At long last, it’s time for the September Roundup of Arthritis & Rheumatism, the premier(?) journal for all things rheumatologic. Sorry it took me so long; I will plead that it was a very busy month, and that the paper journal took a long time to come out. I should also note that abstracts for the annual ACR conference also came out this month – I don’t know about you, but I’m excited! The ACR conference is great fun!

Anyway, as always here’s the disclaimer: I make no claims that this is a complete summary of the contents of this issue. It is a highly personal selection based on what I think is interesting, and therefore heavily weighted towards the clinical and epidemiological. All opinions are mine. All links require a subscription.

Tumor Necrosis Factor alpha antagosinst use and cancer in patients with rheumatoid arthritis. The background is that there’s been persistent worry that giving TNF antagonists (etanercept (Embrel), infliximab (Remicaide), and adalimumab (Humira)) increases the risk of various cancers. Personally I’m convinced that other DMARDs (disease modifying antirheumatic drugs – such as methotrexate) do not increase cancer risk – the increased risk seems to be related to the disease itself. I suspect that this is the case with TNFs too, but lets see what Setoguchi et al. have to say about it.

They used a large health care database and compared RA patients taking TNFs to patients taking methotrexate (MTX). There was no statistically significant difference in hematologic (blood) or solid cancers between the two groups. There are some interesting statistical methods used in this study, and I hope to review it in a little more detail later, but the major potential problem I’m thinking of (‘confounding by indication’) [<- I have no idea why this thing is here!] should bias the result towards showing a difference; so my first impression is that this is probably a valid study.

Associations of HLA-3C and smoking with vasculititis in patients with rheumatoid arthritis appears to be a fairly interesting study that suggests that HLA-3C (a specific genotype), smoking, and th presence of other antibodies (like ANA) are associated with extra-articular manifestations of RA like vasculitits. I’m not going to comment on this further right now as I’m not really familiar with the statistics used to analyse the genetic associations – maybe I’ll figure it out and report more later (or maybe not).

Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. This is an interesting study. Rituximab (Rituxan) has recently been approved for use in RA. It’s actually been around for about a decade and is also used in lymphoma, but the indication for RA is new. The indication is based on trials of rituximab compared to traditional DMARDs (I think) where it was shown to be beneficial when added on to the DMARD. But I believe this is the first time efficacy has been assessed in those who fail TNFs – our other second (or third depending on how you do it) line therapy when DMARDs fail.

Unfortunately, they compare rituximab to placebo rather than a TNF therapy. It seemed to work very well with an ACR20 of 51% vs 18% for placebo (the ACR20 is the standard measure of efficacy in RA trials – it means that 51% of patients had 20% improvement on a number of measures of efficacy). Since we already know that rituximab works, this isn’t a revelation. I would much rather have seen it compared directly to a TNF antagonist.

Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antihrhuematic drugs (phew!) looks at the safety of abatacept (Orencia) compared to placebo in people on other DMARDs or TNF-antagonists. Abatacept is the other new agent that we have for RA. It’s less well studied than rituximab because it’s completely brand new. They find that the side effects are pretty comparable for abatacept compared to placebo. There was a general trend for those receiving both TNF-antagonists and abatacept to have more side effects (serious adverse events 22.3% with those taking both, vs 11.7% for those taking abatacept and a DMARD).

Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. (Even longer!) Yet another biologic agent being evaluated for therpay of rheumatoid arthritis. I don’t know about you, but I’m not convinced that we need all these biologics. Anyhoo, tocilizumab is a humanized anti-IL-6 receptor antibod; IL-6 is a cytokine involved in promoting inflammation. The authors found that when used alone or with MTX that the response rate (ACR20) was about 60% compared to 40% for placebo + MTX. Which is all very nice, but once again you’re going to have to show me that it’s much better than what we’ve already got before I get very excited about this result. This was apparently a phase II study (dose-finding) so we won’t be seeing it on the shelves in the recent future.

Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis is interesting as it suggests that there are some genotypes (AMPD1 34T, ATIC 347CC, and ITPA 94CC) that may repond better to MTX for RA. Odds ratios were about 2.5 for a good response compared to those which didn’t have one, and rose to 27.8 for subjects with all three genotypes.

Unfortunately, I’m not yet ready to give a lot of credence to these genetic studies. These associations often seem to be unreplicable in later studies. I can’t help but wonder whether they are not just the noise of investigating a whole lot of genotypes. But apparently there is some evidence that adenosine, which all these genotypes are involved in the metabolism of (that was an ugly turn of phrase! – has any one ever seen The More the Merrier?), is involved as an inti-inflammatory in RA, so maybe it’s legit.

Immunohistologic analysis of zygapophyseal joints in patients with ankylosing spondylitis. I’m not actually going to review this one, but don’t you just love the word ‘zygapophyseal’?

Walking barefoot decreases loading on the lower extremity joints in knee osteoarthritis. Really? It’s a pretty technical article and I won’t go into it, but does this mean we should tell our knee OA patients to not wear shoes? The authors don’t say.

Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Yet another study of rituximab, this time for lupus and ANCA-associated vasculitis. It’s a case series for 22 patients (half with SLE, half with AAV) treated with rituximab and also a single dose of cyclophosphamide. All patients but one resonded and remained in remission until their B-cells started to regenerate (rituximab appears to work by depleting B-cells).

It’s only a case series, but is still kind of exciting! It would be very nice to have an alternative therapy for both of these diseases. The standard for serious disease in each case is cyclophosphamide, a good drug, but also a very toxic one. Rituximab appears to be quite safe so if it works as well as we hope it will be a very important improvement.

Boy there’s lots of other good stuff in this issue, but the above articles are what caught my eye. I hope to still review a few of them in a little more detail, but will let you know.

I should also point out what might be a very important article in the New England Journal of Medicine of June 22: Stimulatory Autoantibodies to the PDGF Receptor in Systemic Sclerosis. Once again, subscription is required to view. But the point of this article is that the authors present very convincing evidence that antibodies to the PDGF (platelet derived growth factor) receptor are present, perhaps universally, in scleroderma (aka systemic sclerosis) patients but not in other diseases, and that these antibodies may induce ‘reactive oxygen species’ that appear to be important in the skin thickening of scleroderma. If this is verified (and I’ve vastly oversimplified the article) the authors may have found the cause of scleroderma. That would be incredibly exciting! It doesn’t mean that effective treatments are around the corner, but it does give us something to go after, i.e. selective blocking of the PDGF receptor.

So there it is. Any questions?