rheumatoid arthritis --dr magdi sasi 2016

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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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4) Similar properties to IL-1

5) Anti-tumour effect (e.g. phospholipase activation)

TNF-alpha binds to both the p55 and p75 receptor. These receptors can induce apoptosis. It also

causes activation of NFkB.

Endothelial effects include increase expression of selectins and increased production of platelet

activating factor, IL-1 and prostaglandins.

TNF promotes the proliferation of fibroblasts and their production of protease and collagenase. It is

thought fragments of receptors act as binding points in serum.

Systemic effects include pyrexia, increased acute phase proteins and disordered metabolism

leading to cachexia.

Contraindications of usage of TNF- alpha antagonist:

1. Active infection

2. Active TB

3. MS (Multiple sclerosis)

4. Heart failure (NYHA grade 3-4).

5. Pregnancy

6. Breast feeding

WHAT IS THE SIGNIFICANT OF RF?

Rheumatoid factor (RF) is a circulating antibody (usually IgM) which reacts with the Fc

portion of the patients own IgG.

Rheumatoid factor is an IgM antibody with reactivity against Fc portion of IgG

RF can be detected by either:

1)Rose-Waaler test: sheep red cell agglutination –2) Latex agglutination test (less specific)

RF is positive in 70-80% of patients with rheumatoid arthritis; high titer levels are

associated with severe progressive disease (but NOT a marker of disease activity).

A positive rheumatoid factor is associated with:

More severe erosive disease

Extra-articular manifestations including subcutaneous nodules and

Increased mortality.

Other conditions associated with a positive RF include:

1. Sjogren's syndrome (around 100%)

2. Felty's syndrome (around 100%)

3. Infective endocarditis (= 50%)

4. Mixed cryoglobulinaemia (types II and III) (40 to 100%)

5. SLE (= 20-30%)

6. Systemic sclerosis (= 30%)

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7. Polymyositis/dermatomyositis - 5 to 10%

8. General population (= 5%)

9. Rarely: TB, HBV, HIV, EBV, leprosy, syphilis, brucellosis.

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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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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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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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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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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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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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

4. Respiratory system: ((pleura, airways ,parenchyma))

1) Pleural effusion :

More commonly in male ,small and asymptomatic

Characterized by cellular exudates ,high protein,cholestrol &LDH ,low glucose&PH

D/D Empyema

2) Rheumatoid nodules:

May occur in the lung , usually subpleural especially in men.

It is usually solid ,single or multiple which may calcify ,cavitate or become infected.

An aggressive diagnostic work up should be performed when rheumatoid nodules are

detected.

3) Diffuse interstitial fibrosis & bronchiectasis :

52 year old man with seropositive rheumatoid arthritis who presented with dyspnea

and hypoxemia. AP chest x-ray showed increased interstitial markings with volume

loss and tracheal deviation. CT scan showed honeycombing and traction bronchiectasis

consistent with interstitial lung disease associated with rheumatoid arthritis.

Typical finding ---Dyspnea with honeycombing((peripheral& central changes)).

Symptomatic and aggressive in < 10%

4) BOOP:

Carry poor prognosis

May occur with D penicillamine or gold therapy

Patient have dyspnea ,hyperinflated chest x ray and small airways obstruction on PFT.

5) Methotrexate pneumonitis (it is potentially life-threatening and occurs in 1-5%

of patients who are treated with methotrexate)

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6) Pleurisy

7) Pneumonia

8) Bronchitis ,amyloidosis ,pleural thickening

9) Caplan’s syndrome (RA + massive fibrotic nodules with pneumoconiosis

occupational coal dust exposure).

10) EYE: (it is common and occur in 25% of patients) 1. keratoconjunctivitis sicca (most

common): (dry, burning and gritty eyes

caused by decreased tear production)

2. Episcleritis (erythema only)

Scleritis (erythema and pain)

Corneal ulceration (Corneal melts =

perforated corneal ulceration).

3. Keratitis

4. Steroid-induced cataracts

5. Chloroquine retinopathy

6. Scleromalacia performans ---perfoartion of orbit

Rheumatoid nodules involving the sclera of the eye may result in scleromalacia. The

bluish choroid is visible because of thinning of the sclera. The

surrounding bulbar conjunctiva appears slightly atrophic, and

superficial vessels are dilated. Focal chronic inflammatory

cell infiltration and necrosis may appear in the sclera. When

these changes become more extensive, the lesion resembles

the subcutaneous nodule of rheumatoid arthritis

Bluish discoloration ---thining of the sclear

7. Xerostomia

8. Parotid gland sweeling

9. Lymphadenopathy

Episcleritis is not painful, Scleritis is painful

11) Osteoporosis

12) Increased risk of infections (possibly atypical): CMV-associated colitis.

