A. Epidemiology

1. Prevalence ~1% overall
2. Female to Male ~2.5 to 1
3. Peak incidence age 40-70 years (80% of patients)
   1. Polygenic inheritance
   2. Various histocompatibility loci associated with increased risk
4. Classification of Disease
   1. Type I: mild disease, remissions easily induced
   2. Type II: severe, unremitting disease
   3. 20% will have severe disease initially
5. Mortality [3]
   1. 30% of patients with RA will die of the disease within 25 years
   2. Life expectancy for RA patients is ~10 years < general population
   3. In patients with severe disease, 5 year survival is ~50%
   4. Severe RA carries a mortality risk similar to Stage III/IV Hodgkin's Disease
   5. Therefore, aggressive treatment of the disease is critical to long term success

B. Criteria for Classification

1. Required for American College of Rheumatology Classification
   1. Morning Stiffness
   2. Arthritis of at least 3 joint areas
   3. Arthritis of hand joints
   4. Symmetrical swelling of the same joint, Right (R) and Left (L)
   5. Rheumatoid nodules
   6. Serum Rheumatoid Factor (RF)
   7. Autoantibodies to cyclic citrulinated peptide (CCP) are more specific than RF [9]
   8. Radiographic changes (erosions or bony decalcification in periarticular areas)
   9. Must have 4/7 criteria with arthritis present for at least 6 weeks
2. Contributory: Rheumatoid Factor (RF) Positive
   1. Overall, about 80% are RF+ during course of disease
   2. ~60% at initial presentation; additional ~20% will become RF+ within ~1 year
   3. If not RF+ after 1 year, very unlikely to develop RF+
   4. Elderly patients with axial disease usually RF negative
   5. RF is fairly sensitive but not specific for RA (see below)
3. Synovial Changes
   1. Poor mucin clotting of synovial fluid
   2. Histologic synovial changes characteristic of RA - synovial cell proliferation
   3. Joint inflammation with lymphocytes and Macrophages
4. Patient Assessment
   1. Activities of daily living: 8 questions
   2. Joint count for swelling: only 28 of the 70 joints need be counted
   3. Morning stiffness
5. Felty's Syndrome
   1. Seropositive RA (RF+)
   2. Neutropenia, <2,000 neutrophils/µL
   3. Splenomegaly

C. Etiology [2,4,5,6]

1. Genetic
   1. Incidence in monozyogtic (~12%) higher than dizygotic (4%) twins
   2. STAT4 signaling gene polymorphism associated with 60% increased risk for RA [21]
   3. A polymorphism in region between TRAF1 (TNF receptor associated factor 1) and complement C5 on chrom 9 associated with 1.3X increased RA risk [57]
   4. Over 80% of RA patients carry "shared epitopea" of HLA-DRB1*04 cluster
   5. These HLA alleles share highly homologous sequence in third hypervariable region of HLA-DRß chain, which confers binding of specific peptides (antigen presentation) [2]
2. T Cell Activation
   1. Abnormal T cell activation in rheumatoid synovium is believed to be pivotal event
   2. Expansion of Th1 CD4+ T helper cells
   3. Increased production of interleukin (IL) 15 by T cells, IL12 by macrophages
   4. Activated T cells drive production of IL1, IL6, TNFa by synovial fibroblasts, monocytes
   5. These inflammatory cytokines are central to pathogenesis of RA
   6. Regulatory T cells, CD4+CD25+ that express FOXP3 transcription factor deficient in RA
3. B cell proliferation and differentiation to activated cells and plasma cells
   1. Production of autoantibodies (autoAbs)
   2. AutoAbs target citrullinated peptides, RA antigen 33 (RA33), immunoglobulins
   3. Rheumatoid factor (RF) is an anti-Ig autoAb (see below)
   4. RF does not play a pathophysiologic role but is a marker for destructive disease
   5. Most patients with rheumatoid nodules are RF+
4. Joint inflammation with synovial cell proliferation ensues
   1. Detrimental cytokine effects directly on synovial cells
   2. TNFa, IL1 and IL6 play central roles in driving joint destruction in RA
   3. Formation of reactive oxygen species by phagocytes may add to destruction [7]
   4. Cadherin 11, a cell-cell interaction molecule, is involved in localizing inflammation [42]
5. Bone and Joint Destruction
   1. TNFa drives production of IL6 and IL1 (primarily IL1ß)
   2. Osteoclast activation by IL6 and IL1 in the joint space
   3. Activated monocytes and macrophages in joint can transform into osteoclasts
   4. Activated fibroblasts in joint can produce cytokines, contribute to pannus
   5. Pannus is a highly catabolic tissue including fibroblasts, macrophages, osteoclasts
   6. Pannus largely mediates destruction of bone and joint cartilage
   7. IL6 drives serum CRP (C-reactive protein) levels
6. Distinct HLA-DR genes correlate with predisposition to RA in different racial groups
   1. Seropositive RA in white patients correlates with some HLA-DRB1 04XX aleles
   2. DRB1 alleles which predispose to RA often code for a "rheumatoid epitope"
   3. This epitope has the amino acid sequence QorR/KorR/R/A/A
   4. DR4 also associated with RA (~4X risk)
7. Interferon Gamma (IFNg) Gene Polymorphism [11]
   1. Microsatellite polymorphism (dinucleotide repeat) associated with differential IFNg levels
   2. Susceptibility to, and severity of, RA associated with 126bp allele of IFNg
   3. IFNg is believed to be involved in Th1 based pathogenesis of RA
   4. However, this association must be validated in an independent cohort of patients
8. Smoking associated with 1.4X increased RA risk, primarily RF+ disease [33]

