Rheumatoid Arthritis Flashcards
At what age is the peak prevalence of RA?
30-50 years
What is rheumatoid arthritis?
A chronic systemic autoimmune disorder causing a symmetrical polyarthritis
Describe the aetiological role of gender in RA?
Women before the menopause are affected 3x more often than men. After menopause there is an equal sex incidence, suggesting an aetiological role for sex hormones
What antigens confer susceptibility to RA?
HLA-DR4 and HLA-DRB1*0404/0401. This human leukocyte antigens are associated with more severe disease
What is rheumatoid factor? How often is it present in patients with RA?
Rheumatoid factor is autoantibodies directed against the Fc portion of immunoglobulin. These autoantibodies are produced by B cells. It is positive in 70% of patients. It is not, however, specific for RA and occurs in connective tissue disease and some infections
What is citrullination?
The conversion of the amino acid arginine in a protein into the amino acid citrulline. The immune system often attacks citrullinated proteins, leading to autoimmune diseases such as rheumatoid arthritis
What is anti-CCP?
Anti-CCP (anti- cyclic citrullinated peptides) are autoantibodies that are directed against peptides and proteins that are citrullinated. Anti-CCP (also known as ACPA (anti-cirullinated protein antigen) is often present in patients with rheumatoid arthiritis.
What antibody class is most rheumatoid factor?
IgM
Why are anti-CCP antibodies important markers for diagnosis and prognosis of RA?
- They are as sensitive and more specific than IgM RF
- They may predict eventual development into RA when found in undifferentiated arthritis
- They are a marker of erosive disease in RA
- They may be detected in healthy individuals years before onset of clinical RA
- Anti-CCP rarely occurs in healthy people (while healthy people can also have RF)
- Combination of RF and anti-CCP positive results makes RA very likely
- These seropositive patients have a poorer prognosis and often need more aggressive treatment
What is the importance of TNF in RA?
Overproduction and overexpression of tumour necrosis factors is a key inflammatory element in RA, leading to synovitis and joint destruction. TNF-α stimulations overproduction of IL-6. Antibodies to TNF-α and IL-6 produce marked short-term improvements in synovitis demonstration the role of these cytokines in RA
What are the characteristic pathological features of RA?
- Synovitis (inflammation of the synovial lining of joints, tendon sheaths or bursae)
- Thickening of the syovial lining
- Infiltration of the synovial lining by inflammatory cells
Describe the normal synovium
Thin, comprising a lining layer a few cells thick containing fibroblast-like synoviocytes and macrophages overlying loose connective tissue
How do angiogenic cytokines contribute to the development of RA?
They induce generation of new synovial blood vessels
How do activated endothelial cells contribute to the development of RA?
They produce adhesion molecuels such as vascular cell adhesion molecule-1 (VCAM-1) which expedite extravasation of leucocytes into the synovium
What is a pannus?
Proliferation of the synovium causes it to grow out onto the cartilage surface producing a tumour like mass called a pannus.
Why is the development of a pannus damaging to the joint?
The pannus damages the underlying cartilage by blocking its normal route for nutrition and by the direct effects of cytokines on the chondrocytes. The cartilage then becomes thinned, exposing the underlying bone, producing the diagnostic juxta-articular bony ‘erosions’ seen on X-ray
What early damage is caused by fibroblasts in the first 3-6 months of RA?
Fibroblasts from the proleferating synovium grow along the course of blood vessels between the synovial margines and the epiphyseal bone cavity and damage the bone. This early damage justifies the use of DMARDs within 3-6 months of onset of arthritis
What is seronegative RA? How is it diagnosed?
The term ‘seronegative RA’ is used for patients in whom the standard tests for IgM rheumatoid factor are per- sistently negative. They tend to have a more limited pattern of synovitis.
Diagnosis is made based on symptoms and signs and confirmed by ultrasound of joints showing synovitis
What is the difference between seropositive and seronegative RA in terms of Hb and inflammatory markers?
