Current Evidence for the Management of Rheumatoid Arthritis
Of the synthetic DMARDs, methotrexate (MTX) is considered the anchor drug. Pooled results showed MTX to be more efficacious in reducing signs and symptoms, disability and radiographic structural damage than other synthetic DMARDs. The pooled effect size for swollen joint count (SJC) versus pooled DMARDs was 1.42 (95% confidence interval [CI] 0.65–2.18). MTX is generally used first in patients at risk of developing persistent or erosive disease because of its relatively beneficial safety profile, clinical and radiological efficacy, and beneficial properties in treatment combinations with biological DMARDs. Higher weekly doses between 20 and 30mg have been found to be more effective than lower doses of 7.5–15mg.15
Leflunomide and sulphasalazine (SSZ) have shown similar clinical efficacy to MTX and are considered the best alternatives. Injectable gold has also demonstrated efficacy; however, limited availability and the emergence of newer therapies have resulted in less widespread use of this drug. Hydroxychloroquine (HCQ), although not shown to inhibit structural damage, improves signs and symptoms and is also used as part of combination therapies. It may, therefore, be considered in patients with mild disease.
Other DMARDs, including ciclosporin, minocycline and tacrolimus, have shown some efficacy. Safety data, however, have indicated that infection risk is increased with ciclosporin and azathioprine. The risk of malignancy was increased with cyclophosphamide and, potentially, azathioprine. Use of these drugs may therefore be reserved for those patients refractory to all other DMARDs (synthetic and biological).3
Biological Disease-modifying Antirheumatic Drug Therapy
Development of biological DMARDs that target specific pathways in the immune cascade has significantly increased the drug armamentarium for the treatment of RA and transformed expectations. There have been several reviews of the literature evaluating the evidence for the efficacy and safety of nine biological DMARDs in patients with RA.16,17
These
included the three established tumour necrosis factor inhibitors (TNFIs) – infliximab (IFX), etanercept (ETN) and adalimumab (ADA) – and the two newer TNFIs – certolizumab (CZP) and golimumab (GLM). The other biological DMARDs that have been evaluated were the interleukin-1 receptor antagonist anakinra (ANA), the interleukin-6 receptor antagonist tocilizumab (TCZ), the B-cell-depleting agent rituximab (RTX) and the T-cell co-stimulation blocking agent, abatacept (ABT). In an initial evaluation of DMARD-naive patients, efficacy has been demonstrated for IFX in a small RCT of 50 patients18 open-labelled randomised strategy trial.19
In patients who failed a
synthetic DMARD but were MTX-naive, RCT data have shown that biological DMARDs IFX, ETN, ADA, GLM and ABT all improved clinical outcomes. In a post hoc analysis of a trial of 417 early MTX-naive RA patients, the use of ETN + MTX in those with a disease duration of less than four months provided significantly better disease control with better remission (rate increased by 40%) and LDAS than treatment later20
– evidence for the benefit of early biological DMARD therapy. In those who failed MTX or other synthetic DMARDs benefit was seen for all nine biological DMARDs with somewhat lower efficacy documented in several previous literature reviews and meta-analyses for ANA.21
Evidence for switching between IFX, ETN and ADA has mostly been derived from case-control and cohort studies – these have shown the benefit of an alternative TNFI after discontinuing a previous TNFI due to
EUROPEAN MUSCULOSKELETAL REVIEW
Table 1: European League Against Rheumatism Recommendations for the Management of Rheumatoid Arthritis3
with Non-biological and Biological Disease-modifying Antirheumatic Drugs
Recommendations for the Management of RA 1.
2.
Treatment with synthetic DMARDs should be started as soon as the diagnosis of RA is made
Treatment should be aimed at reaching a target of remission or low disease activity as soon as possible in every patient; as long as the target has not been reached, treatment should be adjusted by frequency (every one to three months) and strict monitoring
3. 4. 5. 6.
MTX should be part of the first treatment strategy in patients with active RA
When MTX contraindications (or intolerance) are present, the following DMARDs should be considered as part of the (first) treatment strategy: leflunomide, SSZ or injectable gold
In DMARD-naive patients, irrespective of the addition of GCs, synthetic DMARD monotherapy rather than combination therapy of synthetic DMARDs may be applied
GCs added in low to moderately high doses to synthetic DMARD monotherapy (or combinations of synthetic DMARDs) provide benefit as initial short-term treatment, but should be tapered as rapidly as clinically feasible
7.
If the treatment target is not achieved with the first DMARD strategy, addition of a biological DMARD should be considered when poor prognostic factors are present; in the absence of poor prognostic factors, switching to another synthetic DMARD should be considered
8.
In patients responding insufficiently to MTX and/or other synthetic DMARDs with or without GCs, biological DMARDs should be started; current practice would be to start a TNF inhibitor (adalimumab, certolizumab, etanercept, golimumab, infliximab) which should be combined with MTX
9.
Patients with RA for whom a first TNF inhibitor has failed, should receive another TNF inhibitor (abatacept, rituximab or tocilizumab)
10. In cases of refractory severe RA or contraindications to biological agents, the previously mentioned synthetic DMARDs may also be considered, as monotherapy or in combination with some of the above: azathioprine, ciclosporin A (or, exceptionally, cyclophosphamide)
11. Intensive medication strategies should be considered in every patient, although patients with poor prognostic factors have more to gain
12. If a patient is in persistent remission after having tapered GCs, one can consider tapering biological DMARDs, especially if this treatment is combined with a synthetic DMARD
13. In cases of sustained long-term remission, cautious titration of synthetic DMARD dose could be considered, as a shared decision between patient and doctor
and a larger
14. DMARD-naive patients with poor prognostic markers may be considered for combination therapy of MTX plus a biological agent
15. When adjusting treatment, factors apart from disease activity such as progression of structural damage, comorbidities and safety concerns should be taken into account
DMARD = disease-modifying antirheumatic drug; GC = glucocorticoids; MTX = methotrexate; RA = rheumatoid arthritis; SSZ = sulphasalazine.
.side effects or lack of efficacy.22
has also confirmed the role of tumour necrosis factor cycling,23
An RCT evaluating GLM in TNFI failures with
other studies on RTX, ABT, TCZ and GLM also demonstrating efficacy in this group. After failure of the first biological DMARD, a recent review of the literature has found that the ability of a second in reaching a major response, defined by the American College of Rheumatology 70% improvement criteria (ACR70) or DAS remission, ranged between 5 and 15% (for ACR70) and 9 and 15.4% (for DAS remission) in seven of nine studies.24
A lack of comparative head-to-head trial data, however, 25
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