Can Biomarkers Predict Successful Tapering of Conventional Synthetic Disease-Modifying Anti-rheumatic Drugs in Patients with Rheumatoid Arthritis Achieving Stable Clinical Remission? - European Medical Journal
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Can Biomarkers Predict Successful Tapering of Conventional Synthetic Disease-Modifying Anti-rheumatic Drugs in Patients with Rheumatoid Arthritis Achieving Stable Clinical Remission?

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Authors:
*Hanna L Gul,1 Andrea Di Matteo,1 Kulveer Mankia,1 Jianhua Wu,2 Frederique Ponchel,1 Paul Emery1
Disclosure:

The authors have declared no conflicts of interest.

Citation
EMJ Rheumatol. ;8[1]:65-67. Abstract Review No. AR7.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

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BACKGROUND AND AIMS

It is now accepted that sustained remission is the key treatment goal for rheumatoid arthritis (RA). The availability of biologic therapies and the use of targeted treatment strategies has led to increasing numbers of patients achieving remission; however, specific guidance for the management of patients with RA in sustained clinical remission, treated with conventional synthetic disease-modifying anti-rheumatic drugs (cs-DMARDs), is lacking.1-3 This raises concerns for over-treatment in asymptomatic patients. Tapering of treatment is encouraged, although there are no validated biomarkers predicting sustained remission.4,5 As such, there is an unmet need for predictors of sustained remission for tapering cs-DMARDs, which can be used in clinical practice.

The authors conducted a prospective observational study of two treatment strategies for patients with RA in stable remission. The primary objective was to assess the rate of sustained remission after 12 months, without flare in patients who were offered either structured cs-DMARD tapering or continued therapy. Secondary objectives were to determine baseline predictors of sustained remission following tapering and to develop a predictive model to help aid risk stratification of patients for tapering in clinical practice.

MATERIALS AND METHODS

Patients with RA in clinical remission (Disease Activity Score 28 for Rheumatoid Arthritis with C-reactive protein, [3v-DAS28CRP] <2.6) for ≥6 months on stable cs-DMARD therapy were sequentially recruited from a National Health Service (NHS), UK remission clinic. Patients were offered structured tapering, with 117 accepting tapering and 83 continuing therapy. Clinical, ultrasound (US), immunological (T-cell subsets), and patient-reported outcome (PRO) data were collected. The primary endpoint was the proportion of patients in each group in sustained remission without relapse after 12 months. Flare was defined as loss of DAS28 remission or evidence of at least one new clinically swollen joint. Logistic regression analyses were performed to identify predictors of sustained remission.

RESULTS

Two hundred patients fulfilled the inclusion criteria. No difference in baseline drug regimens (mono- versus combination therapy) was seen between the two groups. Male sex (p=0.036) and longer length of remission (p=0.015) were associated with the patient’s decision to taper, although not significantly after correction for multiple testing. The tapering group demonstrated lower levels of inflammation-related T-cells (IRC; p=0.001), inflammatory markers, and joint counts. No significant difference between groups was observed for PROs, although there was a trend towards lower PROs in the tapering group.

Of those who tapered, 64% remained in clinical remission after 12 months compared with 80% (p=0.018) of patients on stable therapy. In the tapering group, higher CRP, tender joint count, percentage of IRC, and higher PROs were associated with flare (all p<0.05), with a trend for higher total power doppler score on US (p=0.066). A multi-variable model (using clinical, US, PRO, and T-cell subset variables) predicting sustained remission (Figure 1) retained Rheumatoid Arthritis Quality of Life score (RAQoL), total power doppler score, and percentage IRC (85% accuracy; area under the curve of the receiver operating characteristic [AUROC]: 0.893; p<0.0001). A reference model using clinical variables only (as would be available in clinical practice) demonstrated only 69% accuracy (AUROC: 0.725). Other models, including combinations of two or three variables, demonstrated accuracies between 72–84% (Figure 1). In the non-tapering group, higher CRP, erythrocyte sedimentation rate, swollen joint count, and shorter disease duration (all p<0.05) were associated with flare, with no parameter able to predict sustained remission.

Figure 1: AUROC Models 1–8.
Clin: Clinical; PRO: patient-reported outcome; US: ultrasound.

CONCLUSION

The combination of clinical, PRO, US, and T-cell parameters demonstrated added value for predicting sustained remission compared with clinical parameters alone in the tapering group. These data could inform best tapering practice.

References
Aga AB et al. Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000–2010.Ann Rheum Dis. 2015;74(2):381-8. Combe B et al. Five-year favorable outcome of patients with early rheumatoid arthritis in the 2000s: data from the ESPOIR cohort. J Rheumatol. 2013;40(10):1650-7. van den Broek M et al. Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study. Ann Rheum Dis. 2011;70(8):1389-94. Smolen JS et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-99. Schett G et al. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis. 2016;75(8):1428-37.