Rheumatoid arthritis (RA)

Updated

September 25, 2026

What is RA?

An auto-immune whole-body (systemic) disease. Requires life-long treatment. Individual patients with RA appear to have different disease-causing (pathogenic) mechanisms, due to different treatment response. Two major “types”: positive or negative for RA-linked antibodies in the blood (seropositive and seronegative), with seropositive presenting more severe symptoms.

Risk factors

  • Parent, sibling or child (first-degree relative) with RA
  • Gene HLA-DR
  • Smoking
  • Overweight
  • Infections

What are the symptoms?

Typical patient

  • Age 30-70
  • 70% women
  • Symmetrical multi-joint inflammation (polyarthritis) of hands and feet.
  • Common to have morning stiffness lasting more than 30 minutes.

Diagnosis

  • Number and location of affected joints
  • Duration of disease >= 6 weeks
  • Blood markers of inflammation (acute-phase reactants)
  • X-ray for bone erosion
  • Serum samples to determine seropositive/seronegative
    • Rheumatiod factor (RF)
    • Anti-citrullinated protein antibodies (ACPAs)

How can it be treated?

  • DMARDs (Disease-Modifying Antirheumatic Drugs)
    • Conventional
      • Methotrexate (folate antagonist, L04AX03)
        • Typical treatment, 33% response rate.
      • Leflunomide (L04AK01)
      • Sulfasalazine (A07EC01)
      • Hydroxychloroquine (P01BA02)
    • Biologic (either alone or combo with conventionals)
      • Anti TNF-alpha
        • Adalimumab (L04AB04)
        • Certolizumab pegol (L04AB05)
        • Etanercept (L04AB01)
        • Golimumab (L04AB06)
        • Infliximab (L04AB02)
      • Anti IL6
        • Tocilizumab (L04AC07)
        • Sarilumab (L04AC14)
      • B-cell depletion
        • Rituximab (L01FA01)
      • T-Cell co-stimulatory inhibitor
        • Abatacept (L04AA24)
    • Targeted synthetic
      • JAK inhibitor
        • Tofacitinib (L04AF01)
        • Baricitinib (L04AF02)
        • Upadacitinib (L04AF03)

Clinical studies

The European Medicines Agency (EMA) guideline on RA trials asks for randomized, double-blind confirmatory trials with parallel placebo or active comparator arms, run separately in patients new to DMARDs (DMARD-naive) and in patients who have already been treated with them. The primary endpoint should be a target disease state, ideally remission or at least low disease activity, defined by a cut-off on a validated composite score. For the Disease Activity Score for 28 joints, with erythrocyte sedimentation rate or C-reactive protein (DAS28-ESR or DAS28-CRP), remission is a score below 2.6 and low disease activity a score below 3.2. Each patient either reaches the target or not (a binary endpoint), assessed at 3 to 6 months for remission in DMARD-naive patients and at 3 or 6 months for low disease activity in patients who responded inadequately to earlier DMARDs. The American College of Rheumatology response criteria ACR20, ACR50 and ACR70 (20%, 50% or 70% improvement in signs and symptoms from baseline) measure relative change and are in general not primary endpoints, except in patients who have failed several DMARDs from different classes, where ACR20 at month 6 is an acceptable primary endpoint. Placebo control may need to be kept short for ethical reasons, and maintenance of efficacy should be shown in a long-term randomized study lasting 12 months in total [1].

Clinical pharmacology studies

Because phase 2 trials in RA may show efficacy without revealing the full potency of a new drug over time, the EMA guideline considers sensitive endpoints such as ACR20 or the mean DAS28-CRP possibly appropriate as the primary outcome of exploratory dose-finding trials. Assessing them early, for example at weeks 2 to 8, before the effect has reached its plateau, may help detect differences between doses. In dose finding for patients with obesity, both plasma exposure and clinical response should be taken into account, since response may be lower in overweight patients for reasons other than pharmacokinetics. The efficacy and safety effects of interactions with drugs likely to be given alongside in practice, such as methotrexate, should be evaluated [1].

References

  • https://www.nejm.org/doi/full/10.1056/NEJMra2103726
  • https://www.youtube.com/watch?v=e_NZk8nFSPA
[1]
European Medicines Agency. Guideline on clinical investigation of medicinal products for the treatment of rheumatoid arthritis 2017.