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Pathogenesis  (Lancet 2014) / Harrisons 
  • 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)
    • Step1: Initiating events: excessive and immunogenic forms of nucleic acid (DNA, RNA) or protein. 
    • Step 2: Autoimmune innate system 
        • Physical Mucosal Barrier - 
        • Proteins
        • 2a Activation of cells of innate immune system often times by TLRs to the 
          • Dendritic cells - IFN alpha " INF signature" 
          • Macrophage - IL - 12, TNF-alpha, B cell maturation / survival factor 
          • Granulocytes (neutrophils) releasing DNA/RNA/ protein containing nets 
          • NK Cells - decrease ability to kill autoreactive B and T cells; decreased production of TGF-beta to generation of regulatory T cells  
        • 2b 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)
    • Step 3  Autoimmune Adaptive  System
        • T-Cell -  altered metabolism (abnormal mitochondrial electron transport, membrane potential, and oxidative stress), increased glucose utilization, increased pyruvate production, activation of mTOR, and increased autophagy; 
          • T-Cell Development and Maturation : Easily activated and driven into apoptosis than normal cells; Decrease IL 2 (B cell survival factor)
          • 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 - B cell secrete IL6, IL 10 further generating auto reactive B cells (also favored by estrogen)
          • Inflammation is caused by
            • TNF pathways
            • Complement mediated pathways 
    • Step 4 Regulatory Immune System
        • 4a Innate System Regulation
          • NK Cells - decreased production of TGF-beta to generation of regulatoryT cells 
        • 4b 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 leading to generation of auto reactive B cells 
    • Step 5 Inflammation pathways 
      • Innate immune system: IFN signature , TNF 
      • Adaptive immune system: ab deposition or immune complex deposition on tissues - leading to complement activation 
      • Non-immune tissue-fixed cells are then activated to produce more inflammation and damage, such as basal cells of the dermis, synovial fibroblasts, renal mesangial cells, podocytes and tubular epithelium, and endothelial cells throughout the body
    • Step 6 Tissue damage 
      • Inflammation also causes release of vasoactive peptides, oxidative damage, growth factors and fibrosing factors. Sclerosis/fibrosis with irreversible tissue damage can occur in multiple tissues including kidneys, lungs, blood vessels, and skin

  • 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

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.  

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.
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 

SLE Studies
  • BLISS 52
  • BLISS 76
  • TULIP 1
  • TULIP 2 
Clinical Studies Outcome Measures in SLE 

2 main types of activity measures is Lupus has been developed. 
  1. Global score system that provides overall measure of disease activity: 
    • ECLAM (European Consensus Lupus Activity Measurement); Reumatol Clin. 2014;10(5):309–320
    • The ECLAM was described by the European working group

      consensus for measuring activity in SLE in 1992.18 It is an index designed to measure disease activity in the last month in patients

      with lupus. The ECLAM includes evaluation of 10 organs and/or systems and 2 laboratory values that are ESR and complement levels. It consists of a total of 33 items that are evaluated from 0.5 to 2, depending on the type of involvement, and a combined global score ranging from 0 to 17.5. The ECLAM is a simple index that can be used in retrospective studies, since there is a good correlation between the ECLAM calculated immediately and that calculated with data collected on clinical history

    • SLAM (Systemic Lupus Activity Measures) Reumatol Clin. 2014;10(5):309–320
    • The SLAM evaluates specific manifestations in 9 organs and includes 7 laboratory measurements. Some items are scored from 0 to 3, depending on the degree of severity, and others are evaluated only 0–1. The maximum score is 84, being part of the laboratory parameters a maximum 21 points. A score of 7 or more is considered relevant, since the patient will require a change in treatment in 50% of cases. The SLAM is considered by some experts the less appropriate index because it includes subjective measures, such as fatigue and joint pain; however, these variables must be scored by the doctor if 

