rheumatoid arthritis

Question 1

what is rheumatoid arthritis *

Answer 1

NOT a condition of old people

it is a chronic automimmune disease

characterised by pain, stiffness and symettrical synovitis (inflammation of the synovial membrane) of synovial (diarthrodial) joints (the free moving joints)

usually aged 30-50yrs

Question 2

clinical features of rheumatoid arthritis *

Answer 2

chronic arthritis

• POLYarthritis - swelling of the small joints of hand and wrist is common (poly means >5 joints affected)
• symettrical - eg both L and R hand evenly
• early morning stiffness in and around joints - for long periods (hrs)
• may lead to irreversible joint damage and destruction if untreated = loss of function = impact life - these are joint erosions on radiographs

extra-articular disease can occur

• rheumatoid nodules under skin
• vasculitis
• episcleritis (eye)
• affect lung

rheumatoid factor can be detected in blood

• IgM autoAb against IgG Ab - this IgM autoAb is diagnostic, but can be found in other conditions so depends on the context

Question 3

epidemiology of rheumatoid arthritis

Answer 3

1% population affected - relatively common cause of significant disability in young adults

more common in females - effect of female hormones on immune system

Question 4

describe the genetic component in rheumatoid arthritis *

Answer 4

higher concordance for identical to non-identical twins

heritability estimates up to 60%

specific HLA-DRB gene varients mapping to aa 70-74 of the DRbeta-chains are associated with rheumatoid arthritis

there are a number of HLA-DRB alleles associated - they all encode a shared aa sequence in the HLA-DR antigen binding groove - this is called a shared epitope

Question 5

describe the environmental component of rheumatoid arthritis *

Answer 5

smoking - contributes to 25% of population attributable risk

it interacts with the shared epitope to increase the risk

Question 6

what are the joints most commonly affected by rheumatoid arthritis *

Answer 6

MCP

PIP
wrost

knee

ankle

MTP

(shoulder can be affected)

early disease in hand and feety

Question 7

describe the features of RA *

Answer 7

swelling over the MCP joints and PIPJS

deformity in toes

callus formation under head of metatarsals due to joint deformity

these are late stage pictures

Question 8

describe the joint damage and destruction seen in RA *

Answer 8

swan neck deformity - hyperextension at PIP and hyper-flexion at DIP

boutonniere deformity - button like - hyper-flexion at PIPJ

xray - subluxation look like dislocation of the MCPJ, bilateral ulnar deviation of the fingers

Question 9

describe the pathology in the synovium (primary site of pathology for RA) *

Answer 9

in synovial joints - PIPJ synovitis (swelling) - palpate the swelling = soft

in tensynovium surrounding the tendons - extensor tenosynovitis - swelling on back of hand - cant fully extend lttle and ring fingers because of extensor tendon damage

in bursa - olecranon bursitis

Question 10

describe subcutaneous nodules *

Answer 10

there is a central area of fibrinoid necrosis surrounded by histiocytes (macraphage lineage) and peripheral layer of connective tissue

occur ion 30% of pts

associated with sever disease, extra-articular manifestations and rheumatoid factor

rheumatoid nodule - ulnar border of forarm is typical position - if present confirms RA and is invariably associated with rheumatoid factor

in hands - common location - around PIP joints

Question 11

describe rheumatoid factor *

Answer 11

Ab that recognise the Rc part iof IgG

they are typicall IgM anti-IgG Ab

they form an immune complex - this activates complement - trigger inflammation

positive in 70% of disease at onest and further 10-15% become positive over the 1st 2 yrs of diagnosis

if positive called sero+ve RA

sero -ve is better prognosis - inflammation is more mild

Question 12

describe the Ab to citrullinated protein Ag in RA *

Answer 12

Ab to citrullinated peptides (ACPAs) are highly specific for RA - anti-cyclic citrullinated peptide Ab (anti-CCP Ab)

citrulline is not found in normal proteins - created by convergion from arginine with enzyme: peptidyl arginine deiminases (PADs)

PADs are present in high concentrations in neutrophils and monocytes and consequently there is an increased citrullination of autologous peptides in the inflammed synovium

ACPA is strongly associated with smoking and the HLA shared epitope

teh shared epitope preferentially binds non-polar aa like citrulline bot not +ve charged like arginine - so ACPA is more likely to develop among individuals with citrulinated autoag who have a shared epitope

smokers have chronic airwauy inflammation - increase citrulination of peptides - this triggers the autoimmune reponse

Question 13

describe HLA molecules and RA *

Answer 13

individuals are suseptible to RA because they carry the conserved aa sequence in their HLA-DRbeta ag-binding groove (shared epitope)

this epitope preferentially binds to citruline and citruline containing peptide antigens increased during inflammation