In seropositive RA, inflammatory markers are high and Hb may be low
In seronegative RA inflammatory markers are lower and Hb is normal
IgM RF is neither diagnostic of RA, nor does its absence rule disease out. Why then is it still a useful test?
It is a useful predictor of prognosis. A persistently high titre in early disease implies more persistently active synovitis, more joint damage and great disability eventually, and justifies earlier use of DMARDs
What is the most typical presentation of RA, occuring in approx. 70% of cases?
A slowly progressive, symmetrical peripheral polyarthritis, evolving over a period of a few weeks or months
How does RA present less commonly, in approx 15% of cases?
Rapid onset occuring over a few days (or explosively overnight) with a severe symmetrical polyarticular involvement, especially in the elderly.
What factors indicate poor prognosis?
- Older age
- Female sex
- Symmetrical small joint involvement
- Morning stiffness lasting >30 mins
- > 4 swollen joints
- CRP >20
- Positive RF and ACPA
What are the differentials for early signs of RA?
- Post viral arthritis: rubella, hep. B or erythrovirus
- Seronegative spondyloarthopathies
- Polymyalgia rheumatica
- Acute nodal osteoarthritis (PIPs and DIPs involved)
What are the ACR/EULAR 2010 criteria for RA?
- Joint involvement: (0-5)
- 1 medium to large joint= 0
- 2-10 medium to large joints= 1
- 1-3 small joints = 2
- 4-10 small joints= 3
- >10 joints, at least one of which is small= 5 - Serology: (0-3)
- Negative RF and negative ACPA= 0
- Low positive RF or low positive ACPA= 2
- High positive RF or high positive ACPA= 3 - Acute-phase reactants: (0-1)
- Normal CRP and normal ESR= 0
- Raised CRP or raised ESR= 1 - Duration of symptoms: (0-1)
- <6 weeks= 0
- ≥6 weeks= 1
Cut off point for RA is 6 or more points
Why are the ACR/EULAR 2010 criteria more suitable for assessing RA than earlier criteria?
They do not rely on later changes such as erosions and extra-articular disease so are more suitable for assessing early arthritis
In early RA, what criteria identify a patient for earlier treatment to avoid joint damage?
The combination of:
- At least one swollen joint
- For more than 6 weeks
- No associated history or family history of spondyloarthritis or associated conditions such as psoriasis
- A positive ACPA
What is the common presenting complaints in patients with RA?
Pain and stiffness of the small joints of the hands (MCP, PIP, DOP) and feet (MTP).
Fatigue is also a common complaint as pain and stiffness is worst in the morning, disturbing sleep
In 10% of cases, RA patients do not present with polyarticular pain of small joints. Why else might these patients present?
10% present with a monoarthritis of the knee or shoulder or with carpal tunnel syndrome
What is a palindromic presentation of RA?
Unusual (5%). COnsists of short liver (24-72 hour) episodes of acute monoarthritis. The joint becomes acutely painful, swollen and red, but resolves completely. Further attacks occur in the same of other joints. About 50% go on to develop typical chornic rheumatoid synovitis after a delay of months or years. The rest remit or continue to have acute episodic arthritis. Detection of RF or ACPA predicts conversion to chronic destructive synovitis
What is a transient presentation of RA?
A self-limiting disease, lasting less than 12 months and leaving no permanent joint damage. Usually seronegative for IgM rheumatoid factor and ACPA. Some of these may be undetected post-viral arthritis.
What is a chronic persistent presentation of RA?
The most typical form, it may be seropositive or seronegative for IgM rheumatoid factor. The disease follows a relapsing and remitting course over many years. Seropositive (plus ACPA) patients tend to develop greater joint damage and long-term disability. They warrant earlier and more aggressive treatment with disease-modifying agents.
What is a rapidly progressive presentation of RA?
