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SYSTEMIC LUPUS
ERYTHEMATOSUS
June 1& 8, 2015
Outline
Introduction : Definition, epidemiology
Pathogenesis : Etiology, Risk factors, pathology.
Diagnosis : SLICC 201...
Systemic Lupus
• Inflammatory multisystem disease.
• Women>Men- 9:1 ratio.
• 90% cases are women of childbearing age.
• Af...
Systemic Lupus
• Incidence & Prevalence : increasing
– Improved survival, diagnosing milder cases.
• Geographical variabil...
Lupus : History
• Lupus means “wolf” in Latin.
• 10th century- 1st used medically in case reports.
• Described clinically ...
Pathogenesis
Genetics
Abnormal
Immune
response
Environment
Genetic Factors
Environmental Triggers
• UV light (A2 and B component)
• Gender ( female > male, Estrogen)
• EBV
• Vitamin D deficiency
• ...
• Activation of innate immunity.
• Lowered activation thresholds and abnormal
activation pathways.
• Ineffective regulatio...
Development of Autoantibodies
Failure :
accumulation of
nuclear particles
Capturing by
antigen presenting
cells
Attract
Ma...
Mechanisms of organ damage
Organ damage
• Cytokines involved in tissue injury / organ
damage in lupus include :
– B cell maturation/survival cytokine...
Autoantibodies in SLE
Antibody Prevalence Antigen recognized
ANA 98 % Multiple nuclear antigens
Anti-dsDNA 70 Double stran...
Clinical relevance : Autoantibodies
• ANA
– High sensitivity, low specificity.
– Best screening test
– Repeated negative t...
Clinical relevance : Autoantibodies
• Anti dsDNA
– High titers : Specific
– 60% sensitivity.
– In some, Correlates with di...
Clinical relevance : Autoantibodies
• Antiphospholipid Antibodies
– Ig G Anticardiolipin : High titres(>40 IU), Increased
...
Clinical relevance : Autoantibodies
• Anti RNP
– Non Specific, association with RA (Rhupus), black > white.
• Anti La/SS-B...
Diagnosis : SLE
• American Rheumatism Association (ARA) in
1982 (revised in 1997) proposed “criteria for
classification "a...
Systemic Lupus International
Collaborating Clinics (SLICC) classification
• 11 clinical and 6 immunological criteria
• The...
Acute Cutaneous Lupus OR Subacute
Cutaneous Lupus
• Acute cutaneous lupus: lupus malar rash, bullous
lupus, TENvariant of ...
Malar Rash Photosensitive lupus rash
Chronic Cutaneous Lupus
• Classic discoid rash localized (above the neck) or
generalized (above and below the neck)
• Hype...
Classic Discoid Rash
Hypertrophic (verrucous) lupus
Hypertrophic (verrucous) lupus
Lupus profundus
Lupus affecting the fat
underlying skin aka ‘lupus
panniculitis’.
Dented
scar and
Nodule.
lupus erythematosus tumidus
• Tumidus dermal form of lupus.
• Characteristically photosensitive
• Red, swollen, urticaria-...
Oral OR Nasal Ulcers
• Oral: palate, buccal, tongue
• Nasal ulcers
• In the absence of vasculitis, Behcet’s disease,
infec...
• Nonscarring alopecia
– Diffuse thinning or hair fragility with visible broken
hairs.
• Synovitis involving 2 or more joi...
• Serositis
– Typical pleurisy for > 1 day OR pleural effusions OR
pleural rub
– Typical pericardial pain (pain with recum...
Neurologic
• Seizures, psychosis, mononeuritis multiplex.
• Myelitis, peripheral or cranial neuropathy.
• Acute confusiona...
• Hemolytic anemia.
• Leukopenia (<4000/mm3) OR Lymphopenia
(<1000/mm3).
• Thrombocytopenia (<100,000/mm3).
IMMUNOLOGIC CRITERIA
• ANA > reference negative value.
• Anti-ds DNA
• Anti-Sm
• Anti phospholipid
• Low serum complement
...
SLICC : What's new
• Non scarring alopecia added as new entity.
• Old Hematological divided into 3.
• Inclusion of mononeu...
Performance of the SLICC as compared
to old ACR criteria
• SLICC : Sensitivity and specificity were 94% and
93%.
• ACR 199...
Systemic Manifestations : Overview
95
80
85
60
60
50
40
15
15
SLE
Others Thrombosis Gastrointestinal
Renal Cardiopulmonary...
Musculoskeletal
• Intermittent polyarthritis
• soft tissue swelling and tenderness in joints
and/or tendons (hand, wrist, ...
Renal Manifestations
• One of most serious manifestation.
• Classification of Lupus Nephritis is purely
histologic.
• Rena...
ISN/RPS classification of lupus nephritis
Class I Minimal mesangial lupus nephritis (Light microscopy : Normal glomeruli)
...
Neurological Manifestations
• Cognitive dysfunction
• Difficulty with memory and reasoning
• Headaches, when excruciating,...
Cutaneous
• Photosensitivity
• Malar rash
• Oral Ulcers
• Alopecia
• Discoid Rash
• Vasculitis rash
• Urticaria
Cardiopulmonary
• Pleuritic Chest pain, pleural effusion.
• Pericarditis, pericardial effusion, tamponade.
• Myocarditis
•...
Gastrointestinal
• Nausea, vomiting, diarrohea, pain abdomen.
• Transaminitis.
• Mesenteric Vasculitis
• pancreatitis
Hematologic
• Anemia (chronic disease)
• Leukopenia
• Lymphopenia
• Thrombocytopenia
• Lymphadenopathy
• Splenomegaly
• Au...
Life threatening complications
• Cutaneous Digital Gangrene
• Cutaneous Necrosis
• Thrombocytopenia
• Autoimmune Hemolytic...
Management : SLE
• No cure.
• Complete sustained remission, rare.
• Mainstay : Supress symptoms and prevent
organ damage.
...
Management : Algorithm
1.
• Symptom complex suggestive of SLE
• Order tests : ANA, CBC, Urine Me, Platelets
2.
• All resul...
Management : Algorithm
Management : SLE
• Non life- or organ –threatening.
– Non Pharmacological conservative, Risk factor
modification.
– Additi...
Therapies Available
• Glucocorticoids.
• Antimalarials.
• NSAIDs (Asprin)
• Biologicals.
• Cyclophosphamide
• Mycophenolat...
Nonpharmacological management
• Sunscreens, SPF atleast 30, prefered ≥ 55.
• Smoking cessation.
• Weight loss.
• Exercise....
Nonpharmacological management
• Sunscreens, SPF atleast 30, prefered ≥ 55.
• Smoking cessation.
• Weight loss.
• Exercise....
Pharmacological
therapies
NSAIDs
– For minor symptoms.
– Arthralgia, musculoskeletal, fever, headaches and
mild serositis.
– Short periods only.
– A...
Glucocorticoids
– Rapidly reduce inflammation.
– Modulate innate and adaptive immune response.
– Dosages : depend on sever...
Glucocorticoids (Contd…)
– long-term adverse effects
– Infections, HTN, Hyperglycemia, Acne, Asptic
necrosis of bones, Cus...
Antimalarial agents
– MOA : Inhibit endosome function ? Disrupt
class II MHC Decreasing antigen presentation.
– Activates ...
Cyclophosphamide
• Alkylating agent, Cross-links DNA and suppress
DNA synthesis, Prevents division of cells.
• For lupus n...
Cyclophosphamide
• In comparative study no significant difference
between NIH and Euro Lupus.
• Adverse reactions : Severe...
Azathioprine
• Purine analogue, inhibits synthesis of xanthylic
and adenylic acids, supress DNA synthesis.
• Use : systemi...
Azathioprine
• Dosage : For Induction : 2 - 3 mg/kg/day PO;
• For maintenance : 1 -2 mg/kg/day;
• If CrCI <50 ml/min, decr...
Mycophenolate Mofetil
• Monophosphate dehydrogenase Inhibitor,
blocks synthesis of guanosine nucleotides and
proliferation...
Mycophenolate Mofetil
• Dosages : MMF
– For Induction : 2-3 g/d PO.
– For maintenance : 1 -2 g/d.
• Adverse Effects : Naus...
Methotrexate
• Folate antimetabolite, inhibits DNA synthesis.
• Use : for musculoskeletal manifestations, also
good for se...
Biologicals
Belimumab
• Fully human monoclonal antibody against B
lymphocyte stimulator (BLyS), important for
survival of B cells. FDA...
Belimumab
• Dose : 10 mg/kg IV wks 0, 2 and 4, then
monthly.
• Generally, well tolerated, not associated with
a high rate ...
Rituximab
• Chimeric mouse/human monoclonal antibody
specific for human CD20.
• Selectively Depletes CD20+ mature B cells
...
Rituximab
• Currently, not approved for SLE.
• Only in patients with refractory disease esp.
cytopenia, nephritis or neuro...
IV Immunoglobulin
• Off -label use in catastrophic antiphospholipid
syndrome.
• Mechanism of action of IVIG in SLE t/t not...
Therapy for specific SLE
manifestations
• Mainstay of treatment for any inflammatory
life-threatening or organ-threatening
manifestations of SLE is systemic
gluco...
Lupus Nephritis
• In Mild disease : Start with
hydroxychloroquine, RAAS blockers, manage
proteinuria and hypertension.
• T...
Lupus Nephritis
• Patients with ISN grade III or IV disease,
treatment with GCs and CPM reduce
progression to ESRD and dea...
Lupus Nephritis
• Azathioprine (AZA) may be effective for
induction but is slower to influence response
and associated wit...
Crescentic Lupus Nephritis
• Crescents in glomeruli have got worse
prognosis.
• Currently only High dose CPM with High-Dos...
Membranous Lupus Nephritis
• Classified as ISN class V, have proliferative
changes.
