RHEUMATOID ARTHRITIS Prepared by

Rand E. Elkarib Clinical Pharmacy Lecturer Faculty of Pharmacy +249912979877

DEFINITION !  It the chronic autoimmune progressive condition of

the synovial lining of the peripheral joints

!  If left untreated it will lead to substantial morbidity

and mortality

! Characteristics of RA:

! Symmetrical inflammation of the synovium joints

! Inflammation leading to potentially deforming

polyarthritis

AETIOLOGY ! Autoimmune disease ?

! Genetics

-  No clear link to families

-  Greater predisposition in individuals with Human

Leucocyte antigen DR4 (HLA-DR4)

! Gender

-  Greater in women

!  Infectious organisms

- Epstein-Barr virus, Mycobacteria, Parvoviruses

Joints involved !  Proximal interphalangeal joints (PIPs)

! Metacarpophalangeal joints (MCPs) of the hands

! Wrists, knees, ankles and small joints of the feet.

PATHOPHYSIOLOGY !  T-lymphocytes are induced by antigens and

accumulate in the joint

!  The following are released:

-Mast Cells ( release histamine causing constriction)

-Macrophages

-Synovial fibroblasts- produces collagenases and metalloproteinase that break down collagen

-Inflammatory mediators e.g. Tumor Necrosis Factor (TNF) and interlukin-1 (IL-1)

-  Cytokines e.g. IL-6

-  There is a lack of suppressor T-cells and natural killer cells.

!  The result is:

-  The synovium becomes inflammed and is known as pannus that degrades cartilage and bone

-  Matrix degradation and joint destruction

-  Hypertrophy of the synovium

-  Persistent synovitis causes an effusion of synovial fluid rich in proteins and inflammatory cells

-  Immune complexes enter the circulation to cause extra-articular features

!  In the joint:

-loss of cartilage may result in a loss of the joint space

-The formation of scar tissue that can lead to loss of joint motion or bony fusion ankylosis

- Tendon structures become lax and result in a loss of

support to the affected joint, leading to instability.

- Tendon contractures also may occur leading to chronic

deformity.

CLINICAL MANIFESTATIONS !  Early Disease

" Fatigue, malaise, diffuse musculoskeletal pain and

stiffness

" Symmetric involvement of the peripheral joints of the

hands and feet

! Advanced Disease

" Deformed joints

" Extra-articular symptoms

SIGNS AND SYMPTOMS !  Joint pain and stiffness of more than 6 weeks duration

!  Fatigue, weakness, low-grade fever and loss of appetite.

! Muscle pain

!  Joint deformity is generally seen late in the disease

!  Tenderness with warmth and swelling over affected joints usually involving hands and feet

! Distribution of joint involvement is frequently symmetrical

!  Rheumatoid nodules may also be present

Examples of the extra-articular features of rheumatoid arthritis

!  Amyloidosis

!  Carpal tunnel syndrome

!  Episcleritis

!  Felty’s syndrome

!  Fever

!  Lymphadenopathy

!  Nodules; may be subcutaneous or within the lungs, eyes or heart

!  Osteoporosis

!  Pericarditis

!  Pleural and pericardial effusions

!  Scleritis

!  Vasculitis

EXTRA ARTICULAR SYMPTOMS !  Rheumatoid Nodules

-  Occur in 20% of patients who usually have erosive disease

-  Do not require treatment

-  Present on the extensor surfaces of the elbows, forearms, hands, feet and other pressure points

-  May develop in the lung or pleural lining or meninges

! Vascultitis

-  Occur in patients with long standing RA

-  Caused by invasion of blood vessels walls by inflammatory cells resulting in destruction of the vessels.

-  Small-vessel vascultitis has no major consequences

-  Large vessel vasculitits may be life threatening and requires aggressive treatment.

!  Pulmonary involvement:

-RA may involve the pleura of the lung and is often asymptomatic

-  Interstitial pneumonitis and arteritis are rare potentially life-threatening complications of RA.

! Occular Involvment

-  Sjogrens syndrome (dry itchy eyes) (ttt: Artifical tears)

! Cardiac involvement

- Pericarditis and Myocarditis may occur in advanced stage.

