SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)





Acronyms


EPIDEMIOLOGY


RISK FACTORS


DRUG-INDUCED LUPUS (DIL)



PATHOLOGY


SYMPTOMS


DIAGNOSIS


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 seen in SLE 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

  • ✝Reactive arthritis typically occurs 2 - 4 weeks after an infection with Shigella, Salmonella, Campylobacter, Chlamydia, or Strep throat
  • Reference [32,33,34,35]
Features of Different Arthritis Syndromes
Finding Psoriatic arthritis Rheumatoid arthritis Lupus Gout Ankylosing spondylitis Reactive arthritis IBD-associated arthritis
Age of onset
Male:Female		 30 - 40s
1:1		 35 - 50s
1:3		 20 - 30s
1:9		 30 - 60s
3:1		 17 - 30s
3:1		 20 - 30s
5:1		 30s
2:1
Distal joints
 Fingers and toes including DIP
Asymmetric
≤ 4 joints		 Fingers and toes, spares DIP
Symmetric
> 4 joints		 Hands, wrists, knees
Symmetric
> 4 joints		 Great toe, foot, ankle, knees, elbow
Asymmetric
< 4 joints		 Lower limbs (30 - 50%)
Asymmetric
< 4 joints		 Knees, ankles, hips
Asymmetric
< 4 joints		 Hands and knees
Asymmetric
Spine disease Axial joints - 50%
Sacroiliitis - 40%		 Uncommon Uncommon Absent 100% Sacroiliitis - 50%
Back pain - 50%		 30%
Enthesitis 30 - 50%, Plantar fascia and Achilles's tendon Absent Absent Absent Common Common, Achilles tendon and plantar fascia Uncommon
Dactylitis 40 - 50% Absent Absent Uncommon Uncommon Common Absent
HLA-B27 positive 40 - 50% Not associated Not associated Not associated 90 - 95% 75% 30%
Eye disease Uveitis - 8% Dry eyes - 20% Dry eyes - 15% Absent Uveitis - up to 30% Conjunctivitis (common)
Anterior uveitis - 25%		 Uveitis - up to 7%
Other features Psoriasis - 100%
Nail disease - 85%		 Positive RF and Anti-CCP Positive ANA
Joint disease is non-erosive		 Elevated uric acid Primarily affects the spine and pelvis ✝Preceding infection
Urethritis (common)
Self-limited - 80%		 Occurs in 10 - 20% of patients with IBD

MANAGEMENT

Systemic lupus erythematosus drugs
Biologicals
  • B-cell agents
    • Belimumab (Benlysta®)

  • Type I INF inhibitor
    • Anifrolumab (Saphnelo®)
Immunosuppressants
  • Corticosteroids

  • Calcineurin inhibitors
    • Voclosporin (Lupkynis®)
    • Cyclosporine (Neoral®)
    • Tacrolimus (Prograf®)

  • Dihydrofolate reductase inhibitors
    • Methotrexate (Trexall®, etc.)

  • Thiopurines
    • Azathioprine (Imuran®)

  • Other
    • Hydroxychloroquine (Plaquenil®)
    • Mycophenolate (Cellcept®)

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®) - belimumab is a biologic that was FDA-approved to treat refractory SLE in 2011 (see belimumab vs placebo in SLE below)
  • Anifrolumab (Saphnelo®) - anifrolumab is a biologic that was FDA-approved to treat moderate-to-severe SLE in 2021 (see anifrolumab vs placebo in SLE below) [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, causing an influx of inflammatory cells and complement system activation. Low levels of C3 and C4 signify inflammation 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 (patients without a 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
    • Belimumab (Benlysta®) - see belimumab in lupus nephritis below
    • Daratumumab - a case report published in the NEJM described the successful treatment of 2 cases of resistant lupus nephritis with daratumumab, a drug approved to treat multiple myeloma [PMID 32937047]
    • 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]

