Rheumatoid Arthritis Flashcards
What is rheumatology?
medical speciality of diseases of the MSK system
What is a tendon?
cords of strong fibrous collagen tissue attaching muscle to bone
What is a ligament?
flexible fibrous tissue which connects 2 bones
What is synovium?
1-3 deep cell lining containing:
- macrophage-like phagocytic cells (type A synoviocyte)
- fibroblast-like cells that produce hyaluronic acid (type B synoviocyte)
What is synovial fluid?
hyaluronic acid-rich viscous fluid
What is articular cartilage made of?
- Type 2 collagen
- proteoglycan (aggrecan)
What is arthirtis?
Disease of the joints
What are the main 2 different types of arthritis?
- osteoarthritis (degenerative)
- inflammatory (rheumatoid)
What is inflammation?
a physiological response to deal with injury or infection
How does inflammation manifest?
- red
- painful
- hot
- swelling
- loss of function
What are the physiological, cellular and molecular changes caused by inflammation?
- increased blood flow
- WBC migration (leukocytes) into tissues
- activation/differentiation of leucocytes
- cytokine production
What are the different causes of joint inflammation?
- crystal arthritis (gout/pseudogout)
- immune-mediated
- infection
What are the different infectious causes of joint inflammation?
- septic arthiritis
- tuberculosis
Which causes of joint inflammation are primary and secondary?
- immune mediated = primary inflammation
- infection and crystal arthiritis = secondary inflammation in response to noxious insult
Which causes of inflammation are sterile and non sterile?
- crystal arthirtis and immune-mediated = sterile
- infection = nonsterile
What should be assumed when a patient presents with an acute hot, swollen joint
Septic arthiritis because it is a medical emergency
What is the key investigation for septic arthiritis?
Joint aspiration, send fluid for gram stain and culture
What is the management for septic arthiritis?
- Joint lavage
- IV antibiotics
What are some examples of different immune-mediated causes of joint inflammation?
- rheumatoid arthritis
- seronegative spondyloarthropathies
- connective tissue diseases
What is gout?
a syndrome caused by the deposition of uric crystals leading to inflammation
What is pseudogout?
a syndrome cause by the deposition of calcium pyrophosphate dehydrate (CPPD) crystal deposition.
What is tested in a synovial fluid test?
- gram stain, culture and ABx sensitivity
What is rheumatoid arthritis?
- chronic autoimmune disease
- characterised by pain, stiffness and symmetrical synovitis
What is synovitis?
Inflammation of the synovial membrane
What happens in rheumatoid arthritis?
synovium becomes a proliferated mass of tissue (pannus)
What is the aetiology of rheumatoid arthiritis?
Genetic and environmental
What are some environmental risk factors for rheumatoid arthirits?
- smoking
- microbiome
- P. gingivalis
- poor oral health
What do both smoking and P. gingivalis cause?
Citrullination of proteins in the lung epithelium
What are the genetic risk factors for rheumatoid arthiritis?
- female sex
- HLA-DR shared epitope
- cumulative genetic burden of other genetic loci (polygenic disease)
What are class 1 HLAs?
- HLA A, B and C
- expressed on all cells
- presented with antigen to CD8 T cells
What are class 2 HLAs?
- HLA D
- only expressed on APCs
- presented with antigen to CD4 T cells which stimulates B cells
Why are autoantibodies found in rheumatoid arthirtis but not ankylosing spondylitis?
- ankylosing spondylitis is associated with class 1 HLA (HLAB27)
- rheumatoid arthirits associated with class 2 HLA (HLADR4)
- only class 2 HLAs stimulate B cells which secrete antibodies
What causes the synovium to become a proliferated mass of tissue?
- neovascularisation
- lymphangiogenensis
- activated B and T cells
- plasma cells
- mast cells
- activated macrophages
- excess of pro-inflammatory cytokines
What is the dominant pro-inflammatory cytokine in rheumatoid arthritis?
- TNF-alpha
- IL-6, IL-1
- produced by activated macrophages
Which cells are invloved in the pathogenesis of rheumatoid arthiritis?
