1 DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016 RHEUMATOID ARTHRITIS Prevalence in UK = 1% The incidence of rheumatoid arthritis is approximately 25 to 30 per 100 000 per year (1.5 in men and 3.6 in women). Prevalence ----over 65years in males 1.9% ,in females 5% Peak onset = 30-50 years, although occurs in all age groups F:M ratio = 3:1 Some ethnic differences e.g. high in Native Americans Genetic --Associated with HLA-DR 1 and HLA-DR4 (especially Felty's syndrome). RA is associated with several antibodies such as RF, collagen antibody, capable of reaction at sites other than the joints (i.e. the disease is not confined to the joints). Damage is mediated by several means, including macrophages activated by CD4+ T cells, and by complement fixing immune complexes. Age : May present at any age Typical age in female ----child bearing years ((late)) In male ----6 th ---8 th decade 0nset: May be Fulminant (( almost over nieght)) More commonly insidious ---weeks to months Distribution : At onset ,20% monoarticular disease and 80% have multiple joint involvement. First small joints ---MCP ,MTP & PIP Later large joints ----knees ,elbows A number of studies have suggested a link between Proteus mirabilis infection and the development of RA in susceptible individuals, and this may contribute to the increased incidence of RA in women, who are more susceptible to UTI. PATHOGENSIS: Rheumatoid arthritis - TNF is key in pathophysiology TNF is important in the pathogenesis of rheumatoid arthritis. TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe RA. TNF is a pro-inflammatory cytokine with multiple roles in the immune system. TNF is secreted mainly by macrophages and has a number of effects on the immune system, acting mainly in a paracrine fashion: 1) Activates macrophages and neutrophils 2) Acts as co-stimulator for T cell activation 3) Key mediator of bodies response to Gram negative septicaemia
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
RHEUMATOID ARTHRITIS
Prevalence in UK = 1%
The incidence of rheumatoid arthritis is approximately 25 to 30 per 100 000 per
year (1.5 in men and 3.6 in women).
Prevalence ----over 65years in males 1.9% ,in females 5%
Peak onset = 30-50 years, although occurs in all age groups
F:M ratio = 3:1 Some ethnic differences e.g. high in Native Americans
Genetic --Associated with HLA-DR 1 and HLA-DR4 (especially Felty's syndrome).
RA is associated with several antibodies such as RF, collagen antibody, capable of
reaction at sites other than the joints (i.e. the disease is not confined to the joints).
Damage is mediated by several means, including macrophages activated by CD4+ T
cells, and by complement fixing immune complexes.
Age :
May present at any age
Typical age in female ----child bearing years ((late))
In male ----6th ---8th decade
0nset:
May be Fulminant (( almost over nieght))
More commonly insidious ---weeks to months
Distribution :
At onset ,20% monoarticular disease and 80% have multiple joint involvement.
First small joints ---MCP ,MTP & PIP
Later large joints ----knees ,elbows
A number of studies have suggested a link between Proteus mirabilis infection and the development of RA in susceptible individuals, and this may contribute to the increased incidence of RA in women, who are more susceptible to UTI.
PATHOGENSIS:
Rheumatoid arthritis - TNF is key in pathophysiology
TNF is important in the pathogenesis of rheumatoid arthritis. TNF blockers (e.g. infliximab,
etanercept) are now licensed for treatment of severe RA.
TNF is a pro-inflammatory cytokine with multiple roles in the immune system.
TNF is secreted mainly by macrophages and has a number of effects on the immune system, acting
mainly in a paracrine fashion:
1) Activates macrophages and neutrophils
2) Acts as co-stimulator for T cell activation
3) Key mediator of bodies response to Gram negative septicaemia
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
In RA, RF is positive in 80% of patients, whereas in Sjogren’s syndrome and cryoglobulinaemia, it is prevalent in up to 90% of cases.
Anti-CCP Ab (Anti-cyclic citrullinated peptide antibodies)
Anti-cyclic citrullinated peptide antibody may be detectable up to 10 years before
the development of rheumatoid arthritis.
It may therefore play a key role in the future of rheumatoid arthritis, allowing
early detection of patients suitable for aggressive anti-TNF therapy.
It has sensitivity similar to rheumatoid factor (70-80%, see below) with a much
higher specificity of 90-95%.
NICE recommends that patients with suspected RA with RF negative should be
tested for Anti-CCP Abs.
Anti-CCP antibodies are associated with rheumatoid arthritis (highly specific)
STAGES OF THE DISEASE:
1. RECENT ONSET DISEASE:
Patients meet ACR criteria for the diagnosis and classification of RA and have had evidence
of active disease for a period not more than 3 months.
2. ESTABLISHED OR PERSISTENT DISEASE:
Is characterized by active, well-defined disease for at least 6 months to 12 months .
Significant and irreversible damage may be observed at this stage, leading to functional
disability.
