Joint Diseases

Conrol inflammation

Prominent, including fatigue

Insidious, affects multiple joints

more than 1h

Morning

• Lessens with activity
• Worse after periods of rest
• May hurt with use

Unusual

• Gradual
• 1 joint or a few weight bearing joints

<30 mins

as day progresses

• worsen with activity
• lessen with rest

• A chronic, systemic inflammatory disirder characterised by inflammation and deformity of the synovial joints and inflammation o the surrounding tissues such as tendons, ligaments and muscles
• It is a lymphocyte mediated autoimmune disease

35-64

Female

Synovial

• synovial fluid contains phagocytic cells which remove debris and microbes.
• Joint bones are covered with hyaline cartliage. Composed of: collagen, water, proteoglycans and chrondocytes (synthesise and enzymatically digest the matrix)
• Synovitis is an abnormal inflammatory response of the synovial membrane. It occurs when the synovium become hyperplastic, increases vascularity and becomes infiltrated with inflammatory cells (predominantly CD4+ T cells).
• Antigen activated CD4+ T cells stimulate monocytes, macrophages and synovial fibroblasts to produce IL-1, IL-6 and TNF-alpha to secrete matrix metalloproteinases. Activated CD4+ T cells also stimulate B cells. These changes cause formation of pannus which is rich in inflammatory cytokines that causes destruction of bone and cartliage.

• -Soft tissue swelling or effusion of the affected part
• -morning stiffness in the affected part
• -local soft tissue swelling with warmth and redness
• -weakness, fatige, anorexia, weight loss
• -low grade fever

• Joint and tendon destruction
• -deformity and loss of function (ulnar deviation, swan-neck, hammer toes)
• -functional limitations
• -pain, reduced mobility, fatigue and depression (disrupts family life, makes social interactions difficult, reduced learning capacity)

• Juxta-articular osteoporosis
• Joint erosion
• Joint space narrowing

• Rheumatiod factor (RhF)
• Antibodies to anti-citrullinated peptide antibodies (anti CCP or ACPA)
• Elevations in CRP and ESR - non specific can be used to monitor treatment response
• Mild anaemia

• Pericardial and myocardial inflammation which can progress to heart failure and increased risk of MI
• Severe rheumatiod vasculitis may occur
• Mild anaemia due to excess cytokines that inhibit EPO production
• High risk of cardiovascular disease due to drug induced hypertension and reduced ability to exercise

Shortness of breath due to inflammation of the lung pleura, pulmonary fibrosis or pulmonary nodules

Subcutaneous rheumatoid nodules, usually on hands or arms. Painless

• Saliva and tear production can be reduced -- associated to sjogrens syndrome
• Eyes in 1% of people, can cause episcleritis

• Peripheral sensory neuropathy due to compression of nerves near inflammed joints and tendons
• Presents as muscle weakness and/or pins and needles. Affects hands, wrists and ankles
• Soles of feet, spinal cord and fingers = less common.

Muscle weakness and atrophy

• No one test for diagnosis
• Clinical observations and lab tests

• Untreated RA results in joint damage, deformities and some degree of diasbility
• Aggressive and early therapy critical to improving long term outcomes

• Monocyclic - complete sustained remission within two years ~33%
• Polycyclic - most common course, acute flares and remissions ~40%
• Progressive - constant and destructive, responsible for deformity, disfigurement and premature death ~20%

• Pain management with analgesics
• Disease modification with DMARDs or bDMARDs
• Agressive management of co-morbidities such as cardiovascular risk factors

For drug toxicity and to minimise rheumatiod athritis co-morbidities such as osteoporosis and atherosclerosis

as symptom relief. They do not modify disease progress

• Used at the lowest dose possible and for the shortest period of time
• Should be used in conjunction with a DMARD
• No NSAID is better than any other

15mL fish oil daily or ~12 fish oil capsules

May have anti-platelet activity -- careful in anticoagulants and antiplatelet agents

To control severe inflammation in early disease or active flares

They provite symptomatic disease and slow disease progression

• as initial bridging therapy until DMARDs take effect (corticosteriods take hours-days to work, DMARDs take 6weeks-6 months). If used more than 2-3 weeks, generally taper to reduce risk of rebound flare
• In the management of acute flares (dose variable. Short-term pulse therapy can supress an active flare).
• In combination with DMARDs when DMARD therapy is suboptimal

• Limit disease progression
• Good toxicity profile
• Preserve joint function
• Reduce symptoms
• Induce clinical remission

• Azathiopurine
• Cyclophosphamide
• Hydroxychloroquinone
• Methotrexate
• Penicilliamine
• Cyclosporin
• Gold salts
• Leflunomide
• Sulfasalazine

• TNF-a inhibitors: Adalimumab
• Entanercept
• Infliximab
• Certolizumab

• Cytokine modulators: Abatacept
• Anakinra
• Rituximab
• Tocilizumab
• Golimumab

• 75% of joint erosions occur within the first two years and 25% of patients already have erosions at diagnosis
• Early DMARD use decreases the rate of joint damage
• Early DMARD use makes the disease easier to control int he long term
• Delayed DMARD therapy decreases the ability of single drug therapy to induce remission

• With recent onset of RA
• Those not adequately controlled on monotherapy

Methotrexate + sulfasalazine or hydroxychloroquinone. Or both.

For short term flares or as briding therapy

• Folic acid analogue - binds to dihydrofolate reductase to antagonise folic acid. Impairs cell division.
• Can also increase intracellular adenosine which inhibits inflammatory cell activation.

