Week 2 Flashcards
RA - aetiology, and how is it mediated?
- Can affect both sexes, but women are 3 times as commonly affected
- Can affect any age group
- Cause is unknown
- Potential triggers could include infections, stress and cigarette smoking
- HLA-DR4 mediated
Main structure affected in RA is the synovium. Name some synovium-lined joints
- C1/C2 joint in the spine
- Hands
- Wrists
- Elbows
- Shoulders
- TMJs
- Knees
- Hips
- Ankles
Importantly, which joints are spared in RA?
DIP joints are not affected by RA due to low amounts of synovial fluid.
This is an important diagnostic distinction from other forms of arthritis.
Tendon sheaths can also become inflamed (appears as something similar to a large ganglion cyst)
Generally speaking, what is the difference between RA and OA regarding pathological mechanism?
RA - inflammation/swelling of synovial membrane
OA - loss of/thinning of cartilage, leading to bone-on-bone abrasion and “creaking”
What does “pannus” mean? When is it present?
Pannus is the term for spongy inflammation felt at a joint in RA. Release of inflammatory cytokines by e.g. macrophages, dendritic cells, B and T cells etc. cause damage to the joint, and this must be treated relatively quickly in order to prevent permanent damage.
Osteoclasts are also present, and ‘eat up’ bone.
Pannus is seen in RA but not seen in OA
What pro-inflammatory cytokines are released by macrophages in RA?
Name some medications that target each of these.
What medications can be used to target B cells producing antibody and to blockade T cell co-stimulation?
- TNF-alpha
- infliximab, etanercept, adalimumab, certolizumab, golimumab
- IL-1
- anakinra
- IL-6
- tocilizumab
Rituximab can be used to target B cells, and abatacept can be used to prevent T cell co-stimulation
What is the name of the new classification system for RA, and what categories does it contain?
ACR/EULAR classification criteria for RA (2010)
- Joint distribution
- Serology
- Symptom duration
- Acute phase reactants
Greater than or equal to 6 score = RA
What investigations could be performed if RA is suspected?
History and clinical examination - forms the bulk of the diagnosis
- Pain?
- Stiffness? (early in the morning? Lasting longer than 30 mins?)
- Swelling?
- Symmetrical? DIP joints spared?
Blood tests - anaemia due to chronic disease? Raised plateletes?
Inflammatory markers present? (CRP, ESR/plasma viscosity)
Screen for autoantibodies - may be present, but absence does not mean disease isn’t present
Imaging - changes can only be seen after damage has occurred
What quick physical test can be performed if RA is suspected?
Squeeze test of hands/feet - areas will be very sensitive in patients with RA
What are some of the clinical presentations that could be seen with RA?
- PIPs, MCPs, wrist inflammation
- Monoarthritis, progressing to polyarthritis
- Tenosynovitis, inflammation in the fluid surrounding tendon sheaths
- Trigger finger
- Carpal tunnel syndrome, compression of nerve
- Polymyalgia rheumatica, pain/weakness/stiffness in shoulders
- Palindromic rheumatism
- Systemic symptoms
- Poor grip strength
What auto-antibodies can be tested for in RA?
Rheumatoid factor (rheumatoid IgM) - somewhat old-fashioned
- sensitivity 50-80%
- specificity 70-80% - not confirmatory!
Cyclic citrullinated peptide antibodies (anti-CCP antibodies)
- sensitivity 60-70%
- Specificity 90-99% - almost certain!
- can be present for several years prior to symptoms
- co-related with disease activity
- also associated with a previous or current smoking history
- patients will remain anti-CCP-positive despite treatment
In terms of imaging, what is the gold standard for RA patients?
MRI - bone marrow oedema on MRI is associated with inflammatory joint disease and be a forerunner of erosion
Also allows assessment of tendon intergrity, can be used to monitor disease activity and allows for earlier detection of erosions.
Cost is prohibitive
What system is used to assess disease activity in RA patients?
