Systemic Lupus Erythematosus

Systemic Lupus Erythematosus

Shane M. Meehan, MBBCH

Endocapillary hypercellularity image, “wire loop” thickened capillary walls image, fibrinoid exudate image, and the rarely seen hematoxylin bodies image are indicative of active lupus glomerulonephritis.

PAS shows lupus glomerulonephritis with prominent mesangial hypercellularity and segmental “wire loop” thickening of the capillary walls image. Lupus has a great spectrum of renal lesions.



  • Systemic lupus erythematosus (SLE); lupus nephritis (LN)


  • Lupus nephritis; lupus glomerulonephritis (GN)


  • Systemic autoimmune disease manifested by inflammation of skin, joints, kidneys, and central nervous system, and with pathogenic IgG autoantibodies targeting nuclear, cell surface, and plasma protein self-antigens


Autoimmune Disease

  • Autoantibodies to nuclear antigens in 95%: Double-stranded (ds) DNA (nucleosomes), Ro (a ribonucleoprotein), La (an RNA binding protein), Sm (a ribonucleoprotein)

    • Other autoantigens

      • C1q and membrane phospholipids such as phosphatidylserine

      • Laminin, heparan sulfate proteoglycans, and podocyte antigens

      • Some autoantibodies promote coagulation: Lupus anticoagulant, antiphospholipid antibodies, and ADAMTS13

  • Autoantibodies may be detectable years before disease onset

  • Breakdown of tolerance to self-antigens, trigger unknown

    • “Waste disposal” hypothesis

      • Defective phagocytosis of apoptotic cells leads to abnormal pathways of disposal of these cells

      • Abnormal disposal allows exposure of immune system to intracellular sequestered antigens

      • Exposure to these self-antigens activates self-reactive T and B cells and development of autoantibodies

Environmental Triggers and Aggravating Factors

  • Sunlight (UV)

  • Drugs: Hydralazine, procainamide, quinidine

Genetic Factors

  • 10% have relatives with SLE

  • Higher concordance for monozygotic twins (25-69%) than dizygotic twins (1-2%)

  • Polymorphisms/mutations of > 25 genes increase risk in genome-wide association studies

    • C1, C2, or C4 deficiency, probably causing defective clearance of immune complexes and apoptotic cells

    • Fcγ receptor IIB (inhibitory receptor on B cells)

    • Toll-like receptors (TLR 7 and 9)

    • Interferon (IFN) and tumor necrosis factor (TNF) signaling

    • HLA-DR2 and 3

    • TREX1, a DNA-degrading enzyme


  • Immune complex (IC) formation and deposition in the kidney

    • Circulating IC trapped in capillaries and mesangium

      • Histone-rich nucleosomal antigens are trapped in glomeruli, possibly initiating immune complex (IC) deposition

    • In situ formation of IC due to planted or intrinsic antigen

    • Complement fixation

      • C3a and C5a attract neutrophils and macrophages

      • Endothelial activation by cytokines and complement

    • Inflammatory cells bind IC via Fc and complement receptors and are activated

    • Persistent or recurrent inflammation leads to changes in intrinsic glomerular cell numbers and function and matrix homeostasis

  • Thrombotic microangiopathy

    • Associated with lupus anticoagulant, antiphospholipid antibodies, and, rarely, antibodies to ADAMTS13

    • Arises independently of glomerular inflammation and IC

  • Vasculitic glomerulonephritis

    • Necrosis with little or no IC deposition

    • Endothelial damage by uncertain mechanism

  • Podocytopathy

    • Minimal change lesion, FSGS, or collapsing glomerulopathy

  • T-cell-mediated autoimmune reactivity may also play a role

Insights from Animal Models

  • Several spontaneous inbred mouse strains develop lupus-like glomerulonephritis, shown to be multigenic

