ARTHRITIS

Pages: 782-790

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4

Dr. Khurshid Anwar

 CLASSIFICATION OF ARTHRITIS

 Non-inflammatory arthritis
Osteoarthritis

 Inflammatory arthritis  Autoimmune -

Infectious  Rheumatic, Rheumatoid,
Bacterial (including M. Tuberculosis) Ankylosing spondylitis, Reiter
Fungal syndrome etc.
Non-Infectious  Degenerative –
Rheumatoid arthritis Osteoarthritis
Seronegative arthropathies
Crystal induced arthritis  Crystal Deposition -
Trauma  Gout – Monosodium urate
Neoplastic  Pseudo - Gout CPPD
 Infective - Septic, TB, Lyme
 RHEUMATOID ARTHRITIS [RA]

Rheumatoid arthritis is a chronic systemic inflammatory disorder of autoimmune origin

that may affect many tissues and organs (skin, blood vessels, heart, lungs, and
muscles) but principally attacks the joints, producing a non-suppurative proliferative
and inflammatory synovitis that often progresses to destruction of the articular
cartilage and ankylosis of the joints.

 
 General Characteristics

Most common form of inflammatory arthritis, affects 1% of world population.

M : F 1:3-5
Onset usually between second and seventh decade, peak incidence in 20-40
The course of RA is marked with exacerbations and remissions
Difficult to predict the course of disease—mostly progressive

Life expectancy reduced by 5–10 years compared with that of people without the
condition, and 35–50% of this excess risk is accounted for by cardiovascular mortality
 PATHOGENESIS OF RHEUMATOID ARTHRITIS

Currently believed that rheumatoid arthritis is

triggered by exposure of a genetically susceptible
host to an arthritogenic antigen resulting in a
breakdown of immunological self-tolerance and a
chronic inflammatory reaction

Continuing autoimmune reaction, the activation

of CD4+ helper T cells, and the local release of
inflammatory mediators and cytokines that
ultimately destroys the joint
 Morphological (pathological) changes
  
Inciting agent activates immune system

Perivascular infiltration of sensitized CD4+ lymphocytes, activated B cell,

macrophages (elaborate cytokines TNF & IL-1) and neutrophils & synoviocytes
(contribute proteases & elastases destroying hyaline cartilage)

Edema, vascularity, hemosidrin, organizing fibrin (rice bodies) and thickening of

proliferative synovium (synovitis) creeping over articular surface forming a pannus
causing erosion of underlying cartilage and bone

Eventually leading to juxta-articular erosions, subchondral cysts, osteoporosis, joint

destruction & deformity. 

Fibrocellular pannus may bridge apposing bones forming fibrous and later on bony
ankylosis.

The pannus is a mass of synovium and synovial stroma consisting of inflammatory cells, granulation tissue,
and synovial fibroblasts, which grows over the articular cartilage and causes its erosion. Inflammation in
many other tissues (glands of eyes & mouth, blood vessels, outer lining of the heart and lungs) can be
observed.  There is increase laxity of ligaments around joint and sublaxation of tendons and joints
Morphological (pathological) changes
 Clinical Features

Articular features
Fatigue, and generalized musculoskeletal pain
Involved joints are swollen, warm, painful, and particularly stiff on arising or following inactivity
Stiffness generally last an hour or more.
Symmetrical pattern (if one knee is affected, the other one is also)
Joint inflammation often affecting the wrist and finger joints closest to the hand (PIP, MCP, wrist
joint) and feet; ankle, knee, elbow, shoulder, neck (sublaxation of atlanto-occipital joint).
Lumbosacral spine and hip joints are relatively spared.
Progressive joint enlargement and decreased range of motion (ROM) pursuing a chronic waxing
and waning course.
Ulnar deviation at MCP joints often is associated with radial deviation at wrist.
Swan-neck and boutonnière deformities are also common.
Disease course may be slow or rapid, and fluctuates over the years, with the greatest damage
Early RA with soft tissue swelling, involving PIPs
Joints

Swan neck and Boutonniere

 Extra-articular features
Non-organ specific
Subcutaneous (rheumatoid) nodules over bony prominences or extensor surfaces or in juxta-
articular regions (forearm, elbow occiput, lumbosacral region).
Fatigue, malaise, Lack of appetite, Weight loss, Fever, Lymphadenopathy, Amyloidosis
Felty’s syndrome (leucopoenia, an enlarged spleen, and rheumatoid arthritis)
Sjogren’s syndrome (keratoconjunctivitis & xerostomia)

• Rheumatoid subcutaneous nodules

– 25% of patients
– Areas of mechanical trauma: extensor surface of the forearm,
tibia, Achilles tendon
– Central fibrinoid necrosis surrounded by palisaded
macrophages and granulation tissue
 Organ specific
Rheumatoid vasculitis
Rheumatoid nodules, Small nail fold infarcts, Palpable purpura, Mononeuritis multiplex, Organ
ischemia, CNS infarctions, MI. Most other systemic lesions are due to vasculitis.

Neurological:
Peripheral neuropathy
Mononeuritis multiplex Respiratory:
Entrapment syndromes Pleural effusions
Carpal Tunnel Syndrome Pulmonary fibrosis
Cardiovascular: COPD
Caplan’s syndrome
Valvular pathology
Pericarditis Haematological:
Anaemia
Pericardial effusions
Felty’s syndrome
Coronary artery disease Lymphoma
Ophthalmological: Renal:
(Epi)scleritis Vasculitis
Scleromalacia Amyloidosis
Brown’s syndrome
 Diagnosis
Difficult to diagnose in its early stages.
No single test for the disease & symptoms differ from person to person
Symptoms can be similar to those of other types of arthritis and joint conditions
Clinical criteria for the disease must have been present for at least 6 weeks
Medical history & Physical examination

X rays
X rays are used to determine the degree of joint destruction, can be used later to monitor the
progression of the disease).
Typically postero-anterior hand and wrist radiographs show erosion or unequivocal bony
decalcification localized or most marked adjacent to the involved joints, subchondral cysts and
osteoporosis. Joint effusion & narrowing of joint space may be seen.

Biopsy
FOUR OF THE FOLLWING CRITERIA SHOULD BE PRESENT FOR
THE DIAGNOSIS (American Association of Rheumatologists)

MORNING STIFFNESS
ARTHRITIS IN THREE OR MORE JOINT AREAS
ARTHRITIS OF HAND JOINTS
SYMMETRIC ARTHRITIS
RHEUMATOID NODULES
SERUM RHEUMATOID FACTOR
TYPICAL RADIOGRAPHIC CHANGES 
 Laboratory Features
Rheumatoid Factor
70-80% of patients
IgM or IgA against Fc portion of IgG
Overlap with HCV/Cryoglobulinemia
More severe disease & poorer outcome
Non-specific: SLE, Sjögren's, Sarcoidosis, Chronic infections

Anti-citrullinated protein antibodies (ACPA)

Rare overlap with HCV
IgG against synovial membrane peptides damaged via inflammation
Value in IgM-RF negative
Sensitivity (65%) & Specificity (95%)
Predictive of Erosive Disease: Disease severity, Radiologic progression, Poor functional
outcomes

Acute Phase reactants

ESR, CRP  monitoring disease activity

Other Lab findings

Thrombocytosis, Leukocytosis, ANA, inflammatory synovial fluid, Hypoalbuminemia
Antibodies to citrulline-modified peptides –anti citrullinated protein antibody [ACPA]
present in many people with rheumatoid arthritis are relatively specific for
rheumatoid arthritis.

Evidence suggests that the raised levels of ACPA in combination with a T-cell response
to the citrullinated proteins contribute to the disease becoming chronic
 Juvenile Rheumatoid Arthritis (JRA)
• ACR Criteria

– Age at onset: < 16 years of age;

– Arthritis - swelling or effusion or the presence of 2 or more of the following signs:
• Limitation of range of motion,
• Tenderness or pain on motion and
• Increased heat in one or more joints;

– Duration of disease > 6 weeks;

– Onset type is defined by the type of disease in the first 6 months:

• Oligoarticular (Pauciarticular) < 5 inflamed joints;
• Polyarticular: > 5 inflamed joints;
• Systemic onset: arthritis with characteristic fever.

