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Systemic Lupus Erythematosus Chapter 349 Harrison’s Principles of Internal Medicine (21st edition)
Definition • autoimmune disease in which organs and cells undergo damage initially mediated by tissue- binding autoantibodies and immune complexes • Most patients have autoantibodies present a few years before clinical symptoms • 90% in women of child bearing years • In US, non-white races especially in African- American and Afro-Carribean women
Pathophysiology • The abnormal immune response leads to production of increased quantities and immunogenic forms of nucleic acids, their accompanying proteins, and other self- antigens
• Net = decrease IL2, increase IL17
• SLE is a multigenetic disease. • Rare single-gene defects confer high hazard ratios for SLE (5–25), including homozygous deficiencies of early components of complement (C1q,r,s; C2; C4) and a mutation in TREX1 (encoding a DNAase) on the X chromosome. • In most genetically susceptible individuals, normal alleles of multiple genes each contribute a small amount to abnormal immune/inflammation/tissue damage responses; if enough predisposing variations are present, disease results.
• Approx 50% of known predisposing genes influence IFN production or function – the most characteristic increased gene expression pattern of SLE patients. • Female sex is permissive for SLE with evidence for hormone effects, genes on the X chromosome, and epigenetic differences between genders playing a role. • Females of many mammalian species make higher antibody responses than males.
• Women who use oral contraceptives are at increased risk as well. – Estradiol binds to the receptors of B and T cells increasing their activation and survival, favoring prolonged immune response • Smoking, infection (especially that of EBV), UV light, occupational exposure to silica increases risk
Pathology • Skin biopsies: deposition of Ig at the derma epidermal junction, injury to basal keratinocytes and inflammation dominated by T lymphocytes in the DEJ and around the blood vessels and dermal appendages. – Finding is suggestive but not specific • Renal biopsies: class III, IV, V should be treated with aggressive immunosuppressants because they are at high risk for ESRD – Treatment not recommended if with class I and II or with extensive irreversible changes
• In the SLICC criteria, a diagnosis can be established on the basis of renal class II or IV histology in the presence of lupus auto antibodies without meeting the additional criteria totalling 4. • Histologic abnormalities in blood vessels may also determine therapy. • Patterns of vasculitis are not specific for SLE but may indicate active disease – Leukocytoclastic vasculitis is most common • LN biopsies can be done to rule out infection or malignancies – in SLE it shows non specific diffuse chronic inflammation
Diagnosis • BASED on clinical features and autoantibodies • Combination of 4 or more criteria, with at least 1 in the clinical and one in the immunologic category, well documented at any time during the patient’s history • ANA is positive in >98% – Repeated negative tests by immunofluorescence suggest that SLE is less likely, unless other autoantibodies are present
• High-titer IgG antibodies to DS DNA and antibodies to the Sm antigen are both specific for SLE • The presence in an individual of multiple autoantibodies without clinical symptoms should not be considered diagnostic for SLE, although such persons are at increased risk
Interpretation of Clinical Manifestations • At the onset, it may affect multiple organs and over time, additional manifestations may occur • Most of the autoantibodies characteristic of each person are present at the time clinical manifestations appear • Severity varies from mild and intermittent to severe and fulminant • 85% have either continuing active disease or one or more flares of active disease annually
• Permanent complete remissions are rare • Treatment target is remission on therapy (no clinical manifestations; abnormal laboratory tests permitted)
Musculoskeletal Manifestation • Polyarthritis – Most, mild to disabling – Soft tissue swelling and tenderness in joints and or tendons, most in hands, wrist and knees • Only 10% have joint deformities • Erosions on the joints in 10-50% • If pain persists in a joint, a diagnosis of ischemic necrosis of the bone should be considered • Myositis with or without clinical muscle weakness may also occur, though may be a side effect of the medication
Cutaneous Manifestations • Can be acute, subacute and chronic • Discoid lupus erythematosus – Most common chronic dermatitis in lupus – 5% of people with DLE have SLE, in those with SLE up to 20% have DLE – Roughly circular with slightly raised, scaly hyperpigmented erythematous rims and depigmented atrophic centers in which all dermal appendages are permanently destroyed – Can be disfiguring to the face and scalp
• Butterfly rash – Most common acute SLE rash – Photosensitive, slightly raised erythema, occasionally scaly on the face, ears, chin, V region of the neck and chest, upper back and extensor surfaces of the arms – Worsening of the rash often accompanies flare of systemic disease
• Subacute cutaneous lupus erythematosus (SCLE) – Scaly red patches similar to psoriasis or circular flat red rimmed lesions – Exquisitely photosensitive – Most (+) anti-Ro (SS-A) • Other rashes: recurring urticaria, lichen planus like dermatitis, bullae, and panniculitis (lupus profundus) – can be minor or severe and be the major presentation of the disease
Renal Manifestations • Nephritis is usually the most serious manifestation of SLE – Nephritis and infection are the leading cause of mortality in the first decade of disease • Usually asymptomatic, hence urinalysis must be ordered • Renal biopsy is recommended in those with nephritis • Those with proliferative forms of glomerular damage (ISN III and IV) usually have microscopic hematuria and proteinuria (>500 mg per 24 hours), ½ develop nephrotic syndrome, and most develop hypertension
• If diffuse proliferative glomerulonephritis (DPGN) is inadequately treated, virtually all patients develop ESRD in 2 years of diagnosis • Aggressive immunosuppression is indicated unless the damage is irreversible • African Americans are more likely to develop ESRD than whites
• 20% of SLE patients with proteinuria (usually nephrotic) have membranous glomerular changes without proliferative changes on renal biopsy – Their outcome is better than for those with DPGN – but patients with class V and nephrotic range proteinuria should be treated in the same way as those with classes III or IV proliferative disease. • Tends to be an ongoing disease • Accelerated atherosclerosis becomes important after several years of disease; attention must be given to control of systemic inflammation, blood pressure, hyperlipidemia, and hyperglycemia.