3. END-STAGE DISEASE:
Manifest significant destruction of previously involved joints and other affected organs but
may have little or no evidence of ongoing inflammation.
SYMTOMS AND SIGNS: ----pain ,swelling ,stiffness dominating in the morning
The RA may have a fulminant presentation or insidious course or pain with swelling and
stiffness for months or years before diagnosis.
RA may present with monoarthritis ,oligoarthritis before typical symmetrical polyarthritis.
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Systemic :
Low grade fever < 38 c
Fatigue
Malaise
Chronic anemia
Elevation of ESR
Articular manifestation:
Any synovial joint may be affected
Is symmetric from one side to the
body to other.
Is symmetric within the individual
joint with the entire joint surface
area involved ex; knee , the
medial and lateral compartments are both severely narrowed in RA.
Most commonly ---MCP ,PIP ,MTP followed by wrists ,knees, elbows ,ankles , hips&
shoulders.
AIM ----early diagnosis enable for early treatment to limit the number of joints involved.
It may involve tempomandibular ,cricoarytenoid ,sternoclavicular joints.
DIP is spared and involved in osteoarthritis and psoriasis.
Patients with RA are at an increased risk of osteoporosis.
RHEUMATOID ARTHRITIS AND OSTEOPOROSIS ARE COMMON &COEXSIST.
Deformities :
1. Ulnar deviation
Ulnar deviation, also known as ulnar drift, is a hand deformity in which the swelling of the
metacarpophalangeal joints (the big knuckles at the base of the fingers) causes the fingers
to become displaced, tending towards the little finger. Its name comes from the
displacement toward the ulna . Ulnar deviation is likely to be a characteristic of
rheumatoid arthritis, more than of osteoarthritis.
2. Swan neck deformity: The swan neck deformity is caused by joint swelling
and associated tenosynovitis with subsequent
contracture of the intrinsic (lumbrical and
interosseous) hand muscles. There is flexion at the
metacarpophalangeal, hyperextension at the
proximal interphalangeal, and flexion at the distal
interphalangeal joint evident in fingers, especially the
third, fourth, and fifth, but to a lesser extent also in
the index finger. In early disease the deformity can be passively corrected; later, functional
impairment may result from inability to flex at the proximal interphalangeal joint so that the patient
is unable to make a fist.
3. Button hole deformity Boutonniere deformity is a deformed position of the
fingers or toes, in which (PIP) is permanently bent
toward the palm while the farthest joint (DIP) is bent
back away (PIP flexion with DIP hyperextension). It is
commonly caused by injury or by an inflammatory
condition like rheumatoid arthritis, or genetic
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
conditions like Ehlers Danlos Syndrome.
This flexion deformity of the proximal interphalangeal joint is due to interruption of the central slip
of the extensor tendon such that the lateral slips separate and the head of the proximal phalanx pops
through the gap like a finger through a button hole (thus the name, from French boutonnière "button
hole"). The distal joint is subsequently drawn into hyperextension because the two peripheral slips of
the extensor tendon are stretched by the head of the proximal phalanx (note that the two peripheral
slips are inserted into the distal phalanx, while the proximal slip is inserted into the middle phalanx).
This deformity makes it difficult or impossible to extend the proximal interphalangeal joint.
4. Tendon rupture Rupture of the extensors of the fourth and fifth digits is caused by active synovitis and invasive
synovial proliferation. Wrist instability with prominence of the eroded ulnar styloid process can also
shear the ulnar tendons.
If the clinical disease remains active ,hand function will slowly deteriorate.
The wrists ---radial deviation ,volar subluxation ,carpel tunnel
syndrome
The feet ((MTP)) Involved early in almost all cases
Are secondary only to hand involvement in problems
Subluxation of the toes at MTP is common and leads to the dual problem of
skin ulceration on the top of toes and painful ambulation.
Synovial cyst:
A Baker's cyst((popliteal cyst)) is a benign swelling of the semimembranosus or more rarely some other
synovial bursa found behind the knee joint. (( William Morrant Baker (1838–1896) )). This is not a "true" cyst,
as an open communication with the synovial sac is often
maintained.
Baker's cysts arise between the tendons of the medial head of
the gastrocnemius and the semimembranosus muscles. They
are posterior to the medial femoral condyle.
The knee produces excess synovial fluid that may accumulate
in the poplitael space.
The synovial sac of the knee joint can, under certain
circumstances, produce a posterior bulge, into the popliteal
space. When this bulge becomes large enough, it becomes
palpable and cystic. Most Baker's cysts maintain this direct
communication with the synovial cavity of the knee, but sometimes, the
new cyst pinches off. A Baker's cyst can rupture and produce acute pain
behind the knee and in the calf and swelling of the calf musclesThe cyst
may cause problems by:
A. Pressing on the popliteal nerve ,artery and vein
B. Rupture
C. May dissect into the tissues of the calf
Dissections may produce only minor symptoms ,feeling of
fullness.
