BOTTOM LINE

SLE is heterogenous disease with many different but characteristic organ manifestations associated with auto-antibody production and complement deposition. Patients are often pre-menopausal women presenting with characteristic features like malar (photosensitive) rash, inflammatory arthritis, cytopenias, effusions/serositis, and nephritis. History, exam, and basic investigations are key to detecting characteristic unifying manifestations and a diagnosis can be supported by the presence of autoantibodies against nucleic acids (ex: dsDNA, Smith). Virtually all patients should be ANA positive. Hydroxychloroquine is an important anchor therapy, reducing disease flares and improving long term outcomes. Immunosuppressive or newer targeted biologic therapies may be used depending on disease manifestations and to spare exposure to Prednisone. Life threatening disease manifestations (ex: cerebritis, severe hemolysis, alveolar hemorrhage) often requires more aggressive immunosuppression with high dose steroids and cyclophosphamide.
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EPIDEMIOLOGY

• ANNUAL INCIDENCE:
  • 3.58/100,000 (Canada)
  • Incidence varies by region and population under study
• PREVALENCE:
  • ~0.5/1000 (Canada)
    • African ethnicity: 2-4X higher prevalence
    • Aboriginal: 2-4X higher prevalence
    • Indo-Asian: 6-8X higher prevalence
  • Prevalence rates can vary based on ethnicity, geographic location, and study design
• AGE at onset:
  • mostly 15-45 years-old; 20% onset <15 years-old and 15% onset >55 years-old.
• SEX:
  • Female >>> male, 9:1 ratio.
• RISK FACTORS
  • Environmental:
    • Smoking, silica dust, pesticides, UV light, viral infections (EBV, CMV), gut microbiome changes, certain drugs (ex: procainamide, minocycline, hydralazine, carbamazepine, anti-TNF)
  • Genetic
    • 16X risk SLE in first-degree relatives
    • Numerous mutations: Low-frequency single-gene mutations with high risk, >100 genetic loci with small but incremental risk
    • Generally speaking, genetic variants affect:
      1) Availability of self antigens via cell clearance
      2) Activation of innate immune system
      3) Dysfunction of adaptive immune system
      4) Type 1-Interferon Pathway (increase IFN signaling or the responsiveness of immune cells to nucleic-acid sensing)
  • Sex
    • Predisposing genes on X chromosome; estrogen modulates lymphocyte activation, 14X SLE risk in men with XXY karyotype

CLINICAL MANIFESTATIONS

SLE is a heterogeneous disease that may affect nearly every organ in the body; patients can initially present with a few features and evolve over time. Clinicians must consider other etiologies for each presenting manifestation. One way to review SLE manifestations is careful consideration head to toe with a systems/anatomical approach.

—Constitutional

• Fatigue, Fever, unexpected weight loss
  • Fatigue (80-100%) and fever (50%) are common in SLE but very non-specific

—Ocular

Most common ocular manifestation: dry eyes

• Periorbital:
  • Proptosis, lid rash or swelling (blepharitis), diplopia from inflammation of lacrimal gland, extra-ocular muscles, or peri-orbital tissues
• Sclera/conjunctiva:
  • Dry eyes (keratoconjunctivitis sicca), keratitis, episcleritis, scleritis
• Uvea:
  • Anterior uveitis
• Retina:
  • Retinal vasculopathy/vasculitis (“cotton wool spots” on exam)
• Optic nerve:
  • Optic neuropathy

—Cutaneous

70% of SLE patients; Most common skin manifestation: acute cutaneous lupus rashes

• Mucosal:
  • Oral ulcers (usually painless aphthous ulcers, “canker sores”), nasal ulcers
• Acute:
  • Localized: malar rash (photosensitive rash not crossing malar folds)
  • Generalized: maculopapular eruption in sun-exposed areas, “reverse Gottron’s sign”, TENS-like, Erythema Multiforme-like, bullous
• Subacute
  • Annular scaly plaques, psoriasiform on photo-distributed areas leaving behind fading hypopigmentation after resolution of symptoms.
  • Serology: anti-Ro/SSA and anti-La/SSB association
• Chronic
  • Discoid: localized (head/neck only) generalized — most common chronic subtype
  • Hypertrophic: thick scaling over discoid lesion usually on extensor surface
  • Panniculitis/lupus profundus:
    • Panniculitis: firm SC nodules on face, shoulder, girdle, buttock
    • Lupus Profundus: panniculitis over overlying discoid lupus
  • Tumid lupus: erythematous induration without scale or follicular lupus
  • Urticarial: can look like tumid lupus
  • Lichenoid: 7 P’s, Pruritic, Planar, Polygonal, Penile, Purple, Papules and Plaques
  • Chilblain’s: red/purple macules/papules/plaques on fingers, toes, ears, calves, heels triggered by cold
• Scarring:
  • Acute lupus rashes do not scar, chronic lupus rashes do
• Drug-induced:
  • CHAT’N’PIG (CCBs/ACE/B-blocker, HCTZ, Anti-inflammatories, TNFi, NSAIDs, PPI, INFα, Griseofulvin). Isoniazid. Meythldopa.
• Histology
  Usually lymphocytic infiltration, vacuolization of basal layer, keratosis
  • Acute/Subacute: epidermal/upper-dermal lymphocytic infiltration, less follicular plugging and keratosis. Interface dermatitis.
  • Discoid: Epidermal/upper+lower-dermal infiltration, more follicular plugging, keratosis, basement membrane thickening
  • Tumid lupus: lower dermal infiltration, deep mucin deposition without significant epidermal changes
  • Panniculitis: under the dermis infiltration (subcutaneous fat)
• Association between cutaneous-only and systemic lupus
  Is this just isolated skin lupus or is the skin lupus a manifestation of underlying systemic lupus erythematosus?”