    • NZB/NZW F1, MRL/lpr, BSXB

  • Many specific genetic deficiencies promote murine lupus in susceptible strains

    • C4, C3, FcγRIIB, CD19, fas, Ro



  • Incidence

    • 12-64/100,000 worldwide

    • ˜ 80% have nephritis during the course of the disease

      • 20% of patients have nephritis at onset

      • > 90% have nephritis at autopsy

  • Age

    • Peak incidence from 15-40 years

      • Also occurs in infants and the elderly

  • Gender

    • Female:male = 9:1

  • Ethnicity

    • Less frequent in Caucasians

      • 1:250 females of African ancestry in USA

      • 1:1,400 females of European ancestry in USA


  • Gradual or sudden onset

  • Variable presentation, correlates with pathologic classification

    • Isolated hematuria: ISN/RPS class I, II, and III

    • Nephritic syndrome: Class III and IV

    • Isolated proteinuria: Class II and III

    • Nephrotic syndrome: Class IV and V

    • Acute renal failure: Class IV

    • Chronic renal failure: Class VI

  • Other features: Serositis, skin rash (malar, butterfly), anemia, arthritis, lymphadenopathy, thrombotic manifestations

Laboratory Tests

  • Autoantibodies

    • 95% have autoantibodies to nuclear components

      • > 95% ANA (speckled pattern)

      • 30-70% anti-dsDNA

      • 30-50% anti-Ro (SSA)

      • 30-40% anti-U1RNP

      • 20-40% anti-Sm (highly specific for SLE)

    • 40-50% anticardiolipin

      • 15% antiphospholipid

    • 30-50% anti-C1q

      • Associations with lupus nephritis strongest for antibodies to dsDNA and C1q

  • Complement levels

    • ↓ C3 in 30-50%, ↓ C4 in 67-80%, more common in active disease


  • Drugs

    • Immunosuppressive therapy used to decrease or arrest IC deposits, inflammation, and necrosis

      • Glucocorticoids, mycophenolate mofetil, cyclophosphamide

      • Chlorambucil and azathioprine

    • Anti-B-cell antibodies targeting CD20 (rituximab) under evaluation

  • Transplantation

    • Clinically significant recurrence is rare (˜ 2%)

      • IF studies detect subclinical recurrence in ˜ 40%


  • Typically remitting and recurring course

  • 25% develop end-stage renal failure

    • 10-year renal survival is ˜ 75%

    • 10-year patient survival is 72-98%

  • Common causes of death

    • Infection, especially pneumonia

    • Chronic renal failure

    • Neoplasms: B-cell lymphomas, lung carcinoma

General Approach

  • Kidneys are biopsied in SLE to determine type of renal disease, acute inflammatory activity, and extent of glomerular and tubulointerstitial scarring

  • Accurate assessment requires at least 20 glomeruli

  • 2004 ISN/RPS classification is standard for lupus glomerulonephritis


Histologic Features

  • Lupus nephritis affects glomeruli, peritubular capillaries, muscular blood vessels, tubules, and interstitium with a spectrum of lesions

  • Glomeruli

    • Glomerular lesions determine ISN/RPS classification (classes I-VI)

      • Lesions can be active (acute) or chronic (sclerosing)

      • Focal (< 50% of glomeruli affected; III) or diffuse (≥ 50% of glomeruli affected; IV)

      • Segmental (part of a glomerulus) or global (> 50% of a glomerulus)

      • Distinction between III and IV is only by extent of these lesions (< or ≥ 50%, respectively)

    • Normal (I)

      • Requires mesangial IgG to diagnose lupus class I

      • Class I is seen in < 1% of biopsies for cause

    • Mesangial hypercellularity (II)

      • By itself is not considered an active lesion

      • Class II is seen in 10-15% of biopsies

    • Endocapillary hypercellularity (III, IV)

      • Proliferation of intrinsic glomerular cells and accumulation of leukocytes with capillary luminal reduction

      • Class III is seen in 15-25% of biopsies

      • Class IV is seen in 40-60% of biopsies

    • Extracapillary hypercellularity (crescents) (III, IV)

      • Proliferation of parietal epithelium, accumulation of leukocytes, especially macrophages

      • Defined as > 2 cells thick, > 25% of circumference of capsule

      • Cellular or fibrous

      • GBM rupture associated with crescents

    • Karyorrhexis, fibrinoid necrosis (III, IV)

    • Prominent subendothelial deposits (“wire loops”) (III, IV)

      • Trichrome stain useful

    • Hyaline “pseudothrombi” (III, IV)

    • Hematoxylin bodies specific but rare (III, IV)

      • In vivo LE cell

    • Membranous lesions (V)

      • Diffuse thickening of GBM with granular subepithelial deposits (trichrome) with silver-positive “spikes”

      • Class V is seen in 10-15% of biopsies

    • Chronic glomerular lesions

      • Included in count of involved glomeruli for III vs. IV, if believed to be due to LN

