Dr. Lamia El Wakeel, PhD.

Lecturer of Clinical Pharmacy
Ain Shams University
• Female gender (3:1 females to males)
• Increasing age (peak onset 35 ‐ 50 yrs of age)
• ÁCurrent tobacco smoking (Studies; tobacco 
users have increased risk of pulmonary 
manifestations of RA)
• Á Family history of RA (RA & presence of major 
histocompatibility complex class II human 
leukocyte antigens (HLA; a molecule associated 
w presentation of antigens to T lymphocytes)
• Á Potential environmental exposures
• Á Oral contraceptive use & high ingestion of 
vitamin D & tea are associated with a decreased 
risk of RA
• Polycyclic patients; (70% of pts); 
9 Initially mild intermittent symptoms; resolve over (wks‐mo)
9 Pt symptom free (wks‐ mo) & then experience symptoms 
(more severe) 
• Monocyclic patients; (~20% of pts) sudden onset of 
symptoms followed by prolonged clinical remission
• Progressive patients (~10% of pts) progressive uninterrupted 
disease (evolves over few mo). Rate of disease progression; 
rapid or slow. 
Divided further into;
¾ subgroup that responds to “aggressive” therapy 
¾ subgroup that does not
Pts w aggressive disease (multiple joint involvement, +RF); 
>70% probability of developing damage or erosions to joints (2 
yrs of disease onset) 
The characteristics of a synovium
affected by RA are;
(1) presence of a thickened, inflamed
membrane lining called pannus
(2) development of new blood
vessels
(3) an influx of inflammatory cells in
the synovial fluid (predominantly
T lymphocytes)
The pathogenesis of RA is driven by
T lymphocytes, but initial
catalyst causing this response is
unknown
The components of most
significance are;
T lymphocytes, cytokines &
B lymphocytes
• The development & activation of T lymphocytes are important to maintain
protection from infection without causing harm to the host
• Activation of mature T lymphocytes requires two signals;
1st presentation of an antigen by antigen-presenting cells to the T-lymphocyte
receptor
2nd a ligand-receptor complex (i.e., CD80/CD86) on antigen-presenting cells
binds to CD28 receptors on T lymphocytes
• Once a cell successfully passes through all stages, the inflammatory cascade is
activated
• Activation of T lymphocytes;
(1) stimulates the release of macrophages or monocytes, which causes release of
inflammatory cytokines
(2) activates osteoclasts
(3) activates the release of matrix metalloproteinases or enzymes responsible for
the degradation of connective tissue
(4) stimulates B lymphocytes &the production of antibodies
• Cytokines, proteins secreted by cells, serve as intercellular 
mediators
• An imbalance of proinflammatory & anti‐inflammatory 
cytokines in the synovium leads to inflammation & joint 
destruction
• Proinflammatory cytokines include; interleukin 1 (IL‐1), tumor 
necrosis factor α (TNF‐α), IL‐6, and IL‐17
9 found in high conc. in synovial fluid
9 cause the activation of other cytokines & adhesion molecules 
responsible for attracting lymphocytes to site of inflammation
• Anti‐inflammatory cytokines; IL‐4, IL‐10 & IL‐1 receptor 
antagonist
9 present in the synovium (conc. not high enough to overcome 
effects of proinflammatory cytokines)
• Serve as antigen‐presenting cells to T lymphocytes & 
produce proinflammatory cytokines and antibodies
• Antibodies of significance in RA; rheumatoid factors 
(antibodies reactive with the Fc region of IgG) & 
antibodies against cyclic citrullinated peptide (CCP)
• Rheumatoid factors are not present in all pts with RA 
(their presence is indicative of disease severity & 
likelihood of extraarticular manifestations)
• CCPs are produced early in the course of disease (High 
levels are indicative of aggressive disease & a greater 
likelihood of poor outcomes)
• Monitoring anti‐CCP antibodies may be useful to predict 
the severity of disease & match aggressive treatment  
1. General
• 60% of pts develop symptoms 
gradually over wks ‐months.
• Patients may present w systemic 
findings, joint findings, or both.
2. Symptoms
• Nonspecific systemic symptoms; 
fatigue, wkness, anorexia &  
musculoskeletal pain
• Patients complain of pain in 
involved joints & prolonged 
morning joint stiffness.
3. Signs
• MCP, PIP > MTP & wrist 
joints are involved frequently
• Any or all diarthoridal; 
elbows, knees, shoulders, ankles, hips, 
temporomandibular sternoclavicular & 
glenohumeral joints
• Symmetric joint involvement 
• ROM limited .
• Signs of joint inflammation 
are present 
• +/‐ Low‐grade fever 
• Extraarticular
manifestations:
3. Signs
• Extraarticular manifestations:
9 Subcutaneous nodules (mostly RF +ve)
9 Ocular: Keratoconjunctivitis sicca, scleritis
9 Pulmonary: Interstitial fibrosis, pulmonary nodules, 
pleuritis, pleural effusions
9 Vasculitis: ischemic ulcers, skin lesions
9 Neurologic: Peripheral neuropathy, 
9 Hematologic: Anemia, thrombocytosis
9 Á Cardiac: pericarditis or myocarditis, conduction or 
valve defects
9 Á Syndromes; Felty’s syndrome (neutropenia, hepato & 
splenomegally & arthritis; anemia, thrombocytopenia & 
lymphadenopathy)
Sjogren’s ; Keratoconjunctivitis sicca & Xerostomia
Progressive disease is
characterized irreversible joint
deformities;
• ulnar deviation of the fingers
• boutonniere deformities;
(hyperextension of the DIP &
flexion of the PIP joint)
• swan neck deformity
(hyperextension of the PIP &
flexion of the DIP joint

PIP; proximal interphalangeal

DIP; distal interphalangeal
boutonniere deformities
4. Laboratory Tests
• Positive rheumatoid factor (‐ve in up to 30% of patients); titre
• Elevated erythrocyte sedimentation rate (ESR: > 20 mm/hour men;
> 30 mm/hour women)
• Elevated CRP (greater than 0.7 mg/dL )
• Complete blood count: Slight elevation in white blood cell count with 
a normal differential; slight anemia, thrombocytosis
• ANA; rule out SLE. RA may be present.
• Positive anti‐CCP

5. Other Diagnostic Tests Á
• Synovial fluid analysis: Straw colored, slightly cloudy, 5000 to 25,000 
WBCs/mm3, negative if cultured
• Joint x‐rays: To establish baseline and evaluate joint damage
• MRI; detects erosions earlier in course of disease > X‐rays (but not 
required for diagnosis)
Seven criteria must be met to diagnose RA appropriately:
1.Morning joint stiffness lasting more than 1 hour before disappearing
2. Arthritis (swelling) of three or more joint areas
3. Arthritis of hand joints (PIP, MCP or wrist)
4. Symmetric joint involvement
5. Presence of rheumatoid nodules
6. Positive rheumatoid factor
7. Radiographic changes in hand or wrist joints
A patient may be diagnosed with RA if ≥ 4 of these are present
Criteria 1 - 4 must be present for at least 6 weeks
Criteria 5- 7 must be observed by a clinician