SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

























Reference [6]
Positive ANA serum dilution % of healthy individuals with positive ANA at this dilution
1:40 32%
1:80 13%
1:160 5%

ANA subtypes Prevalence in SLE
Anti double-stranded DNA (anti-dsDNA)
  • anti-dsDNA antibodies have a very high specificity (> 97%) for SLE
  • Associated with kidney and skin disease
  • Anti-dsDNA antibody titers can be used to monitor disease activity [4]
70 - 80%
Antichromatin antibodies
  • Chromatin is a complex of protein and DNA found in the cell nucleus
  • Associated with proteinuria and drug-induced lupus [7]
50 - 90%
Antihistone antibodies
  • Found in 95% of patients with drug-induced lupus
  • Present in 20% of patients with Rheumatoid arthritis
  • Histones are proteins that DNA wraps around in the cell nucleus [7]
30 - 60%
Sjögren's Antibody / Anti-SSA (Anti-Ro)
  • Found in 60 - 70% of patients with Sjögren's syndrome
  • Patients who are ANA-positive and who have SS-A but not SS-B are very likely to have nephritis
  • Ro proteins are RNA complexes that are expressed on the surface of glandular cells that are undergoing necrosis or apoptosis [7]
30 - 40%
Anti-Sm antibodies (Smith antibodies)
  • Smith antibodies have a very high specificity (99%) for SLE
  • Smith antibodies are antibodies to small components of ribonucleoproteins [4,8]
10 - 30%
Ribonucleoprotein antibodies (RNP antibodies, anti-u1)
  • May be associated with a more benign disease course [4,8]
15 - 25%
Sjögren's Antibody / Anti-SSB (Anti-La)
  • Found in 50 - 60% of patients with Sjögren's syndrome
  • Associated with congenital heart block and neonatal lupus erythematosus
  • La proteins are RNA complexes that are expressed on the surface of glandular cells that are undergoing necrosis or apoptosis [4,7]
10 - 15%


  • JIA - juvenile idiopathic arthritis; MCTD - mixed connective tissue disease; SLE - systemic lupus erythematosus; SS - Sjögren’s syndrome; SSc - systemic sclerosis; UCTD - undifferentiated connective tissue disease; IM - inflammatory myopathies DM - dermatomyositis; PBC - primary biliary cirrhosis
  • Reference [6]
ANA pattern Associated condition
Nuclear patterns
Homogenous SLE, drug induced SLE/vasculitis, JIA
Coarse speckled MCTD, SLE, Raynaud, SSc, SS, UCTD
Fine speckled SLE, SS, SSc, IM, MCTD
Centromere SSc (limited), Raynaud’s
Nucleolar SSc, Raynaud’s, IM, overlap
Cytoplasmic patterns
Diffuse SLE, IM
Fine speckled IM, DM, PBC, interstitial lung disease


Other autoantibodies Prevalence in SLE
N-methyl-D-aspartate receptor antibodies (NMDA receptor antibodies)
  • Associated with neuropsychiatric lupus
  • NMDA receptors are found on nerve cells in the brain where they play an important part in learning and memory [4]
33 - 50%
C1q complement antibodies
  • Associated with kidney disease
  • Complement proteins are involved in immune responses to foreign organisms and in clearing damaged cells [4]
40 - 50%
Antiphospholipid antibodies (anticardiolipin, anti-Beta 2 glycoprotein I)
  • Associated with hypercoagulable state, pregnancy loss, accelerated atherosclerosis, pulmonary hypertension, and neuropsychiatric lupus [1,3,4]
  • See antiphospholipid antibodies for more
20 - 30%



ACR 1997 SLE Classification Criteria
To establish a classification of SLE, any 4 of the following must be present:
  • Malar rash
  • Discoid rash
  • Photosensitivity
  • Oral ulcers
  • Nonerosive arthritis - involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion
  • Pleuritis or pericarditis
    • Defined as:
      • Pleuritis - convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion
      • Pericarditis - documented by electrocardiogram or rub or evidence of pericardial effusion
  • Kidney disease
    • Defined as one of the following:
      • Persistent proteinuria > 0.5 grams per day or > 3+ on a urine dip
      • Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed
  • Seizures or psychosis
  • Positive antinuclear antibody (ANA)
  • Hematological disorder
    • Defined as one of the following:
      • Hemolytic anemia with reticulocytosis
      • Leukopenia (< 4,000/mm³ on ≥ 2 occasions)
      • Lymphopenia (< 1,500/ mm³ on ≥ 2 occasions)
      • Thrombocytopenia (< 100,000/mm³ in the absence of offending drugs)
  • Immunologic disorder
    • Defined as one of the following:
      • Anti-dsDNA antibodies
      • Anti-Sm antibodies
      • Antiphospholipid antibodies (anticardiolipin, lupus anticoagulant, ≥ 6 month false-positive Treponemal test)

