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ACR 2022 - year in review 

1) GLORIA Trial 

Adding 5 mg / day for 2 yrs in >65 yrs, decrease disease activity, reduced damage, but had increased 24% adverse effects

2) ORAL Surveillance Trial, NEJM 2022 (Post-surveillance trial)


3 arm: Tofacitinib 5 mg, or 10 mg (had increased PE, and hence dose decreased to 5 mg during the trial), TNFi

MACE: higher 

Cancer incidence: higher 

Zoster infection was increased


3) FU analysis of above study ARD 2022 

Increased risk for patient with prior ASCVD. NNH: 16 patient. NNH: 223 without ASCVD

1987 Rheumatoid Arthritis Classification


2010 ACR /EULAR criteria for RA 

page1image1047348672page1image1047347168 page1image1047344896 

  • While MRI is a highly sensitive tool for identifying and tracking the progression of erosions, erosions detected by MRI with measures commonly used in a rheumatologist's office (no contrast, imaging in 1 plane) provide low specificity for RA. Bone marrow edema is the most specific MRI lesion for RA in this setting. Journal of Rheumatology - Volume 37, Issue 2, pp. 265-74 - published 2010-01-01

  • RA
    • : (highlighted in purple are processes involved in pathogenesis of RA; added information in black is to show the comparison of RA pathogenesis to the rest of the clinical immunology)
      • Innate and Adaptive Immune mechanisms are involved in pathogenesis. 
        • Innate Immune System
          • Phagocytic defects:
          • Cell Signalling including IFN Gamma
            • NF-κB pathway in T cell after APC (dendritic cells) interaction with T cell via CD 80 / 86 costimulation- this leads to T cel activation
          • Complement (Alternate and Lectin Pathways)
        • Adaptive Immune System
          • T-Cell: 
            • T-Cell Development
            • T-Cell Maturation
            • T-Cell Activation and antigen presentation or Functioning 
              • Th1: Classically it is implicated in RA
              • Th2
              • Th17: Newer studies suggest the role of this pathway of T-Cell activation as well in RA. This pathway produces IL 17A, 17F, IL 21, IL 22, and TNF-alpha. NEJM 2011
              • TNF, GM-CSF, and IL-6 can be expressed by Th1 and Th2 cells and are abundant in synovial fluid and produced by RA synovial tissue. However, the primary sources of these cytokines in the rheumatoid joint are macrophages and fibroblasts. Kelly and Firestein's 

          • B-Cell
            • Impaired Development
            • Impaired Functioning 
              • T-cell mediated
                • Hence, Rituximab works
              • T-cel independent 
        • Regulatory Immune System
          • APC (dendritic cells) interaction with T cell leads to T cel activation
          • Innate System Regulation
            • Macrophage, Mast cells, and Neutrophils are activated by Cell Signalling mechanism (TLR)
              • Macrophage and its production of TNF alpha is central to synovitis 
          • Adaptive System Regulation
            • Th17 activation leads to suppression of regulatory T cell shifting T-Cell Homestasis towards inflammation. Macrophage and dendritic cells derived TGF beta, IL 1 beta, IL6, IL 21, IL 23 provide the differentiation of Th17 pathway, and suppression of regulatory T cells.
        • Effector cells: Synovial macrophage and Synovial fibroblasts
        • Thus FINAL Pathway is activation of various INFLAMMATORY CASCADES mediated by
          • TNF Alpha
          • IL 6 (Note: IL 1 family cytokines i.e IL 1 alpha, IL 1 beta, IL 18, IL 33, are abundantly expressed in local milieu in RA, but IL 1 inhibitor had only modest effect. Of note, IL 1 does play a more central role in JIA (Juvenile Idiopathic Arthritis) and AOSD (Adult Onset Still's Disease) is NOT a major player in RA)
        • All these end in the activation of enzymes causing synovial and bony destruction
        • S
The Pathogenesis of Rheumatoid Arthritis NEJM 2011