HLA-DRbeta is a class 2 allele - so presents to CD4 T cells - suggesting T cell involvement in the pathogenesis

the epitope is responsible for presenting specific peptides to T cells

Question 14

what are the extra-articular features of RA *

Answer 14

malaise, fever, weight loss, SC nodules

uncommon:

vasculitis - inflammation of bv - can lead to tissue ischemia and necrosis of finger tips

ocular inflammation - episcleritis - red area of eye

neuropathies - inflammation damage peripheral nerves = weak/loss of sensation of hand/foot

amyloidosis - inflammation for a long time get increased serum amyloid a - can deposit in organs and cause organ failure eg renal/enlarged spleen

lung disease - nodules (do chest xray), fibrosis (SOB - fibrosis also caused by methotrexate so need to determine if drug or RA causing it), pleuritis (inflammation of plura - pain on inspiration)

fetty’s syndrome - triad of splenomegaly, leukopenia and RA

Question 15

describe the radiographic abnormalities for RA *

Answer 15

very early - normal - want to catch it here - once see signs start to have missed boat for treatment

early - juxta-articular osteopenia - thin bone - reduced white colour

later- joint erosions at margins of the joint

later still - joint deformity and destruction

all carpal bones coelece, in MCPjs - less joint space and irregular, erosion, erosion of ulnar styloid, ragid irregularities of MCPjs

Question 16

describe the pathology of RA *

Answer 16

bone erosion

proliferation of pannus - inflammatory tissue

synovium has hypertrophied

Question 17

describe features of the synovial joint *

Answer 17

synovium - 1-3 cell deep lining containiong macrophage like phagocytic cells (type A synoviate) amd fibroblast-lke cells that produce hyaluronic acid (type B synoviate) - there is type 1 collagen

synovial fluid - hyaluronic acod rich viscous fluid

articular cartilagde - type 2 collagen and proteoglycan (aggrecan)

Question 18

summarise the pathogenesis of rheumatoid arthritis *

Answer 18

synovial membrane is abnormal

the synovium becomes a pannus because of neovascualrisation (more bv carrying inflammatory cells), lymphangiogenesis, inflamm cells (activated t and b cells, plasma cells, mast cells and acrtivated macrophages)

recruitment, activation and effector function of these cells is controlled by a cytokine network

there is excess pro-inflamm vs anti-inflamm cytokines

TNF-alpha is the dominant cytokine

Question 19

describe the role of TNF-a in RA *

Answer 19

it causes:

• osteoclast activation = bone resorption
• chondrocyte activation = metalloproteinase production and cartilage destruction
• angiogenesis
• leukocyte accumulation - induction/maintenance of HLA class 2 expression
• endo cell activation - upregulation of E-selectin and VCAM-1, leukocyte accumulation
• chemokine release = leukocyte accumulation
• proinflamm cytokine release
• hepcidin induction = acute phase response
• PGE2 production

Question 20

descrieb TNFa inhibition *

Answer 20

achieved through parenteral administration (mainluy SC injection) of Ab/fusion proteins - was originally monoclonal Ab - IV

Question 21

describe the biological therapy for RA *

Answer 21

block IL6 - inflammatory cytokine - tocilizumab and sariumab are Abs against IL6 receptors

IL1 blockade is less effective and have to do daily injection - the cost doesnt justify the marginal benefit, so not done in the UK

deplete B cells by IV admin of anti-CD20 this is Rituximab - 2 injetions 2 wks apart - works because the produce the Ab, also APC to T cells

inhibito TNFa - Ab (infliximab) and fusion proteins (etanercept - decoy receptor for TNF so mops it up

modulation of T cell co-stimulation (abatacept - fusion protein, extracellular domain of human cytotoxic T-lymphocyte-associated ag 4, linked to modified Fc - hinge, CH2, and CH3 domains of IgG1

Question 22

describe management for RA *

Answer 22

goal is to prevent joint damage

MDT approach

physio - build back lost muscle through lack of use

OT - in advanced disease - make sure you can still function

hydrotherapy

surgery

med: early and aggressively

• disease modifying anti-rheumatic drugs (DMARDs) - started early in disease because level of joint destruction = inflammation x time, they are steroid sparing agents
• there are important roles for glucocorticoid therapy - steroids - aim to avoid long term because of SE, useful short term to control flare of disease/inflammation in 1 joint
• biological therapies

Question 23

describe DMARD therapy *

Answer 23

they are drugs that may induce remission and prevent joint damage - they dont cure

tehy reduce the amount of inflammation in the synovium and slow or prevent structural damage in the synovium

slow onset of action

start with methotrexate in combination with hydroxychloroquine or sulphasalazine - they are immune modulators

leflunomide is uncommonly used

janus kinase inhibitors are new drugs - tofacitinib and baricitnib - rarely used

gold and penicillamine are rarely used

methotrexate upsets the liver and blood count therefore need to monitor these systems

Question 24

what is the downside of biological therapies *

Answer 24

expensive treatrments - therefore use is limited to severe disease - have to fail 2 standard therapies - therefore give 2 standard drugs straight away

there is an increased risk of infection for all of them

TNF-a is associated with increased suseptibility to mycobacterial infection eg TB - so need to screen all patients for TB before starting treatment - may use prophylactic Ab for all at high risk

B cel depeltion associated with Hep B reactivation - so need to screen all patients for hep B before treatment

B cell depletion therapy can be associated with JC virus infection nad progressive leukoencephalopathy - neurological condition that affects the brain - can be fatal

Question 25

what type of Ab are adalimumab and golimumab and rituximab and infliximab

Answer 25

adalimumab and golimumab are anti Tnf and are full human ab

rituximab and infliximab are anti CD20 and TNF respectively and are chimeric (human/mouse Ab)