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Risk factors Pathology/Symptoms Labs Diagnostic criteria Management
Known risk factors
  • Female sex
  • African-American
  • Asian
  • Family history

Possible risk factors
  • Ultraviolet radiation
  • Smoking
  • Epstein-Barr virus
  • Female hormones
  • Hormone replacement therapy
  • Oral contraceptives
  • Occupational exposure: silica, pesticides, mercury

Drug-induced lupus
Pathology
  • Lupus is believed to be caused by deficiencies in the complement system that lead to defective apoptotic (programmed) cell death and clearance
  • During apoptotic cell death, cellular debris are engulfed by phagocytes. Failure of proper and complete phagocytosis can lead to nuclear debris being captured by antigen presenting cells.
  • Antigen presenting cells with captured nuclear debris interact with T and B cells, and antinuclear antibodies are produced [21]

Symptoms
  • Malar rash - red rash of nose and cheeks often in shape of a butterfly
  • Discoid rash - red, raised, disc-shaped patches
  • Photosensitivity - sun exposure causes rash or worsens existing
  • Oral ulcers - sores in mouth
  • Arthritis - joint pain and swelling of two or more joints, typically nonerosive
  • Serositis - Inflammation of the lining around the lungs (pleuritis) or inflammation of the lining around the heart that causes chest pain, which is worse with deep breathing (pericarditis)
  • Kidney disorders - persistent protein or cellular casts in the urine
  • Neurologic disorders - seizures and psychosis
  • Hemolytic anemia - red blood cell lysis
  • Leukopenia - low white blood cell count
  • Thrombocytopenia - low platelet count
  • Fever
  • Fatigue
  • Weight loss
  • Raynaud's syndrome - vasoconstriction in hands when exposed to cold (about 20% of patients)
  • Sicca syndrome - causes dry eyes and mouth (10-20% of patients) [2, 4, 5]
Antibody test % of lupus patients
with positive test
Other Four of the following must be present (ACR criteria):
  • 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)

American College of Rheumatology 1997 SLE criteria
General treatment in patients without major organ involvement
  • Hydroxychloroquine and corticosteroids as needed
  • In non-responsive patients or patients who cannot reduce steroids below doses acceptable for chronic use, immunosuppressive agents such as azathioprine, mycophenolate mofetil (CellCept®) and methotrexate should also be considered
  • Decreased sun exposure (especially in skin disease)
  • Smoking cessation [13]
  • Belimumab (Benlysta®), a biological that inhibits B-cell survival factor, was approved in 2011 for refractory SLE. Requires monthly IV infusions. Expensive.
Antinuclear antibodies
(ANA)
> 96% A dilution of 1:160 considered significant in most patients (see ANA below for more). ANA should not be used to monitor disease activity. [5,6]
Anti double-stranded DNA
(anti-dsDNA)
70 - 80% Associated with kidney and skin disease. Anti-dsDNA antibody titers can be used to monitor disease activity. [4] Lupus Nephritis (LN) - 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]

  • 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
    • 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 / Corticosteroids / Cyclophosphamide / Azathioprine / Hydroxychloroquine / Calcineurin inhibitors (e.g. tacrolimus) / Rituximab / ACE inhibitors or ARBs [9,21]
Anti-Sm antibodies
(Smith antibodies)
10 - 30% High specificity for lupus [4,8]
Antiphospholipid antibodies
(anticardiolipin, anti-Beta 2 glycoprotein I)
20 - 30% Associated with hypercoagulable state, pregnancy loss, accelerated atherosclerosis, pulmonary hypertension, and neuropsychiatric lupus. [1,3,4]
Complement levels (C3/C4) Decreased levels can
signify disease activity
Used to monitor disease activity, particularly in lupus nephritis [7]
Ribonucleoprotein antibodies
(RNP antibodies, anti-u1)
15 - 25% May be associated with a more benign disease course [4,8]
Antichromatin antibodies 50 - 90% Associated with proteinuria and drug-induced lupus [7] Skin disease - affects > 80% of patients with SLE at some point during the disease. Lupus skin disease may occur independent of systemic lupus. [10]

