Arthritis

(Pathology 3)

Presenter:
Shifaa’ Al Qa’qa’, MD
Assistant professor of pathology
Renal and genitourinary pathologist
Faculty of Medicine, Al-Balqa Applied University
Fifth floor, room 505
Al-salt, Jordan
Email: shqaqa@bau.edu.jo
Objectives:

Describe different types of arthritis including:

1. Osteoarthritis.
2. Rheumatoid arthritis.
3. Crystal induced arthritis.
Joints-----movement/providing mechanical stability.

1. The solid (nonsynovial) joints

A. Fibrous synarthroses
B. Cartilaginous synarthroses (synchondroses):

2. Synovial (cavitated) joints-----have a joint space that allows for a wide range of motion.
Synovial membranes enclose these joints, lined by:
- Type A synoviocytes------specialized macrophages.
- Type B synoviocytes-----similar to fibroblasts----synthesize hyaluronic acid and various proteins.

The synovial lining-----lacks a basement membrane----allows for efficient exchange of nutrients, wastes, and
gases between blood and synovial fluid.
Thank you
Arthritis:

- Osteoarthritis (m.c)

- Rheumatoid Arthritis

- Juvenile Idiopathic Arthritis

- Seronegative Spondyloarthropathies

- Infectious Arthritis (Suppurative Arthritis, Lyme Arthritis)

- Crystal-Induced Arthritis (Gout, Calcium Pyrophosphate Crystal

Deposition Disease (Pseudogout))
Osteoarthritis (OA): degenerative joint disease
The most common disease of joints.

- An intrinsic disorder of cartilage.

- Biochemical and mechanical stresses---breakdown of the matrix

and failure of its repair.

- Inflammatory mediators----released and triggered by joint injury----

worsen the damage.
 The prevalence of OA increases
Types of OA: exponentially beyond the age of 50, and
about 40% of people older than 70 are
affected.
Idiopathic (primary) osteoarthritis:
- The most common Females >males

- age >50
- Appears insidiously, without apparent initiating cause, as an aging phenomenon.
- Usually oligoarticular (affects few joints).

Secondary osteoarthritis:
- Only 5% of cases.
- Younger individuals.
- Predisposing conditions: joint deformity, a previous joint injury (e.g. certain sports), or an
underlying systemic disease.

Other risk factors: gene susceptibility, obesity, vitamin D insufficiency, high bone mass/density…..
Pathogenesis
In normal situation, the articular cartilage :
- Serves as a low-friction surface that transmits loads to the underlying bone.
- Cartilage resists compression----viscoelastic properties of the extracellular matrix (type II collagen,
proteoglycans, and water) secreted by chondrocytes.

The lesions of OA stem from degeneration of the articular cartilage and its disordered repair;
(chondrocyte injury) due to:
1. Repeated biomechanical stress.
2. Genetic factors, including genes encoding components of the matrix and signaling molecules.
OA:

1. Initiated by chondrocyte injury----changes in the extracellular matrix----

increased water, decreased proteoglycan.

2. Chondrocytes may proliferate and attempt to repair damaged matrix,

Continued degradation exceeds repair in early OA.
- Degradation ultimately exceeds synthesis.
- The composition of proteoglycans changes.
- MMPs secreted by chondrocytes degrade the type II collagen network.
- Cytokines and diffusible factors from chondrocytes and synovial cells; TGF-β
(which induces MMPs), TNF, prostaglandins, and nitric oxide, have been
implicated in OA.

3. Late OA is evidenced by loss of both matrix

and chondrocytes with subchondral bone damage.

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

---Inflammation is minimal and secondary
Morphology:

1. Subchondral bone--- bone eburnation (polished ivory)

2. Subchondral (fibrous) cyst; Small fractures through the
Fibrillation/fissuring of the articular cartilage.
articulating bone allow synovial fluid to be forced into the
subchondral regions in a one-way, ball valve–like
Eventually, full-thickness portions of the cartilage are
mechanism.
sloughed.
3. Residual articular cartilage
The dislodged pieces of cartilage and subchondral
Osteophytes (bone spur)
bone tumble into the joint, forming loose bodies (joint
Synovium may show scattered chronic inflammatory cells.
mice).
Clinical course: The joints commonly involved: Any joint; hips, knees, lower lumbar
and cervical vertebrae, proximal and distal interphalangeal joints of
the fingers, first carpometacarpal joints, and first tarsometatarsal
joints.

Joint pain -----worsens with use, morning stiffness, crepitus, and limitation of range of movement.
Impingement on spinal foramina by osteophytes-----cervical and lumbar nerve root compression----radicular
pain, muscle spasms, muscle atrophy, and neurologic deficits.

Heberden nodes:
- Prominent osteophytes at the distal interphalangeal joints
- Common in women.

joint deformity can occur (unlike rheumatoid arthritis, joint fusion does not take place)
The level of disease severity detected radiographically.