Nervous System Manifestation • Ask first whether the symptoms result from SLE or another condition (such as infection in immunosuppressed individuals or side effects of therapies). • If symptoms are related to SLE – it should be determined whether they are caused by a diffuse process (requiring immunosuppression) – or vascular occlusive disease (requiring anticoagulation).
• Cognitive dysfunction – Most common manifestation of diffuse CNS lupus – Difficulties with memory and reasoning – Headaches (usually indicate SLE flare), when milder, they can be difficult to differentiate from migraine and tension headache • Seizures – Tx: anti seizure medications and immunosuppressive therapy
• Psychosis – Can be a dormant manifestation of SLE, must be distinguished from glucocorticoid induced psychosis – Glucocorticoid related: usually in the first weeks of therapy and with a daily dose of ≥40g/day prednisone or equivalent, it resolves after a several days of it has been decreased or stopped • Myelopathy – Not rare, often disabling – Tx: rapid initiation of immunosuppressive therapy and high dose glucocorticoids
Vascular Occlusions Including Stroke and Myocardial Infarctions • Increased in the this population, especially in those with antibodies to phospholipids (APAS) • Brain: ischemia caused by focal occlusion or by embolization from the carotid artery plaque or from fibrinous vegetations of Libmann Sacks endocarditis – When it is most likely that a cerebral event results from clotting, long term anticoagulation is the therapy of choice
• 2 processes can occur at once – vasculitis plus bland vascular occlusions – in which case it is appropriate to treat with anticoagulation plus immunosuppression • MI – primarily manifestation of accelerated atherosclerosis – Increased risk of 3-10X – Highest in women <49 years old
– Characteristics associated with increase risk: male, older, hypertension, dyslipidemia, diabetes, dysfunctional proinflammatory high density liproproteins, repeated high scores for disease activity, high cumulative or daily doses of steroids and high serum level of homocysteine and leptin – Statin therapies reduce LDL and cardiac events
Pulmonary Manifestations • Most common manifestations of pleuritis with or without effusion • When mild may respond to NSAIDs, when more severe, patients will need a brief course of steroid therapy • Pulmonary infiltrates also occur as a manifestation and is difficult to distinguish from infection on imaging • Life threatening: interstitial inflammation leading to fibrosis, shrinking lung syndrome, and intraalveolar hemorrhage
Cardiac Manifestations • Most common manifestation: pericarditis – Usually responds to anti inflammatory therapy and infrequently leads to tamponade • More serious manifestations: myocarditis, fibrinous endocarditis of Libmann-Sacks • Endocardial involvement can lead to valvular insufficiencies, most commonly mitral and aortic, or embolic events • Common practice to give trial of high dose steroids although improvement has not been proven • Increased risk of MI: from immune attack, chronic inflammation and or chronic oxidative damage to arteries
Hematologic Manifestations • Most common manifestation: anemia – Normochromic, normocytic reflecting chronic illness – Hemolysis can be rapid in onset and severe • Leukopenia also common, almost always consists of lymphopenia, this rarely predisposes to infections and rarely needs therapy • Thrombocytopenia: recurring problem, if >40k and (-) bleeding, therapy may not be required – High dose steroids (1mg/kg/day of prednisone or equivalent) • If the anemia and thrombocytopenia is recurrent, additional strategies such as rituximab, platelet growth factors and or splenectomy are needed
Gastrointestinal Manifestations • Nausea sometimes with vomiting, and diarrhea can be manifestations of SLE in flare • Diffuse abdominal pain can be caused by autoimmune peritonitis and or intestinal vasculitis • ALT/AST can be elevated when SLE is active • Vasculitis involving the intestines may be life threatening; perforations, ischemia, bleeding and sepsis are frequent complications • Improve with systemic steroids
Ocular Manifestations • Sicca syndrome and nonspecific conjunctivitis are common in SLE and rarely threaten vision • Renal vasculitis and optic neuritis are serious manifestations: blindness can occur in days to weeks • Aggressive immunosuppression is recommended • Complications of systemic and intraorbital steroids including cataracts (common) and glaucoma
Laboratory Tests establish or rule out the diagnosis follow the course of disease, particularly to suggest that a flare is occurring or organ damage is developing identify adverse effects of therapies
Tests for Autoantibodies • ANA – Most important to detect – Positive in >95% usually at the onset of symptoms – Immunofluorescent methods is more reliable than ELISA – ANA negative lupus exists but is rare, usually associated with other autoantibodies • DsDNA – Specific – Titers vary over time, increase in levels herald flares esp for vasculitis or nephritis, assoc with decrease in C3 or C4
• Anti-Sm – Specific – Do not usually correlate with disease activity or clinical manifestations • Antiphospholipid antibodies – Not specific – Identify patients at increase risk for venous or arterial clotting, thrombocytopenia and fetal loss – Quantities vary markedly over time, repeated testing is recommended if clinical manifestations of APAS appear • one or more clotting episodes and/or repeated fetal losses • plus at least two positive tests for antiphospholipid antibodies, at least 12 weeks apart • Not all patients with APAS meet this criteria
• Anti Ro/SS-A – Indicates increased risk for neonatal lupus, sicca syndrome, and SCLE – Women with child bearing potential and SLE should be screened for APAS and anti Ro because both antibodies have the potential to cause fetal harm
Standard Test for Diagnosis • CBC • Urinalysis
