pharmacotherapy of rheumatoid arthritis

Rheumatoid Arthritis

& Osteoathritis

RVS Chaitanya koppala

Rheumatoid arthritis is one of the most common inflammatory disorders affecting the population worldwide.

It is a systemic inflammatory disease which affects not only the joints but a wide range of extra-articular organs.

The disease, if not treated early, will lead to progressive joint deformity and increased morbidity and mortality

potentially fatal illness, with mortality twofold and an average decrease life expectancy : 7–10 years.

The predominant conditions leading to this increased co-morbidity and mortality include infections, renal impairment, cardiovascular disease and lymphomas.

The incidence of lymphoma is twofold higher than expected before taking into account the disease-modifying immunosuppressant drugs used in treating rheumatoid arthritis.

Rheumatoid Arthritis Definition

Multisystem Autoimmune Inflammatory Condition

SymmetricalPolyarthropathySmall joints

Epidemiology Approx 1% of the population worldwide is

affected by RA with females being two times common

Nearly 5% of women and 3% of men over the age of 65 years are affected by the disease

It can develop at any age Peak age of incidence if about 30-50years in

women and slightly older in men Female: Male (3:1) Common Arthritis: 1 in 100 develop RA at

some stage in their life

Pathophysiology Cause of rheumatoid arthritis

remains unclear with hormonal, genetic and environmental factors playing a key role,

Autoimmune Trigger Synovial cell

hyperplasia and endothelial cell activation uncontrolled inflammation bone destruction

Genetics

Genetic factors contribute 53-65% of the risk of developing this disease.

HLA-DR4 allele is associated with RA

Cigarette smoking is a strong risk factor for developing RA

Rheumatoid arthritis is characterised by the infiltration of a variety of inflammatory cells into the joint.

The synovial membrane becomes highly vascularised and hypertrophied, creating a so-called pannus formation.

There is proliferation of synovial fibroblasts and an increase in the number of inflammatory cells present within the joint.

The inflammatory cells involved include T-cells (CD4) B-cells, macrophages and plasma cells.

Cytokines cause the synovium to release proteolytic enzymes, results in destruction of bone and cartilage.

Key cytokines involved in rheumatoid arthritis include Tumour necrosis factor (TNF)-α, interleukin-1, interleukin- 6 and granulocyte macrophage colony-stimulating factor (GM-CSF).

Symptoms and Signs Morning stiffness lasting ≥1 hour* Swelling in ≥3 joints* Swelling in hand joints* Symmetric joint swelling* Erosions or declacifications on xray of hand Rhematoid nodules Abnormal serum RF*Must be present ≥6 weeks

Extra-articular manifestations Pluera (effusions) Lymph nodes (reactive sympadenopathies) Kidneys (amyloidosis) Gout (amyloidosis) Bone marrow (anemia, thrombocytosis) Nervous system (peripheral neuropathy) Eye (scelaritis, keratoconjuctivitis) Pericardium (effusions) Lungs (fibrosis nodules, effusions) Muscles (wasting) Skin (thinning, ulceration )

Investigations Familial history Bloods

FBC (Flood Blood Count), U&Es (urine and electrolytes) , LFTs (liver function tests), ESR (erythrocytes sedimentation rate), CRP (C-reative protein), RF anti (rheumatoid factor anti) CCP (cyclic citrullinated peptide)

Inflammatory markers

rheumatoid markers

Alkaline phosphatase Serum albumin Normochromic Normocytic anaemia Antinuclear antibodies (ANA) Extractable nuclear antibodies (ENA)

Imaging (ultrasound and Xrays)

Imaging

Note: RF is not specific to rheumatoid arthritis and is also present in patients with chronic lung and liver disease, other connective tissue diseases, neoplasia, infections (particularly bacterial endocarditis) and cryoglobulinaemia.

Management There are four primary goals in the treatment of

rheumatoid arthritis: Symptom relief including pain control Slowing or prevention of joint damage Preserving and improving functional ability Achieving and maintaining disease remission

Target different cytokine pathways involved in the pathogenesis of rheumatoid arthritis.

There are four main categories of drugs employed in the management of rheumatoid arthritis:

NSAIDs including cyclo-oxygenase (COX)-2 inhibitors, Glucocorticoids, DMARDs and Biological therapies.

Simple analgesia also has a small role to play in basic symptom relief and includes paracetamol, codeine, and paracetamol and opiate combination products.