Rupture of the cyst with extravasation of the inflammatory content produce significant pain and
swelling which may be confused with thrombophlebitis or DVT.
Diagnosis:
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
1. CLINICALLY: Diagnosis is by examination. A Baker's cyst is easier to see from behind with
the patient standing with knees fully extended.
It is most easily palpated (felt) with the knee
partially flexed.
2. DOPPLER USS: Diagnosis is confirmed by
ultrasonography, although if needed and there is
no suspicion of a popliteal artery aneurysm then
aspiration of synovial fluid from the cyst may be
undertaken with care.
3. MRI: An MRI image can reveal presence of a
Baker's cyst.
Baker's cyst on axial MRI with communicating channel
between the semimebranosus muscle and the medial head
of the gastrocnemius muscle.
An infrequent but potentially life-threatening complication is
a deep vein thrombosis (DVT). Quick assessment of the
possibility of DVT may be required where a Baker's cyst has
compressed vascular structures, causing leg edema, as this
sets up conditions for a DVT to develop.
A burst cyst
commonly causes
calf pain, swelling
and redness that
may mimic
thrombophlebitis.
Treatment -----
intra-articular
glucocorticoids
1. Baker's cysts usually require no treatment unless they are symptomatic.
2. Initial treatment should be directed at correcting the source of the increased fluid production.
3. Often rest and leg elevation are all that is needed.
4. If necessary, the cyst can be aspirated to reduce its size, then injected with a corticosteroid to reduce
inflammation.
5. Surgical excision is reserved for cysts that cause a great amount of discomfort to the patient.
6. A ruptured cyst is treated with rest, leg elevation, and injection of a corticosteroid into the knee.
7. Recently, prolotherapy has shown encouraging results as an effective way to treat Baker's cysts and
other types of musculoskeletal conditions.
8. Cryotherapy
Ice pack therapy may sometimes be effective way of controlling the pain caused by Baker's cys
The spine ----most of the spine is spared except C1 C2 articulation.
RA have cervical spine involvement between 11% and 58% of these patients having neurological involvement.
Many of these patients have cervical myelopathy.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
Whatever the underlying disease process, the compression is usually progressive and will often require surgical
intervention to prevent further disability. Many patients experience significant improvement in symptoms
after surgery, so operative intervention should be considered for almost all patients.
Epidemiology
Cervical myelopathy is more common in men and tends to present earlier than in women. Changes
are more common in patients with RA where 85% of those with moderate to severe disease will
have x-ray changes Bony ,erosions and ligament rupture .
Subluxation is the end result.
The underlying cause of the condition is compression of the long tracts in the spinal cord. The
normal diameter of the cervical spinal canal is between 17 mm and 18 mm. When this diameter
falls below 12 mm to 14 mm for any reason this is likely to cause stenosis and myelopathic
symptoms. The average diameter of the spinal cord in the cervical spine is 10 mm.
Symptoms:
Patients may present with a range of symptoms and many of these are non-specific. It is important to
remember that although cervical myelopathy is a disease of the cervical spine it may manifest with
lower as well as upper limb symptoms.
The classical presentation is loss of balance with poor coordination, decreased dexterity, weakness,
numbness and in severe cases paralysis. Pain is a symptom in many patients but it is important to
remember that it may be absent which often leads to a delay in diagnosis. In older patients it often
manifests with a rapid deterioration of gait and hand function.
Common presenting complains are:
heavy feeling in the legs
poor exercise tolerance
radiculopathy
poor fine motor skills
L’Hermitte’s phenomenon - intermittent electric shock sensations in the limbs,
exacerbated by neck flexion
numbness and tingling in the limbs
Late in the disease where compression is severe, if surgical decompression is not
performed the symptoms progress to sphincter dysfunction and quadriparesis. CSM is the
most common cause of acquired spastic paraparesis in adults.
Examination findings
Patients present with a number of clinical findings which are predominantly upper motor neuron
signs.
Weakness is more severe in the upper limbs.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
Ataxic broad based gait.
Hypertonia .
Hyperreflexia .
Ankle clonus - (more than three beats is considered pathological).
Babinski sign .
Hoffman’s reflex - flicking of the terminal phalynx of the middle or ring finger
causing concurrent flexion at the terminal phalynx of the thumb and index finger.
Finger escape sign - the small finger spontaneously abducts due to weak intrinsic
muscles.
DIAGNOSIS:
Where instability is suspected to be the cause of symptoms (especially in RA) flexion and
extension views of the cervical spine will show abnormal motion
Advice ------ TO AVOID NECK FLEXSION
Atlanto axial subluxation
Cervical dislocation Spinal cord copmression
The cricoarytenoid ----responsible for adduction and abduction of vocal cords.
