember to stop drug A before trying drug B.

Plant of the Week: Nemesia fruticans “Elph Dark Blue”
We bought this plant last year from our favourite nursery, and as usual forgot its name and existence until it came into flower a couple of months ago, when its existence became clear but its name had disappeared into the cognitive mist that now softens the edges of our lives.

By dint of searching the mud where it is planted, I came across its label, and am thus able to instruct you about its name and its merits. It has nice little leaves, which seem unaffected by the first hard frost. It has nice flowers too, which also don’t seem to have minded the frost in the least. So here you have an unassuming little perennial, which gives you lots of flowers when everything else is dead or dying. This has to be good.

Looking it up, I’m not quite sure how hardy it is or how long it will live. And Elph is stretching the truth by calling it Dark Blue. More bluish purple really. But while it lives and flowers, we shall not complain. About this plant, I mean. We shall certainly complain about everything else.