rheumatoid and other inflammatory arthiritis Flashcards
2 main divisions of arthritis
osteoarthritis (degenerative arthritis) where there is a lack of space due to joint space narrowing
inflammatory arthritis where you see redness,hot/warm,swelling and fluid
causes of joint inflammation
infection eg septic arthritis or tuberculosis
crystal arthritis eg gout or pseudogout
immune mediated/autoimmune
unfection and crystal arthritis are secondary inflammation in response to a noxious insult whereas autoimmune is primary inflammation
non sterile vs sterile inflamation
non sterile is infection eg septic or tb
sterileis Crystal eg gout or pseudogout or autoimmune arthritis
degenerative arthritis (OA)
no or little inflammation
slow onset
no inflammatory cells found in synovial fluid analysis thus sterile
crp normal
wcc normal
immune mediated arthritis
inflammation present
subacute speed of onset
inflammatory cells present in synovial fluid and is sterile
crp high
wcc usually normal
crystal arthrits
inflammation present and is secondary to crystals
rapid speed of onset
inflammatory cells and crystals present in synovial fluid,sterile
crp is high or very high
wcc usually normal
septic arthritis
inflammation secdonary to infection
rapid speed of onset
inflammatory cells and bacteria present in synovial fluid
crp is very high
wcc high
what do you see in spetic arthritis,management and ivx
Acute hot, swollen joint = SEPTIC ARTHRITIS until proven otherwise
Key investigation: joint aspiration
send fluid for Gram stain and culture
management via joint washout (lavage) and iv abx
rheumatoid arthritis
chronic autoimmune disease
prumary site of pathology is synovium
synovium found at synovial (diarthrodial) joints where you may see joint synovitis,tenosynovium where you may see extensor tenosynovitis, and bursa where you see olecranon bursitis
prevalence of RA
female to male 2:1
age of onset is 30-50
key features of RA
Chronic arthritis
Polyarthritis
Pain, swelling and early morning stiffness in and around joints
May lead to joint damage and destruction - ‘joint erosions’ on radiographs
Systemic disease with extra-articular manifestations
Auto-antibodies usually detected in blood
RA aetiology
twin studies show that ra concordance is 15% in monozygotic and 4% in dizygotic twins
environment has an imapct:smoking,microbiome,porphyromonas gingivalis (poor oral health) linked to RA
RA and anti-citrullinated protein antibodies (ACPA)
Smoking -> citrullination of proteins in lung epithelium
P. gingivalis can also cause citrullination
RA genetics
Strongest genetic risk factor = HLA-DR
HLA-DRb chain amino acids 70-74 (‘shared epitope’). Smoking & shared epitope synergistically increase risk
Genome-wide association studies (GWAS):
>100 other genetic loci that contribute to RA risk (polygenic)
E.g. PTPN22, IL6R
> Effect of a risk allele at any given locus typically modest
> Cumulative genetic burden rather than any one variant determines risk
how to do gwas
-Compare allelic frequencies at a given genetic single nucleotide polymorphism (SNP) between cases vs controls
-Repeat across the genomes for millions of SNPs
-Identify the SNPs associated with disease risk
HLA class 1
HLA class 1 = HLA A, B and C
HLA class 1 expressed on all cells
Cells present peptide in association with HLA class 1 to CD8 (‘killer’) T cells
HLA class 2
HLA D = class 2
HLA class 2 only expressed on professional antigen presenting cells (APCs), including dendritic cells, macrophages, B cells
APCs present peptide in association with HLA class 2 to CD4 (‘helper’) T cells
CD4 T cells provide “help’ to B cells
implications of hla
HLA class 1 association (eg HLA-B27 in Ankylosing spondylitis) implicates CD8 T cells in pathogenesis
HLA class 2 association (HLA-DR4 in RA) implicates CD4 T cells and B cells
This fits with autoantibodies (made by B cells) in RA but not in Ank Spond
RA joint pattern involvement
symmetrical
polyarthritis
can affect both small and large joints but nearly almost all small joints affected
Metacarpophalangeal joints (MCP)
Proximal interphalangeal joints (PIP)
Wrists
Knees
Ankles
Metatarsophalangeal joints (MTP)
RA vs OA
RA: prolonged morning and inactivity stiffness affecting PIPJ MCPJ wrist
OA:pain worsens with activity affects DIPJ PIPJ
extra articular features of RA
Systemic inflammation
Fatigue (v common)
Fever
Weight loss
Organ-specific
Subcutaneous nodules
