A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

• Polman et al., NEJM 354 (9): 899-910, 2006
• PMID: 16510744

(see also: Rudick et al., NEJM 354 (9): 911-923, 2006)

Natalizumab is a monoclonal antibody against alpha-4 integrins. The alpha-4 family of adhesion molecules on lymphocytes (most importantly T-cells) binds to Ig-superfamily receptors (notably VCAM-1) on endothelium during early phases of the extravasation process. By blocking these interactions, T-cells can be prevented from entering tissue and thus inflammation can be prevented.

Natalizumab has been tested in Crohn’s disease and multiple sclerosis. The drug has been largely successful, but a series of major adverse events last year temporarily halted all trials (see references 25-27 in title paper). A subsequent evaluation of the data concluded that studies could continue, but this situation raises serious issues about the balance between drug risks and drug benefits. Adhesion molecule inhibition promises to be a potent strategy for blocking inflammation, especially where organ- and process-specific targets can be found (e.g. alpha-4 integrins are reportedly most relevant in the brain and gut). However, the consequences of such therapies must be considered. Certainly we are in an era where the concept of "do no harm" must be viewed in context (i.e. drug toxicity is a given), but inducing death in any fraction of patients where there was no imminent risk seems like an excessive trade-off.

While monoclonal antibodies are clearly powerful drugs, they may sometimes be too powerful, taking too long to wash out if an adverse event is reported and/or too potently inhibiting the target systems. Note similarities between this case and the reactivation of tuberculosis in patients treated with infliximab (Remicade). Perhaps the use of less-specific yet more pharmacokinetically manipulable drugs, e.g. designer small molecules, is the answer in such cases, or else more advanced monitoring need be implemented. Remicade has been successful with the added safety net of proper TB screening - could natalizumab succeed safely if we ensure proper PML screening?

Variable hematologic presentation of autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion

• Blood 107 (4): 1673-1679, 2006
• PMID: 16239424

As many of you likely already know, H. pylori has reached the penultimate in scientific fame as winner of the 2005 Nobel Prize in Physiology or Medicine. Independently of that, the topic of infectious triggers to autoimmune disease has been popular for some time, too. This article ties these two topics together nicely.

This study examines three cohorts of patients with autoimmune gastritis: those with iron deficiency anemia (IDA), those with normocytic blood indices, and those with macrocytic anemia. They find that all groups have evidence for an autoimmune polyendocrine syndrome and for antibodies against intrinsic factor, suggesting a similar pathologic process occurring. The IDA group was largely younger with a high incidence of H. pylori seropositivity, while the macrocytic anemia group, all meeting the criteria for pernicious anemia, was older with a low incidence for H. pylori infection. The RBC indices additionally show positive correlation with increasing age. The authors suggest that these data suggest that the three cohorts may be different phases of the same disease process. If true, this would open new doors to understanding pernicious anemia, and possibly help devise earlier routes for intervention prior to full-blown disease development.

The authors admit that this study is simply correlative and suggest that a study be done to follow the IDA cohort over time to determine if they really develop PA as per the model proposed. I would ask that if their model is strictly true, why is the serologic incidence of antibodies against H. pylori so low in the PA group? Does anyone know whether IgG against H. pylori really disappears that reliably after eradication?

Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice

• J. Clin. Invest. 116:495-505, 2006
• PMID: 16440060
• Available on PubMed Central
• Evaluated by Faculty of 1000 Biology

Well, hear it is, my attempt at a first article choice for Bench & Bedside.

This isn't my area of expertise, but I figured I had to start with something with wide-spread appeal. This article integrates genetics, neurology, endocrinology, physiology, and more, and has clear clinical implications. To reinforce the importance of the topic, and hopefully spark conversation, I point out that Nature Medicine did a recent focus on metabolic syndrome. The article also has obvious connections to the management of diabetes and pre-diabetic conditions, recently a major focus in The New York Times.

Please feel free to comment on any aspect of this article - the science, each individual figure, the implications, other related articles, projected clinical strategies, etc. I don't really know how this experiment in online journal clubs will mature, so hopefully we can all figure that out together.

Thanks, and happy reading!