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)• Current tobacco smoking (Studies; tobacco users have increased risk of pulmonary manifestations of RA)

• 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)

• Potential environmental exposures• Oral contraceptive use & high ingestion of vitamin D & tea are associated with a decreased risk of RA

• Polycyclic patients; (70% of pts); Initially mild intermittent symptoms; resolve over (wks‐mo)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;subgroup that responds to “aggressive” therapy 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 synoviumaffected 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

receptor2nd 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‐17found in high conc. in synovial fluidcause 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 antagonistpresent 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 • Extraarticularmanifestations:

3. Signs• Extraarticular manifestations:

Subcutaneous nodules (mostly RF +ve)Ocular: Keratoconjunctivitis sicca, scleritisPulmonary: Interstitial fibrosis, pulmonary nodules, pleuritis, pleural effusionsVasculitis: ischemic ulcers, skin lesionsNeurologic: Peripheral neuropathy, Hematologic: Anemia, thrombocytosis

Cardiac: pericarditis or myocarditis, conduction or valve defects

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 interphalangealDIP; 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 • 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 disappearing2. Arthritis (swelling) of three or more joint areas3. Arthritis of hand joints (PIP, MCP or wrist)4. Symmetric joint involvement5. Presence of rheumatoid nodules6. Positive rheumatoid factor7. Radiographic changes in hand or wrist jointsA patient may be diagnosed with RA if ≥ 4 of these are presentCriteria 1 - 4 must be present for at least 6 weeksCriteria 5- 7 must be observed by a clinician