Tests for Following Disease Course • Urinalysis: hematuria and proteinuria • CBC: Hgb, platelet levels, • Creatinine, albumin • Autoantibodies • None are uniformly agreed upon as a reliable indicator for flare or response to therapy – Decrease complement, rising anti DNA, increasing proteinuria, worsening anemia
Management • No CURE • Complete sustained remissions are rare • Aim for now is low level disease activity (mild symptoms on the lowest possible doses of medications) – achieved in 30-50% of patients • LLDAS is defined as – As SLEDAI 2K score <=4 – No new lupus activity compared to the previous visit – Physicians global assessment <=1 – Current prednisone dose <=7.5mg daily – Well tolerated stable doses of antimalarials and or immunosuppresives
Management • Therapeutic choices depend on 1. Whether disease manifestations are life threatening or likely to cause organ damage, justifying aggressive therapies 2. Whether manifestations are potentially reversible 3. The best approach to prevent complications of the disease and treatments
Conservative Therapies • Fatigue + pain + autoantibodies = SLE, but without organ involvement, management can be directed to suppression of symptoms • Analgesics – NSAIDS but • SLE patients are at increased risk for NSAID-induced aseptic meningitis, elevated serum transaminases, hypertension, and renal dysfunction • All NSAIDS esp COX 2 inhibitors may increase risk of MI • Helpful to control pain
• Anti-malarials (hydroxychloroquine, chloroquine, and quinacrine) – HCQ prolongs survival and reduces accrual of tissue damage, including renal damage over time – Recommended HCQ blood level of ≥750 ng/ml – Ophthalmologic examination: risk of renal toxicity
• Belimumab and anifrolumab – Effective in those with persistent disease activity and fatigue despite therapies – Usually patients with SLEDAI score of ≥10, (+) anti-DNA and low complement are most likely to respond. • Lupus dermatitis: topical sunscreens, antimalarials, topical glucocorticoids and/or tacrolimus, and if severe or unresponsive, systemic steroids with or without mycophenolate mofetil, azathioprine, or belimumab/anifrolumab
Life Threatening SLE: Proliferative Forms of Lupus Nephritis • The mainstay of treatment for any inflammatory life- threatening or organ-threatening manifestations is systemic glucocorticoids (0.5–1 mg/kg per day PO or 500–1000 mg of methylprednisolone sodium succinate IV daily for 3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent) • Currently, high dose are recommended for shorter periods in severe SLE 4-6 weeks (from 4-6 months), thereby the dose is tapered usually to a maintenance dose of 0.5-1mg/kg of prednisone a day
• Need to reduce the dose because of the possible side effects of the steroids over time • Addition of cytotoxic/immunosuppressive agents are recommended on top of steroids for treatment of serious SLE (esp nephritis) – Cyclophosphamide (alkylating agent) or mycophenolate mofetil (a lymphocyte specific inhibitor of inosine monophosphates therefore a of purine synthesis) – Azathioprine (a purine analogue and cycle specific antimetabolite) may be effective but is associated with more flares
• MMF: diarrhea • Cyclophosphamide: amenorrhea, leukopenia, nausea • High-dose cyclophosphamide (500–1000 mg/m2 body surface area given monthly IV for 6 months, followed by azathioprine or mycophenolate maintenance) • The ovarian failure in cyclophosphamide can be avoided with the use of gonadotropin releasing hormone agonist (leuprolide 3.75 mg intramuscularly) prior to each cyclophosphamide dose • For maintenance therapy: MMF and azathioprine probably are similar in efficacy and toxicity, both safer than cyclophosphamide
• For those patients with high crea (≥3 mg/dL) many months in duration and high chronicity scores on biopsy are not likely to respond to the above treatment • MMF, cyclophosphamide, methotrexate, and calcineurin inhibitors is potentially teratogenic, hence patients must be off medications 3 months before attempting to conceive • Azathioprine can be used during pregnancy – Screen for TMPT enzyme deficiency: risk for BM suppression
• Methotrexate (a folinic acid antagonist) may have a role in arthritis and dermatitis but probably not in nephritis and other life threatening disease • Hydroxychloroquine (HCQ): prevents damage in skin and kidney and reduces overall damage scores • Those with proteinuria >500mg daily should receive ACEI or ARBs as they reduce chance of ESRD
• anti-CD20 (rituximab) is controversial – recent prospective placebo-controlled randomized trials, one in renal and one in nonrenal SLE, did not show a difference between anti-CD20 and placebo when added to standard combination therapies. • Belimumab, which is approved by the FDA for use lupus nephritis • Telitacicept (fusion protein) – ongoing trials
• Pregnancy and Lupus – Fertility rates are probably normal – Rate of fetal loss is increased – Disease activity can be controlled with steroids • A placental enzyme, 11-β-dehydrogenase 2, deactivates glucocorticoids; it is more effective in deactivating prednisone and prednisolone than the fluorinated glucocorticoids dexamethasone and betamethasone – Categories • Fetal risk cant be ruled out: steroids, HCQ, belimumab, cyclosporine • May cause fetal harm: rituximab, azathioprine, cyclophosphamide, tacrolimus, voclosporin • Fetal risk has been demonstrated/avoid in pregnancy: MMF, methotrexate Special Conditions in SLE that may Require Additional or Different Therapies
• Pregnancy and Lupus – active SLE in pregnant women should be controlled with HCQ and, if necessary, prednisone/prednisolone at the lowest effective doses for the shortest time required – Azathioprine can be added if disease activity isn’t suppressed – ADR of steroids: low birth weight, developmental abnormalities in the CNS, and predilection toward adult metabolic syndrome – Likely that each of the medications reach breast milk hence breast feeding is discouraged
