- ACRONYMS AND DEFINITIONS
- ACR - American College of Rheumatology
- Ada - Adalimumab
- Anti-CCP antibodies - Anti cyclic citrullinated peptide antibodies
- CRP - C-reactive protein
- DMARD - Disease-modifying antirheumatic drug
- ESR - Erythrocyte sedimentation rate
- EULAR - European League against Rheumatism
- MTX - Methotrexate
- RA - Rheumatoid arthritis
- RCT - Randomized controlled trial
- RF - Rheumatoid factors
- TNF - Tumor necrosis factor
- Tof - Tofacitinib
- ULN - Upper limit of normal
- EPIDEMIOLOGY
- Rheumatoid arthritis is prevalent in approximately 1% of the worldwide population. It has a peak incidence between 35 and 50 years fo age, and women are three times more likely to be affected than men. [29]
- RISK FACTORS
- Known risk factors
- Female sex - women are affected 3 times more than men
- Family history - first-degree relatives of affected individuals have 2 - 3 times the average risk
- Increasing age - incidence increases with age peaking around 50 years
- Smoking
- HLA-DRB1 alleles [1,22,24]
- Possible risk factors
- Silica exposure
- Infections (e.g. Epstein–Barr virus, cytomegalovirus, proteus species, and Escherichia coli)
- Periodontal disease
- Gut microbes (Prevotella copri) [1,24,29]
- SYMPTOMS
- Joint swelling and pain - RA typically affects multiple joints of the hands. Affected joints are swollen, tender, warm, and have decreased range of motion. The metacarpophalangeal, proximal interphalangeal (PIP), and wrist joints are most commonly affected while the distal interphalangeal (DIP) joints are typically spared. Other joints that can be involved include the knee, metatarsophalangeal (MTP) joints, shoulder, ankle, cervical spine, hip, elbow, and temporomandibular joints.
- 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 [2,3,29]
- 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.
- Inflammation is believed to occur through 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]
- LABORATORIES
- Rheumatoid factor
- 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 rheumatoid arthritis at some point over the course of their disease
- Diagnostic value
- About 80% of all patients with rheumatoid arthritis (RA) 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]
RF value | Range |
---|---|
≤ 14 IU/ml | negative |
> 14 IU/ml | positive |
- Cyclic Citrullinated Peptide Antibodies (Anti-CCP antibodies, ACPA)
- 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 rheumatoid arthritis (RA)
- Anti-cyclic citrullinated peptide (CCP) antibodies are a very specific marker for RA
- Anti-CCP antibodies also have prognostic value in patients without RA. In one study, an estimated 46% of patients without RA at baseline who had anti-CCP antibody titers > 3 X ULN progressed to RA within 5 years. [PMID 30570827]
- 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%
- Sensitivity: ∼ 50 - 70%
- Anti-CCP antibody levels are not recommended for monitoring disease activity [5,7]
Anti-CCP value | Range |
---|---|
< 20 units | negative |
20 - 39 units | weak positive |
40 - 59 units | moderate positive |
> 59 units | strong positive |
- Erythrocyte Sedimentation Rate (ESR)
- The ESR is a nonspecific measure of inflammation. Patients with RA often have an elevated ESR.
- See erythrocyte sedimentation rate for a full review
- C-Reactive Protein (CRP)
- Like the ESR, CRP is also a nonspecific measure of inflammation. Patients with RA often have an elevated CRP.
