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RA

  • 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 
LIVER 
ADIPOCYTES
MUSCLE 
BONE
BLOOD VESSELS
BRAIN
    • DDx: The new ACR/EULAR classification criteria for RA: how are the new criteria performing in the clinic? Rheumatology 2012
    • Epidemiology
      • 1 % in West 
      • 5-7 % in native American
      • 2: 1 F:M, Peak in F: 55-64, Peak in M: 75-84 

    • CF
      • Articular :
      • Extra-articular: BBBLMF
        • Brain
        • Bone 
        • Blood  / CVS 
        • Liver 
        • Muscle 
        • Fat 
      • Pericarditis is the most common cardiac manifestation of RA 
    • Diagnosis (MKSAP 16)
    • 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
        Obesity

        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 
        • Tofacitinib (small molecule Janus Kinase inhibitor)
    • 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 

ABC

AMPLE ABA ADALIMUMAB
BEST 
BECON
BEAM
CHOICE- SELECT -UPA, ABA
  • 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 inhibitors

  • 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
    • 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 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


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
    MedicationCost
    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



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