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Risk factors Symptoms/Pathology Labs Diagnostic criteria Management
Known risk factors
  • Female sex
  • Family history
  • Increasing age
  • Smoking
  • HLA-DRB1 alleles [1,22]

Possible risk factors
  • Silica exposure
  • Infections (e.g. Epstein–Barr virus, cytomegalovirus, proteus species, and Escherichia coli)
  • Periodontal disease
  • Gut microbes [1]
Symptoms
  • Joint swelling and pain - typically multiple joints; metacarpophalangeal or metatarsophalangeal joints are most often involved; large joints may be involved too
  • Morning stiffness - for at least one hour in AM
  • Symmetrical arthritis - occurs on both sides of the body (ex. both hands)
  • Rheumatoid nodules - occur in 30 - 40% of patients. Rheumatoid nodules are granuloma-like lesions that form under the skin [2,3]


Pathology
  • The pathology of RA is not entirely understood
  • RA is characterized by swelling and inflammation of the cellular lining of the joints (synovium). Cartilage and bone are also affected.
  • RA is marked by the formation of autoantibodies to the Fc portion of IgG antibodies (Rheumatoid factors) and citrullinated proteins (ACPA)
  • These autoantibodies incite an inflammatory process that leads to joint and bone destruction
  • How and why this process occurs primarily in joints and bones is not completely understood [1,18]
Rheumatoid factor (RF)
  • Pathology: Rheumatoid factors are antibodies to the Fc fragment of IgG antibodies. The rheumatoid factors are typically IgM antibodies, but may also be IgG or IgA. Rheumatoid factors are present in the majority of patients with RA at some point over the course of the disease.
  • Diagnostic value:
    • About 80% of all patients with rheumatoid arthritis will eventually be positive for rheumatoid factors
    • Only 40% of patients with RA are RF-positive at first symptoms of the disease [6]
    • In studies, the sensitivity of RF for RA has been found to be 69%, the specificity has been found to be 85% [5]
    • The higher the level of RF, the greater the risk of developing RA
    • Patients with RF levels < 25 IU/ml have a very low risk of developing RA [6]

Cyclic Citrullinated Peptide Antibodies (Anti-CCP antibodies, ACPA)
  • Pathology: Citrullination is a chemical process in proteins where the amino acid arginine is replaced with the amino acid citrulline. Cyclic citrullinated proteins serve as significant antigens for the formation of the autoantibodies seen in RA. Anti-cyclic citrullinated peptide (CCP) antibodies are a very specific marker for RA. [7]
  • Diagnostic value:
    • Most modern Anti-CCP antibody tests have a very high specificity meaning there are a low number of false-positives, so a positive test result means RA is very likely. A negative test result is not as helpful since the test sensitivity is low (high false-negative).
    • Specificity: ∼ 95% [5,7]
    • Sensitivity: ∼ 50 - 70% [5,7]
    • Anti-CCP antibody levels are not recommended for monitoring disease activity [7]

Erythrocyte Sedimentation Rate (ESR)
  • Test: The ESR test measures how fast red blood cells separate from plasma and fall to the bottom of a test tube. Results are reported in millimeters of clear plasma that are present at the top portion of the tube after one hour. Cells tend to fall faster when inflammatory markers such as fibrinogen, immunoglobulins, and acute phase reactants are present; therefore, a higher ESR indicates more inflammation. [8]
  • Diagnostic value: The ESR is used to determine if inflammation is present. A big drawback to the ESR test is that it is nonspecific, and a number of noninflammatory processes can cause an elevated ESR.

