Three renowned experts in the field of rheumatoid arthritis, Prof. Edward Keystone, MD, Toronto, Prof. Ronald van Vollenhoven, MD, Stockholm, and Prof. Peter Taylor, MD, Oxford, gave an overview of current desiderata in the therapy of this disease at this year’s EULAR Congress in Madrid. The different assessment of the disease on the part of the patient and the physician as well as poor adherence have a decisive influence on the success of treatment. Glucocorticoids can be used effectively in the treatment of early RA. Intracellular-based agents could be an important pillar in the treatment of RA in the future.
Prof. Edward Keystone, MD, Toronto, first presented an overview of important issues that must be considered if therapeutic success is to be achieved in rheumatoid arthritis (RA). Among other things, he addressed the following points:
The patient’s assessment need not correlate with the physician’s general examination: It is quite possible that the patient’s assessment of disease activity in RA does not correlate with the physician’s findings. This can fundamentally affect therapeutic decision-making. It is therefore important to understand the mechanisms that lead to such a discrepancy. A study by Akhavan et al. (2012) shows: The discrepancy between the patient global assessment (PTGA) and the physician global assessment (MDGA) in early RA is significantly influenced by the swollen joint count (SJC) and the pain scale (1 to 10). Previous studies had already indicated the pain scale as an important influencing factor, and the authors newly found significance in the SJC as well [1].
The patient’s goal is primarily symptom reduction, while the physician’s goal is moreover to prevent structural damage. For this reason, according to Prof. Keystone, it is not surprising if the PTGA does not agree with the physician’s assessment regarding disease activity.
Adherence to the treat-to-target strategy: results from the DREAM cohort showed good adherence in 80.5% of patients in the remission group (DAS28 <2.6) with early RA. 19.5% of patients did not follow the physician’s recommendations, meaning that they discontinued or were lax in following the recommended drug therapy (7.2%), or that they continued one even though the physician did not advise it (6.2%). Intensification on contrary medical advice occurred in 4.3% of cases [2].
In the non-remission group (DAS28 ≥2.6), the results were slightly worse: only 57.9% were adherent, whereas 42.1% continued or discontinued therapy, although intensification was advised [2].
Although the study shows that it is possible to use a treat-to-target strategy in early RA because adherence is generally high, Prof. Keystone said certain problem factors need to be considered for implementing this therapy into the physician’s daily routine:
- The physician’s assessment of disease activity differs from that of the patient.
- The summary index or timing of therapeutic adjustment may not reflect clinical reality for the clinician.
- Adherence is not always a given.
According to Prof. Keystone, these problems can be solved primarily by the physician himself, but also by the patient, being convinced that the treat-to-target strategy works, regardless of his symptoms.
Combined therapies
As the second speaker, Prof. Roland van Vollenhoven, MD, Stockholm, discussed forms of therapy with glucocorticoids. The BARFOT study by Svensson et al. 2005 demonstrated that low-dose therapy with glucocorticoids can lead to success. Treatment with prednisolone in addition to initial therapy with a disease-modifying antirheumatic drug (DMARD) resulted in high remission rates, delayed the progression of radiographic damage, and was well tolerated. Thus, the data support the use of low-dose prednisolone as an adjunct to DMARDs in early RA [3].
Hetland et al. investigated in 2006 on the one hand the success of a combined therapy with methotrexate and intraarticular betamethasone in early RA and on the other hand the additional effect of adding cyclosporine. The results show very good disease control with the combined administration of methotrexate and intra-articular glucocorticoid. Cyclosporine supplementation improved ACR20 and ACR-N, while ACR50 and ACR70, remission rates, and radiographic changes did not differ between the two study groups [4].
Regarding the role of biologics, there are some open issues that need to be further discussed and explored. TNF inhibitors do not work universally, according to Prof. van Vollenhoven, and it is not clear which agent to switch to after the initial TNF inhibitor has failed. Despite these unresolved issues, the broad body of research that exists to date provides hope for further progress in this area [5].
Therapy on an intracellular basis
Finally, Prof. Peter Taylor, MD, Oxford, went into more detail about the great heterogeneity regarding the disease. RA, according to Prof. Taylor, is a heterogeneous syndrome that can follow many different inflammatory pathways. Current biologic therapies target extracellular cytokines, receptors, as well as cell surface targets. However, synthetic small molecules can be created that exhibit selectivity for intracellular targets or enzymes. Several Janus kinase (JAK) inhibitors are in development or already on the market.
- Tofacitinib is a JAK-3 inhibitor, meaning it interferes with the so-called JAK-STAT signaling pathway, which transmits extracellular information to the cell nucleus.
- Baricitinib is an oral JAK-1 and JAK-2 inhibitor currently in phase III development for its effect on RA. Current results show clinical efficacy vs. placebo in combination with MTX.
- GLPG0634 is the first selective JAK-1 inhibitor (currently Phase II). Its selectivity could lead to a high level of anti-inflammatory response, according to Prof. Talyor.
- VX-509 is a selective oral JAK-3 inhibitor that is also in Phase II development. It has been shown to be effectively used as monotherapy in RA patients with active disease.
In addition, other agents that function on an intracellular basis are also in development (PDE-4 inhibitor apremilast or Syk inhibitor fostamatinib). Given the increasing choice of therapeutic targets, stepping up research is all the more important, Prof. Taylor concluded. In the future, an individual risk assessment with a precise cost-benefit balance would have to take place for each patient with RA.
Source: “How Today’s Evidence Is Shaping Tomorrow’s RA Therapy,” Satellite Symposium at EULAR, June 12-15, 2013, Madrid.
Literature:
- Akhavan P, et al: Discrepancy between patient and physician global assessments in early rheumatoid arthritis (ra) – the need for swollen joint evaluation. Ann Rheum Dis 2012; 71(3): 340.
- Vermeer M, et al: Adherence to a treat-to-target strategy in early rheumatoid arthritis: results of the DREAM remission induction cohort. Arthritis Research & Therapy 2012, 14: R254. doi:10.1186/ar4099.
- Svensson B, et al: Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum 2005 Nov; 52(11): 3360-3370.
- Hetland ML, et al. (CIMESTRA Study Group): Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum 2006 May; 54(5): 1401-1409.
- Van Vollenhoven RF: Unresolved issues in biologic therapy for rheumatoid arthritis. Nat Rev Rheumatol. 2011 Apr; 7(4): 205-215. doi: 10.1038/nrrheum.2011.22. Epub 2011 Mar 8.