• Pregnancy and Lupus – Those with APAS: recommended to take heparin and low dose aspirin to increase probability of live births – Warfarin is teratogenic – DOACs: avoided – Anti Ro: associated with neonatal lupus consisting of rash, congenital heart block with/out cardiomyopathy • HCQ treatment shows to decrease the change of heart block • Dexamethasone may decrease progression of heart block – Women usually tolerate the pregnancy without flares – Some develop severe flares requiring aggressive steroid therapy or early delivery
• SLE and APAS – venous or arterial clotting and/or repeated fetal losses and or at least 2 positive tests for APAS antibodies should be on long term anticoagulant – Warfarin, • INR goal is 2-2.5 if with 1 episode of venous clotting • INR of 3-3.5 in those with recurrent clots or arterial clots especially in the CNS – DOACs not effective
• Microvascular Thrombotic Crisis (Thrombotic Thrombocytopenic Purpura, Hemolytic-Uremic Syndrome) – High mortality rate – Common in young with lupus nephritis – Most useful lab test is to identify schistocytes, elevated LDH, low ADAMS13 activity – Plasma exchange or extensive plasmapheresis is usually life saving, most authorities recommend concomitant steroid therapy – Rituximab and eculizumab in refractory cases
• Lupus Dermatitis – Minimize UV exposure, use proper clothing, sunscreen with at least SPF 30 – Topical steroids and anti-malarials are effective in reducing lesion severity – Retinoic therapy: causes fetal abnormalities – Extensive, pruritic, bullous, or ulcerating dermatitides usually improve promptly after institution of systemic steroids; tapering may be accompanied by flare of lesions, thus necessitating use of a second medication such as HCQ, retinoids, or belimumab.
• Lupus Dermatitis – In therapy-resistant lupus dermatitis there are reports of success with topical tacrolimus (caution must be exerted because of the possible increased risk for malignancies) or with systemic dapsone or thalidomide (the extreme danger of fetal deformities from thalidomide requires permission from and supervision by the supplier; peripheral neuropathy is also common).
Preventive Therapies • Vaccination: influenza and pneumococcal • Supressing recurrent UTI • Vaccination with attenuated live viruses is generally discouraged in patients who are immunosuppressed; however, a recent study of vaccination of a small number of SLE patient with Zostavax • If on >20 mg prednisone – protect from PCP with TMPSMX or atovaquone – Recurrent herpes simplex with acyclovir – In generally on steroids, prevent osteoporosis: calcium supplements, vitamin D, bisphosphonates or denosumab • Control hypertension – Dyslipidemia, hyperglycemia, obesity • Increase in cancers: non Hodgkins lymphomas and cancers of the thyroid, lung, liver and vulvar/vaginal tissues
Patient Outcomes, Prognosis and Survival • In the United States, African Americans and Hispanic Americans with a mestizo heritage have a worse prognosis • Poor prognosis (~50% mortality in 10 years) is associated with (at the time of diagnosis) – high serum creatinine levels (>124 μmol/L [>1.4 mg/dL]), – Hypertension – nephrotic syndrome (24-h urine protein excretion >2.6 g) – anemia (hemoglobin <124 g/L [<12.4 g/dL]) – Hypoalbuminemia – Hypocomplementemia – antiphospholipid antibodies – male sex – ethnicity (African American, Hispanic with mestizo heritage) – low socioeconomic status
• Overall patient survival in SLE with renal transplant is 85% in 2 years • Lupus nephritis occurs in ~5% of transplanted kidneys • 30–50% of patients may achieve low disease activity (defined as mild activity on HCQ with or without low dose glucocorticoids) • fewer than 10% experience remissions (defined as no disease activity on no medications) • The leading causes of death in the first decade of disease are systemic disease activity, renal failure, and infections; subsequently, thromboembolic events become increasingly frequent causes of mortality.
Drug Induced Lupus • Syndrome of positive ANA + fever, malaise, arthritis, or intense arthralgias/myalgias, serositis or rash • appears during therapy with certain medications and biologic agents – predominant in whites, has less female predilection than SLE, rarely involves kidneys or brain, is rarely associated with anti-dsDNA, is commonly associated with antibodies to histones – Resolves over several weeks after discontinuation of the medication
Causative agents • Anti-arrhythmics: procainamide, disopyramide, and propafenone • anti-hypertensive: hydralazine, several ACEI and beta blockers • Anti-thyroid: PTU • Antipsychotics: chlorpromazine and lithium • Anticonvulsants: carbamazepine and phenytoin • Antibiotics: isoniazid, minocycline, and nitrofurantoin • Anti-rheumatic: sulfasalazine • Diuretic: hydrochlorothiazide • Anti-hyperlipidemics: lovastatin and simvastatin • Biologics: inhibitors to IFNs and TNF • ANA usually appears before symptoms • However many of the above medications induce ANA without causing any symptoms • It is appropriate to test for ANA at the first hint of relevant symptoms to help decide if medications should be discontinued
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This ppt is a detailed explanation about SLE

  • 1.
    Systemic Lupus Erythematosus Chapter349 Harrison’s Principles of Internal Medicine (21st edition)
  • 2.
    Definition • autoimmune diseasein which organs and cells undergo damage initially mediated by tissue- binding autoantibodies and immune complexes • Most patients have autoantibodies present a few years before clinical symptoms • 90% in women of child bearing years • In US, non-white races especially in African- American and Afro-Carribean women
  • 3.
    Pathophysiology • The abnormalimmune response leads to production of increased quantities and immunogenic forms of nucleic acids, their accompanying proteins, and other self- antigens
  • 4.