Cutaneous lupus rash	Association with SLE
Acute cutaneous lupus	90%
Subacute cutaneous lupus	50%
Discoid lupus	5-10%: Localized discoid lupus (head/neck only) 15-25%: Generalized discoidlupus
Lupus profundus/panniculitis	5-10%
Tumid lupus	rarely associated with systemic lupus

Acute lupus rashes often reflect active systemic disease elsewhere in patients with SLE

—Musculoskeletal

65-70% of SLE patients; Most common MSK manifestation: inflammatory arthritis

• Inflammatory arthritis
  • Pattern:
    Symmetrical migratory inflammatory polyarthritis of small joints; common in SLE. Non-erosive on X-ray (however, erosions can be detected on advanced imaging techniques). Can cause reducible MCP ulnar deviation (“Jaccoud arthropathy”), reducible swan-neck, soft tissue laxity.
  • Differences from RA:
    Symptoms more intermittent, migratory, with less obvious swelling and less inflammatory synovial fluid. Deformities in SLE are reducible whereas in RA they are fixed. Inflammatory arthritis in SLE can be subtle
• Osteonecrosis aka avascular necrosis
  • Can be asymptomatic or present with pain in groin (if femoral-acetabular osteonecrosis)
  • Risk factors: steroids, cyclophosphamide, antiphospholipid antibodies
  • Get X-ray, if normal and high suspicion, get MRI and if still normal ?bone scan
  • MRI is most sensitive imaging modality for early detection of AVN
  • Treatment is controversial; arthroplasty or joint preservation surgery may be required.
• Other
  • Osteoporosis/osteopenia, fractures, fibromyalgia

—Cardiac

20% of all SLE patients; Most common cardiac manifestation: pericarditis or pericardial effusion

• Coronary
  • Increased rates of coronary artery disease and MI due to traditional risk factors and SLE activity.
• Pericardial
  • (A)symptomatic pericardial effusion +/- pericarditis +/- tamponade.
  • Pericarditis usually recurrent and associated with fever.
• Myocardial
  • Myocarditis; can be minimally symptomatic (tachycardia, ECG changes, CHF); however, may also present acutely with life-threatening severity.
    • Exclude other causes of myocarditis (drugs like cyclophosphamide; coronary disease, infection).
• Valvular
  • Verrucous/Marantic (Libman-Sacks) nonbacterial endocarditis; asymptomatic or cause of valvular insufficiency, embolic events.
    • Occurs any time unrelated to disease activity
    • Can lead to significant valvular dysfunction and embolic events.

—Respiratory

40% SLE patients (20-90% reported); Most common pulmonary manifestation: pleuritis +/- effusion

• Pleura
  • Pleuritis +/- pleural effusion (usu. Exudative and bilateral, lymphocytic or PMNs)
    • Presents with pleuritic chest pain
• Diaphragm
  • Shrinking lung (?diaphragmatic weakness from myositis).
    • Rare, can develop at any time during the course of SLE with dyspnea, episodic pleurisy, and worsening lung volumes and DLCO on PFT.

• Parenchyma
  • Acute interstitial pneumonia (uncommon). Presents like typical pneumonia with patchy ground glass on CT; exclude infection (may require BAL)
  • ILD, variety of CT patterns: NSIP, UIP, OP, LIP, follicular bronchiolitis, nodular lymphoid hyperplasia.
    • Uncommon.
    • Presents with slow worsening dyspnea; may be more commonly associated with myositis antibody positivity or overlap. Rarely severe
    • PFT shows low DLCO and possible restrictive pattern.
    • Get high-res CT chest and PFTs. Rarely, can also get acute pneumonitis.
• Alveolar
  • Diffuse alveolar hemorrhage (rare).
    • Present acutely ill with hemoptysis. Can be life threatening with high mortality. Requires prompt diagnosis and treatment.
    • CT shows diffuse multifocal ground glass. BAL sequential lavage shows bleeding. Send for phospholipid antibodies, evaluate for infection, nephritis, CHF, and bleeding disorder.

• Vascular
  • VTE: Increased risk with or without phospholipid antibodies
  • Pulmonary hypertension: Can be from any WHO Group, through a variety of mechanisms including thromboembolic disease and pulmonary vasculitis.

—Gastrointestinal

Most common GI manifestation: nausea, anorexia, abdominal pain  (non-specific)

• Upper GI Tract
  • Dysphagia/dysmotility, reflux, peptic ulcer disease (may be related to steroids and NSAIDs)
  • May be due to SLE-related myositis or secondary to medications
• Lower GI Tract
  • Pneumatosis cystoides intestinalis, pseudo-obstruction, rare protein losing enteropathy (presents as hypoalbuminemia and peripheral edema)
• Liver
  • Significant liver involvement is uncommon.
  • Mild ↑ALT can mirrors disease activity elsewhere; ddx drug toxicity
  • Lupus hepatitis: rare acute ↑↑ALT, may have RNP association, ddx liver clot/APS
  • Type I autoimmune hepatitis overlap (rare)
• Pancreas
  • Acute pancreatitis (rare), ddx drug related (ex: rarely azathioprine)
• Other
  • Mesenteric vasculitis, primary peritonitis and ascites

—Hematologic

50% SLE patients; Most common: anemia

• Anemia (>50%). Most common: anemia from chronic inflammation, iron deficiency, or  hemolysis
  • Chronic inflammation
    • Mild normochromic normocytic, low reticulocyte count 
  • Iron deficiency:
    • Hypochromic microcytic low reticulocyte count; from GI/Gynecological bleeding
  • Medications:
    • Cyclophosphamide, hydroxychloroquine (rare marrow suppression or hemolysis if ↓G6PD), MMF/MPA, methotrexate, azathioprine.
  • Hemolysis:
    • 5-10% of cases. Spherocytes. ↑retics, LDH, Bili; ↓Hapto. DAT+. 
    • Warm > cold hemolysis.
  • MAHA: Microthrombi shearing RBCs, schistocytes:
    • SLE-related-TTP, drug-induced-TTP, DIC, CAPS.
  • Pure red cell aplasia:
    • Antibodies to RBC pre-cursor in bone marrow. Rare.
  • Pernicious anemia:
    • Antibodies to gastric parietal cells or intrinsic factor. Uncommon
• Leukopenia (~35%)
  • Neutropenia:
    • Common and usually mild, from viral infection, meds, hypersplenism, or immune mediated.
    • Monitor; if severe (ex: ANC <1000/uL) and worsening secondary to medication, reduce medication dose.
  • Lymphopenia:
    • Can correlate with disease activity if immune mediated; also infection or med related.
• Thrombocytopenia (16%). Most common: ITP
  • Destruction/Consumption
    • ITP: immune mediated destruction. Can precede SLE by years or as part of disease
    • Evan’s syndrome: hemolytic anemia + ITP
    • TTP
    • APS
  • Production
    • Drug induced: marrow suppression (see drug induced anemia)
  • Sequestration
    • Hypersplenism
• Pancytopenia: less common, wide differential
  • Potentially life-threatening: HLH/MAS, marrow toxicity from meds/infection, heme malignancy.
  • Mild causes: autoimmune, splenomegaly/sequestration, ↓B12