OTHER COMPLICATIONS !  Felty’s syndrome (enlargement of spleen,

neutropenia)

!  Lymphadenopathy

!  Renal involvement

! Amyloidosis (infilteration Liver, Kidneys and Spleen)

DIAGNOSIS !  Based on the American Rheumatism Association – 4 of

the following criteria:

1.  Morning stiffness, lasts >1hr for > 6 weeks

2.  Arthritis of 3 area- soft tissue swelling or exaduation > 6 weeks

3.  Arthritis of the hand joints

4.  Symmetrical arthritis

5.  Rheumatoid nodules

6.  Serum rheumatoid arthritis

7.  Radiographic changes

INVESTIGATIONS !  Laboratory:

# Inflammatory markers, ESR, C-RP- present in inflammation (high)

# Plasma Viscosity (lhigh)

# Rheumatoid factor- IgM autoantibodies (present)

# Antinuclear antibodies- to rule out other disease e.g. SLE

# Anemia

# ALP

# Albumin

!  Radiography

AIMS OF TREATMENT !  Symptom relief including pain control

!  Slowing or prevention of joint damage

!  Preserving and improving functional ability

! Achieving and maintaining disease remission

RA TREATMENT

NON-DRUG TREATMENT OF RA !  Physiotherapy

" Heat and cold electrotherapy

" Exercise Programmes

! Occupational therapy

!  Surgery

DRUG TREATMENT OF RA !  Simple Analgesics

! NSAIDs

! Disease Modifying Anti-rheumatic Drugs (DMARD’s)

! New Agents

A. Simple Analgesics !  Paracetamol

!  Paracetamol combinations

! No anti-inflammatory action

!  Reduce pain associated with muscle weakness

B. NSAIDs !  Pharmacological properties:

" Anti-pyretic

" Anti-inflammatory

" Analgesic

!  Half-life classification

" Short Half Life: aspirin, ibuprofen, diclofenac, indomethacin

" Long Half Life: meloxicam, piroxicam, celecoxib, refecoxib, sulindac

! Not to be used as monotherapy

!  Reduce stiffness associated with RA

!  Factors to be considered when choosing an NSAID;

" Relative efficacy

" Toxicity

" Concomitant drugs

" Concurrent disease states

" Patient age

" Renal function

" Dosing frequency

" Cost

! NSAIDs MOA:

" Inhibit cycloxygenase via blockade of the enzyme site

" Interfere with a variety of inflammatory processes:

1.  Leukotrine synthesis

2.  Superoxide generation

3.  Neutrophil and lymphocyte function

4.  Lysosomal enzyme release

5.  Cartilage metabolism

" Cycloxygenase convert the fatty acids arachidonic acid into endoperoxidases, prostaglandins and thromboxanes

" Discuss the difference between COX 1 and COX 2?

! Adverse Effects of NSAIDs

" Common in elderly and chronic users

" GIT symptoms include dyspepsia, nausea, vomitting and bleeding due to peptic ulceration ( prostaglandins synthesized via COX 1 normally inhibit acid secretion and stimulate protective mucus secretion)

" Skin reactions

" Renal impairment

-  Inhibit prostaglandins involved in maintenance of renal blood flow

-  Usually reversible

-  Pts with hepatic impairment or renal damage are at more risk

-  Bronchospasms in 5% of asthmatics

!  Risk factors for ADRs

1.  Advanced age

2.  History of GI damage

3.  Co-morbidity

4.  Other ulcergenic drugs

5.  Life style

6.  Combination of NSAIDs

7.  NSAIDs +Anticoagulant

8.  High NSAID dose

9.  Choice of NSAID

NSAID Factors

Pt Factors

!  Strategies to minimize ADRs

1.  Use the lowest dose

2.  Withdraw if response is achieved with DMARD therapy

3.  Simple analgesia

4.  One NSAID at a time

5.  Avoid in certain diseases

6.  Consider local therapy

7.  Choice of NSAID, relative risk of GI complications (Azapropazone- highest risk, Ibuprofen- Least risk)

8. Gastroprotection

" Recommended in high risk patient

-  > 65 of age

-  Concomitant ulcerogenic meds

-  Serious co-morbidity

-  Previous history of gastric bleeding

-  Prolonged use

" PPI ( Omeprazole)

" Prostaglandins Anaglogues (Misoprostol)

-Misoprostol reduces GI complications

C/I in females of child bearing age

" H2 recetptor antagonist ( Cimetidine)

- Ranatidine protect against NSAID induced duodenal ulcer not gastric ulcer.

