The Concern about Seronegative RA Save

Know-it-now

• Seronegative RA is a biologically different, distinct entity with a minority of patients having non-conventional autoantibodies such as anti-CarP.
• Prevention is possible but must be stratified: MTX cut progression from 29% to 9% in increased-risk ACPA-negative CSA. The benefit was confined to patients with MRI-defined inflammation and absent in low-risk patients.
• “Benign”? Erosions are less common, but PRO burden equals seropositive disease and long-term outcomes are not improved with treat-to-target.
• Weaker drug responses in seronegative RA: especially with MTX, rituximab, abatacept and tofacitinib. Sadly seronegative patients are underrepresented in trials.
• Divergent fates: Seronegative patients more often reach drug-free remission (~40%), which is partly predictable from early response, MBDA and MRI. Their D2T risk is uncertain, and its drivers are often non-inflammatory.

A current review of seronegative RA (SNRA) by D’Onofrio, et al in npj Autoimmunity shows the diverse fate of seronegative RA - which can resolve, persist or become refractory.  Clearly dedicated trials of SNRA are needed to better predict.

SNRA makes up 40–50% of modern early arthritis cohorts. The heterogeneity of SNRA underlies the fact that this is not just seropositive RA without antibodies. “Seronegative” is also an imperfect label often driven by CCP2 negativity. Beyond CCPm there may be another autoantibody repertoire in such patient - anti-CarP antibodies appear in 10–25% of RF/ACPA-negative patients.  Long term followup of SNRA patients (eg, ESPOIR) shows that a minority can be reclassified as PMR, CPPD, parvovirus B19 infection or CTD.  The SNRA diagnosis needs revisiting during each follow-up visit.

Lessons from Preclinical Phase and Prevention Trials

• Risk factors: Modifiable risk factors are poorly defined. A shorter reproductive span or early menopause raises RA progression risk in clinically suspect arthralgia (CSA), but only in ACPA-negative patients.
• Symptoms: The ACPA-negative at-risk phase is longer, and onset is often abrupt. Symptom burden (pain, stiffness, fatigue, presenteeism) is higher than in ACPA-positive CSA. (Interpretation: if seronegative you may have to have more symptoms and findings to classify as RA - SNRA)
• Prediction: Predictive factors have been largely studied in seropositive RA. As such those factors either havent been studies or perform poorly in seronegative CSA patients.
• TREAT EARLIER: The trial missed its primary endpoint overall and failed to show the efficacy of MTX in CSA. However, a post-hoc analysis showed MTX efficacy but only in the ACPA-negative patients (RA development in 9% with MTX versus 29% with placebo; HR 0.27, p=0.034). MRI burden of ≥2 tenosynovitis sites, or osteitis plus tenosynovitis, identified MTX responders regardless of ACPA status.

Lessons from Established SNRA 

• Just as bad; but delayed! In the Leiden EAC (n=942), ACPA-negative RA was as severe as ACPA-positive RA on PROs. Since the 2010 criteria, seronegative patients have had longer diagnostic delays and more severe presentations.
• Less structural damage with SNRA. In BARFOT (n=608), 30% of ACPA-negative versus 14% of ACPA-positive patients remained erosion-free at 8 years.
• Long-term outcomes same regardless of serology. Over 25 years in Leiden (n=1,285), treat-to-target reduced disease activity in both groups. Only seropositive patients gained in drug-free remission, mortality and disability.
  • In difficult-to-treat (D2T) RA: Most cohorts show no serostatus association with outcomes. But there is conflicting data owing to the heterogeneity of D2T-RA cohorts:
    • Takanashi found RF/ACPA positivity in 80% of D2T versus 68% of non-D2T patients (p=0.001).
    • An Italian cohort found double seronegativity independently predicted D2T
    • Leon et al. found RF negativity in 32% of D2T versus 16% of non-D2T patients.
    • Non-inflammatory (NIRRA) drivers such as central sensitization and comorbidity likely matter more in seronegative D2T.
• Drug response: Responses were weaker in seronegative RA therapies:
  • MTX: lower 4-month remission in IMPROVED (n=610), and less benefit from combination therapy in CARDERA (n=467).
  • Rituximab: reduced benefit in a meta-analysis of 4 RCTs.
  • Abatacept: greater benefit with the highest ACPA titers (AMPLE).
  • Tofacitinib: lower ACR and DAS28 remission rates in double-negative patients across 5 pooled RCTs.
  • Less Drug-free remission: Sustained drug-free remission occurs in about 40% of seronegative patients versus 5–10% of seropositive patients.

More research and dedicated trials of SNRA cohorts are needed.