D. Symptoms

1. Early presentation
   1. Symmetric (or nearly so) bilateral swelling and pain in extremities
   2. Early disease usually distal: hands, wrists, elbows, knees, ankles, feet
   3. Early axial / proximal joint involvement is highly atypical
   4. Involvement of shoulders, hips, back, neck may occur in elderly patients
   5. Flexion contractions may occur later in the disease
2. Malaise, fatigue are not uncommon; may constitute "prodrome"
3. Joint Stiffness
   1. Morning Stiffness (± pain) - improves with activity
   2. In osteoarthritis, stiffness and pain typically worsen with activity
4. Classic Joint Changes
   1. "Boutonniere" deformity: flexed proximal interphalangeal joints (PIP)
   2. "Swan-Neck" deformity: hyperextension of PIP with flexed distal IP joints
5. Rheumatoid Nodules [10]
   1. Lymphocytes and epithelioid histiocytes (similar to true granulomas)
   2. Proliferating fibroblasts in the surrounding area
   3. Usually in severe cases with positive rheumatoid factor (RF)
   4. Associated with tendons and various organs including lungs
6. Extra-articular Disease
   1. Cardiac: pleurisy, pericarditis, pericardial effusion, rarer myocarditis
   2. Nerve entrapment syndromes
   3. Nail fold thrombi
   4. Keratoconjunctivitis sicca (with or without Sjogren's Syndrome)
   5. Rheumatoid Lung Changes (see below)
   6. Ulcerative keratitis
   7. Frank skin ulcers (vasculitic)
   8. Rheumatoid Vasculitis
7. Increased Incidence of Malignancy
   1. Mainly non-Hodgkin lymphomas: T cell type, large granular morphology, CD3+, CD57+
   2. Large granular T lymphocytic leukemias similar to lymphomas
8. Atherosclerosis
   1. Systemic inflammation in RA may predispose to atherosclerosis
   2. Aymptomatic carotid atherosclerosis ~5X increased in RA versus age-matched controls [8]

