SYSTEMIC LUPUS

ERYTHEMATOSUS
DEFINITION

• Systemic lupus erythematosus (SLE) is an autoimmune

disease in which organs and cells undergo damage
mediated by tissue-binding autoantibodies and immune
complexes.
PREVALENCE
• Prevalence of SLE in the United States is 20–150 per 100,000
women
• The reported prevalence of SLE ranges from 14 to 60 per
100,000 in India.

. Women>Men- 9:1 ratio.

• 90% cases are women of childbearing age.
PATHOGENESIS
ENVIRONMENTAL TRIGGERS

• UV light (A2 and B component)

• Gender ( female > male)
• EBV
• Other organic compounds. – Silica dust, Smoking.
• Drugs
GENETIC FACTORS

• High Hazard ratios >6

• -C2, C4, C1
• -TREX 1 mutations
• Affecting Ag presentation
• -HLA DRB1,DR3, DQA2, FCGR2A/B
• ENHANCE INNATE IMMUNITY
• -ITGAM, TNFAIP3

• ALTER ADAPTIVE IMMUNITY

• -STAT4
EPIGENETIC FACTORS

• Epigenetic modifications affect gene expression and alter

cellular functions without modifying the genomic sequences.
• CpG-DNA methylation, histone modifications, and miRNAs
are the main epigenetic factors of gene regulation.
CLINICAL RELEVANCE : AUTOANTIBODIES

• ANA
• High sensitivity, low specificity.
• Best screening test
• Repeated negative tests makes SLE unlikely
• • 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.
• Anti phospholipid antibodies:
• Women with child bearing potential and SLE should be screened
for both Antiphospholipid and anti-Ro antibodies

• • Anti Ro/SS-A
• – Non Specific
• – Associated with : Sicca syndrome, Neonatal Lupus
• – Decreased risk for nephritis
• Anti RNP – Non Specific, association with RA (Rhupus)
• Anti La/SS-B – Decreased risk for nephritis, associated with anti
Ro.
• Anti histone – Drug induced lupus.
• Antierythrocyte – Measured by DCT
• Antineuronal – Positivity in CSF : Active CNS Lupus
•Antiribosomal P – Positivity in Serum : Depression, Psychosis in
Lupus.
SYSTEMIC LUPUS INTERNATIONAL COLLABORATING
CLINICS (SLICC) CLASSIFICATION

• 11 clinical and 6 immunological criteria

• The patient should satisfy at least 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.
MUSCULOSKELETAL
• Polyarthritis
• Soft tissue swelling and tenderness in joints and/or tendons (hand,
wrist, knee)
• Joint deformities develop in only 10%
• Ischemic necrosis of bone
• Individuals having rheumatoid-like arthritis with erosions who fulfill
criteria for both RA and SLE ("rhupus") may be coded as having
both diseases.
RENAL MANIFESTATIONS
• One of most serious manifestations.
• Classification of Lupus Nephritis is purely histologic.
• Renal biopsy indicated in every SLE patient with evidence
of nephritis.
Patients with ISN 3 and 4 usually have microscopic
hematuria and proteinuria
• UPCR >0.5, RBC casts.
• Lupus nephritis results from the deposition of circulating
immune complexes, which activate the complement
cascade leading to complement-mediated damage
• Patients with lesions limited to the renal mesangium have
an excellent prognosis and generally do not need therapy
for their lupus nephritis.
• Class III lesions have the most varied course
• Nephrotic-range proteinuria in 25–33% of patients.
• Patients with mild proliferation involving a small percentage of
glomeruli respond well to therapy with steroids alone
• 50% of patients with class IV have nephrotic-range proteinuria.
• A remission with administration of high dose steroids and
either cyclophosphamide or mycophenolate mofetil for 2–
6 months, followed by maintenance therapy with lower
doses of steroids and mycophenolate mofetil or
azathioprine
• Patients with lupus nephritis class V, are predisposed to
renal-vein thrombosis and other thrombotic complications.
• Lupus patients with class VI lesions have >90% sclerotic
glomeruli and ESRD with interstitial fibrosis.
NEUROLOGICAL MANIFESTATIONS
• Cognitive dysfunction
• Difficulty with memory and reasoning
• Headaches, when excruciating, often indicates SLE flare
• Psychosis
• Seizures.
• Stroke, TIAs
CUTANEOUS

• Photosensitivity
• Malar rash
• Oral Ulcers
• Alopecia
• Discoid Rash
CARDIOPULMONARY

• Pleurisy, pleural effusion.