In addition to Synovitis, and structural damage in the joint, RA additional coexisting condition includes CABBS (or as noted below LAM BBB)
CV - metabolic 
A - arterial / vascular disease 
Brain - Cognitive, Disability
Socioeconomic status 

The Pathogenesis of Rheumatoid Arthritis NEJM 2011

The Pathogenesis of Rheumatoid Arthritis NEJM 2011

LAM BBB - another way to remember is CRABS 
    • DDx: The new ACR/EULAR classification criteria for RA: how are the new criteria performing in the clinic? Rheumatology 2012
      • CPPD in polyariticular pattern, a pseudo RA presentation
      • PsA with polyaritcular pattern
      • Gout, especially with tophi mimicking subcutaneous RA nodules 
      • PMR and RS3PE in elderly 
      • Parvovirus B19 in young adults 
    • Epidemiology
      • 1 % in West 
      • 5-7 % in native American
      • 2: 1 F:M, Peak in F: 55-64, Peak in M: 75-84 

    • RA Onset patterns
      • Insidious onset: 55-60 %
        • Classic
        • monoarticular or oligoarticular involving large joints (elbow, knees, hips) similar to seronegative SpA '
        • systemic features predominant similar to PMR or RS3PE (Mostly in age > 60 yrs, DDx. also includes malignancy)
      • Acute or Intermediate Onset 
        • Acute 8-15 %: explosive polyarticular involving small or big joints (often described as "elderly onset" or "later onset" RA 
        • Intermediate 20% incident cases: days. to weeks 
      • Atypical Onset 
        • Simple bursitis or tendinitis evolving into tenosynovitis 
        • Early carpel tunnel syndrome
      • Other Pattern
        • Palindromic Rheumatism (lasting few hours to few days) : Knees , Fingers and Shoulders but any joint can be affected. Test RF and CCP ab
          • 1/3 patient turn into classic RA presentation eventually especially with ACPA positive and hand involvements
          • Others remain as palindromic or turn into HBV, HCV, HIV (these patients can be RF positive)
    • CF
      • Articular :
        • Hand: 
          • Effusion often symmetrical, Synovitis, TTP, Restricted range of motion (inability to make a fist), flexor tenosenoviitiis , nodules along the tendon and trigger finger, tendon rupture 
          • Palmar erythema
          • Reduced grip strength, whole hand swollen, carpel tunnel syndrome (1/5 patient); 
          • MCP subluxation, ulnar deviation or "ulnar drift", swan neck and Boutonniere deformities of the fingers (
          • the "bow string" sign (prominence of the tendons in the extensor compartment of the hand). 
          • extensor tendon rupture, most commonly affecting the thumb or little or ring fingers of either hand. 
          • The nails and fingertips may show evidence of digital infarcts in patients with rheumatoid vasculitis. 
        • Wrists 
          • Early in the disease there is a loss of extension. 
          • Late changes due to erosive damage lead to volar subluxation and radial drift of the carpus, resulting in increasing prominence of the ulnar styloid and lateral deviation. Tendon rupture can also occur at the wrist.
        • Elbows 
          • with loss of extension (fixed flexion) both in early and late disease
          • an effusion or synovitis may be detected as a bulge between the head of the radius and the olecranon. 
          • a compressive neuropathy of the ulnar nerve, with dysesthesias of the fourth and fifth fingers, can result from elbow synovitis. 
          • Olecranon bursitis is also common. 
          • Destruction of the joint may occur due to erosion of cartilage and bone.
          • The extensor surface of the elbow is the most common site for subcutaneous rheumatoid nodules. These should always be looked and felt for in view of their diagnostic and prognostic importance
        • Shoulders 
          • The shoulder, being more proximal, tends to be involved later in the disease. A prospective study performed prior to the widespread availability of biologic agents assessed shoulder involvement over time in 74 patients with RA. At 15 years, 55 percent had developed radiographic evidence of erosive glenohumeral joint disease. The most common site for erosions was the superolateral aspect of the humerus.
          • Disease in the glenohumeral joint leads to painful restriction of movement resembling a capsulitis, and can result in the development of a "frozen" shoulder. This will typically cause pain at night, when the patient lies on the affected shoulder and marked restriction of range of motion due to the accompanying pain. 
          • Rotator cuff injury is common. 
          • Effusions are relatively rare, but when they occur, they may be detected in the anterior glenohumeral joint as a filling of the depression under the clavicle anterior to the head of the humerus.
        • Lower extremity — Lower extremity joints are often involved in RA, particularly in the forefoot and ankles; the knees and hips may also be affected, but hip involvement tends to occur in more severe or longstanding disease. Synovitis in the knee may predispose to the development of popliteal (Baker's) cysts
        • Feet and ankles – Foot involvement, especially of the MTP joints, is common in early disease, with a pattern that mirrors that occurring in the hand. Involvement of the feet is typically under-recognized, making it imperative for the clinician to closely inspect the bare feet.
        • Tenderness of the MTP joints may be marked, resulting in the tendency to bear weight on the heels and hyperextend the toes. The fifth MTP is the most frequently involved, and swelling of this joint may be most readily appreciated on examination.