    • Causes of elevated ESR:
      • Infection
      • Inflammation
      • Anemia
      • Pregnancy
      • Advanced age
      • Immune disorders (Multiple Myeloma, Waldenstrom's macroglobulinemia)
      • Menstruation
      • Medications (oral contraceptives, methyldopa, theophylline)
      • Vitamin A
      • Obesity
      • Fatty liver [8]

C-Reactive Protein (CRP)
  • Test: C-Reactive Protein (CRP) is an "acute phase reactant." CRP is made in the liver and released into the bloodstream within a few hours of the start of an inflammatory process (ex. infection, tissue injury, trauma, etc.) [8]
  • Diagnostic value: CRP is used to determine if inflammation is present. Much like the ESR test, it is nonspecific and can be elevated in patients who do not have an inflammatory process. CRP increases faster and decreases more rapidly than the ESR therefore it is a more acute measure of inflammation.

    • Causes of elevated CRP:
      • Infection
      • Inflammation (CRP is often elevated in RA, but not SLE)
      • Pregnancy
      • Cancer
      • Medications (oral contraceptives, estrogens)
      • Obesity [8, 9]

The ACR recommends testing the following patients for RA:
  • Patients that have at least 1 joint with definite clinical synovitis (swelling) and the synovitis is not better explained by another disease (e.g. SLE, gout, psoriatic arthritis)

The diagnosis of RA is based on the following criteria (ACR 2010):

RA diagnosis - score of ≥ 6 based on the following 4 criteria
NOTE: Patient receives one score for each criteria
Joint involvement
  • Joint must be swollen or tender. May be confirmed on imaging.
  • Joints excluded from assessment - DIP joints, 1st carpometacarpal joints (involved in OA), and 1st metatarsophalangeal joints (involved in gout)
Finding Score
1 large joint
  • Large joint - shoulders, elbows, hips, knees, and ankles
0
2 - 10 large joints 1
1 - 3 small joints
  • Small joint - metacarpophalangeal joints, PIP joints, 2nd through 5th metatarsophalangeal joints, thumb interphalangeal joints, and wrists
2
4 - 10 small joints 3
> 10 joints with at least 1 small joint
  • may also include TMJ, AC joint, etc.
5
Serology
  • Either RF or ACPA (Anti-CCP antibodies) is needed for classification
  • Low positive - low-positive refers to IU values that are higher than the upper limits of normal (ULN) but ≤ 3 times the ULN for the laboratory and assay
  • High positive - refers to IU values that are > 3 times the ULN for the laboratory and assay
  • Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored as low-positive for RF
Finding Score
Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
Acute-phase Reactants
Finding Score
Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
Duration of symptoms
  • Refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status
Finding Score
< 6 weeks 0
≥ 6 weeks 1
  • Phase I - Initial diagnosis

    • Methotrexate or combo of csDMARDs +/- Low-dose corticosteroids +/- Leflunomide or Sulfasalazine (alone or in combination)

      • Low-dose corticosteroids defined as a dose of 7.5mg/day or less of prednisone or equivalent
      • csDMARD combinations combination should include methotrexate unless it is contraindicated. The most frequently used combination is methotrexate + sulfasalazine + hydroxychloroquine.
      • csDMARDs - methotrexate, sulfasalazine, hydroxychloroquine, leflunomide
        • *csDMARD stands for "conventional, synthetic disease-modifying antirheumatic drug"

    • If there is no change after 3 months, or target is not achieved at 6 months, then Phase II



  • Phase II - Adjust therapy for non/incomplete responders

    • Prognostically unfavorable factors present - Add biological agent


    • Prognostically unfavorable factors NOT present - Change to second csDMARD strategy

      • Second csDMARD therapy - Leflunomide, sulfasalazine, methotrexate alone or in combination (ideally with addition of corticosteroids as above)
      • Combinations of leflunomide or sulfasalazine without methotrexate have not been well-studied
      • For patients who do not achieve targets on second csDMARD therapy, add biological agent



  • Phase III - Adjust therapy for non/incomplete responders to Phase II

    • Change biological agent

      • Replace any first biological drug with any other biological drug
      • Tumor Necrosis Factor (TNF) inhibitors may be replaced with another TNF inhibitor
      • Continue csDMARD
      • Tofacitinib +/- csDMARD may be considered in patients who do not respond to biological medications

  • Reference [10]



