Case 23- Arthritis Flashcards
Conditions classified as Spondyloarthropathies (autoimmune)
- Ankylosing spondylitis
- Psoriatic arthritis
- Enteropathy arthritis
- Juvenile Spondyloarthropathies
- Reactive arthritis
- Undifferentiated Spondyloarthropathy
HLA- B27
- Present in 50-95% of patients with SpA (white AS =95%)
- Prevalence ~10% in general population.
- 5-10% of those with HLA-B27 go on to develop SpA
Extra-articular features of Spondylarthropathies (SpA)
- Anterior uveitis
- Apical lung fibrosis
- Aortic insufficiency/ AV block/ IHD
- IgA nephropathy, Amyloidoses
- Autoimmune bowel disease
- (Achilles tendon) Enthesitis
Psoriatic arthritis (autoimmune)
- Joint pain character- inflammatory
- An inflammatory arthritis, associated with psoriasis of the skin or nails
- Affects 5-25% of patients with psoriasis
- Risk factors- Psoriasis, Western Caucasian, Middle age (35-55)
- Genetics (HLA-B27)
Psoriatic arthritis- joint involvement pattern
- Usually an asymmetrical oligoarthritis, but can present as a symmetrical polyarthritis
- Commonly affects wrists, hands (DIP joints rather than MCP unlike Rheumatoid), feet, ankles
- Can also involve tendons/ligaments (enthesitis)
- May also involve the Axial skeleton (spine)
- May see swelling of Entire digit (Dactylitis)
Psoriatic arthritis clinical examination/investigations
Psoriatic arthritis clinical examination= Pitting, Yellowing, Onycholysis (separation of nail from nail bed)
Psoriatic arthritis investigations- Usually Seronegative, unlike Rheumatoid factor, negative anti-CCP.
Septic arthritis (infective)
- Infection driving joint inflammation/destruction. Most commonly staph Aureus
- Risk factors- joint surgery/injection, Prosthesis, Immunosuppression, IVDU
- Joint pain character and pattern= regard a hot, swollen, acutely painful joint with restriction of movement as septic arthritis until proven otherwise. Delay will cause increased destruction
- Urgent recognition and treatment required as it can be limb and life threatening. Mortality rate is 10-20%
- Most commonly the knee joint is effected
- Diagnosis is confirmed by a positive culture from joint aspiration, it requires several weeks of IV and oral antibiotics
Gout (Crustal Arthropathy) Mechanism
- Uric acid is byproduct of purine degradation – humans can’t oxidise it – puts us at risk of monosodium urate deposition in states of hyperuraemia.
- Hyperuraemia is usually due to under excretion (alcohol, renal disease, drugs) rather than overproduction
- Gout is painful inflammatory response to monosodium urate crystals in joints
Rheumatoid arthritis pathology
- Post translational change of the amino acid Arginine into Citrulline
- Arginine is found in Type II collagen
- Susceptible genes= HLA-DR1, HLA-DR4
- Immune cells attack these Citrulline proteins and antibodies are produced against them
- Infiltration of the Synovial fluid with immune cells. Autoantibodies are produced
Gout (Crystal Arthropathy)
- Gout can be diagnosed via aspiration of the joint to look for crystals
- Monosodium urate crystals are, ‘strongly negative birefringent needle shaped crystals under polarised light microscopy
- If its clinically gout in MTP you do not need to routinely aspirate
- Clinical presentation is severe pain, swelling, warmth in <24 hours usually 1st MTP (big toe joint). In 75% the theory of cooler periphery leads to crystal deposition
Ankylosing spondylitis
- Chronic inflammatory arthritis affecting the Axial Skeleton – leads to inflammatory back pain from sacroiliitis (inflammation of the sacroiliac joints), pain and stiffness worse with rest, improves with movement, may awake from sleep.
- Associated to extra-articular features as described earlier in Spondyloarthropathy – enthesitis, uveitis, may also have some peripheral joint involvement
- Inflammation of the ligaments in the spine eventually leads to calcification forming syndesmophytes and eventual fusion of the spine – giving xray findings like bamboo spine and in chronic disease, the classic question mark posture – loss of lumbar lordosis, exaggerated throacic kyphosis
Ankylosing Spondylitis risk factors
- Male 2:1
- HLA-B27
- Young age of incidence (20-30)
Reactive arthritis
- Asymmetrical inflammatory oligoarthritis (sometimes with axial involvement), tending to affect the large joints of lower limb – reactive as it’s usually preceded by a gastrointestinal or genitourinary infection by 2-4 weeks prior. (Chlamydia, Salmonella, Campylobacter, Shigella, and Yersinia common preceeding organisms)
- Belonging to the spondyloarthropathy family it has a strong HLA B27 relation, with associated symptoms of enthesitis and uveitis being common.
