5.7 - Introduction to Rheumatology Part 2 Flashcards
What is the structural classification of joints?
- fibrous joints
- cartilaginous joints
- synovial joints
What is the functional classification of joints?
- synarthroses
- amphiarthroses
- diarthroses
Define and give examples of fibrous joints.
- no space between the bones
- e.g. sutures in skull, syndesmosis (sheet of connective tissue) in tibia and fibula joint (ankle)
Define and give examples of cartilaginous joints.
- joints in which the bones are connected by cartilage
- e.g. joints between spinal vertebrae
Define and give examples of synovial joints.
- have a space between the adjoining bones (synovial cavity)
- this space is filled with synovial fluid
What are synarthroses and which joint structures do they belong to?
- generally allow no movement
- fibrous and cartilaginous joints can be this type
What are amphiarthroses and which joint structures do they belong to?
- allow very limited movement
- fibrous and cartilaginous joints can be this type
What are diarthroses and which joint structures do they belong to?
- allow for free movement of the joint
- synovial joints are the type
What are the components of a synovial joint?
- bone
- articular cartilage
- joint cavity containing synovial fluid
- articular cartilage
- bone
What is a synovium made up of?
- 1-3 cell deep lining containing macrophage-like phagocytic cells (type A synoviocyte) and fibroblast-like cells that produce hyaluronic acid (type B synoviocyte)
- type I collagen
What is synovial fluid made up of?
Hyaluronic acid-rich viscous fluid
What is articular cartilage made up of?
- ECM: type II collagen, water, proteoglycans (mainly aggrecan)
- chondrocytes - specialised cells
- avascular - no blood supply, so it heals poorly after injury
Describe aggrecan.
- a proteoglycan that possesses many chondroitin sulfate and keratin sulfate chains
- characterised by its ability to interact with hyaluronan (HA) to form large proteoglycan aggregates
What is rheumatoid arthritis?
- chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis
- primary site of pathology is in the synovium
- synovitis - inflammation of synovial membrane
- synovium found at synovial (diarthrodial) joints, tenosynovium surrounding tendons and bursa
What are the key features of rheumatoid arthritis?
- chronic arthritis
- polyarthritis
- early morning stiffness in and around joints
- may lead to joint damage and destruction - ‘joint erosions’ on radiographs
- extra-articular disease can occur
- auto-antibodies may be detected in blood (against IgG) - rheumatoid factor
What is the pattern of joint involvement in rheumatoid arthritis?
- symmetrical
- affects multiple joints (polyarthritis)
- affects small and large joints, but particularly hands, wrists and feet
- commonest affected joints: metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), wrists, knees, ankles, metatarsophalangeal joints (MTP)
- tends to spare DIP joints in contrast to osteoarthritis
What are the common extra-articular features of rheumatoid arthritis?
- fever
- weight loss
- subcutaneous nodules
What are the uncommon extra-articular features of rheumatoid arthritis?
- lung disease - nodules, fibrosis, pleuritis
- ocular inflammation - episcleritis
- vasculitis - blood vessel
- neuropathies - nerve damage = motor weakness/loss of sensation
- Felty’s syndrome - triad of splenomegaly, leukopenia and rheumatoid arthritis
- amyloidosis - chronic untreated inflammation
What are subcutaneous nodules?
- found just distal to elbow and on fingers
- characterised by central area of fibrinoid necrosis surrounded by histiocytes (macrophages) and peripheral layer of connective tissue
- occur in 30% of patients
- associated with severe disease, extra-articular manifestations, rheumatoid factor
What is the pathogenesis of rheumatoid arthritis?
- synovial membrane is abnormal
- synovium becomes a proliferated mass of tissue (pannus) due to:
- neovascularisation - formation of new blood vessels
- lymphangiogenesis - formation of new lymph vessels
- inflammatory cells - activated B and T, plasma, mast, activated macrophages
- recruitment, activation and effector functions of these cells is controlled by a cytokine network
- there is an excess of pro-inflammatory vs anti-inflammatory cytokines
What is the dominant pro-inflammatory cytokine and what effects does it have?
- TNF-alpha in the rheumatoid synovium
- has pleotropic actions (affects multiple processes)
- activates osteoclasts –> bone resorption to bone erosion
- affects synoviocytes –> joint inflammation and swelling
- activates chondrocytes –> cartilage degradation –> joint space narrowing
- angiogenesis, leukocyte accumulation, endothelial cell activation, chemokine release, proinflammatory cytokine release, hepcidin induction, PGE2 production
How is TNF-alpha treated?