If involved , it manifest as feeling of fullness in throat ,hoarsness ,stridor ,acute respiratory
stress
The extra articular manifestation:
More common in patients with positive rheumatoid factor.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
1. Subcutaneous nodules:
o Seen in 25% of RA with positive RF
o Patient with nodules but negative RF should be
carefully evaluated for an alternative diagnosis ---
((GOUT))
o May occur anywhere ----lungs ,heart ,eyes
o Occur most commonly subcutaneous on extensor
surface ,over joints or pressure joints ,sacrum
,occipit.
o Non tender ---unless traumatized
o Firm ,have a characterized histologic picture
,triggered by
small vessel
vasculitis.
o A
syndrome of increased nodulosis
((despite good control of the
disease )) has been described with
methotrexate.
o Have a central area of
fibrinoid necrosis surrounded by a
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
zone of palisades of elongated histocytes and peripheral layer of
connective tissue
2. Vasculitis : Rheumatoid Vasculitis (RV) is an
unusual complication of longstanding,
severe rheumatoid arthritis. The active
vasculitis associated with rheumatoid
disease occurs in about 1% of this
patient population.
RV is a manifestation of “extra-
articular” rheumatoid arthritis and
involves the small and medium-sized
arteries in the body. In many of its
disease features, RV resembles
polyarteritis nodosa.
Symptoms depend on which
arteries are involved and which organ
they supply blood to.
For instance, if there is vasculitis of
arteries that supply the skin, then
symptoms will vary with the area of skin
to which the affected artery supplies
blood. If say the artery supplies blood to
the fingertips and nails, then the area
around the tips of fingers and nails may
become red and swollen. If larger arteries
and veins are involved, then painful red
rashes may appear on the hands and legs.
Excessive inflammation may lead to
formation of ulcers, and managing them
can be an uphill task.
If vasculitis involves the nerves, there may
be a loss of sensation leading to
weakness and a tingling sensation in hands and feet.
Vasculitis that affects larger arteries can lead to complete blockage of blood supply to
hands and feet, causing gangrene of the toes and fingers. The worst cases could display
stomach pain, cough, chest pain, heart attack, stroke etc.
Systemic vasculitis, which spreads to multiple organs from the original site usually also,
shows up as fever, loss of appetite, loss of energy and weight loss.
a) Digital infarcts
b) Leucocytoclastic vasculitis --- palpable purpura --if present DMARDS is
adviced.
c) Pyoderma gangrenosum
The ulcer is extensive and threatens the underlying bone.
3. CVS:
Uncommon
Increased mortality & mobidity from CAD.
Risk factors --- sedentary life ,medications , chronic inflammations
Pericardial effusion
Common
Detected in 50% of patients by ECHO.
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Asymptomatic
Can cause constrictive pericarditis
Heart block by rheumatoid nodules.
PERICARDITIS Pain 1% .can lead to temponade ,constriction((in 30%)) NODULES Causes conduction abnormalities and valvular CORONARY ARTERITIS Causes IHD ((RA carries a similar risk to T2DM)) ,MI , CCF MYOCARDITIS
Rheumatoid arthritis: patients have an increased risk of IHD
Baseline x-ray of hands and feet. Repeated 6-12 monthly. CT scan, USS, MRI are more sensitive.
CBP---anemia :
Seen in the majority of patients
Proportional to the activity of disease
Therapy that controls the disease will result in normalization of HB
Thrombocytopenia is common.
Acute phase reactants:
ESR and CRP parallel the activity of disease
Persistent elevation carry poor prognosis with joint destruction and
mortality
WBC: increased /decreased
DIAGNOSIS:
There is no single finding on physical examination or laboratory testing that is
pathognomic for RA.
NICE have stated that clinical diagnosis is more important than criteria such as
those defined by the American College of Rheumatology.
The most commonly used classification criteria are the American College of
Rheumatology criteria. These criteria do not perform well in early disease.
The criteria for diagnosis :
A) Not designed specifically for diagnosis ,used as diagnostic aid.
B) The first five criteria are all clinical ,met by physical examination /talking
to the patient.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
C) The first four criteria need to be present for at least 6 weeks before
diagnosis of RA can be made. WHY?
Many viral related syndromes often cause self limited polyarthritis that
looks identical to RA but usually lasts 2—3 weeks .
This leads to delay of diagnosis and therapy of RA.
Rheumatoid arthritis is a clinical diagnosis.
The diagnosis reguires the presence of inflammation.
The classic features are:
Symmetrical inflammatory polyarthritis
Arthritis affecting the small joints of the hands and feet.
Diagnostic tests are:
1) RF: there are many false positive and negatives.
2) Anti CCP antibody: more specific for rheumatoid arthritis.
3) ANA: present in 20-30% of patients with rheumatoid arthritis.
