RHEUMATOID ARTHRITIS (RA)





















  • Reference [26]
RF value Range
≤ 14 IU/ml negative
> 14 IU/ml positive

  • Reference [27]
  • Normal range may vary by lab
Anti-CCP value Range
< 20 units negative
20 - 39 units weak positive
40 - 59 units moderate positive
> 59 units strong positive






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
  • 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


  • Reactive arthritis typically occurs 2 - 4 weeks after an infection with Shigella, Salmonella, Campylobacter, Chlamydia, or Strep throat
  • Reference [30,31,32,33]
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











ACR 2021 RA Treatment Guidelines
Initial therapy in DMARD-naive patients
  • Patients with moderate-to-high disease activity (see disease activity score)
    • Methotrexate monotherapy is strongly recommended over: hydroxychloroquine, sulfasalazine, bDMARD or tsDMARD monotherapy, and a combination of methotrexate plus a non–TNF inhibitor bDMARD or tsDMARD
    • Methotrexate monotherapy is conditionally recommended over: leflunomide, dual or triple csDMARD therapy, and a combination of methotrexate plus a TNF inhibitor
    • Initiation of a csDMARD without short-term (<3 months) glucocorticoids is conditionally recommended over initiation of a csDMARD with short-term glucocorticoids
    • Initiation of a csDMARD without longer-term (≥3 months) glucocorticoids is strongly recommended over initiation of a csDMARD with longer-term glucocorticoids

  • Patients with low disease activity
    • Hydroxychloroquine is conditionally recommended over other csDMARDs
    • Sulfasalazine is conditionally recommended over methotrexate
    • Methotrexate is conditionally recommended over leflunomide

  • Patients with moderate-to-high disease activity who are csDMARD-treated, but methotrexate-naive
    • Methotrexate monotherapy is conditionally recommended over the combination of methotrexate plus a bDMARD or tsDMARD
Methotrexate recommendations
  • Oral methotrexate is conditionally recommended over subcutaneous methotrexate for patients initiating methotrexate
  • Initiation/titration of methotrexate to a weekly dose of at least 15 mg within 4 to 6 weeks is conditionally recommended over initiation/titration to a weekly dose of less than 15 mg
  • A split dose of oral methotrexate over 24 hours or subcutaneous injections, and/or an increased dose of folic/folinic acid, is conditionally recommended over switching to alternative DMARD(s) for patients not tolerating oral weekly methotrexate
  • Switching to subcutaneous methotrexate is conditionally recommended over the addition of/switching to alternative DMARD(s) for patients taking oral methotrexate who are not at target
Adjusting therapy
  • Treatment target should be remission or low disease activity
  • Patients receiving methotrexate who are not at target: addition of a bDMARD or tsDMARD is conditionally recommended over triple therapy (hydroxychloroquine, sulfasalazine, methotrexate) for patients taking maximally-tolerated doses of methotrexate
  • Patients taking a bDMARD or tsDMARD who are not at target: switching to a bDMARD or tsDMARD of a different class is conditionally recommended over switching to a bDMARD or tsDMARD belonging to the same class
  • Patients receiving glucocorticoids: addition of/switching to DMARDs is conditionally recommended over continuation of glucocorticoids for patients taking glucocorticoids to remain at target
  • Patients taking DMARDs who are not at target: addition of/switching to DMARDs (with or without intraarticular glucocorticoids) is conditionally recommended over the use of intraarticular glucocorticoids alone
Tapering therapy
  • Continuation of all DMARDs at their current dose is conditionally recommended over a dose reduction of a DMARD
  • Dose reduction is conditionally recommended over gradual discontinuation of a DMARD
  • Gradual discontinuation is conditionally recommended over abrupt discontinuation of a DMARD
  • Gradual discontinuation of sulfasalazine is conditionally recommended over gradual discontinuation of hydroxychloroquine for patients taking triple therapy who wish to discontinue a DMARD
  • Gradual discontinuation of methotrexate is conditionally recommended over gradual discontinuation of the bDMARD or tsDMARD for patients taking methotrexate plus a bDMARD or tsDMARD who wish to discontinue a DMARD