Lung disease – nodules, interstitial lung disease (ILD)/ fibrosis, pleuritis
Ocular inflammation e.g. episcleritis
Vasculitis
Neuropathies
Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis
Amyloidosis
RA subcutaneous nodules
Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
Occur in ~30% of patients
Associated with:
Severe disease
Extra-articular manifestations
Rheumatoid factor
RA histopathological changes
usually we have 1-3 cell layer that lines synovial joints which contains macrophage like (type A synovioctyes) and fibroblast (type b synovioctyes) and type 1 collagen. Functions to mainain synovial fluid
in RA synovium becomes proliferatedmass of tissue (pannus) due to neovascularisation,lymphangiogenesis,inflammatory cells -activated b and t cells,plasma cells,mast cells,activated macrophages
RA pathogenesis
- Autoreactive B cells
(treatment: rituximab) - Autoreactive T cells
(treatment: abatacept) - Cytokines
TNF-alpha
Interleukin-6
(Interleukin-1)(treatment: anti-TNFa, anti-IL6R)
Excess of pro-inflammatory vs. anti-inflammatory cytokines (‘cytokine imbalance’)
TNF-alpha
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium
Its pleotropic actions are detrimental in this setting:
Inflammatory cell recruitment, angiogenesis, lymphangiogenesis -> Pannus formation
Matrix metalloproteases -> Cartilage loss
Osteoclast activation -> Bone loss (erosions, osteopenia)
RA arthritis IVX
Inflammatory response
↑ ESR ↑ CRP
sometimes normocytic anaemia, ↑PLT
Autoantibodies*: Rheumatoid factor (RF) = antibodies that bind IgG Anti-CCP antibodies
RF can be positive in other autoimmune and infective conditions, and in individuals without disease.
Therefore, RF positive in the absence of clinical features does not necessarily indicate rheumatoid arthritis
CCP antibodies most specific for rheumatoid arthritis and associated with more aggressive/erosive disease
autoantibodies in RA
Studies of stored samples from blood donors who later developed RA:
RF and ACPAs precede symptom onset
ACPAs predate first clinical symptoms of RA by a median of 4.5 years
therefore:
genetic predispostion (asymptomatic)—->pre clinical autoimmunity (asymptomatic)—>tissue inflammation and injury (symptms)
RA investigations imaging
1)x ray show soft tissue swelling,peri-articular osteopenia,bony erosions. Erosions only occur in esabilished disease thus treatment must occur before erosions present. Info from x rays limited to bony structures
2) Ultrasound (US) is a much better test for detecting synovitis. US changes in RA:
Synovial thickening (synovial hypertrophy)
Increased blood flow (seen as doppler signal)
May detect erosions not seen on plain X-ray
US (usually of hands and wrists) can be performed alongside clinical assessment in a dedicated early arthritis clinic
3) MRI can also be used but expensive and time-consuming
management of RA
Treatment goal: prevent joint damage
Requires:
Early recognition of symptoms, referral and diagnosis
Prompt initiation of treatment: joint destruction = inflammation x time
Aggressive pharmacological treatment to suppress inflammation
Multidisciplinary input where needed e.g. physiotherapy, occupational therapy, surgery
RA pharmacological treatment
Glucocorticoid therapy (‘steroids’) useful acutely but avoid long-term use because of side-effects.
DMARDs’ = disease-modifying anti-rheumatic drugs
Immunomodulatory drugs that halt or slow the disease process
First line
combination of DMARD therapy:methotrexate+hydroxychloroquine and or sulfasalazine plus IM or short course of oral steroids
if disease still active then second line
Biological therapies usually therapeutic monoclonal antibofies targetting specific molecules eg anti TNF alpha blockade
are nsaids used in RA
NSAIDs (non-steroidal anti-inflammatory drugs)
e.g. ibuprofen, naproxen, diclofenac
Historically used but increasingly less relevant
Can provide partial symptom relief but do not prevent disease progression
Unfavourable long-term side-effect profile
glucocorticoids
Glucocorticoids bind the glucocorticoid receptor (GR)
GR resides in cytoplasm
On binding by glucocorticoids, steroid-GR complex translocates to the nucleus and binds DNA response elements, affecting transcription
Methods of steroid administration:
Oral prednisolone
Intramuscular (IM) methyl prednisolone
Intravenous (IV)
Intra-articular (IA)
Steroid side effects:
Many and bad!