" Mucosal protective agents (Sucraflate)

9. Use of COX 2 selective NSAIDs

A.  50% selectivity

- Etodolac

-  Meloxicam

-  Associated with fewer GIT side-effects

B. Selectively inhibit cyclooxygenase 2

-  Celecoxib

-  Rofecoxib- associated with increased mycocardial side-effects.

-  Benefits may be lost in patients taking aspirin for cardiac problems

-  ADRs of COX 2 inhibitors- some GIT disturbances, increase blood pressure, increase risk of CVS reactions, reduce renal perfusion in the elderly.

C. Disease Modifying Anti-Rheumatic Drugs !  Should be started within months of diagnosing RA

because rheumatoid arthritis progression is rapid within the first few years of onset.

! Methotrexate, Leflunomide and Ciclosporin inhibit T-cells

!  Inhibit the cytokines: Tumour Necrosis Factor, Interleukin-1, Interleukin-6 and Interleukin-2

!  Leflunomide inhibit proliferation of B cells

!  Infliximab neutralise the activity of TNF

!  Etanrecept binds to TNF and renders it biologically inactive

! Choice of DMARD

# Toxicity +/- loss of efficacy, limit continuation of therapy

# Methotrexate and sulfaslazine have a 5 year continuation rateof 50-60%

# Parentrral gold and Penicillamine have a 5 year continuation rate of 20%

# Oral gold has a 5 year continuation rate of 5%

# Combination of two or three DMARD’s OR 2 DMARD’s + corticoteroids- step up or step down approach

Screening tests to be performed before commencing biologic disease-modifying anti

rheumatic drugs !  Full clinical/infection screen to exclude the presence of infection

!  Urea and electrolytes plus urinalysis

!  FBC

!  Chest radiograph to exclude infection, TB or lung fibrosis

!  QuantiFERON-TB or T Spot to establish TB status

!  Hepatitis B and C screening

!  Assess risk factors for HIV and consider screening

!  Check vaccination status

!  Check family/patient history with regards to demyelinating disease

!  Previous history of malignancy

!  Antibody profile: ANAs and DNA

!  Check blood pressure and review cardiac function

1. Methotrexate !  Inhibits cytokine production, inhibits purine biosynthesis

and may stimulate release of adenosine all of which may lead to its anti-inflammatory properties.

! Most effective DMARD –’Gold Standard DMARD’

!  Rapid onset of action: 4-6 weeks

!  Low ADR’s at low doses

!  Improve QOL and reduce joint destruction

! Weekly oral dosage or IM

! ADR’s

" GIT: Nausea, vomitting, diarrhoea and stomatitis

" Hematologic; Thrombocytopenia and leukopenia

" Hepatic: elevates ALP, AST

" Pulmonary: fibrosis

" Teratogenic

" Folate deficiency (Methotrexate is a folic acid antagonist and acts by reversibly inhibiting dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid)

! Management of Methotrexate toxicity

" Monitoring

-  FBC every 2 weeks for 12 weeks than monthly

-  LFT’s monthly

" Hepatic fibrosis and liver toxicity: reduce or refrain from alcohol intake

" Severe alveolitis: report dyspnoea

" Nausea and stomatitis: Folic Acid administrationg to improve continuation of therapy and adherence)

" Bone marrow toxicity- report unexplained fever.