          Erosive damage results in lateral drift of the toes and plantar subluxation of the metatarsal heads (picture 3), resulting in "cock-up" deformities. The latter may be palpable as bony lumps on the sole with associated callosities.

          Involvement of the tarsus and the associated tendon sheaths is also common, leading to pain on inversion or eversion of the foot and diffuse edema and erythema over the dorsum of the foot.

          Heel pain may be associated with retrocalcaneal bursitis or tarsal tunnel syndrome, caused by impingement of the posterior tibial nerve. Tarsal tunnel syndrome is also associated with paresthesia of the toes and is important because it can be diagnosed by ultrasound and treated by local injection or surgical release. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Tarsal tunnel syndrome'.)

          Arthritis of the ankle can lead to a diffuse swelling around the tibiotalar joints, which may be red and edematous. These findings may be wrongly attributed to fluid retention or an infective cellulitis of the skin.

          Knees – The knee manifests many changes in RA. Synovial thickening is easily detected at the knee, extending the suprapatellar recess around the patella. Effusion is a common feature of knee involvement and can be elicited by patellar tap. Restriction of movement, particularly flexion, is also a common physical finding. If knee synovitis is not controlled, ligamentous laxity leading to deformities and quadriceps atrophy may occur. Erosion of the femoral condyles and tibial plateau can result in either genu varus or genu valgus.

          Patients with RA may develop popliteal (Baker's) cysts, which can be detected by palpation of the popliteal fossa [17]. Ruptured Baker's cysts extending down the calf are of clinical importance because they can resemble a deep vein thrombosis or acute thrombophlebitis [18]. A history of arthritis, morning stiffness, lack of a palpable occluded venous cord, and edema below the posterior of the knee all suggest a Baker's cyst. Ultrasonography is generally used for the detection of intact or ruptured Baker's cysts (image 2A-B), and they can be readily imaged by magnetic resonance imaging (MRI), although historically a ruptured Baker's cyst was usually demonstrated using arthrography (picture 4) [19]. (See  "Popliteal (Baker's) cyst".)

          Hips – Involvement of the hips typically occurs only in well-established disease. Hip disease is most frequently manifested as pain in the groin, thigh, or low back, or referred to the knee on standing or movement. Restriction of movement, detected by "log rolling the leg" or rotation of the hip, also may be seen. Pain in the lateral thigh suggests trochanteric bursitis. (See  "Greater trochanteric pain syndrome (formerly trochanteric bursitis)".)