– Exclusion of other forms of childhood arthritis.

– Only about 10% develop serious functional disability.

In contrast to RA, in JRA: (1) oligoarthritis is more common, (2) systemic disease is more frequent, (3)
large joints are affected more often than small joints, (4) rheumatoid nodules and rheumatoid factor
are usually absent, and (5) anti-nuclear antibody (ANA) seropositivity is common.
Modified from JT Cassidy, JT Levinson, RM Laxer, CB Lindsley. Textbook of Pediatric Rheum. 2005
 Current Management of Rheumatoid arthritis
Lifestyle
(Education, Rest and exercise, Physiotherapy , Stress reduction, Dietary advice, Climate)

Pharmacotherapy
NSAIDs, Corticosteroids, DMARDs, Immunosuppressive drugs, TNF blocker etc. IL6
antibody in JRA?

Surgery
Surgical procedures include joint replacement, tendon reconstruction, synovectomy etc.

Social
(Occupational therapy & Social services)

Routine monitoring and ongoing care

 OSTEOARTHRITIS (OA)

Osteoarthritis (OA), also called degenerative joint disease, is characterized by

degeneration (softening, splitting and fragmentation-fibrillation) of articular
cartilage, not attributable to direct contact with inflammatory tissue, that results
in structural and functional failure of synovial joints.

Although the term osteoarthritis implies an inflammatory disease, it is considered an intrinsic disorder of
cartilage in which chondrocytes respond to biochemical and mechanical stresses resulting in the breakdown of
the matrix and failure of its repair. Nevertheless there is little doubt that inflammatory mediators whose release
is triggered by joint injury perpetuate and worsen the damage.

Most common joint disease

 Classification
• Primary OA
• Idiopathic and appears insidiously
– arises without obvious predisposing influences, mostly oligoarticular
• Age
• Genetic – familial tendency
• Obesity – OA knee

• Secondary OA – presence of other predisposing factor

– Previous trauma
– Intrarticular fracture, recurrent dislocation, repeated use or misuse of joints
– Infection
– Septic arthritis
– Congenital deformity of a joint
– Perthe’s disease, Slipped capital femoral epiphysis
– Inflammatory
– RA
– Underlying systemic diseases
– Diabetes mellitus, Hemochromatosis, Obesity, Paget disease
OSTEOARTHRITIS
Age
Prevalence increases exponentially beyond age 50 and in those with multiple joint involvement, 40%
of people older than 70 are affected.
Race
Occurs in all populations but hip disease is less common in Chinese and Asians than in those of
Western origin
Genetic predisposition
Strong genetic component is thought to be present particularly in women. It is twice as common in
first degree relatives of pro-bands with osteoarthritis. 20% have family history
Gender & hormonal factors
<45 year more common in men and usually involves one or 2 joints
>55 year more common in women and involve several joints specially knee joint.  
Obesity
It is causal but relationship is stronger in women than in men
Physical and occupational factors
Relationship between long duration high-intensity weight bearing exercise & OA of hip and knee is
observed. Excessive bending of hip in farmers and occupational knee bending in men increase the risk
of OA. Trauma (macro-traumatic or repeated micro-traumatic injuries) & menisectomy are associated
with increased risk of OA.

Biomechanics of joint & Biochemical factors

Pathogenesis has been classified into four stages
Initial repair
Characterized by increased proliferation and metabolic activity of the chondrocytes including increase
synthesis of ECM & DNA 

Early stage OA
Increased synthesis of ECM components is exceeded by their degradation because synthesis and
activity of proteases (MMP) is increased resulting in net degradation and loss of articular cartilage 

Intermediate stage OA
It is associated with a failure the synthesis of ECM components while the synthesis and activity of
proteases remains increased leading to progressive degradation and loss of articular cartilage.
Histologically there is fibrillation, detachment and thinning of the cartilage 

Late stage OA
The synthesis and activity of proteases may remain increased or may be reduced when articular
cartilage is extremely thinned or almost completely destroyed and bony outgrowth may occur at the
joint margins (osteophytes).
 The equilibrium between anabolism and catabolism is
weighted in favor of latter (degradation). Disruption of
the integrity of the collagen network as occurs early in
OA allows hyper hydration and reduces stiffness of
MMP: TIMP cartilage
Cytokines and diffusible factors from chondrocytes and synovial
cells, particularly TGF-β (which induces MMPs), TNF, prostaglandins,
and nitric oxide, have been implicated in OA,

Chronic, low-level inflammation contributes to the progression of the

disease. Ultimately, chondrocyte loss and a severely degraded matrix
mark the late stage of the disease.
OA has always been classified as a non-inflammatory arthritis; yet, there is
increasing evidence for inflammation occurring with cytokine and matrix
metalloproteinase (MMP) release into the joint. Therefore, the term
degenerative joint disease is no longer appropriate when referring to OA.
 Morphology
• Early stage:
– Increased in chondrocytes
– Subsequently  fibrillation & cracking of the matrix

• Gross
– Granular surface
– Small fractures & dislodging & sloughing of cartilage and subchondral bone producing
loose bodies or ‘joint mice’
– Bone “eburnation” (polished ivory)
– Subchondral sclerosis & subchonral cysts
– Osteophytes formation at margins of joints
 Osteophytes

Joint Mice or Loose Bodies

 Clinical features

Gradual development of joint pain (worsen with use)

Commonly involved joints are hips, knees, lower lumber and cervical vertebrae,
proximal & distal IP joints and first CMC joint & first TMT joint

Morning Stiffness (is less pronounced typically half an hour or less)

Swelling (less pronounced due to effusion or osteophyte formation)

Joint deformity (bony enlargement accompanying osteophyte formation)

Limitation of movement/ loss of function (swelling & deformity, joint instability)

Pain & deformity at weight bearing joint (hip & knee) immobilize the patient while similar
changes in distal IP joints cause less functional impairment

Impingement on spinal foramina by osteophytes results in cervical and lumber nerve root
compression with radicular pain, muscle spasm, muscle atrophy and neurologic deficit
 Diagnosis
No specific laboratory abnormalities are associated with OA.
The acute-phase reactants and erythrocyte sedimentation rate are not elevated.
Synovial fluid analysis usually indicates a white cell count less than 2000 per mm3 with a
mononuclear predominance.
Radiography:
Affected joint characteristically shows presence of osteophytes (ie, spurs at the joint margins). Other
findings include asymmetric joint space narrowing, subchondral sclerosis, and cyst formation. X-ray
findings are often poor predictors of the degree of symptomatology in a particular patient.

Histologic Findings:
Histologically, the earliest changes occur in the cartilage. Proteoglycan staining is diminished, and,
eventually, irregularity of the articular surface with clefts and erosions occurs.

Arthrocentesis of the affected joint can help exclude inflammatory arthritis, infection, or crystal
arthropathy.
 Osteoarthritis (OA) Rheumatoid Arthritis (RA)
Main Mechanism Cartilage destruction, localized Synovial inflammation, systemic

Etiology Primary: Unknown, possibly genetic Antigen-antibody reaction

Secondary: Injury, infection etc. leading to overstimulation of
inflammatory response
Age of onset More than 50 years old 30 to 40 years old

Course Insidious Insidious or acute

Joint Characteristics Asymmetrical Symmetrical
Monoarticular or polyarticular Usually polyarticular
Cool, bony, crepitus Boggy, tender
Joints Involved DIP (Heberden's nodes) Asymmetrical Small joints of hands and
feet: wrist, PIP, MCP, TP
PIP (Bouchard's nodes) PIPs, MCPs, MTPs,
Hips, knees, Cervical and lumbar
spine, 1st CMC, 1st MTP
Pain Morning stiffness <1 hour Morning stiffness >1 hour
Increased with weight bearing Nocturnal pain
Decreased with rest Pain at rest