Management Conservative- weight loss, smoking cessation

Pain relief- paracetamol + NSAIDS, Steroids

Disease modification – DMARDs and Biologics (Etanercept + Adalimumab)

DMARDS Joint damage is known to occur early in rheumatoid

arthritis and is largely irreversible. The need for early intervention with DMARDs as part of

an aggressive approach to minimize disease progression. Early introduction of DMARDs also results in fewer

adverse reactions and withdrawals from therapy Methotrexate, Sulphasalazine, Leflunomide,

Intramuscular gold, Hydroxychloroquine, d-penicillamine, Oral gold, Ciclosporin and Azathioprine

METHOTREXATE (first line)- oral ulcers, alopecia, GI upset, hepatotoxic

SULFASALAZINE- GI upset, less hepatotoxic LEFLUNOMIDE- Liver cirrhosis, GI upset, alopecia Auranofin (Oral GOLD)- Rash, Glomerulo-nephropathy PENICILLIAMINE- Rash, lupus-like illness Azathioprine Ciclosporin Hydroxy-chloroquine Sodium aurothiomalate (IM Gold)

Keypoints in DMARDS therapy Introduce DMARD therapy early (within 3 months ideally) Use combination DMARDs involving methotrexate and at least

one other DMARD Use monotherapy where combination DMARD therapy is not

appropriate, with rapid escalation to therapeutic dose Withdraw cautiously when disease is stable to doses that

maintain disease control All DMARDs inhibit the release or reduce the activity of

inflammatory cytokines, TNF-α, Interleukin-1,Interleukin-2 Interleukin-6

Biological therapy:

Biological therapy

Osteoarthritis

Osteoarthritis is a chronic disease and the most common of all rheumatological disorders.

It particularly affects individuals over the age of 65 years and is the major cause of hip and knee replacements in developed countries.

Degenerative joint disease A clinical syndrome of joint pain accompanied by functional

limitation and reduced QOL Hips Knees Small joints of hands

Osteoarthritis

Epidemiology The prevalence OA increases with age. Generally, osteoarthritis is uncommon under the age of 35

years with 0.1% of people (25–34 years), but 80% of people affected above the age of 55 years.

Obesity is the strongest modifiable risk factor and particularly affect the knees.

Trauma or injury due to diseases, such as rheumatoid arthritis, will predispose a joint to developing OA.

Type II collagen genes is linked to the development of early onset polyarticular osteoarthritis.

Aetiology Osteoarthritis is a complex disease involving bone,

cartilage and the synovium.

It is generally believed to be an imbalance in erosive and reparative processes.

There are a wide variety of factors predisposing an individual to this condition including the following:

Predisposing factors for OA Obesity Previous injury either due to sport or occupation Previous disease such as rheumatoid arthritis or gout Systemic disorders such as acromegaly Neuropathic joint disease such as a charcot joint Increasing age Gender Genetic predisposition Congenital abnormality such as Perthes disease of the hip

Symptoms and Signs

Square thumb

Pathogenesis The pathogenesis of osteoarthritis has been classified into four stages:1. Initial repair2. Early-stage osteoarthritis3. Intermediate-stage osteoarthritis4. Late-stage osteoarthritis

Initial repair (proliferation of chondrocytes synthesising the extracellular matrix of bone.

Early stage osteoarthritis results in degradation of the extracellular matrix as protease enzyme activity

Intermediate osteoarthritis is associated with a failure of extracellular matrix synthesis

Late-stage osteoarthritis may result in complete loss of cartilage with joint space narrowing in the most severe of cases.

Bone outgrowths (osteophytes) appear at the joint margins.

Investigation Synovial fluid analysis Arthroscopy normal cartilage / crystal arthropathy Bloods

FBC, U&Es, LFTs, ESR, CRP Imaging- 4 cardinal signs on Xray?

Subchondrial sclerosis ( thin layer of bone beneath the cartilage in the joints)

Osteophytes (bony projection) Narrowing of joint space Subchondrial cysts ( fluid-filled sac that forms inside of and

extends from the bone of a joint)

Management Conservative- muscle strengthening exercises + aerobic

exercise Drugs- Paracetamol + NSAIDS (top/oral)

Paracetamol (first line treatment) Topical NSAIDS, capsaicin and rubefacients Opoids for uncontrolled pain Hyaluronan (synthetic ) Glucosamine and chondroitin Intrarticular steroid injections as adjunct therapy

Surgery- indicated when PAIN/stiffness have a substantial impact on QOL

On examination Not grossly defomed Squaring of the thumb

joint Tender over PIPs and DIPs

Do her buttons and write her name with slight discomfort

Management

Transcutaneous electric nerve stimulation= TENS

Hand Changes in RA

Hand Changes in OA

Square thumb

RA Vs. OAFeatures Rheumatoid

ArthritisOsteoarthritis

Age of onset Can happen at any age

Usually later in life

Speed of onset Rapid- weeks to months

Slow- over years

Distribution Symmetrical polyarthritis

Initially asymmetrical monoarthritis polyarthritis

Joints affected Small joints of hands and feet

Weight bearing joints- knees, hips

Duration of morning stiffness

Stiffness worse in the morning >1hour

Stiffness <1hour and worse at the end of the day (after activity)

Systemic symptoms

Fatigue, fever, night sweats

-

Urates

Is the final breakdown product of purine degradation in humans

The ionized forms of uric acid, predominante in plasma, extracellular fluid and synovial fluid.

