New ACR RA-ILD Treatment Guidelines – What Were They Smoking!? Save

Rheumatoid arthritis related interstitial lung disease (RA-ILD) is common, with symptomatic RA-ILD affecting approximately 8% of RA patients. Median survival is around 5 years. There is a very limited evidence base supporting treatment, and therefore the recent release of ACR guidelines is to be welcomed. However, the published guidelines appear discordant with the best available evidence base. 

RA-ILD is unique among the rheumatic disease related ILDs in that it presents most commonly with a usual interstitial pneumonia (UIP) pattern, rather than non-specific interstitial pneumonia (NSIP) pattern. This is different to all of the other rheumatic diseases included in the guidelines. Part of the difficulty may arise from this attempt to encompass all rheumatic disease related ILDs in one guidelines as the RA-ILD recommendations closely mirror those of the other diseases. However, there are individualised guidelines described for each disease and I don’t think this is a valid mitigating factor. 

The concern for me here is that given the deficit in available evidence to guide treatment and the severity of the disease process, many rheumatologists may closely follow the presented guidelines, despite the lack of evidence supporting these. To my mind these guidelines represent an almost historic perspective, and aside from the inclusion of anti-fibrotic drugs, they could be from 20 years ago. 

The guidelines present three options for first line treatment of RA-ILD; in order of preference these are mycophenolate, azathioprine, and rituximab. Let’s look at the three of these in order and consider the rationale for these in order.

Mycophenolate has good evidence of efficacy in other rheumatic disease related ILD, in particular that associated with systemic sclerosis, where the evidence clearly shows that mycophenolate should be the first line treatment option. As discussed above, systemic sclerosis ILD is most commonly NSIP rather than UIP. I am not aware of any convincing evidence of efficacy for mycophenolate in UIP. There is certainly no clinical trial evidence of efficacy in RA-ILD. I am willing to allow the potential value of mycophenolate from a pulmonary perspective in RA-ILD. However, my biggest concern with mycophenolate in this setting is that in contrast to the lack of evidence for any specific drug in the treatment of RA-ILD, we have very good evidence that RA joint disease activity is associated with RA-ILD. Therefore, to my mind, the absolute first step in the treatment of RA-ILD is optimisation of RA joint disease control. This should be achieved by using whatever medication is needed to put the RA into remission. In this context, it is prudent to remember that mycophenolate is clearly inferior to most of our other agents in terms of arthritis disease control. Therefore, if we are using mycophenolate for lung disease alone, this implies that many RA-ILD patients will potentially end up taking mycophenolate, another csDMARD, and a biologic DMARD. This seems unwise from a safety aspect. The evidence base does not support sacrificing joint disease optimisation in order to facilitate mycophenolate usage for RA-ILD.

Things really take a turn for the bizarre, when we get to the recommended second medication, azathioprine. They become potentially reckless when we incorporate the other guideline suggestion to use short-term glucocorticoids in RA-ILD. Again, there are no good clinical trials of azathioprine in RA-ILD. We have randomised controlled trial evidence from PANTHER-IPF that the combination of azathioprine and glucocorticoids leads to increased mortality in the prototypical UIP disease, idiopathic pulmonary fibrosis (IPF) – a disease which is very similar to RA-ILD UIP. Prior to PANTHER-IPF the perceived wisdom was that this combination was the treatment of choice for IPF, echoing the approach seen in the current guidelines.

The two medications with arguably the best evidence to support their use in RA-ILD are rituximab and abatacept. Rituximab is included as a third preference treatment, arguably it should be first given its potential efficacy on both joint and lung disease. Abatacept, which has been the subject of large observational studies demonstrating potential efficacy from both Italy and Spain in recent years is not only conspicuous by its absence from the guidelines, it is specifically recommended against.

Needless to say, I for one won’t be following these guidelines.