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Locomotor > Inflammatory Joint Disease- Rheumatoid Arthritis > Flashcards

Inflammatory Joint Disease- Rheumatoid Arthritis Flashcards

1
Q

What is the epidemiology of Rheumatoid Arthritis?

A
  • Prototype of chronic inflammatory joint disease
  • Prevalence 1%
  • Annual incidence of new cases 0.02%
  • Female: male ratio 3:1
  • 5% women; 2% men> 55 years of age are affected
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2
Q

Describe fully developed typical RA

A
  • Chronic symmetrical, predominantly peripheral, polyarthritis
  • Exacerbations and remissions
  • Erosions and deformities of joints
  • Subcutaneous nodules
  • Positive serological tests for rheumatoid factors and anti-citrullinated protein antibodies (ACPA)
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3
Q

What are the signs and symptoms of RA?

A
  • Symmetrical inflammatory polyarthritis
  • Affects small and large synovial joints
  • Deforming and destructive
  • Exacerbations and remissions
  • Atypical, asymmetrical and incomplete forms are not uncommon
  • Associated systemic disturbance
  • Affects bursae and tendon sheaths
  • Extra-articular features
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4
Q

How much joint involvement on presentation is there in RA?

A 
Polyarticular= 75%
-Small joints of hands and feet= 60%
-Large joints= 30%
-Large and small joints= 10%
Monoarticular= 25%
-Knee= 50%
-Shoulder, wrist, hip, ankle, elbow= 50%
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5
Q

What are the extra-articular features of RA?

A
  • Eye= scleritis, keratoconjunctivitis
  • Pleura= effusions
  • Lung= fibrosis, nodules
  • Lymph nodes= reactive, lymphadenopathies
  • Pericardium= effusions
  • Spleen= splenomegaly
  • Kidney and gut= amyloidosis
  • Bone marrow= anaemia, thrombocytosis
  • Muscle= wasting
  • Skin= thinning, ulceration
  • Nervous system= peripheral, neuropathy
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6
Q

What are the neurological complications of cervical spine disease?

A
  • Atlantoaxial subluxation: C2 nerve root pressure, damage to the sensory nucleus of fifth nerve (ophthalmic division), high cervical cord compression
  • Vertebral artery pressure: drop attacks, ophthalmoplegia, cerebellar signs, dizziness, nausea and vomiting
  • Subaxial subluxation: cervical root involvement (often C5), cervical cord compression
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7
Q

What are the disease burden and outcomes in RA?

A

Decline in physical function
-Active disease
-Permanent joint damage (cartilage damage and bone erosion within one year in 80%)
Physical disability= 30% work disabled within 2 years, 50%within 10 years
Psychological morbidity (anxiety, depression and helplessness)
Decline in socioeconomic status
Increased mortality

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8
Q

Describe the pathogenesis of RA

A

Genetic, Susceptibility factors- immunological response, trigger or insult/ infectious agent- clinical manifestations of RA

  • Genetic factors; 60% susceptibility
  • Genes on short arm chromosome 6
  • Major histocompatibility genes (MHC)
  • HLA DR4 subtypes Dw4 and 14 and HLA DR1 subtype Dw1
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9
Q

What is the shared epitope of RA?

A
  • The disease-associated-HLA-DRB1 alleles share an amino acid sequence with normal HLA at positions 70-74 in the third hypervariable regions of the HLA-DR-chain
  • This is associated with production of anti-citrullinated peptide (CCP) antibodies and worse disease outcomes
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10
Q

Describe the HLA class 2 molecule

A
  • Expressed on antigen presenting cells (macrophages and T cells)
  • Antigen binding cleft
  • Hypervariable region of the beta chain containing the ‘shared epitope’ (amino acid residues 70-74)
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11
Q

Describe the initiation of Rheumatoid arthritis

A
  • Initial event T cell activation by primed APC
  • Primed APC= IL-1, TNFa, IL-6
  • T cell= IL-2/15/17
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12
Q

Describe the onset of synovitis of Rheumatoid arthritis

A
  • Angiogenic cytokines= growth of new vessels (Scaffold)
  • TNFa, IL-1, IL-6, IFNy activate endothelium
  • Lymphocytes/ monocytes/ neutrophils are drawn in along with oedema fluid, become activated and produce more cytokines (positive feedback loop)
  • IL-1 and OPGL activate osteoclasts and with fibroblasts (MMPs) erode bone and cartilage
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13
Q

What are the pro and anti inflammatory mediators?