      considered to be due to lupus activity.8 Training is required, since 

      it is necessary to reach a consensus to assess the subjective aspects, especially in multicenter studies
    • SLEDAI Systemic Lupus Erythematosus Disease Activity Index
      • Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): Is a global score Original version developed in 1992. Jesus et al BMJ 
        • Performance of SLEDAI in detecting clinically meaningful changes in disease activity is limited, since each item of SLEDAI is scored dichotomically, with the same numerical weight regardless of the severity of change observed. Only remission of any lupus feature, but not partial improvement, is captured as a change in SLEDAI score; likewise, an increased severity of any previously active manifestation cannot be scored 
        • In addition, potentially severe lupus manifestations, such as haemolytic anaemia, pneumonitis or gastrointestinal involvement, are not scored in SLEDAI.
        • For this reason, the SLEDAI was revised to take account of ongoing activity, and two versions have been used the safety of oestrogens in lupus erythematosus national assessment–SLEDAI 56 score (SELENA–SLEDAI) and SLEDAI 2000 https://ard.bmj.com/content/70/1/54
  2. Individual Organ system Assessment Scale that assess disease activity in single organ 
    • The British Isles Lupus Assessment Group (BILAG) DOI: 10.1016/j.reumae.2014.01.011

      • The British Isles for the Assessment of Lupus Group (BILAG) began to meet regularly in 1984 and in 1988 developed for the first time an index to measure disease activity in patients with SLE.4 This index was developed based on the physicians intention to treat and evaluates specific manifestations requiring treatment in a total of 8 organs or systems
      • Subsequently, certain minor modifications of this index were conducted and assessed for both their reliability and validity. A study of Hay et al.,5 evaluated the BILAG version 3, which includes a glossary with explanations and recommendations for ease of use. BILAG showed good intraobserver reliability, with kappa ranging from 0.79 to 0.97, depending on the target system
      • Assessment of Flare 
        • The presence of a severe flare is defined as a score of A, new appearance, and a moderate flare is defined with a rating of B, if it was previously in D or E.
  3. Methods used to asses Disease Flare 
    • BILAG 2004 Flare Index 
      • There were problems, however, with the ‘classic’ BILAG index, which incorporated a small number of items that were more clearly due to damage than to disease activity and that failed to capture adequately disease activity in the gastrointestinal or ophthalmic systems. The substantially revised version, the BILAG 2004 index, has now been shown to be reliable and sensitive
    • SLEDAI 2000 
    • SELENA Flare Index (SFI) (the Safety of Estrogens in Lupus Erythematosus National Assessment)
      • For each organ system, suggested clinical manifestations are given but the categorisation is dictated by the treatment decision. 
        • In particular, a ‘mild flare’ is assigned if there is either no treatment, or if there is initiation of hydroxychloroquine, prednisone 7.5 mg per day or less or a non-immunosuppressive therapy. 
        • Definition of a ‘moderate flare’ requires the use of prednisone greater than 7.5 mg per day but less than 0.5 mg/kg per day, or immunosuppressive therapy (other than cyclophosphamide), and 
        • ‘severe flare’ is defined as prednisone (or equiva- lent) 0.5 mg/kg per day or greater, cyclophosphamide, biological treatment, or hospitalisation https://ard.bmj.com/content/70/1/54
    • PGA - Physician Global Assessment 
      • The BILAG 2004 had the highest ICC (0.54 [95% CI: 0.32–0.78]) compared to the SFI (0.21 [95% CI: 0.08–0.48]) and PGA (0.18 [95% CI: 0.06–0.45]).
      • https://ard.bmj.com/content/70/1/54
Not sure if following is a global outcome measure or composite index
  • SLEDAI-2K 10 days - Systemic Lupus Erythematosus Disease Activity Index 2000 10 days Reumatol Clin. 2014;10(5):309–320
    • In 2002 a revised and updated version of the SLEDAI, SLEDAI

      2000 (SLEDAI-2K), which scored rash, alopecia, ulcers or persistent

      proteinuria, not only recently introduced but also of new appearance,

      as occurred in the previous version.26 The SLEDAI-2K was

      validated against the original SLEDAI with an evaluation within

      10 days prior to the visit and it was validated with a temporal space

      of 30 days for use in RCTs.30,31 The SLEDAI-2K and the previous

      version had a high correlation (r=0.97) and both indices similarly

      predict mortality. The SLEDAI-2K reflects aspects of the disease as present or

      absent and may not reflect partial improvement, which limits their

      use in RCT.

