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SLE

Pathogenesis  (Lancet 2014) 
  • highlighted in purple are processes involved in pathogenesis of SLE; added information in black is to show the comparison of SLE pathogenesis to the rest of the clinical immunology)
    • Innate and Adaptive Immune mechanisms are involved in pathogenesis. 
      • Innate Immune System
        • Physical Mucosal Barrier
        • Proteins
        • Cells like Granulocytes, NK Cells, Macrophages, Dendritic Cells
        • Phagocytic defects
          • Failure of phagocytes to remove apoptotic material efficiently leads to fragments of antigen being capture by APC - APC then activate T and B Cells
          • Type 1 IFN is a CENTRAL player of this pathogenesis of SLE (also SS, Dermatomyositis), and can activate INTERFERON SIGNATURE
        • Cell Signalling including IFN Gamma: TLR activation from IFN produced by plasmacytoid dendritic cells 
        • Complement (Alternate and Lectin Pathways)
      • Adaptive Immune System
        • T-Cell
          • T-Cell Development
          • T-Cell Maturation
          • T-Cell Activation and antigen presentation or Functioning 
              • T cells are also dysfunctional in lupus 
            • Th1: Th1 pathway is not involved in SLE. Hence, CRP is not elevated in SLE flare up. If CRP is increased, then it likely could be infection and not SLE flare up. 
            • Th2 : Systemic lupus erythematosus is described as a T-helper- 2-driven disease with increases in the serum concentration of interleukins 4, 6, and 10 Lancet 2013
            • Th17: These highly pro inflammatory subsets are seen in high number in SLE
              • TGF B in the presence of IL6 leads to Th 17 activation and increased IL 17 production
              • Localised to organs affected
              • implicated in local inflammation and tissue damage
        • B-Cell
          • Impaired Development
          • Impaired Functioning 
            • T-cell mediated
            • T-cel independent 
        • APC causing activation of T and B cells, particularly intense polyclonal B Cell activation producing ANA that are typical of SLE 
          • Inflammation is caused by
            • TNF pathways
            • Complement mediated pathways 
      • Regulatory Immune System
        • Innate System Regulation
        • Adaptive System Regulation
          • Disturbance in memory B cells in peripheral blood leads to formation of
            • CD27+/IgD– post-switched memory cells that are less susceptible to immunosuppression, and 
            • CD27–/ IgD– memory B cells are increased and associated with disease activity and renal lupus 
          • Regulatory B cells that secrete IL 10 but are non-functional are also seen in lupus patients



Diagnosis
  • The patient satisfies four of the criteria listed above, including at least one clinical criterion and one immunologic criterion. OR 
  • The patient has biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA antibodies
Treatment:


26 yo F with SLE, SLE nephritis (mesangioproliferative), has low C3, Low C4. Anti-smith was positive. Anti- DNA is 1: 320 (used to be 1:640). Had been on chronic steroids and has bilateral hip pain due to early AVN. Was on Cellcept, which was discontinued due to pancytopenia. Thiopurine Methyltransferase level is 22.2 (normal: 25-65). How do you manage the patient. She has had sub-acute skin lesions as well. You diagnose the paitent with moderate activity of SLE. She has received BCG vaccination as a child. 
1. Steroid, taper over 2-3 month, and start Azathioprine
2. Steroid, taper over 2-3 month, and start MTX
3. Cellcept
4. IFN -gamma release assay to consider starting her on Biologics.  
  • 12 Class of Drugs Used in the  treatment of SLE (Lancet 2014)
    1. Steroids
      • MOA:
        • Induce anti-inflammatory cytokines (IL10, IL1Ra, and annexin-1)
        • Decrease production of the adhesion molecules and inflammatory cytokines (IL 2, IL 6, and TNF); 
        • Inhibit processing of antigens by monocytes for presentation to lymphocytes; and 
        • Inhibit cyclooxygenase 2 and inducible nitric oxide synthase. 
      • Used for all features of systemic lupus erythematosus. 
      • Monitoring:
    2. NSAIDs
      • Inhibit cyclooxygenase, types 1 and 2. 
      • Used for fever, serositis, and arthritis. 
    3. HCQ
      • MOA: Lancet 2013
        • Immunomodulative properties without immunosuppression.
        • Increases lysosomal pH and interferes with antigen processing and possibly modulation of the immune response mediated by TLR 9 and TLR 7
        • Thus inhibits Antigen Processing and Co-stimulation activation. 
      • Used for arthritis, skin rashes, and fatigue. Might have a useful role in nephritis, have antithrombotic properties, and reduce cholesterol concentrations.
      • Monitoring:
        • Retinal deposits is dose and duration dependent. 
    4. Cyclophosphomide
      • MOA:
        • Forms active alkylating metabolites (4-hydroxycyclophosphamide, phosphor amide mustard, and acrolein). 
        • Prevents division of the cells by cross-linking DNA and suppressing DNA synthesis.
      • Monitoring: 
        • CBC, Liver Function Test, UA (at regular interval)
    5. Azathioprine
      • MOA:
        • Purine analogue that suppresses DNA synthesis by inhibiting synthesis of xanthylic and adenylic acids. 

