Anti-TNF and B-cell targeting in rheumatoid arthritis

Question 1

What is rheumatoid arthritis?

Answer 1

An inflammatory joint disease characterised by: activated immune system and chronic inflammation.

The arthritis is symmetrical, mainly of the small hand/foot joints. There can be extra-articular manifestations (because it is not just a joint disease, it is a systemic auto-immune disease). e.g. episcleritis, vasculitis, nodules (subcutaneous, pulmonary), serositis

Question 2

What are the symptoms of arthritis?

Answer 2

Pain, stiffness, limited functions (in daily activities, work), joint destruction (cartilage, bone)

Question 3

When are synovial tissue biopsies done?

Answer 3

During mini-arthroscopy

Question 4

What are synovial tissue biopsies good for?

Answer 4

To help gain insight into inflammatory tissue in rheumatoid arthritis patients

Question 5

What radiological change can be seen in rheumatoid arthritis patients?

Answer 5

Erosion of the joints

Question 6

What is the epidemiology of rheumatoid arthritis?

Answer 6

Epidemiology of rheumatoid arthritis:
•Cause still unknown
•It is a multifactorial disease
o genetic predisposition/genetics (i.e. association with HLA-DRB1 (shared epitope, SE)
o other factors (i.e. smoking, obesity)
•Prevalence ~1% of worldwide population
o in NL approx. 170.000 patients
• In NL 25-50/100.000 new patients per year (incidence)
• All ages; peak-incidence 40-60 year
•Female : male = 3:1, probably an hormonal aspect involved

Question 7

What is the etiology of rheumatoid arthritis?

Answer 7

•Genetic predisposition
    o Known because of twin studies
         Monozygotic 15-30%
	Dizygotic 5%
     o Recurrence risk in siblings
• Environment
     o Smoking
     o Overweight
     o Hormonal factors
           Male : female ratio 
           Often (in 2/3 patients) improvement during pregnancy

Question 8

How can (genetic) biomarkers help understand rheumatoid arthritis?

Answer 8

(genetic) biomarkers help understand rheumatoid arthritis by:
• Building a more accurate, more complex model of the disease
• Understand how genetic heterogeneity explains phenotypic heterogeneity
–> Helps to stratify disease in research settings
•Pathway identification –> therapeutic targeting!

Question 9

What are the possible relations between factor X and rheumatoid arthritis if they are associated with each other?

Answer 9

Factor X is associated with RA, so either:

a. X causes RA,
b. RA causes X,
c. Y causes RA and X

Question 10

Which advances in genetics can help with the identification of rheumatoid arthritis risk genes?

Answer 10

• Complete human genome sequenced and > 3.000.000 genetic polymorphisms identified
• Powerful DNA technology for genetic studies and genome analysis available
• Large genetic databases: easy access and in public domain

Question 11

What are the genetic clues in rheumatoid arthritis?

Answer 11

More than 100 genes are associated with RA. Many of these genes are involved in lymphocyte activation

Question 12

What is genetic clue 1 in rheumatoid arthritis?

Answer 12

Human Leukocyte Antigen (HLA). Especially HLA-class 2-DR is associated with polymorphisms that increase susceptibility for development of RA. This is especially true for the shared epitope (SE) DRB1. Relation to immune system: antigen presentation to T-cells. Presentation of self-peptides? Probably

Question 13

What is genetic clue 2 in rheumatoid arthritis?

Answer 13

Genetic clue 2 in rheumatoid arthritis:
PTPN22 on chromosome 1p13. It codes for intracellular protein “lymphoid tyrosine phosphatase (LYP)”, an inhibitor of T-cell receptor (TCR) signalling
The 1858-T allele is associated with multiple autoimmune diseases –> Lymphocyte activation is likely to play a role!

Question 14

What is genetic clue 3 in rheumatoid arthritis?

