1b// Rheumatoid and Other Inflammatory Arthritis Flashcards
What is arthritis?
disease of the joints
What are the 2 major divisions of arthritis?
osteoarthritis
arthritis with signs of inflammation
What is osteoarthritis?
degenerative arthritis
What are the clinical examination signs of joint inflammation?
red
hot/ warm
swelling/ fluid
What is this showing? (smth about space)
Lack of space indicates loss of articular cartilage leading to bone in contact with bone
What are the causes of joint inflammation?
- infection
- crystal arthritis
- immune mediated (autoimmune)
What are examples of joint inflammation caused by infection?
septic arthritis
Tuberculosis
What are examples of joint inflammation caused by crystal arthritis?
Gout
Pseudogout
What type of joint inflammation is secondary and primary?
secondary inflammation in response to a noxious insult
immune= primary inflammation
What type of joint inflammation is sterile and which are non-sterile?
infection= non-sterile
immune and crystal= sterile
What are the 4 major arthritis you need to know?
degenerative (osteoarthritis)
immune mediated
crystal arthritis
septic arthritis
How is the inflammation in…
degenerative (osteoarthritis)
immune mediated
crystal arthritis
septic arthritis
degenerative (osteoarthritis)= none or little
immune mediated= yes- autoimmune
crystal arthritis= yes- secondary to crystals
septic arthritis= yes- secondary to infections
How is the speed of onset with…
degenerative (osteoarthritis)
immune mediated
crystal arthritis
septic arthritis
degenerative (osteoarthritis)= slow
immune mediated= subacute
crystal arthritis= rapid
septic arthritis= rapid
What is the synovial fluid analysis like in…
degenerative (osteoarthritis)
immune mediated
crystal arthritis
septic arthritis
degenerative (osteoarthritis)= no inflammatory cells,sterile
immune mediated= inflammatory cells, sterile
crystal arthritis= inflammatory cells, sterile, crystals
septic arthritis= inflammatory cells and bacteria
What is the CRP like with…
degenerative (osteoarthritis)
immune mediated
crystal arthritis
septic arthritis
degenerative (osteoarthritis)= normal
immune mediated= high
crystal arthritis= high/ very high
septic arthritis= very high
What is the white cell count like with…
degenerative (osteoarthritis)
immune mediated
crystal arthritis
septic arthritis
degenerative (osteoarthritis)= normal
immune mediated= usually normal
crystal arthritis= usually normal
septic arthritis= high
Is septic arthritis an emergency?
yes an orthopaedic emergency
When should you assume it’s septic arthritis until proven otherwise?
acute, hot, swollen joint
What is the key investigation for septic arthritis?
joint aspiration
send fluid for Gram stain and culture
What is the management of septic arthritis?
joint washout (lavage) and IV antibiotics
lavage bc anti-b amy not reach
What are the types of autoimmune inflammatory arthritis?
Rheumatoid arthritis
Seronegative arthritis
Lupus and related disorders
How would you simply describe the clinical features rheumatoid arthritis?
Subacute/chronic Polyarthritis
Small & large joints
Symmetrical
What are the types of seronegative arthritis?
Psoriatic arthritis Reactive arthritis
Ankylosing spondylitis
IBD-associated
How would you simply describe the clinical features seronegative arthritis?
Subacute/chronic
Mono and/ or oligo large joint*
May involve spine
Asymmetrical
How would you simply describe the clinical features of lupus and related disorders?
Subacute/Chronic
Polyarthralgia (often little swelling)
Frank arthritis usually non-erosive
Describe the classification of arthritis.
What is rheumatoid arthritis?
Rheumatoid arthritis (RA) : synovial inflammation
chronic autoimmune disease
Systemic disease with extra-articular manifestations
What is the primary site of pathology of rheumatoid arthritis?
the synovium
What is the inflammation of
the synovial membrane called?
synovitis
Where is the synovium found?
joints= synovial diarthrodial joints
tendons= tenosynovium surrounding tendons
bursa
What is the sex bias and age of onset for rheumatoid arthritis?
F:M = 2:1
30s-50s
What are the key features of rheumatoid arthritis?
Chronic arthritis
Polyarthritis
Pain, swelling and early morning stiffness in and around joints
May lead to joint damage and destruction - ‘joint erosions’ on radiographs
What is normally detected in the blood with rheumatoid arthritis? And give examples.