Target population. Patients who
1) Have at least 1 joint with definite clinical synovitis
2) With the synovitis it is not better explained by another disease
Classification criteria for rheumatoid arthritis (add score of categories A-D; a
score of 6/10 is needed definite rheumatoid arthritis)
Aletaha et al. 2010 Rheumatoid arthritis classification criteria: an American
College of Rheumatology / European League Against Rheumatism
collaborative initiative
A. Joint involvement 1 large joint 0
2 - 10 large joints 1
1 - 3 small joints (with or without involvement of large joints)
2
4 - 10 small joints (with or without involvement of large joints)
3
10 joints (at least 1 small joint) 5
B. Serology (at least 1 test result is needed for classification)
Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
C. Acute-phase reactants (at least 1 test result is needed for classification)
Normal CRP and normal ESR 0
Abnormal CRP and abnormal ESR 1
D. Duration of symptoms < 6 weeks 0
> 6 weeks 1
WHAT ARE THE X RAY CHANGES?
Early x-ray findings:
soft-tissue swelling
loss of joint space
Periarticular (juxta-articular) osteopenia and
osteoporosis
Periarticular decalcification
Late x-ray findings:
o Periarticular erosions
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
o Subluxation
In the early stages of an insidious onset of the RA
disease, the acute phase markers CRP and ESR are
often normal, particularly when small joints are
involved.
o At this stage of early RA , the diagnostically most
informative test is hand and feet X-ray which
shows periarticular osteopenia and marginal
erosions at affected joints.
o Foot joints are often radiologically affected
beforehand joints
Periarticular osteopenia and osteoporosis would point towards a diagnosis of (RA). Loss of joint space is common in both RA and OA also in Pseudogout
1- mild disease:
Arthralgia.
At least 3 inflamed/swollen joints.
No extra-articular disease.
Negative or positive RF and/or anti-CCP Ab.
High ESR or serum C-RP.
NO evidence of erosions or cartilage loss on plain radiographs.
2-Moderate disease:
6-20 inflamed joints.
No extra-articular disease.
High ESR and C-RP.
Positive RF and/or anti-CCP Ab.
Evidence of inflammation on plain radiographs: osteopenia, peri-articular swelling,
minimal joint space narrowing and small peripheral erosions.
3- Severe disease:
>20 Persistently inflamed joints, or rapid decline in functional capacity.
High ESR, C-RP.
Anemia of chronic disease.
Hypo-albuminemia.
Positive RF( often high titer) and/or anti-CCP Ab.
Extra-articular disease.
Plain radiographs demonstrating rapid progression of bony erosions and loss of cartilage
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TREATMENT:
There is no cure for RA.
It is a lifelong disease process that requires lifelong therapies.
The patient-physician interaction is mandatory.
For care of RA patients ,we need :
1. Primary care physicians
2. Rheumatologist
3. Physical therapist
4. Occupational therapist
5. Orthopedic surgeons
The goal of therapy for RA is :
A) To put the disease in remission
B) To maintain the remission
Non-pharmacological and preventive treatment 1-Pateints education and counseling:
About the disease. Remove miss-concepts. Treatment strategies and plan.
2-REST. 3-EXERCISES:
Exercises to increase muscle strength (isometric, isotonic and iso-kinetic) Aerobic exercises: walking, swimming and cycling.
4-PHYSICAL THERAPY: Application of heat and cold. Rest and rest splinting. Passive and active exercises. Relaxation techniques.
4- OCCUPATIONAL THERAPY: Education regarding joint protection and self-care. Assistive devices and splints.
5-NUTRITION AND DIATRY THERAPY: Anorexia should be treated. Diet rich in fish oil. Decrease body weight.
6-BONE PROTECTION: Bone loss due to: disease, immobility, use of GC. Limit use of GC to < 6 months and doses <7.5 mg/day. Elemental calcium 1000-1500 mg /day and 400-800 IU of vitamin D /day. Consider anti-resorptive therapy with a bisphosphonate.
7-MODIFYING RISK FACTORS FOR ATHEROSCLEROSIS: Increased risk of CAD associated mortality and morbidity. Modify risk factors: cigarette smoking, hyper-lipidemia, HTN, sedentary life style. Consider HMG-COA reductase inhibitors.
8-VACCINATIONS: Patients receiving immuno-suppressive drugs should not receive live vaccines. If otherwise indicated use killed viruses or poly-saccharide vaccines.
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Patients with evidence of joint inflammation should start a combination of disease
modifying drugs (DMARD) as soon as possible.
Other important treatment options include analgesia, physiotherapy and surgery.
Initial therapy:
In NICE guidelines it is recommend that patients with newly diagnosed active RA
start a combination of DMARDs (including methotrexate and at least one other
DMARD, plus short-term glucocorticoids) (EX: Methotrexate + sulfasalazine +
short-course of prednisolone as bridging therapy).
DMARDs:
a. Methotrexate is the most widely used DMARD.
b. Sulfasalazine (500 mg tab)
c. Leflunomide (Arava® 20 mg tab)
d. Hydroxychloroquine (HCQ) (plaquenil® 200 mg tab): less effective.
