Rheumatoid Arthritis Part 2: The Immunology of RA (Kremer, 8/26/2020)

This week, Dr. Lisa Kremer, a local Sutter Medical Group of the Redwood's Rheumatologist, gave Part 2 of her Grand Rounds presentation on Rheumatoid Arthritis (Part 1 from 2/26/2020 is available on this blog here)-- this one on the Immunology of Rheumatoid Arthritis (RA).

Dr. Kremer reminded us that RA is a symmetrical, poly-articular inflammatory process of small and medium joints on more than one occasion over more than six weeks (with supporting lab and/or x-ray findings and the absence of an alternative diagnosis).

• Of note, RA does NOT involve the low back or SI joints (can sometimes include the hips, shoulders and upper cervical spine)

RA has 3 phases (see image below):

• Pre-clinical
• Early "clinically evident: disease
• Chronic established disease

Source: https://www.sciencedirect.com/science/article/pii/S1074761317300419

RA has its roots in an environment of autoimmunity

• lung exposure: e.g. tobacco, silica, and textile dust (risk is increased with greater pack year, declines at 10 years after quitting tobacco
• increased citrillination of peptides
• oral mucosa: chronic gingivitis (inflammation)
• GI tract: microbiome, including inflammatory diets

RA is environment PLUS genetics

• production of antibodies recognizing citrillinated peptides that differentiates individuals at risk for developing RA
• monozygotic twins share RA 12-15% of the time
• fraternal twins and other 1st degree relatives share RA dx 2-5% of the time
• 40% of genetic influence is in MHC class IIa-DR4 alleles
• more than 90% of patients with RA express "susceptibility isotopes" on the DRB chain that are associated with increased disease severity

As RA moves from a pre-clinical to early RA, multiple autoimmune conditions are precipitated:

• macrophages in the synovium are activated
• cytokines are released, activating T cells and creating a positive feedback loop that leads to more cytokine and chemokine release
• T cells release inflammatory cytokines (TNFa, IL1, IL6)
• Fibroblast-like synoviocytes (FLS) and macrophages make up the thickened synovium of early RA
• FLS drive erosive bone damage

Our current therapeutics have been created in direct response to this immunology. Treatments for RA are named for their immune targets. Note that methotrexate is still mainstay treatment for RA and steroids should only ever be given for short-term management.

• Antimetabolites: Methotrexate, Leflunomide
• TNF: Adalimumab, Etanercept, Infliximab
• IL-6: Tociluzimab
• Co-stimulation (CD28-CD80/86): Abatacept
• B cell depletion (anti-CD20): Rituximab
• JAK inhibitors: Tofacitinib, Baricitinib
• IL-1: Anakinra

Untreated, RA shortens life by 5-10 years. Aggressive RA therapy decreased mortality due to CV disease, lung, alanto-axial subluxation, and drug toxicity (e.g. steroids, NSAIDs). Treatment reduces the need for joint replacements by 50%

Lifestyle matters!

• diet, exercise weight management
• tobacco cessation and limited alcohol
• stress management