    • Net =decrease IL2, increase IL17
  • 5.
    • SLE isa multigenetic disease. • Rare single-gene defects confer high hazard ratios for SLE (5–25), including homozygous deficiencies of early components of complement (C1q,r,s; C2; C4) and a mutation in TREX1 (encoding a DNAase) on the X chromosome. • In most genetically susceptible individuals, normal alleles of multiple genes each contribute a small amount to abnormal immune/inflammation/tissue damage responses; if enough predisposing variations are present, disease results.
  • 6.
    • Approx 50%of known predisposing genes influence IFN production or function – the most characteristic increased gene expression pattern of SLE patients. • Female sex is permissive for SLE with evidence for hormone effects, genes on the X chromosome, and epigenetic differences between genders playing a role. • Females of many mammalian species make higher antibody responses than males.
  • 7.
    • Women whouse oral contraceptives are at increased risk as well. – Estradiol binds to the receptors of B and T cells increasing their activation and survival, favoring prolonged immune response • Smoking, infection (especially that of EBV), UV light, occupational exposure to silica increases risk
  • 8.
    Pathology • Skin biopsies:deposition of Ig at the derma epidermal junction, injury to basal keratinocytes and inflammation dominated by T lymphocytes in the DEJ and around the blood vessels and dermal appendages. – Finding is suggestive but not specific • Renal biopsies: class III, IV, V should be treated with aggressive immunosuppressants because they are at high risk for ESRD – Treatment not recommended if with class I and II or with extensive irreversible changes
  • 9.
    • In theSLICC criteria, a diagnosis can be established on the basis of renal class II or IV histology in the presence of lupus auto antibodies without meeting the additional criteria totalling 4. • Histologic abnormalities in blood vessels may also determine therapy. • Patterns of vasculitis are not specific for SLE but may indicate active disease – Leukocytoclastic vasculitis is most common • LN biopsies can be done to rule out infection or malignancies – in SLE it shows non specific diffuse chronic inflammation
  • 11.
    Diagnosis • BASED onclinical features and autoantibodies • Combination of 4 or more criteria, with at least 1 in the clinical and one in the immunologic category, well documented at any time during the patient’s history • ANA is positive in >98% – Repeated negative tests by immunofluorescence suggest that SLE is less likely, unless other autoantibodies are present
  • 12.
    • High-titer IgGantibodies to DS DNA and antibodies to the Sm antigen are both specific for SLE • The presence in an individual of multiple autoantibodies without clinical symptoms should not be considered diagnostic for SLE, although such persons are at increased risk
  • 17.
    Interpretation of ClinicalManifestations • At the onset, it may affect multiple organs and over time, additional manifestations may occur • Most of the autoantibodies characteristic of each person are present at the time clinical manifestations appear • Severity varies from mild and intermittent to severe and fulminant • 85% have either continuing active disease or one or more flares of active disease annually
  • 18.
    • Permanent completeremissions are rare • Treatment target is remission on therapy (no clinical manifestations; abnormal laboratory tests permitted)
  • 20.
    Musculoskeletal Manifestation • Polyarthritis –Most, mild to disabling – Soft tissue swelling and tenderness in joints and or tendons, most in hands, wrist and knees • Only 10% have joint deformities • Erosions on the joints in 10-50% • If pain persists in a joint, a diagnosis of ischemic necrosis of the bone should be considered • Myositis with or without clinical muscle weakness may also occur, though may be a side effect of the medication
  • 21.
    Cutaneous Manifestations • Canbe acute, subacute and chronic • Discoid lupus erythematosus – Most common chronic dermatitis in lupus – 5% of people with DLE have SLE, in those with SLE up to 20% have DLE – Roughly circular with slightly raised, scaly hyperpigmented erythematous rims and depigmented atrophic centers in which all dermal appendages are permanently destroyed – Can be disfiguring to the face and scalp
  • 23.
    • Butterfly rash –Most common acute SLE rash – Photosensitive, slightly raised erythema, occasionally scaly on the face, ears, chin, V region of the neck and chest, upper back and extensor surfaces of the arms – Worsening of the rash often accompanies flare of systemic disease
  • 25.
    • Subacute cutaneouslupus erythematosus (SCLE) – Scaly red patches similar to psoriasis or circular flat red rimmed lesions – Exquisitely photosensitive – Most (+) anti-Ro (SS-A) • Other rashes: recurring urticaria, lichen planus like dermatitis, bullae, and panniculitis (lupus profundus) – can be minor or severe and be the major presentation of the disease
  • 27.
    Renal Manifestations • Nephritisis usually the most serious manifestation of SLE – Nephritis and infection are the leading cause of mortality in the first decade of disease • Usually asymptomatic, hence urinalysis must be ordered • Renal biopsy is recommended in those with nephritis • Those with proliferative forms of glomerular damage (ISN III and IV) usually have microscopic hematuria and proteinuria (>500 mg per 24 hours), ½ develop nephrotic syndrome, and most develop hypertension
  • 28.
    • If diffuseproliferative glomerulonephritis (DPGN) is inadequately treated, virtually all patients develop ESRD in 2 years of diagnosis • Aggressive immunosuppression is indicated unless the damage is irreversible • African Americans are more likely to develop ESRD than whites
  • 29.
    • 20% ofSLE patients with proteinuria (usually nephrotic) have membranous glomerular changes without proliferative changes on renal biopsy – Their outcome is better than for those with DPGN – but patients with class V and nephrotic range proteinuria should be treated in the same way as those with classes III or IV proliferative disease. • Tends to be an ongoing disease • Accelerated atherosclerosis becomes important after several years of disease; attention must be given to control of systemic inflammation, blood pressure, hyperlipidemia, and hyperglycemia.