• Thrombosis (>10%)
  • Higher risk of arterial and venous thrombosis compared to general population
  • Due to traditional risk factors, disease activity, lower Protein S in SLE,  phospholipid antibodies
  • Risk of thrombosis higher if positive lupus anticoagulant and/or anticardiolipin antibodies
• Antibodies
  • aPL (antiphospholipid antibodies): 30-40% of SLE.
  • If associated with clinical recurrent vascular thrombosis or pregnancy morbidity, can give clinical diagnosis of APS (antiphospholipid antibody syndrome). See separate section on APS
• Lymph nodes, spleen
  • Lymphadenopathy 50%.
    • Reactive in cervical/inguinal/axillary. Presents at SLE onset or with flare.
    • Versus lymphoma: SLE lymphadenopathy is more prednisone responsive; not usually treated. Biopsy lymph nodes if large/growing nodes
  • Splenomegaly: 10-45%. Can reflect disease activity. Mechanism unclear.

—Neurological

Epidemiology

• Heterogenous estimates due differences in classification criteria
• Pooled prevalence 56.3% (95% CI 42.5–74.7%);
  • Varies across studies from 4-91%; due to lack of standardized consideration of non-SLE causes, inconsistent diagnostic methodology, differing definitions of neuropsychiatric lupus
• Risk factors:
  • Non-neuropsychiatric SLE activity, steroid use, male sex, concurrent non-SLE neuropsychiatric events (excluding headaches), African ancestry, Antibodies (antiphospholipid, anti-ribosomal P, Anti-Aquaporin 4)
• Onset:
  • Typically within 1-2 years of diagnosis, but can occur any time during disease
• Most common neuropsychiatric events attributable to SLE:
  • Mood disorders
  • Seizure disorder
  • Cerebrovascular disease
  • Cognitive dysfunction
  • Mononeuropathy, Cranial neuropathy

Peripheral Nervous System (8% of neuropsychiatric lupus)

• Small fiber:
  • Neuropathic pain in “stocking-glove” or patchy length-dependent distribution. EMG normal.
• Single/multi-mononeuropathy:
  • Painful sensorimotor dysfunction localized to specific nerves related to vasculitis
• Sensorimotor polyneuropathy:
  • Gradual symmetrical sensory length-dependent symptoms (feet first) spreading proximally (then arms) followed by weakness. EMG usually shows axonal-predominant pattern of injury.
• Demyelinating polyneuropathy:
  • AIDP (acute ascending motor weakness, ↓reflexes) or CIDP (slow version of AIDP)
• Autonomic:
  • Rare; gastroparesis, urinary retention, orthostatic hypotension.
• Plexopathy:
  • Very rare.

Central Nervous System (92% of neuropsychiatric lupus)

• Focal (15%)
  • Stroke:
    • Ischemic or hemorrhagic. Due to accelerated atherosclerosis, aPL antibodies, cardioembolic (Libman-Sacks), microangiopathic vasculopathy, TTP (rare), CNS vasculitis (very rare). CT/MRI, echo, carotid US, aPL testing, ?holter, CV risk factors (A1c, lipids, etc); r/o common stroke causes first.
  • Seizure:
    • Focal with complex partial seizures or secondary generalization. Risks: aPL, steroids, disease activity; metabolic, HTN, infection, stroke, vasculopathy, drugs, PRES. Get MRI, EEG, metabolic work-up (ex: Na, Cr, glucose). PRES is a significant cause of seizures in SLE.
  • Demyelinating/inflammatory syndromes
    • Myelitis: acute/subacute para/quadriparesis, sensory or bowel/bladder impairment depending on level. MR to exclude compression.  Ddx MS, NMOSD, clot/stroke, infection
    • Optic neuritis: acute vision loss/scotoma, usually relative afferent pupillary defect on exam, MR evidence of neuritis. Ddx MS, NMOSD, clot
    • Chorea: involuntary, abrupt, brief, nonstereotyped movements. +/- anti-phospholipid (aPL) positive with basal ganglia infarcts on MR.

• Diffuse (85%)
  • Delirium:
    • Wax/waning level of consciousness.  Requires broad differential, including metabolic disturbances and infections.
  • Psychiatric:
    • Psychosis; delusions, hallucinations, mania; usually. monophasic occurs early in disease, but may happen at any stage of disease. Related to lupus-inflammation,  stroke, seizure, steroids, etc
  • Cognitive impairment.
    • “Brain fog” with objective cognitive decline — up to 80% prevalence. Can be subtle and require neuropsychological testing for diagnosis
  • Aseptic meningitis:
    • Rare. Requires broad differential including drug-induced meningitis (ex: IVIG, NSAIDs)
• Complications of disease or of treatment
  • PRES (drugs, renal/hypertension, SLE), PML (drugs), infectious meningitis/cerebritis due to immunosuppression, other medication side effects (ex: mood changes from steroids)
• Other: headache, depression/anxiety, fatigue.

Attribution of neurological manifestations to SLE is challenging: what is caused by disease activity, disease complication, treatment complication, or something not SLE?

General approach: 1) Confirm diagnosis of SLE 2) Exclude all other explanations for neurological symptoms 3) Gather evidence of SLE activity elsewhere. As indicated: CSF (?infection ?multiple sclerosis) Antibodies (antiphospholipid, anti-ribosomal P, anti-AQP4) EEG, EMG or NCS Neuropsychological consultation Neuroimaging Indications for escalated immunosuppression include: refractory seizures, lupus psychosis, optic neuritis, myelitis, peripheral mono/polyneuropathy, demyelinating.  Treatment includes – antiplatelet, heparin/warfarin – Steroids, Cyclo or MMF/MPA or RTX or IVIG

—Renal

• Epidemiology
  • Prevalence:
    Up to 30-50% over disease course; 10% with nephritis develop end-stage renal disease
  • Ethnicity:
    African, Hispanic, and Asian more prevalent lupus nephritis than Caucasian
  • Age:
    More prevalent in younger onset SLE
  • Other risk factors:
    Low socioeconomic status
  • If proteinuria within first year of SLE diagnosis, 20% will have ESRD by 20 years.

• Clinical:
  • Usually presents within first 6-36 months of SLE diagnosis and spans a spectrum from silent to severe disease:
    • Silent nephritis: normal urinalysis and renal function
    • Asymptomatic abnormal urinalysis (proteinuria, hematuria, pyuria, with or without casts or creatinine elevation
    • Symptomatic sub-nephrotic or nephrotic-range proteinuria, red cell casts, hypertension, and renal dysfunction.
• Diagnosis
  • Clinically:
    SLE + urinary sediment (proteinuria, hematuria +/- casts, leukocytouria)
    May have hypertension, increasing creatinine, declining GFR, elevated dsDNA and low complements
  • Definitions of nephritis:
    • ACR 1982: Proteinuria (0.5g/d or 3+ dipstick) or urinary casts
    • SLICC 2012: Proteinuria 0.5g/d (per protein/creatinine ratio or 24h urinary protein) or RBC casts
    • 2019 ACR/EULAR: ANA+ and biopsy-proven proliferative class III or IV lupus nephritis
  • Biopsy important to diagnose and classify nephritis with treatment implications; indications:
    • Increasing creatinine without compelling alternate cause
    • Proteinuria ≥0.5g/24-hour
    • Proteinuria ≥0.5g/24-hour + hematuria ≥5 RBC/hpf or
    • Proteinuria ≥0.5g/24-hour + RBC casts
  • Repeat renal biopsy: debated, but could consider if
    • Suspected flare of nephritis when previously in remission
      • Increased proteinuria, hematuria, and/or worsening kidney function
    • Worsening renal function despite ≥6 months of appropriate treatment
      • Ongoing/worsening proteinuria, hematuria, and/or decreased kidney function
    • Worsening renal disease in patient with previously known Class II or V lupus nephritis (might suggest transformation to proliferative nephritis requiring treatment modification)
    • Assessing disease activity or chronicity
    • Desire to inform decision about treatment tapering in stable patients
• Differential Diagnosis: Mimics of immune-complex mediated lupus nephritis
  • Lupus podocytopathy: 1.3% of lupus nephritis, nephrotic syndrome in SLE that on kidney biopsy shows diffuse foot process effacement and no subendothelial or subepithelial immune deposits.
  • aPL antibody-mediated nephropathy, thrombotic microangiopathy
  • Diabetic nephropathy
  • Hypertensive nephrosclerosis
  • Drug toxicity
  • IgA Nephropathy
  • Thin basement membrane disease
  • Collapsing glomerulosclerosis

CLASSIFICATION OF LUPUS NEPHRITIS (2003 International Society of Nephrology/Renal Pathology Society )

CLASS	DEFINITION	HISTOLOGY	CLINICAL
I	Minimal mesangial	Normal LM, mesangial immune deposits on IF	∙ None
II	Mesangial proliferative	Mesangial hypercellularity Mesangial >>  subepithelial/subendothelial immune deposits on IF	∙ Microscopic hematuria +/- proteinuria ∙ Rare hypertension
III	Focal – active or chronic	Focal, segmental or global endocapillary or extra-capillary GN Glomeruli <50% affected Focal subendothelial immune deposits +/-mesangial alterations on IF	∙ Microscopic hematuria and proteinuria ∙ +/- Hypertension. +/- nephrotic syndrome ∙ ↓ renal function
IV	Diffuse segmental (IV-S) Diffuse global (IV-G) – active or chronic	Diffuse, segmental or global endocapillary or extra-capillary GN Glomeruli ≥50% affected Diffuse subendothelial immune deposits +/-mesangial alterations on IF	∙ Microscopic hematuria, proteinuria, casts ∙ Hypertension, often nephrotic syndrome ∙ ↓ renal function, often ↑dsDNA, ↓C3, C4
V	Membranous	Global or segmental subepithelial immune deposits	∙ Proteinuria, usually nephrotic +/- hematuria ∙ Renal function usually normal
VI	Advanced sclerotic	≥90% of glomeruli globally sclerosed without residual activity	∙ Usually proteinuria and hematuria ∙ End stage chronic kidney disease

—Infection

• Higher infection risk due to disease (ex: leukopenia, hypocomplementemia) and drug-specific factors (immunosuppression with steroids or other immunosuppressives); skin, respiratory, urinary infection
• All should get routine vaccinations (influenza, pneumococcal, herpes zoster, HPV), consider Hep B and C screening.

