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Treating to target in established rheumatoid arthritis: Challenges and opportunities in an era of novel targeted therapies and biosimilars

Best Practice & Research Clinical Rheumatology, Volume 29, Issue 4-5, August - December 2015, Pages 543 - 549

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).

Keywords: Rheumatoid arthritis, Treat-to-target, Disease activity, Remission, Disease modifying antirheumatic drugs, Biologics and biosimilars.

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 [1], 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 [2] and [3] 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 [4]. We also identified one estRA report in the abstract form (EULAR 2015 [5]). 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.

Table 1

T2T studies in estRA patients.

 

Author [ref] Design Patients (N) Treatment management Outcomes/results
Pope et al. [4] 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. [5] 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 [6]. 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)).

gr1

Fig. 1

T2T algorithm (adapted from 2014 International Task Force Recommendations [1]).

 

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 [7]. 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.

Monitoring options for clinical practice

An ACR Task Force conducted a comprehensive review of available disease activity measures [8]. They recommended the Clinical Disease Activity Index (CDAI), Disease Activity Score with 28-joint counts (DAS-28) (erythrocyte sedimentation rate or C-reactive protein), Patient Activity Scale (PAS), PAS-II, Routine Assessment of Patient Index Data with three measures, and Simplified Disease Activity Index (SDAI) because they are accurate reflections of disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity states; have remission criteria; and are feasible to perform in clinical settings. Table 2 provides an overview of those that are commonly used in clinical practice.

Table 2

Measures of disease activity for T2T in clinical practice [10].

 

Measure Components/Formula Remission LDA MCII [9]
DAS28-ESR 0.56√TJC28 + 0.28√SJC28 + 0.70xlogESR + 0.14Global Health <2.6 ≤3.2 −1.2
DAS28-CRP [11] 0.56√TJC28 + 0.28√SJC28 + 0.36 × ln[CRP+1] +0.14Global Health <2.4 ≤2.9 −1.0
CDAI SJC + TJC + PGA + EGA ≤2.8 >2.8 ≤ 10 −12
SDAI SJC + TJC + PGA + EGA + CRP ≤3.3 ≤11 −13
RAPID3 [12] and [13] sum of three 0–10 patient self-report scores: pain, functional impairment on MDHAQ, and patient global estimate ≤3/30 + SJC ≤1 NA NA
Tools for calculation of these measures can be found on the Internet
http://www.rheumatology.org/Practice-Quality/Clinical-Support/Quality-Measurement/Disease-Activity-Functional-Status-Assessments
http://www.nras.org.uk/the-das28-score
http://www.4s-dawn.com/DAS28/DAS28.html
http://www.corptransinc.com/sites/mdhaq-rapid3/original-developer

Abbreviations: DAS28 PGA: 100 mm global health; ESR: erythrocyte sedimentation rate; SJC: swollen joint count (n of 28); TJC: tender joint count (n of 28); PGA: patient global health assessment and EGA: evaluator global health assessment (1–10-cm visual analogue scale); CRP: C-reactive protein (mg/dl); LDA: low disease activity; RAPID: Rapid assessment of Patient Index Data; MDHAQ: multidimensional health assessment questionnaire; MCII: minimal clinically important improvement; NA: not available.

Also included are recently published minimal clinically important improvements (MCIIs) for DAS28-ESR, SDAI, and CDAI [9], In addition, MCIIs with a specificity for improvement of 0.80 were: patient global assessment − 18, pain score − 20, HAQ − 0.375, DAS-28-ESR − 1.2, DAS28-CRP (C-reactive protein) − 1.0, SDAI − 13, and CDAI − 12.

Mitigation of risks for serious infection

Infection and serious infection are recognized to be a significant source of morbidity and mortality for estRA patients, and this risk is increased with T2T regimens. Biologic agents increase this risk, so also prednisone in a dose-related manner above 5 mg daily. It appears that the risk associated with biologics can be mitigated somewhat when such agents act as prednisone-sparing therapies (24401994). In the analysis conducted to inform the 2014 International Recommendations, patients on TNFi, compared with patients on conventional csDMARDs, had a higher risk of serious infections (adjusted HR (aHR) 1.1–1.8), and a higher risk of tuberculosis. An increased risk of herpes zoster infection could not be excluded.