  • SLEDAI-2K SRI-50 - Systemic Lupus Erythematosus Disease Activity Index 2000 Responder Index 50
    • Reumatol Clin. 2014;10(5):309–320
    • The SLEDAI-2K reflects aspects of the disease as present or

      absent and may not reflect partial improvement, which limits their

      use in RCT. For this reason, in 2011 Touma et al. developed a

      response rate of 50% (SRI-50) to document a 50% improvement

      in SLEDAI.32 This study evaluated the construct validity using

      assessment of response to treatment by a physician as an external

      comparator on a Likert scale (LS) that ranged from 7 (significant

      improvement) to 1 (much worse). A 50% improvement on this scale

      would be greater than or equal to a change of 6. In patients with

      an improvement 6 in the LS, there was a decrease in the SRI-50 of

      4.15 ± 3.01 (P<0.0001).

Composite Index: 
  • The British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA): 
    • Is primary endpoint in the EMBLEM trial of epratuzumab in lupus
    • was derived by expert consensus 
    • BICLA response is defined as 
      • (1) at least one gradation of improvement in baseline BILAG scores in all body systems with moderate or severe disease activity at entry (eg, all A (severe disease) scores falling to B (moderate), C (mild), or D (no activity) and all B scores falling to C or D);
      • (2) no new BILAG A or more than one new BILAG B scores; 
      • (3) no worsening of total SLEDAI score from baseline; 
      • (4) 10% deterioration in physicians global assessment and 
      • (5) no initiation of non-protocol treatment

  • The Systemic Lupus Responder Index (SRI): Used in Phase III study BLISS-52, BLISS-76. Derived from post-hoc analysis of Phase 2 study. 
    • SRI consists of scores derived from the SLEDAI and the BILAG Index: 
      • (1) 4-point reduction in SLEDAI global score, 
      • (2) no new severe disease activity (BILAG A organ score) or more than one new moderate organ score (BILAG B) and 
      • (3) no deterioration from baseline in the physicians global assessment (10% of scale)

Thanou A, Chakravarty E, James JA, et al. Which outcome measures in SLE clinical trials best reflect medical judgment? Lupus Science & Medicine 2014

According to recommendations by the Food and Drug Administration, European League Against Rheumatism and Outcome Measures in Rheumatology, the ideal endpoint should be able to detect both improvement and wor- sening in different manifestations and discern acute lupus disease activity from chronic damage and changes related to other causes. 

Detection of both improvement and worsening is not possible using a global measure of disease activity such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). It is not a trivial undertaking even with an organ-based assessment such as the British Isles Lupus Assessment Group (BILAG) since different events within one organ may not be differentiated even with that complex instrument. This led to the development of composite endpoints to detect improvement without worsening. 

For Reseaerch

ECLAM is measure of disease activity in the past 30 days. 10+2. 33 item - 0 to 2, total max of 17.5. can be used in retrospective study

SLAM 9+7.  0 to 3 for some/0-1 for others; total max of 84, lab max 21; . can be used in retrospective study; 7 or more is relevant; change in 50%; subjective measures so less appropriate index; 


Mild-to-moderate flares were defined as one or more of the following 5 features: 

A > 3-point change in the SELENA–SLEDAI score, with a total score of  12; 

1)     new or worsening discoid, photosensitivity, or other rash attributable to lupus (including lupus profundus,

cutaneous vasculitis, or bullous lupus), nasopharyngeal ulcers, pleuritis, pericarditis, arthritis, or fever not attributable to infection; 

2)     an increase in the prednisone dosage, but not to 0.5 mg/kg of body weight per day; 

3)     initiation of therapy with either hydroxychloroquine or nonsteroidal anti-inflammatory drugs, without an increase in the prednisone dosage; and 

4)     a change of 1.0 in the physician’s global assessment score, but with the score remaining 2.5.


Severe flares were defined as one or more of the following 5 features: 

1)     a SELENA–SLEDAI score   greater than 12; 

2)     new or worsening central nervous system (CNS) involvement, vasculitis, glomerulonephritis, myositis, thrombocytopenia (platelet count 60  10 9 cells/liter), or hemolytic anemia (hemoglobin level 70 gm/liter or a decrease in the hemoglobin level of 30 gm/liter over a 2-week period), each of which required doubling of the corticosteroid dosage to a final dosage of 0.5 mg/kg/day or hospitalization; 

3)     any manifestation requiring an increase in the dosage of prednisone or equivalent drug to 0.5 mg/kg/day, or initiation of therapy with cyclophosphamide, azathioprine, mycophenolate mofetil, or methotrexate; 

4)     hospitalization because of lupus activity; or

5)     a change from baseline in the physician’s global assessment score to 2.5.