• In pure Membranous variant,
immunosu...
Pregnancy and Lupus
• Lupus does not affects fertility.
• Rate of fetal loss increased.
• Demise is higher in mothers with...
Pregnancy and Lupus
• Glucocorticoids are Category A
• Cyclosporin, Tacrolimus Rituximab in Category C
• AZA, HCQs, MMF, C...
Neonatal Lupus
• Rare condition
• Not true lupus, passively transferred
autoimmune disease
• Transplacental transfer of Ig...
Neonatal Lupus
• Trans-placental fluorinated corticosteroids,
dexamethasone and betamethasone.
• Hydroxychloroquine during...
Drug Induced Lupus
• Appears during therapy.
• Fever, malaise, arthritis, intense arthralgia, myalgia,
serositis, and or r...
Microvascular Thrombotic Crisis
• Hemolysis, thrombocytopenia, and
microvascular thrombosis in kidneys, brain
and other ti...
Lupus and antiphospholipid
syndrome
• Repeated fetal losses, venous or arterial clotting,
with atleast 2 positive tests fo...
Disease Activity Assessment
WHY IMPORTANT..??
• For quantification of lupus disease activity
primarily to check effectiven...
Disease Activity Assessment
Most commonly used disease activity
instruments
• SLEDAI
– SLEDAI, SLEDAI-2000, SRI-50
– SELEN...
SLEDAI
• 24 lupus manifestations
• Parameters scored only if present ( ie active lupus)
• 16 Clinical, 8 lab parameters.
•...
SLEDAI Limitations
• Cannot measure partial improvement of
individual parameter.
• Cannot measure worsening of an existing...
SELENA-SLEDAI
• Seizures that are due to past irreversible
central nervous system damage are excluded.
• Some other descri...
BILAG
• Measures improvement/ worsening in disease
activity by organ system domain.
• Individual parameters grouped into 9...
Composite Responder Indices
• For assessing disease activity in response to
therapy.
• Identify both improvement and worse...
Take home message
• SLE : Multifactorial disease.
• No cure, but disease activity can be limited if
detected early and rem...
Systemic Lupus Erythematosus
Systemic Lupus Erythematosus
Systemic Lupus Erythematosus
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Systemic Lupus Erythematosus

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Systemic lupus erythematosus, SLE, SLE Nephritis, SLE management, SLE classification, ACR vs SLICC criteria, New Drugs in SLE.

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Systemic Lupus Erythematosus

  1. 1. SYSTEMIC LUPUS ERYTHEMATOSUS June 1& 8, 2015
  2. 2. Outline Introduction : Definition, epidemiology Pathogenesis : Etiology, Risk factors, pathology. Diagnosis : SLICC 2012 v/s ACR 1997. Autoantibodies in Lupus. Systemic Manifestations : overview and life threatening complications. Management : Therapies old and new, special conditions, monitoring disease activity, Flare definition and management, pipeline therapies.
  3. 3. Systemic Lupus • Inflammatory multisystem disease. • Women>Men- 9:1 ratio. • 90% cases are women of childbearing age. • African Americans>Whites. • Onset usually between ages 15 and 45 years, but can occur in childhood or later in life. • Highly variable course and prognosis, ranges from mild to life threatening. • Characterized by flares and remissions. • Tissue-binding autoantibodies and immune complexes.
  4. 4. Systemic Lupus • Incidence & Prevalence : increasing – Improved survival, diagnosing milder cases. • Geographical variability : •African-Americans > Caucasians (3x) •Asian-American and Hispanics > Caucasians •Age at diagnosis: •16-55 years of age: 65% of cases •< 16: 20% •> 65: 15% US UK Japan Incidence (per 100000 per year) 5.1 3.8 2.9 Prevalence (per 100000) 52.2 26.2 28.4
  5. 5. Lupus : History • Lupus means “wolf” in Latin. • 10th century- 1st used medically in case reports. • Described clinically in the 19th century • Butterfly rash in 1845 • Arthritis in 1892 • Nephritis in 1895 by Osler • Serologic tests become available in the 20th century • LE cell in 1948 • Lupus anticoagulant in 1952 • ANA in 1954 • 1971- First set of classification criteria.
  6. 6. Pathogenesis Genetics Abnormal Immune response Environment
  7. 7. Genetic Factors
  8. 8. Environmental Triggers • UV light (A2 and B component) • Gender ( female > male, Estrogen) • EBV • Vitamin D deficiency • Other organic compounds. – Silica dust, solvents, petroleum products, Smoking. • Drugs – Long list : Sulfonamide, Hydralazine, Isoniazid, d- Penicillamine, Antiarrhythmic drugs : Propafenone, procainamide, disopyramide… – Interferons and TNF inhibitors.
  9. 9. • Activation of innate immunity. • Lowered activation thresholds and abnormal activation pathways. • Ineffective regulation of CD4+ and CD8+ T cells, B cells and myeloid derived suppressor cells. • Reduced clearance of immune complexes and apoptotic cells.