E. Laboratory Analysis

1. Elevation of Acute Phase Reactants
   1. CRP - IL6 drives CRP expression
   2. Ferritin and Haptoglobin
   3. Hyperglobulinemia
   4. ESR (erythrocyte sedimentation rate) - typically in 50-60mm/hr range
2. Rheumatoid Factors (RF) - see below
3. Other Blood Anomalies
   1. Thrombocythemia
   2. Eosinophilia may be present (usually <15% of WBC)
   3. Neutrophilia
   4. Anemia - bone marrow suppression due to chronic inflammation (low iron, high ferritin)
   5. ANA is present in ~20% patients with positive RF
   6. Complement levels usually normal in serum
   7. TNF alpha levels are generally increased
4. Joint Fluid Analysis
   1. Synovial fluid usually turbid
   2. Typically with high protein, normal or low glucose; no crystals
   3. WBC 5K-50K/µL (usually <20K/µL), mostly neutrophils (PMN)
   4. Joint fluid C3 and C4 decreased relative to serum
5. Chest Radiograph
   1. Variety of changes including effusions
   2. Kaplan's Syndrome = rheumatoid nodules, RA, pneumoconiosis
   3. Major concern is rheumatoid lung with pneumonitis, interstitial fibrosis
6. No marker has yet been found that predicts occurrance or severity of disease

F. AutoAbs in RA

1. RF
   1. Antibody (Ab) against the Fc region of self IgG
   2. Usually IgM; may be IgG
   3. May have properties of "cryoglobulin"
2. RF in RA
   1. RF present in ~50-70% of RA at initial presentation
   2. Over time, ~80% of cases of RA develop RF
   3. If RF not present with 1st year of disease, patient will usually not seroconvert
   4. Sensitivity ~70%; Specificity 75-85% [9]
   5. Positive likelihood ratio (LR) 4.9; negative LR 0.38
   6. Found in many conditions other than RA
   7. Presence of RF indicates severe, unremitting disease, nodules
   8. Very poor clinical correlation between titers of RF and disease status
3. Anti-CCP AutoAbs [9]
   1. More specific (95%) than RF+ for RA; sensitivity 67%
   2. CCP Abs: positive LR 12.46, negative LR 0.36 for RA
4. Other Autoantibodies
   1. Anti-SSA (Ro) may be present (few cases)
   2. High ANA+ suggests overlap systemic lupus with arthritis
   3. Anti-Collagen Abs [6] found only in a small proportion of RA patients

G. Bone and Joint Radiographs

1. Characteristic of classic RA
2. Thickened synoveum with soft tissue swelling
3. Periarticular osteopenia usually occurs next
4. Bone erosions will ensue (periarticular) with joint destruction
5. Ulnar Deviation - usually late changes
6. Joint fusion with loss of function may occur
7. Most patients have radiographic evidence of changes within 2 years of diagnosis

H. Pulmonary Disease

1. Pleurisy ~20% symptomatic, ~40% on autosopsy, of patients
2. Pleural effusions ~5-10% of patients (may precede joint disease in ~25% of patients)
3. Pneumonitis (often with interstitial fibrosis)
4. Chest Radiograph
   1. Rheumatoid lung - Interstitial fibrosis typically at bases (bilateral)
   2. May also have BOOP, Kaplan's Syndrome, Pleural effusions
   3. Rheumatoid nodulosis usually peripheral, asymptomatic, may cavitate
5. Pleural Fluid []
   1. Typically yellow-green (possibly related to cholesterol crystals)
   2. WBC 100-8000 cells/µL, usually lymphocytic, may be PMN
   3. Glucose usually 0-25mg/dL (extremely low)
   4. Exudative properties, LDH often >1000IU/L
   5. Complement levels in fluid usually decreased
   6. RF often high in fluid
6. Pleural Biopsy - may show rheumatoid nodules; more often non-specific
7. Treatment for pleural effusions includes intrapleural glucocorticoid injection