  • 30.
    Nervous System Manifestation •Ask first whether the symptoms result from SLE or another condition (such as infection in immunosuppressed individuals or side effects of therapies). • If symptoms are related to SLE – it should be determined whether they are caused by a diffuse process (requiring immunosuppression) – or vascular occlusive disease (requiring anticoagulation).
  • 31.
    • Cognitive dysfunction –Most common manifestation of diffuse CNS lupus – Difficulties with memory and reasoning – Headaches (usually indicate SLE flare), when milder, they can be difficult to differentiate from migraine and tension headache • Seizures – Tx: anti seizure medications and immunosuppressive therapy
  • 32.
    • Psychosis – Canbe a dormant manifestation of SLE, must be distinguished from glucocorticoid induced psychosis – Glucocorticoid related: usually in the first weeks of therapy and with a daily dose of ≥40g/day prednisone or equivalent, it resolves after a several days of it has been decreased or stopped • Myelopathy – Not rare, often disabling – Tx: rapid initiation of immunosuppressive therapy and high dose glucocorticoids
  • 33.
    Vascular Occlusions IncludingStroke and Myocardial Infarctions • Increased in the this population, especially in those with antibodies to phospholipids (APAS) • Brain: ischemia caused by focal occlusion or by embolization from the carotid artery plaque or from fibrinous vegetations of Libmann Sacks endocarditis – When it is most likely that a cerebral event results from clotting, long term anticoagulation is the therapy of choice
  • 34.
    • 2 processescan occur at once – vasculitis plus bland vascular occlusions – in which case it is appropriate to treat with anticoagulation plus immunosuppression • MI – primarily manifestation of accelerated atherosclerosis – Increased risk of 3-10X – Highest in women <49 years old
  • 35.
    – Characteristics associatedwith increase risk: male, older, hypertension, dyslipidemia, diabetes, dysfunctional proinflammatory high density liproproteins, repeated high scores for disease activity, high cumulative or daily doses of steroids and high serum level of homocysteine and leptin – Statin therapies reduce LDL and cardiac events
  • 36.
    Pulmonary Manifestations • Mostcommon manifestations of pleuritis with or without effusion • When mild may respond to NSAIDs, when more severe, patients will need a brief course of steroid therapy • Pulmonary infiltrates also occur as a manifestation and is difficult to distinguish from infection on imaging • Life threatening: interstitial inflammation leading to fibrosis, shrinking lung syndrome, and intraalveolar hemorrhage
  • 37.
    Cardiac Manifestations • Mostcommon manifestation: pericarditis – Usually responds to anti inflammatory therapy and infrequently leads to tamponade • More serious manifestations: myocarditis, fibrinous endocarditis of Libmann-Sacks • Endocardial involvement can lead to valvular insufficiencies, most commonly mitral and aortic, or embolic events • Common practice to give trial of high dose steroids although improvement has not been proven • Increased risk of MI: from immune attack, chronic inflammation and or chronic oxidative damage to arteries
  • 38.
    Hematologic Manifestations • Mostcommon manifestation: anemia – Normochromic, normocytic reflecting chronic illness – Hemolysis can be rapid in onset and severe • Leukopenia also common, almost always consists of lymphopenia, this rarely predisposes to infections and rarely needs therapy • Thrombocytopenia: recurring problem, if >40k and (-) bleeding, therapy may not be required – High dose steroids (1mg/kg/day of prednisone or equivalent) • If the anemia and thrombocytopenia is recurrent, additional strategies such as rituximab, platelet growth factors and or splenectomy are needed
  • 39.
    Gastrointestinal Manifestations • Nauseasometimes with vomiting, and diarrhea can be manifestations of SLE in flare • Diffuse abdominal pain can be caused by autoimmune peritonitis and or intestinal vasculitis • ALT/AST can be elevated when SLE is active • Vasculitis involving the intestines may be life threatening; perforations, ischemia, bleeding and sepsis are frequent complications • Improve with systemic steroids
  • 40.
    Ocular Manifestations • Siccasyndrome and nonspecific conjunctivitis are common in SLE and rarely threaten vision • Renal vasculitis and optic neuritis are serious manifestations: blindness can occur in days to weeks • Aggressive immunosuppression is recommended • Complications of systemic and intraorbital steroids including cataracts (common) and glaucoma
  • 41.
    Laboratory Tests establish orrule out the diagnosis follow the course of disease, particularly to suggest that a flare is occurring or organ damage is developing identify adverse effects of therapies
  • 42.
    Tests for Autoantibodies •ANA – Most important to detect – Positive in >95% usually at the onset of symptoms – Immunofluorescent methods is more reliable than ELISA – ANA negative lupus exists but is rare, usually associated with other autoantibodies • DsDNA – Specific – Titers vary over time, increase in levels herald flares esp for vasculitis or nephritis, assoc with decrease in C3 or C4
  • 43.
    • Anti-Sm – Specific –Do not usually correlate with disease activity or clinical manifestations • Antiphospholipid antibodies – Not specific – Identify patients at increase risk for venous or arterial clotting, thrombocytopenia and fetal loss – Quantities vary markedly over time, repeated testing is recommended if clinical manifestations of APAS appear • one or more clotting episodes and/or repeated fetal losses • plus at least two positive tests for antiphospholipid antibodies, at least 12 weeks apart • Not all patients with APAS meet this criteria
  • 44.
    • Anti Ro/SS-A –Indicates increased risk for neonatal lupus, sicca syndrome, and SCLE – Women with child bearing potential and SLE should be screened for APAS and anti Ro because both antibodies have the potential to cause fetal harm
  • 45.