DAS28 scoring - 28 separate areas on the body
- Objective, patient’s response to treatment can be measured
- Score cut offs
- >5.1 = active disease
- 3.2 - 5.1 = moderate disease
- 2.6 - 3.2 = low disease activity
- <2.6 = disease is in remission
RA - management
- Aim for early recognition and diagnosis to prevent permanent changes
- Involve care with a rheumatologist and a multi-disciplinary team
- Early use of DMARDs in all patients (disease-modifiying anti-rheumatic drugs)
- Use of NSAIDs and steroids only as adjuncts
- patients may be started on a combo therapy of DMARD and steroid, and gradually weaned off the latter - important not to suddenly stop treatment!
- Patient education
DMARDs - examples and order of treatment
-
Methotrexate (1st line) start at 15mg a week with rapid escalation. Max dose is 25mg a week (systemic toxicity can develop), then add in the following order…
- Sulfasalazine
- Hydroxychloroquine - doesn’t prevent erosions!
- Leflunomide
- Gold injections, penicillamine, azathioprine - hardly ever used now
What important side effect should patients be aware of with use of methotrexate?
Methotrexate use has a risk of pneumonitis, so if patients experience SoB/dry cough etc. they need to notify their GP immediately and look at alternative medications
Methotrexate is also teratogenic, so advise effective contraception
Provide some examples of biologics.
What important side effect should be kept in mind?
- anti-TNF-alpha agents - Infliximab, Etanercept, Adalimumab, Certolizumab, Golimumab
- T cell receptor blockers - Abatacept
- B cell depletor - Rituximab
- IL-6 blocker - Tocilizumab
Use of these leaves the patient at increased risk of infection. If the patient has a latent TB infection present in the lungs as granulomas, these could break down and lead to a development of active infection.
Biologics are expensive! What are the guidelines for use of biologics in the UK?
What is always co-prescribed?
Failure to respond to 2 DMARDs including methotrexate and DAS28 greater than 5.1 on two occasions 4 weeks apart.
Methotrexate is also always co-prescribed when giving biologics
What is the primary target of treatment in RA?
Remission
This is defined as the absence of signs and symptoms of significant inflammatory arthropathy.
What are some of the complications of untreated RA?
- Joint damage and deformities - swan necking of the fingers
- Boutonniere deformity of the thumb (loss of space between thumb and palm)
- Subluxation and loss of fat pad at the soles of the feet, feels like walking on pebbles/marbles
- Atlanto-axial subluxation - odontoid process is eroded away leading to spinal cord compression
Osteoarthritis - general description of pathophysiology
Progressive degenerative condition affecting the joints due to a gradual thinning of the cartilage, loss of joint space and the formation of bony spurs (osteophytes)
What is cartilage mostly made up of? How is this affected in osteoarthritis?
Cartliage is mostly made up of Type II collagen, and the matrix is formed by the chondrocytes which are embedded within it.
In disease…
- loss of matrix
- release of inflammatory cytokines by the chondrocytes - IL-1, TNF alpha, metalloproteinases, prostaglandins
- fibrillation of the cartilage surface and attempted repair with osteophyte formation
Osteoarthritis - symptoms
- gradual onset, taking months to years
- mechanical pain i.e. worse on activity and at the end of the day, relieved by rest
- Crepitus - grinding/creaking of the joints
- Stiffness for less than 30 minutes
- Bony swellings and joint deformities
- can result in effusions and soft tissue swelling
Osteoarthritis - commonly affected areas
- Neck
- Lower back
- Hips
- Base of thumbs
- Ends of fingers - DIPs, PIPs and 1st CMC joints, not red, hot or “spongy” as in RA
- Knees
- Base of big toe
What are bony enlargements called when they are…
- seen at DIPs
seen at PIPs?
- DIPs - Heberden’s nodes
- PIPs - Bouchard’s nodes
What deformities may be seen at the knees in osteoarthritis?
- Genu varus - bowing of the legs
- Genu valgus - knock-knees
- Baker’s cysts
Osteoarthritis - risk factors
- Age - typically 40+
- Gender - more common in women
- Genetic factors
- Occupation - heavy lifting, repetitive strain
- Previous injury/joint abnormalities
- Obestiy
- Other underlying health conditions e.g. RA, gout etc.
