clinical topic updates

Radiographic Progression From Factors Other Than High Disease Activity in the Current Treat-to-Target Paradigm

by Eric M. Ruderman, MD


For nonbiologics such as methotrexate (MTX), there is a correlation between the degree of disease activity achieved and the risk of radiographic progression. In contrast, biologics are associated with an inhibition of radiographic progression regardless of the degree of clinical response.

Expert Commentary

Eric M. Ruderman, MD

Professor of Medicine
Associate Chief for Clinical Affairs
Division of Rheumatology
Northwestern University Feinberg School of Medicine
Chicago, IL

“Overall, my ideal treatment goal for patients with RA is to make them feel as though they do not have the disease; a medical student should be able to examine 
patients and determine that they do not have any signs of RA.”

Eric M. Ruderman, MD

In the pre-biologic era, there was a subgroup of patients with rheumatoid arthritis (RA) receiving MTX who appeared to be in remission but still had progressive joint damage. These patients were a challenge to treat, as it can be difficult to identify someone who may clinically respond but is going to have progressive structural damage. There was some hope that biomarker assays, such as the multi-biomarker disease activity score, could do this, although their clinical benefit has been limited and we have never been able, proactively identify such patients very well. These types of concerns have largely faded with the advent of biologic therapy. Post hoc analyses of studies with tumor necrosis factor inhibitors have shown that there is virtually no correlation between the degree of response (eg, ACR20, ACR50, ACR70) and radiographic progression. If patients have any type of clinical response to biologics, then they have significant inhibition of progression of radiographic damage. In contrast, with MTX, an effect-response relationship was observed, with a better clinical response associated with less radiographic progression. Thus, the use of MTX is more challenging and has resulted in patients having a very low threshold for moving on from MTX to biologic therapy.

My personal approach is to target disease remission in patients on MTX monotherapy; if they are only in a state of low disease activity, then you have not done your job as a rheumatologist. Patients who are not in remission are clearly at a higher risk for structural progression and are likely at a higher risk for cardiovascular complications. Thus, if a patient cannot achieve remission on MTX monotherapy, I add a biologic. On the other hand, once a patient is on a biologic, I am not certain that there are adequate data to suggest that going from low disease activity (eg, slightly above target) to remission will improve structural outcomes. If, in that situation, the patient is happy with their treatment response, then there is not much evidence to tell me that I should adjust or accelerate their therapy. Certainly, in terms of structural damage, that approach is likely adequate. Overall, my ideal treatment goal for patients with RA is to make them feel as though they do not have the disease; a medical student should be able to examine patients and determine that they do not have any signs of RA. A challenging scenario is the patient who is currently in remission while at the office visit but is having flares between visits. The challenge is to figure out how significant the flare is and whether it is severe enough to warrant different long-term therapy. This is an area of ongoing research.  


Aletaha D, Smolen JS. Joint damage in rheumatoid arthritis progresses in remission according to the Disease Activity Score in 28 joints and is driven by residual swollen joints. Arthritis Rheum. 2011;63(12):3702-3711.

Curtis JR, Greenberg JD, Harrold LR, Kremer JM, Palmer JL. Influence of obesity, age, and comorbidities on the multi-biomarker disease activity test in rheumatoid arthritis. Semin Arthritis Rheum. 2018;47(4):472-477.

Dasgupta A, Ward MM. Translating treatment effects between rheumatoid arthritis activity measures and American College of Rheumatology responses in direct comparison trials. Arthritis Care Res (Hoboken). 2019 Jan 10. doi: 10.1002/acr.23825. [Epub ahead of print]

Knevel R, van Nies JA, le Cessie S, Huizinga TW, Brouwer E, van der Helm-van Mil AH. Evaluation of the contribution of cumulative levels of inflammation to the variance in joint destruction in rheumatoid arthritis. Ann Rheum Dis. 2013;72(2):307-308.

ten Klooster PM, Steunebrink LMM, Versteeg L, et al. Association between disease activity and radiographic progression in the current treat-to-target paradigm of rheumatoid arthritis: real world data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) Registry [abstract]. Arthritis Rheumatol. 2018;70(suppl 10).

Wick MC, Lindblad S, Klareskog L, Van Vollenhoven RF. Relationship between inflammation and joint destruction in early rheumatoid arthritis: a mathematical description. Ann Rheum Dis. 2004;63(7):848-852.

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