- The classical triad is of arthritis, non-gonococcal urethritis, and conjunctivitis is frequently described but found only in a minority of cases and not required for diagnosis (“Can’t see, can’t pee, can’t climb a tree)
- 30-50% go on to develop a chronic arthritis
Reactive arthritis- multisystem effects
- Oligoarthritis
- Eye= Uveitis, sterile conjunctivitis
- Bladder- Sterile balantitis urethritis
- Skin= Keratoderma blennorrhagicum (12% of patient)
Pseudogout (CPPD)
- Calcium pyrophosphate crystals are shed into the intra-articular space and induce the inflammatory reaction, it can be diagnosed via aspiration and identification of the crystals
- Commonly present as monoarthritis
- Chondrocalcinosis (calcification of cartilage)- a potential sign of calcium pyrophate crystals
- Secondary causes should be investigated for in the <50’s, including hyperparathyroidism, hypomasnesmia, hemochromatosis and Wilson disease etc
Differentiating between CCPD and Gout
- CPPD- Positively birefringent rhomboid-shaped crystals under polarised light microscopy
- Gout- Strongly negative birefringent needle shaped crystals under polarised light microscopy
The Extra-articular features of Rheumatoid arthritis
- Fatigue, weight loss, fever
- Heart- Increased CVS risk, Pericarditis, Pericardial effusion
- Lungs- Pleural effusion, Interstitiail lung disease
- Eye- Sicca (dry eyes/mouth), Episcleritis/scleritis (inflammation of the sclera)
- Osteoporosis
- Carpal tunnel
Disease modifying anti rheumatic drugs (DMARDS)
These slow and even reverse the joint damage caused by an inflammatory arthritis generally by immunomodulation
Adjuncts of DMARDS
Non steroid anti-inflammatory drugs (NSAIDS) and steroids are used as adjuncts as there is a delay in the effect of DMARDS
Measuring severity of Rheumatoid arthritis
To measure level of disease activity in Rheumatoid arthritis we use DAS28. This is a combination of tender and swollen joint counts and a global assessment of health using ESR/CRP (0-100)
DAS-28
- 0 to <2.6- Remission
- 2.6 to 3.2- Low disease activity (LDA)
- > 3.2 to 5.1- moderate disease activity
- > 5.1= high disease activity
Medical management principles in rheuamtoid arthritis
- If patients are not reaching desired target (low disease activity) therapy is escalated
- NSAID + PPI +/- Steroids= adjuncts to DMARDS, given at the start of treatment before DMARD’s have their effect
- After the initial DMARD therapy you should re-assess at 3 months
- There should be a combination or change in DMARDs if not reaching the target
Two categories of DMARD’s
- Synthetic or conventional DMARD’s- these are older more established generally oral medication such as Methotrexate, Sulfasalazine, Leflunomide, Hydroxychloroquine etc
- Biological DMARD’s or targeted therapies- these are more modern medications targeted to particular inflammatory/immune pathways. They can be infusions, self-injected subcutaneously. Some newer ones are oral medication. Generally reserved for when treatment targets are not met by synthetic DMARD’s alone
Treatment for moderate and severe rheumatoid arthritis at presentation
Methotrexate monotherapy is preferred for initial management
AICAR
An analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity – leads to increased adenosine release – anti-inflammatory properties
Methotrexate- mechanism of action
- An inhibitor of dihydrofolate reductase, an important enzyme in folate metabolism
- This leads to reduced purine synthesis- important for DNA replication
- Impairs rapidly dividing cells, arresting them in the S phase
- In arthiritis with methotrexate at lower doses, the more significant mechanism of action is likely increased AICAR and adenosine release
- Methotrexate is potentially myelosuppressive, hepatotoxic and teratogenic so can be used in cancer and ectopic pregnancies. Dont give Trimethroprin at the same time
Methotrexate clinical considerations
- In arthritis- its always given once weekly in a 2.5mg tablet only or a pre-dosed injection subcutaneously to prevent overdose
- It given alongside Folic acid (on any other day)
- It requires close monitoring with blood tests and initial pulmonary function testing and chest xrays (can cause pulmonary fibrosis/hypersensitivity reaction)
- Tetragenic- shouldn’t be given in pregnancy
- Don’t use if there are hepatic or pulmonary co-morbidities. Cant use with Trimethroprim for UTI’s
Rheumatoid arthritis- Sulfasalzine
- Mechanism of action- The medication is broken down by intestinal bacteria into sulfapyridine and 5-aminosalicylic acid downregulating local inflammatory pathways
- Twice a day oral tablets
- Side effects- GI upset, orange urine, yellow tears
- Can be used in pregnancy
Rheumatoid arthritis- Leflunomide