      • Glomerular sclerosis, segmental or global

      • Glomerular fibrous adhesions

      • Fibrous crescents

      • GBM duplication

    • Variants

      • Some patients with minimal lupus (I-II) present with podocytopathy (minimal change disease and focal segmental glomerulosclerosis)

      • Focal segmental glomerular sclerosis can be a late scarring phase of lupus nephritis or secondary to loss of nephrons

      • Pathology may be dominated by lesions of thrombotic microangiopathy with little immune complex disease

  • Tubules and interstitium

    • Tubulointerstitial lesions are most commonly seen in association with class III and IV glomerular lesions

      • May be active or chronic

      • Occur ± IgG and C3 positive immune deposits

    • Active lesions are composed of T cells, macrophages, B cells, plasma cells, and neutrophils; with edema and tubulitis

      • Tubulointerstitial immune deposits may be associated with lymphoid aggregates

    • Chronic lesions are characterized by interstitial fibrosis and tubular atrophy

    • Occasional cases have predominately tubulointerstitial disease with only minimal glomerular disease (e.g., class II)

  • Vessels: 6 patterns observed

    • Normal (negative IF)

    • Uncomplicated vascular immune deposits

      • Normal-looking vessels with IgG, IgA, IgM, C3, and C1q by IF

    • Noninflammatory lupus vasculopathy

      • Hyaline deposits with Ig and C by IF

    • Necrotizing lupus vasculitis

      • Fibrinoid necrosis and leukocytoclasis ± immune deposits

    • Thrombotic microangiopathy

      • ± class III or IV glomerular lesions

    • Arterial and arteriolar sclerosis

      • Nonlupus vasculopathy without immune deposits



  • Detection of IgG deposits in glomeruli essential for diagnosis

    • Usually accompanied by IgA, IgM, C3, and C1q (“full house”)

    • Kappa and lambda equal

    • IgG1 and IgG3 are predominate subclasses

    • Fibrin in necrotizing lesions and thrombi

  • Glomerular patterns

    • Mesangial only (class I, II)

    • Capillary wall, focal or diffuse, coarse granular, elongated (class III, IV)

    • Capillary wall, diffuse, finely granular (class V)

  • Tubules

    • Granular IgG with variable other components common in tubular basement membrane (˜ 50% of cases)

  • Vessels

    • IgG and other components sometimes seen in small arteries, arterioles, and peritubular capillaries

Electron Microscopy

  • Amorphous electron-dense deposits present in glomeruli in varied locations and extent

    • Mesangium, subendothelium, subepithelium

    • Subepithelial deposits sometimes penetrate GBM

    • Substructure may be focally manifested as “thumbprint” pattern

  • Extraglomerular deposits of similar nature

    • Tubular basement membrane, Bowman capsule, peritubular capillaries, interstitium, small arteries

  • Glomerular endothelial cells have tubuloreticular structures

    • Clusters of vesicles and tubules of diameter 20-25 nm in endoplasmic reticulum

    • Consequence of elevated levels of interferon


Type II Mixed Cryoglobulinemia

  • Fibrillary substructure of deposits

  • Macrophage predominance in glomerular capillaries

  • Deposits can be sparse, usually little subepithelial

    • IgM-predominant immunoglobulin

  • “Pseudothrombi” do not distinguish

  • Often associated with hepatitis C virus

Membranoproliferative GN, Type I/III

  • C3-dominant deposits, IgG, and IgM in a band-like pattern along capillary walls

  • Usually no C1q

  • Lupus serologies negative

Postinfectious GN

  • IgG and C3 in a characteristic coarse granular (“lumpy-bumpy”) pattern, with hump-like deposits along subepithelium

  • Usually little C1q

  • Deposits in GBM (“humps”) do not have “spikes”

Idiopathic Membranous GN

  • Absence of subendothelial, mesangial, and extraglomerular deposits, and tubuloreticular inclusions

  • Antibodies to phospholipase A2 receptors

  • Deposits typically do not penetrate the GBM

Drug-induced LN

  • Many drugs implicated, e.g., propylthiouracil, isoniazid, hydralazine, procainamide, chlorpromazine

  • Few have anti-ds DNA antibodies or renal disease (5%)