- See C-reactive protein for a full review
- DIAGNOSIS
- Whom to test
- The ACR recommends testing 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)
ACR 2010 Rheumatoid Arthritis Diagnostic Criteria | |
---|---|
RA diagnosis is made if score ≥ 6 based on the following 4 criteria (patient receives one score for each criteria) | |
Joint involvement
|
|
Finding | Score |
1 large joint
|
0 |
2 - 10 large joints | 1 |
1 - 3 small joints
|
2 |
4 - 10 small joints | 3 |
> 10 joints with at least 1 small joint
|
5 |
Serology
|
|
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
|
|
Finding | Score |
< 6 weeks | 0 |
≥ 6 weeks | 1 |
Features of Different Arthritis Syndromes | |||||||
---|---|---|---|---|---|---|---|
Finding | Psoriatic arthritis | Rheumatoid arthritis | Lupus | Gout | Ankylosing spondylitis | Reactive arthritis | IBD-associated arthritis |
Age of onset Male:Female |
30 - 40s 1:1 |
35 - 50s 1:3 |
20 - 30s 1:9 |
30 - 60s 3:1 |
17 - 30s 3:1 |
20 - 30s 5:1 |
30s 2:1 |
Distal joints |
Fingers and toes including DIP Asymmetric ≤ 4 joints |
Fingers and toes, spares DIP Symmetric > 4 joints |
Hands, wrists, knees Symmetric > 4 joints |
Great toe, foot, ankle, knees, elbow Asymmetric < 4 joints |
Lower limbs (30 - 50%) Asymmetric < 4 joints |
Knees, ankles, hips Asymmetric < 4 joints |
Hands and knees Asymmetric |
Spine disease | Axial joints - 50% Sacroiliitis - 40% |
Uncommon | Uncommon | Absent | 100% | Sacroiliitis - 50% Back pain - 50% |
30% |
Enthesitis | 30 - 50%, Plantar fascia and Achilles's tendon | Absent | Absent | Absent | Common | Common, Achilles tendon and plantar fascia | Uncommon |
Dactylitis | 40 - 50% | Absent | Absent | Uncommon | Uncommon | Common | Absent |
HLA-B27 positive | 40 - 50% | Not associated | Not associated | Not associated | 90 - 95% | 75% | 30% |
Eye disease | Uveitis - 8% | Dry eyes - 20% | Dry eyes - 15% | Absent | Uveitis - up to 30% | Conjunctivitis (common) Anterior uveitis - 25% |
Uveitis - up to 7% |
Other features | Psoriasis - 100% Nail disease - 85% |
Positive RF and Anti-CCP | Positive ANA Joint disease is non-erosive |
Elevated uric acid | Primarily affects the spine and pelvis | ✝Preceding infection Urethritis (common) Self-limited - 80% |
Occurs in 10 - 20% of patients with IBD |
- EXTRA-ARTICULAR DISEASE
- Overview
- 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
- Felty syndrome - Felty syndrome is a condition seen in RA patients that is marked by splenomegaly and neutropenia. It has been reported to occur in up to 3% of patients and is usually only seen in severe, deforming disease. With the advent of effective disease-modifying therapies, Felty syndrome has become rare.
- Large granular lymphocyte leukemia (LGL) - LGL leukemia is a type of chronic leukemia that has a higher incidence in RA patients [1,34,35]
- TREATMENT
- Overview
- RA is an incurable disease, but with the advent of biologic and targeted therapies, it has become a very manageable condition, with up to 80% of affected patients now able to achieve remission or very low disease activity
- DMARD classes
- Disease-modifying antirheumatic drugs (DMARDs) are medications that treat RA pathology and prevent disease progression. They are are subdivided into groups based on their mechanism and drug class.
- Conventional synthetic DMARDs (csDMARDs)
- Aminosalicylates
- Sulfasalazine (Azulfidine®)
- Calcineurin inhibitors
- Cyclosporine (Neoral®)
- Dihydrofolate reductase inhibitors
- Methotrexate (Trexall®, etc.)
