CHICAGO—Josef S. Smolen, MD, professor of internal medicine and chair of the Department of Rheumatology, Vienna General Hospital, Austria, presented the prestigious Paul Klemperer, MD, Memorial Lecture at the 2018 ACR/ARHP Annual Meeting. Dr. Smolen, whose work is frequently cited, created the treat-to-target strategy for rheumatoid arthritis (RA).
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Dr. Smolen began by noting a simple examination of the pathology of RA reveals it is an inflammatory disease of the synovial membrane that leads to disability. Unfortunately, researchers still do not know what elicits the disease or which type of T cell is activated in the disease. Instead, most of the knowledge about RA centers on the final stages and the destructive work of the disease.
The realization that cells and cytokines are associated with the damage of RA still leaves unresolved the question of which abnormalities drive the progression of joint damage. The damage is clearly associated with inflammation, which is clinically visible as joint swelling and a higher affected joint count, Dr. Smolen explained. A confounder in this association is that patients with no swollen joints can have a high inflammatory serological response with no progression of joint damage.
Although composite measures of disease activity should include joint counts, Dr. Smolen stated, another important factor drives damage in RA: autoimmunity. Autoimmunity results in the formation of immune complexes that can activate complement and increase the inflammatory response. From this information, Dr. Smolen derived the hypothesis that it may be possible to prevent joint damage by interfering with inflammation and achieving remission.
From this goal, Dr. Smolen explained, stem the questions: How is the progression of joint damage best stopped? Is it possible to achieve early remission and sustained remission? When attempting to answer these questions, rheumatologists discovered even patients who achieved remission shortly before their second year had some disease progression.1 In contrast, patients who were able to achieve an earlier and durable remission were able to halt the progression of joint damage. Further research suggested tumor necrosis factor inhibitors were the most effective drugs for inhibiting joint damage.2
Typically, RA outcomes are measured by the ACR70 criteria. What rheumatologists began to see, however, was patients could more easily achieve remission than they could meet the ACR70 criteria. This suggested remission was somehow separate from the response to treatment documented by the ACR70. Dr. Smolen explained this difference is probably at least partly due to the way the hand is constructed. The patient with early disease has disability as a result of stiffness or pain from disease activity, and the disability can be fully reversed with treatment. In contrast, a patient with longstanding disease has disability, not from disease activity, but from the damage itself. The disability in this patient is the consequence of joint destruction. So this latter patient will experience permanent disability in the face of clinical remission.
Dr. Smolen explained that a patient with a modified Sharp score of 50 or higher will likely not show much response to treatment because such a patient has physical disability associated with cartilage damage. The treatment goal for patients with RA becomes to stop inflammation as quickly as possible to optimize physical function.
‘We should aim for at least 50% improvement in disease activity by three months.’ —Josef S. Smolen, MD
Treat to Target
In many cases, however, physicians do not treat patients with RA to target. Patients may, for example, initially be prescribed methotrexate, and insufficient responders are then prescribed alternative disease-modifying anti-rheumatic drugs. This process can take years, during which time the patient may never achieve remission. “I believe thousands, if not millions, of RA patients in the world are managed inadequately,” said Dr. Smolen.
He then described the 2014 algorithm to treat RA to target, noting the importance of reaching remission or low disease activity. He explained the best way to achieve this goal is to adapt therapy in a timely fashion. This means calculating a composite measure of disease activity every one to three months. “Given the fact that we have many therapies available now, … we should be able to rapidly adapt therapy of patients who do not reach a response,” he said.
Predictors of Long-Term Response
Dr. Smolen reminded the audience that response at three months from treatment initiation predicts long-term response. Thus, the way to the target is also a target.
“We should aim for at least 50% improvement in disease activity by three months. … Anything else is just too low. … By six months, the target should be reached, or the drug or treatment strategy switched,” he said.
Dr. Smolen also counseled the gathered rheumatologists to forget personalized medicine and focus on abating disease activity with the goal of getting patients into remission.
Unfortunately, Dr. Smolen noted, although remissions increase with a treat-to-target approach, approximately 25–30% of patients with RA are refractive to treatment, and their inflammation remains consistently active. At least two factors seem to contribute to this treatment refractory state: time to treatment and high disease activity. The two factors are interrelated because the longer the disease is untreated, the higher the level of disease activity. “This speaks for early therapy and rapid intervention,” he emphasized.
Dr. Smolen concluded by acknowledging that RA continues to be a chronic disease without a cure. He suggested the best approach is early intervention using treat to target. Such an approach makes it possible to achieve remission in an unprecedented proportion of patients, prevent joint damage and minimize the progression of RA.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
- De Cock D, Vanderschueren G, Meyfroidt S, et al. Two-year clinical and radiologic follow-up of early RA patients treated with initial step up monotherapy or initial step down therapy with glucocorticoids, followed by a tight control approach: Lessons from a cohort study in daily practice. Clin Rheumatol. 2014 Jan;33(1):125–130.
- Kavanaugh A, van Vollenhoven RF, Fleischmann R, et al. Testing treat-to-target outcomes with initial methotrexate monotherapy compared with initial tumour necrosis factor inhibitor (adalimumab) plus methotrexate in early rheumatoid arthritis. Ann Rheum Dis. 2018 Feb;77(2):289–292.