Some of the important causes of infection morbidity in this setting are preventable with screening (e.g., tuberculosis, reactivation of hepatitis B and C) or vaccination (e.g., herpes zoster).

Screening for potential reactivation of infection
Test Interpretation/action Reference
Tuberculosis: Tuberculin Skin Test (TST) or Quantiferon TB Gold testing (QFT-G) Low to moderate agreement (κ = 0.305) between TST and QFT-G. In the absence of clearly defined gold standard and limitations associated with both tests, early screening in two-step process recommended for patients to be treated with bDMARDs: initial screening with TST and if negative, QFT-G testing. Patients positive for either test should be promptly treated. 26294972
Hepatitis B: hep B Ag, Ab Avoid TNFi, B cell depleting therapy if positive
Hepatitis C: viral titers, antigen, antibody Treat with antivirals before bDMARD
Immunizations
Dose/Frequency Efficacy Benefit
Influenza High/yearly Modest unclear
Pneumovax Every 5 years Modest unclear
Herpes zoster Prior to initiation of bDMARD Modest To be determined
Practice points
  • Persistent joint inflammation in rheumatoid arthritis (RA) is well documented to predict damage, disability, and poor quality of life.
  • Clinically useful composite measures of remission and low disease activity (LDA) are reliable to identify the absence of joint inflammation and can be assessed quickly in clinical settings; these include Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Disease Activity Score with 28-joint counts (DAS)-28, and Rapid assessment of Patient Index Data RAPID3.
  • To facilitate shared decisions when planning a treat-to-target (T2T) strategy for an individual patient, the choice of the target measure may include discussing impact of comorbidities on that measure: for example, fibromyalgia, obesity, and (inflammatory) osteoarthritis.
  • While established RA is not in remission/LDA, treatment changes should be considered at least every 3 months to enable achievement of remission/LDA.
  • Treatment change decisions should be considered relative to risks of change, and the potential impact of comorbidities on the target measure.
  • Risk mitigation of intensive T2T treatment includes attention to limiting risk for serious infection by:
    • o Assuring that immunizations are current
    • o Screening and treatment for infections such as hepatitis B and C and tuberculosis that may reactivate
  • While several composite index measures have been validated to sensitively and specifically identify remission and LDA, none are 100% accurate, as sensitive imaging methods identify active synovitis in a significant proportion of patients in clinical remission. Magnetic resonance imaging (MRI) and/or ultrasound (US) to examine synovitis/tenosynovitis, osteitis in questionable joints may assist in decision making, although addition of these imaging modalities has not yet been shown to improve outcome of T2T.
Research agenda
  • Definition and role of imaging remission for treat to target (T2T) requires further study in randomized controlled trials (RCTs) with sufficient duration of follow-up to assess impact on joint damage, function, and quality of life.
  • Development methods are warranted that can identify whether targeted biologics available and in development can mechanistically alter fundamental rheumatoid arthritis (RA) biology and enable sustained drug-free remission.
  • Strategies that enable personalized selection from among T2T therapeutic strategies are needed.
  • Cost-effectiveness studies are needed to provide evidence-based treatment choices and reimbursement for T2T strategies, especially those that require biologics.
  • Role of biosimilars to enable T2T success remains to be determined
  • Long-term studies are needed to determine the impact of various remission/LDA states on morbidities, quality of life, and mortality.

Appendix A. Supplementary data

The following is the supplementary data related to this article:

References

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Footnotes

a Division of Rheumatology, David Geffen School of Medicine, University of California (UCLA), Los Angeles, USA

b Dept. of Rheumatology, Sint Maartenskliniek, PO Box 9011, 6500 GM, Nijmegen, The Netherlands

Corresponding author. Tel.: +1 772 324 8844, +1 401 692 0103 (mobile).

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