SLE

Question 1

Define SLE

Answer 1

A chronic autoimmune disease, characterized by multisystem clinical manifestations, as the complex pathogenesis can cause inflammation of any organ. The key pathogenesis relates to a dysfunctional immune system that results in overproduction of autoantibodies usually against cell nuclei, deposition of antibodies into tissues and complement activation and induction of chronic inflammation, ultimately culminating in end-organ damage and dysfunction.

Question 2

Briefly describe the pathophysiology of SLE

Answer 2

An interplay of genetic factors and environmental factors can trigger the inflammatory process.
Inflammatory process engages the innate and adaptive immune systems.
These interacting roles of innate and adaptive immunity allow the production of autoantibodies, acute tissue inflammation, and damage. Dendritic cells, macrophages, and B cells are involved in innate immunity, whilst subsets of T and B lymphocytes are involved with adaptive immunity. B cells are certainly central players in the pathogenesis. Loss of self-tolerance in B cell development contributes to the development of autoimmunity. B cells also play a key role in T cell activation and contribute to the production of inflammatory cytokines.

Question 3

Briefly describe the epidemiology of SLE

Answer 3

• Prevalence influenced by age, gender, race, and genetics
• Prevalence: 1:2000 (<0.1% population)
• Peak incidence 14-45 years
• Black > White (1:250 vs. 1:1000) & SE Asian populations
• Female predominance 10:1
• Gene associations, Family History
• Severity is equal in male and female

Question 4

List the components of ACR criteria

Answer 4

1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Renal disease.
   
   • > 0.5 g/d proteinuria
   • ≥ 3+ dipstick proteinuria
   • Cellular casts
8. Neurologic disease.
   
   • Seizures
   • Psychosis (without other cause)
9. Hematologic disorders.
   
   • Hemolytic anemia
   • Leukopenia (< 4000/uL)
   • Lymphopenia (< 1500/uL)
   • Thrombocytopenia (< 100,000/uL)
10. Immunologic abnormalities
    
    • Positive LE cell
    • Anti-ds-DNA
    • Anti-Sm
    • Any antiphospholipid
11. Positive ANA (95-100%)

Question 5

Discuss issues with ACR criteria

Answer 5

• Many patients could only fulfill 3 or less of the old ACR criteria who were then termed undifferentiated CTD or lupus like disease AND
• Could have a Dx of SLE made without an immunological criteria
• Over-representative of skin findings
• Under-representative of other organs (CNS)
• Which then lead to the 2012 SLE International Collaborating Clinics(SLICC) revised classification criteria

Question 6

List the components of the SLICC criteria and why it is an improvement on ACR

Answer 6

• Expansion on neuropsych manifestations
• Haematology and immunological criteria are expanded
• Need 4 or more criteria with at least **1 clinical +1 **immunological laboratory criteria EXCEPT WHEN Biopsy-proven lupus nephritis
• Criteria are cumulative and need not be present concurrently

1. butterfly rash/malar rash
2. photosensitivity
3. skin biopsy (Acute cutaneous lupus rash)
4. subacute cutaneous lupus rash
5. chronic cutaneous lupus - discoid rash
6. chilblains lupus
7. livedo reticularis and vasculitis
8. oral or nasal ulcers
9. non scarring alopecia
10. arthritis or tenderness
11. nons pecific lupus MSK manifestations
12. other organs: serositis, renal neurologic
13. haematological and immunological criteria

Question 7

Describe butterfly or malar rash

Answer 7

1. Acute Cutaneous Lupus (first example lupus malar “butterfly” rash)
   - Occurs in up to 50%, usually after UV exposure, may precede other symptoms
   - Fixed erythema, flat or raised, over the malar eminences (cheeks/nose), tending to spare the nasolabial folds
   - May be associated with generalized body erythematous maculopapular rash
   - Worsening of rash usually accompanies a flare of systemic disease

Question 8

Describe photosensitivity

Answer 8

• Refers to the development of a rash after exposure to UV-B radiation in sunlight or fluorescent lights
• Lymphocytes are activated by light and various molecules altered
• Heightened activity results in tissue damage and exposure of an autoantigen that further stimulates immune complex deposition