    Other
    • RA is primarily a synovium, bone, and joint destructive disease
    • Extra-articular sequelae do occur
    • In one study, the estimated 10-year incidence of any extra-articular sequelae in RA patients was 50%
    • New biological therapies will likely lower the incidence of these sequelae

      • Extra-articular sequelae of RA (% of patients over 10 years):
        • Rheumatoid nodules - 31%
        • Keratoconjunctivitis sicca (dry eye syndrome) - 20%
        • Sjögren's syndrome - 10%
        • Pulmonary fibrosis - 5%
        • Pericarditis - 3%
        • Pleuritis - 2%
        • Neuropathy - 1%
        • Vasculitis - 1% [11]

      • Other sequelae of RA
        • Sarcopenia - loss of muscle mass
        • Osteoporosis
        • Cancers and infections secondary to treatment and disease activity
        • Increased risk of cardiovascular and cerebrovascular disease
        • Anemia of chronic disease [1]





Study Criteria Intervention Primary outcome Results

Addition of
Etanercept
vs
sulfasalazine + hydroxychloroquine
in methotrexate failure

NEJM 2013

PubMed abstract
Main inclusion criteria:
  • Patients meet ACR 1987 criteria for RA
  • Receiving methotrexate at dose of 15 - 25 mg/week for ≥ 12 weeks
  • DAS28 score of ≥ 4.4
Group 1 (178 patients)
  • Continue methotrexate at current dose +
  • Sulfasalazine 2g daily +
  • Hydroxychloroquine 400 mg once daily +
  • Placebo injection
Group 2 (175 patients)
  • Continue methotrexate at current dose +
  • Etanercept 50 mg every week +
  • Placebo pills

  • NSAIDs and prednisone (≤ 10 mg/day) were allowed
  • About 50% of patients in each group were taking oral glucocorticoids

  • If the DAS28 score decreased by < 1.2 at 24 weeks, the patient was switched to the competing regimen
  • Improvement in the DAS28 score at week 48
  • Analysis was done on an intention-to-treat basis
Primary outcome:
  • At 48 weeks, there was no significant difference between the 2 groups for the primary outcome (Group 1 -2.12, Group 2 -2.29, p=0.26)
  • In Group 1, 27% of patients switched therapies at 24 weeks compared to 26.7% in Group 2
Other outcomes:
  • At 24 weeks, there was a borderline significant difference between the 2 groups for change in DAS28 score (Group 1 -1.79, Group 2 -2.06, p=0.06)
  • There was no significant difference between the two groups for radiographic progression of disease at 48 weeks
  • The frequencies of adverse events were similar in the two groups. Gastrointestinal disorders were more frequent in Group 1 (30% vs 22%). Infections were more frequent in Group 2 (37% vs 25%). SKin and subcutaneous disorders were more frequent in Group 2 (16% vs 10%)