  10. 10. Development of Autoantibodies Failure : accumulation of nuclear particles Capturing by antigen presenting cells Attract Macrophages and dendritic cells. (Phagocytes the complex) Circulating immune cells engulf and Release “find me” signal Early Apoptotic cells (“eat me” signal) Formation of Antinuclear antibodies
  11. 11. Mechanisms of organ damage
  12. 12. Organ damage • Cytokines involved in tissue injury / organ damage in lupus include : – B cell maturation/survival cytokines B-Lymphocyte Stimulator (BLyS/BAFF). – Interlukin 6, 17, 18. – Proinflammatory type 1 and 2 interferons (IFNs)
  13. 13. Autoantibodies in SLE Antibody Prevalence Antigen recognized ANA 98 % Multiple nuclear antigens Anti-dsDNA 70 Double stranded DNA Anti-Sm 25 Protein complexed to 6 species of nuclear U1 RNA Anti-RNP 40 Protein complexed to U1 RNA Anti-Ro (SS-A) 30 Protein complexed to hY RNA (60kDa and 52 kDa) Anti-La (SS-B) 10 Protein complexed to hyRNA (47 –kDa) Antihistone 70 Histone proteins associated with DNA. Antiphospholipid 50 β2G1, Phospholipids, prothrombin Antierytherocyte 60 RBC membrane Antiplatelet 30 Surface and altered cytoplasmic antigens on platlets Antineuronal 60 Neuronal and lymphocyte surface antigens Antiribosomal P 20 Ribosomal protein
  14. 14. Clinical relevance : Autoantibodies • ANA – High sensitivity, low specificity. – Best screening test – Repeated negative tests makes SLE unlikely – Can be positive in upto 10-15% of normal individuals. – Immunofluorescent technique (IF) more reliable than ELISA and/or bead assays.
  15. 15. Clinical relevance : Autoantibodies • Anti dsDNA – High titers : Specific – 60% sensitivity. – In some, Correlates with disease activity (Nephritis, vasculitis) • Anti- Sm – Specific to SLE. – More common in Blacks and Asians. – No definite clinical correlation.
  16. 16. Clinical relevance : Autoantibodies • Antiphospholipid Antibodies – Ig G Anticardiolipin : High titres(>40 IU), Increased risk for clotting – Anti β2 glycoprotein. – Lupus anticoagulant (By DRVVT) • Anti Ro/SS-A – Non Specific – Associated with : Sicca syndrome, Neonatal Lupus, Subacute cutaneous lupus – Decreased risk for nephritis Women with childbearing potential and SLE should be screened for both Antiphospholipid and anti-Ro antibodies
  17. 17. Clinical relevance : Autoantibodies • Anti RNP – Non Specific, association with RA (Rhupus), black > white. • Anti La/SS-B – Decreased risk for nephritis, associated with anti Ro. • Anti histone – Drug induced lupus. • Antierythrocyte – Measured by DCT • Antiplatelet – Not useful clinically • Antineuronal – Positivity in CSF : Active CNS Lupus • Antiribosomal P – Positivity in Serum : Depression, Psychosis in Lupus.
  18. 18. Diagnosis : SLE • American Rheumatism Association (ARA) in 1982 (revised in 1997) proposed “criteria for classification "and not for diagnosis. • Pitfalls of ACR 1997. – Overly biased and weighted toward cutaneous lupus, with four cutaneous criteria. – Omission of Hypocomplementemia. – Only psychosis and seizure were included. – Biopsy-proven nephritis compatible with SLE was not included
  19. 19. Systemic Lupus International Collaborating Clinics (SLICC) classification • 11 clinical and 6 immunological criteria • The patient should satisfies atleast four of the criteria including at least one clinical criterion and one immunologic criterion. • Biopsy-proven nephritis compatible with SLE in the presence of ANA or anti-dsDNA antibodies in the absence of other lupus features is regarded as sufficient for a patient to be diagnosed as having lupus.
  20. 20. Acute Cutaneous Lupus OR Subacute Cutaneous Lupus • Acute cutaneous lupus: lupus malar rash, bullous lupus, TENvariant of SLE, maculopapular lupus rash, photosensitive lupus rash (in the absence of dermatomyositis). • Subacute cutaneous lupus: nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring.
  21. 21. Malar Rash Photosensitive lupus rash
  22. 22. Chronic Cutaneous Lupus • Classic discoid rash localized (above the neck) or generalized (above and below the neck) • Hypertrophic (verrucous) lupus • lupus panniculitis (profundus) • Mucosal lupus • lupus erythematosus tumidus • chilblains lupus • discoid lupus/lichen planus overlap
  23. 23. Classic Discoid Rash
  24. 24. Hypertrophic (verrucous) lupus Hypertrophic (verrucous) lupus
  25. 25. Lupus profundus Lupus affecting the fat underlying skin aka ‘lupus panniculitis’. Dented scar and Nodule.