I. Treatment Overview [12,13]

1. Therapy Goals
   1. Patients remain active and chronic joint damage prevention
   2. Complete remission in ~33% at 1 year and ~45% at 2 years now achievable [25]
   3. Combination therapy generally required to minimize disease activity, induce remission
   4. Remission induction is main goal of therapy
   5. Pain control with NSAIDs and/or glucocorticoids accompanies disease modifying drugs
2. Disease Modifying Antirheumatic Drugs (DMARDs) [12,16,17,25]
   1. DMARDs used early in disease course to prevent long term joint destruction [14]
   2. Glucocorticoids improve symptoms rapidly and have some disease modifying actions
   3. Methotrexate (MTX) alone and in combination is current cornerstone of DMARD therapy
   4. However, many DMARDs show similar activity and optimal first choice is not clear [38]
   5. Combinations provide most rapid disease control versus MTX alone or sequential stepped therapy [15,16,25]
   6. Prednisolone 7.5mg po qd for 2 years added to DMARDs reduced joint damage [17,18,25]
   7. DMARDs provides substantial symptomatic benefits at 6 and 12 months
   8. Glucocorticoids, MTX, TNFa blockers, CTLA4Ig, anti-CD20, anti-IL6 reduce bone erosions
   9. Milder Disease: HCQ, sulfasalazine (SSA), IL1 blockers are typically used
   10. Liberal use of glucocorticoid injections into active joints is very effective [28]
3. DMARDS for Moderate to Severe RA
   1. MTX and/or TNFa blockers are first line in moderate and severe RA [12,15,16]
   2. TNF alpha blockade or leflunomide for suboptimal MTX response or MTX intolerance
   3. MTX+abatacept (CTLA4Ig) or rituximab (anti-CD20) effective in MTX-resistant RA [2,35,40]
   4. Combination induction therapy for early moderate or severe disease is more effective than single agents [3,15,16,25]
   5. Cyclosporine A (CsA) or Protein A column (Prosorba®) now 4th line in refractory RA
   6. Once disease is controlled, one or more of the agents may be weaned slowly
4. Combination Therapy [2,12,13,28]
   1. Combination therapy is more active than monotherapy; optimal regimen(s) not clear [38]
   2. Aggressive combination therapy to achieve tight RA disease control substantially improves disease activity, prevents joint progression, improves quality of life [25,28]
   3. MTX + TNFa blockade (infliximab) more rapidly acting than MTX+sulfasalazine+prednisone and single agents (including MTX) in early active RA [25]
   4. MTX + abatacept is also very effective in MTX resistant RA [35,40]
   5. Rituximab + MTX superior to MTX alone with rituximab effects lasting ~6 months [2]
   6. Anti-IL6 mAb tocilizumab + MTX superior to MTX alone (see below) [2,58]
   7. Combination induction therapy should be used in patients who present with severe or moderately severe disease including any bone erosions [3,25,28]
5. Atorvastatin (Lipitor®) 40mg po qd added to DMARDs reduced joint inflammation and inflammatory markers in RA [49]