Answer 14

Genetic clue 3 in rheumatoid arthritis:
In GWAS studies (screening of whole genome) there was also association of CD40 with RA.
CD40 is important in the interaction between APC and T cells
Development of targeted therapy that blocks the interaction (monoclonal antibody) were effective in first trials.

Question 15

What are the serology clues in rheumatoid arthritis?

Answer 15

“Rheumatoid factor”, mainly IgM-Rheumatoid factor (IgM-RF)

“Anti-citrullinated protein antibodies” (ACPA)

Question 16

What is IgM-RF?

Answer 16

An immunoglobulin (product of activated plasma cells) directed against Fc tail IgG
It can be detected with IgM-RF ELISA.
~50% of RA patients is positive at first visit outpatient clinic. 70-80% will become positive in course of disease, BUT: also 5-10% of normal population are positive!
This means that you can’t use it as a golden standard for diagnostics. It is probably a bystander effect of inflammatory responses

Question 17

Wat are anti-CCP antibodies (ACPA)

Answer 17

Antibodies directed against citrullinated proteins (vimentin/fibrinogen).
ACPA are very specific for RA, but the sensitivity is lower than IgM-RF

It is prognostically unfavourable (more joint destruction). They maybe have a pathogenetic role in activating osteoclasts that can destruct bone.

Question 18

What is citrullination?

Answer 18

Citrullination: positively charged arginine is converted via peptidyl arginine deiminase (PAD) into a neutrally charged citrulline.

Question 19

What is the preclinical phase of rheumatoid arthritis?

Answer 19

Sometimes already 10 years before the onset of the disease, patients have circulating autoantibodies that rise prior to development or RA.

Question 20

What is the current treatment of rheumatoid arthritis?

Answer 20

Goal = remission!

Treatments:
o Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
o Corticosteroids (prednisolon) (lots of side effects, use as short as possible)
o(Disease modifying) anti-rheumatic (drug)s (“DMARDs”)
oBiologics and other targeted therapies (new, since 20 years)
(a.o. anti-TNF en Jak-inhibitors)

Question 21

What are the 3 different types of RA and their prevalence?

Answer 21

types of RA:
•Type 1 = Self-limiting — up to 5% of patients
•Type 2 = Minimally progressive — 5% to 20% of patients
•Type 3 = Progressive — 60% to 90% of patients

Question 22

How can joint damage be prevented?

Answer 22

Loss of function is difficult/impossible to revert!
•Early recognition
• Early treatment
• Aggressive treatment
• ‘Window of opportunity’: early intervention can alter the course of the disease!

Question 23

How is treatment efficacy evaluated in rheumatoid arthritis?

Answer 23

It is evaluated using DAS28 score: a clinical score that evaluates 28 joints and looks if they are swollen or painful together with how the patient views their disease at the moment and some biomarker of inflammation

Question 24

How has the care for rheumatoid arthritis patients improved over time?

Answer 24

Less inflammation, less vasculitis. The difference is the advant of anti-TNF treatment.

Question 25

What is the current treatment algorithm for rheumatoid arthritis?

Answer 25

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

Question 26

What are anti-TNFs?

Answer 26

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

Question 27

Which parts of rheumatoid arthritis can you interfere with?

Answer 27

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

Question 28

What is rituximab?

Answer 28

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.

Question 29

What is Abatacept?

Answer 29

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.

Question 30

What are JAK inhibitors?

Answer 30

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

Question 31

What is a downside of using biologics?

Answer 31

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)!

Question 32

What can be used to stratify patients early and guess which treatment is the most effective?

Answer 32

Tissue profiling techniques, such as OMICs.

Question 33

What is a downside of synovial tissue biopsies and what is an alternative?

Answer 33

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

Question 34

What is the role of B-cells in (pre-)rheumatoid arthritis?

Answer 34

•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

Question 35

What was the objective of the PRAIRI trial?

Answer 35

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

Question 36

What was the setup of the PRAIRI trial?

Answer 36

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

Question 37

What were the outcomes of the PRAIRI trial?

Answer 37

• 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.