Cushing’s syndrome
treat to target concept in RA
Concept: suppress disease activity to improve outcome
Achieved by regular objective measurement of disease activity e.g. DAS28 score
DAS28 = composite of
no. of tender joints,
no. of swollen joints,
patient visual analogue score (VAS),
ESR (or CRP)
If DAS28 not suppressed -> escalate treatment
biological therapies for RA antibodies
Biological therapies are proteins (usually antibodies) that specifically target a protein
Biologics targeting cytokines:
- Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)
antibodies (infliximab, adalimumab, golimumab, certolizumab)
fusion proteins (etanercept) - Inhibition of interleukin-6 (IL-6) signalling
Antibodies against IL-6 receptor:
Tocilizumab (RoActemra)
Sarilumab (Kevzara)
biological therapies targetting lymphocytes
1.B cell depletion
Rituximab – antibody against the B cell antigen, CD20
Given as two iv infusions, 2 weeks apart
Results in rapid depletion of peripheral B cells
Usually repopulate after ~6-9 months
Side effects: infusion reactions, infection, hypogammaglobulinaemia
- Blocking T cell co-stimulation
Abatacept - fusion protein - extracellular domain of CTLA-4 linked to modified Fc portion of human immunoglobulin G1
T cells require 2 signals to activate:
MHC + peptide on APC binding to TCR on T cell
CD80/CD86 on APC binding to CD28 on T cell
Abatacept blocks signal 2
seronegative inflammatory Arthritis
Family of conditions with overlapping clinical features and pathogenesis
Unlike rheumatoid arthritis, RF and CCP antibodies not present in blood (“seronegative”)
BUT they are immune-mediated
Psoriatic arthritis
reactive arthritis
ankylosing spondylitis
IBD associated arthritis
psoriatic arthritis
Psoriasis is an immune-mediated disease affecting the skin
Scaly red plaques on extensor surfaces (eg elbows and knees)
~10% of psoriasis patients also have joint inflammation
Unlike RA, rheumatoid factors are not present (“seronegative”)
Dominant pathogenic pathway is interleukin-17/interleukin-23 (IL17-IL23)
Skin disease severity not correlated to joint manifestations
Examine skin carefully for small areas of psoriasis (NB scalp, umbilicus)
Sometimes nail changes may be only manifestation
psoriatic arthritis presentation
Varied clinical presentations:
-Classically asymmetrical arthritis affecting IPJs
-Enthesitis (inflammation of tendon insertions)
But also can manifest as:
-Spinal and sacroiliac joint inflammation
-Oligoarthritis of large joints
-Arthritis mutilans
-Symmetrical involvement of small joints (rheumatoid pattern
reactive arthritis
Sterile inflammation in joints following infection elsewhere in the body
Common infections:
urogenital (e.g. Chlamydia trachomatis)
gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections)
Important extra-articular manifestations include:
Enthesitis (tendon inflammation)
Skin inflammation
Eye inflammation
Reactive arthritis may be first manifestation of HIV or hepatitis C infection
Commonly young adults with genetic predisposition (e.g. HLA-B27) and environmental trigger (e.g. Salmonella infection)
Symptoms follow 1-4 weeks after infection and this infection may be mild
Reactive arthritis NOT the same as infection in joints (septic arthritis)
septic vs reactive arthritis
septic
postive synovial fluid culture,IV abx given,joint lavage done
reactive
sterile synovial fluid culture,treat underlying disease,joint lavage not done
Swan neck deformity
A sign of chronic RA which can also occur in lupus but less likely
Hyper flexion of DIPJ and hyper extension of PIPJ
OA X ray
Joint space narrowing
Subchondral sclerosis (increased whiteness)
Osteophytes