Skin Biopsy (Acute Cutaneous Lupus rash)
- The histopathology may be unimpressive; basal layer vacuolation and follicular plugging, mucin-dermal deposition
- Immunofluorescence may detect immunoglobulins and complement at the dermo-epidermal junction giving a “lupus band test” in lesional and non-lesional skin in active lupus

Question 9

Describe subacute cutaneous lupus rash

Answer 9

• Lesions begin as small, erythematous, slightly scaly papules that evolve into either a psoriaform (papulosquamous) and/or annular lesions coalesce to form characteristic ring or polycyclic patterns
• Usually neck, shoulders, upper torso, forearms (not face)
• Does not scar but can leave depigmentation
• Extremely photosensitive(UVL)
• Also association with drug-induced lupus, SSA autoantibody, arthritis

Question 10

Describe chronic cutaneous lupus

Answer 10

• Can occur alone or with other features of SLE, localized(above the neck) or generalized
• Discrete, erythematous plaques covered by a scale that extend into hair follicles (follicular plugging)
• Slowly expand with active peripheral inflammation then heal leaving central scars, atrophy, telangiectasia and hyper or de-pigmentation

Question 11

Describe other cutaneous manifestations

Answer 11

Some lupus non-specific vascular lesions are a bad sign for other organ involvement:
- Livedo Reticularis: Reddish cyanotic, reticular pattern – vasospasm of dermal ascending arterioles. Fine but…
- Livedo Vasculitis: Capillary walls thickened and narrowed sometimes with intravascular thrombi. Bad sign.

Also chilblains lupus

Question 12

describe oral or nasal ulcers

Answer 12

• Causes excluded: herpes virus, Behcet’s, IBD, etc.
• Locations: Oral (palate, buccal, tongue) or nasal ulceration.
• Usually painless, observed by a physician.

Question 13

Describe non-scarring alopecia

Answer 13

• Distinguished from scarring alopecia from discoid lupus (now in criterion 2).
• Non-scarring.
• Associated with lupus activity – hair thinning or hair fragility with visible broken hairs e.g., hair frontal line which easily fractures.

Question 14

Describe lupus arthritis

Answer 14

• Common (95%), often migratory (a.k.a comes and goes), gone in 24 hours.
• Usually affects finger PIPs (or tenosynovitis), wrists, knees.
• The degree of tenderness/pain exceeds objective physical findings.
• Rarely erosive on x-ray.
• If hand deformity, it is reducible (Jaccoud’s) ^[an issue of ligaments, but can mimic RA], due to lax tendons, ligaments, and joint capsule causing instability.
• Association with SSA/SSB ^[aka Ro and La] autoantibodies, longstanding disease.

Question 15

Describe other nonspecific MSK manifestations

Answer 15

• Avascular Necrosis: Most commonly affects the femoral head, rarely humerus, often bilateral. Begins by interruption of blood supply to the bone, followed by demineralization, trabecular thinning and, if stressed, collapse. Initially asymptomatic (visible on MRI) then with collapse pain (e.g., in groin and visible then on X-ray). Risk factors include SLE, steroids.
• Osteoporosis: Loss of trabecular bone. Risk factors include SLE, age, post-menopausal, steroids, higher lupus disease activity, renal disease, less UV exposure. Symptomatic if fracture occurs. Detection with bone mineral density (DEXA) test.
• Muscle Disease: Severe myositis and muscle weakness uncommon. Myalgia and mild muscle weakness very common. Steroid myopathy common. Fibromyalgia also commonly affects quality of life.

Question 16

Describe the haematological and immunological criteria

Answer 16

e.g. haemolytic anaemia, leukopenia, thrombocytopenia.
- also the presence of autoantibodies ****
- Immunological Criteria:

1. ANA above laboratory reference range
2. Anti-dsDNA above laboratory reference range, except ELISA: twice above laboratory
3. Anti-Sm
4. Antiphospholipid antibody: any of the following
5. Low complement
6. Direct Coombs test in the absence of hemolytic anemia

Question 17

Describe the principles of treatment for SLE

Answer 17

The treatment is still limited and there is a clear need for a Treatment to Target strategy for the disease process (similar to Rheumatoid Arthritis) versus drugs used to treat symptoms.

The general principles include monitoring disease activity e.g. via autoantibodies and clinical signs (Aim remission (SLEDAI REM<2, LDA 2-4)), preventing flares of disease but not treating serology alone, preventing damage (15-20% irreversible organ dysfunction 1st 2 years, 40-50% in 5 years), limiting steroid use and tapering off ASAP, and using antimalarial drugs (hydroxychloroquine) at all stages.