DISEASE ACTIVITY INDICES


STUDIES

RCT
Belimumab vs Placebo for Active SLE, Lancet (2011) [PubMed abstract]
  • The trial 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 Bel 1mg Bel 10mg Placebo Comparisons
Primary outcome (response rate) 51% 58% 44%1 vs 3 p=0.012 | 2 vs 3 p=0.0006
Time to first disease flare (median days) 126 119 841 vs 3 p=0.002 | 2 vs 3 p=0.003
Prednisone dose reduced by ≥ 50% at 52 weeks 23% 28% 18%1 vs 3 p=0.16 | 2 vs 3 p=0.012
Median decrease in anti-dsDNA levels 35% 38% 12%1 or 2 vs 3 p<0.000
  • 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


RCT
TULIP-2 trial - Anifrolumab vs Placebo in Active SLE, NEJM (2020) [PubMed abstract]
  • The TULIP-2 trial enrolled 362 adults with moderately to severely active SLE.
Main inclusion criteria
  • Moderate-to-severe SLE
  • Positive ANA, anti-dsDNA, or anti-Smith
  • Stable treatment with ≥ 1 of the following: steroid, antimalarial agent, azathioprine, mizoribine, mycophenolate, methotrexate
Main exclusion criteria
  • Active severe lupus nephritis
  • Neuropsychiatric SLE
  • Serum creatinine > 2 mg/dl
Baseline characteristics
  • Average age 42 years
  • Female - 93%
  • BILAG-2004: ≥1 A item - 49%
  • BILAG-2004: No A item and ≥2 B items - 47%
  • Baseline therapy: Steroids - 80% | Antimalarial - 69% | Immunosuppressant - 48%
Randomized treatment groups
  • Group 1 (180 patients): Anifrolumab 300 mg by IV infusion every 4 weeks for 48 weeks
  • Group 2 (182 patients): Placebo
  • Other treatments were stable throughout the trial except for glucocorticoids. For patients receiving oral prednisone or equivalent at ≥ 10 mg/day, an attempt at tapering to ≤ 7.5 mg/day was required between weeks 8 and 40. Glucocorticoid doses were required to be stable for the last 12 weeks of the trial.
Primary outcome: difference between the two groups in the percentage of patients who had a BICLA response at week 52, defined as all of the following: a reduction of all severe (BILAG-2004 A) or moderately severe (BILAG-2004 B) disease activity at baseline to lower levels (BILAG-2004 B, C, or D and C or D, respectively) and no worsening in other organ systems (with worsening defined as ≥ 1 new BILAG-2004 A item or ≥ 2 new BILAG-2004 B items); no worsening in disease activity, as determined by the SLEDAI-2K score (no increase from baseline) and by the PGA score (no increase of ≥ 0.3 points from baseline); no discontinuation of the trial intervention; and no use of restricted medications beyond protocol-allowed thresholds.
Results

Duration: 52 weeks
Outcome Anifrolumab Placebo Comparisons
Primary outcome 47.8% 31.5% p=0.001
Steroid reduction 51.5% 30.2% p=0.01
≥ 50% reduction in swollen/tender joints 42.2% 37.5% p=0.55
Annual flare rate 0.43 0.64 p=0.08
SRI(4) response 55.5% 37.3% p<0.001
Upper respiratory infection 21.7% 9.9% N/A
Herpes zoster 7.2% 1.1% N/A
  • Anifrolumab was evaluated in a previous trial (TULIP-1), where it did not have a significant effect on the primary outcome of SLE Responder Index 4 (SRI(4)). A secondary endpoint in TULIP-1 was the BICLA response, and anifrolumab showed a favorable effect on this measure. When TULIP-1 data was made available, the design of TULIP-2 was amended so that BICLA response became the primary outcome. In TULIP-2, anifrolumab did have a significant effect on SRI(4).

Findings: Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo.

BIBLIOGRAPHY