  26. 26. lupus erythematosus tumidus • Tumidus dermal form of lupus. • Characteristically photosensitive • Red, swollen, urticaria-like bumps and patches • Ring-shaped (Annular)
  27. 27. Oral OR Nasal Ulcers • Oral: palate, buccal, tongue • Nasal ulcers • In the absence of vasculitis, Behcet’s disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, and acidic foods.
  28. 28. • Nonscarring alopecia – Diffuse thinning or hair fragility with visible broken hairs. • Synovitis involving 2 or more joints – Characterized by swelling or effusion OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness
  29. 29. • Serositis – Typical pleurisy for > 1 day OR pleural effusions OR pleural rub – Typical pericardial pain (pain with recumbency improved by sitting forward) for > 1 day OR pericardial effusion OR pericardial rub OR pericarditis by electrocardiography. • Renal – Urine PCR (or 24-hour urine protein) > 500 mg protein/24 hours OR RBC casts.
  30. 30. Neurologic • Seizures, psychosis, mononeuritis multiplex. • Myelitis, peripheral or cranial neuropathy. • Acute confusional state.
  31. 31. • Hemolytic anemia. • Leukopenia (<4000/mm3) OR Lymphopenia (<1000/mm3). • Thrombocytopenia (<100,000/mm3).
  32. 32. IMMUNOLOGIC CRITERIA • ANA > reference negative value. • Anti-ds DNA • Anti-Sm • Anti phospholipid • Low serum complement • Positive direct Coomb’s test
  33. 33. SLICC : What's new • Non scarring alopecia added as new entity. • Old Hematological divided into 3. • Inclusion of mononeuritis multiplex, myelitis, and acute confusional state in CNS manifestation. • Biopsy proven lupus nephritis • Addition of Low complement levels in immune criteria. • Antiphospholipid antibodies.
  34. 34. Performance of the SLICC as compared to old ACR criteria • SLICC : Sensitivity and specificity were 94% and 93%. • ACR 1997: Sensitivity and specificity were 86% 93%. • The new criteria retain the specificity while being more sensitive. • The new criteria retains the goal of simplicity of use, yet reflects current knowledge of SLE obtained in 29 years since the initial ACR criteria.
  35. 35. Systemic Manifestations : Overview 95 80 85 60 60 50 40 15 15 SLE Others Thrombosis Gastrointestinal Renal Cardiopulmonary Neurologic Hematologic Cutaneous Musculoskeletal Prevalence, % Manifestations
  36. 36. Musculoskeletal • Intermittent polyarthritis • soft tissue swelling and tenderness in joints and/or tendons (hand, wrist, knee) • Joint deformities develop in only 10% • Individuals having rheumatoid-like arthritis with erosions who fulfill criteria for both RA and SLE ("rhupus") may be coded as having both diseases.
  37. 37. Renal Manifestations • One of most serious manifestation. • Classification of Lupus Nephritis is purely histologic. • Renal biopsy indicated in every SLE patient with evidence of nephritis. • UPCR >0.5, RBC casts. • Nephrotic Syndrome • ESRD
  38. 38. ISN/RPS classification of lupus nephritis Class I Minimal mesangial lupus nephritis (Light microscopy : Normal glomeruli) Class II Mesangial proliferative LN (few isolated subepithelial/endothelial deposits visible by IF or electron microscopy) Class III Focal lupus nephritis (<50% glomerulli, sub endothelial deposits) III A Active lesions III A/C Active and Chronic Lesions III C Chronic Lesions Class IV Diffuse lupus nephritis( >50% glomeruli involved, Segmental and Global lesions) IV – S (A) Active lesions - Diffuse segmental proliferative lupus nephritis IV – G (A) Active lesions - Diffuse global proliferative lupus nephritis IV – S (A/C) Active & chronic lesions - Diffuse segmental proliferative & sclerosing lupus nephritis IV – G (A/C) Active & chronic lesions - Diffuse global proliferative & sclerosing lupus nephritis IV – S (C) Chronic inactive lesions with scars - Diffuse segmental sclerosing lupus nephritis IV – G (C) Chronic inactive lesions with scars - Diffuse segmental global lupus nephritis Class V Membranous lupus nephritis Class VI Advanced sclerosing lupus nephritis
  39. 39. Neurological Manifestations • Cognitive dysfunction • Difficulty with memory and reasoning • Headaches, when excruciating, often indicates SLE flare • Psychosis : must be distinguished from glucocorticoid induced psychosis. • Disabling myelopathy. • Stroke, TIAs • Aseptic meningitis.
  40. 40. Cutaneous • Photosensitivity • Malar rash • Oral Ulcers • Alopecia • Discoid Rash • Vasculitis rash • Urticaria
  41. 41. Cardiopulmonary • Pleuritic Chest pain, pleural effusion. • Pericarditis, pericardial effusion, tamponade. • Myocarditis • Coronary artery disease. • Lupus pneumonitis. • Interstitial fibrosis. • Pulmonary HTN • Alveolar hemorrhage, ARDS.