Additional needs include monitoring for adverse therapy side effects & treating infection, osteoporosis, monitoring for & treating co-existent vascular risk factors (BP, lipids, smoking), if associated hypocomplementemia – pneumococcal immunization, if thromboembolism-anticoagulation with aspirin, warfarin, heparins, NOACs; photo-protective measures (Sunscreen creams, hat, long-sleeve clothing, Vit D), care with contraception and timing of family issues, and education on disease, diet, exercise.

Question 18

Discuss hydroxychloroquine

Answer 18

• Direct immunomodulatory effects have resulted in its use in Rheumatoid Arthritis, Primary Sjogren’s Syndrome, SLE, and Antiphospholipid Syndrome.
• In SLE, should be used in most patients during the entire course of the disease, particularly useful for skin and joint manifestations. Immunomodulatory capacity also prevents disease flares, promotes long-term survival in SLE, controls autoimmune disease activity during pregnancies without evidence of fetotoxic or embryonic effects, can delay or prevent organ damage, and has antithrombotic effects in SLE. Helps successful tapering corticosteroids.
• For this and other inflammatory rheumatic diseases, can also reduce rates of atherosclerosis, improve hyperglycemia, and protect against infections

Pharmacokinetic Properties of Hydroxychloroquine and Chloroquine*
- Pharmacokinetic Properties: Hydroxychloroquine (HCQ) and chloroquine.
- Cellular Effects HCQ During Autoimmunity: HCQ has a positive net charge, allowing it to insert into lysosomal membranes, decreasing Toll-like receptors 9,8,7, and 3 activation by alkalinization of the lysosome.
Note: HCQ is preferred to CQ because it is easier to manage and is cleared more quickly
### Antimalarial drugs - emphasis on hydroxychloroquine

• Start 6.5mg/kg body weight/day. Reduce maintenance dose 5mg/kg/day
• Adverse events ;Drug rash(usually first month, means that drug cannot be used long-term, occurs in about 1% of patients), GI(nausea/diarrhoea), Neurotoxicity+- myotoxicity, myasthenia syndromes, Eye monitoring (but OCT scans can detect early retinopathy which is uncommon unless higher dose used over many years in renal patients). Consider adverse effects a genuine concern if rena issues presence

Question 19

Discuss treatment of skin and MSK manifestations

Answer 19

• Simple analgesics and creams – paracetamol and topical steroids.
• NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) – ibuprofen, naproxen. Especially if not old and no vascular issues
• Antimalarial drugs – hydroxychloroquine (Plaquenil) <6.5mg/kg/day 200mg to 600mg daily.
• Tricyclic antidepressants (amitriptyline) or SNRIs (duloxetine) if fibromyalgia.
• Calcium, Vitamin D.
• Low dose steroids for a limited period.
• Weight-bearing exercise.

Question 20

Briefly discuss some other treatments

Answer 20

• Methotrexate: If hydroxychloroquine not tolerated especially in moderately active disease with arthritis, pleural or pericardial serositis.
• Cyclophosphamide: As cornerstone of therapy for induction therapy in severe disease with renal, CNS, or HPS involvement.
• Azathioprine: As maintenance therapy and steroid-sparing effect.
• Mycophenolate: For some renal disease and CNS disease as maintenance therapy(not usually induction therapy), occasionally use for refractory SCLE, Haemolytic Anemia, Thrombocytopenia, Interstitial Lung Disease.
• Belimumab: (Monoclonal antibody blocks B Lymphocyte Stimulator/B cell Activating Factor (BAFF) that binds to B cells, a molecule overexpressed in lupus patients) so all cells that express one or more BAFF receptors which are predominately B cells are targeted approved for use by TGA.
• Anifrolumab: (Monoclonal antibody targeting interferon a/b receptor) has mixed reports on effectiveness and not PBS approved in Australia.
• Rituximab: (Depletes all lineage B cells except plasma cells and pro-B cells) effective for severe arthritis, vasculitis, thrombocytopenia, lung and CNS lupus.
• Autologous Stem Cell Transplant: Has 12% mortality versus lifesaving in potential fatal disease.