        • Monitoring: 
          • Metabolised by metabolism involves the enzyme thiopurine methyltransferase (TPMT). Consider testing for TPMT activity prior to initiation of Azathioprine. 
          • Metabolites cleared by Xanthine Oxidase. Hence, Xanthine Oxidase inhibitors (i.e Allopurinol, Fuboxostat) are relatively contraindicated when using Azathiopurine.
    6. MTX
      • MOA:
        • A folate antimetabolite that inhibits DNA synthesis. 
        • Binds to dihydrofolate reductase, resulting in decreased purine synthesis and cell proliferation. 
        • Monitoring:
          • 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; 
                  • Frequency can be adjusted for each individual patients based on actual lab values and symptoms
              • Pulmonary Damage: Shortness of Breath 
            • Avoid Regular Alcohol Consumption 
        • Anti-inflammatory mechanisms of methotrexate in RA ARD 2001
        • Anti-inflammatory mechanisms of methotrexate in RA ARD 2001

    7. Cyclosporin
      • MOA: 
        • Forms complex with cyclophylin that disrupts the activation of calcineurin (complex of pho sphatases). 
        • Inhibits production of interleukin 2 and arrests T-cell cycle between G0 and G1.
          • Thus, preferentially, inhibits T cells
        • Clinica Use:
          • RA
          • Lupus
          • Inflammatory myositis
          • Psoriasis
          • Pyoderma Gangrenosum 
          • IBD
        • Monitoring:
          • Toxic medications. Hence, used as 3rd line agents in most illness.  
    8. Mycophenolate Mofetil
      • MOA:
        • Mycophenolate (mycophenolic acid as active metabolite) inhibits monophosphate dehydrogenase and blocks synthesis of guanosine nucleotides and proliferation of T and B cells.  
          • Thus, preferentially inhibits T and B cells 
        • Monitoring:
    9. Tacrolimus 
      • MOA: Calcineurin inhibitor  
        • Monitoring:
    10. Leflunomide
      • Inhibits dihydroorotate dehydrogenase necessary for pyrimidine and cellular protein kinases synthesis. 
      • Has immunosuppressive and antiviral effects. 
      • Monitoring:
        • Extremely long half-life; needs to be stopped 3 months prior to pregnancy
        • Cholestyramine will help in rapid excreation by inhibiting the enter-hepatic circulation (Three times a day for 8 days)
          • Measure medication twice before conception after cholestyramine used
    11. Biologics
      1. Targeting B Cells
        • B-cell depleting therapy:rituximab
        • B-cell modulating therapy: epratuzumab
        • Inhibition of B-cell survival: belimumab, atacicept
        • Other potential B-cell (plasma cell) targeting strategies:bortezomib 
        • Monitoring:
      2. Targeting T Cells
        • Inhibition of T-cell function: abatacept, ruplizumab, toralizumab, lupuzor 
        • Monitoring:
      3. IL - 6: See in RA 
      4. TNF - Alpha Inhibitors : See in RA 
      5. Type 1 IFN Inhibitors
        • Sifalimumab 
        • Rontalizumab 
          • Monitoring:
      6. Complement Inhibitors
        • Eculizumab 
          • Otheruses: 
          • Monitoring:
      7. General Points on Biologics
        • Monitor for opportunistic infections or infectious complications
        • Hold these agents during intercurrent infections
        • PPD or IFN-Gamma release assay prior to starting all biologics
          • Consider CXR in patient at risk of latent TB
          • Subsequent periodic surveillance is needed
        • Avoid Live Vaccines 
        • Response to vaccines is suboptimal in Rituximab, and Abatacept. Use of all vaccines prior to initiation of these agents is suggested. 
    12. IV IG
Clinical Manifestation and Pathophysiology
  • Jaccoud’s Arthropathy in SLE NEJM Image/Video 2015
    • the deformities result mainly from soft-tissue abnormalities, such as laxity of ligaments, fibrosis of the capsule, and muscular imbalance, rather than from destruction of the bone of joints, as occurs in rheumatoid arthritis. The mainstay of the management of Jaccoud’s arthropathy includes physical therapy and the use of orthotic devices
    • Manifestation of Jaccoud's Arthropathy in Hand includes: Swan Neck Deformity, Z deformity of thumb, Ulnar Deviation of fifth digit 