J. Specific Therapeutics

1. Non-Steroidal Anti-Inflammatory Agents [13]
   1. NSAIDs have anti-inflammatory and anti-pain activity
   2. Once daily agents taken at night are often effective and convenient
   3. None of these agents has disease-modifying activity
   4. COX-2 inhibitor celecoxib 200mg po bid is as effective as diclofenac
   5. Endoscopically proven ulceration occurred in 15% of diclofenac versus 4% celecoxib
   6. Cox-2 inhibitor rofecoxib as effective as naproxen 500mg bid; >50% less GI bleeding [22]
   7. Capsaicin topical cream applied to painful areas bid can also reduce symptoms of RA [23]
   8. Misoprostol, double-dose H2-blockers, and proton pump inhibitors are equally effective at preventing endoscopic and clinically significant ulcers from non-selective NSAIDs
2. Glucocorticoids [17,18]
   1. Initiate therapy with prednisone for severe flares at ~1mg/kg/day with taper over 4-6 weeks to 5-10mg/d [15]
   2. Chronic treatment with prednisolone 7.5mg po qd reduces radiographic joint destruction, even in patients on other second line agents [17,18]
   3. Glucocorticoids work as rapidly as NSAIDs and have clear disease modifying effects
   4. Test for tuberculosis prior to glucocorticoid treatment
   5. May be used safely in pregnancy
   6. Osteoporosis prophylaxis should be strongly considered
   7. Nearly all patients on chronic glucocorticoids should take vitamin D and calcium
3. Hydroxychloroquine (HCQ, Plaquenil®) [27]
   1. For mild disease or in combination with other drugs such as MTX
   2. May take 2-3 months to observe results
   3. Clear benefits versus placebo have been demonstrated
   4. Also effective for elderly onset RA
   5. Initially, 600-800mg/d for 1-2 weeks then 400mg/day
   6. Ophthalmological evaluation q6-12 months is recommended to rule out rare retinal spots
   7. Mild and uncommon nausea and headache
   8. Use in RA patients associated with ~75% reduced risk of developing diabetes [56]
4. SSA (Azulfidine®) [29]
   1. Slow onset of action (>6-12 weeks) with some disease modifying activity [29]
   2. May be used in combination with MTX, HCQ, and/or glucocorticoids
   3. Begin 500mg po qd-bid then escalate dose weekly to 2gm/d in divided doses
   4. Side Effects: sulfa allergy, bone marrow suppression, nausea, diarrhea, pancreatitis
   5. Complete blood counts and LFT must be monitored
   6. Patients intolerant to sulfa agent may try olsalazine
   7. Lefluonamide or TNFa blocking agents are preferred for moderate disease
5. Leflunomide (Arava®) [19,29]
   1. Blocks dihydro-orate dehydrogenase and reduces cellular UTP (pyrimidine) levels
   2. Single agent reduces joint destruction over 24-48 weeks as effective as MTX
   3. Combine cautiously with MTX with added benefit [30]
   4. Metabolized by liver with half life of ~14-15 days
   5. Active metabolite blocks CYP2C9
   6. Dose is 100mg qd x 2-3 days (loading), then 20mg/d (or 10mg/d if not tolerated)
   7. Diarrhea, rash and reversible alopecia are most common side effects
   8. LFT (aminotransferase) levels increase >3X normal in ~10% of patients
   9. If leflunomide must be removed, cholestyramine tid for 8-11 days is required
   10. This is a 3rd line agent after MTX and TNFa blockers
6. IL1 Receptor Antagonist (IL1-RA; anakinra, Kineret®) [31,32]
   1. Recombinant non-glycosylated form of natural antagonist to IL1
   2. Moderate activity in moderate RA
   3. May be used alone or in combination with MTX
   4. May improve rheumatoid tenosynovitis [32]
   5. Side Effects: ruritus, rash, erythema, pain at injection site, neutropenia (8%)
   6. Combination with etanercept led to 7% rate of serious infection
   7. Dose is 100-150mg daily sc
7. Abatacept (CTLA4-Ig, Orencia®) [2,24,26,35,40]
   1. Soluble fusion molecule of cytotoxic T lymphocyte antigen 4 (CTLA4) with human IgG1 Fc
   2. Blocks costimulation of T cells through CD80 and CD86 binding to T lymphocyte CD28
   3. Activity in psoriasis and RA
   4. Abatacept 10mg/kg IV over 30 minutes on days 1,15, 30 and then monthly for 6 months
   5. Improved responses in RA patients with active disease on MTX
   6. Abatacept on days 1,15,29 then monthly x 6 months induced ACR20 responses in 50% of TNFa blocker refractory RA compared with 20% with placebo [24]
   7. May also be given once monthly x 12 months, effective in MTX-resistant active RA [40]
   8. No increase in serious infections and minimal adverse events
   9. Strongly consider for patients with suboptimal response to TNFa blockers
8. Rituximab (Rituxan®) [2,50,52]
   1. Anti-CD20 IgG1 kappa chimeric mouse/human mAb targets all mature B cells
   2. Depletes all CD20 expressing cells, including normal and malignant B cells
   3. Good efficacy alone or in combination with MTX or cyclophosphamide in patients with MTX resistant rheumatoid arthritis [51]
   4. Rituximab mon- and combination therapies were very well tolerated and showed efficacy on disease symptoms and signs, reduction in RF, at 24 and 48 weeks [51]
   5. Dose of rituximab 1000mg IV on days 1 and 15
   6. FDA approved with MTX for poor response to TNFa inhibitors
   7. Unclear efficacy compared with abatacept
9. Minocycline [36]
   1. May be effective for mild RA over 11-12 months
   2. Dose is 100mg po bid
   3. Well tolerated, but may cause dizziness, especially in elderly persons
   4. Treated groups had ~55% decrease in joint pain/swelling versus ~40% in placebo group
   5. No clear advantage over HCQ
10. CSa (Sandimmune®) [34]
    1. Low doses very effective in MTX resistant disease but now 4th line
    2. Typically 2-4mg/kg/day; aim for levels <200ng/dL (maximum 5mg/kg/day)
    3. 3mg/kg/day reduces radiographic joint destruction at 12 months
    4. Discontinue after 3 months if no response
    5. CSa has been combined safely with MTX and is very effective but is infrequently used
11. Gold (Auranofin®, others)
    1. Only recommended after failures of MTX, TNFa blockade, leflunomide, other biologicals
    2. Except for patients with rheumatoid nodules, use of gold in RA is no longer recommended
12. Azathioprine (Imuran®) is no longer recommended for RA treatment
13. Tocilizumab [58]
    1. Humanized mAb binds both cell-bound and soluble forms of interleukin 6 (IL6) receptor
    2. Results in RA patients on Methotrexate with Suboptimal Responses
    3. Doses 4-8mg/kg IV q4 weeks for 24 weeks
    4. At 24 weeks, ACR50 in >40% at 8mg/kg versus >10% on placebo
    5. At 24 weeks, ACR20 in >55% at 8mg/kg versus >20% on placebo
    6. Serious adverse events in 3% at 8mg/kg, 1.5% at 4mg/kg, 1% on placebo
    7. Otherwise, generally well tolerated
14. Protein A Column (Prosorba®) Plasmapheresis [37]
    1. Protein A is a staphylococcal protein that binds to human immunoglobulin G
    2. Approved for use for treatment of resistant RA
    3. May be effective in ~30% of patients who fail or are intolerant of MTX
    4. Treatment is weekly for 12 weeks; responses seen after 12 weeks of therapy
15. Nerve growth factor applied topically to chronic RA vasculitic ulcers led to rapid healing [39]
16. Chaperonin 10 (HSP 10) protein IV weekly improved RA symptoms in early study [55]