  • Reference [24]
ACR / EULAR 2019 SLE Classification Criteria
Entry criteria
  • All patients must have an ANA titer ≥ 1:80 to be considered
A score of ≥ 10 based on the criteria below classifies a patient as having SLE
  • Within each domain, only the highest weighted criterion is counted toward the total score
  • Occurrence of a criterion on at least one occasion is sufficient
  • At least one clinical criterion is required
  • Criteria need not occur simultaneously
  • Do not count a criterion if an explanation other than SLE is more likely
Clinical domains and criteria Weight
Constitutional
  • Fever
2
Cutaneous
  • Non-scarring alopecia
2
  • Oral ulcers
2
  • Subacute cutaneous or discoid lupus
4
  • Acute cutaneous lupus
6
Arthritis
  • Either synovitis characterized by swelling or effusion in ≥ 2 joints or tenderness in ≥ 2 joints plus ≥ 30 min of morning stiffness
6
Neurological
  • Delirium
2
  • Psychosis
3
  • Seizure
5
Serositis
  • Pleural or pericardial effusion
5
  • Acute pericarditis
6
Hematological
  • Leukopenia
3
  • Thrombocytopenia
4
  • Autoimmune hemolysis
4
Renal
  • Proteinuria (> 5 grams/24 hours)
4
  • Renal biopsy class II or V lupus nephritis
8
  • Renal biopsy class III or IV lupus nephritis
10
Immunological domains and criteria Weight
Antiphospholipid antibodies
2
Complement proteins
  • Low C3 or low C4
3
  • Low C3 and low C4
4
Highly specific antibodies
  • Anti-dsDNA antibody
6
  • Anti-Smith antibody
6



SLE treatment recommendations
General recommendations in patients without major organ involvement
  • Hydroxychloroquine - should be used in most patients. Has been associated with prolonged survival and is important in managing skin disease and arthritis.
  • Decreased sun exposure (especially in skin disease) and sun protection (sunscreen)
  • Smoking cessation
  • Corticosteroids - used as part of induction therapy and for disease flares
  • Non-responsive patients or patients requiring higher doses of steroids - immunosuppressive agents such as azathioprine, mycophenolate mofetil (CellCept®) and methotrexate may be considered
  • Belimumab (Benlysta®) - a biological approved in 2011 for refractory SLE (see Belimumab vs Placebo below). Requires monthly IV infusions. Expensive. [13,24,25]
Lupus Nephritis (LN)
  • Incidence - affects 50 - 60% of patients during first 10 years of disease [9]
  • Pathology - Immune complexes formed from antinuclear antibodies accumulate in the kidneys and cause an influx of inflammatory cells by activating the complement cascade. Low levels of complement (C3 and C4) signify inflammatory activity and kidney damage. [2,9]
  • Prognosis - At least 10% of patients with LN will progress to end-stage kidney disease. Relapse is common after remission, occuring in up to 50% of patients. At 12 months after disease onset, only half of patients achieve complete remission. Obtaining proteinuria of 500 - 700 mg/day predicts good short-term outcomes. [25]
  • Monitoring (in patients with no history of LN)
    • Blood pressure every 3 months
    • Urinalysis every 6 months - look for 3+ protein by dipstick, and/or cellular casts (red blood cells, hemoglobin, granular, tubular, or mixed)
    • Spot protein/creatinine ratio every 6 months - positive if > 0.5 g
    • Serum creatinine every 6 months - look for unexplained increase
    • C3/C4 complement levels every 6 months - look for decrease signifying increased inflammatory activity
    • Anti-dsDNA titer every 6 months - look for increase in titer [9]
  • Treatment
    • Mycophenolate - first-line therapy
    • Corticosteroids - induction and maintenance therapy
    • Azathioprine
    • Calcineurin inhibitors (e.g. tacrolimus, cyclosporine) - resistant cases
    • Rituximab - resistant cases; mixed results in studies
    • ACE inhibitors or ARBs - proteinuria [9,21,26]
Skin disease
  • Incidence - affects > 80% of patients with SLE at some point during the disease [10]
  • Isolated skin disease - Lupus skin disease may occur independent of systemic lupus. Up to 28% of patients with lupus skin disease may go on to develop systemic lupus. Female patients with widespread lesions are at greater risk for progressing to systemic disease. [10,23]
  • Pathology - Immune complexes formed from antinuclear antibodies accumulate in the skin and cause an influx of inflammatory cells. Sun exposure may worsen the condition. Plaques with scarring (discoid lupus) occur when the condition is chronic. Mucosal involvement is common. [2,10]
  • Treatment
    • Avoid sun exposure. Use sunscreen.
    • Hydroxychloroquine (Plaquenil®) - first-line treatment
    • Topical corticosteroids and intralesional steroid injections
    • Topical calcineurin inhibitors (Protopic®, Elidel®)
    • For recalcitrant cases: retinoids, methotrexate, thalidomide, mycophenolate, azathioprine, and dapsone [10]
Neuropsychiatric lupus
  • Incidence - cerebrovascular disease and seizures (5 - 15% of lupus patients); severe cognitive dysfunction, major depression, acute confusional state, and peripheral nervous disorders (1 - 5% of lupus patients); psychosis, myelitis, chorea, cranial neuropathies, and aseptic meningitis (< 1% of lupus patients) [11]
  • Pathology - not completely understood. Associated with antiphospholipid antibodies (cerebrovascular disease, seizures, chorea) and NMDA-receptor antibodies (neurocognitive defects). [2,11]
  • Treatment - workup and treatment should be similar to that in non-SLE patients presenting with the same conditions [11]
Other related conditions
  • Antiphospholipid antibody syndrome - occurs in 10 - 15% of SLE patients; associated with hypercoagulable state, accelerated atherosclerosis, and pulmonary hypertension [1,21]
  • Osteoporosis - secondary to decreased sun exposure and corticosteroid treatment [12]
  • Immunosuppression from medications - increased risk of infections and cancer [12]
  • Musculoskeletal complaints and serositis - treat with NSAIDs, steroids, and hydroxychloroquine [12]
  • Raynaud's phenomenon (20% of patients) - treat with dihydropyridine CCB
  • Cardiovascular disease - lupus greatly increases the risk of cardiovascular disease particularly in younger patients (35 - 50 years) [21]
  • Plaquenil® (hydroxychloroquine) retinopathy - See Plaquenil for eye exam recommendations. [12]