          Axial skeleton — Cervical spine involvement is relatively common in RA, especially in longstanding disease, compared with the very infrequent involvement that occurs in the thoracolumbar spine or sacroiliac joints. Symptoms of pain and stiffness in the neck are the most typical manifestation, but disease affecting the joints of the cervical spine can be of critical clinical importance, as longstanding disease may lead to instability and cause symptoms related to subluxation such as neck pain, stiffness, and radicular pain. If the subluxation is causing spinal cord compression, there may be signs of long tract involvement such as hyperreflexia or up going toes on Babinski testing. The clinical manifestations of cervical spine subluxation and the approach to diagnosis and management are discussed in detail separately. (See  "Cervical subluxation in rheumatoid arthritis".)

          Involvement of the facet joints of the lumbar spine and occasionally discitis has been reported to occur in RA, both from radiographic and post-mortem studies [20]. However, in clinical practice, it is important to exclude more common and serious causes of back pain, such as vertebral compression fractures associated with low bone mass, before attributing back pain to rheumatoid involvement of the lumbar spine.

          Cricoarytenoid joint — Approximately 30 percent of patients with RA have involvement of the cricoarytenoid joint demonstrated by indirect laryngoscopy, with the prevalence increasing when advanced imaging techniques are used. As an example, one study from 1984, involving 45 patients with RA, found laryngeal involvement in 32 percent by laryngoscopy and 54 percent by computed tomography (CT) [21]; symptoms may include hoarseness and an inspiratory stridor.

      • Extra-articular: LAM BBB
        • Brain
        • Bone 
        • Blood  / CVS 
        • Liver 
        • Muscle 
        • Fat (adipocytes)
      • Pericarditis is the most common cardiac manifestation of RA 
    • Diagnosis (MKSAP 16)
      • anti-CCP ab present in 60 % of patients 
      • Specificity: Anti-CCP ab: > 95 %; RF > 80 % 
        • RF is also present in: 
          • Mixed Cryoglobunemia (100%)
          • SS (70%)
          • SLE (20-30%)
          • Healthy population (>10 %)
        • Up to 30% of RA patients have positive ANA at low to moderate titer. That is a non-specific finding
        • RF present in 70% at the time of diagnosis,additiona 15% develop it over time 
        • ACPA is essentially always present at the disease onset (if present) 
        • Although the 2010 cri- teria yield excellent sensitivity (97%) in identifying patients with RA, the specificity is substantially lower than that of the 1987 cri- teria (55% vs. 76%, respectively).41
      • Other Labs: 
        • 1/3rd patient will have normal ESR and CRP on initial presentation
      • 2010 RA classification criteria
      • 2010 RA classification criteria: An ACR/EULAR collaborative initiative Arth Rheum 2010 
    • Poor Prognostic Features: FABE as in FAVORITE 
    • Function, Ab, Bone, Extra-articular
      • Functional Limitations (HAQ  Score - Health Assessment Questionnaire)
      • Extraarticular Disease (Rheumatoid Nodule, Rheumatoid Vasculitis, Felty Syndrome)
      • Positive RF or Anti-CCP Antibody
      • Bony Erosion
      • TABLE71-6 Factors Associated With Poor Prognosis in Rheumatoid Arthritis
      • Presence of rheumatoid factor and titer
        Presence of antibodies to CCP and titer
        Presence of shared epitope and number of alleles
        Presence of erosive disease at presentation
        Disease activity at presentation
        Magnitude of ESR or CRP elevations
        Presence of nodules or extraarticular features
        Female gender
        Smoking currently and in the past