13) Depression

14) CNS:

Paraesthesia in hands that may let him awake from sleep

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Peripheral nerve entrapment syndromes ---carpel & tarsal tunnel syndrome

Mononeuritis multiplex secondary to vasculitis

Myelopathy due to subluxation of C1 C2

15) Amyloidosis >>> Renal failure (Nephrotic range proteinuria) >>> high levels of

serum amyloid A protein which is also an acute phase reactant, the kidneys are

usually normal size, or slightly large and hepatomegaly.

16) AIHA (autoimmune haemolytic anaemia): warm type, +ve DGT (direct globulin

test) (Coomb’s test), spherocytosis, ↑RTX & ↑ LDH.

17) FELTY SYNDROME—1%:

RA + splenomegally + neutropenia

It is usually occurs in patients with long-standing seropositive RA.

Two third of the patients are female (60-70% female predominance).

It is usually recognised from the 5th decade onwards in patients who have

had RA for an average of 10 years or more.

It may be accompanied by hepatomegally ,thrombocytopenia

,lymphadenopathy and fever.

C/P: Active RA + Leukopenia + Lymphadenopathy + Splenomegaly + also leg

ulcers, recurrent infections (URTI) and Episcleritis may be present.

ANA is positive in more than 90% of patients with Felty’s syndrome.

No specific treatment

Splenctomy may be indicated if sever neutropenia exsists < 500 cells/ml with

chronic non healing leg ulcers or recurrent bacterial infections.

Seen in 1% of RA with RF positive .subcutaneous nodules

95% of patients are HLA DR4 with positive RF.

The leukopenia is generally neutropenia (( < 2000/mm3))

Active RA on methotrexate with leukopenia >>>? Methotrexate-induced or Felty’s syndrome (+ve ANA).

Complications:

Bacterial infections ((20 fold increase))

Chronic non healing leg ulcers

Non hodgkins lymphoma (( 13 fold increase))

Nodular regenerating hyperplasia of the liver with portal HTN & varices.

Sever bacterial infections correlate with neutrophil count of < 1000/mm3

2002--- Now days ,splenectomy & lithium are out of favour.

G-CSF---has been used & shown effective at increasing WBC count &

decreasing in some patients.

Dose Neupogen 2—5 micg/kg/day to patient with RA + recurrent infections

until neutrophils > 1500 /mm3 THEN weekly for maintenance.

G-CSF –can increase arthritis and vasculitis when WBC count is raised.

LGL syndrome---large granular lymphocyte

Have a natural killer and antibody dependent cell mediated cytotoxicity

activity ,bearing CD2 ,CD3 ,CD8 ,CD16 ,CD53 surface phenotypes on PBF.

A few RA patients have WBC counts dominated by large granular lymphocytes

and have almost complete absence of neutrophils

Thought to be a variant of T cell leukemia.

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When seen in patient with RA ,these patients have a good prognosis with

neutropenia often responding dramiatically to methotrexate.

D/D: Viral syndromes----HBV ,HCV ,EBV ,parvovirus Prsoriatic arthritis Reactive arthritis Tophaceous gout SLE Sarcoidosis Lyme disease Osteoarthritis Rheumatic fever Polymylgia rheumatic Calcium pyrophosphate DISEASE

D/D of subcutaneous nodule and arthritis:

1. Rheumatoid arthritis

2. Rheumatic fever

3. Gout

4. Sarcoidosis

5. Xanthoma

PHYSICAL EXAMINATION:

At intervals not more than 6 months.

Examination to assess changes in previously inflamed joints or appearance of inflammation

in an uninvolved joints.

If the hands but not the feet are involved, a 28 joint examination is appropriate: wrist,

elbows, shoulders, knees, MCP’S, PIP’S of hands.

If the feet but not the hands are involved: MTP; PIP, of feet can be assessed instead of

hand joints.

The joints should be evaluated for the presence of: swelling, tenderness, loss of motion

and deformity.

In addition ,examination for extra-articular manifestations is mandatory.

HOW TO PREDICT PATIENTS WITH SEVER DISEASE AND POOR PROGNOSIS ?

1. Female sex. 2. Insidious onset 3. Generalized polyarthritis ---small &large >20 4. Extra articular disease ----nodules and vasculitis 5. Poor functional status at presentation 6. Persistently elevated CRP or ESR 7. Rheumatoid factor positive – RF+ve 8. Anti-CCP antibodies 9. HLA DR4 10. X-ray: early articular erosions (e.g. within the first 6 months of

presentation and in less than < 2 years).

