Remission and Beyond in Rheumatoid Arthritis

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Advances in treatment of rheumatoid arthritis (RA) in recent decades have meant that far more patients are able to achieve remission. For example, in one Norwegian registry, approximately 40% of patients achieved remission as defined by a Disease Activity Score (DAS) below 2.6, and in the French ESPOIR cohort, fully half of patients were in remission 5 years after diagnosis. These improvements reflect better use of disease-modifying antirheumatic drugs (DMARDs), a treat-to-target approach, tight control, and frequent adjustments to treatment.

But debate continues as to what true remission is in RA and how it should be defined, so international societies such as the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR, formerly known as the European League Against Rheumatism) have worked to refine the definition of remission, as well as to provide advice on important concerns such as tapering therapy once patients are in sustained remission. The ACR also recently developed a guideline on the use of integrative interventions to be used for all stages of disease to complement pharmacologic therapy.

Remission Revision

ACR and EULAR first published provisional criteria for remission more than a decade ago, establishing that remission should reflect little or no disease activity and a low risk for functional impairment and radiographic progression.

Two types of definitions were proposed:

• A Boolean definition that required that each of four core set variables -- total joint count, swollen joint count, patient global assessment, and C-reactive protein level -- have a score of 1 or less

• A definition based on the cutoff for remission for the Simplified Disease Activity Index (SDAI), which takes into account those factors, plus physician global assessment of disease activity, but adds up the individual scores, allowing an increase in one variable if compensated for by a lower score in another variable, with a total cutoff score of 3.3 or less

"Since their publication, arguments have been made claiming that remission definitions may, on the one hand, be too stringent, with the risk of overtreatment if used as treatment targets, or, on the other hand, too lenient, proposing addition of imaging confirmation of remission," wrote Paul Studenic, MD, PhD, of the Medical University of Vienna in Austria, and colleagues in a 2022 revision of the RA remission criteria.

In addition, there has often been discordance between the rates of remission based on the Boolean definition compared with the SDAI definition, with higher rates being seen with the SDAI definition. The reason for the rate difference has been attributed to higher scores on the patient global assessment in the Boolean definition, with patients' scores potentially reflecting non-disease activity related problems such as residual pain from irreversible joint damage. The patient global assessment is intended to provide a holistic or "gestalt" assessment of disease and well-being, and therefore can have discordant findings compared with objective measures.

Accordingly, the ACR and EULAR have published revised criteria for remission in RA, in an attempt to bring the Boolean definition of remission more closely in line with index-based criteria such as the SDAI. The newly proposed definition increased the cutoff for patient global assessment from 1 or less to 2 or less.

The Analysis

The proposed change resulted from a post-hoc analysis of four clinical trials:

• GO-AFTER was a phase III trial of golimumab (Simponi) among patients who had not responded to tumor necrosis factor inhibitors

• FUNCTION evaluated tocilizumab (Actemra) in patients with early RA

• LITHE evaluated joint damage and physical function among patients with inadequate response to methotrexate given tocilizumab

• SERENE assessed rituximab (Rituxan) in biologic-naive methotrexate nonresponders

The four studies included a total of 2,048 patients with varying disease duration and treatment histories. Among these, 1,101 had early RA, with a mean duration of 0.8 years, and 947 had established disease, with a mean duration of 7.1 years. Rates of remission were assessed at 6 months, and radiographic outcomes and functional disability on the Health Assessment Questionnaire (HAQ) were evaluated at 1 year.

Using the Boolean definition with the patient global score of 2, remission rates among patients with early RA were 20.6% at 6 months compared with 14.8% using the patient global score of 1, while among those with established disease the rates were 6% compared with 4.2%. These represented relative remission rate increases of 39% and 42% in early and established disease, respectively.

These low remission numbers reflect the fact that "patients in these trials had very active disease so that remission was a challenging goal with low rates. For patients with milder disease than seen in these trials, rates should be higher," co-author David T. Felson, MD, of Boston University School of Medicine, told MedPage Today.

Also in the analysis, "near misses" on the Boolean definition of remission -- meaning patients who fulfilled three of the four criteria, were seen in 15.2% of the study population. In 60%, this was attributed to the patient global score not being 1 or less, but the proportion of near misses fell to 47% when analyzed using a patient global score of 2 or less.

The researchers then looked at rates of patients achieving good functional outcomes at 12 months, finding similar mean HAQ scores on SDAI (0.27), Boolean 1 point cutoff (0.24) and Boolean 2 point cutoff (0.31). Comparison of changes in radiographic scores at 1 year also were similar, at 0.27, 0.29, and 0.25, respectively. "This observation is consistent with previous findings that patient global assessment score is not associated with radiographic progression," Studenic and colleagues emphasized.

"Our analyses support the notion of a slight increase of the patient global assessment threshold since it provides better agreement with the SDAI remission definition and higher rates of Boolean-defined remission, without jeopardizing the prediction of good long-term functional and radiographic outcomes," the team concluded.

Tapering Treatment

Because of the potential risks of aggressive RA treatment and the attendant costs to the individual and society, considerable interest exists in considering de-escalating or stopping treatment among patients who are in sustained remission. Efforts are underway to develop strategies to address this.

