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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
          • 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.
        • 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
The Pathogenesis of Rheumatoid Arthritis NEJM 2011


The Pathogenesis of Rheumatoid Arthritis NEJM 2011

The Pathogenesis of Rheumatoid Arthritis NEJM 2011

    • DDx: The new ACR/EULAR classification criteria for RA: how are the new criteria performing in the clinic? Rheumatology 2012
    • CF
      • Pericarditis is the most common cardiac manifestation of RA 
    • Diagnosis (MKSAP 16)
    • Poor Prognostic Features: 
      • Functional Limitations (HAQ  Score - Health Assessment Questionnaire)
      • Extraarticular Disease (Rheumatoid Nodule, Rheumatoid Vasculitis, Felty Syndrome)
      • Postive RF or Anti-CCP Antibody
      • Bony Erosion
    • Treatment Principle (Early start of the DMARD / Biologics): 
      • EARLY RA (<6 months) (Disease Activity) (Figure 1):
        • LowDMARD Mono
          • MTX
        • 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
    • Goal of Treatment: 
    • Commonly used drugs and MOA
      • HQ: Please see in SLE
      • Leflunomide:
        • Teratogenic
        • Used mostly in older patients  
      • MTX: 
        • MOA:
          • Mechanism in Rheumatic diseases is likely due to its ability to raise extracelluar Adenosine, as against folic acid antagonism.  This leads to 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)
        • Monitoring: 
          • Clinical Evaluation for symptoms of 
            • Myelosuppression: Fever, and other manifestations of infection, easily bruisability, and bleeding, shortness of breath
            • Pulmonary Damage: Shortness of Breath; dry, non-productive cough
            • Hepatotoxicity: RUQ and pain, N, V
            • Lymphoproliferation: Lymph node swelling 
          • Laboratory / Imaging Evaluation: 
            • Myelosupression 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 week by medicare recommendation 
                • Frequency can be adjusted for each individual patients based on actual lab values and symptoms
            • Pulmonary Damage: Shortness of Breath 
            • Pregnancy tests should also be done intermittently 
      • Anti-TNF alpha (TNF alpha is one of the main mediators of RA)
        • A, C, E, G, I (alternate letters)
          • Adalimulab (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 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



JRA (IL-1 mediated)
Adult onset stills Disease (IL -1 mediated)
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