Approximately 98% existing as monosodium urate at pH 7.4

Plasma is saturated with monosodium urate at a concentration of 6.8 mg/dl.

At higer concentrations, plasma is therfore supersaturated, creating the potential for urate crystal precipitation.

Urate production varies with the purine content of the diet and the rates of purine biosyntesis, degradation and salvage.

2/3 to ¾ of urate is excreted by kidneys, and most of the remainer is eliminated through the intestines.

Renal handling Glomerular filtration Tubular reabsorption Secretion Postsecretory reabsorption

Serum urate levels vary with age and sex.

Children: 3 to 4 mg/dl Adult men: 6 to 6.8 mg/dl

Uric acid is more soluble in urine than in water. The pH of urine greatly influences its solubility. pH 5 urine is saturated with uric acid at concentrations

ranging from 6 to 15 mg/dl. At pH 7 saturation is reached at concentration

between 158 and 200mg/dl Defined as a plasma urate concentration > 7.0 mg/dl

= ?

Hyperuricemia Can result from:

Increased production of uric acid Decreased excretion of uric acid Combination of the two processes.

Increased Urate Production Diet provides an exogenous source of purines and,

accordingly, contributes to the serum urate in proportion to its purine content.

Foods high in nucleic acid: liver, thymus and pancreas, kidney. Restriction intake: reduces: 1 mg/dl

Endogenous sources: De novo purine biosynthesis: 11 step

Decreased Uric Acid Excretion Alterated uric acid excretion could result from

decreased glomerular filtration, decreased tubular secretion or enhanced tubular reabsorption.

Decreased tubular secretion of urate causes the secondary hyperuricemia of acidosis.

Diabetic ketoacidosis, starvation, ethanol intoxication, lactic acidosis, and salicylate intoxication are accompanied by accumulations of organic acids (B-hydroxybutyrate, acetoacetate, lactate or salicylates) that compete with urate for tubular secretion.

Combined Mechanisms Alcohol intake promotes hyperuricemia:

Fast hepatic breakdown of ATP and increases urate production.

Can induce hyperlacticacidemia, and inhibition of uric acid secretion.

The higher purine content in some alcoholic beverages such as beer may also be a factor.

Complications of Hyperuricemia The most recognized complication of hyperuricemia is

gouty arthritis

Nephrolithiasis Urate Nephropathy Uric Acid Nephropathy

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Nephrolithiasis The prevalence of nephrolithiasis correlates with the

serum and urinary uric acid levels. (Serum urate levels 13 mg/dl & Urinary uric acid excretion > 1100 mg/d)

Urate Nephropathy

Deposits of monosodium urate crystals surrounded by a giant cell inflammatory reaction in the medullary intrerstitium

Uric acid nephropathy Precipitation in renal tubules and collecting ducts cause

obstruction to urine flow.

An acute attack of gout has a rapid onset, with pain being maximal at 6–24 h of onset.

The first attack affects a single joint in the lower limbs in 85–90% of cases (the first metatarsophalangeal joint (big toe).

The next affected are the mid-tarsi, ankles, knees and arms.

The affected joint is hot, red and swollen with shiny overlying skin.

Presentation and diagnosis

Crystal-induced arthritides MSU (monosodium urate) CPPD (calcium pyrophosphate dihydrate) HA (calcium hydroxyapatite) Calcium oxalate (CaOx)


Monosodiumurate Gout Affecting middle-aged to elderly men.

Women represent only 5 to 17% of all patients.


Monosodiumurate Gout

Associated with an Increased uric acid, Hyperuricemia, Episodic acute and chronic arthritis, Deposition of MSU crystals in connective tissue tophi

and kidneys.


Acute and chronic arthritis Acute arthritis is the most frequent early clinical

manifestation of MSU gout. Usually only one joint is affected initially Polyarticular acute gout is also seen in male

hypertensive patients with ethanol abuse as well as in postmenopausal women.


The metatarso phalangeal joint of the first toe is often involved.

Ankles, and knees are also commonly affected. In elderly patients, finger joints may be inflamed.


The patient may also have a fever, leucocytosis, raised erythrocyte sedimentation rate (ESR).

The attack may also be preceded by prodromal symptoms such as anorexia, nausea or change in mood.

Following resolution of the attack, there may be pruritis and desquamation of the overlying skin on the affected joint.

Several events may precipitate acute gouty arthritis: Dietary excess Genetics Comorbidities (obesity, dyslipidemia, glucose intolerance and

hypertension) Renal disease (urate crystals in the interstitium and tubules of the

kidney.) Trauma Surgery Excessive alcohol ingestion Medication (Glucocorticoid withdrawal)


Risk factors

Laboratory Diagnosis Even the clinical appearance strongly suggests gout. The

diagnosis should be confirmed by needle aspiration of acute or chronically inflamed joints or tophaceous deposits.