—Malignancy

• Cervical cancer 1.5X more prevalent in SLE patients
• Increased risk of hematological, lung, thyroid, liver, and vulvovaginal cancer
• Decreased risk of breast and prostate cancer

INVESTIGATIONS

• CBC
  • Disease or drug-related cytopenias
  • ↓Hb, ↓WBC (neutropenia, lymphopenia), ↓PTL.
  • If ↓Hb, consider sending hemolytic markers (LDH, bilirubin, smear, haptoglobin)
• ALT
  • Mostly for baseline; especially if starting potentially hepatotoxic meds
• CK
  • Baseline, ?myositis
• Creatinine, urinalysis, urine ACR or Urine PCR
  • In SLE patients without known kidney disease, screen for proteinuria at least every 6-12 months or if experiencing extra-renal flaures
  • If active urine sediment (see indications above) send for renal biopsy.
  • Treat empirically for lupus nephritis while awaiting renal biopsy results if acutely ill and high clinical suspicion (ex: AKI, hypertension, RBC casts).
• ESR, CRP
  • ESR: may rise with disease flare; may remain elevated if monoclonal gammopathy/paraproteinemia
  • CRP: usually normal or mild elevation with disease flare ≤6xULN.
    If high, consider infection, malignancy, systemic vasculitis, or significant serositis
• Complement
  • C3, C4 can be low and can reflect disease activity
  • C3, C4 high with infection
• Antibodies
  • ANA
    • Virtually all SLE patients should be ANA positive; ideally by indirect immunofluorescence testing
    • Very rare exceptions include: severe proteinuria/hypogamma (not enough immunoglobulin to bind Hep-2 cells on assay; goes positive with renal treatment), after cytotoxic therapy or remission
    • ANA positive at 1:80 titre in ~15-20% of normal healthy population (U.S.)
  • dsDNA
    • 50-70%. Specific. Reflects disease activity in some, esp lupus nephritis patients
    • With new assays (e.g. Multiplex assays), low positive dsDNA levels are found in non-SLE diagnoses (ex: infection or other immune disease like rheumatoid arthritis). New assays have reduced the specificity of dsDNA testing
    • It is important to know which assay was utilized when evaluating a patient.
  • ENA Panel
    • Sm (20-30%): SLE specific; renal neurologic, vasculitis, and hematologic SLE.
    • RNP (30-35%): SLE; overlap mixed connective tissue disease if at high titre
    • Ro/SSA (30%): neonatal lupus, fetal heart block, photosensitivity, Sjogren’s
    • La/SSB (15%): Neonatal lupus, Sjogren’s; associated with anti-Ro
    • Ribosomal P (15%): specific for SLE, possible association with neuropsychiatric lupus
  • Other
    • Histone: SLE and drug-induced lupus
    • Phospholipids (30-40%): thrombosis, miscarriages, stroke, thrombocytopenia
    • RF and CCP antibodies: overlap rheumatoid arthritis
• Other
  • Imaging: Consider BMD, X-ray chest if indicated. Further imaging not routine unless indicated from presentation. Echocardiogram if suspicion for Libman-Sacks endocarditis.
  • Metabolic: Baseline Vitamin D, TSH
  • Cardiovascular risk factors: monitor blood pressure, lipids, HbA1c, smoking history
  • Miscellaneous, if indicated: biopsy (skin, kidney), PFTs, EMG, ECG, MRI (if suspected neuropsychiatric lupus)

DIAGNOSIS

SLE is a clinical diagnosis. It is a heterogenous disease of varying severity that can affect multiple organs and requires artful consideration of clinical evidence. Probability of SLE increases in a patient (often a pre-menopausal female) presenting with a characteristic unifying constellation of symptoms and signs on history and exam—acute lupus rashes and inflammatory arthritis are common but not universal. Diagnosis is further supported by positive serologic studies and excluding alternate diagnoses.

CLASSIFICATION CRITERIA

—Diagnostic versus Classification Criteria

Diagnostic criteria	Used on individual patients to make a diagnosis (ex: DSM criteria in psychiatry).
Classification criteria	Standardized way to recruit a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease  In reality, classification criteria can be useful for documenting patients’ clinical features and be helpful when combined with rigorous clinical reasoning for a SLE diagnosis.

2 hypothetical illustrative examples:

Elderly 75 year-old man has respiratory viral infection with viral arthritis and pleuritis with pleural effusion. Viral infection causes lymphopenia. ANA 1:80.

Young 35 year-old woman has new Raynaud’s and malar rash. Review otherwise negative. All investigations normal, except ANA 1:640, ENA negative.

The elderly gentleman may meet lupus classification criteria (both 2019 ACR/EULAR and 2012 SLICC); however clinical reasoning tells us that new-onset SLE in a 75 year-old man is unlikely and this is a para-infectious illness. The young woman does not meet classification criteria for SLE, but clinical reasoning tells us that an early SLE/undifferentiated systemic rheumatic disease is possible given her age, sex, and malar rash with ANA+.

—2019 ACR/EULAR SLE Criteria:

96% sensitive, 93% specific. SLE classified if ≥10 points and ≥1 clinical criterion

Entry criterion: must have ANA ≥1:80 on Hep-2 cells or equivalent test ever.

At least 1 clinical criterion is required; additive criteria are counted towards total score

• Do not count a criterion if there is a more likely explanation than SLE.
• Occurrence of a criterion on ≥1 occasion is sufficient.
• Criteria need not occur simultaneously.
• Within each domain (eg, mucocutaneous, complement proteins), only the highest-weighted criterion is counted toward the total score if more than 1 is present.

CLINICAL DOMAIN	CRITERION	WEIGHT
Systemic	Fever	2
Hematologic	Leukopenia	3
	Thrombocytopenia	4
	Autoimmune hemolysis	4
Neuropsychiatric	Delirium	2
	Psychosis	3
	Seizure	6
Mucocutaneous	Nonscarring alopecia	2
	Oral ulcers	2
	Subacute cutaneous or discoid lupus	4
	Acute cutaneous lupus	6
Serosal	Pleural or pericardial effusion	5
	Acute pericarditis	6
MSK	Inflammatory arthritis	6
Renal	Proteinuria >0.5 g per 24 hours	4
	Class II or V lupus nephritis	8
	Class III or IV lupus nephritis	10
IMMUNOLOGIC	CRITERION	WEIGHT
Phospholipid AB	Anticardiolipin or anti B2GP or lupus anticoagulant	2
Complement	Low C3 or C4	3
	Low C3 and C4	4
SLE antibodies	Anti-dsDNA or Anti-Smith	6

—SLICC 2012: 97% sensitive, 84% specific.

≥4/17 criteria (≥1 clinical and ≥1 immunologic) or lupus nephritis on biopsy

CLINICAL	DEFINITION	FREQUENCY
Acute cutaneous	Malar rash, bullous lupus, TEN variant, maculopapular, photosensitive, subacute cutaneous	60-70%
Chronic cutaneous	Classic discoid, hypertrophic, lupus panniculitis/profundus, mucosal, lupus erythematosus tumid, chilblains lupus, discoid/lichen planus overlap.	15-30%
Alopecia	Nonscarring, diffuse hair thinning or visible broken hairs	30-50%
Oral ulcers	Oral (palate, buccal, tongue) or nasal ulceration	15-45%
Synovitis	≥2 peripheral joints	90%
Serositis	Pleuritic chest pain for >1 day or pleural rub or imaging of effusion Pericarditis on ECG, pericardial rub, pericardial effusion	30-60% 10-40%
Renal	Persistent proteinuria ≥ 0.5 g/day (24 hour urine or urine protein/creatinine ratio) or red blood cell casts	40-60%
Neuro	Seizures, psychosis, myelitis, mononeuritis multiplex, peripheral or cranial neuropathy, acute confusional state	15-20%
Hemolytic anemia	Direct Coombs positive	5-10%
Leukopenia	Leukopenia < 4000/mm3 at least once, or Lymphopenia < 1000/mm3 at least once	15-20% 15-20%
Thrombocytopenia	Platelets < 100,000/mm3	15-20%
IMMUNOLOGIC	DEFINITION	FREQUENCY
ANA	Above lab reference range	98%
Anti-dsDNA	Above lab reference range (or >2X enzyme-linked immunosorbent assay reference range)	60-70%
Anti-Sm	Positive	20-30%
Phospholipid AB	Any one of · Positive test for lupus anticoagulant · False-positive test result for rapid plasma regain · Medium- or high-titer anticardiolipin antibody level (IgG, IgM, or IgA) · Positive test result for anti-β2-glycoprotein I (IgG, IgM, or IgA)	30-50%
Complement	Low C3, low C4, or low CH50	55-60%
Direct Coombs	In absence of hemolytic anemia	10-30%

DISEASE MEASURES

• By context:
  • Research trial measures: BILAG, BICLA, SRI-4
  • Clinical measures: SLEDAI-2K, LLDAS, DORIS
• By purpose:
  • Disease Activity: SLEDAI, SLEDAI-2K, SRI-4, LLDAS, BILAG/BICLA, DORIS remission
  • Damage: SLICC/ACR-DI (SDI), BILD

TREATMENT

—MONITORING DISEASE

• Clinical Assessment:
  • Assess known disease features, identify new symptoms or complications
  • Detailed history, review, and physical exam, including musculoskeletal, cutaneous, cardiovascular, lymphatic, renal and neuropsyciatric symptoms
  • Carefully consider attribution of each feature to active SLE versus chronic damage, drug toxicity, or other comorbidity.
• Laboratory tests, including:
  • CBC:
    • To monitor for cytopenias (for example, related to disease activity or drug toxicity)
    • If anemia present, consider sending for hemolytic markers (LDH, bilirubin, smear, haptoglobin)
  • Creatinine, urinalysis, urine albumin:creatinine ratio
    • At least every 6-12 months in patients without known renal lupus or if experiencing extra-renal flares to assess for renal lupus; protein quantification helps assess severity of glomerular disease
  • ALT:
    • May be necessary to monitor for drug toxicity
  • ESR, CRP:
    • ESR may increase with dsiease flare and may remain elevated if paraproteinemia is present
    • CRP usually normal or mildly elevated; very high CRP may suggest infection, systemic vasculitis, or significant serositis
  • C3, C4:
    • Low complement may indicate disease activity in some patients
    • High complement may indicate infection
  • dsDNA:
    • Increases in dsDNA may indicate disease activity in some patients
• Disease indices
  • Consider using a validated disease activity index (ex: SLEDAI-2k)
  • Guidelines from ACR/EULAR recommend Treat-to-Target strategy for best outcomes, particularly LLDAS, Doris Remission
• Medication monitoring
  • Monitor adherence and tolerances
  • Monitor for toxicity (ex: eye exams for hydroxychloroquine maculopathy)
  • Monitor for complications of glucocorticoid toxicity (osteoporosis, diabetes, etc.)