- Thiopurines
- Azathioprine (Imuran®)
- Other
- Hydroxychloroquine (Plaquenil®)
- Leflunomide (Arava®)
- Biologic DMARDs (bDMARDs)
- B-cell agents
- Rituximab (Rituxan®)
- IL-1 inhibitor
- Anakinra (Kineret®)
- IL-6 inhibitor
- Sarilumab (Kevzara®)
- Tocilizumab (Actemra®)
- TNF inhibitors
- Adalimumab (Humira®)
- Certolizumab (Cimzia®)
- Etanercept (Enbrel®)
- Golimumab (Simponi®)
- Infliximab (Remicade®)
- T-cell agents
- Abatacept (Orencia®)
- Targeted synthetic DMARDs (tsDMARDs)
- Janus kinase inhibitors
- Baricitinib (Olumiant®)
- Tofacitinib (Xeljanz®)
- Upadacitinib (Rinvoq®)
ACR 2021 RA Treatment Guidelines |
---|
Initial therapy in DMARD-naive patients
|
Methotrexate recommendations
|
Adjusting therapy
|
Tapering therapy
|
ACR Recommendations for Patients with Certain Comorbidities |
---|
Subcutaneous (rheumatoid) nodules
|
Congestive Heart Failure
|
Nonalcoholic fatty liver disease
|
Pulmonary disease
|
Tuberculosis (TB)
|
Nontuberculous mycobacterial lung disease
|
Hepatitis B
|
Hepatitis C
|
Non-melanoma skin cancer (current or past)
|
Melanoma (current or past)
|
Lymphoproliferative disorder
|
Solid organ tumor (previously-treated)
|
Previous serious infection
|
Persistent hypogammaglobulinemia without infection
|
EULAR 2016 Recommendations for the Treatment of RA |
---|
Phase I - Initial therapy
|
Phase II - Adjust therapy for non/incomplete responders
|
Phase III - Adjust therapy for non/incomplete responders to Phase II
|
- Therapy-specific response rates
- With available therapy, low disease activity or remission is obtainable in up to 80% of patients
- The table below gives the general response rates seen in trials for different therapies
Response rates for RA therapies | |
---|---|
Treatment | ✝Response rate (% of treated patients) |
Methotrexate (MTX) | 20 - 40% |
Leflunomide (Arava®) | 10% |
Sulfasalazine (Azulfidine®) | 8% at 2g/daily |
Hydroxychloroquine (Plaquenil®) | N/A |
bDMARDs | MTX-insufficient responders: 20 - 22% *TNF inhibitor-insufficient responders: 10 - 12% |
tsDMARDs | MTX-insufficient responders: 20 - 24% TNF inhibitor-insufficient responders: 14 - 17% |
- DISEASE ACTIVITY SCORE (DAS28)
- Overview
- The DAS28 score is a measure of RA disease activity that is incorporated into treatment recommendations and used as an outcome measure in RA trials
- Components
- The score is based on 4 components outlined in the table below
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" |
- Score calculation
- Values for each component are inserted into a formula that calculates a composite score
- Score interpretation
DAS28 score | Disease activity |
---|---|
< 2.6 | Remission |
2.6 - 3.2 | Low disease activity |
3.2 - 5.1 | Moderate disease activity |
> 5.1 | High disease activity |
- STUDIES
- The ORAL Strategy Study enrolled 1146 RA patients who were uncontrolled on methotrexate
Main inclusion criteria
- Meet ACR and EULAR RA criteria
- ≥ 4 swollen and tender joints
- Receiving MTX 15 - 25 mg/week
- CRP ≥ 3 mg/L
Main exclusion criteria
- > 1 episode of herpes zoster or serious herpes infection
- History of TNF inhibitor failure
- History of TNF inhibitor adverse event
- Previously received tofacitinib or adalimumab
Baseline characteristics
- Average age - 50 years
- Median duration of disease - 5.7 years
- Average DAS28(ESR) - 6.5
- Steroids at baseline - 57%
Randomized treatment groups
- Group 1 (384 patients): Tofacitinib 5 mg twice daily
- Group 2 (376 patients): Tofacitinib 5 mg twice daily + methotrexate
- Group 3 (386 patients): Adalimumab 40 mg every other week + methotrexate
- Methotrexate was dosed at 15 - 25 mg/week
- Patients were required to discontinue all csDMARDs, other than methotrexate, for at least 4 weeks or five half-lives, whichever was longer, before baseline
- NSAIDs and corticosteroids (≤ 10 mg prednisone) were allowed during the study
Primary outcome: Proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at 6 months
Results
Duration: 12 months | ||||
Outcome | Tof | Tof + MTX | Ada + MTX | Comparisons |
---|---|---|---|---|
Primary outcome (6 months) | 38% | 46% | 44% | 1 vs 2 or 3 not noninferior |
Primary outcome (12 months) | 39% | 48% | 46% | 1 vs 2 or 3 not noninferior |
Remission by DAS28-ESR (6 months) | 10% | 12% | 12% | N/A |
Remission by DAS28-ESR (12 months) | 11% | 15% | 17% | N/A |
Serious infection | 2% | 3% | 2% | N/A |
Herpes zoster | 1.3% | 2.7% | 1.5% | N/A |
ALT ≥ 3 X ULN | 2% | 8% | 7% | N/A |
Findings: Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of
rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination.