1. NSAIDS: Important for symptomatic relief
They play a minor role in altering the disease process
Many clinicians waste valuable time switching from one NSAIDS to another before starting DMARD
therapy.
COX 2 agents are used more widely with small doses of aspirin.
Two types of COX:
COX-1: constitutional, vasodilatation, increase PG synthesis, and inhibit PLT aggregation.
Folic acid 5mg once daily should be co-prescribed, taken more than 24 hours after methotrexate
dose. Only one strength of methotrexate tablet should be prescribed (usually 2.5 mg).
Avoid prescribing trimethoprim or cotrimoxazole concurrently - increases risk of marrow aplasia.
NB: Methotrexate is a folic acid antagonist which can result in multi-organ failure in overdose. Folinic acid (Calcium folinate) (Leucovorin) IVI is the antidote for the effect of methotrexate on the haematopeic system and should be given IV infusion as soon as possible, regardless of the liver function tests Dose: 75 mg in the first 12 hrs, and can then be followed by 6-12 mg every 4 hrs. Blood transfusion may be required in exceptional circumstances. Supportive measures by good hydration and urinary alkalinization may be used. Standard dialysis is ineffective in removing methotrexate, although intermittent high flux dialysis may be of value.
Complications to be in mind due to methotrexate:
An MCV greater than 105 fL warrants checking B12, folate and TSH and treating any abnormality.
Liver function tests should be checked 3 monthly.
Urea, C. and electrolytes should be checked 6 monthly (( eGFR < 50 mL/minute –stop methotrexate)
In addition to this monitoring, any clinical signs of toxicity should be monitored for. If the patient
develops rash, oral ulceration, sore throat, easy bruising or bleeding, shortness of breath,
abdominal pain, nausea, vomiting, diarrhoea or jaundice, methotrexate should be withheld until
discussed with the specialist team.
In the setting of acute infection, most DMARDs (except hydroxychloroquine) should be discontinued until the infectious process has resolved. IF patient on methotrexate and develop lower respiratory tract infection with normal CXR, CBC, LFTs, U&E. The most appropriate action is to Stop methotrexate temporarily + Antibiotics (oral/IV).
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Methotrexate-related lung toxicity:
A large spectrum of diseases ranging from interstitial pneumonitis to cough, pleuritic chest pain
and SOB related to lung infiltration, associated with bilateral pleural effusions.
TTT: Methotrexate withdrawal and replace with anti-TNF or anti-CD20 antibody.
Sulfasalazine
PHARMACOLOGY:
3O% absorbed rapidly by small intestine and then returned via entero-hepatic circulation
into bile unaltered.
90% of the ingested drug reaches the large intestine as an intact molecule.
In the colon sulfasalazine is reduced by action of bacterial enzyme……Azoreductase to
sulfapyridine and 5-ASA.
All sulfapyridine is absorbed and 5-ASA is largely excreted in feces.
Sulfapyridine is subsequently metabolized in liver via hydroxylation and acetylation.
The half-life of the drug is prolonged in slow acetylators.
MECHANISMS OF ACTION:
Sulfapyridine is the active moiety in RA.
Mechanism of action is uncertain in RA.
Inhibition of a nuclear factor kappa B …….decrease in inflammatory cytokines.
Inhibition of TNF-a expression via apoptosis of macrophages.
Chloroquine decreases bioavailability of MTX. Cimetidine decrease chloroquine clearance by 50%
Cigarette smoking increases metabolism of antimalarial drugs. Actions:
Changes the acid milieu of the cell---lysosomotropic effect Decreseas lymphcyte proliferation. Decreases TNF-ALPHA. HC has a mild anti-coagulant effect.
DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
2-Skin changes: skin rash occurs in 10% of patients with HC and chloroquine. Hyperpigmentation of skin hypopigmentation of hair. Quinacrine causes yellowish discoloration of skin.
3-Ophthalmologic disease: Corneal deposit Retinopathy: permanent vision loss occurs in 3-4% of patients on HC, and in 10% of
5- Weight loss. > 10%-----weather decrease the dose or stop it
6-neuropathy.
Generally, most hepatic events occur within the first 6 months of use. It is recommended liver
function tests (LFTs) be checked monthly for 6 months and, if stable, 2 monthly thereafter.
If AST or ALT is between 2 and 3 times the upper limit of normal, and the leflunomide dose is more
than 10 mg daily, the dose should be reduced to 10 mg and LFTs rechecked weekly until normalised.
Azathioprine (Imuran)
Azathioprine is metabolised to the active compound mercaptopurine, a purine analogue that
inhibits purine synthesis (inhibits DNA synthesis). A thiopurine methyltransferase (TPMT) test may
be needed to look for individuals prone to azathioprine toxicity.