TNF-alpha inhibition has been successful using parenteral administration (subcutaneous injection usually) of antibodies / fusion proteins
What are blood test results like for rheumatoid arthritis (RA), osteoarthritis (OA) and septic arthritis (SA)?
- Hb - decreased/normal, normal, normal
- MCV - normal, normal, normal
- white cell count - normal, normal, increased (leukocytosis)
- platelet count - normal/increased, normal, normal/increased
- ESR - increased, normal, normal/increased
- CRP - increased, normal, increased
What is rheumatoid factor?
- antibody found in the blood of RA patients
- antibodies that recognise the Fc portion of IgG as their target antigen
- typically IgM antibodies e.g. IgM anti-IgG antibody
- positive in 70% at disease onset and further 10-15% become positive over first 2 years of diagnosis
What are antibodies to citrullinated protein antigens (ACPA)?
- antibody found in the blood of RA patients
- highly specific for RA
- sometimes called anti-cyclic citrullinated peptide antibodies (anti-CCP antibody)
- citrullination of peptides is mediated by peptidyl arginine deaminases (PADs) which convert arginine to citrulline
How can X-rays be used to image RA?
- soft tissue swelling
- peri-articular osteopenia - darkening of bone
- bony erosions
- erosions only occur in established disease - the aim of modern therapy is to treat early before erosions (permanent damage) has ocurred
- information from X-rays is limited to bony structures
How is ultrasound (US) used to image RA?
- much better test for detecting synovitis - detects:
- synovial hypertrophy (thickening)
- increased blood flow (seen as doppler signal)
- may detect smaller 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
Why is MRI not used much to image RA?
Can also be used but is expensive and time-consuming
Describe the principles of management of RA.
- treatment goal - prevent joint damage (irreversible)
- requires:
- early recognition of symptoms, referral and diagnosis
- prompt initiation of treatment: joint destruction = inflammation x time
- aggressive pharmacological treatment to suppress inflammation
- MDT input where needed e.g. physiotherapy, occupational therapy, surgery
What are pharmacological treatment options for RA?
- glucocorticoid therapy (steroids) - useful acutely but avoid long-term use due to side-effects
- NSAIDs (non-steroidal anti-inflammatory drugs e.g. ibuprofen) - symptoms relief but increasingly less important
- DMARDs (disease-modifying anti-rheumatic drugs) - drugs that control the disease process (usually immunosuppressive)
What is the first line treatment regime for RA?
- IM or short course of oral steroids
- start combination DMARD therapy - usually methotrexate + hydroxychloroquine and/or sulfasalazine
What is the second line treatment regime for RA?
- biological therapies offer potent and targeted treatment strategies
- new therapies include Janus Kinase inhibitors - Tofacitinib & Baricitinib
How does steroids/glucocorticoid therapy work?
- glucocorticoids bind the glucocorticoid receptor (GR)
- GR resides in cytoplasm
- on binding to glucocorticoids, steroid-GR complex translocates to nucleus and binds DNA response elements, affecting transcription
What are methods of steroid administration?
- oral prednisolone
- intramuscular (IM) methyl prednisolone
- intravenous (IV)
- intra-articular (IA)
What are the side effects of steroids?
- Cushing’s syndrome
- mood disturbance - mania, depression, anxiety
- cataracts
- sleep apnoea (weight gain)
- increased BP, CVD risk
- T2DM
- weight gain, central obesity
- osteoporosis
- skin thinning
- myopathy
- increased infection risk
What is the mechanism for methotrexate?
- inhibits dihydrofolate reductase (‘folate antagonist’)
- side effects: nausea, hair loss, fall in white cell count, abnormal liver function, pneumonitis, infection risk
How do biological therapies work?
- biological therapies are proteins (usually antibodies) that specifically target a protein such as an inflammatory cytokine
- inhibition of TNF-alpha
- B cell depletion
- modulation of T-cell co-stimulation
- inhibition of IL-6 signalling
What is seronegative arthritis?
- rheumatoid factors not present
- psoriatic arthritis
- reactive arthritis
- ankylosing spondylitis
- IBD-associated
- subacute/chronic
- mono/oligo large joint
- may involve spine
- asymmetrical
What is psoriatic arthritis?