Autoreactive B and T cells
What is the impact of the excess TNF-alpha production?
- osteoclast activation
- chemokine release
- endothelial cell activation
- leukocyte accumulation
- angiogenesis
- lymphangiogenesis
- inflammatory cell recruitment
- matrix metalloproteinases
- chondrocyte activation
- pro-inflammatory cytokine release
What causes pannus formation?
- inflammatory cell recruitment
- angiogenesis
- lymphangiogenesis
What do matrix metalloproteinases cause?
Cartilage loss
What does osteoclast activation cause?
bone loss
What are the key features of rheumatoid arthritis?
- chronic
- polyarthritis (swelling of small joints)
- symmetrical
- early morning stiffness
- may cause joint damage and destruction
- rheumatoid nodules
- systemic with extra-articular manifestations
- autoantibodies usually detected in blood
What can be used to detect rheumatoid arthritis?
rheumatoid factor, autoantibody against IgE
What are the most commonly affected joints with rheumatoid arthritis?
- Metacarpophalangeal joints (MCP)
- Proximal interphalangeal joints (PIP)
- Wrists
- Knees
- Ankles
- Metatarsophalangeal joints (MTP)
- nearly always invloves small joints
Where are the primary sites of the pathology of rheumatoid arthritis?
- synovial joints
- tenosynovium surrounding tendons
- bursa
What are the extra-articular features of rheumatoid arthritis?
- fever
- fatigue
- weight loss
- subcutaneous nodules
- vasculitis
- ocular inflammation
- neuropathies
- amyloidosis
- lung disease (nodules, fibrosis and pleuritis)
- Felty’s syndrome
What is Felty’s syndrome?
- splenomegaly
- leukopenia
- rheumatoid arthritis
What are subcutaneous nodules in rheumatoid arthritis?
central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
What are subcutaneous nodules associated with?
- severe disease
- extra-articular manifestations
- rheumatoid factor
Where do subcutaneous nodules tend to be found?
- the ulnar border of the forearm
- in the hands
Which blood tests are done for rheumatoid arthiritis?
- ESR
- CRP
- PLT
- autoantibodies
- all increased
What antibodies are found in those with rheumatoid arthritis?
- rheumatoid factor
- antibodies to citrullinated protein antigens (anti-CCP)
Is rheumatoid factor only present in people with rheumatoid arthiritis?
No
What imaging is done for rheumatoid arthiritis?
- X-ray
- US (best at picking it up early)
- MRI
What are the features of rheumatoid arthiritis which show on a radiograph?
- soft tissue swelling
- peri-articular osteopenia
- bony erosions
- limited to information on bony structures only
Which ultrasound changes are seen in rheumatoid arthirtis?
- synovial thickening
- increased blood flow
- erosions which can’t be seen on plain radiograph
Which imaging is used in sn early arthiritis clinic?
Ultrasound
What does rheumatoid arthritis treatment require?
- Early recognition of symptoms, referral and diagnosis
- Prompt initiation of treatment
- Aggressive treatment to suppress inflammation
- multidisciplinary input
- goal is to prevent joint damage
What are the main pharmological treatments for rheumatoid arthiritis?
- glucocorticoid therapy (acute use)
- disease-modifying anti-rheumatic drugs (DMARDS)
What is the action of glucocorticoids?
- bind to GR receptor in cytoplasm
- steroid-GR complex translocates to nucleus and binds to DNA
- affects transcription
What are the different methods of steroid administration?
- oral
- intramuscular
- intravenous
- intra-articular
What are the side effects of steroid use?
Cushing’s syndrome
What is the first line treatment of rheumatoid arthritis?
- DMARD therapy (methotrexate in combination with hydroxychloroquine or sulfasalazine)
- IM or oral steroids
What is the second line treatment of rheumatoid arthritis?
- Biological therapies offer potent and targeted treatment strategies
- New therapies include Janus Kinase inhibitors : Tofacitinib & Baricitini
What are the targets of the biologics used in the treatment of rheumatoid arthritis?
- Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)
- B cell depletion
- Modulation of T cell co-stimulation
- Inhibition of IL-6 signalling
What is treat to target?
- suppress disease activity to improve outcome
- uses DAS28
What is DAS28?
- score, if not suppressed then escalate treatment
- number of tender joints
- number of swollen joints
- patient visual analogue score
- ESR/CRP
What is the mechanism of infliximab and etanercept?
- Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)
- infliximab targets antibodies
- entanercept targets fusion proteins
What is the mechanism of rituximab?
- B cell depletion
- antibody against B cell antigen CD20
What is the mechanism of Abatacept?
- Modulation of T cell co-stimulation
- blocks CD80/CD86 on APC binding to CD28 on T cell
What is the mechanism of Tocilizumab and Sarilumab?
Inhibition of interleukin-6 signalling
What is seronegative arthiritis?
- inflammatory arthiritis where RF and CCP antibodies are not present in blood
- still immune mediated
What are the different types of seronegative arthiritis?
- psoratic arthiritis
- reactive arthiritis
- ankylosing spondylitis
- IBD-associated arthiritis
What is reactive arthritis?
- Sterile inflammation in joints following infection
- especially urogenital (e.g. Chlamydia trachomatis) and gastrointestinal (e.g. Salmonella, Shigella, Campylobacter infections) infections
What are the extra-articular features of reactive arthritis?
- Enthesitis (tendon inflammation)
- Skin inflammation
- Eye inflammation
What can reactive arthritis be a sign of?
- HIV
- Hep C
What are the risk factors of reactive arthritis?
- genetic predisposition (HLA-B27) and environmental trigger
How long does it take for reactive arthritis to present after an infection?
1-4 weeks
What is Psoriasis?
- an autoimmune disease affecting the skin
- scaly red plaques on extensor surfaces eg elbows and knees
- 10% of patients have joint inflammation
What is the dominant pathogenic pathway for psoratic arthiritis?
IL-17 and IL-23
What is the relationship between skin disease and joint manifestations of psoratic arthiritis?
- skin disease severity is not correlated to joint manifestations
- nail changes may be the only skin manifestations
- need to carefully examine the skin for small areas of psoriasis
How does Psoriatic arthritis present?
- Classically asymmetrical arthritis affecting IPJs
- Enthisitis
- Symmetrical involvement of small joints (rheumatoid pattern)
- Spinal and sacroiliac joint inflammation
- Oligoarthritis of large joints
- Arthritis mutilans
What is lupus?
a multi-system autoimmune disease associated with antibodies to self antigens (‘autoantibodies’) which are directed against components of the cell nucleus
What is associated with lupus?
- Multi-site inflammation: can affect any almost any organ.
- Often joints, skin, kidneys, haematology.
- Also: lungs, CNS involvement
What clinical tests can be done when lupus is suspected?
- Antinuclear antibodies (ANA)
- Anti-double stranded DNA antibodies (anti-dsDNA Abs):
Why are antinuclear antibodies measured for suspected lupus?
- High sensitivity for SLE but not specific.
- A negative test rules out SLE, but a positive test does not mean SLE.
Why are Anti-double stranded DNA antibodies measured for suspected lupus?
High specificity for SLE in the context of the appropriate clinical signs.
When is lupus most common?
- 15-40 years old
- asian and african populations
What is management plan for Ankylosing spondylitis?
- physiotherapy
- exercise regimes
- NSAIDs
- peripheral joint deposition (DMARDs)
Can you definitively test for Ankylosing spondylitis?
no, seronegative spondyloarthropathy – no positive autoantibodies
What happens in Ankylosing spondylitis?
- Chronic sacroillitis (inflammation of sacroiliac joints)
- Results in spinal fusion (ankylosis) and deformity
What is Ankylosing spondylitis associated with?
HLA B27
When is Ankylosing spondylitis most common?
- 20-30 years old
- male
What tests should be done in suspected Ankylosing spondylitis?
