SLE

S.L.E.(SYSTEMIC LUPUS ERYTHEMATOSUS)

By:Ibiwoye O. O.

A chronic multisystem autoimmune disease of protean manifestation and variable behavior

Lots of organs affected, affect any organ but skin, kidneys, serosal membrane, joints and heart stand out

Lots of autoantibodies and variable clinical presentation with so many overlaps with other autoimmune diseases

Reason for the development of the criteria with features ≥ 4 = diagnostic during interval of observations

F : M = 9:1 Just like all autoimmune diseases Affects any age, even early childhood but common in 2nd/3rd decade of

life (15-44 years), 1 in 700 women of childbearing age, 15-50 in 100, 000 of general population. Blacks > Hispanics > Asians

Its all about the failure of the body to maintain self tolerance (self-tolerance means that lymphocytes should not incite an immune response against human cellular antigens i.e. non-responsiveness of immune system to substance or tissue with capacity to elicit an immune response)

PATHOPHYSIOLOGYInherited susceptibility

genes Class II MHC HLA-DQ,

DR3 Complement

Others

Environmental triggerse.g. UVR, drugs, sex hormones,

infectious agents, stress

Increased burden of nuclear protein

fragments, other self antigens

Cellular apoptosis

Activation of T helpers and B cells specific for self antigens

IgG autoantibody production

Immune complex and autoantibody mediated tissue injury

DIAGNOSTIC CRITERIA/CLINICAL PRESENTATION

DOPAMIN RASH criteria by ACR has been supplanted by SLICC In 2015, revised criteria, both ACR/SLICC = combined. The patients with 4 points out of 16,

have definite diagnosis of SLE. With 3 points highly suggestive SLE, with 2 points probable SLE and with one point possible SLE are the diagnosis.

Radiological CBC Hormonal assay HLA Renal/Skin biopsy Autoantibody screening (serology, IF, ELISA) Urinalysis LE bodies/cells in 70% patients, now history, not in use anymore. It’s a

neutrophil or macrophage that has engulfed the denatured nucleus of another injured cell by the immune complex in vitro. Damaged nucleus lose their chromatin pattern = homogenous = hematoxylin/LE bodies in vivo

The highly specific markers Anti-dsDNA antibodies Anti-sm antibodies (99% of people without SLE lack it)

THE AUTOANTIBODIES ANAs subtypes

All ANAs – SS, Scl., MCTD, DM/PM (inflammatory myopathies) anti-nuclear RNP antibodies (U1RNP) – Sharp’s syndrome(MCTD) anti-Sm antibodies (core proteins of small nRNP particles – Smith antigen), anti-Scl-70 antibodies (DNA topoisomerase1) – Scl. anti-dsDNA antibodies (Native DNA), anti-histone antibodies – Scl. RA, DIL, MCTD antibodies to nuclear pore complexes, anti-centromere antibodies – Scl., PBC anti-sp100 antibodies - PBC anti- Jo 1 antibodies (Histidyl-Trna synthetase) - DM

Each of these antibody subtypes binds to different proteins or protein complexes within the nucleus. They are found in many disorders including autoimmunity, cancer and infection. This allows the use of ANAs in the diagnosis of some autoimmune disorders like SLE, SS, scleroderma, MCTD, AIH, inflammatory myopathies (PMs, DMs) and drug induced lupus.

So ANA = sensitive but not specific

Anti cytoplasmic antibodies Ribosomes (P proteins) Mitochondria Lysosomes anti-Ro (SS-A) antibodies (RNP) – SS, PBC, Celiac disease, PM, neonatal lupus + congenital heart

block anti-La (SS-B) antibodies (RNP) – SS, PBC

Antibodies react with various complexes of phospholipids with proteins = secondary APLS Anti-cardiolipin Lupus anticoagulant Antibodies to beta2-glycoprotein 1

Others Rhematoid factors (antibody reactive with self - IgG) C1q Heat shock proteins (hsp 70, 90)

Anti-cellular antibodies; RBCs - Anemia Platelets - Thrombocytopenia WBCs – Leukopenia, lymphopenia Thyroid - Hypothyroidism Neurons – diffuse CNS lupus

DDX Overlapping autoimmune diseases – difficult to differentiate

e.g. MTCD = features of SLE, RA, PMs, Scl. + high titers of anti-RNP

RA lupus arthritis causes less destruction of the joints than rheumatoid arthritis.