  42. 42. Gastrointestinal • Nausea, vomiting, diarrohea, pain abdomen. • Transaminitis. • Mesenteric Vasculitis • pancreatitis
  43. 43. Hematologic • Anemia (chronic disease) • Leukopenia • Lymphopenia • Thrombocytopenia • Lymphadenopathy • Splenomegaly • Auto Immune Haemolytic anemia
  44. 44. Life threatening complications • Cutaneous Digital Gangrene • Cutaneous Necrosis • Thrombocytopenia • Autoimmune Hemolytic Anemia • Catastrophic Antiphospholipid Syndrome. • Pericardial Tamponade • Myocarditis • Pulmonary Alveolar Hemorrhage • Myelitis • Mesenteric Vasculitis
  45. 45. Management : SLE • No cure. • Complete sustained remission, rare. • Mainstay : Supress symptoms and prevent organ damage. • Depends on severity of disease. • Prevention of complications of disease and its treatment.
  46. 46. Management : Algorithm 1. • Symptom complex suggestive of SLE • Order tests : ANA, CBC, Urine Me, Platelets 2. • All results normal, Symptoms subside: No SLE • Results normal, symptoms persist : Repeat ANA & anti dsDNA, anti Ro. (3) • ANA positive : SLICC criteria, ≥4: Definite SLE, <4 : Probable SLE (Treatment) 3. • Repeat ANA, Anti dsDNA and Anti Ro : All negative. NO SLE • Some Positive : SLICC ≥4 : Definite SLE (Treatment)
  47. 47. Management : Algorithm
  48. 48. Management : SLE • Non life- or organ –threatening. – Non Pharmacological conservative, Risk factor modification. – Addition of Low dose Corticosteroids, belimumab. • Life- or organ –threatening. – Nephritis, Myelitis, vasculitis. – High dose iv steroids + Immunosuppressant. • Special conditions – Pregnancy, Dermatitis, Thrombotic crisis.
  49. 49. Therapies Available • Glucocorticoids. • Antimalarials. • NSAIDs (Asprin) • Biologicals. • Cyclophosphamide • Mycophenolate mofetil • Azathioprine • Methotrexate • Tacrolimus • Lefunomide • IV Ig FDA approved. “Off label” but standard of care “Borrowed drugs”
  50. 50. Nonpharmacological management • Sunscreens, SPF atleast 30, prefered ≥ 55. • Smoking cessation. • Weight loss. • Exercise. • Optimal Blood pressure control. • Supplemental Vit D. • Avoid High-dose oestrogen therapy, Oral contraceptive* • Avoids culprit meds : Sulphonamides. • Avoid pregnancy
  51. 51. Nonpharmacological management • Sunscreens, SPF atleast 30, prefered ≥ 55. • Smoking cessation. • Weight loss. • Exercise. • Optimal Blood pressure control. • Supplemental Vit D. • Avoid High-dose oestrogen therapy, Oral contraceptive* • Avoids culprit meds : Sulphonamides. • Avoid pregnancy
  52. 52. Pharmacological therapies
  53. 53. NSAIDs – For minor symptoms. – Arthralgia, musculoskeletal, fever, headaches and mild serositis. – Short periods only. – Adverse effects : Aseptic meningitis, Transaminitis, Decreased renal function, GI bleed, Vasculitis. (NSAID) – All esp. COX 2 inhibitors : increase risk of MI
  54. 54. Glucocorticoids – Rapidly reduce inflammation. – Modulate innate and adaptive immune response. – Dosages : depend on severity. Low dose prednisone (0.1–0.2 mg/kg) Mild SLE cutaneous and musculoskeletal symptoms Medium dose prednisone (0.5 mg/kg) Moderate SLE Pleuropericarditis or Hematological manifestsations High dose oral prednisone (1.0–1.5 mg/kg) or IV methylprednisolone (1 g or 15 mg/kg) Severe disease renal or neuropsychiatric manifestations or vasculitis
  55. 55. Glucocorticoids (Contd…) – long-term adverse effects – Infections, HTN, Hyperglycemia, Acne, Asptic necrosis of bones, Cushings syndrome, CHF, Fragile Skin, Insomnia, Menstrual irregularities, osteoporosis, psychosis… – Add calcium (1,500 mg /day) & vitamin D (800 IU/day), If prednisone or equivalent ≥5 mg /day.
  56. 56. Antimalarial agents – MOA : Inhibit endosome function ? Disrupt class II MHC Decreasing antigen presentation. – Activates endosomal TLR: decrease IFN α. – Use : constitutional, musculoskeletal, skin and mild pleuritic symptoms. – Dose : 200-400 mg daily. – Adverse effects :Retinal damage, agranulocytosis, aplastic anemia, cardiomyopathy, myopathy, peripheral neuropathy, pigmentation of skin, Quinacrine : diffuse yellow skin.