- Mechanism of action- Active metabolite of leflunomide, A77 1726, reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate limiting step in the de novo synthesis of pyrimidines – therefore DNA synthesis inhibited, affecting lymphocyte replication
- Once a day tablet
- Side effects- low blood count, hepatoxic, increasing blood pressure
- Not safe in pregnancy
- Long half life- can be washed out with another medication
Rheumatoid arthritis- Hydroxychloroquine
• Mechanism of action- Increased intracellular pH preventing the activity of lysosomal enzymes. Inhibition of lysosomal activity can prevent MHC class II-mediated autoantigen presentation + other direct and indirect inflammatory pathway effects
• Once or twice a day tablets
• Generally used in mild disease
• Very lipophilc- risk of retinopathy over time, need eyes checking regularly
Less potent then methotrexate
Biologics
Medications that use a biological product (e.g. a monoclonal antibody in the case of adalimumab) to target a specific part of a cellular/metabolic pathway to bring about a desired effect.
Biologics= TNF alpha inhibitor
- A monoclonal antibody which targets part of the inflammatory cascade/signalling network
- Used in rheumatoid, Psoriatic arthritis and Ankylosing spondylitis
- Infliximab recombinant DNA-derived chimeric human-mouse IgG monoclonal antibody (intravenous infusion)
- Adalimumab (Humira) Human Monoclonal antibody (subcutaneous injection)
- Etanercept is a fusion protein - It fuses the TNF receptor to the constant end of the IgG1 antibody (subcutaneous injection)
- Others include certolizumab pegol, and golimumab
Other biologics- Abatacept, Tocilizumab, Rituximab
- Abatacept – fusion protein of CTLA-4-IgG, binds to CD80 and inhibits T-cell co-stimulation (intravenous infusion)
- Tocilizumab – IL-6R Inhibitor (intravenous infusion or subcutaneous injection)
- Rituximab – B-cell modulator by targeting CD20 (intravenous infusion)
Other biologics- Ustekinumab, Secukinumab, targeted synthetic DMARDS
- Ustekinumab - inhibits the receptor binding of interleukin 12 and interleukin 23 (pro-inflammatory cytokines that increase production of Th17 lymphocytes). Not used in Rheumatoid but used in Psoriatic arthritis
- Secukinumab, a monoclonal antibody to interleukin 17. Not used in Rheumatoid but used in Psoriatic arthritis and ankylosing spondylitis
- Targeted synthetic DMARDS- Jak kinase inhibitors. Sometimes referred to as ‘oral biologics’ although they arent technically a biological product, they are a smaller molecule. Examples include tofacitinib, barictinib, filgotinib and upadactinib
Sequence of medications in Rheumatoid arthritis
- At diagnosis- Methotrexate
- 2nd step- Methotrexate and Leflunomide
- 3rd step- Methotrexate and Adalimumab
- 4th step- Methotrexate and Rituximab infusion
- 5th step- Methotrexate and Filgotnib
Spinal nerves
- Each segment of the spinal cord gives rise to a pair of spinal nerves, one for each side of the body
- The dorsal root ganglion contains sensory nerve cell bodies
- The dorsal root contains centrally projecting sensory axons into the dorsal horn. The dorsal root is posterior
- The ventral root contains motor axons from motoneurones in the ventral horn. The ventral root is anterior
- Motor axons and peripherally projecting sensory axons mix to form the spinal nerve
- The spinal nerve splits to give the dorsal ramus, which supplies the dorsal surface of the body (back), and the ventral ramus, which supplies the ventral surface and limbs (front). Each contains a mixture of sensory and motor axons. The ventral ramus tends to be bigger then the dorsal ramus
Proprioception, Exterorecption, Myotome, Dermatome
Proprioreception: awareness of the movement and position of parts of the body. Involves muscle spindles and organs in the tendon
Exteroreception: awareness of somatosensory stimuli such as heat, pain, touch, vibration. Sensory fibres
Myotome: a group of muscles innervated by a particular segment of the spinal cord
Dermatome: An area of skin innervated by a particular segment of the spinal cord
Axillary nerve
Motor innervation to the Deltoid and Teres minor. Goes through the quadrilateral space with the circumflex arteries. From the posterior cord of the brachial plexus. Provides sensory innervation to the ‘Sargents patch’- skin on the lateral surface of the upper arm/shoulder. Can be damaged by anterior shoulder dislocation and fracture to the neck of the humerus
Upper and lower brachial plexus
C5, C6, C7- upper brachial plexus
C8, T1- lower brachial plexus
The long thoracic nerve
The long thoracic nerve is formed from C5, C6 and C7. It supplies the Serratus anterior muscle which anchors the scapula to the rib cage. Damage to this nerve causes a winged scapula.