Important points to cover when counselling a patient who is receiving methotrexate

!  Why the patient is taking methotrexate

!  How long it will take for methotrexate to work

!  The dose and the frequency

!  For oral methotrexate the strength and number of tablets

!  The importance of regular blood monitoring

!  The side effects including warnings symptoms for urgent

!  referral to the doctor

!  Interactions with other medicine, including over-the-counter and herbal remedies

!  The need for adequate contraception in males and females

!  Inform healthcare professionals that methotrexate is prescribed

2. Sulfasalazine ! A prodrug, which is cleaved by bacteria in the colon into

sulfapyridine and 5-aminosalicylic acid

! Antirheumatic effects should be seen within 2 months

!  High benefit: risk ratio

!  Used in mild disease

! Dose should be titrated from 500mg od increased at weekly intervals up to 1g BD

! ADR’s

" Nausea and other GI symptoms- can be managed by slow titration of therapy

" Rash and uriticaria- managed with antihistamines or corticosteroids. Stop therapy in case of hypersensitivity reaction

" Leukopenia

" Leukopenia and hepatic dysfunction

" Colour of urine

! Monitor:

" FBC 2 weekly

" LFT’s 4 weekly for 12 weeks then 3-6 monthly

3. Gold !  Sodium aurthiomalate (gold injection)

!  Effective

!  High toxicity: stomatitis, proteinuria, leucopenia, thrombocytopenia

!  Used in treatment failure

! Monitor FBC and U+E before each injection

! Auranofin (oral gold)

" Different from injectable

" Not as effective

4. Penicillamine !  Poor long term efficacy and toxicity problems

!  Absorption reduced by food

!  Common ADR’s

" Thrombocytopenia, proteinuria and taste disturbances

!  Monitor:

"  FBC every 2 weeks and monthly after stable dose

" U+E

5. Ciclosporin !  Immunosuppressant

!  Effective in early and late disease

!  Reserved for treatment failures

!  Baseline creatinine before initiating therapy and when changing dose

! Monitor U+E’s and BP every 2 weeks for 2 months then 1-2 monthly

6. Hydroxychloroquine and antimalarials !  Least toxic

!  Least effective of the DMARD’s

7. Azathioprine

!  Steroid sparing

! Cytotoxic drug

8. Cyclophosphamide !  Potent cytotoxic

! Oral or IV

9. Corticosteroids !  Interfere with antigen presentation to T lymphocytes

!  Inhibit prostaglandin and leukotriene synthesis

!  Inhibit neutrophil and monocyte superoxide radical generation.

! Corticosteroids also impair cell migration

!  Blunt the immune response

!  Produce a rapid:

" Decrease in inflammatory process

" Slow joint erosion

!  Therapy limited due to ADR’s

! Oral

" Step up or step down approach to reach a target dose of 7.5mg of prednisolone.

!  Intrarticular Steroid Injections.

" Relieve pain, reduce deformity and increase mobility

" Methylprednisolone acetate, triamcinolone acteonide

" Given at intervals of 1-5 weeks

!  Intramuscualr

" Acute flare-ups

!  Intravenous

" Pulsed methylprednisolone to control rheumatoid vasculitis

! ADR’s of Corticosteroids.

"  hypothalamic pituitary adrenal suppression

" Cushing’s syndrome

" Osteoporosis

" Myopathies

" Glaucoma

" Gastritis

" HTN and electrolyte imbalances

" Hirsutism

" Glucose intolerance

" Skin atrophy

" Increased susceptibility to infections

10. Leflunomide ! Newer agent

!  Inhibit synthesis of RNA and DNA in immune response cells

! Cytotoxic drug

!  Inhibits production of pro-inflammatory

! Overall

" Anti-inflammatory

" Immuno-modulatory

! Well tolerated with reported alopecia, rash, GIT disturbances, hypertension, abnormal liver tests.

!  Reserved for treatment failures

11. Biologic Agents !  Etanercept

" Recombinant human soluble TNF receptor

" Competes with TNF in binding with cells involved in the inflammatory process

" Given twice weekly

" Well tolerated: mostly infusion related reactions, few reported upper respiratory tract infections, demyelinating disorders and fatal infections

!  Infliximab

" Chimeric human-murine monoclonal antibody

" Administered every 4-8 weeks with methotrexate

" Neutralises the biological activity of TNF

" Serious sepsis and infections reported

! Adalimumab

" Is a human IgG1 antibody to TNF

! Anakinara

" Anakinara is interleukin 1- receptor antagonist

" Binds to IL-1 receptors on target cells, it prevents the interaction between IL-1 and the cell

D. Monitoring Treatment !  Efficacy by monitoring C-RP

!  Radiological examination of the affected joints