Constitutional Symptoms Not present Fatigue, anorexia, depression,

malaise, lymphadenopathy
Laboratory No abnormalities Elevated ESR, RF, anti-CCP
Radiographic Later in course of disease Can occur within first year
Joint space narrowing Joint space narrowing
Osteophytes Bony erosion, Osteopenia (bone loss)
 SERONEGATIVE ARTHRITIS
(SPONDYLOARTHOPATHIES)

Absence of rheumatoid factor or other autoantibody serologic abnormalities

Involvement of sacroiliac and spinal joints with or without involvement of other joints
Peripheral arthritis (predominantly lower limb)

Enthesopathy
(inflammation at sites where tendons, ligaments & joint capsule fibers attach to bone, with a
strong tendency to produce fibrosis and calcifications)

Familial clustering
Increased incidence of HLA-B27
Bony proliferation leading to ankylosis

Common spectrum of extra-articular features [predominantly muco-cutaneous, eye(uveitis) ,

CVS (aortic regurgitation) & lung (apical fibrosis)]
Types of Seronegative arthritis & their association
with HLA-B27
SERONEGATIVE ARTHRITIS Degree of associations

Ankylosing spondylitis >90%

Reiter’s syndrome/reactive arthritis >80%
IBD related arthritis ~75%
Psoriatic arthritis ~50%

Normal Associations
Native Americans 13%
Caucasians 8%
Blacks 4%
 Ankylosing Spondylitis (AS)
An inflammatory disease of the spine and axial joints causing destruction of articular cartilage
Involvement of peripheral joints, such as the hips, knees, and shoulders, occurs in at least one-third of affected individuals
Typically affects young men ages 15-30 (3:1 men : women)
Affects about 1 in 1000
Women with AS may present differently from men, complaining of neck and breast pain without the typical inflammatory
low back pain
Inflammatory phase with extreme pain & prolonged morning stiffness, followed by ankylosis characterized by increased
stiffness, reduced ROM & abnormal posture
Enthesitis may involve heel, patella, tibial tubercle, base of 5 th metatarsal bone etc.
90% of patients are HLA-B27 positive
Psoriatic Arthritis

Most common age of onset is 30-50 years old, rare (1;1000)

1-3% of the population has psoriasis & 6-42% of these may get psoriatic arthritis
Typical presentation is a peripheral inflammatory joint disease – usually a mono or oligo arthritis,
mostly knees & wrist
May occasionally present with polyarthritis
Initial presentation of inflammatory spinal disease is rare
5% with arthritis mutilans
Mucocutaneous Involvement, Psoriatic skin lesions/ Psoriatic Nail lesions
Entheseal involvement, dactylitis (sausage shaped finger) & ocular involvement
 Reactive arthritis (Reiter’s Syndrome)
Reactive arthritis is defined by a triad of arthritis, nongonococcal urethritis or cervicitis, and
conjunctivitis or uveitis.
Most affected individuals are men in their 20s or 30s, and more than 80% are HLA-B27 positive.

The disease is probably caused by an autoimmune reaction initiated by previous infection of the
genitourinary system (Chlamydia) or the gastrointestinal tract (Shigella, Salmonella, Yersinia,
Campylobacter).

Within several weeks of urethritis or diarrhea, patients experience low back pain.
The ankles, knees, and feet are affected most often, frequently in an asymmetric pattern.

