Akademik Veri Yönetim Sistemi
GENÇ TRASD ROMATOLOJİ OKULU, İzmir, Türkiye, 20 - 22 Ekim 2023, cilt.1, sa.1, ss.11-12
Difficult to Treat Rheumatoid Arthritis
Doç. Dr. İsmihan Sunar
Ankara University School of Medicine, Rheumatology Division, Ankara
Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of the adult population. Recent improvements in
comprehension of the disease etiopathogenesis and consecutive novel drugs in the last two decades have led to
better outcomes (1). However, despite the current innovative medications, a nonignorable porsion of patients are
still challenging for rheumatologists. Approximately 10-20% of RA patients in whom therapeutic goals which are
sustained remisson or at least low disease activity can not be met by means of conventional synthetic or biologic
disease modifying anti-rheumatic drugs (DMARDs) are assumed recalcitrant patients. The patients with refractory
course were first described in 2018 and are also referred to as “difficult to treat; D2T RA”, “treatment resistant” or
“refractory” RA (2,3). According to the British Society of Rheumatology Biologics Register for RA data, 6% of 13502
patients had refractory RA. However, in this paper the authors only reckoned patients with TNF inhibitor failure as
the first bDMARD (4). The factors underlying refractory RA may be epigenetic alterations driven by ageing,
treatments, and environmental factors including smoking. Inflammation also plays bi-directional relationship with
epigenetic changes. The predictors to develop D2T RA were reported as treatment delay, female gender, and high
disease activity scores at baseline (2,5).
In 2021, the European League Against Rheumatism (EULAR) published an official definition for D2T RA which is
as follows: 1) failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs
(with different mechanisms of action) after failing conventional synthetic DMARDs and 2) presence of at least one
of the following conditions to indicate active disease; a) at least moderate disease activity according to composite
indices (DAS28-ESR>3.2 or clinical disease activity index (CDAI)>10), b) laboratory, clinical, or imaging
signs/symptoms indicating active disease, c) inability to reduce/stop glucocorticoid therapy below 7,5 mg/day
prednisone or equivalent, d) rapid radiographic progression, e) RA symptoms impairing quality of life; and 3)
perception as problematic to manage by the rheumatologist and/or the patient (6). In the following year, EULAR
published another paper on management of patients with D2T RA. Containing 2 overarching principles and 11
recommendations, the guideline first suggests to omit the risk of misdiagnosis or coexistency of a mimicking disease
in patients with presumed D2T RA. These mimicking conditions may be crystal arthropathies, spondyloarthritis,
Still’s disease, polymyalgia rheumatica, psoriatic arthritis, systemic lupus erythematosus, Rhupus syndrome,
inflammatory myopathies, remitting symmetric seronegative synovitis and pitting oedema, reactive arthritis,
vasculitis, paraneoplastic syndromes, osteoarthritis, and fibromyalgia. Also in case any doubt arises about
inflammatory activity, ultrasound imaging is offered for further evaluation. Composite index scores and clinical
evaluation are recommended to be reviewed carefully in case of certain comorbidities (including obesity and
fibromyalgia) due to the possible contribution by chronic pain or ongoing central sensitization processes which
should also be taken into account to avoid overestimating disease activity. Patient compliance to medications is
poor in RA and estimated to reach rates of 30-80%. Therefore, adherence is another issue to be checked and
optimised via shared treatment decisions by the patient and physician. If a patient has D2T RA, then he/she passes
to phase 3 for the current EULAR 2022 RA Management algorythm. According to uptodate recommendations, in
case of D2T RA, treatment with a b/tsDMARD targeting a different pathway should be considered in the maximum
dose. Non-pharmacological interventions (including education and support, exercise, psychological, and selfmanagement programs) were also appraised by the expert committee to optimise functional competence and
prevent pain and fatigue (5, 7).
Nowadays, it is widely acknowledged that refractory RA is also a heterogeneous group. Some sub-categorizations
within D2T RA are offered for a better management. Some authors prefer dividing patients as D2T RA-inefficacy
and D2T RA-other (toxicity, comorbidity, adherence or expectation problems, etc) while others categorize as
persistent inflammatory refractory RA (PIRRA) and non-inflammatory refractory RA (NIRRA). While persistent
inflammation is the main problem and the number of swollen joints, CRP level, and erosive disease are prognostic
features for PIRRA subgroup, patients in the NIRRA group lack ongoing inflammatory activity and have high patientreported outcome scores, deteriorated quality of life, but better long-term prognosis compared to PIRRA (5,8).
The optimal management strategy in these patients and prediction methods for development of D2T RA are still
lacking. Serum biomarkers to predict drug response is among topics of the research agenda. Pharmacologic and
non-pharmacologic treatment approaches should be employed to exert best outcomes.
Genç TRASD Romatoloji Okulu | 20-22 Ekim 2023
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References
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Review. JAMA. 2018;320(13):1360–1372.
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JS, Aletaha D. Risk profiling for a refractory course of rheumatoid arthritis. Semin Arthritis Rheum.
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need, Rheumatology, 2018;57(7):1135–1144
4. Kearsley-Fleet L, Davies R, De Cock D, Watson KD, Lunt M, et al. Biologic refractory disease in
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Arthritis. Ann Rheum Dis. 2018;77(10):1405-1412.
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