 
Clinical Situation
  1. ANA +
    • Needs UA with Microscopy, and Urine Proteinuria Assessment : may lead to renal biopsy
  2. Anti-TNF lupus
    1. ANA +
    2. ds DNA +
    3. Anti-histone ab - (unlike other cause of drug induced lupus)
      • Postulated Mechanism: Anti-TNF-induced lupus Rheumatology 2009
        • The ‘cytokine shift’ hypothesis proposes that pharmacological systemic blockade of TNF-alpha suppresses production of Th1 cytokines, thereby driving the immune response towards Th2 cytokine production, IL-10 and IFN-alpha. This change in cytokine balance would then induce a cascade of downstream events ultimately resulting in production of the autoantibodies and a lupus-like syndrome. 
        • Apoptosis Hypothesis
          • Another hypothesis is based on the assumption that systemic inhibition of TNF-alpha could interfere with apoptosis, affect the clearance of nuclear debris  and thus promote autoantibody production against DNA and other nuclear antigens. 
          • Similarly, TNF-alpha-induced apoptosis of mature cytotoxic T cells is an important mechanism for termination of T lymphocyte-driven responses. Anti-TNF-alpha therapy may interfere with this process and thereby promote autoantibody formation against nuclear antigens. 
          • Alternatively, inhibition of cytotoxic T cells by anti-TNF-alpha therapy could reduce the elimination of autoanti-body-producing B cells.
        • Some nuclear antigens, namely nucleosomes, become detectable in the plasma of RA patients after the start of anti-TNF-alpha therapy. Interestingly, such a rise in plasma nucleosome levels might contribute to a break of tolerance and thereby induce autoantibodies in susceptible individuals. This notion is supported by a recent study, which found that the occurrence of anti- nucleosome antibodies correlated strongly with the presence of ANA in anti-TNF-alpha-treated RA patients.
References
MKSAP 16
Classification of SLE: SLICC versus ACR criteria Arthritis Care Research 2015



Case Discussion

45 yo M patient is seen for Acute on Chronic Renal Failure. CMP is as follow. 


UA is as below. USG showed no obstruction. Ur - E was normal


Spot Ur-Pr/Cr is as follow. 


Patient was diagnosed previously of SLE with Nephritis. Unknown what pathological diagnosis patient had. However, was on Cellcept since diagnosis of SLE with Nephritis in 2014. Rheumatological work up revealed the following. 


Renal Biopsy is Done because of the worsening AKI. Before we discuss the findings of the biopsy, what are the renal manifestation of SLE? 







Given the current patient finding, what kind of Nephritis would you expect. 

Ans: Type 4
  • Carries worse prognosis. 
  • Associated with low c3, C4 during flare up
  • Acute renal failure is more commong
  • Not much of proteinuria may be present
Biopsy came as Lupus Nephritis Class V. Why is this unusual. 
  • Usually, Cr does not go high
  • Protenuria is more prominent in the nephrotic range
How is Lupus Neprhitis treated for Type III, Type IV, Type V. 

  • Type III
  • Type IV
  • Type V 








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