—LIFESTYLE, PREVENTION, COMORBIDITY MANAGEMENT

• Lifestyle
  • Exercise
    • Incremental moderate/vigorous aerobic and strength training exercise at least several times weekly tailored to the individual’s disease activity and physical capacity.
  • Diet:
    • No proven “anti-inflammatory diet”; however a diet high in vegetables and fruits such as a “Mediterranean diet” may reduce risk of cardiovascular disease. Vitamin D supplementation and 3-servings of daily calcium may be indicated depending on steroid use and bone density
  • Sun protection:
    • UV rays can flare lupus; patients should use broad-spectrum sunscreen with SPF 50 or higher and wear protective clothing
  • Smoking cessation:
    • Smoking associated with active disease and adds to CV and thrombosis risk
• Patient Education and Support
  • SLE patients often benefit from psychosocial support, including counseling and support groups, to manage the psychological burden of the disease.
  • Ongoing education about disease management, lifestyle modifications, and the importance of medication adherence.
• Prevention and Comorbidity Management
  • Vaccinations
    • Routine vaccinations as indicated per general population
    • Live vaccines are generally contraindicated in patients on immunosuppressive therapy, and if needed, may require interruption of therapy (at risk of disease flare)
    • Consider evaluating vaccination status before initiating immunosuppressive therapies
  • Cardiovascular risk assessment:
    • Assess cardiovascular risk factors including obesity, smoking status, arterial hypertension, diabetes, and dyslipidemia
    • Estimate risk according to national guidelines (Canadian Cardiovascular Society, Framingham risk calculator)
    • Periodically repeat screening and initiate management as per usual national guidelines for general population (ex: for hypertension, dyslipidemia, and diabetes)
  • Osteoporosis screening:
    • Estimate fracture risk and treat according to national guidelines (Osteoporosis Canada, FRAX calculator)
    • All patients ≥50 years: assess osteoporosis risk factors and signs of undiagnosed vertebral fracture
    • Osteoporosis risk factors:
      • BMI < 20 kg/m2
      • Prior low trauma fracture after age 40 years
      • Falls ≥ 2 in the last year
      • Prednisone ≥5mg/d for ≥3 months
      • Current smoking or alcohol ≥3 units/day
      • Parent had hip fracture
      • Secondary Osteoporosis (includes RA, and SLE)
    • Signs of possible vertebral fracture
      • Prospective height loss > 2 cm or historical > 6 cm
      • Rib-to-pelvis distance ≤ 2 finger-breadths in midaxillary line
      • Occiput-to-wall distance > 5 cm
    • Obtain Bone Mineral density if:
      • Previous hip or spine fracture, or ≥2 fracture events
      • Age 50–64 yr with previous fracture or ≥ 2 risk factors
      • Age 65–69 yr with 1 risk factor
      • Age ≥ 70 yr with no risk factors
    • Treatment
      • Exercise, Calcium 1200mg/d (preferably via diet), Vit D 1000IU/day
      • Pharmacotherapy: Bisphosphonates first line, further treatment (bisphosphonate holiday, denosumab, romosozumab and anabolic agents) per national guidelines.
      • Repeat BMD in 3 years if on pharmacotherapy, 3-5 years if not on pharmacotherapy
  • Contraception:
    • Hormonal contraception (favouring progestin-only methods or intrauterine devices) is permissible in SLE patients with stable/inactive disease, negative antiphospholipid antibodies, and low risk of thrombosis. 
    • The presence of antiphospholipid antibodies is an absolute contraindication to estrogen-containing contraceptives due to substantially increased thrombotic risk, and the safety of estrogen-containing oral contraceptives in SLE remains incompletely defined even in antibody-negative patients.
    • Intrauterine devices (both levonorgestrel-releasing and copper) represent highly favorable contraceptive options across all SLE disease states and antiphospholipid antibody profiles.
  • Cancer
    • Pap smears for all sexually active patients per national guidelines
    • Strongly recommend HPV vaccine for all SLE patients
    • Other age appropriate cancer screening as indicated (ex: mammograms, colon cancer screening)

—PHARMACOLOGIC

—All patients

• HYDROXYCHLOROQUINE 5mg/kg/day. Particularly helpful for skin and joint manifestations. Many benefits include:
  • Reduces flares, organ damage, seizures, hyperlipidemia, thrombosis
  • Improves Mycophenolate mofetil response
  • Improves survival, mortality
  • Safe in context of pregnancy and improves pregnancy outcomes, reduces risk of congenital heart block in patients with SSa+/SSb+
  • Patients will require regular retinopathy screening at baseline then repeated yearly, or yearly starting after 5 years of exposure
• Glucocorticoid: minimized to 5mg/d prednisone equivalent or ideally withdrawn

—Disease activity approach to treatment

Definitions of Disease Severity (EULAR 2023) These definitions should be used in conjunction with clinical judgment and patient-specific factors

• Mild Activity
  • Constitutional symptoms
  • Mild arthritis
  • Rash ≤9% BSA
  • PLTs 50–100×10⁹/L
  • SLEDAI <6
  • BILAG C or ≤ 1 BILAG B manifestations
• Moderate Activity
  • Moderate–severe arthritis ‘RA-like’
  • Rash 9%–18% BSA
  • PLTs 20–50×10⁹/L
  • Serositis
  • SLEDAI 6–12
  • ≥2 BILAG B manifestations
• Severe Activity
  • Major organ threatening disease (cerebritis, myelitis, pneumonitis, mesenteric vasculitis)
  • Thrombocytopenia PLTs <20×10⁹/L
  • TTP-like disease or acute haemophagocytic syndrome
  • Rash >18% BSA
  • SLEDAI >12
  • ≥1 BILAG A manifestations

Treatment options in non-renal lupus, by disease activity (In addition to hydroxychloroquine and short-term steroids as needed)

• Mild Activity
  • Methotrexate 20-25mg weekly
  • Azathioprine 1.5-2.0mg/kg/day ** pregnancy compatible
  • Mycophenolate Mofetil 500-1500mg BID
  • Belimumab 10 mg/kg every 4 weeks or 200mg SC weekly
  • Anifrolumab 300mg IV q4 weeks
• Moderate Activity
  • Methotrexate
  • Azathioprine
  • Mycophenolate Mofetil
  • Belimumab
  • Anifrolumab
  • Cyclosporine ≤2mg/kg/d
• Severe Activity
  • Prednisone 0.5-1.0mg/kg/d and/or methyl-prednisolone 500mg/d IV x 1-3
  • Mycophenolate Mofetil 500-1500mg BID
  • Cyclophosphamide
  • Belimumab
  • Anifrolumab (not severe active lupus nephritis or neuropsychiatric SLE)
  • Role of Rituximab in SLE is uncertain and is often given “off-label”
• Other
  • Raynaud’s: lifestyle modification (including avoiding significant cold expsosure) calcium channel blockade, sildenafil
  • Recurrent pericarditis: can benefit from colchicine 0.6mg BID x 6 months
  • Phospholipid antibody syndrome: refer to the phospholipid antibody syndrome chapter

—Organ specific treatment

• Skin
  • Topical corticosteroids, topical calcineurin inhibitors, hydroxychloroquine;
  • Refractory: anifrolimab, belimumab, methotrexate, dapsone, mycophenolate
• Neuro
  • Inflammatory: steroids, cyclophosphamide, rituximab, mycophenolate mofetil; IVIG may be used as an adjunctive treatment
  • Atherothrombotic/aPL-related: anti-platelet/anticoagulation
• Cytopenias
  • Acute severe thrombocytopenia: high dose steroids (ex: prednisone 0.5-1mg/kg/d), IVIG
  • Maintenance: mycophenolate, azathioprine. Cyclosporine; refractory: rituximab, cyclophosphamide
• Thrombosis
  • Primary prevention: high-risk aPL (persistently positive medium/high titre or multi-positive apL): ASA 81mg/d if no bleeding risk
  • Secondary prevention: same approach as anti-phospholipid antibody syndrome (see chapter)