  • U-Act-Early Study - Tocilizumab + MTX vs Tocilizumab vs MTX in Early RA, Lancet (2016) [PubMed abstract]
    • The U-Act-Early study enrolled 317 patients with RA who were DMARD-naïve
    • Main inclusion criteria: meet criteria for RA (1987 ACR or 2010 ACR/EULAR); DMARD-naïve; diagnosed within past year; DAS28 score ≥ 2.6
    • Main exclusion criteria: uncontrolled serious comorbidities; active or recurrent infections; presence of other rheumatic disease; oral corticosteroids within 6 weeks
    • Baseline characteristics: median age 54 years; female - 67%; median symptoms duration - 26 days; average DAS28 score - 5.2; RF positive - 72%; Anti-CCP Ab positive - 70%; average ESR - 25 mm/hr
    • Patients were randomized to 1 of 3 groups:
      • Group 1 (106 patients) - Tocilizumab + methotrexate
      • Group 2 (103 patients) - Tocilizumab + placebo
      • Group 3 (108 patients) - Methotrexate + placebo
      • Tocilizumab was given as 8 mg/kg (max 800 mg) IV every 4 weeks
      • Methotrexate was started at 10 mg once weekly and increased every 4 weeks by 5 mg to a max of 30 mg
      • If remission was not achieved at maximal methotrexate/methotrexate-placebo doses, then hydroxychloroquine 200 mg twice daily for 3 months was added
      • The study had an extended phase where nonresponders could be switched to other regimens. That phase is not detailed here.
    • PRIMARY OUTCOME: Sustained remission defined as a DAS28 of < 2.6 and a swollen joint count of ≤ 4 joints of the 28 joints assessed during at least 24 weeks. During this period, at ≤ 2 of the seven visits a DAS28 of more than 2.6 but less than 3.2 (low disease activity) was allowed, to account for nonspecificity of small increases in DAS28.
    • During the initial treatment phase, the following was seen:
      • Primary outcome: Group 1 - 86%, Group 2 - 83%, Group 3 - 44% (1 vs 3, p<0.0001; 2 vs 3, p<0.0001; 1 vs 2, p=0.62)
      • Number of patients achieving good EULAR response at 24 weeks: Group 1 - 89%, Group 2 - 87%, Group 3 - 49% (1 vs 3, p<0.0001; 2 vs 3, p<0.0001; 1 vs 2, p=0.43)
      • Serious infections (entire study): Group 1 - 3.8%, Group 2 - 5.8%, Group 3 - 4.6% (p>0.05 for all comparisons)
      • ALT > 3 X ULN (initial + extended phase): Group 1 - 13.2%, Group 2 - 4.9%, Group 3 - 11.1% (p>0.05 for all comparisons)
      • ANC < 1000 cells/mm3 (initial + extended phase): Group 1 - 6.6%, Group 2 - 5.8%, Group 3 - 0.9% (p>0.05 for all comparisons)
      • Platelet count < 100,000/mm3 (initial + extended phase): Group 1 - 3.8%, Group 2 - 2.9%, Group 3 - 0.9% (p>0.05 for all comparisons)
      • Lipid-lowering drug needed during study (initial + extended phase): Group 1 - 15.1%, Group 2 - 23.3%, Group 3 - 20.4% (p>0.05 for all comparisons)



Study Criteria Intervention Primary outcome Results

Tapering etanercept

PRESERVE trial

Lancet 2013

PubMed abstract
Main inclusion criteria:
  • RA with moderate disease activity (DAS28 score of 3.2 - 5.1)
  • Receiving methotrexate 15 - 25 mg/week for 8 weeks prior
Main exclusion criteria:
  • Current or past biologic agent
  • Any disease-modifying agent (other than methotrexate) within 28 days of enrollment
  • More than one NSAID
  • Prednisone > 10mg a day or dose changed within 14 days of enrollment

Pre-randomization treatment
  • All patients received open-label etanercept 50mg a week + methotrexate at current dose with increase to 25mg/week if needed
  • Treatment was for 36 weeks
  • After 36 weeks, patients who achieved low disease activity (average DAS28 ≤ 3.2 from weeks 12 to 36 and DAS28 ≤ 3.2 at week 36), were randomized to one of three, double-blinded tapering regimens
Group 1 (202 patients)
  • Methotrexate at current dose +
  • Etanercept 50 mg every week

Group 2 (202 patients)
  • Methotrexate at current dose +
  • Etanercept 25 mg every week

Group 3 (200 patients)
  • Methotrexate at current dose +
  • Placebo injection
  • Proportion of patients with low disease activity (DAS28 ≤ 3.2) at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period
Primary outcome at week 88:
  • In Group 1, 83% of patients had low disease activity compared to 43% in Group 3 (p<0.0001)
  • In Group 2, 79% of patients had low disease activity (Group 2 vs Group 3, p<0.0001)
Other outcomes:
  • Radiographic progression of disease was worse in Group 3 when compared to the other 2 groups
  • The rate of adverse events was similar across groups



  • ACR treatment recommendations for certain conditions

    • Overview
      • In 2015, the ACR published RA guidelines that included treatment recommendations for certain patient populations
      • The recommendations are summarized in the table below
      • It's important to note that all of the recommendations are based on "very low" levels of evidence [24]