  57. 57. Cyclophosphamide • Alkylating agent, Cross-links DNA and suppress DNA synthesis, Prevents division of cells. • For lupus nephritis, neuropsychiatric lupus, severe systemic vasculitis. • Dosing Protocols. – NIH : I/V CPM (0.5–1.0 g/m2 bsa) once /month X 6 months, f/b once / 3 months for 2 years. – Euro Lupus : I/V CPM 500 mg / 2 weeks X 3 months, f/b AZA or NIH regimen as maintenance.
  58. 58. Cyclophosphamide • In comparative study no significant difference between NIH and Euro Lupus. • Adverse reactions : Severe infections, alopecia, lymphomas and bladder Ca and infertility. • I/V mesna decrease risk of bladder Ca. • Gonadotropin releasing hormone use prevents premature ovarian failure.
  59. 59. Azathioprine • Purine analogue, inhibits synthesis of xanthylic and adenylic acids, supress DNA synthesis. • Use : systemic features of lupus, & maintenance dose for Lupus Nephritis, ISN class III & IV. • Option as induction agent in patients with LN, concerned with risk of infertility with CPM.
  60. 60. Azathioprine • Dosage : For Induction : 2 - 3 mg/kg/day PO; • For maintenance : 1 -2 mg/kg/day; • If CrCI <50 ml/min, decrease frequency. • Adverse effects : BM suppression, GI intolerance, hypersensitivity and hepatotoxicity. induction therapy for selected
  61. 61. Mycophenolate Mofetil • Monophosphate dehydrogenase Inhibitor, blocks synthesis of guanosine nucleotides and proliferation of T and B cells. • Use : Induction and maintenance therapy in lupus nephritis & moderate to severe SLE. • NB : More effective in Hispanic, African- Americans and non-Asians, non white races with lupus nephritis, compared to CPM.
  62. 62. Mycophenolate Mofetil • Dosages : MMF – For Induction : 2-3 g/d PO. – For maintenance : 1 -2 g/d. • Adverse Effects : Nausea, abdominal pain, diarrhoea, myelosuppression and infections.
  63. 63. Methotrexate • Folate antimetabolite, inhibits DNA synthesis. • Use : for musculoskeletal manifestations, also good for serositis and to some extent for skin manifestations. • Dosage : 10-25 mg/week PO or SC along with folic acid. Requires dose modification renal impairment. • Adverse Effects : stomatitis, bone marrow suppression, hepatitis, alopecia and pneumonitis, pulmonary fibrosis.
  64. 64. Biologicals
  65. 65. Belimumab • Fully human monoclonal antibody against B lymphocyte stimulator (BLyS), important for survival of B cells. FDA approved. • Use : reduce disease activity in SLE patients with mild–moderate disease, without severe renal or central nervous system. (FDA approved)
  66. 66. Belimumab • Dose : 10 mg/kg IV wks 0, 2 and 4, then monthly. • Generally, well tolerated, not associated with a high rate of adverse events.
  67. 67. Rituximab • Chimeric mouse/human monoclonal antibody specific for human CD20. • Selectively Depletes CD20+ mature B cells from circulation. • Use : For non responders to above therapy.
  68. 68. Rituximab • Currently, not approved for SLE. • Only in patients with refractory disease esp. cytopenia, nephritis or neuropsychiatric lupus. • Dose : 375 mg/m2/wk x 4 or 1g/2 wks x 2, along with corticosteroids and other immunosuppressive agents. • Infection (including PML), infusion reactions, headache, arrhythmias, allergic responses.
  69. 69. IV Immunoglobulin • Off -label use in catastrophic antiphospholipid syndrome. • Mechanism of action of IVIG in SLE t/t not clear. • Small clinical trials, have reported variable efficacy of IVIG. • Off label : in patients with refractory SLE, concomitant infection.
  70. 70. Therapy for specific SLE manifestations
  71. 71. • Mainstay of treatment for any inflammatory life-threatening or organ-threatening manifestations of SLE is systemic glucocorticoids. • Pulse, 1 g of methylprednisolone IV daily for 3 days followed by high dose (0.5- 1 mg/kg/day) prednisone or equivalent.
  72. 72. Lupus Nephritis • In Mild disease : Start with hydroxychloroquine, RAAS blockers, manage proteinuria and hypertension. • Treatment with hydroxychloroquine have higher rates of renal response, fewer relapses, and reduced accrual of renal damage.
  73. 73. Lupus Nephritis • Patients with ISN grade III or IV disease, treatment with GCs and CPM reduce progression to ESRD and death. • For Induction : GCs + CPM or MMF – Both CPM and MMF were found to be equally effictive. – MMF preferred in Hispanic, African-Americans and non-Asians, non white races .
  74. 74. Lupus Nephritis • Azathioprine (AZA) may be effective for induction but is slower to influence response and associated with more flares. • For Maintenance : either MMF or AZA can be used, in some studies MMF was found more efficacious. • For Refractory cases : consider rituximab / alternate therapy.
  75. 75. Crescentic Lupus Nephritis • Crescents in glomeruli have got worse prognosis. • Currently only High dose CPM with High-Dose GC, in induction phase is recommended.
