Non-infectious arthritis and drugs

Osteoarthritis (OA)

A degenerative joint disease caused by progressive loss of articular cartilage with secondary bone changes.

Etiology

• Aging (most common)

• Mechanical stress

• Obesity

• Previous joint injury

• Genetic predisposition

Pathogenesis

• Chondrocyte injury → ↓ collagen & proteoglycans

• Increased MMPs → cartilage degradation

• Subchondral bone sclerosis

• Osteophyte (bone spur) formation

Pathologic Features

• Cartilage thinning and fissuring

• Subchondral bone sclerosis

• Osteophytes

• Joint space narrowing

Clinical Features

• Pain worsens with activity

• Morning stiffness (< 30 min)

• Crepitus

• Decreased range of motion

• Common joints: knees, hips, spine, DIP & PIP joints

Treatment

• Weight loss

• NSAIDs

• Intra-articular steroids

• Physical therapy

• Joint replacement (advanced cases)

Rheumatoid Arthritis (RA)

A chronic autoimmune inflammatory disease affecting synovial joints symmetrically.

Epidemiology

• Females > males (3:1)

• Peak age: 30–50 years

Pathogenesis

• Autoimmune reaction mediated by CD4+ T cells

• Cytokines involved: TNF-α, IL-1, IL-6

• Autoantibodies:

• Rheumatoid Factor (RF)

• Anti-CCP (ACPA)

Pathologic Features

• Synovial hyperplasia

• Pannus formation

• Cartilage destruction

• Bone erosion → ankylosis

Clinical Features

• Symmetric joint involvement

• Morning stiffness >1 hour

• MCP & PIP joints affected

• Deformities:

• Ulnar deviation

• Swan-neck

• Boutonnière

Extra-articular Manifestations

• Rheumatoid nodules

• Lung involvement

• Vasculitis

• Anemia

Treatment:slow the course,induce remission,and prevent further destruction of the joints

• Methotrexate (first-line)

• TNF inhibitors

• Adjuvant drugs:Corticosteroids and NSAIDs

• DMARDs:classify into

1)non-biological:

-Immunosuppressants: methotrexate

-Chloroquine or hydroxychloroquine

-Leflunomide

2)biological:

-TNF inhibitors: etanercept.

-Anti-interleukin 6 (IL-6): tocilizumab

- Abatacept

- Five Janus kinase (JAK) inhibitors: tofacitinib

Methotrexate

Mechanism of action:

Inhibits dihydrofolate reductase →inhibits inflammatory cytokinase

Use:

• First-line drug for rheumatoid arthritis

• Given once weekly

Important safety points:

• Causes bone marrow suppression

• Causes oral mucositis and palpus

• Teratogenic (contraindicated in pregnancy)*belong to catogry X

• Folic acid supplementation required

Hydroxychloroquine

Used w malaria

Alternative therapy of RA

Leflunomide

Mechanism of action:

Inhibits dihydroorotate dehydrogenase →

Blocks pyrimidine synthesis → reduces lymphocyte proliferation

Use

• Alternative to methotrexate in RA

Warnings

• Hepatotoxic

• contraindicated in pregnancy

TNF-alpha inhibitors (e.g. Etanercept)

Mechanism of action:

Bind and neutralize TNF-α → decrease inflammation

Use:

• Subcatenous injection

Risks

• Infection:tuberculosis

IL-6 receptor inhibitor:Tocilizumab

Action:

It is a monoclonal antibody

 It is an antagonist of the interleukin-6 (IL-6) receptor.

 Endogenous IL-6 is a pro-inflammatory cytokine  that is induced by inflammatory stimuli and

mediates a variety of immunological responses

  Uses: 1) Rheumatoid arthritis (Moderate to severe)

 Adults experiencing poor management with DMARD treatment  SE:

 Elevated liver enzyme

 Increased risk of developing serious infections

Abatacept

Mechanism of action

Blocks T-cell activation by inhibiting co-stimulation (CD80/86)

Use

• Moderate to severe rheumatoid arthritis

Important notes

• Do not combine with TNF inhibitors because its Increase risk of infection

JAK inhibitors (Tofacitinib)

Mechanism of action:

Inhibits Janus kinase → blocks intracellular inflammatory signaling

Use:

• Moderate to severe RA when DMARDs fail

Side effects:

• Upper respiratory infections

• Urinary tract infections

• Opportunistic infections

🛑Warnings:

• Avoid liver vaccines

• Increased risk of infections and thrombosis

Juvenile Idiopathic Arthritis (JIA)

Chronic inflammatory arthritis in children <16 years.

Types

1. Oligoarticular – ≤4 joints (most common)

2. Polyarticular – ≥5 joints (RF + or −)

3. Systemic (Still’s disease) – fever, rash, organ involvement

Features

• Joint swelling

• Growth disturbances

• Uveitis (especially in oligoarticular)

Seronegative Spondyloarthropathies

Includes

• Ankylosing spondylitis

• Reactive arthritis

• Psoriatic arthritis

• Enteropathic arthritis

Common Features

• HLA-B27 positive

• Negative RF

• Sacroiliac joint involvement

• Enthesitis (tendon insertion inflammation)

• Spinal stiffness

Reactive Arthritis

Sterile arthritis following infection (GI or GU)

Triggers

• Chlamydia

• Salmonella

• Shigella

• Campylobacter

Classic Triad (Reiter syndrome)

• Arthritis

• Urethritis

• Conjunctivitis

Gout

Is a metabolic disorder that allows pf uric acid in blood and tissues

Inflammatory arthritis caused by high level of monosodium uric acid crystal deposition

Marked by transient attacks

Pathogenesis

• Hyperuricemia (>6.8 mg/dL)

• Overproduction or underexcretion of uric acid

2types of gout:

1ry gout(90%):most commonly result from ⬇excretion,due to genetic error(x-linked mutation resulting in ⬆activity of PRPP sysnthate)

2ry gout:from overproduction as a result of enzyme(HGPRT) by ⬆rate of cell death(cancer)

+⬇uric acid excretion

chemotherpy →key word

Acidosis

Clinical Stages

1. Asymptomatic

2. Acute gouty arthritis(⬆neutrophils)

3. Intercritical period

4. Chronic tophaceous gout(pannus)

*gouty neropathy:renal complications

Crystal Type

• Needle-shaped

• great toe w a (tophi):Depostion of sadium urates crystals in soft tissue around the joint

Treatment

Life style modifacation:Diet

-⬇meat,seafood and ethanol

*(SAQ)-No Alcohol→aggravates the symptoms of gout due to

1-Ethanol ccelerated breakdown of ATP adenine (nucleotide degradation)

2-High purine content in some alcoholic beverages,

such as beer.

3-Inhibition of renal excretion of urate by lactic acid

• Drugs:

1)Uricostatic Agents: Xanthine oxidase inhibitors: Interfering with uric acid synthesis with allopurinol. *ادوية تقلل التصنيع

• 2) Uricosuric agents: Increasing uric acid excretion with probenecid or

  sulfinpyrazone *ادوية تزيد الاخراج

3) Anti-inflammatory effects by colchicine.

-Non steroidal:

naproxen,proxicam,doclofence

*تهدي الالتهاب

4) Recombinant uricase drugs: Rasburicase

*تحول uric acid الى شي اسهل للاخراج

• 5) Administration of NSAIDs (indomethacin, diclofenac)

SAQ:

1)Explain two biochemical mechanisms of this disease?

Superactivity in PRPP: increased purine synthesis by de novo and salvage pathways

HGPRT gene mutation (lesch nyhan syndrome): purines are broken down and not recycled, leading to excessive uric acid production then hyperuricemia

2)Explain why alcohol consumption has an affect on this disease?

A.Accelerated breakdown of ATP

b. High purine content in some alcoholic beverages, such as beer.

Allopurinol

Mechanism of action(SAQ):

Reduce the production of uric acid by*competitively inhibiting*the last 2 steps

1-Allopurinol inhibits xanthine oxidase(enzyme converts hypoxanthine and xanthin into uric acid)⬇

2-↓ conversion of hypoxanthine and xanthine into uric acid →

3-↓ serum uric acid level

Therapeutic use:

1-Used for chronic gout and hyperuricemia(important)

2-Prevents future gout attacks (not for acute attack)*prophylaxis➡وقاية

Symptomatic hyperuricemia(Preferred agent)

Important points:

• First-line drug for chronic gout

• Prevents uric acid synthesion

• Not used during acute gout attack

Adverse effects:

• Rash

• Stevens–Johnson syndrome،Toxic epidermal necrolysis

• Hypersensitivity reactions

Probenecid

Mechanism of action:

Blocks urate reabsorption in renal tubules (URAT1 inhibition) →

Increases uric acid excretion in urine

Therapeutic use:

• Chronic gout

• Used as second-line or add-on therapy with allopurinol

Important notes:

• Requires good kidney function

• May cause kidney stones

• Not used in patients with renal disease

Colchicine

Mechanism of action:

Like anti-inflammatory

Narrow therapeutic margin(جرعة قريبة للسميّة)

Therapeutic use:

• Acute gout attack

• Used only when NSAIDs are ineffective

Adverse effects

• Diarrhea

• Vomiting

• Abdominal pain

• Bone marrow suppression (high doses)

Rasburicase

Mechanism of action:

Converts uric acid into allantoin (water soluble)

Use:

• Severe hyperuricemia in cancer patients who receving chemotherapy

Notes

• Acts rapidly within 4 hours

• Used short-term only 1-7 days

once daily by IV

Anti-Inflammatory Agents(naproxen, piroxicam, and diclofenac)

1-First choice for treating acute gout attacks. They rapidly reduce inflammation and pain.

2. Duration:

After the acute attack resolves(انتهت), NSAIDs may be continued at lower doses for 3–4 weeks(intra-articular)while urate-lowering therapy begins to work.

3. Contraindications to NSAIDs:

• Gastric disease

• Renal insufficiency

4. Why Aspirin Is Contraindicated in Gout?

Low-dose aspirin reduces uric acid excretion by inhibiting renal urate transporters, which leads to increased serum uric acid and can precipitate a gout attack.

5. Effect of Aspirin Dose on Uric Acid

• Low dose (81–325 mg): Decreases uric acid excretion(blocks OAT) → worsens gout

• High dose (>3 g/day): Increases uric acid excretion, but is not used due to toxicity

Pseudogout (CPPD Disease)

Cause

Deposition of calcium pyrophosphate crystals

Crystal Shape

• Rhomboid

• Weakly positive birefringence

Common Joints

• Knee

• Wrist

Associated Conditions

• Hyperparathyroidism

• Hemochromatosis

• Aging