Combined Therapy in Rheumatoid Arthritis Interstitial Lung Disease Save

Rheumatoid arthritis interstitial lung disease (RA-ILD) represents a major therapeutic evidence void in our current treatment paradigm. RA-ILD is common, with clinically significant disease seen in 8% of patients. In the past RA-ILD was frequently under-diagnosed, leading to identification of a disproportionate volume of severe cases and subsequently inflating the mortality statistics. However, RA-ILD, particularly in the progressive pulmonary fibrosis phenotype, retains a poor prognosis.

It is curious therefore that frequently the treatment strategy in RA-ILD seems to gravitate towards monotherapy. RA-ILD represents the most severe form of RA and is frequently associated with commensurate severe joint disease. It is surely inconceivable to most rheumatologists that we would, as a rule, treat severe RA joint disease with monotherapy, however it frequently appears to become the default once the lung is involved. If we follow the ACR SARD-ILD recommendations and favour azathioprine, mycophenolate mofetil, or rituximab for RA-ILD treatment, monotherapy becomes even less attractive given the relative lack of efficacy of the first of these two agents on the articular manifestations of RA.

I would propose a new framework for RA-ILD treatment. To harken back to the (not too distant) past, triple (or even quadruple) therapy.

The first arm of this treatment approach involves maximising the benefit of csDMARDs. We as rheumatologists are in general very adept at doing this in RA, but once ILD enters the equation we display an over-abundance of caution, being dissuaded from the use of agents such as methotrexate and leflunomide by the rare possible occurrence of pneumonitis. While this can occur, the frequency is around 0.3% of methotrexate initiators, and being over-cautious is therefore denying the majority of patients of an effective treatment option. I would advocate that only those patients with insufficient baseline pulmonary reserve to survive an episode of pneumonitis should not be given a trial of methotrexate or leflunomide.

The second arm of the algorithm involves optimising the RA disease control further. There is now an abundance of evidence that RA-ILD is associated with RA disease activity. While there is some, actually relatively weak, evidence to suggest that rituximab or abatacept, or even tocilizumab and JAKi, may be more effective than TNFi for RA-ILD, the fundamental here is that you use the agent which controls the RA best. If the RA is in remission on a TNFi, the presence of non-progressive RA-ILD should not alter the treatment approach. If however, the RA-ILD is progressing on a TNFi it makes sense to switch to an alternative biologic.

The third proposed arm of treatment is likely to evoke some controversy. 

It is our practice that all patients with progressive RA-ILD despite the optimisation of the first two arms is given a trial of anti-fibrotics; nintedanib initially, and subsequently pirfenidone if nintedanib is not tolerated. There is very good evidence from randomised controlled trials that anti-fibrotics reduce the rate of loss of lung function. While some may question the magnitude of this benefit, if we are talking of a, hopefully, prolonged patient survival, the cumulative benefit accumulates. The first major issue with anti-fibrotics is tolerability – which is why I term this a “trial of anti-fibrotics”, if the anti-fibrotic is detrimental to the patient’s quality of life we would generally stop it. The second issue is cost, but the arguments around not utilising anti-fibrotics due to cost remind me of the past similar arguments around biologics; if they prevent declining lung function and the consequent increase in respiratory related hospital admissions and oxygen use, I would expect them to have a positive cost-benefit balance in the long term.

The fourth, and for me more optional, treatment consideration, is whether to add a lung specific immunosuppressant (mycophenolate mofetil or azathioprine) to a fully optimised triple therapy strategy. I think in the setting of ongoing significant disease progression despite the triple therapy approach, then this is a reasonable consideration, and something that we do employ in daily practice.

Hopefully this can be a herald of the era of triple therapy 2.0 in RA-ILD.