Azathioprine - check thiopurine methyltransferase deficiency (TPMT) before treatment
Thiopurine methyltransferase (TPMT) deficiency is present in about 1 in 300 people and predisposes to azathioprine related pancytopenia. The enzyme activity of TPMT is under the control of a genetic polymorphism. 90% of the population have normal or high enzyme activity, that is, are homozygous for the wild-type allele. 10% of the population have intermediate levels of TPMT activity, that is, one wildtype and one variant allele. One in 300 people have no functional enzyme activity.
Adverse effects include:
1) Bone marrow depression >>> Pancytopenia
2) Hepatotoxicity
3) Pancreatitis
4) Nausea/vomiting
A significant interaction may occur with allopurinol and hence lower doses of azathioprine should
be used (so you may give only 25% of the usual dose of azathioprine).HOW?
The prodrug azathioprine is metabolised to its active compound 6-mercaptopurine (6-MP).
6-MP undergoes catabolic oxidation to 6-thiouric acid by xanthine oxidase.
Allopurinol has a peak onset of action of one to two weeks and works by inhibiting
xanthine oxidase.
Co-administration of these drugs (Imuran + Allopurinol) may lead to accumulation of 6-MP
(6-MP toxicity) and increases the risk of myelosuppression (aplastic anaemia).
The newer xanthine oxidase inhibitor, Febuxostat, can also result in the same problem and
is also contraindicated.
Febuxostat is a non-purine, selective xanthine oxidase inhibitor unlike allopurinol, which is
a purine analogue inhibitor of xanthine oxidase.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
Anti-cytokine therapy in RA --TNF-inhibitors (Biologic therapy):
THE CONCEPT:
T-CELL SUBSETS:
Th1 cells:
Act as inflammatory cells.
Induce cell-mediated response, which predominate in : RA, acute allograft rejection, GVH
disease, psoriasis, PSA.
Secrete the following pro-inflammatory cytokines:
1. IL-2
2. IFNg
3. TNF-a
4. IL-15
5. IL-18
Th2 cells:
A. Stimulate Ab production by B cells.
B. Augment eosinophil response.
C. Stimulation of Th2 cells is associated with chronic GVH disease, SLE, PSS
D. Th2 cells secrete the following cytokines:
1. IL-4
2. IL-5.
3. IL-9.
4. IL-10.
5. IL-13.
Down-regulation of pro-inflammatory cytokines
IL-1b and TNF-a are considered to be the major pro-inflammatory cytokines
involved in the pathogenesis of RA and chronic inflammatory diseases.
Secreted by synovial macrophages…proliferation of synovial cells and increase
synthesis of collagenase….degrading cartilage, bone resorption and inhibit
proteoglycan synthesis.
IL-1b and TNF-a also induce the expression of cellular adhesion
molecule……inflammatory cell recruitment……release more cytokines.
To down-regulate or inhibit the effector function of these cytokines in vivo:
4 general approaches have been used:
1-Cell surface receptor antagonist.
2-Soluble receptor antagonist.
3-Anti-bodies.
4-Anti-sense oligodeoxynucleotides
Up-regulation of inhibitory cytokines
IL-10, IL-4 suppress Th1 responses.
IL-10 up-regulates IL-1ra
The current indication for a TNF-inhibitor is an inadequate response to at least two DMARDs
including methotrexate
Adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelination.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
The risk of TB reactivation is most pronounced in the first 3 months of treatment.
The current British Thoracic Society BTS guidelines therefore recommend a clinical examination,
chest radiograph and thorough history taken to check for prior TB.
In the UK, patients have a baseline CXR and assessment of risk of infection with Mycobacterium
tuberculosis prior to starting treatment with anti-TNF α.
Any patient with an abnormal chest radiograph or previous history of TB should be referred for
assessment by a specialist with an interest in TB.
Those with symptoms raising a suspicion of TB should be thoroughly investigated to exclude active
disease.
Any patient with active TB, either pulmonary or non-pulmonary, should receive standard
chemotherapy. They must complete 2 months full treatment before starting anti-TNF alpha
treatment.
Patients with an abnormal chest radiograph consistent with past TB, or a history or prior extra
pulmonary TB but who have received previous adequate therapy can be started on anti-TNF alpha
therapy but need to be monitored regularly.
Where there is an abnormal chest radiograph, or a history of prior pulmonary or extra pulmonary TB
not previously adequately treated, chemoprophylaxis with isoniazid for 6 months should be given
before commencing anti-TNF alpha treatment.
The BTS guidelines have not been updated to include recommendations regarding Quantiferon Gold
test and Elispot tests. Practice does vary between individual NHS trusts regarding who to test with
one of these, and which to use. However, the most accepted recommendations are that patients who
test positive with either of these should be treated with chemoprophylaxis (either isoniazid for 6
months, or dual therapy Rifampicin + INH for 2 months) at the same time as being started on anti-
TNF alpha treatment.
