‘Treat to target’ for rheumatoid arthritis in 2014 – time tested triple therapy or logical Biologics?
Article first published online: 28 JAN 2014
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
International Journal of Rheumatic Diseases
Volume 17, Issue 1, pages 1–3, January 2014
How to Cite
Mok, M. Y. and Danda, D. (2014), ‘Treat to target’ for rheumatoid arthritis in 2014 – time tested triple therapy or logical Biologics?. International Journal of Rheumatic Diseases, 17: 1–3. doi: 10.1111/1756-185X.12313
- Issue published online: 28 JAN 2014
- Article first published online: 28 JAN 2014
Difficulty in finding a patient of RA with advanced and classical deformities in hand for undergraduate and postgraduate teaching is a common experience of all rheumatologists in recent years. Thanks to the RA revolution in the last 2 decades which came after a period of lull following the introduction of magical methotrexate in eighties. It is not newer medications alone; conceptualisation of the entity of early or preclinical RA and its recognition by new diagnostic armamentarium like anti citrullinated peptide antibody (ACPA), musculoskeletal ultrasonography and peripheral/extremity MRI, introduction of multiple sensitive and user friendly composite disease assessment tools like DAS28 and C-DAI, new ACR_EULAR classification criteria and above all, the recent concept of ‘treat to target’ (‘T2T’) made no lesser contributions.
Dramatic entry of biologics starting with TNF blockers gave the momentum in late nineties and there was no going back since then. Whole range of them came out targeting B cells (Rituximab), co-stimulatory pathways (Abatacept), IL-6 (Tocilizumab), IL-1 (Anakinra) and now the small molecules or oral biologics (Tofacitinib). And the process is on targeting different other cytokine pathways. A shortlived journey with coxibs during the same period goes down the memory lane as another exciting pastime.
Since the onset of the biologic era, conventional disease modifying anti-rheumatic drugs (DMARDs) were pushed to the backseat in the western world. Global economic slowdown forced a rethink and relook at these agents like old wine in a new bottle. Several studies, especially those using ‘T2T’ have shown that the most important trick to achieve remission or low disease activity in RA is early aggressive approach rather than the choice of the medications. Modern management of RA should, therefore, be directed by this approach. Early and continued suppression of rogue autoimmune cells and their products to delay or abort their attempt to gain autonomy seems to be the key to successful treatment in RA.
A number of studies in the recent past have reaffirmed the faith in the conventional DMARDs with favourable efficacy profile such as hydroxychloroquine, sulphasalazine, methotrexate (MTX) and leflunomide, especially when used in a combination regimen. One such combination popularly called ‘triple therapy’ (hydroxychloroquine + sulphasalazine + methotrexate) with or without very low dose steroid has passed the test of time. Much to the disappointment of proponents of biologics as the first line therapy, new studies have found combination of synthetic DMARDs non-inferior to the coveted biologics alongwith greatest economic advantage to their credit, provided the treatment is started early and intensity of dosage is guided and adjusted by T2T approach. Addition of other inexpensive agents like vitamin D and fish oil can add even further benefit and have been variably reported.
However, the strongest point that remains in favour of the biologics is the rapid onset of action and radiological healing; these advantages, unfortunately, are enjoyed only by privileged few with funding support from state, insurance or self.
Whether to use biologics in early disease or in patients who have persistently active disease despite conventional DMARDs, therefore, is more of a sociopolitical issue than a scientific one. In the following paras, we will dissect out these issues with facts.
All biological agents including tumour necrosis factor (TNF) inhibitors namely Infliximab, Etanercept, Adalimumab, Golimumab and Certolizumab, interleukin-6 antagonist Tocilizumab, T cell costimulatory antagonist Abatacept, B cell depleting agent Rituximab and the upcoming JAK signaling inhibitor Tofacitinib have proven their efficacy in active RA patients who failed MTX in clinical trials.
In addition to the treatment goal of achieving symptomatic relief, these biologic agents in combination with MTX as an anchor drug have also shown superiority over MTX monotherapy in clinical outcomes including induction of remission, retardation of structural deformity and preservation of physical function in established RA as well as in early RA, with the exception of Tocilizumab which has been shown to be superior to MTX even as monotherapy by itself alone.