Osteoarthritis - investigations
- Inflammatory markers will usually appear normal!
- Rheumatoid factor will appear negative
- Anti-CCP antibody will also appear negative
- X-ray changes
- joint space narrowing
- subchondral sclerosis
- bony cysts
- osteophytes
Osteoarthritis - management (pharmacological and non-pharmacological)
Pharmacological
- Analgesia - paracetamol, compound analgesics, topical analgesia
- NSAIDs - consider risk/benefit ratio
- Pain modulators - tricyclics e.g. amitriptyline
- Intra-articular steroids - only provide short-term relief
Non-Pharmacological
- Education
- Physiotherapy
- Weight loss
- Appropriate footwear
- Mobility aids
- Ultimately - surgery if required, joint replacement or arthroscopic wash outs
What are the two different crystal types seen in gout and pseudogout?
Gout - monosodium urate
Pseudogout - calcium pyrophosphate dihydrate (CPPD)
What is the pathogenesis of gout? What part of this pathway does Allopurinol/Febuxostat affect?
From our diet we get purines, which are broken down into hypoxanthine, then into xanthine, and finally into plasma urate which is excreted by the kidneys
Purine formation is also caused by any breakdown of cells in our body e.g. crash diets, chemotherapy, trauma etc.
Allopurinol is a xanthine oxidase-inhibitor and prevents the conversion of hypoxanthine to xanthine, thus reducing blood uric acid levels.
What level of serum uric acid is defined as hyperuricaemia?
Broadly speaking, what could cause this?
Hyperuricaemia is defined as serum uric acid > 7mg/dl
Could be caused by 1) over-production or 2) under-excretion
1)
- Genetic
- Lesch-Nyan (v. rare)
- Von Gierke
- High cell turnover
- Psoriasis
- Myeloproliferative/lymphoproliferative disorders
- Chemotherapy
- Haemolytic and pernicious anaemia
- Bleeding
- Excessive exercise
- Obesity
- Infection
2)
- Renal insufficiency
- Starvation
- Dehydration
- Hypothyroidism
- Hyperparathyroidism
- Drugs - diuretics, levodopa, cyclosporin A, pyrazinamide
- Alcohol abuse
Does everyone with hyperuricaemia get gout?
When is the best time to measure serum uric acid levels?
No! Diagnosis should be based on clinical presentation, not hyperuricaemia alone
Level of serum uric acid alone does not precipitate gout, but rather acute changes in uric acid levels
Best time to measure levels is two weeks after an acute attack
Monoarticular gout - presentation and differentials
Presentation
- Rapid onset, usually overnight
- Red hot joint
- Severe pain
- Duration of up to 2 weeks
- 1st MTP joint (big toe) > ankle > knee > upper limb > spine
Differentials
- Septic arthritis!!!
- Trauma
- Seronegative arthritis e.g. psoriatic arthritis, ankylosing spondylitis, reactive arthritis, IBD
Who gets gout?
- Overall prevalence of 1.5% in UK
- Men more likely to get it than women, 4:1 - 9:1 ratio
- Prevalence increases with age
- Likelihood increases with hyperuricaemia - higher level = greater risk
Gout - investigations
Inflammatory markers - CRP, PV/ESR will be very raised, similar to infection
WCC may be raised
X ray - normal in an acute attack, but may see erosions, overhanging osteocytes, joint destruction etc. after chronically suffering
Joint aspirate - GOLD STANDARD
Gout - management
Pain relief
- NSAIDs if no contraindication
- Colchicine - too much can precipitate diarrhoea
- Corticosteroids (oral, IM, intra-articular)
- (Other analgaesia e.g. opiates, paracetamol)
Lifestyle modifications
- Restrict red meat, offal, beans, shellfish
- Reduce alcohol - at least 3 alcohol-free days a week
- Lose weight
Prophylaxis
- Indicated if > 2 attacks, appearance of tophi, erosions, renal stones etc.