A 
Pro= TNFa, IL-1
Anti= soluble TNF receptor, IL-10, IL-1 receptor antagonist
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14
Q

Describe synovial tissue in RA

A
  • Hyperplasia of the synovial lining layer

- Sub-lining inflammatory infiltrate of lymphocytes, plasma cells and macrophages

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15
Q

What are the risk factors of RA?

A 
Genetic risk factors (60% of risk)
-Susceptibility genes (for example, HLA-DRB1)
-Epigenetic modifications
Non-genetic risk factors (40% of risk)
-Smoking
-Microbiota
-Female sex
-Western diet
-Ethnic factors
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16
Q

Describe initiation of autoimmunity/ preclinical RA

A
  • Post-translational modifications (citrullination)
  • Loss of immunotolerance at mucosal sites
  • Asymptomatic autoimmunity (increased levels of cytokines, chemokines and CRP in the circulation)
  • Autoantibody formation (ACPAs and RF)
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17
Q

Describe the propagation of autoimmunity/ early RA

A
  • Expansion of the autoantibody profile

- Early symptomatic autoimmunity to undifferentiated arthritis to classifiable RA

18
Q

What are the main features of RA?

A 
Pannus
Erosion
Areas of cartilage loss
Synovial granulation tissue
Loss of bone trabeculation with infiltrating granulation tissue
PIP and MCP erosions in hand
19
Q

How is MRI used in RA diagnosis?

A
  • Magnetic Resonance Imaging
  • Sensitive imaging of synovitis
  • MRI of wrist
  • Pannus invading the ulnar styloid and carpal bones
20
Q

How is ultrasound used in RA diagnosis?

A

-Sensitive imaging of synovitis
-Effusion
Synovial hypertrophy
-Increased Doppler activity

21
Q

How is Rheumatoid arthritis tested?

A

-Circulating anti-globin antibodies (rheumatoid factors)
-Agglutination tests for IgM Rheumatoid Factor:
=Sheep cell tests- sheep RBC coated with rabbit anti-sheep RBC antibody
=Latex tests- polystyrene particles carrying absorbed human IgG
IgG coated particles + IgM rheumatoid factor = agglutinated particles

22
Q

How useful is IgM rheumatoid factors in testing?

A 
Reasonable sensitivity (positive in 70-80% patients with RA) but not very specific (some infections and autoimmune diseases= 5-10% of healthy people)
-50% patients with RA have antibodies several years before onset of symptoms
23
Q

How useful is anti-cyclic citrullinated peptide (anti CCP) antibodies?

A
  • Eventually positive in 96-98% RA patients
  • 50% in early RA (3-6 months symptoms)
  • Can predate the onset of symptoms by years
  • Very few false positives
  • 93% patients with anti-CCP antibodies and undifferentiated inflammatory arthritis progressed to RA in 3 years (OR 37.8)
  • More specific and predictive than IgM RF
24
Q

How can autoimmune rheumatic disease be prevented?

A
  • Smoking is an important risk factor for anti-CCP+ and RF+ RA but not sero negative disease
  • Smoking interacts with HLA-DR shared epitope genes conferring high risk of anti-CCP+ RA
  • Without smoking 33% cases would not have occurred in Sweden
  • Former smokers at increased risk of developing RA for 20 years
25
Q

What are the stages of RA pathogenesis?

A

Environment= smoking, microorganisms, stress
Genotype= HLA-DR4 alleles, PTPN22, Other genes such as CTLA4, PAD14 and cytokines
-Pre-articular or lymphoid phase= autoimmunity, CCP-specific antibody, rheumatoid factor, collagen-specific response, GP39-specific response
-Transition phase= microbial insult, biomechanical events, neurological events, microvascular dysfunction
-Articular phase= articular localisation, cardiovascular disease, osteoporosis, functional decline

26
Q

What is the traditional pyramid approach to RA treatment?

A

Mild- Analgesia/ physiotherapy/ appliances/ occupational therapy
Moderate- NSAIDs
Severe- Experimental SAARDs
Overlapping

27
Q

What are DMARDS?