Various forms of dermatitis Neurologic disorders e.g. epilepsy, MS, psychiatry disorder Hematologic diseases e.g. ITP Drug-induced Lupus-like syndrome – chronic use and

depends on drug acetylation. ANA/Anti-histone antibodies but no antibodies to dsDNA and hypocomplementemia which are all present in idiopathic SLE

Infections e.g. bacterial endocarditis, histoplasmosis Primary/Idiopathic APLS – HLA DR7

MANAGEMENT/TREAMENT No cure Complete sustained remissions are rare Early diagnosis and treatment manages the symptoms and lessen

the chance of permanent damage to organs or tissues. For drugs to work effectively, higher doses are needed = more side

effectsNon life threatening manifestations/Mild/Remittent

Fever, arthralgia, myaldia, mild serositis, fatigue NSAIDs – toxicities common in SLE especially ↑ Liver enzymes,

aseptic meningitis, renal impairment – watch out for it Dermatitides, fatigue, lupus arthritis

Anti-malarials (TLR antagonist) like hydroxychloroquine 400 mg daily, topical/intralesional corticosteroids, quinacrine, retinoids, dapsone.

Life threatening, severely disabling manifestations Nephritis, CNS disease, Vasculitis

Corticosteroids (high dose 1-2mg/kg/day). In SLE active (divided doses every 8-12h). In SLE controlled (just 1 morning dose), then convert to alternate-day therapy with a single morning dose of short acting glucocorticoids (prednisolone 0.02 mg/kg/d) to minimize side effects. For flare-ups on the off-days, use the lowest single daily dose.

Immunizations against influenza/pneumococcal infections should be done to avoid the infections due to corticosteroids-induced immunosuppression. Give calcium 1000mg/day and vit D 50,000 units 3 times/week or calcitonin or bisphosphonates (alendronate) to minimize osteoporosis.

To avoid steroids side effects and for those unresponsive to steroids in active SLE, cytotoxic agents can be used Azathioprine (least toxic) 3mg/kg/day PO, methotrexate 20 mg once/week PO or SC, Cyclophosphamide (most effective/toxic) 15 mg/kg once/month IV. PO = increase side

effects give with MESNA 250 mg, mycophenolate mofetil 2.5 g/kg/day PO N.B Side effects = BM suppression, increased infection with opportunistic organism. After active SLE is controlled for a few months, taper the dose, then discontinue

NB – give Ondansetron 0.15 mg/kg/dose before/after the chemotherapy to prevent chemotherapy-induced nausea and vomiting.

Some manifestations of SLE don’t respond to immunosuppression (clotting disorders, behavioral abnormalities, end stage GN), Give anticoagulants high dose warfarin with INR maintained at 2.5-3.0, psychoactive drugs (duloxetine), renal transplantation/hemodialysis

Combination therapy high dose IV of glucocorticoids + cyclophosphosmaide + azathioprine = increase risk of infections

Plasmapharesis + cytotoxic agents + intravenous Immunoglobulins New/experimental therapies in patients with no response to above treatments

Induce tolerance to DNA by DNA vaccination to modulate immune responses affecting the Th1, Th2 and, importantly, the T Helpers cell

Interruption of T/B cell second signals with antibodies to CD40L, Immunoablation with high dose cyclophosphamide + or - autologous stem cell

transplantation, anti IFN alpha (Rontalizumab , rhuMAb IFNalpha), BENLYSTA (belimumab) inhibits B-cell activating factor Voclosporin, cyclosporine analog, calcineurin inhibitor, were twice as likely to

achieve complete remission than other drugs, Rituximab (treat diseases which are characterized by having too many B cells,

overactive B cells, or dysfunctional B cells with CD20 on their surfaces)

Prognosis Survival in patients with SLE is;

90-95% at 2 years 82-90% at 5 years 71-80% at 10 years 63-75% at 20 years

Factors with poor prognosis are; Serum creatinine > 124 μmol/L, hypertension, nephrotic syndrome (> 2.6 g excretion of

protein/24h, anemia (hb > 12.5 g/dl), hypoalbuminemia, hypocomplementemia at the time of diagnosis, low socioeconomic status

Thrombocytopenia, serious CNS involvement, antibodies to phospholipids, African-American race, Male sex

Infections and active SLE (renal failure) = death in 1st decade of disease Thromboembolic events = death in the 2nd decade. N.B Autoantibodies are typically present many years before the diagnosis of SLE.

Furthermore, the appearance of autoantibodies in patients with SLE tends to follow a predictable course, with a progressive accumulation of specific autoantibodies before the onset of SLE, while patients are still asymptomatic = “Invisible disease”- 4-6 years before diagnosis. SLE = GREAT IMITATOR!!!

An ongoing research ……. How We are Advancing Research on Lupus: Funding Promising Research - We fund groundbreaking studies into

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Reference Harrison’s principles of internal medicine http://

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http://www.amjmed.com/article/0002-9343(65)90199-3/abstract. American Journal of Medicine.

http://www.lupusresearchinstitute.org/lupus-news. Dhar JP, Sokol RJ. Lupus and pregnancy: complex yet manageable.

Clin Med Res. 2006 Dec;4(4):310-21. Uva L, Miguel D, Pinheiro C, Freitas J, et al. Cutaneous Manifestations

of Systemic Lupus Erythematosus. Autoimmune Diseases. 2012; 2012:15.

Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

SLE?SLE?