Brachial plexus and Dermatome map
Each dermatome is supplies by a group of different nerves. The C5 nerves including the Axillary nerve, the Radial nerve and the Lateral cutaneous nerve which is a branch of the musculocutaneous nerve. The dermatome map is not the same as the map of where the nerves send their projections to
Brachial plexus injury
- Involves severe stretching of nerves in neck and axilla leading to breaking of axons (axonetmesis) and sometimes the nerve itself.
- Potential for recovery depends on whether nerve sheaths are intact, how far the injury is from the muscle and whether the axon is injured in the periphery or very close to the motoneurone cell body in the spinal cord.
- Can have recovery in brachial plexus injury- more likely in the upper brachial plexus because in the lower brachial plexus there is more distance for the nerves to grow (big distance from axilla to hand)
- You can have either upper or lower brachial plexus injury.
- Upper brachial plexus injury is far more common
Nerve supply to the hand
- Ulnar nerve- median part of the hand (little finger)
- Radial nerve- lateral back part of the hand (thumb)
- Median nerve- thumb and tips of the fingers
Upper brachial plexus injury
- Nerve roots affected: C5, C6
- Motor loss: Flexion, abduction, lateral rotation of the shoulder joint (affects supply to the deltoid, rotator cuff muscles and bicep brachii). Flexion of the elbow joint
- Sensory loss- lateral aspect of the upper limb
- Cause- violent separation of the head and shoulder such as falling off a motor bike or childirth, stab wounds to the neck
Lower brachial plexus injury
- Nerve roots affected: C8, T1
- Motor loss: wrist and finger movements
- Sensory loss: medial aspect of the arm, forearm and hand
- Cause: sudden upwards pull on the upper limbs- pulling the arm from the trunk
Injury to the long thoracic nerve
• Nerve roots: C5-C7
• Motor loss: Serratus anterior, winging of the scapula
• Cause: nerve damage after stabbing, surgery to remove lymph nodes, weight lifting
You get some regeneration in the PNS but not in the CNS
Injury to the Axillary nerve
- Nerve root supply: C5, C6
- Motor loss: Deltoid, Teres minor, abduction and lateral rotation of the arm
- Sensory loss: lateral side of the proximal arm (Sargents patch)
- Cause: shoulder dislocation, humeral fracture
Injury to the thoracodorsal nerve
- Nerve root supply: C6-C8
- Motor loss: Latissimus dorsi (in the back), adduction of arm
- Cause: Nerve damaging after stabbing or surgery to axilla
Factors affecting regeneration and repair in the nervous system
- The nature of axonal injury
- Factors inhibiting axonal regeneration in the CNS
- Strategies for encouraging axonal regeneration
The mammalian nervous system is vulnerable to illness and disease because:
- Neurons communicate via long thin axonal processes that are easily injured and also prone to ischaemic insult
- In the PNS axonal regeneration can be achieved under certain circumstances, but in the mature CNS, axon regeneration is actively inhibited.
- Axons regenerate at the rate of about 1mm a day, maximum.
What may cause neurones to be damaged?
By laceration (stab wounds, broken bones), traction (stretch), pressure or prolonged ischaemia
Neuropraxia
Damage is minimal, axons remain intact but conduction ceases due to local ischaemia and demyelination. Loss of oxygen and glucose, nerves are still attached to their targets. Spontaneous recovery in a few days/weeks.