    Standard Test forDiagnosis • CBC • Urinalysis
  • 46.
    Tests for FollowingDisease Course • Urinalysis: hematuria and proteinuria • CBC: Hgb, platelet levels, • Creatinine, albumin • Autoantibodies • None are uniformly agreed upon as a reliable indicator for flare or response to therapy – Decrease complement, rising anti DNA, increasing proteinuria, worsening anemia
  • 47.
    Management • No CURE •Complete sustained remissions are rare • Aim for now is low level disease activity (mild symptoms on the lowest possible doses of medications) – achieved in 30-50% of patients • LLDAS is defined as – As SLEDAI 2K score <=4 – No new lupus activity compared to the previous visit – Physicians global assessment <=1 – Current prednisone dose <=7.5mg daily – Well tolerated stable doses of antimalarials and or immunosuppresives
  • 48.
    Management • Therapeutic choicesdepend on 1. Whether disease manifestations are life threatening or likely to cause organ damage, justifying aggressive therapies 2. Whether manifestations are potentially reversible 3. The best approach to prevent complications of the disease and treatments
  • 51.
    Conservative Therapies • Fatigue+ pain + autoantibodies = SLE, but without organ involvement, management can be directed to suppression of symptoms • Analgesics – NSAIDS but • SLE patients are at increased risk for NSAID-induced aseptic meningitis, elevated serum transaminases, hypertension, and renal dysfunction • All NSAIDS esp COX 2 inhibitors may increase risk of MI • Helpful to control pain
  • 52.
    • Anti-malarials (hydroxychloroquine, chloroquine,and quinacrine) – HCQ prolongs survival and reduces accrual of tissue damage, including renal damage over time – Recommended HCQ blood level of ≥750 ng/ml – Ophthalmologic examination: risk of renal toxicity
  • 53.
    • Belimumab andanifrolumab – Effective in those with persistent disease activity and fatigue despite therapies – Usually patients with SLEDAI score of ≥10, (+) anti-DNA and low complement are most likely to respond. • Lupus dermatitis: topical sunscreens, antimalarials, topical glucocorticoids and/or tacrolimus, and if severe or unresponsive, systemic steroids with or without mycophenolate mofetil, azathioprine, or belimumab/anifrolumab
  • 54.
    Life Threatening SLE:Proliferative Forms of Lupus Nephritis • The mainstay of treatment for any inflammatory life- threatening or organ-threatening manifestations is systemic glucocorticoids (0.5–1 mg/kg per day PO or 500–1000 mg of methylprednisolone sodium succinate IV daily for 3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent) • Currently, high dose are recommended for shorter periods in severe SLE 4-6 weeks (from 4-6 months), thereby the dose is tapered usually to a maintenance dose of 0.5-1mg/kg of prednisone a day
  • 55.
    • Need toreduce the dose because of the possible side effects of the steroids over time • Addition of cytotoxic/immunosuppressive agents are recommended on top of steroids for treatment of serious SLE (esp nephritis) – Cyclophosphamide (alkylating agent) or mycophenolate mofetil (a lymphocyte specific inhibitor of inosine monophosphates therefore a of purine synthesis) – Azathioprine (a purine analogue and cycle specific antimetabolite) may be effective but is associated with more flares
  • 56.
    • MMF: diarrhea •Cyclophosphamide: amenorrhea, leukopenia, nausea • High-dose cyclophosphamide (500–1000 mg/m2 body surface area given monthly IV for 6 months, followed by azathioprine or mycophenolate maintenance) • The ovarian failure in cyclophosphamide can be avoided with the use of gonadotropin releasing hormone agonist (leuprolide 3.75 mg intramuscularly) prior to each cyclophosphamide dose • For maintenance therapy: MMF and azathioprine probably are similar in efficacy and toxicity, both safer than cyclophosphamide
  • 57.
    • For thosepatients with high crea (≥3 mg/dL) many months in duration and high chronicity scores on biopsy are not likely to respond to the above treatment • MMF, cyclophosphamide, methotrexate, and calcineurin inhibitors is potentially teratogenic, hence patients must be off medications 3 months before attempting to conceive • Azathioprine can be used during pregnancy – Screen for TMPT enzyme deficiency: risk for BM suppression
  • 58.
    • Methotrexate (afolinic acid antagonist) may have a role in arthritis and dermatitis but probably not in nephritis and other life threatening disease • Hydroxychloroquine (HCQ): prevents damage in skin and kidney and reduces overall damage scores • Those with proteinuria >500mg daily should receive ACEI or ARBs as they reduce chance of ESRD
  • 59.
    • anti-CD20 (rituximab)is controversial – recent prospective placebo-controlled randomized trials, one in renal and one in nonrenal SLE, did not show a difference between anti-CD20 and placebo when added to standard combination therapies. • Belimumab, which is approved by the FDA for use lupus nephritis • Telitacicept (fusion protein) – ongoing trials
  • 60.
    • Pregnancy andLupus – Fertility rates are probably normal – Rate of fetal loss is increased – Disease activity can be controlled with steroids • A placental enzyme, 11-β-dehydrogenase 2, deactivates glucocorticoids; it is more effective in deactivating prednisone and prednisolone than the fluorinated glucocorticoids dexamethasone and betamethasone – Categories • Fetal risk cant be ruled out: steroids, HCQ, belimumab, cyclosporine • May cause fetal harm: rituximab, azathioprine, cyclophosphamide, tacrolimus, voclosporin • Fetal risk has been demonstrated/avoid in pregnancy: MMF, methotrexate Special Conditions in SLE that may Require Additional or Different Therapies
  • 61.
