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Rheumatoid Arthritis

Definition of Rheumatoid Arthritis: a chronic inflammatory, multisystem illness involving primarily the joints with a history of exacerbations and remissions.

A. General

1.First recognized in the mid 18th century (no skeletal remains from earlier time demonstrating RA)

B. Prevalence

1. Worldwide distribution

2. Most frequently cited prevalence is 1% of adult population

3. Age--increases into 7th decade

4. Increased in some populations, esp. American Indian tribes 

a. Yakima 6% 

b. Chippewa 5.3 

c. Pima 5.3%

5. Lowest rates in Asian and African populations (genetics v. life expectancy v. other factor)

C. Incidence

1.More difficult to assess but usually quoted as 2--4/10,000 (Mayo Clinic Data from Minnesota)

a. Seattle HMO with women 18-64, incidence of 2.39 cases/10,000

2.Age-peak age between 4th and 6th decades put occurs at any age

3.Gender

a. Female to male = 2-3:1 

b. In older patients may approach 1:1

4. Higher in low socioeconomic groups

5. Higher incidence in first degree relatives of patients with RA

6. Diet has not been shown to affect incidence or prevalence

II. Morbidity and mortality

A. More severe disease = more extra-articular features

B. Seropositivity bad prognostic feature compared with seronegativity for RF

C. Toxicity of medications is also important consideration

1. NSAID with gastropathy

2. Steroids with osteoporosis, osteonecrosis, fractures, cataracts, diabetes, skin effects, heart disease, etc.

3. Immunosuppressants increase risk of infection, both typical and atypical.

D. RA has clearly been shown to significantly decrease life expectancy (work of Pincus and others)

1. Increased mortality predicted by persistent synovitis, seropositivity, lower functional capacity and lower levels of education

2. Older patients and males also significantly affected

3. Causes of death are typical (myocardial infarction or malignancy, etc.) but usually at younger age, but also higher incidence of infections

4. Investigation into NSAID related gastrointestinal disease and renal causes is underway

III. Etiologic considerations

A. Genetic factors

1. In Caucasians: HLA-Dw4, HLA-DR4 and others

a. ?influence susceptibility to disease by controlling the binding of arteriogenic peptides

b. ?trigger disease by expanding or deleting particular T-cell clones

2. RA can be seen clustered in families with other rheumatic diseases

3. It has been estimated that the risk attributable by genetic factors is app. 20-30%, leaving up to 80% of the cause of RA attributable to other factors (Gregerson, et al)

B. Infectious and other factors

1. Infectious agents - infection triggering immune reaction with cross reacting antibodies 

a. Parvovirus etc. has been shown to cause arthritis similar to RA

b. Mycoplasma 

c. Rubella virus (JRA) has been isolated from the blood and synovium of RA patients 

d. Diphtheroids have been frequently isolated from synovial tissue in RA 

e. HTLV-I and other retro-viruses 

f. EBV and other herpes viruses (RA patients with increased B cells infected with the virus and have a diminished cytotoxic T-cell response to virus)

g. Mycobacteria 

h. Enteric organisms (heat shock proteins have been implicated in exp. arthritis)

i. Proteins from strain of EBV and E. coli heat shock protein mimic portion of HLA-DRDw4

2. Toxins (chemicals)

C. Hormones - though no role established

1. Women have greater risk than men, predominantly in younger years

2. Pregnancy tends to produce a remission in many patients with postpartum flare

3. Possible protective role or oral contraceptives

D. Animal models.

1. Mycoplasma induced arthritis in pig.s, mice, turkeys.

2. Erysipelothrix induced arthritis in pigs.

3.Adjuvant arthritis in rats - injection of Freund's adjuvant induces arthritis in genetically susceptible rats.

4.Peptidoglycan in bacterial cell wall is cross-reactive with Fc portion of Ig.

