Anti-TNF and B-cell targeting in rheumatoid arthritis Flashcards

Question

What is the current treatment algorithm for rheumatoid arthritis?

Answer 1

Phase I: After clinical diagnosis, contraindication for methotrexate is checked. If the patient has no contraindication for methotrexate, methotrexate and short-term glucocorticoids is started. If the patient has a contraindication for methotrexate, leflunomide or sulfasalazine and short-term glucocorticoids is started. Is improvement achieved at 3 months and target at 6 months? Yes: continue and do dose reduction in sustained remission. No: go to phase 2. Phase II: Check for prognostically unfavourable factors. If these are present: add a bDMARD (current practice) or JAK-inhibitor. Is improvement achieved at 3 months and target at 6 months? Yes: continue and do dose reduction or interval increase in sustained remission. No: go to phase 3. If prognostically unfavourable factors are absent: change to or add a second conventional synthetic DMARD. Is improvement achieved at 3 months and target at 6 months? Yes: continue and do dose reduction in sustained remission. No: add a bDMARD (current practice) or JAK-inhibitor. Is improvement achieved at 3 months and target at 6 months? Yes: continue and do dose reduction or interval increase in sustained remission. No: go to phase 3. Phase III: Change the bDMARD, replace any first bMARD by any other bMARD, or use a JAK inhibitor. (1) Is improvement achieved at 3 months and target at 6 months? Yes: continue and do dose reduction or interval increase in sustained remission. No: repeat phase III

Answer 2

The first biologics in RA (widely available since 2000). They were a revolution in the field and game changer for patients! The are effective in approximately 2/3 of patients

Answer 3

``` Environmental triggers Protein modifications Antigen presentation T-cell activation B-cell activation Autoantibodies Synovial inflammation ```

Answer 4

An anti-CD20 that has multiple mechanisms of action that cause B-cell depletion. It has a long term effect. It doesn’t target the cells that mainly produce the auto-antibodies: the plasma cells. This is because they don’t express CD20. However, eventually there is a reduction in plasma cells because old, dead plasma cells are not replaced by new ones because the B-cells have been depleted. This means that there is still not always reduction of auto-antibodies It has better effects in ACPA+ RA, because that fits with Rituximab's mechanism of action.

Answer 5

Abatacept is a CTLA4-Ig that results in T-cell modulation and less T-cell activation. It is possibly more effective in ACPA+ RA. Side-effects are typically mild, not a lot of problems with infections etc.

Answer 6

New! They are from the last 5 years. They are oral, small molecules --> easy! • Tofacitinib (JAK1/3 specific) • Baricitinib (JAK1/2 specific) • More types in development! They are safe and effective in RA • Downsides: o more Varicella-zoster virus infection: shingles/”gordelroos” o High doses: increased risk of thrombosis, maybe because of a JAK isoform

Answer 7

Biologics cause an increased risk of infection: • Increased risk of infection and more severe course, especially in elderly patients o Pneumonia, urinary tract infection, cellulitis, herpes zoster, etc. • During treatment with biologics: o Fever is reported o Masked infections: may not seem severe, especially during tocilizumab (IL6 blocker) treatment (CRP low)!

Answer 8

Tissue profiling techniques, such as OMICs.

Answer 9

They are invasive. PET-CT might be used as an alternative.

Answer 10

•Production of cytokines and antibodies, including auto-antibodies such as ACPA •Antigen presentation and activation of T cells They are present at sites of inflammation as well as in bone marrow and lymph nodes. Rituximab (anti-CD20 therapy) is safe and effective in early, as well as late established RA

Answer 11

To delay or prevent development of arthritis in subjects at risk of RA using Rituximab.

Answer 12

Setup of the PRAIRI trial: • Individuals with arthralgia, elevated serum levels of both IgM-RF and ACPA, and/or CRP ≥ 0.6 mg/L or subclinical synovitis (no arthritis in history) • Exploratory randomised, double-blind, placebo-controlled clinical trial • 1:1 randomisation between single infusion of 1000 mg rituximab or placebo i.v. (n=41/group) • Premedication: 100 mg methylprednisolone i.v. in all subjects • Primary outcome: time to occurrence of clinical evident arthritis • Follow up 1, 2, 3, 6, 9, 12 months; yearly thereafter

Answer 13

• Safety: only mild infusion-related symptoms, no serious infections • A single infusion of 1000 mg rituximab delays the development of RA up to 12 months o Could repeated treatment with rituximab prevent RA? •These results strongly support the rationale for future clinical trials aimed at prevention of RA by targeted interventions This was the first study evaluating the effects of a biologic in subjects at risk There are other studies to prevent RA. E.g. APIPPRA study: abatacept is tested.