- The EXXELERATE Study enrolled 915 RA patients with active disease despite MTX and prognostic factors for severe disease
Main inclusion criteria
- Minimum of 12 weeks of MTX therapy
- bDMARD naïve
- Positive RF and/or ACPA
- DAS28-EXR > 3.2
- ≥ 4 swollen joints
- CRP ≥ 10 mg/L or ESR ≥ 28 mm/h
Main exclusion criteria
- Serious infection within 12 months
- Congestive heart failure
- History of cancer
- Demyelinating disorder
Baseline characteristics
- Average age - 53 years
- Average duration of disease - 6 years
- Average DAS28-ESR - 6.5
- Average ESR - 46 mm/h
- Average CRP - 15.6 mg/L
Randomized treatment groups
- Group 1 (457 patients): Certolizumab pegol 400 mg at weeks 0, 2, and 4, then 200 mg once every 2 weeks + methotrexate
- Group 2 (458 patients): Adalimumab 40 mg once every 2 weeks + methotrexate
- NSAIDs and oral glucocorticoids (≤ 10 mg/day prednisolone equivalent) were allowed
- At week 12, nonresponders in each group crossed over to the other therapy. Nonresponders were patients who did not achieve low disease activity defined as DAS28-ESR ≤ 3.2 or DAS28-ESR reduction ≥ 1.2 from baseline.
Primary outcome: Percentage of patients achieving a 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 12 and low disease activity at week 104
Results
Duration: 104 weeks | |||
Outcome | Certolizumab | Adalimumab | Comparisons |
---|---|---|---|
Primary outcome (12 weeks) | 69% | 71% | OR 0.90, 95%CI [0.67 – 1.20], p=0.467 |
Low disease activity (week 12) | 30% | 30% | OR 1.0, 95%CI [0.75 – 1.34] |
Low disease activity at week 104 | 35% | 33% | OR 1.09 95%CI [0.82 – 1.45]; p=0.532 |
Serious infections | 3% | 3% | p=0.861 |
Findings: These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate. The data also show the clinical
benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor.
- The trial enrolled 353 RA patients who had failed methotrexate therapy
Main inclusion criteria
- Met ACR 1987 RA criteria
- MTX therapy (15 - 25 mg/wk) for ≥ 12 weeks
- DAS28 ≥ 4.4
Main exclusion criteria
- Prior MTX + sulfasalazine + hydroxychloroquine for > 4 weeks
- Prior TNF inhibitor for > 5 weeks
- NYHA class III or IV heart failure
Baseline characteristics
- Average age - 57 years
- Male sex - 55%
- Average duration of disease - 5.3 years
- Average DAS28 - 5.8
- Receiving corticosteroids - 48%
Randomized treatment groups
- 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
- If the DAS28 score decreased by < 1.2 at 24 weeks, the patient was switched to the competing regimen
Primary outcome: Improvement in the DAS28 score at week 48
Results
Duration: 48 weeks | |||
Outcome | Sulfa + Hydroxy | Etanercept | Comparisons |
---|---|---|---|
Change in DAS28 at 24 weeks | -1.79 | -2.06 | p=0.06 |
Change in DAS28 at 48 weeks | -2.12 | -2.29 | p=0.26 |
DAS28 decrease < 1.2 at 24 weeks | 27% | 27% | p>0.05 |
DAS28 ≤ 2.6 at 24 weeks | 12.7% | 21.7% | p=0.03 |
DAS28 ≤ 2.6 at 48 weeks | 20.8% | 25.2% | p=0.36 |
Gastrointestinal disorders | 29.7% | 21.5% | p<0.05 |
Infection | 25.2% | 37.4% | p=0.006 |
|
Findings: With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy.
