Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the joints, causing swelling, warmth, pain, and stiffness. It results from an autoimmune reaction where the immune system mistakenly attacks healthy joint tissue. This leads to a proliferative synovitis that can cause cartilage and bone destruction over time. RA is characterized by symmetrical inflammation of multiple joints that typically involves the hands, feet, wrists, and knees. It has both articular and extra-articular effects and is associated with an increased risk of comorbidities such as lung or heart disease. The cause is unknown but involves genetic and environmental factors.

1. Pathophysiology
Rheumatoid Arthritis
NEM KUMAR JAIN
MS (PHARM.) PHARMACOLOGY & TOXICOLOGY
ASSISTANT PROFESSOR, SCHOOL OF PHARMACY
ITM UNIVERSITY GWALIOR

2. Rheumatoid arthritis (RA)
 Chronic inflammatory disorder of autoimmune origin
 principally attacks the joints, producing a nonsuppurative proliferative and
inflammatory synovitis
 Articular lesions: destruction of the articular cartilage and, in some cases
ankylosis (adhesion) of the joints.
 Extraarticular lesions: may occur in the skin, heart, blood vessels, and
lungs
 Causes Symmetrical Polyarthritis: affects several joints in pairs on both
sides of your body
 Epidemiology
• it is three times more common in women than in
men
• The peak incidence between the ages of 30 and
50 years
• There is an increased incidence in those with a
family history of RA

3. Etio-pathogenesis
 Etiology:
 Genetic predisposition: Human leucocyte antigen (HLA)-DR4 and HLA-DRB1*
0404/0401 alleles confer susceptibility to RA
 Insults such as infection (including periodontitis) and smoking
 Hormonal: Sex hormones In premenopausal women
 Pathogenesis: as autoimmune diseases, genetic predisposition and
environmental factors contribute to the development, progression, and
chronicity of the disease
 The pathologic changes are mediated by antibodies against self-antigens
(arthritogens: chemical or microbial modified self antigen)
 and inflammation caused by cytokines, predominantly secreted by CD4+ T
cells
 The T cells produce cytokines that stimulate other inflammatory cells to
effect tissue injury:

4. Pathogenesis continued
 IFN-γ from TH1 cells activates
macrophages and synovial cells.
 IL-17 from TH17 cells recruits
neutrophils and monocytes.
 RANKL expressed on activated T
cells stimulates osteoclasts and
bone resorption
 TNF and IL-1 from macrophages
stimulate resident synovial cells to
secrete proteases that destroy
hyaline cartilage.
 Plasma cells produces Seum
antibodies against Citrullinated
peptides in which arginine residues
are posttranslationally converted to
citrulline
 Ex. citrullinated fibrinogen, type II
collagen, α-enolase, and vimentin
deposit in the joints.
 Serum antibodies are k/n as anti-
citrullinated protein antibodies
(ACPA)
 Another antibodies About 80% of
patients have serum IgM or IgA
autoantibodies that bind to the Fc
portions of their own IgG. These
autoantibodies are called
Rheumatoid factor and may also
deposit in joints as immune
complexes

5. Pathogenesis continued
 The inflammation localizes to the
joint, recruiting macrophages and
triggering activation and/or
proliferation of synovial cells,
chondrocytes, and fibroblasts.
 The production of proteolytic
enzymes and cytokines contributes
to the destruction of cartilage and,
through increased osteoclast
activity, bone

6. Morphology
 the synovium becomes
edematous, thickened, and
hyperplastic, transforming its
smooth contour to one covered by
delicate and bulbous villi
 The characteristic histologic
features include:
(1) Synovial cell hyperplasia and
proliferation;
(2) dense inflammatory infiltrates of
CD4+ helper T cells, B cells, plasma
cells, dendritic cells, and
macrophages
(3) increased vascularity resulting
from angiogenesis;
(4) neutrophils and aggregates of
organizing fibrin on the synovial and
joint surfaces;
(5) Osteoclastic activity in underlying
bone, allowing the synovium to
penetrate into the bone, causing
periarticular erosions and
subchondral cysts.
Pannus Formation: a mass of
edematous synovium, inflammatory
cells, granulation tissue, and
fibroblasts that grows over the
articular cartilage and causes its
erosion
Pannus can lead to fibrous ankylosios
and bony ankylosis

7.  Clinical Diagnosis:
 ACPA and RF in blood and Radiographic findings
(x-rays)
 Sign and symptoms
 Early symptoms: malaise, fatigue, and
generalized musculoskeletal pain.
 After several weeks to months the joint
become involved generally Symmetrical
 Commonly joints of the hands and feet,
wrists, ankles, elbows, and knees
 joints are swollen, warm, and painful
 Stiffness of the joints when patient rises
in the morning or following inactivity
 joint enlargement and decreased range
of motion
 Inflammation in the tendons, ligaments,
and occasionally the adjacent skeletal
muscle
 produces the characteristic ulnar
deviation of the fingers and flexion-
hyperextension of the fingers (swan-
neck deformity, boutonnière deformity).
 Radiographic hallmarks are joint
effusions and juxtaarticular osteopenia
with erosions and narrowing of the joint
space and loss of articular cartilage
Joint effusion

9. Extra-articular RA
•Systemic – Fever, Fatigue, Weight loss
•Eyes- Scleritis, Scleromalacia perforans (perforation of the eye)
•Neurological- Carpal tunnel syndrome, Atlanto-axial subluxation, Cord
compression
•Haematological-
• Felty’s syndrome (rheumatoid arthritis, splenomegaly, neutropenia),
• Anaemia (chronic disease, NSAID-induced, gastrointestinal blood loss, haemolysis,
hypersplenism),
• Thrombocytosis
 Pulmonary - Pleural effusion, Lung fibrosis, Rheumatoid nodules,
Rheumatoid pneumoconiosis
 Heart and peripheral vessels – Pericarditis, Pericardial effusion, Raynaud’s
syndrome
 Vasculitis - Leg ulcers, Nail fold infarcts, Gangrene of fingers and toes
 Kidneys - Amyloidosis causes the nephrotic syndrome and renal failure

10. Rheumatoid nodules
 An infrequent manifestation of RA and
 typically occur in subcutaneous tissue including the forearm, elbows,
occiput, and lumbosacral area.
 Microscopically, they resemble necrotizing granulomas