  76. 76. Membranous Lupus Nephritis • Classified as ISN class V, have proliferative changes. • In pure Membranous variant, immunosuppression is not recommended unless proteinuria in nephrotic range. • ACE inhibitors and ARB’s are recommended. • Alternate day GC’s plus CPM/ MMF / Cyclosporine all effective in reducing proteinuria.
  77. 77. Pregnancy and Lupus • Lupus does not affects fertility. • Rate of fetal loss increased. • Demise is higher in mothers with – high disease activity – SLE nephritis – APLA • Women with AntiRo SSA need additional monitoring, high risk for neonatal Lupus. • APLA with SLE treated with heparin and low dose Asprin.
  78. 78. Pregnancy and Lupus • Glucocorticoids are Category A • Cyclosporin, Tacrolimus Rituximab in Category C • AZA, HCQs, MMF, CPM as category D (benefits outweighs risk) • MTX is Cat X (risk outweighs benefits) • Mgx : HCQs and if required prednisone at lowest dose for short time. • AZA may be added. • Breast feeding should be avoided ( glucocorticoids and immunosuppressants get into breast milk).
  79. 79. Neonatal Lupus • Rare condition • Not true lupus, passively transferred autoimmune disease • Transplacental transfer of IgG anti SSA or SSB antibodies • 5-7% transient rash, resolves by 6-8 months • 2% cardiac complications, congenital heart block.
  80. 80. Neonatal Lupus • Trans-placental fluorinated corticosteroids, dexamethasone and betamethasone. • Hydroxychloroquine during pregnancy associated with reduced rates of NLS. • IVIg was reported to prevent recurrence of CHB in one study, but two large RCTs failed to show any beneficial effect.
  81. 81. Drug Induced Lupus • Appears during therapy. • Fever, malaise, arthritis, intense arthralgia, myalgia, serositis, and or rash (less common). • ANA positivity very high. • Differs from SLE – White predominance, less female predilection, rare involvement of kidneys or brain. – Commonly antihistone antibody positive, Anti dsDNA and RNP rare • Management: – Withdraw offending drug – Low doses of systemic corticosteroids if severe disease.
  82. 82. Microvascular Thrombotic Crisis • Hemolysis, thrombocytopenia, and microvascular thrombosis in kidneys, brain and other tissues. • High mortility. • LAB : PS shows schistocytes, LDH is elevated, Antibodies to ADAMS13. • Management : Plasma exchange, along with GC therapy.
  83. 83. Lupus and antiphospholipid syndrome • Repeated fetal losses, venous or arterial clotting, with atleast 2 positive tests for APLA(12 weeks apart). • Target INR – Between 2.0 – 2.5 (One episode of venous clotting). – Between 3.0 – 3.5 (recurring clots or arterial clotting) • Heparin and Warfarin. • Statins, hydroxychloroquine, and rituximab might be useful.
  84. 84. Disease Activity Assessment WHY IMPORTANT..?? • For quantification of lupus disease activity primarily to check effectiveness of a new drug. • Not used in routine medical practice.
  85. 85. Disease Activity Assessment Most commonly used disease activity instruments • SLEDAI – SLEDAI, SLEDAI-2000, SRI-50 – SELENA-SLEDAI • BILAG – Classic and BILAG 2004 • Composite indices – SRI – BICLA
  86. 86. SLEDAI • 24 lupus manifestations • Parameters scored only if present ( ie active lupus) • 16 Clinical, 8 lab parameters. • Manifestation items are weighted with scores 1 to 8. • Total score is sum – Mild : 0-5 – Moderate : 6-12 – Severe: 13-20 • Score reduction requires complete resolution. • 3 to 7 point reduction = clinically meaningful improvement.
  87. 87. SLEDAI Limitations • Cannot measure partial improvement of individual parameter. • Cannot measure worsening of an existing abnormality • Some items are “unfairly” scored (eg thrombocytopenia)
  88. 88. SELENA-SLEDAI • Seizures that are due to past irreversible central nervous system damage are excluded. • Some other descriptors were modified like “cerebrovascular accident” was modified to exclude hypertensive cause. • Detects less severe items than SLEDAI 2K. • Easy to use.
  89. 89. BILAG • Measures improvement/ worsening in disease activity by organ system domain. • Individual parameters grouped into 9 organ domains and scored: 0,1,2,3,4 meaning “not present”, “improving” , “same” , “worse” and “new” respectively. • made with intention to treat. • Scores A to E, A = severe disease activity; E = no activity.
  90. 90. Composite Responder Indices • For assessing disease activity in response to therapy. • Identify both improvement and worsening in same and different organ system.
  91. 91. Take home message • SLE : Multifactorial disease. • No cure, but disease activity can be limited if detected early and remissions can be reached. • Management : requires both lifestyle modification and pharmacotherapy. • Severe disease : managed by GC’s and Immunosuppressants. • Disease activity assessment : For future prospects.

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