Clinical manifestations diagnostic and drug therapy of arthritis

1. Rheumatoid Arthritis
&
Osteoathritis
RVS Chaitanya koppala

2.  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

3.  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.

4. Rheumatoid Arthritis
 Definition
 Multisystem Autoimmune Inflammatory
Condition
Symmetrical
Polyarthropathy
Small joints

5. 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

6. 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

7.  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

8.  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.

9.  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).

10. 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

11. 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 )

13. 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

14.  Alkaline phosphatase
 Serum albumin
 Normochromic
 Normocytic anaemia
 Antinuclear antibodies (ANA)
 Extractable nuclear antibodies (ENA)
 Imaging (ultrasound and Xrays)

15. Imaging

16.  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.

17. Management
 There are fourprimary 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

18.  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.

19. Management
 Conservative- weight loss, smoking cessation
 Pain relief- paracetamol + NSAIDS, Steroids
 Disease modification – DMARDs and Biologics
(Etanercept + Adalimumab)

20. 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

21.  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)

22. 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

23. Biological therapy:

24. Biological therapy

26. Osteoarthritis

27.  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

28. 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.

29. 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:

30. 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

31. Symptoms and Signs
Square thumb

32. Pathogenesis
 The pathogenesis of osteoarthritis has been classified into
 four stages:
1. Initial repair
2. Early-stage osteoarthritis
3. Intermediate-stage osteoarthritis
4. Late-stage osteoarthritis
 Initial repair(proliferation of chondrocytes synthesising the
extracellular matrix of bone.

33.  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.


34. 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)

36. 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

37.  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

38. Management
Transcutaneous electric nerve stimulation= TENS

39. Hand Changes in RA

40. Hand Changes in OA
Square thumb

41. RA Vs. OA
Features Rheumatoid Arthritis Osteoarthritis
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
-

42. 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

43.  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.

44. 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

45.  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 = ?

46. Hyperuricemia
 Can result from:
 Increased production of uric acid
 Decreased excretion of uric acid
 Combination of the two processes.

47. 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

48. 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.

49. 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.

50. Complications of Hyperuricemia
 The most recognized complication of hyperuricemia is gouty
arthritis
 Nephrolithiasis
 Urate Nephropathy
 Uric Acid Nephropathy
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51. 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.

52. 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

53. Crystal-induced arthritides
 MSU (monosodium urate)
 CPPD (calcium pyrophosphate dihydrate)
 HA (calcium hydroxyapatite)
 Calcium oxalate (CaOx)
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54. Monosodiumurate Gout
 Affecting middle-aged to elderly men.
 Women represent only 5 to 17% of all patients.
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55. Monosodiumurate Gout
 Associated with an
 Increased uric acid,
 Hyperuricemia,
 Episodic acute and chronic arthritis,
 Deposition of MSU crystals in connective tissue tophi and
kidneys.
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56. 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.
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57.  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.
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58.  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 orchange in mood.
 Following resolution of the attack, there may be pruritis
and desquamation of the overlying skin on the affected
joint.

59.  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)www.freelivedoctor.com
Risk factors

60. 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.
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61. Radiographic Features
 Cystic changes, well-defined erosions described as punched-
out lytic lesion.
 Soft tissue calcified masses (chronic tophaceous gout)
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62. 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

63.  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

65. 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.

66.  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.

69. 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

70. 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 othermedical problems including
obesity, hypertension, excessive alcohol and the metabolic syndrome
of insulin resistance, hyperinsulinaemia, impaired glucose intolerance
and hypertriglyceridaemia.

71.  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.

72. Management of acute attackof 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

73. 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.

74. 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.

75. Criteria for starting prophylactic therapy for
gout
 One ormore 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

76. 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,
Sulphinpyrazone
Uricolytic agents: Rasburicase,
Polyethylene glycol-uricase
Inhibit the xanthine
oxidase enzyme
Increase excretion
of uric acid
Uric acid to allantoin
(urate oxidase)