- FBC
- CRP, ESR
- test for HLA-B27
- XR
- MRI
What would blood tests show in Ankylosing spondylitis?
FBC: normocytic anaemia
CRP, ESR: raised
HLA-B27: present
What would imaging (MRI/XR) show in Ankylosing spondylitis?
- Squaring Vertebral bodies, Romanus lesion
- Erosion, sclerosis, narrowing SIJ
- Bamboo Spine
- Bone Marrow Oedema
What are some other examples of connective tissue disorders?
- Systemic Sclerosis
- Myositis
- Sjogrens syndrome
- Mixed connective tissue disease
What is the site of inflammation in Ankylosing spondylitis?
enthesis
what are the seronegative spondyloarthropathies?
- Ankylosing spondylitis
- Reactive Arthritis (Reiters syndrome)
- Psoriatic arthritis
- Arthritis associated with GI inflammation (enteropathic synovitis)
What is SLE?
Chronic tissue inflammation in the presence of antibodies directed against self antigens
(multi-site inflammation: joints, skin and kidney)
What autoantibodies are associated with SLE?
- Antinuclear antibodies
- Anti-double stranded DNA antibodies
- Anti-phospholipid antibodies
What are the connective tissue diseases?
- SLE
- Sjogren’s syndrome
- Autoimmune Inflammatory muscle disease
- Systemic sclerosis (scleroderma)
- Overlap syndromes
What is common in connective tissue disorders?
Reynaud’s phenomenon
What is Reynaud’s phenomenon?
Intermittent vasospasm of digits on exposure to cold
(white to blue to red)
- leads to blanching of digit
- Cyanosis as static venous blood deoxygenates
- Reactive hyperaemia
What information do serum autoantibodies provide?
- correlate to disease activity
- directly pathogenic
- can aid in diagnosis
What is typically non-erosive?
- arthralgia
- arthritis
When is SLE typically diagnosed?
in females aged 15-45 years old
What are the different clinical manifestations of SLE?
- Malar rash
- Photosensitive rash
- Mouth ulcers
- Hair loss
- Raynaud’s phenomenon
- Arthralgia and sometimes arthritis
- Serositis (pericarditis, pleuritis, less commonly peritonitis)
- Renal disease – glomerulonephritis (‘lupus nephritis’)
- Cerebral disease – ‘cerebral lupus’ e.g. psychosis
What is a Malar rash?
erythema that spares the nasolabial fold
What is the pathogenesis of SLE?
- Apoptosis leads to translocation of nuclear antigens to membrane surface
- Impaired clearance of apoptotic cells results in enhanced presentation of nuclear antigens to immune cells
- B cell autoimmunity
- Tissue damage by antibody effector mechanisms e.g. complement activation and Fc receptor engagement
What are anti-phospholipid antibodies associated with?
risk of arterial and venous thrombosis
What autoantibodies are associated with systemic vasculitis?
antinuclear cytoplasmic antibodies (ANCA)
What is the significance of antinuclear antibodies in SLE?
- seen in all SLE cases
- not specific for SLE
What is the significance of anti-double stranded DNA antibodies in SLE?
- specific to SLE
- serum level correlates to disease activity
What is the significance of anti-phospholipid antibodies in SLE?
- associated with risk of arterial and venous thrombosis in SLE
- may also occur in absence of SLE in what is termed the ‘primary anti-phospholipid antibody syndrome
What is the significance of anti-Sm antibodies in SLE?
- specific to SLE
- serum level does not correlate to disease activity
What is the significance of anti-Ro and Anti-La antibodies in SLE?
- secondary sjögren’s syndrome
- neonatal lupus syndrome (transient rash, permanent heart block)
What is the significance of anti-ribosomal P antibodies in SLE?
cerebral lupus
What are the two different types of twin studies?
- monozygotic twins = identical DNA
- dizygotic twins = share 50% DNA
What does the concordance rate of twin studies indicate?
- concordance rate of monozygotic twins higher than dizygotic twins indicates genetic cause
- if a disease is purely genetic the concordance rate for monozygotic twins is 100% the disease is purely genetic
