Rheumatoid arthritis

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]

Reference [26]
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]

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

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 Joint must be swollen or tender. May be confirmed on imaging. Joints excluded from assessment - DIP joints, 1^st carpometacarpal joints (involved in OA), and 1^st 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, 2^nd through 5^th 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

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®)

See **disease activity score (DAS28)**

Triple therapy = hydroxychloroquine, sulfasalazine, and either methotrexate or leflunomide

Reference [36]
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

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 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%

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

Ref: **Merck Manual**
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

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

Outcome	Tof	Tof + MTX	Ada + MTX	Comparisons
Duration: 12 months
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

Outcome	Certolizumab	Adalimumab	Comparisons
Duration: 104 weeks
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

Outcome	Sulfa + Hydroxy	Etanercept	Comparisons
Duration: 48 weeks
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

Outcome	Placebo	Baricitinib	Adalimumab	Comparisons
Duration: 52 weeks
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

Outcome	Non-TNF inhibitor	Second TNF inhibitor	Comparisons
Duration: 52 weeks
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

Outcome	Toc + MTX	Toc	MTX	Comparisons
Duration: Results are for 24 weeks. Entire study was up to 104 weeks.
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

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

Outcome	Etanercept 50mg	Etanercept 25mg	Placebo	Comparisons
Duration: 88 weeks
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.

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RHEUMATOID ARTHRITIS (RA)