Mucocutaneous manifestation (balanitis, oral ulceration, or keratoderma)

 IBD associated arthritis

IBD (Crohn’s disease/ulcerative colitis)

Arthritis peripheral specially lower extremities
Self limited 4 to 6 weeks
Central sacro-iliac joints and enthesitis frequency 7 to 21 %
No relation between the activity of the Arthritis and the IBD.
Pyoderma gangrenosum can be associated with ulcerative colitis
 SINDROME DE SAPHO

Synovitis
Acne — commonly involving the face and upper back.
Pustulosis — usually involving the palms of the hands and/or soles of the feet
(palmo-plantar pustulosis).
Hyperostosis
Osteitis
 SUPPURATIVE (SEPTIC) ARTHRITIS
Bacterial infection of synovium and synovial fluid
Frequently Hip joint in children & Knee in adults
Sacroiliac joint is affected in brucellosis
Interphalangeal joints: human and animal bites

Causative Agent
S. Aureus (in every ages), H. influenza (6 mo-5 years), N. gonorrhoeae (>10 years, adults in Western populations), Gram negative
bacilli ( Immune deficiency, urinary or intestinal invasive procedures, elderly people, renal failure, chronic joint disorders and
diabetes)
Pathogenesis
Hemotogenous spread, Spread through adjacent tissues, Direct inoculation (aspiration/arthrotomy)
Clinical Manifestations
Usually, there is a history of recent trauma/infection-Acute onset
Fever, fatigue, anorexia, nausea & Local findings of inflammation (Hot, red, swollen, painful joint)
Diagnosis
Aspiration (purulent fluid), Leukocytosis, increased ESR

Treatment
Needle aspiration and irrigation immediately
Antibiotics
 Viral

Usually begins suddenly

In developed countries, Parvovirus-B19, rubella
In children, fever, headache, rash, fatigue, polyarthralgia, symmetrical joint pain
Diagnosis; clinical/serological and polymerase chain reaction (PCR)
Resolves spontaneously within 2 weeks

Mycobacterial Arthritis
Chronic granulomatous monoarthritis
Hematogenous spread after primary infection
A long latent period without sign & symptom- Knee, hip, ankle
Fever may not be seen, a draining sinus can be observed
Synovial fluid analysis:
Leukocytes 10 000-20 000/ml, Acid-fast bacilli (AFB), Culture, Synovial biopsy, AFB culture, PCR
Anti-TB therapy (with 4 drugs)
 CRYSTAL ARTHROPATHIES

These disorders are characterized by articular crystal deposits

associated with a variety of acute & chronic disorders.

Endogenous pathogenic crystals

Monosodium urate
Calcium pyrophosphate dihydrate
Basic calcium phosphate (hydroxyapatite)

Exogenous pathogenic crystals

Corticosteroid ester crystals, Talcum, Silicone, Polyethylene, Methyl methacrylate 
 Gout
  
Gout is a term used to describe the constellation of clinical features that result
from the deposition of micro-crystals of monosodium urate monohydrate or
uric acid from hyperuricemic body fluids. These features include acute
transient arthritis, tenosynovitis, bursitis or cellulitis, tophaceous deposits,
chronic tophaceous arthritis, renal disease & urolithiasis.
 

Prolonged hyperurecaemia is necessary but not sufficient for development of gout

 Epidemiology

Related with a high standard of living.

Environmental factors (diet in particular) play a major role.

Predominantly a disease of adult men with a M:F 7-9:1

Predominant age group is 30-60

Most common cause of inflammatory arthritis in men > age 40.

Incidence & prevalence of gout increases with level of serum uric acid
 Etiology

Primary gout (90%)

Elevated uric acid most commonly results from reduced excretion, the basis of which is
unknown in most patients.
A small minority of primary gout is caused by uric acid overproduction as a result of
partial deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT)

Secondary gout (10%)

Caused by increased production (rapid cell lysis during chemotherapy for leukemia, so-
called tumor lysis syndrome)
Decreased excretion (chronic renal disease).
Complete absence of HGPRT (Lesch-Nyhan syndrome)
 Biochemical Facts about Uric acid & Gout

Uric acid is end product of purine metabolism in human

Source of purines: Diet & de novo synthesis
Miscible body pool of urate in normal individuals is about 1000-1200 mg
2/3 of urate formed each day is excreted by kidney & 1/3 via GIT
urate transporter 1 gene (URAT1) has an important role in the reabsorption process