The open BeSt trial revealed that early aggressive combination of infliximab with MTX in recent onset RA offered significant functional improvement and retardation in radiographic progression when compared with sequential monotherapy and step-up combinational DMARDs. The current variety of biologic agents with their quick onset of action and favourable data on long-term safety and sustainability has, thus, elicited much excitement in the treatment of RA. Has biologic therapy provided an answer to the management of RA?
On the other hand, use of MTX in the control arm of clinical trials with biologics found 25-30% of patients with early RA to be consistently good responders to MTX monotherapy alone. Moreover, studies demonstrated a beneficial effect of add-on therapy with one or more conventional DMARDs to MTX and concomitant glucocorticoid in high dose tapering regimen or in low dose may further increase DMARD efficacy in patients with persistently active early RA refractory to MTX. In the BeSt study, immediate combination of conventional DMARDs with prednisolone in early RA was found to be superior to step-up regimen of combinational DMARDs and had clinical efficacy comparable to infliximab plus MTX at 2 years. A number of other recent studies also provide evidences to show initial triple therapy involving hydroxychloroquine, sulphasalazine and MTX is non-inferior to biologic agent plus MTX in terms of remission and even radiographic progression in early RA. The double-blind TEAR trial demonstrated comparable efficacy between triple therapy with concomitant glucocorticoid and MTX plus etanercept as immediate-treatment or step-up therapy in patients with early RA. While most data comes from studies on early RA, triple therapy has also been shown to be as efficacious as etanercept plus MTX among patients with early and established RA in the RACAT trial.
Thus, patients who are good responder to MTX and combination conventional DMARDs may be overtreated by early use of biologics, not to mention its pharmacoeconomic implications in countries with restricted resources. In fact, recent clinical studies revealed that tight disease control is the key to superior clinical outcomes in active patients with established RA as well as in early RA. The treat-to-target approach involves close monitoring of disease activity and regular adjustment of treatment regimen driven by predefined treatment target and have been shown to be associated with significantly better clinical and radiographic outcomes compared with conventional management. Composite scores such as DAS28 are good and practical measures to reflect on the level of disease activity and to provide guidance on treatment plans. Indeed, a treat-to-target approach involving triple therapy and prednisolone has been shown to induce remission and retard radiographic progression in early RA regardless of initial short course of infliximab in the 5 year follow up in the FIN-RACo study.
With the present clinical evidences, triple therapy of hydroxychloroquine, sulphasalazine and MTX with concomitant glucocorticoids can be as efficacious as biologic agents based on a treat-to-target approach with a realistic target of remission in patients with early RA or a state of low disease activity in established RA. Indeed, the 2013 update of EULAR recommendations for management of RA emphasized the role of conventional DMARDs and stated a number of key issues to favourable outcomes including early commencement of MTX after RA is diagnosed, close monitoring of disease activity every 1–3 month and adjustment of treatment regimen if no improvement is observed at 3 months or if failure to meet a target of low disease activity or remission in 6 months of methotrexate based conventional DMARD regimen. This is followed by the use of any biologic agent (first line rituximab in special conditions) with MTX as the anchor drug in the treatment algorithm for patients who have poor prognostic factors like high disease load, positive rheumatoid factor or anti-citrullinated peptide antibody and early erosive disease.
In this issue of IJRD, Alten R and van den Bosch F conducted a literature review to evaluate the effect of dose optimization on clinical response in infliximab-treated RA patients and observed a trend of improvement after dose increase among small number of studies of different study design. While increase in dose or reduction in infusion interval may benefit some patients who have inadequate response and those who subsequently lose response to this TNF inhibitor, a balance between efficacy and risk of high dose biologics and the heterogeneity of pathophysiology of RA are important issues to be considered in the management of RA patients on biologic based regimen.
Up to this point in time, a few recent studies have suggested a potential role of biologics as induction therapy to achieve clinical remission in patients with early RA. This finding has not been confirmed in other studies which found high relapse rates upon withdrawal of biologics. Before clear evidences are there, RA patients with active disease are likely to benefit as much from early aggressive treatment with combinational conventional DMARD based regimen targeting tight disease control as biologic therapy.
- 12005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52, 3381–90., , et al. (
- 22012) A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of early aggressive rheumatoid arthritis trial. Arthritis Rheum 64, 2824–35., , et al. (
- 52013) Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 4-year follow-up results of a randomized clinical trial, the NEO-RACo trial. Ann Rheum Dis. [Epub ahead of print]. 10.1136/annrheumdis-2013-203497., , et al. (