Reference [24]
Condition Treatment recommendation
Tuberculosis (TB) Before starting biologic or tofacitinib therapy:
  • Screen all patients for TB
  • Latent TB - treat TB for at least 1 month before starting therapy
  • Active TB - patients should complete TB treatment before starting therapy
Congestive Heart Failure
  • Use csDMARDs or non-TNF biologic or tofacitinib over TNF inhibitors
  • If CHF worsens on TNF inhibitor, switch to one of these other therapies
Hepatitis B
  • Untreated patients should be referred for treatment before starting
    immunosuppressive therapy
  • If patient is receiving or has received effective treatment,
    then recommendations are the same as those in patients without Hepatitis B
Hepatitis C
  • If patient is receiving or has received effective treatment,
    then recommendations are the same as those in patients without Hepatitis C
  • In patients who have not been treated effectively,
    use csDMARDs over TNF inhibitors
Melanoma
(current or past)
  • Use csDMARDs over biologicals or tofacitinib
Non-melanoma skin cancer
(current or past)
  • Use csDMARDs over biologicals or tofacitinib
Lymphoproliferative disorder
(previously-treated)
  • Rituximab is preferred over TNF inhibitors
  • Use csDMARDs or abatacept or tocilizumab over TNF inhibitors
Solid organ tumor
(previously-treated)
  • Recommendations are the same as those in patients without a
    history of solid organ tumor
Previous serious infection
  • Use csDMARDs over TNF inhibitors
  • Use abatacept over TNF inhibitors



  • DAS28 score

    • Overview
      • The DAS28 score is a measure of disease activity in rheumatoid arthritis
      • The score is often used as an outcome measure in rheumatoid arthritis trials
      • It is also used in guidelines as part of treatment recommendations

    • Components
      • The score is based the measurement of 4 components:

      • Component Measurement
        Number of tender joints 28 joints are measured
        (10 MCP joints; 10 PIP joints; 2 wrists, 2 elbow; 2 shoulder; 2 knee)
        Number of swollen joints 28 joints are measured
        (10 MCP joints; 10 PIP joints; 2 wrists, 2 elbow; 2 shoulder; 2 knee)
        ESR or C-reactive protein Either one can be used
        Global assessment of health Patients makes a mark on a 10 cm line
        with 1 being "very bad" and 10 being "very good"

    • Calculating score

    • Score interpretation




  • PRICING

    • $ = 0 - $50
    • $$ = $51 - $100
    • $$$ = $101 - $150
    • $$$$ = > $151

    • Pricing based on one month of therapy at standard dosing in an adult
    • Pricing based on survey of GoodRX.com®, HEB®, and Costco®, [accessed 1/2015]
    • Pricing may vary by region and availability



  • References:
  • 1 - PMID 22150039 - Pathogenesis of RA
  • 2 - PMID 16166104 - Nodules
  • 3 - PMID 12480677 - Nodules
  • 4 - LabCorp® website
  • 5 - PMID 17548411 - MA on RF
  • 6 - PMID 22956589 - BMJ RF study
  • 7 - PMID 24340846 - Anti-CCP study
  • 8 - Clin Chem website
  • 9 - PMID 24653858 - CRP paper
  • 10 - PMID 24161836 - EULAR treatment recs
  • 11 - PMID 21459933
  • 12 - PMID 14963199
  • 13 - PMID 11096165 - MTX RCT
  • 14 - PMID 19581281 - MTX SEs
  • 15 - Methotrexate PI
  • 16 - PMID 18512708 - ACR MTX recs
  • 17 - PMID 19033291 - Multinational MTX recs
  • 18 - PMID 20870100 - Lancet review
  • 19 - Sulfasalazine PI
  • 20 - PMID 11014343
  • 21 - Arava® PI
  • 22 - PMID 25919528
  • 23 - PMID 26545940 - ACR 2015 RA GL