K. Methotrexate (MTX) [12]

1. MTX is the classical first line DMARD for moderate to severe RA
2. Efficacy
   1. Usually observed within 4-6 weeks
   2. Reduces radiographic joint damage
   3. MTX associated with reduced risk of overall and cardiovascular death in RA patients [6]
   4. May be combined with various agents generally with added efficacy [16]
3. Tests required prior to starting MTX
   1. Liver function tests (LFT) and viral hepatitis screen
   2. Baseline chest radiograph (consider pulmonary function tests)
   3. Complete blood count
   4. Discontinue all alcohol
   5. Rule out pregnancy; agent is highly teratogenic
4. Dosing
   1. Initially as 7.5mg po q week, usually in three 2.5mg doses12 hours apart once per week
   2. Elderly or smaller patients may begin at 5.0mg weekly
   3. Single dose versus split dosing may not have any difference
   4. May be increased to 15-20mg q week orally; up to ~50mg / week sc
   5. Combine with folate, 1-2mg po qd, reduces hepatitis and stomatitis from MTX
   6. Folinic acid (Leukovorin®) 2.5mg-5mg after MTX dose also reduces side effects from MTX
   7. At these doses, folate and folinic acid do not decrease efficacy of MTX
   8. Contraception must be used
5. Laboratory Monitoring
   1. LFT monthly: if >2X increase in transaminases, stop drugs for 2-4 weeks, then reinitiate at lower dose with careful monitoring
   2. Hematocrit and MCV q month
   3. Chest radiograph (CXR) baseline in all patients
   4. Pulmonary Function Tests in all patients with abnormal CXR or underlying lung disease
   5. Pregnancy must be ruled out before starting medication
   6. Smoking is relatively contraindicated due to increased pneumonitis risk
6. Side Effects
   1. Rash and stomatitis - ~5%
   2. Gastrointestinal - Nausea (~15%), Vomiting (~4%), Diarrhea (~8%)
   3. Headache, Hair Loss, Dizziness
   4. Macrocytosis - may have MCV up to 115 fL
   5. Leukopenia - usually mild
   6. Drug induced hepatitis
   7. Patients with liver or lung disease are at increase risk for severe side effects
   8. May cause worsening of rheumatoid nodules
   9. Overall well tolerated when folate or folinic acid added
7. Severe Side Effects
   1. Cirrhosis / Fibrosis - up to 10% with total of 1.5-2gm
   2. Hematologic - leukopenia (discontinue MTX if WBC < 1K/µL); thrombocytopenia
   3. Infection - ~4% of patients
   4. Hypersensitivity Pneumonitis
   5. Highly teratogenic
   6. No increased risk of hematologic malignacies in RA patients compared with other second line RA drug
8. MTX Pneumonitis
   1. Allergic, idiopathic reaction in 1-5% of patients (eosinophil pulmonary infiltrates)
   2. Peripheral eosinophilia in ~35% of cases
   3. Chest XRay usually with interstitial or mixed alveolar-interstitial infiltrates, bilaterally
   4. Prediliction for the involvement of lung bases
   5. Stop MTX, treat with high dose glucocorticoids
   6. May require intubation, but highly responsive to glucocorticoids