The disease progresses remorselessly over a few years and leads rapidly to severe joint damage and disability. It is usually seropositive (plus ACPA), has a high incidence of systemic complications and is difficult to treat.
How may seronegative RA present?
Typically affects the wrists more often than the fingers and has less symmetrical joint involvement. It has a better long-term prognosis but some cases progress to severe disability.
What condition may seronegative RA be confused with?
Psoriatic arthropathy, which has a similar distribution
What are the complications of RA?
Ruptured tendons Ruptured joints (Baker's cysts) Joint infection Septic arthritis Spinal cord compression Amyloidosis (rare)
How does septic arthritis present?
Affect joints are often painful, swollen, red and hot. Symptoms develop quickly over a few hours or days. May also present with fever. There is usually neutrophil leucocytosis. Any effusion in RA, particularly of sudden onset, should be aspirated
What is the most common causative agent of septic arthritis?
Staph. aureus
What deformities are seen on the hands of patients with RA?
Ulnar drift Palmar subluxation of the MCPs Boutonniere deformity Swan neck deformity Swelling and subluxation of the ulnar styloid causing wrist pain
What is a potential complication of swelling and subluxation of the ulnar styloid?
Rupture of the finger extensor tendons, leading to a sudden onset of finger drop of the little and ring fingers, which needs urgent surgical repair
Describe the impact RA may have on the shoulder?
Initially symptoms mimic rotator cuff tendonosis- painful arc syndrome and pain in the upper arms arms at night. AS the joints become more damaged, global stiffening occurs. Late in the disease, rotator cuff tears are common and interfere with ADLs e.g. dressing, feeding an personal toilet
Describe the impact RA may have on the elbow?
Synovitis of the elbow causes swelling and a painful, fixed flexion deformity. In late disease, felxion may be lost and severe difficulties with feeding result, especially combined with shoulder, hand and wrist deformities
Describe the impact RA may have on the feet?
- Painful swelling of the MTP joints is one of the earliest manifestations of RA
- The foot becomes broader and hammer-toe deformity develops
- Exposure of the metatarsal heads to pressure by forward migration of the protective fatty pad causes pain
- Ulcers of calluses may develop under the metatarsal heads and over the dorsum of the toes
- May be a flat arch and loss of flexibility of the foot
Describe the impact RA may have on the knees?
- Massive synovitis and knee effusions occur but respond well to aspiration and steroid injection
- A persistant effusion increases risk of popliteal (Baker’s) cyst formation and rupture
- In later disease, erosion of the cartilgae and bone causes loss of joint space on X-ray and damage to the medial and/or lateral compartments of the knees
- Total knee replacement may be required
What are the common non-articular manifestations of RA seen in the soft tissue surrounding joints?
- Subcutaneous nodules are firm, intradermal and generally occur over pressure points, typically the elbows, the finger joints and the Achilles tendon
- The nodules may ulcerate and become infected
- The olecranon and other bursae may be swollen (bursitis)
- Tenosynovitis of flexor tendons in the hand cause stiffness and occasionally a trigger finger.
- Muscle wasting around joints is common
What are the systemic manifestations of RA?
- Fever
- Fatigue
- Weight loss
What manifestations of RA are seen in the eyes?
- Sjorgren’s syndrome (dry eyes)
- Scleritis
- Scleroma perforans (perforation of the eye)
What are the neurological manifestations of RA?
- Carpal tunnel syndrome
- Cord compression
What are the pulmonary manifestations of RA?
Pleural effusion
Lung fibrosis
Rheumatoid nodules
What are the cardiovascular manifestations of RA?
Pericarditis (rare)
Pericardial effusion
Raynaud’s
What are the renal manifestations of RA?
Amyloidosis (rare, although the most common cause of secondary amyloidosis)
What investigations are done to confirm suspected RA?