        CCP, Cyclic citrullinated peptide; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
    • Treatment Principle DURATION and DS SEVERITY AND  PROGNOSTIC FACTORS(Early start of the DMARD / Biologics): However, prognostic factors affecting the treatment outcome has not been fully verified per KF pg 1193
      • EARLY RA (<6 months) (Disease Activity) (Figure 1):
        • LowDMARD Mono
          • MTX
          • Although: Triple therapy increases the chance of remission from 30% Monotherapy to 60-70% triple therapy in 6 months (Jane Pope podcast) 
        • Moderate: Features of Poor Prognosis
          • Absent: DMARD Mono
            • MTX
          • Present: DMARD Combination (Double or Triple)
            • MTX
        • High: Features of poor prognosis 
          • Absent: DMARD Mono  or Simple Combination (MTX + HQ)
          • Present: DMARD Combination or Anti-TNF Biologics with/without MTX
      • ESTABLISHED RA (>6 months) (Disease Activity) (Figure 2)
        • Low without features of Poor Prognosis: 
          • DMARD Mono - Reassess & Add DMARD - Reassess & Add / Switch to Anti-TNF
        • Low with features of Poor Prognosis / Moderate / High
          • DMARD Mono / Combination - Reassess & Add / Switch DMARD - Reassess & Add / Switch to Anti-TNF Biologics or Non-TNF Biologics
    • The goal of Treatment: 
      • Joint damage occurs rapidly early in the disease. Hence, early recognition and aggressive management are critical. 
        • Treat early evidence: Cohort of treatment initiation 123 days vs very early (15 days) of diagnosis , and TICORA trial 
      • Low Disease Activity or Remission
        • T2T (treat to target) is the most important principle of RA management than the choice of agent 
          • Scottish TICORA Trial (The Tight Intensive Control of RA) was the seminal study to highlight the value of this
            • DAS of <2.4 if LDAS
            • Both groups improved significantly, but the T2T group (i.e., the intensive group) did significantly better, with mean DAS scores (1.6) in the remission range at 18 months.
            • In the intensive group, 71% of subjects achieved an ACR 70% composite improvement (ACR70) compared with 18% in the routine care group 
            • This clinical improvement translated to radiographic changes 