L. Tumor Necrosis Factor Alpha (TNFa) Blockade [16,19,41,54]

1. TNFa blockers be used alone or in combination with MTX
   1. Etanercept - recombinant soluble TNFa Receptor (fused to IgFc region)
   2. infliximab - chimeric human/mouse anti-TNFa monoclonal antibody (mAb)
   3. Adalimumab - engineered human IgG1 mAb
   4. May produce significant improvement in symptoms in MTX naive and resistant patients
   5. Strongly recommended in patients with suboptimal MTX responses
   6. May also be used first line in patients with very active RA
   7. Reduce progression of joint damage
   8. Improves rheumatoid tenosynovitis (reduces collagenase levels) [32]
2. Etanercept(Enbrel®) [43,44]
   1. Dose is 10mg or 25mg sc twice weekly (biw)
   2. 40-50% of patients receiving etanercept have 50% ACR criteria improvement [43,44]
   3. Combination with MTX gives up to 70% of patients with >50% ACR improvement [45]
   4. In early RA, etanercept 25mg sc biw is more effective and better tolerated than MTX [41]
   5. Most patients will continue to have good responses for >18 months of therapy
3. Infliximab (Anti-TNFa Antibody, Remicade®) [20]
   1. Approved for moderate to severe RA alone or with MTX (and for Crohn's Disease)
   2. Given as 3mg/kg or 10mg IV infusion every 4-8 weeks
   3. Likely that 10mg IV q8 weeks is simplest regimen
4. Adalimumab (Humira®) [46]
   1. Effective alone or in combination with MTX for moderate to severe RA
   2. Convenient dosing: 40mg sc every other week
5. Side Effects
   1. Injection site interactions, mainly with sc etanercept
   2. Headache, particularly with infliximab
   3. ~30% may become positive for antinuclear antibodies (ANA)
   4. Rare development of low levels anti-dsDNA Ab, usually without symptoms of lupus
   5. Malignancy risk ~3.3X, usually with with higher dose anti-TNFa Abs, mainly non-Hodgkin's lymphomas [53]
   6. Serious infection risk ~2.0X, usually treated with higher dose anti-TNFa Abs [53]
   7. Rare cases of exacerbation or new onset congestive heart failure (CHF) [47]
   8. Reduction in CHF rates in anti-TNF treated versus control RA patients [48]

M. Death from RA

1. Infection
   1. Underlying RA
   2. Progressive collagen vascular disease
   3. Related to immunosuppressive therapy
2. Progressive (and/or mixed) Collagen Vascular disease
   1. Vasculitis
   2. Rheumatoid Lung
   3. Amyloidosis
3. Atlanto-occipital dislocation
4. Neoplasia
   1. Underlying RA
   2. Related to immunosuppressive therapy
5. Other Drug Side Effects

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