Axonotmesis
Axon damaged by compression or traction that the distal portion degenerates. However, investing sheaths (connective tissue) remain intact and delayed recovery is likely as proximal portion regenerates. The axon can regenerate and follow the nerve sheath back to its target
Neurotmesis
Entire nerve with connective tissue is completely divided. Distal portion degenerates and proximal portion can only regenerate if the investing sheaths are repaired. Through surgery
Peripheral nerve lesions
- If a motor axon is cut, transmission ceases, the motor terminal degenerates along with the distal axon segment, Wallerian degeneration causes the myelin to unravel. The muscle undergoes atrophy or degeneration. The synapse disappears
- Schwann cells withdraw leaving myelin debris. Macrophages enter lesion site and phagocytose distal axon/myelin.
- At the motoneuron cell body the nucleus is displaced, Nissl substance dispersed and gene expression and electrical responsiveness changes, called chromatolysis and synaptic contacts are removed. The rough ER degenerates
Wallerian degeneration
- Distal axon degeneration involves the unraveling and disintegration of the myelin sheath outside the axon coupled with clumping of axons and neurofilament inside the axon. Axon swells and breaks up into small, beaded segments. Starts 1 week after injury and lasts 1-2 months.
- Originally thought to be a passive process mediated by proteases activated by calcium entry into axon. Caused by a genetic cascade
- Degeneration delayed in wld^s mutant mice suggesting that it is an active process akin to apoptosis at the cell body.
- Triggered by injury to axon, also by neurotoxins, de-myelination diseases (multiple sclerosis), Ischaemia (compression injuries, stroke), defects in axonal transport, Neurodegenerative disease (motor neuron disease).
Motor axon regeneration
- Takes a month or two
- The motoneurone synthesizes proteins needed for axon growth, ie neurofilalments, microtubules and growth cone proteins.
- The Schwann cells release growth promoting molecules which attract sprouts from the mini axon
- The motor axon sprouts, if lucky a sprout will find an array of Schwann cells/ ECM to guide its growth.
- The extracellular matrix also promotes the axon to grow
- When the motor axon contacts a muscle, retrograde signals change gene expression to allow it to function as a transmitting neuron again. Forms a synapse with the muscle fibre. The Schwann cell starts remyelinating the axon. The gene expression in the cell body changes to transmitting mode
CNS myelin inhibits axon growth
- Myelin produced by oligodendrocytes differs from that produced by Schwann cells. Contains proteins that inhibit axon growth.
- Injecting antibodies against these myelin inhibitory proteins into the injured spinal cord can;
- Promote sprouting and regeneration of injured axons, particularly in association with growth factor treatments.
- Can promote sprouting of uninjured axons
- In the periphery degenerated myelin is removed by Macrophages but in the CNS it tends to stick around
Environment for regeneration- PNS
- Myelin produced by Schwann cells
- Macrophages rapidly clear myelin debris and stimulate Schwann cell proliferation
- Peripheral nerves contain Extracellular matrix molecules that promote axon growth
- Peripheral neurons/motoneurons upregulate expression of growth promoting proteins (i.e GAP43) in response to injury
Environment for regeneration- CNS
- Different myelin, produced by oligodendrocytes
- Microglia only slowly clear CNS myelin and inhibits the axons from growing
- No axon promoting molecules in ECM, inhibitory molecules present instead (glial scar produced by astrocytes).
- Many CNS neurons do not respond to injury by upregulating GAP 43
Repairing the Brachial plexus: Nerve graft
- Injured nerve could be a trunk, cord or proximal part of the major nerve
- In a compressed nerve, the damaged segment is removed and replaced with the Sural nerve which is used as a graft. Nerve axons can grow through this bridge and connect the distal to the proximal part
- The Sural nerve is a cutaneous nerve so its removal does not affect movement
- Other sensory nerves from the foot can sprout and take over the area previously covered by the Sural nerve
Repairing the brachial plexus- Nerve transfer
- Used for serious cases (root avulsion)
- Nerve disconnected from muscle
- Fibres taken from another nerve and connected to the muscle
- Some muscle are weakened by partial denervation but function is restored to completely denervate the muscle. Nerve fibres will regrow through the transplanted nerve which is denervates, in order to innervate the muscle
- So for example, the nerve will move the bicep instead of the hand muscle, as only a few fibres are taken, the hand can be innervated by nearby axons which will take over those axons as well
Spinal nerve root avulsion
- Rupture: neurotmesis, nerve is damaged in the periphery so regeneration can still occur
- Stretch: axonotmesis,
- Rupture- dorsal and ventral root are pulled out of the spinal cord, cant get nerve regeneration unless there is surgical intervention. You can implant human spine cell progenitors where the dorsal root is being reconnected, provides the environment for sensory fibres to grow back. Can also push the axons so they are nearer the cell body so they have a shorter distance to grow back