-
Allopurinol/Febuxostat
- start 2-4 weeks after an acute attack
- begin to lower the dose and titrate
Who gets Pseudogout?
More common in the elderly
Chondrocalcinosis increases with age
Related to osteoarthritis
Affects knees, wrists and ankles
Is not related to diet!
Also related to…
- haemochromatosis/haemosiderosis
- hyperparathyroidism/hypothyroidism
- amyloidosis
- trauma
- Gout
What is the one difference between the treatment of Gout and Pseudogout?
NSAIDs/Colchicine/Steroids given in both, but allopurinol is only given in gout, as the xanthine pathway is not involved in the development of pseudogout.
Give some examples of connective tissue diseases (CTDs)
- SLE
- Sjogren’s
- Systemic sclerosis
- Dermatomyositis
- Polymyositis
- Mixed connective tissue disease
- Anti-phospholipid syndrome
What are CTDs characterised by?
They are not diseases of connective tissue!
Instead, characterised by the presence of spontaneous over-activity of the immune system
Often associated with the presence of specific auto-antibodies
Very generally, what occurs in SLE?
Immune system attacks the body’s cells and tissues, resulting in inflammation and tissue damage.
Antibody-immune complexes precipitate and cause a further immune response
Any part of the body can be affected
Who gets SLE?
- Females more than males - 9:1
- Higher prevalence in…
- Asians
- Afro-Americans
- Afro-Caribbeans
- Hispanic Americans
- Uncommon in African blacks
- Mix of genetic factors, environmental factors, immunological factors and hormonal factors to result in disease
- High concordance in monozygotic twins, increased incidence amongst relatives
- Incidence increased in those with higher oestrogen exposure - early menarche, oestrogen-containing contraceptives and HRT
What are some of the features of SLE’s pathogenesis?
- Loss of immune regulation and generation of auto-antibodies
- Increased and defective apoptosis
- Necrotic cells release nuclear material which can act as potential auto-antigens
- B and T cells stimulated
-
Renal Disease
- likely due to deposition of immune complexes in mesangium, initially formed in circulation
- once deposited, they activate complement, attracting leucocytes and releasing cytokines
SLE - constitutional symptoms
- Fever
- Malaise
- Poor appetite
- Weight loss
- Fatigue
SLE - mucocutaneous features
- Photosensitivity
-
Malar rash
- spares the nasolablial folds
- Discoid lupus erythematosus (may scar - Seale) and subacute cutaneous lupus
- Mouth ulcers
- Alopecia
SLE - MSK features
- Non-deforming polyarthritis/polyarthralgia
- has the same distribution as RA but no radiological erosion seen
- Deforming arthropathy
- Erosive arthritis - rare
- Myopathy - weakness, myalgia and myositis
SLE - possible serositis presentations
- Pericarditis
- Pleurisy
- Pleural effusion
- Pericardial effusion
SLE - neurological features
- Depression/psychosis
- Migraines
- Seizures
- Cranial/peripheral neuropathy
What other condition is strongly associated with SLE?
How does it present?
Anti-phospholipid syndrome
- Venous and arterial thromboses
- Recurrent miscarriages
- Livido reticularis (“granny’s tartan” - blotchy skin appearance)
- Thrombocytopoenia
- Prolonged APTT (activated partial thromboplastin time - measure of blood clotting)
Why might SLE predispose people to developing infections?
Intrinsic Factors
- Low complemenet
- Impaired immune cell function
- Defective phagocytosis
- Poor antibody response to certain antigens
Extrinsic Factors
- Steroid treatments/other immunosuppressive drugs
- Nephrotic syndrome
In diagnosing SLE, what immunological criteria are taken into account?