Serum uric acid levels are 0.42mmol/l in males and 0.36mmol/l in females 

Risk of developing gouty arthritis or urolithiasis are similar in men and women at identical serum
urate concentration and in both rises rapidly when serum uric acid
is > 0.42mmol/l (6.8 mg/dL)
Only about 10% of patients with hyperuricemia develop clinical gout

Gout rarely appears before 20 to 30 years of hyperuricemia

Heavy alcohol consumption, obesity, drugs (thiazide) & lead toxicity may increase risk

Genetically gout follows multifactorial inheritance and run in families. In rare cases it is sex-
linked recessive disorder (HGPRT deficiency)
Pathogenesis of Gout
 Pathogenesis of Gout
Prolonged hyperurecemia
Micro-tophi of urate in synovial lining cells and in joint cartilage
Trauma(?)
Release of crystals into synovial fluid which are chemotactic & activate complement (C3a & C5a)
Accumulation of neutrophils & macrophages in joint and synovial membrane
Phagocytosis of crystals by neutrophils & macrophages
Release of other cytokines, AA metabolitestoxic free radicals & LTB4, IL-1β, IL6, IL8, TNF-alpha
and destructive lysosomal enzymes (proteases).
Synoviocytes also secrete similar mediators
Tissue injury & acute inflammation
Acute arthritis
Repeated attacks of acute arthritis lead eventually to the formation of tophi, aggregates of urate
crystals and inflammatory tissue, in the inflamed synovial membranes and periarticular tissue.
Severe damage to the cartilage develops and the function of the joints is compromised.
Chronic arthritis with formation of tophi in synovial membrane & periarticular tissue
 The Hyperuricemia Cascade
Tissue
Dietary Endogenous
nucleic acids
purines purine synthesis

Urate
Overproduction Underexcretion

Hyperuricemia

Gout
Gouty nephropathies Renal Associated
Acute/Chronic
Manifestations cardiovascular events
Tophaceous arthritis
(nephrolithiasis, pyelonephritis) and mortality
Tophi in the articular cartilage, 
ligaments, tendons,  and bursae
 Gout
Chronic Disease- in 4 Stages (natural history)

Asymptomatic Intercritical Advanced

Acute Flares
Hyperuricemia Segments Tophaceous Gout
Acute inflammation
Elevated serum urate The intervals Long-term gouty
in the joint caused
with no clinical between complications of
by urate
manifestations of gout acute flares uncontrolled
crystallization
hyperuricemia

Uncontrolled Hyperuricemia
 Clinical Manifestations of Acute gout

Usually monoarticular — in 70% Metatarsophalangeal joint of great toe

(instep, ankles, heels, knees, wrist, fingers and elbow may show involvement)

Seldom involves axial skeleton or large joints

May present as tenosynovitis, bursitis or cellulitis
Attack is sudden

Affected joints are hot, red, swollen, extremely painful & tender
Anorexia, nausea, fever and other acute inflammatory reactions may accompany
May last for days & weeks subsiding spontaneously with pruritis & desquamation of overlying skin
Some have single attack others have recurrent attacks

Recurrent attacks are polyarticular and accompanied by progressive cartilage and bone erosion,
deposition of tophi & secondary OA
 Intercritical Segments

• Clinically inactive gout – the asymptomatic intervals between acute flares

• Disease, if untreated, may continue to advance

– Symptom-free segments may shorten over time
– Crystals may still be found in asymptomatic joints
♦ Especially joints previously involved in an acute flare
– Uncontrolled hyperuricemia continues to increase body urate stores
 Chronic tophaceous gout
 Follows recurrent acute attacks
(on average it takes 12 years from initial acute attack)
Asymmetrical joint swelling
Deposits of tophi in periarticular tissues, cartilaginous helix of ear, bursa & tendon sheath, rarely
in eye, tongue, larynx and heart
(related to serum uric acid level and local factors)
 