  • References [23,36]
ACR Recommendations for Patients with Certain Comorbidities
Subcutaneous (rheumatoid) nodules
  • Methotrexate is conditionally recommended over alternative DMARDs for patients with subcutaneous nodules who have moderate-to-high disease activity.
  • Switching to a non-methotrexate DMARD is conditionally recommended over continuation of methotrexate for patients taking methotrexate with progressive subcutaneous nodules
Congestive Heart Failure
  • Addition of a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over addition of a TNF inhibitor for patients with NYHA class III or IV heart failure and an inadequate response to csDMARDs
  • Switching to a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over continuation of a TNF inhibitor for patients taking a TNF inhibitor who develop heart failure
Nonalcoholic fatty liver disease
  • Methotrexate is conditionally recommended over alternative DMARDs for DMARD-naive patients with nonalcoholic fatty liver disease, normal liver enzymes and liver function tests, and no evidence of advanced liver fibrosis who have moderate-to high disease activity
Pulmonary disease
  • Methotrexate is conditionally recommended over alternative DMARDs for the treatment of inflammatory arthritis for patients with clinically diagnosed mild and stable airway or parenchymal lung disease who have moderate-to-high disease activity
Tuberculosis (TB)
  • Latent TB - treat TB for at least 1 month before starting therapy
  • Active TB - patients should complete TB treatment before starting therapy
Nontuberculous mycobacterial lung disease
  • Use of the lowest possible dose of glucocorticoids (discontinuation if possible) is conditionally recommended over continuation of glucocorticoids for patients with nontuberculous mycobacterial lung disease
  • Addition of csDMARDs is conditionally recommended over addition of a bDMARD or tsDMARD for patients with nontuberculous mycobacterial lung disease who have moderate-to-high disease activity despite csDMARD monotherapy
  • Abatacept is conditionally recommended over other bDMARDs and tsDMARDs for patients with nontuberculous mycobacterial lung disease who have moderate-to-high disease activity despite csDMARDs
Hepatitis B
  • Prophylactic antiviral therapy is strongly recommended over frequent monitoring alone for patients initiating rituximab who are hepatitis B core antibody positive (regardless of hepatitis B surface antigen status)
  • Prophylactic antiviral therapy is strongly recommended over frequent monitoring alone for patients initiating any bDMARD or tsDMARD who are hepatitis B core antibody positive and hepatitis B surface antigen positive
  • Frequent monitoring alone is conditionally recommended over prophylactic antiviral therapy for patients initiating a bDMARD other than rituximab or a tsDMARD who are hepatitis B core antibody positive and hepatitis B surface antigen negative
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
Non-melanoma skin cancer (current or past)
  • Use csDMARDs over biologicals or tofacitinib
Melanoma (current or past)
  • Use csDMARDs over biologicals or tofacitinib
Lymphoproliferative disorder
  • Rituximab is conditionally recommended over other DMARDs for patients who have a previous lymphoproliferative disorder for which rituximab is an approved treatment and who have moderate-to-high disease activity
Solid organ tumor (previously-treated)
  • Recommendations are the same as those in patients without a history of solid organ tumor
Previous serious infection
  • Addition of csDMARDs is conditionally recommended over addition of a bDMARD or tsDMARD for patients with a serious infection within the previous 12 months who have moderate-to-high disease activity despite csDMARD monotherapy
  • Addition of/switching to DMARDs is conditionally recommended over initiation/dose escalation of glucocorticoids for patients with a serious infection within the previous 12 months who have moderate-to-high disease activity
Persistent hypogammaglobulinemia without infection
  • In the setting of persistent hypogammaglobulinemia without infection, continuation of rituximab therapy for patients at target is conditionally recommended over switching to a different bDMARD or tsDMARD