E. Rheumatoid Factors

1.Studies in experimental animals suggest that elevated production of rheumatoid factors develops in situations that generate sustained hypergammaglobulinemia, such as chronic infections

2.They play a role in host defense by enhancing the clearance of small antigen-antibody complexes from the circulation or other fluids and may enhance the killing of microorganisms

3.They may augment deleterious inflammation by facilitating complement or inflammatory activation or by altering the size of immune Complexes

IV. Pathogenesis

A. Joint anatomy and physiology

1. Potential space lined by mesenchymal cells - no basement membrane.

2. Articular cartilage is avascular.

3. Motion predisposes joint to inflammation.

4. Alterations in blood flow reflected quickly in synovial fluid.

5. Normally only low molecular weight proteins cross into synovial fluid and are poorly cleared

6. Cartilage can sequester immune complexes.

B. Pathophysiology

1. Unknown antigenic stimulus or stimuli in genetically predisposed host.

2.Autoimmune response with self sustaining inflammatory reaction. 

a. Activation of synoviocytes (expression of la antigens). 

b. Recruitment of T and B lymphocytes.

c. Activation of other inflammatory cells - macrophages, mast cells.

3. Production of RF.

a. Formation of immune complexes.

4. Production of inflammatory mediators - cytokines, complement system, prostaglandins, coagulation system.

a. IL- 1 and TGF-[3 stimulate synoviocytes to proliferate and produce PG and enzymes.

5. Recruitment of PMN leukocytes.

a. Production of proteolytic enzymes and free radicals of oxygen.

6. Synoviocyte proliferation. Pathologic lesion of RA is PANNUS. 

a. Bone resorption. 

b. Ligamentous laxity. 

c. Bony erosions.

d. Cartilage destruction.

(1) Collagen fragments are chemotactic for monocytes and fibroblasts.

V. Clinical

A. Presentation of RA.

1. Often takes time to make diagnosis - weeks to months.

2. Insidious onset, 60-70%.

a. Symmetric polyarthritis.

b. Weeks to months, often in winter. 

c. AM stiffness and pain. 

d. Systemic symptoms - low-grade temperature, fatigue, anorexia, weight loss, anxiety/depression.

e. Muscular atrophy around affected joints.

3. Acute onset, 8-15%. Days. Severe pain and more often asymmetric.

4. Intermediate onset, 15-20%. Days to weeks. Often prominent systemic symptoms.

5. Pattern of joint involvement - hands (MCP, PIP), wrists, feet; larger joints involved later.

6. RF+

a. 80-90% (often lags behind clinical picture).

b. At presentation, app. 60%

7. Unusual patterns of onset

a. Adult Still's disease - females, 30-40 years old, fever, rash. RF-, oligoarthritis. 

b. Palindromic - one acutely painful joint, 25-35% develop RA. 

c. Young females - recurrent synovitis in knees, self limited. 

d. Older men - stiffness, NSAIDs rarely help, low dose steroids. 

e. RA spares paralyzed limbs. f. Arthritis robustus - men, synovitis with little pain or osteopenia.

B. Diagnosis

1. History and physical

a. Symmetric polyarthritis for 6 weeks or longer. 

b. Joints - tender, swollen, warm, decreased ROM and muscle strength.

c. Nodules. 

d. Low-grade temperature.

2. Laboratory evaluation

a. Anemia of chronic disease. 

b. Elevated ESR. 

c. Positive RF.

d. Synovial fluid - Class 11, decreased glucose, decreases C4 and normal C3. 

e. X-rays.

(1) Periarticular osteopenia 

(2) Loss of cortical white line 

(3) Soft tissue swelling 

(4) Joint space narrowing 

(5) Erosions

3.  ACR diagnostic criteria for RA: need 4

a. AM stiffness lasting greater than 1 hour * 

b. Swelling in three or more joints * 

c. Swelling in hand joints * 

d. Symmetric joint swelling * 

e. Subcutaneous nodules 

f. X-ray findings consistent with RA (erosions or decalcification) 

g. Positive RF

•must be present at least 6 weeks