A

Synthetic Conventional Disease Modifying Anti Rheumatic Drugs

  • Methotrexate
  • Sulphasalazine
  • Hydroxychloroquine
  • Leflunomide
  • Gold, penicillamine, azathioprine (now seldom used)
  • Previous philosophy: match therapy to severity
  • Current approach: early intervention and suppress all inflammation
28
Q

What is the early initiation of treatment?

A
  • DMARDs to control symptoms and delay disease progression
  • All patients with persistent inflammatory joint disease (>6-8 weeks duration) already receiving simple analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) should be considered for referral for specialist rheumatology opinion and DMARD therapy, preferably within 12 weeks
  • anti-TNF alpha
29
Q

What are the four overarching principles of RA treatment?

A

A. Treatment shared between patient and rheumatologist
B. Maximise long term HRQL through control of symptoms, prevention of structural damage, normalisation of function and social participation
C. Abrogation of inflammation is the most important
D. Treatment to disease activity target optimises outcome

30
Q

How is RA treated with TNF inhibitors?

A
  • Revolutionized the treatment of aggressive RA
  • All agents have approximately equal efficacy
  • 30% patients fail to respond adequately
  • Non-responders to one agent can respond to another
  • Poorer response in: females, smokers, higher baseline HAQ scores, higher baseline CRP, anti-CCP+ patients
31
Q

What are the established anti-TNF-a drugs?

A

-Infliximab
-Etanercept
-Adalimumab
-Certolizumab
-Golimumab
(+ Biosimilars)

32
Q

What are the other biologic DMARDS drugs?

A
  • IL-1= Anakinra
  • IL-6= Tocilizumab, Sarilumab
  • CTLA4-Ig= Abatercept
  • B cells= Rituximab
33
Q

What are the key modes of action for TNF immune targets?

A
  • Reduced endothelial, stromal cell and chondrocyte activation
  • Reduced osteoclast differentiation/ activation
  • Modified cellular migration
  • Reduced cytokine expression (IL-6)
  • Reduced metabolic/ CVD risk
34
Q

What are the key modes of action of IL-6 targets?

A
  • Reduced endothelial, stromal cell activation
  • Reduced osteoclast activation
  • Reduced cytokine/ chemokine expression
  • Altered lipid metabolism
35
Q

What are the key modes of action of Co-stimulation (CD28- CD80/86) targets?

A
  • Reduced T cell activation
  • Diminished dendritic cell activation, cytokine production and antigen presentation
  • Reduced osteoclast activation
36
Q

What are the key modes of action of B cell depletion (anti-CD20) targets?

A
  • Depletion of CD20+ B cell lineages, sparing plasma cells
  • Reduced cytokine production
  • Reduced antigen presentation
37
Q

What are the key modes of action of JAK inhibitors targets?

A

Inhibition of pivotal cytokine receptors with predictable downstream effects

38
Q

What are the key modes of action of IL-1 targets?

A
  • Decreased endothelial cell, stromal cell activation
  • Decreased cellular migration
  • Altered T cell differentiation
  • Innate immunity activation
39
Q

What are the NICE guidelines for Adalimumab, etanercept and infliximab?

A
  • Active disease (DAS29>5.1)
  • Failed 2 DMARDS including methotrexate (unless contraindicated) >/ 6 months duration
  • Combine with methotrexate (unless contraindicated)
  • Patients should be monitored with DAS28 at least 6 monthly
  • Discontinue if response inadequate (improvement in DAS28
40
Q

What are the NICE guidelines for Rituximab?

A
  • Severe and active disease
  • Failed DMARDS and >- 1 TNF-antagonist
  • Combination with methotrexate
  • Discontinue if response inadequate (improvement in DAS28
41
Q

What are the recent additional synthetic targeted therapies for RA?

A

Kinase inhibitors:
Janus kinase inhibitors= JAK 1,2 AND 3 (tofacitinib), JAK 1 AND 2 (baricitinib)
Tyrosine kinase inhibitor (fostamatinib)
Small molecule DMARDS now used as third-line agents

42
Q

What is the Therapeutic Strategy of RA?

A
  • Early diagnosis
  • Immediate treatment= methotrexate plus low-dose glucocorticoid
  • Upon failure, stratify: with risk factors absent switch to (or add) another csDMARD plus glucocorticoids/ with risk factors present ass any biological agent
  • Upon failure, switch to any other biologic agent (even within same class) plus methotrexate or a tsDMARD (+/- methotrexate)

Locomotor (20 decks)

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