    • Pregnancy andLupus – active SLE in pregnant women should be controlled with HCQ and, if necessary, prednisone/prednisolone at the lowest effective doses for the shortest time required – Azathioprine can be added if disease activity isn’t suppressed – ADR of steroids: low birth weight, developmental abnormalities in the CNS, and predilection toward adult metabolic syndrome – Likely that each of the medications reach breast milk hence breast feeding is discouraged
  • 62.
    • Pregnancy andLupus – Those with APAS: recommended to take heparin and low dose aspirin to increase probability of live births – Warfarin is teratogenic – DOACs: avoided – Anti Ro: associated with neonatal lupus consisting of rash, congenital heart block with/out cardiomyopathy • HCQ treatment shows to decrease the change of heart block • Dexamethasone may decrease progression of heart block – Women usually tolerate the pregnancy without flares – Some develop severe flares requiring aggressive steroid therapy or early delivery
  • 63.
    • SLE andAPAS – venous or arterial clotting and/or repeated fetal losses and or at least 2 positive tests for APAS antibodies should be on long term anticoagulant – Warfarin, • INR goal is 2-2.5 if with 1 episode of venous clotting • INR of 3-3.5 in those with recurrent clots or arterial clots especially in the CNS – DOACs not effective
  • 64.
    • Microvascular ThromboticCrisis (Thrombotic Thrombocytopenic Purpura, Hemolytic-Uremic Syndrome) – High mortality rate – Common in young with lupus nephritis – Most useful lab test is to identify schistocytes, elevated LDH, low ADAMS13 activity – Plasma exchange or extensive plasmapheresis is usually life saving, most authorities recommend concomitant steroid therapy – Rituximab and eculizumab in refractory cases
  • 65.
    • Lupus Dermatitis –Minimize UV exposure, use proper clothing, sunscreen with at least SPF 30 – Topical steroids and anti-malarials are effective in reducing lesion severity – Retinoic therapy: causes fetal abnormalities – Extensive, pruritic, bullous, or ulcerating dermatitides usually improve promptly after institution of systemic steroids; tapering may be accompanied by flare of lesions, thus necessitating use of a second medication such as HCQ, retinoids, or belimumab.
  • 66.
    • Lupus Dermatitis –In therapy-resistant lupus dermatitis there are reports of success with topical tacrolimus (caution must be exerted because of the possible increased risk for malignancies) or with systemic dapsone or thalidomide (the extreme danger of fetal deformities from thalidomide requires permission from and supervision by the supplier; peripheral neuropathy is also common).
  • 67.
    Preventive Therapies • Vaccination:influenza and pneumococcal • Supressing recurrent UTI • Vaccination with attenuated live viruses is generally discouraged in patients who are immunosuppressed; however, a recent study of vaccination of a small number of SLE patient with Zostavax • If on >20 mg prednisone – protect from PCP with TMPSMX or atovaquone – Recurrent herpes simplex with acyclovir – In generally on steroids, prevent osteoporosis: calcium supplements, vitamin D, bisphosphonates or denosumab • Control hypertension – Dyslipidemia, hyperglycemia, obesity • Increase in cancers: non Hodgkins lymphomas and cancers of the thyroid, lung, liver and vulvar/vaginal tissues
  • 68.
    Patient Outcomes, Prognosisand Survival • In the United States, African Americans and Hispanic Americans with a mestizo heritage have a worse prognosis • Poor prognosis (~50% mortality in 10 years) is associated with (at the time of diagnosis) – high serum creatinine levels (>124 μmol/L [>1.4 mg/dL]), – Hypertension – nephrotic syndrome (24-h urine protein excretion >2.6 g) – anemia (hemoglobin <124 g/L [<12.4 g/dL]) – Hypoalbuminemia – Hypocomplementemia – antiphospholipid antibodies – male sex – ethnicity (African American, Hispanic with mestizo heritage) – low socioeconomic status
  • 69.
    • Overall patientsurvival in SLE with renal transplant is 85% in 2 years • Lupus nephritis occurs in ~5% of transplanted kidneys • 30–50% of patients may achieve low disease activity (defined as mild activity on HCQ with or without low dose glucocorticoids) • fewer than 10% experience remissions (defined as no disease activity on no medications) • The leading causes of death in the first decade of disease are systemic disease activity, renal failure, and infections; subsequently, thromboembolic events become increasingly frequent causes of mortality.
  • 70.
    Drug Induced Lupus •Syndrome of positive ANA + fever, malaise, arthritis, or intense arthralgias/myalgias, serositis or rash • appears during therapy with certain medications and biologic agents – predominant in whites, has less female predilection than SLE, rarely involves kidneys or brain, is rarely associated with anti-dsDNA, is commonly associated with antibodies to histones – Resolves over several weeks after discontinuation of the medication
  • 71.
    Causative agents • Anti-arrhythmics:procainamide, disopyramide, and propafenone • anti-hypertensive: hydralazine, several ACEI and beta blockers • Anti-thyroid: PTU • Antipsychotics: chlorpromazine and lithium • Anticonvulsants: carbamazepine and phenytoin • Antibiotics: isoniazid, minocycline, and nitrofurantoin • Anti-rheumatic: sulfasalazine • Diuretic: hydrochlorothiazide • Anti-hyperlipidemics: lovastatin and simvastatin • Biologics: inhibitors to IFNs and TNF • ANA usually appears before symptoms • However many of the above medications induce ANA without causing any symptoms • It is appropriate to test for ANA at the first hint of relevant symptoms to help decide if medications should be discontinued
  • 72.