  • 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
Antihistone antibodies 30 - 60% Found in 95% of patients with drug-induced lupus. Present in 20% of patients with RA. [7]
N-methyl-D-aspartate receptor antibodies
(NMDA receptor antibodies)
33 - 50% Associated with neuropsychiatric lupus [4] Neuropsychiatric lupus - 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]
C1q complement
antibodies
40 - 50% Associated with kidney disease [4]
Sjögren's Antibody/Anti-SSA
(Anti-Ro)
30 - 40% Patients who are ANA-positive and who have SS-A but not SS-B are very likely to have nephritis. Found in 60 - 70% of patients with Sjögren's syndrome. [7] 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 - in low-risk patients, baseline eye exam, next exam in 5 years, then yearly. See Plaquenil for more. [12]

Sjögren's Antibody/Anti-SSB
(Anti-La)
10 - 15% Associated with congenital heart block and neonatal lupus erythematosus. Found in 50% - 60% of Sjögren's syndrome. [4,7]




Study Criteria Intervention Primary outcome Results
Belimumab
vs
Placebo
in active lupus
(BLISS-52 Study)

Lancet

PubMed abstract
Main inclusion criteria
  • Meet 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
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
Response rate at 52 weeks. Response was defined as having a reduction of at least 4 points in the SELENA-SLEDAI score, 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.

See SELENA-SLEDAI score for more.
After 52 weeks, the following was seen:
  • Overall response rates were as follows: Group 1 - 51%, Group 2 - 58%, Group 3 - 44%
  • Odds of response in Group 1 vs Group 3 was 1.55 (95%CI 1.10-2.19, p=0.0129)
  • Odds of response in Group 2 vs Group 3 was 1.83 (95%CI 1.3-2.59, p=0.0006)
  • Adverse event rates were similar between the 3 groups



  • Antinuclear antibodies (ANA)
    • ANAs are antibodies directed at various cellular components. The term, "antinuclear," is outdated because ANAs have come to encompass antibodies directed at cellular components that reside both in and outside the cellular nucleus.
    • ANAs are present in several autoimmune diseases including systemic lupus erythematosus (SLE) and inflammatory myopathies
    • ANA testing is commonly used as a screening tool for SLE because ANAs are present in > 96% of patients with SLE
    • ANAs are also present in healthy individuals
    • The dilution of sera with the ANA test indicates the amount of ANAs that are present. The higher the dilution (for example 1:640 is higher than 1:80), the higher the likelihood that the ANAs are associated with autoimmune disease.

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

    • Antinuclear antibody (ANA) patterns
      • If ANAs are present, a test can be performed where the ANAs are combined with cells. The ANAs will attach to antigens in the cells that they have been formed against. Immunofluorescence techniques are then used to illuminate the attached antibodies. Depending on the type of ANAs present, different patterns may be observed that are associated with specific autoimmune diseases.

          • 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



  • References:
  • 1 - PMID 17307106 - Lancet review 2007
  • 2 - PMID 22129255 - NEJM review 2011
  • 3 - PMID 17974690 - NEJM review 2007
  • 4 - PMID 23993190 - Autoimmune paper
  • 5 - PMID 22553077 - criteria validation
  • 6 - PMID 24126457 - ANA paper
  • 7 - Labcorp® website
  • 8 - Quest® website
  • 9 - PMID 22556106 - ACR nephritis GL
  • 10 - PMID 24616847 - Cutaneous lupus
  • 11 - PMID 20724309 - Neuro lupus
  • 12 - PMID 19892750 - EULAR monitoring GL
  • 13 - PMID 17504841 - EULAR management GL
  • 14 - PMID 23972423 - SLE treatment
  • 15 - PMID 11513909 - Plaquenil RCT
  • 16 - PMID 8239224 - Plaquenil RCT
  • 17 - PMID 10848718 - Pharmacokinetic study
  • 18 - ACR position statement 2011
  • 19 - Minocycline PI
  • 20 - PMID 25275721
  • 21 - PMID 24881804
  • 22 - PMID 26505598 - drug-induced lupus review JAMA