          • Dutch BeST study (Behandel-Strategieen) added further evidence of T2T. 
        • Remission as used for clinical trial is defined as 
          • Boolean-Based Definition
            At any time point, the patient must satisfy all of the following:
             Tender joint count ≤1*
             Swollen joint count ≤1*
             C-reactive protein ≤1 mg/dL
             Patient global assessment ≤1 (on a 0-10 scale)
            Index-Based Definition
            At any time point, the patient must have a Simplified Disease Activity Index score of ≤3.3.
            • Arthritis Rheum 63:573–586, 2011.
            • To add confusion in TEAR trial Treatment of Early Aggressive Rheumatoid (TEAR) trial , all clinical remission patient had evidence of disease in MRI 
        • Remission is not a goal for everyone, hence LDAS is a goal for some. However, how do we decide which is the goal for a given patient upfront? based on benefits and risk in re: AEs, Cost, 
      • Disease activity measurement for T2T
        • DAS28
        • SDAI (Simplified)
        • CDAI (Clinical)
        • RADAI 
        • PAS or PASII (Patient activity score)
        • RAPID (Routine Assessment Patient Index Data)
      • Drug Selection: 
      • Monitoring on Treatment: 
      • Definition of Remission
      • Combination therapy: McCarty was the pioneer for this on RA 
    • Commonly used drugs and MOA (Over 20 drugs to choose from)
      • Steroid 
        • The recent Combinatie therapie Bij Rheumatoide Artritis (COBRA) trial and the COBRA arm of the BeSt study (discussed in a subsequent section of this chapter) again demonstrated the significant clinical and radiographic benefit that glucocorticoids can provide (ref: KF 2016)
      • HQ: Please see in SLE
      • Sulfasalazine:
      • Leflunomide:
        • Teratogenic
        • Used mostly in older patients  
      • MTX: 
        • MOA:
          • The mechanism in Rheumatic diseases is likely due to its ability to raise extracellular Adenosine, as against folic acid antagonism.  This leads to an increase in cAMP in the cells
          • MTX works at the synovial tissue in RA
            • Decreases IL 1 and IL 6 secretion 
            • MTX increases IL 4 and IL 10 and this decreases Th1 pathway (which is classically implicated in RA)
            • MTX indirectly inhibits COX-2 synthesis and neutrophil chemotaxis
            • Also, MTX indirectly inhibits synovial MMP 
          • Anti-inflammatory mechanisms of methotrexate in RA ARD 2001
        • Patient Information: Methotrexate (Rheumatrex, Trexall) ACR
        • Drug-related information: MTX Medscape (Please review Black Box Warning)
        • all drugs esp TNFI work better with MTX as it prevents anti drug ab 
        • Monitoring: 
          • Clinical Evaluation for symptoms of MLLL MYELO, LUNG, LIVER, LN
            • Myelosuppression: Fever, and other manifestations of infection, easily disability, and bleeding, shortness of breath
            • Pulmonary Damage: Shortness of Breath; dry, non-productive cough. Mostly acute Pneumonitis. 
            • Hepatotoxicity: RUQ and pain, N, V
            • Lymphoproliferation: Lymph node swelling 
          • Laboratory / Imaging Evaluation: 
            • Myelosuppression and Hepatotoxicity: 
              • CMP and CBC with diff 
                • Typically 2 wk, 4wk, 6wk, 8wk, 12 wk, 20 wk, 28 wk, then every 3 months; every 8 weeks by medicare recommendation 