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AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA FOR RA :

Morning stiffness Arthritis of three joint areas > 6 weeks Arthritis of the hands Systemic arthritis Rheumatoid nodules Serum rheumatoid factor

Radiologic changes: Erosions of periarticular bone

Cartilage destruction

Loss of joint space

Laboratory investigation:

Acute phase reactants: CRP, ESR. N-N anemia. Hypo-albuminemia. Thrombocytosis. RF titer ? Anti-CCP Ab titer imaging techniques:

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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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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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.

19


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.

COX-2: inducible , increases pro-inflammatory cytokines

Arachidonic acid ------COX--------PG

Selective COX-2 inhibitors have less side effects

Celecoxibe ,Etoricoxib.

COX-1 COX-2

Indomethacine

aspirin

piroxicam

ibuprofen

diclofenac

meloxicam

celecoxib.

Side effects: GIT: 1% OF RA patients are admitted each year

with amajor GIT bleeding

Endoscopic evidence of ulcer is found in 20% even in absence of symptoms

Prevalence of PUD is 14-31%.

Risk factors:

2) Age > 60 years 1) Type of NSAID’S

3) Multiple NSAID’S 7) Dose

4) Corticosteroid use 8) Smoking

5) Anti-coagulant use 9)H/O PUD

6) Alcohol 10)Co-morbidity

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To reduce the incidence of GIT side effects:

A. Use selective COX-2 inhibitors

B. Use of PG analogues: misopristol---40% reduction of GIT toxicity

Other SE of NSAID’S:

a. Renal: ARF, analgesic nephropathy, papillary necrosis, nephritic syndrome.

b. Aseptic meningitis

c. Sodium and fluid retention.

1. GLUCOCORTICOIDS:

RA was chosen as first disease to test this new therapy in 1948

AIM--For symptomatic improvement and significant decreased of the radiological progression.

It Remains the most potent anti-inflammatory treatments available because of rapid onset of action.

They are ideally suited to help control the inflammation of RA while the much slower acting DMARDS

are starting to work.

The guidelines of GC are:

a) Prednisolone > 10gm rarely indicated for articular diseases

b) Avoid using GC without DMARDS

c) Use GC as bridge therapy to affective DMARD .

This is to shut off inflammation rapidly with GC and to taper them as DMARD is kicking in.

d) Minimized dose and duration ---taper to the lowest dose that controls arthritis

e) Consider prophylaxis (( Bisphosphonate )) for osteoporosis.

2. DMARD:

GENERAL FEATURS:

1- They do not have anti-inflammatory effect, but they alter the course of the disease over a

period of months. These medication take 2—6 months to reach maximum effect

2- If started early in the course of the disease , they will delay or prevent radiographic

progression. ((the gold standard of halting or slowing the radiographic progression of RA)).

3-They induce symptomatic remission in 40-60% of patients.

4.They Have been shown to be effective in treating both early & more advanced RA.

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.

Methotrexate is an antimetabolite which inhibits dihydrofolate reductase (DHFR enz), an enzyme essential

for the synthesis of purines and pyrimidines.

Is a structural analogue of folic acid.

FH2-------DHFR---------FH4

In RA; increases extra-cellular adenosine, inhibit methylation reactions, suppression of IL-1

beta production.

Pharmacology: oral, IM, SC routes

80-90% excreted un-changed by the kidney

50% bound to plasma protein

Dose: 7.5 mg/week , increased gradually to 25mg/week

Side effects:

1. Common SE: nausea, abdominal Pain, loose stool, stomatitis, macular punctate rash,

alopecia, fever , headache, fatigue , inability to concentrate , macrocytic anemia.

2. Hepatotoxicity: liver fibrosis:

Base line AST, ALT , S.albumin, S.bilirubin, PT, HBsAg, HCV. Then every 4-8 weeks.

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3. Liver biopsy should be performed if 6 of 12 tests are abnormal in any year.

4. Interstitial lung disease: 3-5% acute-chronic, occurs within the first 2 years of therapy

5. Nodulosis

6. Lymphoproleferative malignancies

7. Terratogenic

8. Osteoporosis

9. Addition of folic acid or folonic acid reduces MTX SE EXCEPT lung and liver toxicities

Adverse effects: 1) Hepatitis and Liver cirrhosis 2) Myelosuppression 3) Pneumonitis 4) Pulmonary fibrosis 5) Mucositis

FBC, U&E and LFTs need to be regularly monitored.