- The RA-BEAM trial enrolled 1307 RA patients with active disease despite receiving MTX therapy
Main inclusion criteria
- ≥ 6 tender and swollen joints
- MTX therapy for ≥ 12 weeks
- hsCRP ≥ 6 mg/L
- ≥ 3 joint erosions or ≥ 1 with positive RF or ACPA
Main exclusion criteria
- Previous bDMARD therapy
- Receiving ≥ 10 mg/day of prednisone or equivalent
- NYHA class IV heart failure
- Chronic liver disease
Baseline characteristics
- Average age 53 years
- Female sex - 77%
- Average duration of RA - 10 years
- Average hsCRP - 21 mg/L
- Average ESR - 49 mm/hr
Randomized treatment groups
- Group 1 (488 patients): Placebo
- Group 2 (487 patients): Baricitinib 4 mg once daily
- Group 3 (330 patients): Adalimumab 40 mg every other week
- Concomitant stable doses of csDMARDs, NSAIDs, analgesics, or glucocorticoids (< 10 mg of prednisone/day or equivalent) were permitted
- At week 16, patients whose counts of tender and swollen joints were reduced by less than 20% from baseline at both week 14 and week 16 received open-label rescue treatment (4 mg of baricitinib)
Primary outcome: Proportion of patients at week 12 with a 20% response
according to the criteria of the American College
of Rheumatology (ACR20 response).
Results
Duration: 52 weeks | ||||
Outcome | Placebo | Baricitinib | Adalimumab | Comparisons |
---|---|---|---|---|
Primary outcome | 40% | 70% | 61% | 1 vs 2 p<0.001 | 2 vs 3 p=0.01 |
ACR70 at week 52 | N/A | 37% | 31% | p>0.05 |
Infection | 27% | 36% | 33% | p>0.05 |
Change in neutrophils at 24 weeks | -300 cells/mm3 | -1040 cells/mm3 | -1400 cells/mm3 | 1 vs 2 or 3 p<0.001 |
Change in lymphocytes at 24 weeks | -20 cells/mm3 | +20 cells/mm3 | +330 cells/mm3 | 1 vs 3 p<0.001 |
Change in platelets at 24 weeks | -8000/mm3 | +9000/mm3 | -43,000/mm3 | 1 vs 2 or 3 p<0.001 |
Change in hemoglobin at 24 weeks | +0.09 g/dl | +0.09 g/dl | +0.53 g/dl | 1 vs 3 p<0.001 |
Findings: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared
with placebo and adalimumab
- The trial enrolled 300 RA patients who were unresponsive to a TNF inhibitor
Main inclusion criteria
- Meet ACR 1987 RA criteria
- Presence of erosions
- DAS28-ESR score ≥ 3.2
- Insufficient response to TNF inhibitor
- Stable dose of corticosteroids (≤ 15 mg prednisone/day)
Main exclusion criteria
- Stopped TNF inhibitor due to side effect
- Previous treatment with ≥ 2 TNF inhibitors
- Previous treatment with abatacept, rituximab, or tocilizumab
Baseline characteristics
- Average age - 56 years
- Median duration of disease - 10 years
- Median ESR - 24 mm/hr
- Average DAS28-ESR - 5.1
- Steroids at baseline - 53%
- Receiving MTX - 63%
- TNF failed: Adalimumab - 30% | Etanercept - 54% | Infliximab - 14%
Randomized treatment groups
- Group 1 (146 patients): Non-TNF inhibitor biologic for 52 weeks
- Group 2 (146 patients): Second TNF inhibitor for 52 weeks
- Dose adjustments of oral corticosteroids and glucocorticoid intra-articular injections were allowed for both groups
Primary outcome: Proportion of patients with good or moderate response according to the EULAR scale at week 24
Results
Duration: 52 weeks | |||
Outcome | Non-TNF inhibitor | Second TNF inhibitor | Comparisons |
---|---|---|---|
Primary outcome (24 weeks) | 69% | 52% | p=0.004 |
Primary outcome (52 weeks) | 60% | 43% | p=0.006 |
DAS28-ESR < 2.6 at 24 weeks | 27% | 19% | p=0.08 |
DAS28-ESR < 2.6 at 52 weeks | 27% | 14% | p=0.008 |
|
Findings: Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was
more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication.