Belimumab (Benlysta®) for SLE
  • In 2011, the FDA approved belimumab (Benlysta®) for SLE. Belimumab was the first FDA-approved treatment for SLE in over 50 years.
  • Belimumab is a fully humanized IgG monoclonal antibody that binds and inactivates soluble B-lymphocyte stimulator (BLyS). BLyS is a growth factor required for B-cell survival, maturation, and activation. See belimumab for more.
  • One of the pivotal trials that lead to belimumab's approval is detailed below
Belimumab vs Placebo in Active SLE, Lancet (2011) [PubMed abstract]
  • A trial published in the Lancet enrolled 867 patients with active SLE
Main inclusion criteria
  • ACR criteria for SLE
  • Active disease defined as score ≥ 6 on SELENA-SLEDAI
  • ANA (titre ≥ 1:80) or anti-dsDNA antibody (≥ 30 IU/mL)
  • Stable treatment regimen defined as prednisone (0–40 mg/day), NSAID, antimalarial, or immunosuppressive drugs for at least 30 days before the first study dose
Main exclusion criteria
  • Severe active lupus nephritis
  • CNS lupus
  • IV cyclophosphamide within 6 months of enrollment
  • IVIG or prednisone (> 100 mg/day) within 3 months
Baseline characteristics
  • Average age - 36 years
  • Female sex - 95%
  • Average duration of disease - 5.5 years
  • Average SELENA-SLEDAI score - 9.8
  • Receiving prednisone - 96%
  • Average prednisone dose - 12.5 mg
Randomized treatment groups
  • Group 1 (288 patients) Belimumab 1 mg/kg by IV infusion on Day 1, 14, 28, and then every 28 days
  • Group 2 (290 patients) Belimumab 10 mg/kg by IV infusion on Day 1, 14, 28, and then every 28 days
  • Group 3 (287 patients) Placebo infusion on Day 1, 14, 28, and then every 28 days
  • Study drug was added to patient's current regimen
  • Changes to standard of care were restricted after 16 weeks of treatment for immunosuppressive drugs and after 24 weeks for antimalarial drugs
  • Prednisone dose was not restricted in the first 24 weeks, but required return to within 25% or 5 mg greater than the baseline dose, with no further increases for the remainder of the study
Primary outcome: Response rate at 52 weeks. Response was defined as having all of the following: reduction of at least 4 points in the SELENA-SLEDAI score (scale 0 [no disease] to 105 [worst disease]); no new BILAG A organ domain score; no more than 1 new BILAG B organ domain score; and no worsening in Physician Global Assessment (PGA) score
Results

Duration: 52 weeks
Outcome Belimumab 1 mg/kg Belimumab 10 mg/kg Placebo Comparisons
Primary outcome (response rate) 51% 58% 44%Group 1 vs Group 3 p=0.0129 | Group 2 vs Group 3 p=0.0006
Time to first disease flare (median days) 126 119 84Group 1 vs Group 3 p=0.0026 | Group 2 vs Group 3 p=0.0036
Prednisone dose reduced by ≥ 50% at 52 weeks 23% 28% 18%Group 1 vs Group 3 p=0.16 | Group 2 vs Group 3 p=0.012
Median decrease in anti-dsDNA levels 35% 38% 12%Group 1 vs Group 3 p<0.0001 | Group 2 vs Group 3 p<0.0001
  • Rates of adverse events were similar between the 3 groups

Findings: Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease