Abstract
There is increasing consensus that periodic monitoring of disease activity status in rheumatoid arthritis (RA) patients to achieve and maintain remission, or at least low disease activity (LDA), the so-called treat to target (T2T) improves outcomes regardless of the duration of disease. Based on systematic literature reviews (SLRs) of clinical trials and registries, International Recommendations published in 2015 represent expert opinion describing efficacy and safety of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic DMARDs (bDMARDs). A total of 10 recommendations are detailed from four “Overarching Principles”: (1) treatment decisions are shared between patient and rheumatologist; (2) the primary goalv is to maximize long-term quality of life by controlling the symptoms, preventing joint damage, and by normalizing the function and social and work participation; (3) abrogation (not just control) of inflammation is the most effective method to achieve this goal; (4) T2T by measuring disease activity regularly and adjusting therapy to achieve remission/LDA optimizes outcomes in RA.
The SLRs provide solid evidence that methotrexate is the “anchor” of csDMARD and that step-up therapy by adding/substituting other csDMARDs, such as sulfasalazine (SSZ), hydroxychloroquine (HCQ), or/and leflunomide (LEF) is as effective as combination therapy to initiate. Tofacitinib, a recently marketed csDMARD, may be more effective in comparison to MTX, and can be used in combination. Rapid disease control can be achieved by “bridging” with various regimens of glucocorticoids (GCs), but tapering to doses ≤7.5 mg/day is critical to limit side effects. In practice settings, use of bDMARDs is influenced by reimbursement. Tumor necrosis factor inhibitors (TNFi) are highly used, but as more data emerge, there appear to be no major differences to more recently available targeted bDMARD monoclonal antibodies such as abatacept (co-stimulation blockade), rituximab (B cell depleting), tocilizumab (TCZ) (interleukin (IL)-6 receptor blockade). Rituximab appears to be most effective for seropositive patients, and tocilizumab may be more effective as a monotherapy in patients intolerant to csDMARDs.
Besides T2T, attention to managing treatment and optimizing outcomes should take into account potential adverse effects, such as risk of serious infection, as well as potential morbidity/mortality related to cardiovascular events, pulmonary disease, osteoporosis, diabetes, and fibromyalgia which often influence some measures, such as the Health Assessment Questionnaire (HAQ).
Introduction
Although there is no consensus on the definition of established RA (estRA), rheumatologists would likely agree that once an RA patient, especially one presenting with poor prognostic factors, has been treated with an initial T2T strategy and not achieved remission, that patient now suffers from estRA. Consistent with 2014 recommendations of an international task force , he/she requires monitoring and changes in treatment to achieve remission, or at least low disease activity, in order to limit/prevent joint damage and disability. In this chapter, we discuss the experience gained in applying recommendations for achieving remission and low disease activity (LDA) with various treatment strategies. We also include updates regarding key clinical trials providing evidence for efficacy and safety, and, in some cases, cost-effectiveness, of available therapies, as well as novel agents in phase II/III clinical development, to try to address the persistent challenges of treating estRA. We also discuss risk mitigation strategies to limit the risk of serious infection, the most prominent safety issue during initial bDMARD therapy, but a persistent risk in treating estRA. The chapter that follows specifically addresses tapering/withdrawal of therapy for patients in sustained remission or low disease activity. Three other chapters discuss the longer-term consequences of persistent chronic inflammation, and in some cases the effects of treatment, in terms of bone quality/fracture risk and joint damage, as well as cardiovascular risk. Two additional chapters focus attention on ongoing research to enable quality of care, and to engage patients as partners in treatment decisions, as an opportunity to optimize adherence, self-management, and outcomes.
Implementing the 2014 International T2T recommendations in estRA
Compared with the recommendations from European League Against Rheumatism (EULAR) (2010, 2013) and the American College of Rheumatology (2012), the International Recommendations published in 2015 provide evidence in terms of the applicability, effectiveness, and safety for T2T (remission and LDA) in estRA patients. A systematic literature review (SLR) not only described five studies in early RA patients but also one study in estRA patients . We also identified one estRA report in the abstract form (EULAR 2015 ). In the latter 2, one evaluates the addition of adalimumab under routine care (RC) compared with two T2T approaches, and the other examines T2T by the addition of conventional DMARDs with monitoring frequency according to initial disease activity. Table 1 summarizes the T2T studies in estRA patients. Interestingly, remission or LDA was achieved in ~50% of patients in the Canadian study, with no significant differences between groups. In the other study, conducted in Columbia, South America and reported in a EULAR abstract, 44% of patients were in remission/LDA at baseline. As a result of application of tight control principles according to baseline DAS28 status, 80% of patients were in remission/LDA at 24 months of study.
| Author [ref] | Design | Patients ( N ) | Treatment management | Outcomes/results |
|---|---|---|---|---|
| Pope et al. | 18-month, 3-arm, real-life, Canadian multicenter, parallel group, single (patient) – blind, cluster-randomized trial in patients initiating adalimumab in routine care (RC), to compare routine care versus T2T. | estRA, 2–3 prior csDMARDs, ~100/group | Physician randomization before the initiation of enrollment using a computer-generated, site-stratified blocked schedule – physicians in same geographic region assigned to one of the three groups at a 1:1:1 ratio; RC, achieving a DAS28 < 2.6 (DAS group), or achieving a swollen joint count (SJC) of zero (0-SJC group); that is, all patients recruited by a specific physician received the same treatment strategy (RC, DAS group, or 0-SJC group); patients seen at any time per judgment of MD – for study, monitoring ± treatment change at 0, 6, 12, and 18 months; for targeted groups, assessments at 2, 4, and 9 months also recommended. | Primary: change in DAS-28, baseline to 12 months. Secondary to absolute changes at 6, 12, and 18 months in DAS components, HAQ-DI, patient global, and patient satisfaction (five-point Likert scale – 1: not satisfied to 5: very well satisfied)/Remission/LDA highest in DAS group: ~50%. Time to achieving EULAR response significantly shorter in targeted treatment groups, compared with RC (adjusted hazard ratio (HR) for the DAS group 2.99 (95% confidence interval (95% CI) 1.71–5.24) and HR for the 0-SJC group 1.86 (95% CI 1.09–3.13)). Dropout rate 52.3% in RC, 27% in the DAS group, and 22.2% in 0-SJC group ( P < 0.001). |
| Santos-Moreno et al. | 24-month observation to assess T2T strategies implemented according to baseline DAS | 1110, 75% female, disease duration ~11 years; 43.6% remission/LDA | Monitoring/medication adjustment per DAS28: >5.1: q3–5 wks <5.1 > 3.1: q7–9 wks <3.1: q11–13 wks | ~80% of patients in remission/LDA at 24 months |
To inform the 2013 and 2014 Recommendations for the treatment of rheumatoid arthritis ( Fig. 1 ), the efficacy of csDMARDs (as monotherapy or combination therapy) in adults with RA was assessed in two SLRs focused on publications from 2009 until January 2013. Another SLR in that time frame assessed the efficacy of glucocorticoids in early RA. A third systematic review was performed until March 2013 to assess the efficacy of tofacitinib by meta-analysis. The results were reported in 2014 . For glucocorticoids, five publications relating to four new trials in early RA were analyzed for efficacy, confirming that initial treatment of RA with low-dose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone. For csDMARDs, only two new randomized controlled trials (RCTs) were identified, comparing MTX monotherapy with MTX in combination with another csDMARD, without differences in glucocorticoid dosing. Using tight control principles, clinical outcomes were no better with immediate triple therapy than with ‘step-up’ therapy. For tofacitinib, the pooled analysis of 10 trials showed that tofacitinib was more efficacious on signs and symptoms, disability and appeared to be more efficacious on structural damage than control treatment with placebo (OR (95% CI) – American College of Rheumatology 20% (ACR20) response: 2.44 (1.97–3.02)) or treatment with MTX (ACR20 response: 2.38 (1.66–3.43)).
Efficacy of bDMARDs is especially pertinent for T2T in estRA patients, since the vast majority of clinical trials have been conducted in this patient population. An SLR identifying trials through 2013 informed the updates of the Recommendations in 2013 and 2014 . A total of 108 publications – 51 articles and 57 abstracts – were identified. RCT publications confirmed the efficacy of bDMARD + conventional synthetic DMARDs (csDMARDs) versus csDMARDs alone. Although there was some evidence in the efficacy of TNFi monotherapy, MTX combination therapy was generally more efficacious. Earlier improvements in signs and symptoms were seen with more intensive initial treatment strategies, but outcomes were similar upon addition of bDMARDs in patients with insufficient response to MTX. In general, radiographic progression was lower with bDMARD use, apparently due to initial treatment effects.
Subsequently, outcomes of additional RCTs investigating bDMARD monotherapy have been published. TCZ monotherapy may be more effective in comparison to monotherapy with other bDMARDs. Patients with an inadequate response to MTX were randomized to add TCZ to MTX, or switch to TCZ. Efficacy in terms of clinical and radiographic end points was not statistically different between the groups.
Implementing the 2014 International T2T recommendations in estRA
Compared with the recommendations from European League Against Rheumatism (EULAR) (2010, 2013) and the American College of Rheumatology (2012), the International Recommendations published in 2015 provide evidence in terms of the applicability, effectiveness, and safety for T2T (remission and LDA) in estRA patients. A systematic literature review (SLR) not only described five studies in early RA patients but also one study in estRA patients . We also identified one estRA report in the abstract form (EULAR 2015 ). In the latter 2, one evaluates the addition of adalimumab under routine care (RC) compared with two T2T approaches, and the other examines T2T by the addition of conventional DMARDs with monitoring frequency according to initial disease activity. Table 1 summarizes the T2T studies in estRA patients. Interestingly, remission or LDA was achieved in ~50% of patients in the Canadian study, with no significant differences between groups. In the other study, conducted in Columbia, South America and reported in a EULAR abstract, 44% of patients were in remission/LDA at baseline. As a result of application of tight control principles according to baseline DAS28 status, 80% of patients were in remission/LDA at 24 months of study.
Related posts:
How does established rheumatoid arthritis develop, and are there possibilities for prevention?
Monitoring in established RA: Role of imaging and soluble biomarkers
Cardiovascular disease in rheumatoid arthritis: Current perspectives on assessing and mitigating risk in clinical practice
Evaluating and mitigating fracture risk in established rheumatoid arthritis
Patient-centred care in established rheumatoid arthritis
Quality in rheumatoid arthritis care
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
