In this blog for health professionals, Professor Paul Bowness, Consultant Rheumatologist in Oxford UK, discusses the implications of the latest Cochrane Review from Lisa Verhoef and colleagues from the Netherlands addressing down-titration and discontinuation of Tumour Necrosis Factor inhibitor (TNFi) therapies (also known as anti-TNF agents or TNF-blockers) in Rheumatoid Arthritis.
This is an important topic because large numbers of patients with Rheumatoid Arthritis (RA) (as well other inflammatory arthritides and skin and bowel diseases) are treated with these drugs. They show good efficacy but are not curative and it has widely been believed that the underlying inflammatory conditions will flare if therapy is discontinued.
The current treatment paradigm for RA (with good supporting evidence) is that early and effective suppression of inflammation leads to greatly reduced long term joint damage (usually assessed radiologically) and preserves function and quality of life. This suppression is usually achieved by “treat to target” strategies involving combinations of standard disease modifying drugs (usually with methotrexate the “anchor” drug) with targeted often local corticosteroid therapy.
In the UK tumour necrosis factor inhibitors (TNFi) and other biologic therapies are currently NICE-approved for resistant disease with persistent high DAS (disease activity) scores. Once someone has commenced TNFi therapy and responded there has been relatively little good quality evidence available to guide subsequent treatment decisions. Patients are frequently keen to discontinue their methotrexate for example because of concerns about side effects.
Cochrane Review may lead to change in practice
This review may lead to widespread change in practice as it provides hard evidence to support a different strategy – that of TNFi dose reduction.
The review includes 14 studies (almost all randomized controlled trials) comprising over 3,000 patients. Broadly they find that TNFi dose reduction (or increased dosage interval) in RA patients with low disease activity is associated with relatively good outcomes. By contrast, they find evidence that discontinuation of TNFi therapy leads to adverse outcomes.
TNFi dose reduction for RA patients in remission is thus a viable option in clinical practice and could be both cost-saving and safe and convenient for patients.
Cautions to consider
There are a number of caveats/cautions to consider. The vast majority of evidence assessed is for the two most widely used agents (at least in our unit) adalimumab and etanercept. It is likely but unproven that other agents could be similarly reduced. Secondly it will be key to establish the role of methrotexate and other standard DMARD drugs in maintaining remission/low disease activity if TNFi reduction is contemplated. Thirdly it will be critical not to reduce therapy in patients who feel better but still have active disease without clinically obvious inflammation.
Where does this leave us?
Therefore, in my opinion, we are not ready to adopt such a policy for all patients and TNFi dose reduction in RA should be guided by robust disease activity assessment perhaps in addition to DAS28 CRP and other currently validated tools. In this respect there is considerable interest in biomarkers that might assist clinical decision making, including ultrasound, gene expression and biochemical markers (or panels of markers) in blood or urine.
In practical terms this suggests that many patients will be reassured that dose reduction is unlikely to lead to disease flare. Rheumatology units could therefore consider TNFi dose reduction strategies for RA patients in remission, whilst maintaining ‘treat to target’ strategy, actively auditing outcomes and contributing to the search for informative biomarkers.
Verhoef LM, van den Bemt BJF, van der Maas A, Vriezekolk JE, Hulscher ME, van den Hoogen FHJ, Jacobs WCH, van Herwaarden N, den Broeder AA. Down‐titration and discontinuation strategies of tumour necrosis factor–blocking agents for rheumatoid arthritis in patients with low disease activity. Cochrane Database of Systematic Reviews 2019, Issue 5. Art. No.: CD010455. DOI: 10.1002/14651858.CD010455.pub3
Dr. Bowness reports grants from Research support from GSK, grants from Research support from Regeneron, grants from Research support from Cellgene, grants from Speaker fee from Pfizer, outside the submitted work.