• Usual dose is 2.5-10mg ONCE A WEEK, dose depending on disease severity.
• Allow 4-6 weeks at each dose level to assess response, response usually seen after 1-2 months
• Max dose 25mg weekly

Nausea and mouth ulcers

• Limit by dose reduction, co-administration of folic acid +/or parenteral delivery of methotrexate.
• Folic acid is usually co-administered with methotrexate, usually 10mg weekly not on the day that methotrexate is adminstered

Used as a monotherapy in mild-moderate RA, or in combination for more severe disease

• Nausea and GI problems -- minimise by starting low dose and titrating slowly
• Rash or more severe allergic reaction -- do not use in patient with an allergy to sulphonamides
• Headache, reversible male infertility and macrocytosis

May take 1-3 months of treatment before benefit is seen. Stop if nothing happens after 4 months.

Usual dose = 2-3g/day in 2-3 doses (start from 500mg daily and increase)

Blocks dihydroorotate dehydrogenase to inhibit de novo synthesis of pyramidines -- inhibits activated lymphocytes

4-12 weeks is the onset of action

the active metabolite has a long half life due to is being enterohepatically recycled. Can be washed out with cholestyramine or charcoal

Usual dose: 10-20mg daily

Diarrohea is common

2-5% of patients develop abnormal LFT's -- raised transaminases. Increased risk of liver disease in combination with methotrexate: monitor liver

Generally better tolerated than other agents

Less active than other agents

400mg daily for 3 months then reduced to 200mg (some patients relapse on 200mg/day though)

• nausea+dizziness -- dose reduction may help
• rash -- need cessation
• ocular toxicity -- rare but requires monitoring by regular eye checkups

It's an immunosupressant that inhibits cytokine release from activated T-cells

Used in moderate to severe RA unresponsive to other DMARDs

• Reversible renal impairment and hypertension common
• Hirsutism, gingival hyperplasia, GI disturbances, weight gain, odema, hepatic dysfunction, hyperlipidaemia, anaemia

Inhibit maturation and function of phagocytes and T-cells

Oral - auranofin, and injectable - aurothiomalate

3-6 months

• Adverse effects: diarrhoea, dyspepsia, stomatitis, nausea, vomiting, taste disturbances, rash, itching, alopecia, conjunctivitis, blood dyscrasias, nephrotoxicity, elevated liver enzymes.
• More: see lecture notes page 55.

Inhibits collagen formation, reduced RhF and circulating immune complex concentrations in blood and synovial fluid

Used for moderate-severe RA due to poor tolerability and delayed effects

May take 3-6 months before benefit is seen, stop if theres no response after 6 months

• Common A/E: rash, stomatisis, dysgeusia
• Rare: myelosupression, proteinuria, renal toxicity & autoimmune syndromes

Prodrug for mercaptopurine. Inhibtis purine synthesis, gene replication and T-cell activation by acting against rapidly dividing cells

Used in moderate to severe RA unresponsive to other DMARDs. Onset of action: 2-3 months, cease after 6 months if no response.

GI intolerance. Rare: myelosupression and hepatotoxicity

For people who fail on DMARDs

Rapid onset of action compared with traditional DMARDs

• Expensive
• Increased risk of infection
• Lymphoma
• Reactivation of latent TB and inactive hepatitis B

All given parentally

They are anti-TNF-a monoclonal antibodies which inhibit binding to cell surface TNF receptors

• It is a chimetic monoclonal antibody.
• Composed of both human and mouse proteins
• Antiboies against infliximab are produced by the body
• Co-prescribed with methotrexate to minimise the formation of antichimera antibodies
• Infusion-related reactions are more severe
• Fully humanised monoclonal antibody
• Retatins antigenic potential so methotrexate is still used commonly

• It's a fusion protein
• Acts as a dummie receptor for TNF-a and TNF-b. Binds to the TNF factor which biologically inactivates it.

New drug, don't know much

• Abatacept
• Anakinra
• Golimumab
• Rituximab
• Tocilizumab

To adjust therapy

• Symptomatic relief
• Normal inflammatory markers
• Absence of joint swelling

• # of swollen/tender joints
• pain
• ADL function
• ESR and CRP measures

• Drugs used to treat RA such as corticosteriods
• Extra-articular manifestations of RA

• Manage: cholesterol,
• anti-platelet therapy
• tight HTN and diabetic control
• diet & exercise
• smoking cessation

Immunosupressants

• Consider vaccinations
• Montior signs of sepsis
• Serious infections may require witholding DMARDs for 1-2 weeks
• Increase steroid to cover the stress response

Medications such as MTX, NSAIDs and corticosteroids

• Minimise dose and duration of NSAIDs and corticosteriods
• Consider co-prescription if proton pump inhibitors if clinicall warranted
• Ensure adequate co-prescription of folate supplements

Resoption of bone due to disease and drugs such as corticosteroids which decrease bone density

• Supplement with vitamin D and calcium
• Bisphosphonates for corticosteriod induced osteoporosis

Blood loss from nsaids - iron deficiency

• Iron, B12 and folate tests to determine the cause
• Treat anaemia
• Adequate co-prescription of folate with MTX

• Ankylosing Spondylitis
• Psoriatic Arthritis
• Colitic Arthritis
• Reactive Arthritis

• Sacroilic joints and spine
• associated with HLA-B27

Inflammation in the attachment sites of tendons and ligaments to bone