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).

22


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.

Adverse effects:

Idiosyncratic: skin reaction ,hepatitis,pneumonitis, agranulocytosis, aplastic anemia

Dose-related: GIT, CNS, leukopenia, megaloblastic anemia

Oligospermia

Dose:500mg/day increased by 500mg per week until 2-3 g/day.

Lab. Monitoring: CBC and LFT at initiation of therapy then every 2 weeks in the first 3

months and then monthly in the second 3m, then every 3 m ,6 months after a year .

Sulphasalazine should be withheld until discussion with the specialist team if:

1. The white cell count is less than 3.5

2. Neutrophils is less than 2, or

3. Platelets are less than 150.

ANTI-MALARIAL DRUGS Chloroquine-hydroxychloroquine---4-aminoquinolones Quinacrine---------9-aminoacridine cpd Pharmacokinetics 70% absorbed, Wide tissue distribution

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.

Adverse effects: 1-GIT: nausea, vomiting , diarrhea, rarely hepatotoxicity.

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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

chloroquine Eye check up every 6-12 months.

4-CNS: headache , dizziness, tinnitus. insomnia. 5- neuromuscular and cardiac: neuromyopathy , cardiomyopathy. 6- agranulocytosis, aplastic anemia.

Anti-malarials are usually given to patients with mild to moderate disease, and may be

combined with NSAIDS or other DMARDS including MTX with or without sulfasalazine.

They improves functional status, although they may not slow joint erosions.

Hydroxychloroquine Hydroxychloroquine ocular toxicity includes:

1)Keratopathy 2) Ciliary body involvement 3) Lens opacities (Lenticular deposits)

4) Retinopathy.

Retinopathy is the major concern; the others are more common but benign.

The incidence of true hydroxychloroquine retinopathy is exceedingly low.

Risk factors include:

1. Daily dosage of hydroxychloroquine

2. Cumulative dosage

3. Duration of treatment

4. Coexisting renal or liver disease

5. Patient age, and

6. Concomitant retinal disease.

Patients usually complain of difficulty in reading, decreased vision, missing central vision, glare,

blurred vision, light flashes, and metamorphopsia. They can also be asymptomatic.

Leflunomide (Arava® 20 mg tab)

Is an isoxazole derivative approved by FDA for treatment of RA.

Orally administered and has a long half-life (15 hours).

Current place of use in RA probably occupies a niche between MTX and biologic agents

It is a prodrug and under goes extensive entero-hepatic circulation.

Converted into the active metabolite MALANONITRILAMIDE (A77-1726).

MODE OF ACTION:

i. It inhibit enzyme DIHYDRO-ORATATE-DEHYDROGENASE…important for pyrimidine

(rUMP) synthesis.

ii. Activated T- lymphocytes needs 8 fold increase in (r UMP) to move from G1 phase

to S phase of cell cycle

iii. It blocks TNF-mediated NF-KAPPA B activation

iv. Inhibits induction of nitric oxide synthetase

v. Decrease production of PGE2 and IL-6 and matrix metalloproteinase.

vi. Inhibits osteoclastogenesis.

DOSE:

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100mg/day for 3 days, followed by 20 mg/day.

ADVERSE EFFECTS:

1- most common: nausea, diarrhea, skin rash, alopecia, respiratory tract infections.

2-hepatotoxicity

3-? Interstitial pneumonitis.

4- HTN.

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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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.

26


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,

TNF therapy-Anti

1-soluble TNF receptor fusion protein ETANERCEPT.

2-chimeric(mouse/human) anti-TNF-a Ab…… INFLIXIMAB.

3-Fully humanized mAb ….ADALIMUMAB.

Etanercept SC: Soluble P75 TNF-a receptor fusion protein

o It is a recombinant human protein, acts as a decoy receptor for TNF-α, it is a fusion protein

that mimics the inhibitory effects of naturally occurring soluble TNF receptors.

o Dose: 25 mg SC administration twice weekly

o It can cause demyelination and risks of TB reactivation.

o It can be used alone in treatment RA or with methotrexate.

27


o New onset and exacerbation of psoriasis.

o INFECTIONS:

Serious infections has been reported in 22 of 754 (2.9%)

Increased rate of lymphoma.

Pregnancy and breast feeding:

Are contraindicated.

o Also can be used in psoriasis and psoriatic arthritis.

o Used with caution in patients with asthma, renal imp.

Infliximab IV: Chimeric (human/murine) IgG 1 mono-clonal Ab to TNF-a.