Auto-antibodies usually detected in blood
such as rheumatoid factor and anti-citrullinated protein antibodies (ACPA)
How do you estimate the contributions of genetic vs environment for diseases?
What is the environmental aetiology of rheumatoid arthritis?
Smoking
Microbiome
Porphyromonas gingivalis
Poor oral health
Why does smoking cause rheumatoid arthritis, and give an example of something else that does this?
Smoking -> citrullination of proteins in lung epithelium P. gingivalis can also cause citrullination
Is rheumatoid arthritis genetic?
mixture of genes and environment
seen from twin studies
RA concordance in twins 1 : monozygotic ~15% dizygotic ~4%
What is the strongest genetic risk factor for rheumatoid arthritis?
HLA-DR
especially HLA-DR(beta)1
and HLA-DR4 (not as much)
What 2 synergistically increase risk of RA?
HLA-DRb chain amino acids 70-74 (‘shared epitope’).
Smoking & shared epitope synergistically increase risk
How many genetic loci found by the genome wide association studies contribute to RA risk? And give examples.
100 other genetic loci (polygenic)
E.g. PTPN22, IL6R
How would you describe the effect of a risk allele for having RA?
modest effect
Cumulative genetic burden rather than any one variant determines risk
What are the classes of HLA?
HLA class 1= HLA A, B, C
HLA D= class 2
Where are HLA class 1 expressed?
on all ells
How do HLA class 1 work?
Cells present peptide in association with HLA class 1 to CD8 (killer) T cells
Where are HLA class 2 expressed?
only expressed on professional antigen presenting cells (APCs), including dendritic cells, macrophages, B cells
How do HLA class 2 work?
APCs present peptide in association with HLA class 2 to CD4 (helper) T cells
CD4 T cells provide help to B cells
What arthritis is HLA class 1 associated with? And how does it work?
HLA class 1 association (eg HLA-B27 in Ankylosing spondylitis) implicates CD8 T cells in pathogenesis
What arthritis is HLA class 2 associated with? And how does it work?
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
Describe the pattern of joint involvement in rheumatoid arthritis?
Symmetrical
Affects multiple joints (polyarthritis)
Can affects both small and large joints, but nearly always small joints involved particularly hands and feet
What are the commonest joints affected in rheumatoid arthritis? (6)
- Metacarpophalangeal joints (MCP)
- Proximal interphalangeal joints (PIP)
- Wrists
- Knees
- Ankles
- Metatarsophalangeal joints (MTP)
Describe the differences between rheumatoid arthritis and osteoarthritis?
RA: prolonged morning and inactivity stiffness
- PIPJs, MCPJs, wrists
OA: pain worse with activity
- DIPJs, PIPJs, thumb CMC, MCPJs spared
What are the domains of extra-articular features of rheumatoid arthritis?
systemic inflammation
organ-specific
What are the systemic inflammation extra-articular features of RA?
fatigue (v common)
fever
weight loss
What are the organ-specific extra-articular features of RA?
- 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
What happens at subcutaneous nodules in RA?
Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
Do all patients with RA experience subcutaneous nodules?
no, occurs in roughly 30% of patients
What are subcutaneous nodules in RA associated with?
Severe disease
Extra-articular manifestations
Rheumatoid factor
What are the histopathological changes in RA?
What are the cellular and molecular players in RA?
- Autoreactive B cells
(treatment: rituximab) - Autoreactive T cells
(treatment: abatacept) - Cytokines TNF-alpha
Interleukin-6 (Interleukin-1)
(treatment: anti-TNFa, anti-IL6R)
What is in excess (cellular and molecular players) in RA?
Excess of pro-inflammatory vs. anti-inflammatory cytokines (‘cytokine imbalance’)
What is the dominant pro-inflammatory cytokine in the rheumatoid synovium?
The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid
synovium
What are the actions of TNFa in 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)
What is seen in bloods for RA investigations?
inflamm response:
- increased ESR and CRP
- sometimes normocytic anaemia, increased PLT
What are the autoantibodies seen in RA?
Rheumatoid factor (RF) = antibodies that bind IgG
Anti-CCP antibodies
What is the most specific autoantibody for RA?
CCP antibodies most specific for rheumatoid arthritis and associated with more aggressive/erosive disease
When can rheumatoid factor be positive?
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
What predates first clinical symptoms of RA?
ACPAs
What do you seen in X-rays for RA?
What do you see in ultrasounds for RA?
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
What are the negatives of MRI for RA investigations?