• Pericarditis, pericardial effusion, tamponade, Myocarditis
• Coronary artery disease.
• Interstitial fibrosis, shrinking lung syndrome
• Pulmonary HTN
• Alveolar hemorrhage, ARDS.
GASTROINTESTINAL

• Nausea, vomiting, diarrhea, pain abdomen.

• Transaminitis.
• Mesenteric Vasculitis
HEMATOLOGIC
• Anemia (chronic disease)
• Leukopenia (Lymphopenia)
• Thrombocytopenia
• Auto Immune Haemolytic anemia
NSAIDS

• Arthralgia, musculoskeletal, fever, headaches.

• Short periods only.
• Adverse effects : Aseptic meningitis, Transaminitis,
Decreased renal function, GI bleed
• – All esp. COX 2 inhibitors : increase risk of MI
GLUCOCORTICOIDS

• Rapidly reduce inflammation.

• Modulate innate and adaptive immune response.
• Dosages : depend on severity.
• Prednisone, prednisolone: 0.5-1mg/kg for severe disease
0.07-0.3mg/kg for milder disease
• Methyl prednisolone: 0.5-1g IV for 3 days
ANTIMALARIAL AGENTS
• MOA : Inhibit endosome function , Disrupt class II MHC Decreasing
antigen presentation.
• – Use : constitutional, musculoskeletal, skin and mild pleuritic
symptoms.
• – Dose : 200-400 mg daily.
CYCLOPHOSPHAMIDE
• Alkylating agent, Cross-links DNA and suppress DNA synthesis,
Prevents division of cells.
• For lupus nephritis, neuropsychiatric lupus
• Dosing Protocols.
• – Euro Lupus : I/V CPM 500 mg / 2 weeks X 3 months, f/b AZA
as maintenance.
• High dose : 7-25mg/kg in a month for 6 doses
AZATHIOPRINE

• Inhibits synthesis of xanthylic and adenylic acids, supress

DNA synthesis.
• Use : systemic features of lupus, & maintenance dose for
Lupus Nephritis, ISN class III & IV and flares
• Option as induction agent in patients with LN
• 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.
 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.
• – For Induction : 2-3 g/d
• – For maintenance : 1 -2 g/d.
METHOTREXATE

• Use : for musculoskeletal manifestations, serositis and to

some extent for skin manifestations.
• Dosage : 10-25 mg/week PO or SC along with folic acid.
• Requires dose modification in renal impairment.
• Adverse Effects : stomatitis, bone marrow suppression,
hepatitis, alopecia and pneumonitis, pulmonary fibrosis.
BELIMUMAB

• Fully human monoclonal antibody against B lymphocyte

stimulator (BLyS), important for survival of B cells
• Use : reduce disease activity in SLE patients with mild–
moderate disease, without severe renal or central nervous
system
• Dose : 10 mg/kg IV wks 0, 2 and 4, then monthly or
subcutaneous 200mg/week
RITUXIMAB

• Only in patients with refractory disease esp. cytopenia,

nephritis or neuropsychiatric lupus.
• Dose : 375mg/m2 in a week for 4 weeks
• along with corticosteroids and other immunosuppressive
agents
CRESCENTIC LUPUS NEPHRITIS

• Crescents in glomeruli have got worse prognosis.

• Currently only High dose CPM with High-Dose GC, in induction
phase is recommended
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.
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.
• Trans-placental fluorinated corticosteroids, dexamethasone
and betamethasone.
• Hydroxychloroquine during pregnancy associated with
reduced rates of NLS.
• IVIg was reported to prevent recurrence of CHB.
 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 Anti Ro SSA need additional monitoring
• APLA with SLE treated with heparin and low dose Asprin.
• Glucocorticoids are Category A
• Cyclosporin, Tacrolimus Rituximab in Category C
• AZA, HCQs, MMF, CPM as category D
• MTX is Category X
• Management : HCQs and if required prednisone at lowest dose
for short time.
• Breast feeding should be avoided ( glucocorticoids and
immunosuppressants get into breast milk).
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.
 DISEASE ACTIVITY ASSESSMENT
• SLEDAI
• 24 lupus manifestations
• 16 Clinical, 8 lab parameters.
• – Mild : 0-5
• – Moderate : 6-12
• – Severe: 13-20
• Score reduction requires complete resolution.
• • 3 to 7 point reduction = clinically meaningful
improvement.
• SLEDAI Limitations
• Cannot measure partial improvement of individual parameter.
• Cannot measure worsening of an existing abnormality