Weight a Minute, It's Not All About (Joint) Load?

If I had a nickel for every time I heard someone call Osteoarthritis "wear and tear" arthritis… well, I'd spend a lot of time rolling sleeves of nickels.

You heard it here first: several types of OA are inflammatory. Actually, no you didn't, OA has been known to be associated with inflammation since the dawn of modern medicine. It's only buried in articles nobody reads because microfiche just isn't hip anymore! But I digress.

It was lovely to see the focus on metabolic OA and hand OA today in the OA Abstracts session. Sadly, it wasn't all good news. 

New treatments likely not on the horizon for hand OA include dual interleukin-1 alpha and beta inhibitors. Dr. Kloppenburg summarized a phase 2A trial of the IL-1alpha/IL-1beta dual inhibitor ABT-981 being tested in erosive hand OA. It failed to meet the primary patient-reported outcome of a change in AUSCAN hand pain at 16 weeks. X-ray outcomes were also not changed. Although, at 26 weeks, I'm not sure I would have expected much difference. MRI measures of synovitis could reasonably be expected to improve, but were nowhere near reaching statistical significance. 

Particularly unfortunate is that this negative hand OA trial comes shortly after the recently reported UK HERO trial of hydroxychloroquine in hand OA. It also failed to meet its primary and secondary outcomes.

Dr. Bowes' provided a well-received assessment of improvements that we need to make to the design of knee OA clinical trials of therapy for structural outcomes. Clearly, Kellgren-Lawrence grades of 3-4 on radiographs is a poor selection criterion for inclusion in studies due to inconsistent grading between readers. Of course, there is also the fact that a KL grade of 3-4 is late-stage disease with severe damage, making it hard to demonstrate further progression in a study. Not to mention, severe damage is unlikely to get better no matter what you do. 

Structural progression is slow in OA, meaning recruitment of individuals into studies that are most likely to progress is critical to giving the study a chance to show an effect. 

Showing data from the OA Initiative, Dr. Bowes concluded that selecting patients with radiographic joint space width (JSW) of 2-4 mm identified patients with the greatest likelihood to progress in terms of structural damage within 2 years. Adding a pain criterion to patient selection was far more likely to demonstrate a meaningful difference in structural progression outcomes. Finally, MRI outcomes are even better when it comes to show differences with smaller numbers of patients, potentially bringing affordable OA trials closer within reach.

The session ended on an interesting note with Dr. Veenbrink's report showing that leptin and adiponectin contribute to the association between BMI and knee or hand OA. 

Another leptin study you say? This one is potentially important. The debate has raged for years (and will continue) between believers and non-believers with respect to whether "metabolic OA" even exists. 

Non-believers claim that high BMI adds load on on the joint (true enough), and no study has previously demonstrated convincingly that a bona-fide metabolic mechanism adds further risk of OA beyond the extra load on knee joints. In this current mediation analysis, leptin partially mediated the association (ranging from 8-30% contribution) between BMI and hand or knee OA in women and men (adiponectin as well but only in men). There is much more to do, and this is just one cross-sectional study. But the mediation analysis is a clever way of looking at this interesting and multifactorial issue.

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