MRI can also be used but expensive and time-consuming
it’s better for harder joints to get an US
What is the treatment goal for RA?
prevent joint damage
What does prevention of joint damage in RA require?
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
What are the pharmacological treatments for RA?
glucocorticoids
DMARDs
What should you be careful about with glucocorticoids?
*Glucocorticoid therapy (‘steroids’) useful acutely but avoid long-term use because of side-effects
What are DMARDs?
disease modifying anti-rheumatic. drugs
immunomodulatory drugs that halt or slow the disease process
What is the first and second line treatment for RA?
Do you use NSAIDs for 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
How do glucocorticoids work?
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
What are methods of steroid (glucocorticoid) administration?
Oral prednisolone
Intramuscular (IM)
methyl prednisolone
Intravenous (IV)
Intra-articular (IA)
What are the side effects of steroids?
many and bad!
Cushing’s syndrome
What is the concept of treat to target? And how is it achieved (RA specific)?
suppress disease activity to improve outcome
achieved by regular objective measurement of disease activity e.g., DAS28 score
What is involved in the DAS28 score?
composite of…
no. of tender joints,
no. of swollen joints,
patient visual analogue score (VAS), ESR (or CRP
What happens if DAS28 is not suppressed?
escalate treatment
What are biological therapies?
Biological therapies are proteins (usually antibodies) that specifically target a protein
What are some biologics targeting cytokines? (RA specific)
- Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)
- Inhibition of interleukin-6 (IL-6) signalling
What are examples of Inhibition of interleukin-6 (IL-6) signalling biological therapies?
Antibodies against IL-6 receptor:
Tocilizumab (RoActemra) Sarilumab (Kevzara)
What are examples of Inhibition of tumour necrosis factor-alpha (‘anti-TNF’) biological therapies?
antibodies (infliximab, adalimumab, golimumab, certolizumab) fusion proteins (etanercept)
What are some biologicals that target lymphocytes? (RA specific)
- B cell depletion
- rituximab - Blocking T cell co-stimulation
- abatacept
How does rituximab work and how is it given?
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
What are the side effects of rituximab?
infusion reactions, infection, hypogammaglobulinaemia
How does abatacept work?
Abatacept - fusion protein - extracellular domain of CTLA-4 linked to modified Fc portion of human
immunoglobulin G1
What do T cells need to activate? And which one does Abatacept block?
T cells require 2 signals to activate:
i) MHC + peptide on APC binding to TCR on T cell
ii) CD80/CD86 on APC binding to CD28 on T cell
Abatacept blocks signal 2
Why is seronegative inflammatory arthritis called seronegative?
Unlike rheumatoid arthritis, RF and CCP antibodies not present in blood (“seronegative”)
BUT they are immune-mediated
What are seronegative inflammatory arthritis?
Family of conditions with overlapping clinical features and pathogenesis
What is psoriasis?
Psoriasis is an immune mediated disease affecting the skin
scaly red plaques on extensor surfaces (eg elbows and knees)
roughly 10% of patients also have joint inflammation
rheumatoid factor not present so seronegative
What is the dominant pathogenic pathway in psoriatic arthritis?
Dominant pathogenic pathway is interleukin-17/interleukin-23 (IL17-IL23)
Does severity of the psoriasis affect the severity of the arthritis?
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
What are other symptoms of psoriatic arthritis?
nail pitting
onycholysis
dactylitis (sausage fingers) due to enthesis
How would you describe the clinical presentation of psoriatic arthritis?
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)
What is reactive arthritis?
Sterile inflammation in joints following infection elsewhere in the body
- Reactive arthritis NOT the same as infection in joints (septic arthritis)
What are the common infections leading to ractive arthritis?
urogenital (e.g. Chlamydia trachomatis)
gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections)
What are important extra-articular manifestations for reactive arthritis?
Enthesitis (tendon inflammation)
Skin inflammation
Eye inflammation
What may reactive arthritis be the first manifestation of?
Reactive arthritis may be first manifestation of HIV or hepatitis C infection
In who is reactive arthritis common?
Commonly young adults with genetic predisposition (e.g. HLA-B27) and environmental trigger (e.g. Salmonella infection)
When do symptoms of reactive arthritis start?
Symptoms follow 1-4 weeks after infection and this infection may be mild
What are the differences between reactive and septic arthritis?
*antibiotics not indicated for joints, but may be warranted to treat underlying infection in the case of STI
The overall classification of arthritis.