- Blood count- normally there is normochromic, normocytic anaemia and thrombocytosis. ESR and CRP are raised in proportion to the activity of the inflammatory process
- Serum autoantibodies. Anti-CCP has high sensitivity and specificity for RA. RF is positive in 70% of cases. Anti-nuclear factor is present in 30%
- X-ray of affected joints shows soft tissue swelling in early disease and later joint narrowing, erosions at the joint margins and porosis of periarticular bone and cysts
- Synovial fluid is sterile with high neutrophil count
Who may be involved in the multi-disciplinary team managing RA?
- Rheumatologist
- Orthopaedic surgeon (joint replacement, arthroplasty)
- Occupational therapists (aids to reduce disability)
- Physiotherapist (improvement of muscle power and maintenance of mobility to prevent flexion deformitites)
What lifestyle change are patients with RA encouraged to make?
Stop smoking to reduce risk of cardiovascular disease
What is a coxib?
Selective inhibitor of COX-2- lower risk of GI side effects than NSAIDs
What drugs may be used in management of RA?
- NSAIDs/coxibs: relieve joint pain but do not slow disease progression. Paracetamol can be added for additional pain relief
- Corticosteroids: Suppress disease activity but only at high doses –> side effects
- DMARDS: inhibit inflammatory cytokines
- Biological DMARDS: e.g. TNF-alpha inhibitor
Describe the role of corticosteroids in the management of RA
- Oral corticosteroids are used in early disease as a short-term intensive regiment.
- May also be use din patients with severe non-articular manifestations e.g. vasculitis
- Local injection of troublesome joints with long-acting corticosteroids improves pain, synovitis and effusion, but repeated injections are avoided because they may accelerate joint damage
- Intramuscular dept methyprednisolone helps to control severe disease flares
Describe the role of DMARDS in the management of RA
- Disease modifying anti-rheumatic drugs inhibit inflammatory cytokines.
- They are used early (6w to 6m of onset of disease)
- They reduce inflammation and thus slow development of joint erosion, irreversible damage and reduce cardiovascular risk
What is sulfasalazine? When is it used?
It is a DMARD. It is used in patients with mild to moderate disease and for many is the drug of choice esp in younger patients and women who are planning a family
What is the drug of choice in patients with more active disease?
Methotrexate
When is methotrexate contraindicated?
It is teratogenic so is contraindicated in pregnancy. It should also not be prescribed to both men and women in the 3 months prior to conception in those planning a pregnancy
What is the mechanism of Leflunomide? What are the benefits of its use?
It blocks T-cell proliferation
It has a similar initial response rate to sulfasalazine but improvement continues and it is better sustained at 2 years.
It is used alone or in combination with methotrexate
What are the side effects of sulfasalazine?
Common: GI upset; headache
Rare: haematological disorder; renal impairment; male infertility
What are the side effects of Methotrexate?
SE related to inhibition of cellular replication:
- Mouth ulcers- Rx with folic acid
- Nausea- Rx with folic acid
- Bone marrow suppression including neutropaenia
Others:
- Acute cutaneous reactions, hepatitis, pneumonitis
- Chronic use can rarely lead to interstitial pneumonitis and hepatic cirrhosis
- Renally excreted so care with chronic renal failure or agents that impair GFR
- Teratogenic- 3 month washout
What are the side effects of Leflunomide?
Diarrhoea
Hypertension
Hepatitis
Alopecia
What are the side effects of TNF-α blockers?
Infusion reactions Infections e.g. TB and septicaemia Demyelinating disease Heart failure Lupus-like syndrome Autoimmune syndromes
What is infliximab?
A TNF-α inhibitor given IV every 8 weeks. Now a first line treatment can slow or halt erosion formation in 70% of patients
In which patients are TNF-α inhibitors currently used?
Patients who have active disease in spite of adequate treatment with at least two DMARDs, including Methotrexate
What are the radiological hallmarks of rheumatoid arthritis?