Therapy:
Management of pain, NSAIDs to reduce inflammation, intra-articular corticosteroids, activity modification, and,
for severe cases, arthroplasty.
Rheumatoid arthritis (RA):

Chronic inflammatory disorder of autoimmune origin----more common in

women, 3rd-5th decades of life

Nonsuppurative proliferative and inflammatory synovitis.

Pathogenesis:
- Autoimmune disease

- Genetic predisposition.
- Environmental factors.

Cellular and humoral immune response against self-antigens:

1. Antibodies against self-antigens
2. Inflammation is caused by cytokines, predominantly secreted by CD4+
T cells.
- Implicated in 50% of the risk of developing
RA.
- MHC class II region HLA-DRB1—ACPA +RA
- PTPN22
ACPA + RA

- anti-citrullinated protein antibodies (ACPA)--

(+) in 70% of cases.
CD4+ T-cells - rheumatoid factor---(+)in 80% of cases

IL-17
Macrophage activation---TNF
IFN-γ and IL1

RANKL- expression on
activated T-cells - TNF has been most firmly
implicated in the pathogenesis of
RA.
- TNF antagonists have proved to
be effective therapies for the
disease.
(A) Pannus
In advanced untreated cases the pannus can bridge the bones---fibrous ankylosis----
bony ankylosis.

(B) Marked synovial hypertrophy with formation of villi.

(C) Subsynovial tissue containing a dense lymphoid aggregate.

Rheumatoid nodules are an infrequent manifestation of RA
and typically occur in subcutaneous tissue including the
forearm, elbows, occiput, and lumbosacral area.

Microscopically, they resemble necrotizing granulomas. Rarely,

RA can involve the lungs (rheumatoid nodules, interstitial lung
disease).
Clinical course:
RA begins slowly and insidiously with malaise, fatigue, and generalized musculoskeletal pain. After several
weeks to months, the joints become involved.

The pattern of joint involvement is generally symmetrical and the hands and feet, wrists, ankles, elbows, and
knees are most commonly affected.
polyarticular
The metacarpophalangeal and proximal interphalangeal joints are frequently involved (in contrast to OA).

RA can be distinguished from other forms of polyarticular inflammatory arthritis by:

- The presence of ACPA
ACPA are highly specific for RA, whereas RF can also be found among healthy (elderly) individuals and
patients with other autoimmune diseases or infection.

- And the characteristic radiographic findings.

Extraarticular lesions may occur in the skin, heart, blood vessels, and lungs.
Involved joints are swollen, warm, and painful.

In contrast to OA, the joints are stiff when the patient rises in the morning or following inactivity.

Progressive joint enlargement.

Decreased range of motion.
Chronic waxing and waning course.
In a minority of patients, especially those lacking RF and ACPA, the disease may stabilize or even regress.

Ulnar deviation of the fingers

Flexion-hyperextension of the fingers (swan-neck deformity, boutonnière deformity).
Cause: Inflammation in the tendons, ligaments, and occasionally the adjacent skeletal muscle.

Radiographic hallmarks are:

Joint effusions and juxtaarticular osteopenia with erosions and narrowing of the joint space and loss of articular
cartilage.
Treatment:

- Corticosteroids, other immunosuppressants such as methotrexate, and,

most notably, TNF antagonists.

- Anti-TNF agents are not curative, and patients must be maintained on

TNF antagonists to avoid disease flares.

- Long term treatment with TNF antagonists carries with it increased risk of
infections (e.g. M. tuberculosis).

Death due to vasculitis, amyloidosis, GI bleeding (NSAIDS), infection

(steroids)
Seronegative Spondyloarthropathies
A heterogeneous group of disorders that share the following
features:
- Absence of rheumatoid factor.
- Pathologic changes in the ligamentous attachments rather than
synovium.
- Involvement of sacroiliac joints, with or without other joints.
- Association with HLA-B27. preferentially
involve the sacroiliac
- Bony proliferation leading to ankylosis (fusion of joints). and vertebral joints

Immune mediated----a T cell response ----- against an undefined

antigen, possibly infectious, that may crossreact with antigens
expressed on cells of the musculoskeletal system.
Ankylosing spondylitis
- Symptomatic in the second and third decades of life.

- Lower back pain and spinal immobility.

- Involvement of peripheral joints, such as the hips, knees, and

shoulders-----occurs in at least one-third of affected individuals.

- Approximately 90% of patients are HLA-B27 positive.

- Anti- IL-17 antibody has shown some efficacy in this disease.

Reactive arthritis:
Triad of :
1. arthritis,
2. nongonococcal urethritis or cervicitis,
3. conjunctivitis.

Most affected individuals are men in their 20s or 30s,

more than 80% are HLA-B27 positive.

- autoimmune reaction---- initiated by previous infection of the genitourinary system (Chlamydia)

or the gastrointestinal tract (Shigella, Salmonella, Yersinia, Campylobacter).

- The ankles, knees, and feet are affected most often, frequently in an asymmetric pattern.

- Patients with severe chronic disease have involvement of the spine that is indistinguishable
from ankylosing spondylitis.
Crystal-Induced Arthritis

Endogenous crystals:
- Monosodium urate (MSU) (gout)
- Calcium pyrophosphate dehydrate (pseudogout)
- Basic calcium phosphate.