- ANA
- positive in almost all SLE patients (95%), but also positive in RA and other autoimmune conditions
- also positive in up to 20% of a healthy population
- used in conjunction with other
-
Anti-dsDNA
- occurs in 60% of patients with SLE, and is highly specific for SLE
- titre correlates with disease activity
- Anti-Sm
- Anti-Ro
- Anti-RNP
-
Anti-phospholipid antibodies
- Anti-cardiolipin antibody
- Lupus anticoagulant
- Anti-beta 2 glycoprotein
SLE - management and treatment
Management
- Counselling
- Regular monitoring
- Avoiding excess sun exposure
- Pregnancy issues
Drug Treatment
- NSAIDs and analgaesia
- Anti-malarials - hydroxychloroquine
- useful for arthritis, cutaneous and general symptoms
- Steroids
- useful but need to weigh up side effects
- different disease manifestations require different doses
- Small - skin rashes, arthritis, serositis
- Med - resistant serositis, haematological abnormalities
- Large - severe/resistant haematological changes, major organ involvement
What other immunosuppressive agents are available to treat SLE?
- Azathioprine
- Cyclophosphamide
- Methotrexate
- Biologics
- Rituximab (anti-CD20)
- Belimumab (anti-Blys)
What are some of the symptoms to be aware of when considering if a patient has an autoimmune disease?
- Arthralgia/arthritis
- FATIGUE
- Myalgia/muscle weakness
- Sicca symptoms - dry mouth/eyes
- Raynaud’s phenomenon
- Alopecia
- Mucosal ulcers
- Unprovoked thrombosis/miscarriages
What is anti-phospholipid syndrome characterised by? What immunological markers are looked for?
Venous/arterial thrombosis and/or persistently poor pregnancy outcomes
Livido reticularis (granny’s tartan) may be seen
Immunological markers are…
- anti-cardiolipin antibody
- lupus anticoagulant
- beta-2 glycoprotein
- must be seen on 2 separate occasions more than 12 weeks apart
Anti-phospholipid syndrome - treatment
- Lifelong anticoagulation for thrombosis
- Aspirin/heparin to prevent pregnancy complications
- Hydroxychloroquine
Sjogren’s - pathogenesis and symptoms
Chronic autoimmune inflammatory disorder characterised by diminished lacrimal and salivary gland function
Most common in women in 50s and 60s
Symptoms
- Dry eyes - gritty feeling
- Dry mouth and throat
- Bilateral parotid gland enlargement
- Joint pain
- Fatigue
What antibodies are associated with Sjogren’s?
Anti-Ro
Anti-La
Also watch out for high ESR, rheumatoid factor and IgG
Sjogren’s - treatment
- Artificial tear supplements
- Ciclosporin eye drops
- Saliva supplements
- Hydroxychloroquine
- Pilocarpin
- Immunosuppression if major organ involvement
- Methotrexate
- Leflunomide
- B cell depletors
Diffuse cutaneous systemic sclerosis - possible presentations
What antibodies are seen in DCSS?
- Skin involvement, proximal to forearms and involving the torso
- Rapid skin changes
- Early organ involvement
- Can cause renal crisis
Antibodies seen
- Anti-topoisomerase
- Anti-SCL-70
- Anti-RNA III polymerase
Systemic sclerosis - possible presentations
What antibody is seen in Systemic Sclerosis?
- Skin involvement distal to the elbow and not involving torso
- Used to be called CREST
- Calcinosis
- Raynaud’s - seen in 90% of patients
- Oesophageal dysmotility
- Sclerodactyly (thickening and tightening of the skin on the fingers and toes)
- Telangiectasia (spider veins)
- Pulmonary hypertension is a common complication
Antibody - anti-centromere antibody
Systemic sclerosis - treatment
- Raynaud’s - calcium channel blockers, phosphodiesterase inhibitors
- If digital ulcers - Iloprost infusions
- Lung disease - immunosuppression
- Pulmonary hypertension - calcium channel blockers, endothelin receptor antagonists, home O2
- Reflux - PPIs, H2 receptor antagonists
Mixed connective tissue disease - what are it’s features, complications and associated antibody?
- Features of SLE, polymyositis and systemic sclerosis
- Pulmonary hypertension is an associated complication
- Antibody is anti-RNP