For patients with a normal chest radiograph who have not started immunosuppressive therapy, a
tuberculin test is helpful.
TNF-inhibitors should be stopped 2-4 wks before any major operation. Stopping earlier may lead to disease flare and thus interfere with the surgery.
Treatment may be restarted postoperatively if there is no evidence of infection
Examples of anti-TNF alpha agents: o Etanercept, o Infliximab, o Adalimumab,
B-cell directed therapies have the potential to ameliorate inflammatory arthritis through a variety of mechanisms:
Impairing auto-anti-body production. By disrupting B cell/T cell cross-talk. By interfering with the antigen presentation or cytokine production.
Rituximab: ((B-cell depleting agents))
Anti-CD20 monoclonal antibody, results in B-cell depletion.
MECHANISM OF ACTION:
Lymphocytes of the B cell lineage undergo an orderly developmental process that includes
the surface expression of CD20, which is B lymphocyte –specific molecule , beginning at the
pre-B cell stage.
Expression of CD20 on the surface of B cells decrease or absent as B cell differentiate into
plasma cells.
RITUXIMAB causes B cell depletion through one of several mechanisms:
1. Fc receptor gamma-mediated Ab dependent cytotoxicity.
2. Complement mediated cell lysis.
3. Growth arrest.
4. B cell apoptosis.
Decreased or absent CD20 protein expression on surface of plasma cells is likely to account for the resistance of these cells to rituximab. As a consequence Ig levels are usually little changed, despite profound lymphopenia that persists for months after a single course of treatment. But level of auto antibodies with a potential role in disease pathogenesis are affected by B cell depletion e.g RF in RA , ANCA in vascultis
Two 1g intravenous infusions are given two weeks apart.
B CELL DEPLETION:
Within 2-4 weeks B cells in peripheral blood reach to undetectable levels.
Remain 6-12 months.
Ig levels:
A small proportion of patients may have Ig levels below the normal levels.
AUTO-ANTIBODIES: RF is significantly reduced.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
The most common side effects:
1) 1-INFUSION REACTIONS:
Common, hypotension, hypertension, skin rash , pruritus, nausea and back pain……..due
and Fc protein of IgG1, CTLA-4 –Ig. It prevents CD28 from binding to its counter receptor, B7-1/B7-2.
Fusion protein that modulates a key signal required for activation of T lymphocytes
Leads to decreased T-cell proliferation and cytokine production
Given as an infusion , Not currently recommend by NICE
In Pregnancy:
Methotrexate (teratogenic) and NSAIDs (1st trimester, risk of abortion) so they are
absolutely contraindicated.
Prednisolone, Sulfasalazine and hydroxychloroquine are safe in pregnancy if these
are necessary for treatment of the mother's disease.
Sulfasalazine can be safely used prior to and during all stages of pregnancy, it is
compatible with breast feeding, although should be advised with cautions because
of the rare possibility that the mother is a slow acylator.
Azathioprine can be used in pregnancy if Sulfasalazine and hydroxychloroquine
are not controlling.
Prednisolone and hydroxychloroquine may be taken whilst breast-feeding.
Azathioprine, cyclophosphamide, methotrexate and cyclosporine are
contraindicated in breast-feeding mothers.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016
Azathioprine can be used during pregnancy if the benefits outweigh the risks.
Azathioprine can be continued at the same dose. No apparent congenital
malformations are known with doses up to 2mg/kg/day.
During pregnancy >>> continue current dose of azathioprine and add folic acid.
Breast feeding is not recommended with azathioprine.
Corticosteroids, the main alternative to azathioprine, are considered relatively safe in pregnancy
when used in low dose ˂ 20 mg daily. However they may increase the maternal risk of HTN,
oedema, gestational diabetes, osteoporosis, premature rupture of membranes (PROM), small-
forgestational-age babies (SGA), and increase in risk of cleft palate in foetus of first trimester. The
lowest possible steroid dose needed to control activity should be used in pregnancy if the choice is
to follow this option. The routine use of oral calcium and Vit D is recommended. Stress doses of
steroids should be used during labour and delivery if the mother received steroids (even low dose)
for more than 2-3 weeks during pregnancy, and the neonate should be monitored for evidence of
adrenal insufficiency and infection.
2002 ACR
Establish diagnosis of RA early Document baseline disease activity + damage Estimate prognosis
Initiate therapy a. Patient education b. DMARDS within 3 months c. Consider NSAID d. Consider local / low dose systemic steroids e. Physical therapy , occupational therapy
PERIODICALLY ASSESS THE DISEASE ACTIVITY
Adequate response with decreased disease activity
Inadequate response Ongoing active disease after 3 months of maximal therapy.
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DR MAGDI AWAD SASI RHEUMATOID ARTHRITIS DIAGNOSIS NOT TO BE MISSED 2016