- 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
Randomized treatment 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
- Oral glucocorticoids were not permitted during the first 3 months of the study and later limited to once per year for a maximum of 2 weeks at maximum daily dose of 10 mg prednisone
- 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.
Results
Duration: Results are for 24 weeks. Entire study was up to 104 weeks. | ||||
Outcome | Toc + MTX | Toc | MTX | Comparisons |
---|---|---|---|---|
Primary outcome (24 weeks) | 86% | 83% | 44% | 1 or 2 vs 3 p<0.0001 |
Good EULAR response at 24 weeks | 89% | 87% | 49% | 1 or 2 vs 3 p<0.0001 |
Serious infections (entire study) | 3.8% | 5.8% | 4.6% | p>0.05 for all |
ALT > 3 X ULN (entire study) | 13.2% | 4.9% | 11.1% | p>0.05 for all |
ANC < 1000 cells/mm3 (entire study) | 6.6% | 5.8% | 0.9% | p>0.05 for all |
Platelet count < 100,000/mm3 (entire study) | 3.8% | 2.9% | 0.9% | p>0.05 for all |
Cholesterol medication needed (entire study) | 15.1% | 23.3% | 20.4% | p>0.05 for all |
Findings: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards
- STUDIES | STOPPING THERAPY
- The trial enrolled 834 RA patients with moderate disease activity (DAS28-ESR 3.3 - 5.1) who were receiving methotrexate
Main inclusion criteria
- RA with moderate disease activity (DAS28-ESR 3.3 - 5.1)
- Receiving MTX (15 - 25 mg/wl) for ≥ 8 weeks
Main exclusion criteria
- Previous biologic
- Taking DMARD other than MTX within 28 days
- Taking prednisose or equivalent at dose > 10 mg/day
Baseline characteristics
- Average age - 47 years
- Female sex - 83%
- Average duration of disease - 6.9 years
- Average DAS28 score - 4.4
- Average ESR - 22.2 mm/hr
Randomized treatment groups
- Initial open-label run-in period
- All patients were initially treated with etanercept 50 mg once weekly plus MTX once weekly for 36 weeks. Patients who achieved low disease activity (DAS28 ≤ 3.2) were then randomized to the three groups below.
- Active treatment phase
- 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
Primary outcome: 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
Results
Duration: 88 weeks | ||||
Outcome | Etanercept 50mg | Etanercept 25mg | Placebo | Comparisons |
---|---|---|---|---|
Primary outcome | 83% | 79% | 43% | 1 or 2 vs 3, p<0.0001 |
DAS28 < 2.8 | 66.7% | 60.2% | 29.4% | 1 or 2 vs 3, p<0.0001 |
DAS28 score | 2.4 | 2.5 | 3.5 | 1 or 2 vs 3, p<0.0001 |
|
Findings: Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low
disease activity than does methotrexate alone after withdrawal of etanercept.
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