Manifestation of gout in urinary tract

Urolithiasis
Acute crystal nephropathy
Chronic urate nephropathy
Renal failure (20% with chronic gout)
 Diagnosis
History
Raised serum uric acid
Characteristic radiological changes
(soft tissue swelling with patchy calcification, cortical erosion of phalanges, punched out erosion
and secondary degenerative changes)

Demonstration of needle shaped negatively birefringent crystals of monosodium urate

in synovial fluid neutrophils by polarizing LM
Biopsy
(aggregates of urate crystals surrounded by macrophages, lymphocytes and large foreign body
giant cells completely or partially engulfing masses of crystals)

But remember!
Asymptomatic hyperuricaemia, normal serum uric acid level at the time of acute attack and radiological
findings indistinguishable from inflammatory and degenerative arthritis may be observed.
 Calcium pyrophosphate crystal deposition
disease (CPPD)- Pseudo-gout

It is a disorder characterized by intermittent attacks of painful arthritis

caused by deposits of calcium pyrophosphate dihydrate crystals

Idiopathic (Sporadic)
Hereditary/Familial
(in some germline mutations in the ANKH gene, encodes a transmembrane
pyrophosphate transport channel)
Secondary (associated metabolic disease)
(previous joint damage, hyperparathyroidism, hypothyroidism, hemochromatosis, ochronosis,
acromegaly, hypomagnesaemia, diabetes etc.)

The disorder usually occurs in older people (>50 years) and affects men and women equally.
Ultimately, it causes degeneration of the affected joints.
 Pathogenesis

Conditions leading to crystal formation are not entirely known but include altered activity of the
cartilage matrix enzymes that produce and degrade pyrophosphate resulting in accumulation and
eventually crystallization with calcium.

Crystals first develop in articular matrix, menisci and intervertebral discs and as the deposits
enlarge, they may rupture and seed the joints.

Crystals are phagocytosed by macrophages, in which they activate the NALP3 inflammasome,
eliciting a series of pro-inflammatory events similar or identical to those induced by urate crystals

The crystals form chalky, white friable deposits, which are seen histologically in H&E
preparations as oval blue-purple aggregates
 Clinical features
Mostly asymptomatic

Monoarthritis, (polyarticular rare)- acute, sub-acute or chronic arthritis

Any joint-common in Knee- wrist, shoulder, ankle, elbow may be involved

Rapid-pain, stiffness and swelling (6-24hrs)-synovitis, fever

Resolve 1-3 weeks, usually spontaneous

Triggers: Trauma, Intercurrent illness (infection), Surgery, Blood transfusion, Thyroid

replacement, Joint lavage

Acute attacks are usually less severe than those in gout. Some people have no pain
between attacks, and some have no pain at any time despite large deposits of
crystals.

Ultimately 50% of patients experience significant joint damage.

 Investigations
Synovial fluid analysis
Calcium pyrophosphate crystals are rhomdoid, measuring 0.5 to 5 um in greatest dimension and positively birefringent.

X-Rays
Radio-opaque Calcium pyrophosphate deposit, narrowing of joint space & degenerative changes

Screening for associated metabolic diseases

Ca , P , Mg , Alk Phos , Fe studies ,TSH etc.
 Management of Gout
Life style modifications
Weight reduction, Decrease alcohol consumption, Avoid excessive intake of purine-rich foods?

Treatment
Goal of treatment
Provide relief of acute attacks,
Prevent further attacks,
Prevent damage to the joints,
Prevent the formation of "tophi" or kidney stones.

Treatment - Acute Attack

Rest, ice and analgesics NSAID, cortisone, or colchicine
Asprin should be avoided unless given in very high doses. (Avoid diuretics, salicylates and allopurinol or uricosuric drugs in acute
attack)

Long term management

Indications! Recurrent attacks of gout, Presence of tophi, or chronic gouty arthritis, Associated kidney disease
Uricosuric agents & Xanthine oxidase inhibitors etc.
LYME DISEASE

Borrelia burgdorferi
transmitted by deer ticks of the Ixodes ricinus complex

migratory joint and muscle pain