“ABCDE” Approach to Difficult-to-Treat Rheumatoid Arthritis Save

Know-it-now

• D2T-RA has a EULAR definition but should be considered a diagnosis of exclusion as there are other issues beyond treatment to be considered
• Compliance, route and dosing strategies matter as much as drug choice
• Consider comorbidity management - smoking cessation and periodontal treatment are disease-modifying interventions
• Seronegative refractory arthritis should trigger a misdiagnosis consideration – CPPD, PMR, PsA and peripheral spondyloarthritis are commonly missed mimics
• TNF-α inhibitor (and other b/tsDMARD) cycling within class is ok with secondary non-response, but not with primary non-response, where switching MOA choice is advised

The proposed approach to difficult-to-treat rheumatoid arthritis (D2T-RA) is based on the EULAR definition (having failed 2 or more b/tsDMARDs). It is estimated that up to 20% of RA patients meet this D2T-RA definition and can be plagued by active or progressive disease; moderate or high disease activity, radiographic progression, inability to taper prednisone and non-response to ≥2 b/tsDMARDs after a csDMARD failure.

The authors provide guidance in the form of an easy acronym, A B C D E F, which covers both diagnostic and therapeutic considerations.

A - Adherence. Non-compliance affects 30–70% of RA patients and must be actively sought by self-report or interview, medication possession ratio, or pharmacy refill data. If possible, re-checking adherence to previously "failed" therapies, may may justify re-challenge. Common drivers include younger age, forgetfulness, side effects, cost, depression, cognitive decline, high pill loads (polypharmacy), etc. Better management of side effects is an easy solution to noncompliance.

B - Bioavailability. Drug exposure should be reassessed rather than assumed. Subcutaneous methotrexate outperforms oral bioavailability at all doses, with oral exposure plateauing above 15 mg/week; split-day oral dosing improved bioavailability by 28% in one pharmacokinetic study of patients on 30 mg/week. Obesity (BMI >30) uniformly reduces bDMARD blood concentrations regardless of fixed or weight-based dosing; methotrexate co-therapy raises TNF-α inhibitor levels by limiting anti-drug antibody formation. Dose-escalated IV TNF-α inhibitor regimens (up to 5 mg/kg) or shortened infusion intervals are options for suspected under-exposure, though proactive therapeutic drug monitoring remains limited by the absence of a validated therapeutic range.

C - Comorbidities. Three modifiable factors are highlighted: a) smoking (independently worsens disease activity and radiographic progression); b) periodontal disease (a bidirectional driver of poor RA control (one exploratory trial showing periodontal treatment improved disease activity at 2 and 6 months); and c) obesity/metabolic syndrome (associated with D2T-RA in a meta-analysis of ~23,000 patients, worsened by chronic glucocorticoid use that perpetuates a weight-gain/poor-control cycle).

D - Differential diagnosis. Could this refractory patient have the wrong diagnosis? Seronegative refractory cases warrant re-evaluation for inflammatory osteoarthritis, PMR, CPPD ("pseudo-RA" with history of pain-free flare intervals, radiographic chondrocalcinosis, synovial fluid crystal analysis), psoriatic arthritis or peripheral spondyloarthritis (hidden psoriatic rashes, nail changes, dactylitis, enthesitis, HLA-B27). Musculoskeletal ultrasound with power Doppler helps identify subclinical synovitis or periarticular disease in patients without overt clinical synovitis, and clinicians should consider co-existing fibromyalgia, reportedly present in 18–29% of RA patients. Other estimates are that nearly 40% of D2T-RA patients can be classified as having noninflammatory refractory RA (NIRRA) – many of whom have fibromyalgia and obesity who would not benefit from added immunosuppression or escalated therapy.

E - Escalation. D2T-RA patients warrant next level care. Second opinions from colleagues or referrals tertiary-center for evaluation would be prudent. Dual bDMARD combinations should generally be avoided given excess infection risk without meaningful benefit; JAK inhibitor–methotrexate combinations may offer superior efficacy but require counseling on infection, cardiovascular, and thromboembolic risk. TNF-α cycling (switching within class) is reasonable for secondary non-response, while class-switching to non-TNF agents is preferred after primary non-response or failure of ≥2 TNF-α inhibitors. For refractory cases, clinical trials, novel or unapproved, “off label” use therapies may need to be considered.

(Editors note: for more on D2T-RA, click on my video)