Acute septic arthritis several of the other crystalline – associated arthropathies, and psoriatic arthritis may present with similar clinical features.

Effusion appear cloudy due to leukocytes and a large amounts crystals ocassionally produce a thick pasty or chalky joint fluid.


Radiographic Features Cystic changes, well-defined erosions described as

punched-out lytic lesion. Soft tissue calcified masses (chronic tophaceous gout)


Monosodium urate crystals form in cartilage and fibrous tissues (protected)

Crystals are shed into the joint space or bursa that inflammatory reaction occurs

The shedding of crystals can be triggered by a number of factors including direct trauma, dehydration, acidosis or rapid weight loss.

Pathogenesis

There is increased urinary urate excretion with a lowering of serum uric acid which leads to partial dissolution of monosodium urate crystals and subsequent shedding of crystals into the joint space.

The shed crystals are phagocytosed by monocytes and macrophages, activating protein-3 (NALP3) inflammasome and triggering the release of interleukin-1(IL-1) and other cytokines, a subsequent infiltration of neutrophils and the symptoms of an acute attack

Course of disease

The course of gout follows a number of stages Initially, the patient may be asymptomatic with a raised

serum uric acid level often a second attack occurs within 6–12 months.

Affect more than one joint and may spread to the upper limbs.

Untreated disease can result in chronic tophaceous gout, with persistent low-grade inflammation in a number of joints resulting in joint damage and deformity.

Tophi deposition can occur anywhere in the body, but they are commonly seen on the helix of the ear, within and around the toe or finger joints, on the elbow, around the knees or on the Achilles tendons.

The skin overlying the tophi may ulcerate and extrude white, chalky material composed of monosodium urate crystals.

Treatment aims in gout Rapid alleviation of the acute attack

Prevention of future attacks

Lower serum uric acid levels to below saturation point

Reduce risk of co-morbidities, for example, cardiovascular disease

Lifestyle modification

Treatment The management of gout can be split into

The rapid resolution of the initial acute attack Long-term measures to prevent future episodes.

Gout is often associated with other medical problems including obesity, hypertension, excessive alcohol and the metabolic syndrome of insulin resistance, hyperinsulinaemia, impaired glucose intolerance and hypertriglyceridaemia.

This contributes to the increased cardiovascular risk and deterioration of renal function seen in patients with gout.

Management is not only directed at alleviating acute attacks and preventing future attacks, but also identifying and treating other co-morbid conditions such as hypertension and hyperlipidaemia.

Pharmacological measures should be combined with non-

pharmacological measures such as weightloss, changes in diet, increased exercise and reduced alcohol consumption.

Management of acute attack of gout

Management of an acute attack of gout Promptly and safely resolve pain First line: NSAID (use maximum dose) Second line: Colchicine Third line: Corticosteroid (consider first line in mono-articular disease) (±Simple and opiate analgesia if needed, for example, paracetamol,

codeine dihydrocodeine) Rest the joint 1–2 days and treat with ice Remove contributing factors

Review medication Review lifestyle

Management of chronic gout The presence of hyperuricaemia is not an indication to

commence prophylactic therapy. Some patients may only experience a single episode and a

change in lifestyle, diet or concurrent medication may be sufficient to prevent further attacks.

Patients who suffer one or more acute attacks within 12 months of the first attack should normally be prescribed prophylactic urate-lowering therapy.

The aim of prophylactic gout treatment The aim of prophylactic gout treatment is to maintain the

serum urate level below the saturation point of monosodium urate (300 μmol/L).

If the serum urate is maintained below this level, crystal deposits dissolve and gout is controlled.

Prophylactic treatment should not be initiated until an acute attack of gout has completely resolved,

Usually 2 to 3 weeks after symptom resolution. Once started, prophylactic treatment should be continued indefinitely even if further acute attacks develop.

Criteria for starting prophylactic therapy for gout One or more acute attacks within 12 months of the

first attack Tophi present at the first presentation of an acute

attack Presence of uric acid stones Need to continue medication associated with raised uric

acid levels, for example diuretics Young patients with a family history of renal or cardiac

disease

Classification of prophylactic agents used to lower serum urate

Drugs that lower serum uric acid can be classified into three groups according to their pharmacological mode of action

Uricostatic agents: Allopurinol, Febuxostat

Uricosuric agents: Benzbromarone, Probenecid, SulphinpyrazoneUricolytic agents: Rasburicase, Polyethylene glycol-uricase

Inhibit the xanthine oxidase enzyme

Increase excretion of uric acid

Uric acid to allantoin (urate oxidase)

pharmacotherapy of rheumatoid arthritis

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