                • Frequency can be adjusted for each individual patient based on actual lab values and symptoms
            • Pulmonary Damage: Shortness of Breath 
            • Pregnancy tests should also be done intermittently 
      • AZA - when MTX  cannot be used 
        • A recent meta-analysis has shown that whereas MTX is most effective at preventing the formation of these antibodies (providing protection at the 77% level), AZA also does so at about the 50% level:   KF
        • “MTX flu,” , pregnancy, liver, pulmonary, or renal disease, may be indications for use of AZA in persons with RA
        • ILD is the most tricky - Clinically meaningful ILD in RA occurs in 3 % patients while overall incidence may be 6-8 % (Dr. Pope Podcast)
        • Neutropenia is the mc AEs, can be predicted by use of genetic test for polymorphism of enzyme TPMT 
          • TPMT homozygous: 0.3 % of population - risk of severe neutropenia
          • TPMT heterozygous: 10 % of population - mild neutropenia
          • Nonfunctional polymorphism: If AZA is added to MTX get acute febrile toxic reaction - Fever, Leucocytosis, Cutaneous vasculitis 

      • CsA
        • inhibits the activation of CD4+helper-inducer T lymphocytes by blocking IL-2 and other T helper type 1 cytokine production and 
        • by inhibiting CD40 ligand expression in T lymphocytes. The latter effect prevents T cells from delivering CD40 ligand-dependent signals to B cells
        • AE: HTN
        • It has antiviral properties to Hep C 

      • Anti-TNF alpha (TNF alpha is one of the main mediators of RA)
        • A, C, E, G, I (alternate letters)
          • Adalimumab (Humira), 
          • Certolizumab pegol (cimzia), 
            • TNF inhibitor, consisting of a humanized Fab fragment (50 kDa) fused to a 40-kDa PEG moiety. This unique structure may avoid potential Fc-mediated effects seen in vitro, such as complement-dependent or antibody-dependent cell-mediated cytotoxicity or apoptosis. The murine part is reduced to a minimum with a parallel reduction in the potential for immunogenicity. Certolizumab is the only TNFi agent that does not kill activated lymphocytes and monocytes by apoptosis Medscape 2015
          • Etanercept (Enbrel), 
          • Golimumab (Simponi), 
          • Infliximab (Remicade)
      • Anti - IL 6 (IL 6 along with TNF alpha is implicated in RA)
        • Toclizumab (Actemra)
      • B -Cell activation is also implicated (T-cell mediated B cell activation): Rituximab (Rituxan)
      • Th 1, Th17 pathway is classically implicated in RA. Hence, anti-T cell treatment is also used in severe cases.: Abatacept (Orencia) Also used in Juvenile RA
      • IL -1 inhibition (only modest effect in RA): Anakinra: does have significant benefit in Inflammasome driven diseases including Stills Disease, Gout, Muckel-Wells syndrome.  NEJM 2011
      • Small molecules - JAKI 
    • References
    • Calculators
    • Pharmacology Additional References
    • Biomarkers
      • MBDA 
        • not for diagnosis
        • panel of 12 markers
        • correlates with DAS 28
      • 14-3-3-eta (n)
        • correlates with disease activity
        • predictive of RA in combination with RF and ACPA 
    • Quality measures in RA 
      • Steroid Use monitoring 
      • TB screening
      • Monitoring of disease activity
      • DMARD Therapy 
adalimumab (Humira)
certolizumab pegol (Cimzia)
etanercept (Enbrel)
golimumab (Simponi)
infliximab (Remicade)
tocilizumab (Actemra)
anakinra (Kineret) 
rituximab (Rituxan)
abatacept (Orencia) 