Soft tissue swelling
Juxta-articular osteopenia
Loss of joint space
Juxta-articular erosions
Describe a swan-neck deformity
DIP hyperflexion with PIP hyperextension
Describe a z-thumb deformity
hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint
Describe a Boutonniere deformity
PIP flexion with DIP hyperextension
What are the GI side effects of NSAIDs?
Dyspepsia
Nausea
Vomiting
Ulcer formation with risk of haemorrhage in chronic users
What are the renal side effects of NSAIDs?
Interstitial nephritis
Nephrotoxicity
Renal failure
What drugs interact with NSAIDs?
Oral anticoagulants Anti-hypertensives Diuretics ACEi's K+ sparing diuretics Methotrexate
What is the effect of co-prescribing NSAIDs and oral anti-coagulants?
Increased risk of GI bleed due to combined anti-platelet effect
What is the effect of co-prescribing NSAIDs and anti-hypertensives/diuretics?
Reduced hypotensive effect
Reduced diuretic effect
What is the effect of co-prescribing NSAIDs and ACE inhibitors??
Hyperkalaemia
What is the effect of co-prescribing NSAIDs and methotrexate?
Increased methotrexate levels
What is the mechanism of methotrexate?
Competitive inhibition of dihydrofolate reductase
Also has other anti-inflammatory and cytokine modulating effects
In what conditions is methotrexate used?
RA
Psoriatic arthritis
Other AI conditions as a steroid-sparing agent
What is the common dose of methotrexate?
Weekly dose (7.5mg-20mg per week). May be taken as tablets or as an injection
Often taken in conjunction with folic acid on the other 6 days of the week.
Describe how a patient taking methotrexate is monitored?
FBCs, LFTs and U&Es every fortnight from when methotrexate is first prescribed until 6 weeks have passed with with no change in monitoring results at a stable dose. Monitoring is then monthly until the dose and disease is stable for 1 year. Thereafter, monitoring may be reduced in frequency, based on clinical judgement, and following discussion with specialist team, to every 2-3 months.
If a patient presents with certain symptoms, methotrexate should be withheld until management can be discussed with a specialist team. What are these symptoms?
- Rash or oral ulceration, nausea and vomiting, diarrhoea
2. New or increasing dyspnoea or dry cough
If a patient taking methotrexate presents with severe sore throat and abnormal bruising, what action should be taken?
Immediate full blood count and withhold until the result is available. Discuss any unusual results with specialist team.
Why is folic acid given in combination with methotrexate?
Reduce side effects, particularly mouth ulceration and nausea
For what conditions is hydroxychloroquinine prescribed?
RA
SLE
In which patients is hydroxychloroquinine not prescribed?
patients with existing maculopathy of the eye
What is the usual dose of hydroxychloroquinine?
Daily oral dose of 200-400mg at first. In well controlled RA may only be taken 2-3 times a week
What are the side effects of hydroxychloroquinine?
Common: GI problems e.g. vomiting, diarhhoea
Rare: corneal and macular retinopathy. Monitoring of eyes should be done at hospital appointments and patients should attend annual opticians appointments
What is the aim for patients taking biological agents?
Improvement in DAS28>1.2 points at 6 months
What is the DAS28 score?
The DAS28 is a measure of disease activity in RA. The score is calculated by a complex mathematical formula based on four variables:
- Tender joint count (out of 28 joints)
- Swollen joint count (out of 28 joints)
- ESR
- Patient’s global assessment of disease
What is score at which a patient is said to have active disease?
> 5.1
What is the score at which a patient is said to have well-controlled disease?
<3.2
What is the score at which a patient is said to be in remission?
<2.6
What is rituximab?
Rituximab is a biological agent used in RA in patients for whom anti-TNF therapy has failed. It works as an antibody against CD20 and depletes B-cells
How frequently is rituximab given?
No more than once every 6 months
Which 28 joints are included in DAS28?
Shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints and the knees