—Lupus Nephritis:

Choose treatment based on 2003 International Society of Nephrology/Renal Pathology Society Class

All lupus nephritis patients should be on hydroxychloroquine and a renin-angiotensin-aldosterone system inhibitor (ACEi or ARB)

• Targets
  • 3 months: ≥ 25% reduction of proteinuria from baseline
  • 6 months: ≥ 50% reduction of proteinuria from baseline
  • 12 months: Urine protein/creatinine ratio <500-700mg/g “complete clinical response”
  • Patients with nephrotic-range proteinuria at baseline may need additional 6–12 months to reach complete clinical response; prompt switches of therapy are not necessary if proteinuria is improving
• Class I or II
  • No specific lupus therapy; treat underlying disease activity. Consider adding ACE inhibitor to hydroxychloroquine
• Class III or IV: Proliferative Nephritis
  • Induction (first 3 months)
    PREFERRED: “TRIPLE THERAPY”
    • IV Methylprednisolone 0.5g/d x 2 days,
      THEN
    • PO Prednisone 0.3-0.5mg/kg/d tapering to ≤5mg/day by 6 months,
      PLUS
    • MMF 2-3g/d x 3 months
      PLUS
    • Belimumab 10mg/kg/month or
      Voclosporin 23.7mg BID or
      Obinutuzumab 1000 mg IV on day 1, week 2, week 24, week 26, and then every 6 months thereafter or
      tacrolimus (target trough level, 4-10 ng/mL)
    • CNIs are preferred for patients with heavy proteinuria, while belimumab is favored for those with significant extra-renal manifestations
  • Induction (first 3 months)
    ALTERNATE: “TRIPLE THERAPY”
    • IV Methylprednisolone 0.5g/d x 2 days, THEN
    • PO Prednisone 0.3-0.5mg/kg/d tapering to ≤5mg/day by 6 months, PLUS
    • Low-dose Cyclophosphamide (“Eurolupus protocol”) PLUS
    • Belimumab 10mg/kg/month
  • Induction:
    “DUAL THERAPY” if TRIPLE THERAPY not tolerated
    • Glucocorticoids plus either CYC or MMF
  • Maintenance (for ≥3 years)
    • ↓proteinuria by ≥ 25% and stable and/or improving kidney function after 3 months of induction?
      • YES:
        MMF 2-3g/d x 3 more months, then MMF 2g/d.
        If started with CYC, switch to MMF at 2g/d.
      • NO:
        MMF 2-3g/d, increase prednisone to 0.3-0.5mg/kg/d,
        If initial TRIPLE THERAPY: change to ALTERNATE TRIPLE THERAPY
        If initial DUAL THERAPY: escalate to TRIPLE THERAPY
    • Duration:
      • MMF x for ≥3 years; Belimumab x ≥3 years; volcosporin x ≥3 years
    • Refractory
      • Confirm adherence to medication regimen
      • SWITCH initial induction to alternate (MMF versus CYC), or consider Rituximab 1g IV day 0 and 14
    • Adjunctive Treatment for renal protection
      • ACE inhibitor or Angiotensin receptor blocker
      • Vitamin K antagonist or heparin as indicated if concomitant APS nephropathy
• Class V: Membranous Nephritis
  • Sub-nephrotic Proteinuria
    • Disagreement in literature; some may not treat with immunosuppression if <1g/d urine protein
    • Consider treating like nephrotic range proteinuria below, especially if >1g/day urine protein
  • Nephrotic-range Proteinuria
    PREFERRED: “TRIPLE THERAPY”
    • IV Methylprednisolone 500-2500mg total, THEN
    • PO Prednisone 20mg/d tapering to ≤5mg/day by 3 months, PLUS
    • MMF 2-3g/d, PLUS
    • Voclosporin 23.7mg BID or tacrolimus (target trough level, 4-10 ng/mL)
    • Refractory: cyclophosphamide, tacrolimus, or rituximab
  • ALTERNATE: “TRIPLE THERAPY”
    • IV Methylprednisolone 500-2500mg total, THEN
    • PO Prednisone 20mg/d tapering to ≤5mg/day by 3 months, PLUS
    • MMF 2-3g/d + Belimumab 10mg/kg/month, OR
    • Low dose cyclophosphamide + Belimumab 10mg/kg/month
  • “DUAL THERAPY” if TRIPLE THERAPY not tolerated
    • Glucocorticoids plus either CYC or MMF

PROGNOSIS

• 3X higher all-cause mortality compared to general population (Standardized mortality ratio 2.98, 95% CI 2.32–3.83)
• Highest risk of death due to renal disease (8X), followed by infection (5X) and cardiovascular disease (3X)
• Prognosis adversely affected by:
  • Sex:
    • Men have more severe manifestations (neuro, vasculitis, clots, renal, cytopenias)
  • Ethnicity:
    • African, Asian, Hispanic, and Aboriginal patients get SLE earlier with more acute and severe manifestations than Caucasian patients. African and Hispanics have worse renal prognosis.
  • Social:
    • Low socioeconomic background have higher rates of renal disease and mortality
    • Limited access to specialized care can adversely affect outcomes, particularly in underserved populations
  • Age:
    • Young age at diagnosis
  • Disease specific:
    • Lupus nephritis, high disease activity, associated hypertension or anti-phospholipid antibodies/syndrome
  • Treatment Adherence: 
    • Poor adherence to treatment regimens is a significant factor affecting prognosis and should be emphasized
  • Comorbidities: 
    • Presence of comorbid conditions such as cardiovascular disease and chronic infections also impacts prognosis and should be considered

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