In one review, a group of international experts led by Georg Schett, MD, who is vice-president of research at Friedrich Alexander Universität in Erlangen, Germany, outlined potential eligibility factors for medication tapering. First, patients should meet standard criteria for remission, such as a DAS28 below 2.6, DAS44 below 1.6, SDAI below 3.3, Clinical Disease Activity Index below 2.8, or the ACR/EULAR criteria discussed above.

Sustained remission should have been consistent over 6 months, DMARD use must have been stable over that time period, and no glucocorticoids were used.

The authors also noted that certain factors are associated with a better outcome with tapering, an absence of synovitis on ultrasound, and normal serum markers of inflammation.

In describing his center's approach when patients with RA are in remission, co-author Paul Emery, MD, director of the University of Leeds Biomedical Research Center in Leeds and professor of Rheumatology, said, "These days once they achieve remission we think about reducing their treatment and see if they stabilize. What has changed is that each time you reduce the therapy you can use biomarkers to help predict what's going to happen. For instance, we measure T-cell subsets. If you have normal T regulatory cells you have a much better chance of sustaining remission when you reduce therapy."

Seropositivity is also considered. A patient without rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) has a better chance of remaining in remission, according to Emery. Duration of disease is also important, with early disease being associated with a greater likelihood of sustained remission.

Many studies have now examined the effects of medication tapering, with most focusing on withdrawal of biologic therapies. Overall, the findings suggest that success is more likely among patients with early disease and sustained remission, but in many of the studies patients with low disease activity (DAS28 <3.2) were included. These patients were much more likely to flare with medication withdrawal than those in remission.

"The concept that residual, mostly subclinical inflammation can be associated with enhanced relapse risk has prompted investigators to test whether imaging can help predict flare risk. This concept is also stimulated by observations that a substantial proportion of patients with RA in remission can show signs of synovitis by ultrasound or MRI," wrote Schett, Emery, and co-authors.

"We use ultrasound for everyone, because if you have active disease detected on ultrasound it's very unlikely that you will be able to reduce therapy without flare," Emery told MedPage Today.

In one study that included 77 patients with RA who were in sustained remission on biologic therapy, 45.5% were considered tapering "failures," and on logistic regression analysis, the presence of synovitis on Doppler ultrasound was the strongest predictor of flare, particularly when combined with baseline DAS28.

Another study demonstrated that synovial hypertrophy detected on ultrasound was associated with a higher risk of flare, and, according to Schett and Emery, "the authors also showed that absence of ultrasound hypertrophy is associated with only minimal synovial changes in the histology, supporting the accuracy of ultrasound examination to detect residual disease activity.... A combination of clinical and imaging remission could, therefore, represent a potentially attractive starting point for successful DMARD tapering."

On the Horizon: Cure?

Patients with RA in remission may nonetheless have persistent subclinical inflammation and changes in the immune system, and a state of cure may require a reversal of autoimmunity and disappearance of autoantibodies such as RF and ACPA. Accordingly, what ultimately may be required is a state of deeper remission, which could consist of "imaging/serological remission defined by the additional absence of synovitis and osteitis in imaging and/or serological inflammation markers such as multi-biomarker disease activity, or on top of that immunological remission characterized by seroconversion from positive into negative RF and/or ACPA," the team stated.

"I think we're getting closer to treating patients very quickly so that there are more patients who can do well off therapy," Emery said. "The alternative to a cure is prevention, and I think we are probably getting closer to some patients not getting the disease at all and we're getting more into drug-free remission. So I think we chipping away at both ends."

Integrative Interventions

At this year's ACR annual meeting, held in Philadelphia in Nov. 2022, the college released a summarized version of its new guideline "Exercise, Rehabilitation, Diet, and Additional Integrative Interventions for Rheumatoid Arthritis," which is intended to complement the 2021 guideline on pharmacologic treatment and fully address patients' overall well-being.

The new guideline contains 28 individual recommendations, with all but one being conditional. The single strongest recommendation was for "consistent engagement in exercise" as opposed to no exercise. Types of exercise conditionally recommended included aerobic, aquatic, and resistance exercises.

Various types of rehabilitation also were conditionally recommended, such as comprehensive physical and occupational therapy, hand therapy exercises, and the use of joint protection and assistive devices. A Mediterranean-style diet was given a conditional recommendation, while dietary supplements were not recommended, but co-principal author Bryant R. England, MD, PhD, qualified this advice. "The voting panel acknowledged, however, that other health indications may exist for alternative diet and dietary supplements, which makes it crucial for clinicians and patients to engage in shared decision-making," said England, of the University of Nebraska Medical Center in Omaha.

Additional recommendations were given to cognitive-behavioral therapy and mind-body approaches, acupuncture, massage, and thermal modalities. The guideline advised against the use of chiropractic and electrotherapy.

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Part 4: Case Study: Patient With RA Develops Dangerous Symptoms

Part 5: Second-Line Treatment of Rheumatoid Arthritis: What Are the Options?

Part 6: Managing Rheumatoid Arthritis in the Time of COVID

Part 7: Reproductive Health in Rheumatoid Arthritis

Part 8: Case Study: A Struggle to Maintain Mobility But Not for the Reason Everyone Thought

Part 9: Psychological and Emotional Health in Rheumatoid Arthritis

Part 10: Cardiovascular Disease in Rheumatoid Arthritis

Part 11: Looking Ahead in Rheumatoid Arthritis Research