Joint Disorders Rheumatoid Arthritis studies.24


A lack of comparative head-to-head trial data, however, means it remains unclear whether one option is better than another; it is likely that certain disease and patient characteristics may argue for a particular treatment. Further investigation in this area is still necessary.


Several biological DMARDs, including ADA, ETN, CZP, RTX and TCZ, have been used as monotherapy with demonstrable efficacy. However, analysis of the data has shown combination therapy with MTX to be superior.17,25,26


The principal safety concerns associated with biological DMARDs centre on the risk of malignancy and infection. Review of safety data from registries and long-term patient follow-up has failed to demonstrate an increase in malignancy risk compared with conventional DMARDs.27


The TNFIs have generally been associated


with an increased risk of serious bacterial infection, particularly within the first six months of treatment initiation.28 were also increased with TNFIs29–31


Rates of tuberculosis (TB) – these have been highest with the


monoclonal antibodies. Improved screening procedures and the use of prophylactic treatment where indicated has, however, reduced the incidence of TB.32


Evidence from clinical trials therefore confirms efficacy of the biological DMARDs both in terms of clinical outcomes and structural damage in RA, with most data in patients failing synthetic DMARDs or TNFIs and some data in patients who are DMARD-naïve. There is increasing evidence for the use of TNFIs early in RA with the suggestion of a window of opportunity in the benefits that could be gained.33,34


As


they are still substantially more expensive than traditional DMARDs, widespread use to date has been relatively limited to those with more established and aggressive disease.35


Selecting patients with


poor prognostic factors, however, may improve this cost–benefit balance and guide the use of these agents earlier in the disease.


Glucocorticoids


GCs rapidly reduce disease activity in patients with early and advanced disease. Eleven publications (including three Cochrane reviews comprising 33 trials) on the subject were reviewed,36


showing


good evidence for GC efficacy as bridging therapy. GCs in combination with DMARD monotherapy or combination therapy demonstrated both clinical benefits and slowing of radiographic progression in early and established RA.37–40


In early RA, the addition of


low-dose GCs (<7.5mg/day) to DMARD therapy has been associated with a reduction in radiographic progression.41


In established RA,


several RCTs and systematic reviews have shown systemic low-dose GCs, typically prednisone (up to 15mg/day), to be effective in relieving signs and symptoms.42


Minimal GC use is usually preferred due to toxicity concerns. These include increased cardiovascular risk, lipid abnormalities and osteoporosis. However, the evidence suggests the side-effect profile is likely to be dose-dependent and influenced by the disease being treated. A review of the published literature has shown that in RA low doses of GCs may have minimal side effects,43


with those known to


occur with higher doses in other diseases treated with higher doses unlikely to be an issue with the lower doses used to treat RA. Evaluating the risk to benefit ratio of GC use, therefore, it is recommended that GCs are used at low or moderately high doses in combination with synthetic DMARD therapy for short-term therapy and tapered as quickly as clinically feasible.


26


Biological Disease-modifying Antirheumatic Drug Strategies


In RA patients who have failed MTX, early addition of a TNFI has shown to be superior to conventional synthetic DMARDs. In an RCT of 487 patients with early RA (symptom duration less than one year), MTX (up to 20mg/week) was prescribed as initial DMARD therapy.53


After


three to four months, 258 patients who had not achieved LDAS but could tolerate MTX were randomly allocated the addition of either SSZ + HCQ or IFX. At 12 months, 32 of 130 patients (25%) who received SSZ + HCQ achieved LDAS (DAS28 ≤3.2) compared with 50 of 128 (39%) assigned IFX (risk ratio 1.59, 95% CI 1.10–2.30; p=0.0160). The addition of IFX also yielded significantly better radiological results through 24 months than the addition of SSZ + HCQ.54


Biological DMARDs are now being evaluated at an even earlier stage. The concept of induction therapy with a biological DMARD and maintenance with conventional DMARDs in early RA was introduced in a placebo-controlled study by Quinn et al.18


Patients with early RA


and poor prognostic factors treated with IFX + MTX developed fewer erosions at 12 months than patients treated with MTX alone. The functional and quality-of-life benefits obtained in patients treated with IFX + MTX after one year was sustained with subsequent MTX


EUROPEAN MUSCULOSKELETAL REVIEW


In DMARD-naïve patients, balancing treatment efficacy against the risks of toxicity, EULAR recommendations therefore suggest commencing synthetic DMARD monotherapy with MTX rather than combination therapy of synthetic DMARDs (irrespective of the addition of GCs). Where disease control is not achieved, switching to an alternative DMARD strategy should be considered.


Strategic Approaches to the Management of Rheumatoid Arthritis


With the availability of highly effective drugs in RA, there has been increasing interest in terms of therapeutic strategies and treatment combinations to determine how best to achieve maximal benefit.


Synthetic Disease-modifying Antirheumatic Drug Strategies


using combination therapy compared with monotherapy. The effects achieved in the combination treatment arms may, however, be attributed to the use of steroids rather than the combination of DMARDs alone (see ‘Glucocorticoids’ section earlier).


Several clinical trials have addressed the issue of combination therapy versus DMARD monotherapy. These have shown greater long-term effects on radiographic progression37,38,44,45 rates38,45,46


and lower work disability


have been unable to identify better outcomes for either treatment arm over the other. In the Behandel Strategieën (BeSt) study, the addition of SSZ to MTX after failure of MTX at 25mg/week resulted in a DAS of ≤2.4 in only 22% of patients, a similar response obtained when switching from MTX to SSZ.49


Other trials comparing the MTX + SSZ combination versus single agents47,48


Conclusions from a recent meta-analysis15 similarly showed no


significant benefit of combination synthetic DMARD therapy over MTX monotherapy in DMARD-naïve patients. The results were inconclusive in DMARD inadequate responders.50


A


combination of MTX with SSZ, ciclosporin or azathioprine showed some beneficial effect versus the same drug (SSZ, ciclosporin or azathioprine) as monotherapy.51,52


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