Monoclonal antibody, binds to TNF-α and prevents it from binding with TNF receptors, IV

administration, risks include reactivation of tuberculosis

Infliximab should normally be used in combination with methotrexate and requires IV

infusion in a hospital setting.

If a patient is intolerant of methotrexate, etanercept (anti-TNF receptor antibody) and

adalimumab (humanised anti-TNF antibody) are alternatives to infliximab which can be

given as monotherapy. Infliximab is also used in active Crohn's disease unresponsive to

steroids.

SIDE EFFECT:

1-COMMON: headache, diarrhea, rash, pharyngitis, rhinitis, cough, URTI, UTI.

2-Infusion reaction (urticaria, pruritus, and chills)…..reduced by use of MTX.

3-INFECTIONS---TB:

The onset of TB typically soon after beginning of treatment, with 15% of cases detected by the 3rd

infusion and 97% by the 6th

infusion.

56%...extra-pulmonary

25%...disseminated.

FDA has recommended for patients considered for treatment with INF should be screened for LTBI :

By taking appropriate H/O TB exposure and by PPD skin testing.

In the case of positive PPD , anti-TB therapy being recommended prior to initiating INF.

28


Current standard include the use of INH or RIF for TB prophylaxis

4-Demyelinating disease

5-Development of human anti-chimeric molecule anti-bodies (HACA): 40%

The development of HACA was inversely related to the dose of INF.

Addition of low dose of MTX 7.5mg/week ….reduces the development of HACA.

6-ANTIBODY INDUCTION:

ANA and anti-ds-DNA AB were found in 45% and 33%, respectively of 42% patients who received 5

infusions of INF. AB to SM and RNA ……30%.

7-NEOPLASIA:In clinical trials 4 cases of lymphoma has been reported.

8-HEART FAILURE:

INF may worsen preexisting HF.

9-CNS VASCULITIS.

10-HEPATOTOXICITY.

11-CYTOPENIAS:PMS

Adalimumab: monoclonal antibody, SC administration

Tocilizumab: (anti-IL 6 receptor).

B-CELL TARGETED THERAPIES FOR RA:

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.

29


The most common side effects:

1) 1-INFUSION REACTIONS:

Common, hypotension, hypertension, skin rash , pruritus, nausea and back pain……..due

cytokine release syndrome.

2) INFECTIONS--- Severe CMV infection

3) 3-OTHER REACTIONS: Steven-johnson syndrome, Vesicubollous dermatitis ,Toxic epidermal

necrolysis.

4) 4-Human anti-chimeric antibodies: HACA

5) Allergic reactions: low BP and facial flushing during IV infusion.

6) Flu-like symptoms: high fever, chills, weakness, muscle aches, tiredness, dizziness and

headache during IV infusion.

7) Nausea and vomiting.

8) Tumour pain.

Uses: Non-Hodgkin lymphoma, Pure red cell aplasia, ITP, Evans syndrome, Rheumatoid

arthritis, Multiple sclerosis, SLE, Vasculitis.

Preventing and treating:

PREMEDICATIONS:

1-Acetaminophen 625 mg , diphenylhydramine 50mg before each infusion.

2- A single dose of methylprednisolone 100mg, 30 min. before beginning of infusion

3-Holding anti-hypertensive medications within 24 h of RIT infusion.

4-Initial infusion: the first infusion is begin at a rate of 50mg/h, the rate is increased by 50mg/h every

30min. To a maximum of 400mg/h.

MANGEMENT OF INFUSION REACTION:

1-Temporarily stopping RIT infusion, waiting for symptoms to subside, and then restarting infusion at

one-half of the initial rate.

An additional dose of acetaminphen 625mg orally and diphenylhydramine 50mg orally are given.

Additional treatment include: saline infusion, inhaled bronchodilator, IM epinephrine, and parenteral

GC.

RECOMMENDATION:

RIT is to be used for patients with RA who have persistent synoviitis despite an adequate

treatment of MTX and at least one anti-TNF agents used for a minimum of one month.

Abatacept:

Cytotoxic T-lymphocyte antigen 4 (CTLA 4) homologue,A soluble fusion protein comprising CTLA-4

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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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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Change /add DMARDS

METHTREXATE NAÏVE SUBOPTIMAL METHOTRXATE RESPONSE

MTX OTHER MONOTR COMBINATION THERAPY

Combination therapy other monoTR Biologies

MULTIPLE DMARDS FAILURE

Symptomatic/structural joint damage

SURGERY

rheumatoid arthritis --dr magdi sasi 2016

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