Tofacitinib (first oral agent) 

The Pathogenesis of Rheumatoid Arthritis NEJM 2011

Clinical Guidelines in RA 

Additional Treat Pearls 
  • MTX naive
  • MTX failed 
  • TNF failed 
  • Combination better than mono but not every one needs combinatoin therapy KF 1194
    • COBRA, with the combination of MTX, SSZ, and prednisolone versus SSZ alone
    • the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, with the combination of MTX, SSZ, HCQ, and prednisone versus SSZ; 
    • the BeSt study, with the multiple combinations compared with step-ups or switchesthe Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial, with the combination of infliximab and MTX versus MTX alone; and 
    • the PREMIER study, with the combination of adalimumab and MTX versus each alone

Clinical Trials in RA 


BECON 2016
BEAM 2017

Other RA Trial 

SWEFOT trial 
TEAR Treatment of Early Rheumatoid Arthritis (TEAR) trial
NEO-RACo trial New Finnish RA Combination Therapy (NEO-RACo) 
(FIN-RACo) Finnish RA Combination trial 

  • Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial Michael Schiff et al Uni of Colorado 2013
    • Phase IIIb, 2-year, randomised, investigator-blinded study with a 1-year primary endpoint. Biologic-naive patients with active RA and an inadequate response to MTX were randomised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX
    • Of 646 patients randomised, 79.2% abatacept and 74.7% adalimumab patients completed year 2. At year 2, efficacy outcomes, including radiographic, remained comparable between groups and with year 1 results
    • The American College Rheumatology 20, 50 and 70 responses at year 2 were 59.7%, 44.7% and 31.1% for abatacept and 60.1%, 46.6% and 29.3% for adalimumab. There were similar rates of adverse events (AEs) and serious adverse events (SAEs). More serious infections occurred with adalimumab (3.8% vs 5.8%) including two cases of tuberculosis with adalimumab. There were fewer discontinuations due to AEs (3.8% vs 9.5%), SAEs (1.6% vs 4.9%) and serious infections (0/12 vs 9/19 patients) in the abatacept group. Injection site reactions (ISRs) occurred less frequently with abatacept (4.1% vs 10.4%)
    • Similar results but there were less discontinuations due to AEs, SAEs, serious infections and fewer local ISRs with abatacept.
  • Baricitinib in Patients with Refractory Rheumatoid Arthritis RA-BEACON NEJM 2016 Peter C. Taylor et al 
    • In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs).
    • In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire–Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose.
    • Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels.
    • In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks
  • Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis Peter C. Taylor et al NEJM 2017 RA-BEAM trial
    • Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 
    • Patients receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio:placebo(switchedtobaricitinibafter24weeks),4mgofbaricitiniboncedaily, or 40 mg of adalimumab (an anti–tumor necrosis factor α monoclonal antibody) every other week. 
    • American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire–Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24
    • More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P = 0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol
    • Baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab
  • Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis Andrea Rubbert-Roth et al (Switzerland) et all NEJM 2020
    • Editorial on SELECT-CHOICE Trial Guro Goll and Tore Kvien Oslo Norway
    • Upadacitinib is a second-generation JAK inhibitor that selectively blocks the signaling molecule JAK1
    • 24-week, 613 patients, inadequate response to at least one biologic DMARD ; oral upadacitinib (15 mg once daily) or intravenous abatacept, a T-cell costimulation modulator, both with continued background use of synthetic DMARDs
    • The primary end point was the change from baseline in the composite DAS for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority of upadacitinib to abatacept. By week 12, the DAS28-CRP decreased significantly more with upadacitinib than with abatacept (−2.52 vs. −2.00); thus, not only was the noninferiority of upadacitinib to abatacept shown by a prespeci- fied margin, but superiority was also shown. Serious adverse events were more frequent in the upadacitinib group, including two throm- boembolic events.
    • The fact that the DAS28-CRP includes the CRP level is important, because upadacitinib and other JAK inhibitors partially block the interleukin-6 pathway and lower levels of acute- phase reactants, irrespective of disease activity in persons with rheumatoid arthritis. Unsur- prisingly, the authors found a major decrease in the CRP level in patients receiving upadacitinib, whereas the swollen-joint count, another com- ponent of the DAS28-CRP, did not differ sig- nificantly between the treatment groups
    • Clinical Disease Activity Index (CDAI), which does not include the CRP level, was an exploratory end point; results showed between-group differences that were in the same direction as those observed for the primary end point. 
    • Critique
      • Abatacept was chosen as the comparator for upadacitinib rather than one of the more wide- ly used TNF-α–blocking agents
      • Abatacept was administered intravenously, where- as a subcutaneous formulation is now more commonly used
      • A 24-week trial may be too short to detect meaningful long-term efficacy and safety. By 24 weeks in the current trial, there were more serious adverse events in the upadacitinib group than in the abatacept group.
      • Will ned to show  data from a longer-term trial and the use of robust outcome measures independent of the CRP level and the erythro- cyte sedimentation rate
      • Cost has to be reasonable 
    • Current ACR/EULAR rec: if patient failed treatment, then can be switched to JAK inhibitor, a TNF-α–blocking agent, or a biologic DMARD such as abatacept with a different modality of mechanism 
    • By showing the superiority of upadacitinib over abatacept in difficult-to-treat patients with rheumatoid arthritis who had had an inade- quate response to a biologic DMARD, Rubbert- Roth et al. position JAK inhibitors in a treat- ment algorithm and help push JAK inhibitor

  • Oxford UK 

JRA (IL-1 mediated)
Adult onset stills Disease (IL -1 mediated)
Outcome measurement in RA studies 
  • ACR 20  response rate 
  • ACR 50  response rate 
  • ACR 70  response rate 
  • HAQ score
  • DAS 28
  • Pain VAS (visual analogue scale)
  • Global VAS 

Cost of therapy 
  • TABLE71-5 Costs of Disease-Modifying Anti-rheumatic Drugs in the United States in 2015
    1 Month oral DMARD from Walgreen’s
    Methotrexate #32, 2.5-mg tablets$101
    Hydroxychloroquine, 200 mg, #60$222
    Sulfasalazine, #120, 500-mg tablets$33
    Tofacitinib (Xeljanz), 5 mg, #60 tablets$3002
    Etanercept, 50 mg, syringe #4$4082
    Adalimumab, 40 mg, syringe #2$4224
    Adalimumab, 40 mg, pen #2$4224
    1 Month IV DMARDs from Good RX*
    Infliximab, 300 mg$3180
    Rituximab, 1500 mg$2350
    Abatacept, 750 mg$2200
    Tocilizumab, 400 mg$1650