    • High frequency of antihistone antibodies

  • Proof requires improvement after drug withdrawal

Lupus-like GN in HIV

  • Negative or low titer ANA and negative dsDNA antibodies by definition

  • 50% diffuse, 45% focal, and 5% membranous pattern

  • ˜ 20% of renal biopsies in HIV-infected patients

IgA Nephropathy

  • IgA-dominant deposits without tubuloreticular inclusions or extraglomerular immune deposits

C1q Nephropathy

  • Abundant mesangial immune deposits, with predominance of C1q

  • No clinical evidence of lupus

Pauci-immune Crescentic GN

  • Little or no endocapillary hypercellularity with little Ig and C deposition

Sjögren Syndrome

  • Distinction based on serology and clinical features


Clinically Relevant Pathologic Features

  • Histologic predictors of poor renal outcome

    • Class of LN broadly correlates with outcome but is less of a predictor because of tendency for class changes in follow-up biopsies

      • In general, mesangial and membranous lesions have better prognosis than focal or diffuse proliferative lesions

    • Amount of subendothelial deposits

    • Activity index

    • Chronicity index

  • ISN/RPS class, activity and chronicity indices, and presence of tubulointerstitial or vascular disease are essential for clinical management

Pathologic Interpretation Pearls

  • Lupus nephritis is in differential diagnosis of almost every renal biopsy

  • Heterogeneity of glomerular lesions by LM, glomerular and extraglomerular IgG, and endothelial tubuloreticular inclusions are most important diagnostic clues to LN

  • Hematoxylin bodies are pathognomonic but rare


ISN/RPS Classification of Lupus Glomerulonephritis (2004)

  • Based on light and immunofluorescence microscopy; electron microscopy not required

    • ≥ 20 glomeruli should be sampled for accurate classification

    • Tubulointerstitial disease and thrombotic microangiopathy scored separately

    • Classification requires distinction of active and chronic lesions and determination of extent of glomerular involvement by these injury processes

      • Single glomerulus may have both acute/active lesions and chronic/sclerosing lesions

      • Heterogeneity of interglomerular and intraglomerular changes makes classification of these lesions difficult

  • Transformation of glomerular lesions in repeat biopsies over months to years

    • Class II lesions upgrade to class III, IV, and V lesions in 33%

    • Class III lesions upgrade to class IV and V in 50%

    • Class IV lesions may upgrade to class V and VI lesions in 15%

    • Class III and IV lesions rarely downgrade to class II

    • Class V lesions may develop proliferative (class III or IV) lesions in ˜ 45% of cases

    • Majority of reported cases (78%) have no change of class in follow-up biopsies

  • Classes broadly correlate with outcome

    • Class I and II: Best survival

    • Class IV: Worse survival than III

      • Debate whether segmental and diffuse forms of class IV are different

    • Class V: Good long-term survival

    • Class VI: End-stage disease

Activity and Chronicity Indices

  • Histologic lesions scored 0, none; 1+, mild; 2+, moderate; 3+, severe and summed

  • Activity index (AI) (0-24)

    • Components: Endocapillary hypercellularity, neutrophils, fibrinoid necrosis/karyorrhexis, cellular crescents, “pseudothrombi”/“wire loops”

      • Scores for necrosis, karyorrhexis, and cellular crescents are doubled

  • Chronicity index (CI) (0-12)

    • Components: Glomerular sclerosis, fibrous crescents, interstitial fibrosis, and tubular atrophy

  • Reproducibility suboptimal


1. Morel L: Genetics of SLE: evidence from mouse models. Nat Rev Rheumatol. 6(6):348-57, 2010

2. Harley IT et al: Genetic susceptibility to SLE: new insights from fine mapping and genome-wide association studies. Nat Rev Genet. 10(5):285-90, 2009

3. Seshan SV et al: Renal disease in systemic lupus erythematosus with emphasis on classification of lupus glomerulonephritis: advances and implications. Arch Pathol Lab Med. 133(2):233-48, 2009

4. Rahman A et al: Systemic lupus erythematosus. N Engl J Med. 358(9):929-39, 2008

5. Furness PN et al: Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis-a UK-wide study. Am J Surg Pathol. 30(8):1030-5, 2006

6. Hill GS et al: Class IV-S versus class IV-G lupus nephritis: clinical and morphologic differences suggesting different pathogenesis. Kidney Int. 68(5):2288-97, 2005

7. Weening JJ et al: The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 15(2):241-50, 2004

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Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Systemic Lupus Erythematosus
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