Exogenous crystals:
- Silicone, polyethylene, methyl methacrylate used in prosthetic
joints.
Gout
Metabolic disorder---crystal induced
- Excessive uric acid in tissues and body fluids. inflammation---inflammatory arthritis

Pathogenesis:
Uric acid metabolism can be summarized as follows:

Synthesis:
- Uric acid is the end product of purine catabolism; two pathways:
- De novo pathway, purine nucleotides are synthesized from nonpurine precursors.
- Salvage pathways ,they are synthesized from free purine bases obtained through the
diet or the catabolism of purine nucleotides.

- Excretion:
- Uric acid is filtered from the circulation by the glomerulus.
- Completely resorbed by the proximal tubule of the kidney.
- A small fraction of the resorbed uric acid is secreted by the distal nephron and excreted
in the urine.
Primary gout:
Elevated uric acid due to Urate transporter dysfunction?
- Reduced uric acid excretion---most common cause---- (sporadic/mostly unknown cause/mechanism).
- Uric acid overproduction----A small minority of primary gout--- enzymatic defects----partial deficiency
of hypoxanthine guanine phosphoribosyl transferase (HGPRT)-----interrupts the salvage pathway-----
purine metabolites cannot be salvaged and degraded into uric acid.

Secondary gout:
Elevated uric acid due to
- Increased uric acid production------ Rapid cell lysis/turnover: during chemotherapy for leukemia
(tumor lysis syndrome), psoriasis…..
- Decreased uric acid excretion----chronic renal disease.
Familial gout:
Complete absence of HGPRT also results in
hyperuricemia, but significant neurologic
manifestations of this condition (Lesch-Nyhan
syndrome).
acute arthritis
acute arthritis
Hyperuricemia (plasma urate level above 6.8 mg/dL) is necessary, but not sufficient, for the development of
gout.

Only about 10% of patients with hyperuricemia develop clinical gout.

Other factors contribute symptomatic gout:

- Sex (more in males)
- Age (>30 yr)
- Menopausal female Gout usually appears after 20 to 30 years of hyperuricemia.
- Duration of the hyperuricemia.
- Well-defined X-linked abnormalities of HGPRT.
- Genetic predisposition - Polymorphisms in genes involved with urate or ion transport and
inflammation.
- Excess alcohol consumption.

- Obesity/metabolic syndrome.

- Drugs (e.g., thiazides) that reduce excretion of urate.

- Renal failure.
Tophus: an aggregate of dissolved urate
crystals is surrounded by reactive fibroblasts,
mononuclear inflammatory cells, and giant
cells.

Urate crystals are needle shaped and

negatively birefringent under polarized light.
Clinical Course, 4 stages:
1. Asymptomatic hyperuricemia:
- Appears around puberty in men
- After menopause in women.

2. Acute arthritis:
- Presents after several years as sudden onset excruciating joint pain, localized hyperemia, and warmth.
- Most first attacks are monoarticular; 50% occur in the first metatarsophalangeal joint.
- Untreated, acute gouty arthritis may last for hours to weeks, but gradually there is complete resolution.

3. Asymptomatic intercritical period:

- Resolution of the acute arthritis leads to a symptom-free interval.
- In the absence of appropriate therapy, the attacks recur at decreasing intervals and frequently become polyarticular.

4. Chronic tophaceous gout:

Gouty nephropathy:
- Develops on average about 12 years after the initial acute attack.
Renal complications caused
- Radiographs show characteristic juxtaarticular bone and loss of the joint space.
by urate crystals or tophi in
Treatment of gout:
the renal medullary
- Lifestyle modification (dietary change, weight loss, substitutions for medications promote hyperuricemia….)
interstitium or tubules.
- Medication to reduce symptoms (e.g., NSAIDs).
- Medications to lower urate levels (xanthine oxidase inhibitor, e.g. allopurinol). Complications include:
- Prophylactic therapy: Colchicine, low dose NSAIDs. - Uric acid nephrolithiasis.
- Pyelonephritis.
Calcium Pyrophosphate Crystal Deposition Disease (CPPD/Pseudogout)

- Male=female
- Age: more than 50 years old and becomes more common with increasing
age.

Can be:
- Sporadic (idiopathic)
- Hereditary---AD--- germline mutations in the pyrophosphate transport
channel-----early in life
- Secondary types---- hyperparathyroidism, hemochromatosis, diabetes

As in gout, inflammation is caused by activation of the inflammasome in

macrophages.

Deposits are present in cartilage and
consist of amorphous basophilic material.
Smear preparation of calcium
pyrophosphate crystals.
Rhomboid
Positively birefringent
Clinical Course: DDx: OA, RA

- CPPD is frequently asymptomatic.

- Acute, subacute, or chronic arthritis

- The joint involvement may last from several days to weeks

- Monoarticular or polyarticular; the knees, followed by the wrists, elbows,
shoulders, and ankles, are most commonly affected.

- 50%---- experience significant joint damage.

- Therapy is supportive.
Thank you