- psoriasis is an autoimmune disease affecting the skin
- scaly red plaques on extensor surfaces (e.g. elbows and knees)
- 10% of psoriasis patients also have joint inflammation
- unlike RA, rheumatoid factors are not present (seronegative)
How does psoriatic arthritis present clinically?
- varied clinical presentations
- classically asymmetrical arthritis affecting IPJs
Can also manifest as:
- symmetrical involvement of small joints (rheumatoid pattern)
- oligoarthritis of large joints
- arthritis mutilans
- spinal and sacroiliac joint inflammation
How do we investigate psoriatic arthritis and what would we see?
- X-rays of affected joints - pencil in cup abnormality
- MRI - sacroiliitis and enthesitis (inflammation of where a tendon/ligament attaches to bone)
- bloods - no antibodies as it is seronegative
How do we manage psoriatic arthritis?
- DMARDs - methotrexate
- avoid oral steroids - risk of pustular psoriasis due to skin lesions
What is reactive arthritis?
- sterile inflammation in joints following infection elsewhere in the body
- common infections - urogenital (e.g. Chlamydia trachomatis), GI (e.g. Salmonella, Shigella, Campylobacter infections)
What are the important extra-articular manifestations of reactive arthritis?
- enthesitis (tendon inflammation)
- skin inflammation
- eye inflammation
- may be the first manifestation of HIV or hepatitis C infection
Who does reactive arthritis affect 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
What are the differences between reactive arthritis and septic arthritis?
- reactive arthritis not the same as infection in joints (septic arthritis) where there is active infection in joint, but with reactive arthritis it is sterile = infection has cleared
- synovial fluid culture: +ve for SA, sterile for RA
- antibiotic therapy: yes for SA, no for RA
- joint lavage: yes (for large joints) for SA, no for RA
What is the pathophysiology of ankylosing spondylitis?
- characterised by enthesitis - inflammation of entheses (sites where tendon and ligaments join to bone)
- large genetic component
- many genetic variants associated with the disease (polygenic)
- HLA-B27 is the strongest genetic risk factor
- HLA-B27 is positive in 90% of AS, 10% in general population
- used as a diagnostic biomarker but HLA-B27 +ve alone does not equal AS
- cytokines play an important role in pathogenesis - TNF-alpha, IL-17, IL-23
- aberrant peptide processing pathways (aminopeptidases) in the endoplasmic reticulum
What is the natural history of untreated AS?
Spinal enthesitis –> bridging syndesmophytes (new bone growth between adjacent vertebra) –> spinal fusion
What can MRIs detect in ankylosing spondylitis?
MRI can detect spinal inflammation before X-rays changes develop
How is ankylosing spondylitis managed?
- physiotherapy and a life-long regular exercise programme
- pharmacological:
- 1st line - NSAIDs e.g. ibuprofen, naproxen, diclofenac
- mechanism: NSAIDs inhibit cyclooxygenase 1&2
- risks: peptic ulcer, renal, asthma exacerbation, increased atherothrombosis risk
- selective COX2 inhibitors reduce GI ulcer risk
- 2nd line: biological therapies
- therapeutic monoclonal antibodies targeting specific molecules
- use if inadequate disease control after trying 2 NSAIDs
- anti-TNF-alpha
- anti-IL17
What is lupus?
A multi-system autoimmune disease
What body parts does systemic lupus erythematous usually affect?
- multi-site inflammation - can affect almost any organ
- often joints, skin, kidneys, haematology, lungs, CNS
- said to be a great mimic - can present as seeming like a lot of other diseases
- malar / butterfly rash common
What is systemic lupus erythematous associated with?
Antibodies to self antigens (autoantibodies) directed against components of the cell nucleus (nucleic acids and proteins)
What are clinical tests for systemic lupus erythematous?
- antinuclear antibodies (ANA) - high sensitivity for SLE but not specific - a negative test rules out SLE but a positive test does not mean SLE
- anti-double stranded DNA antibodies (anti-dsDNA Abs) - high specificity for SLE in the context of the appropriate clinical signs
Who does systemic lupus erythematous affect more?
- F:M ratio 9:1
- presentation 15-40 years
- increased prevalence in African and Asian ancestry populations
- prevalence varies 4-280 per 100k