  • Reference [25]
EULAR 2016 Recommendations for the Treatment of RA
Phase I - Initial therapy
  • First-line: Methotrexate + short-term corticosteroids
    • Methotrexate should be rapidly escalated to a target dose of 25 mg/week. Asian patients may need lower doses (15 - 20 mg/week). Folic acid (at least 5 mg/week) should be taken with methotrexate.
    • Oral corticosteroids may be started at a dose of up to 30 mg/day and tapered as rapidly as tolerated over the course of 3 months. Courses up to 6 months may be used, but only in exceptional cases. Other options for steroids include methylprednisolone 120 mg IM one-time dose or methylprednisolone 250 mg IV one-time dose.
  • Second-line (methotrexate contraindicated): leflunomide or sulfasalazine + short-term corticosteroids
    • Leflunomide should be dosed at 20 mg/day without a loading dose
    • Sulfasalazine should be escalated to 3 grams/day
    • Oral corticosteroids may be started at a dose of up to 30 mg/day and tapered as rapidly as tolerated over the course of 3 months. Courses up to 6 months may be used, but only in exceptional cases. Other options for steroids include methylprednisolone 120 mg IM one-time dose or methylprednisolone 250 mg IV one-time dose.

  • If there is no improvement 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 a bDMARD or tsDMARD
    • Prognostically unfavorable factors - high levels of RF or ACPA; very high disease activity; early joint damage; failure of 2 csDMARDs
    • bDMARD (Biologic agents)
      • Tumor Necrosis Factor inhibitors - adalimumab, certolizumab, etanercept, golimumab, infliximab
      • T-cell agents - abatacept
      • Interleukin-6 inhibitors - tocilizumab, sarilumab
      • B-cell agents - rituximab
    • tsDMARD (JAK-inhibitors)
      • Tofacitinib (Xeljanz®)
      • Baricitinib (Olumiant®)
    • For patients who cannot take a concomitant csDMARD, IL-6 inhibitors and tsDMARDs have some advantages

  • Prognostically unfavorable factors NOT present: change to or add second csDMARD
    • Leflunomide, sulfasalazine, methotrexate alone or in combination
    • Ideally, concomitant short-term corticosteroids should also be used as in Phase I
    • If there is no improvement after 3 months, or target is not achieved at 6 months, then add bDMARD or tsDMARD as above

  • If there is no improvement after 3 months, or target is not achieved at 6 months, then Phase III
Phase III - Adjust therapy for non/incomplete responders to Phase II
  • Change bDMARD or use tsDMARD
    • Replace any first bDMARD with any other bDMARD or change to tsDMARD
    • TNF inhibitors may be replaced with another TNF inhibitor
    • Continue csDMARD


  • Response defined as 70% improvement in the DAS28 score
  • *Response rate for switching from one TNF inhibitor to another or from TNF inhibitor to other bDMARD class
  • Reference [24]
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%



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"

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


ORAL Strategy Study - Tofacitinib vs Tofacitinib + Methotrexate vs Adalimumab + Methotrexate, Lancet (2017) [PubMed abstract]
  • 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.
EXXELERATE Study - Certolizumab vs Adalimumab in RA Resistant to MTX, Lancet (2016) [PubMed abstract]
  • 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.
Addition of Etanercept vs Sulfasalazine + Hydroxychloroquine in RA Patients who Failed Methotrexate, NEJM (2013) [PubMed abstract]
  • 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
  • Participants in both groups who switched therapies had improvement after switching (p<0.001), and the response after switching did not differ significantly between the two groups (p=0.08)
  • There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.

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.
RA-BEAM Trial - Baricitinib vs Adalimumab vs Placebo for RA Patients who Failed MTX, NEJM (2017) [PubMed abstract]
  • 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
Second TNF Inhibitor vs Non-TNF Inhibitor Biologic in RA Unresponsive to First TNF Inhibitor, JAMA (2016) [PubMed abstract]
  • 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
  • In the Non-TNF inhibitor group, 23% received abatacept, 28% received rituximab, and 48% received tocilizumab
  • In the Second TNF inhibitor group, 39% received adalimumab, 16% received certolizumab, 36% received etanercept, and 5% received infliximab

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.
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
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



Maintenance, Reduction, or Withdrawal of Etanercept after Treatment with Etanercept + Methotrexate in Patients with Moderate RA, Lancet (2013) [PubMed abstract]
  • 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
  • Radiographic progression of disease was worse in the Placebo group when compared to the other 2 groups

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.