Systemic Lupus Erythematosus


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Systemic Lupus Erythematosus

  1. 1. Systemic Lupus Erythematosus Sheelendra Shakya Dept. of Pediatrics, KMCTH
  2. 2. Introduction <ul><li>A complex disorder of multifactorial origin resulting from interactions among genetic, hormonal and environmental factors acting in concert to cause activation of helper T cells and B cells that results in the secretion of several species of autoantibodies. </li></ul><ul><li>In this complex web, each factor may be necessary but not enough for the clinical expression of the disease; the relative importance of various factors may vary from individual to individual. </li></ul>
  3. 3. Topics of Discussion <ul><li>Pathogenesis </li></ul><ul><li>Clinical presentation </li></ul><ul><li>Diagnosis </li></ul><ul><li>Useful investigations </li></ul><ul><li>Lupus nephritis </li></ul><ul><li>Treatment </li></ul><ul><li>Prognosis </li></ul>
  4. 4. Pathogenesis <ul><li>Fundamental defect is a failure of the regulatory mechanisms that sustain self-tolerance. </li></ul><ul><li>Anti-bodies identified against </li></ul><ul><ul><ul><li>Nuclear components </li></ul></ul></ul><ul><ul><ul><li>Cytoplasmic components </li></ul></ul></ul><ul><ul><ul><li>Cell surface antigens of blood elements incl. phospholipids </li></ul></ul></ul>
  5. 5. Pathogenesis <ul><li>Genetic factors </li></ul><ul><li>Hormonal Influences </li></ul><ul><li>Environmental Triggers </li></ul><ul><li>Immune Dysregulation </li></ul>
  6. 6. Pathogenesis
  7. 7. Pathogenesis <ul><li>Most visceral lesions are mediated by immune complexes (Type III hypersensitivity) </li></ul><ul><li>Autoantibodies against red cells, white cells and platelets mediate their effects via Type II hypersensitivity. </li></ul><ul><li>In tissues, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogeneous, to produce LE bodies. </li></ul>
  8. 8. Case study <ul><li>Swastika Maharjan </li></ul><ul><li>8yrs/F from Baneshwor </li></ul><ul><li>DOA: 065.1.3 </li></ul><ul><li>c/o puffiness of face, swelling of lower limbs, oral ulcer and skin rash, fever since 3 days. </li></ul><ul><li>Started e fever followed by facial puffiness and generalized body swelling 1 mth back. Diagnosed as AGN at Kanti and treated with antibiotics, diuretics and steroid. Discharged on improvement. </li></ul><ul><li>On follow up, antibiotics changed, Urine albumin +++; Diuretics continued. </li></ul><ul><li>After 12 days of stopping diuretics, swelling reappeared. Diagnosed as Nephrotic Syndrome e culture proven UTI. Treated with Ofloxacin. </li></ul>
  9. 9. HPI <ul><li>After 7 days of treatment with Oflo, child developed oral ulcers and skin rashes suspected to be drug rash and was switched to Cefixime. Was brought to KMC. </li></ul><ul><li>Also h/o fever, multiple oral ulcers and skin rashes, more on face and few on the thigh, erythematous, macular, non itching e h/o decreased urine output. Occassional c/o joint pains. </li></ul><ul><li>No h/o SOB, photosensitivity, burning micturition. </li></ul>CRP >6mg/dl, Urine RME : RBC and pus plenty, albumin + TC8400cumm N82L17M1 Hb 13gm% ESR 52mm in 1 st hr
  10. 10. O/E <ul><li>Ill looking, oral ulcers, facial puffiness, malar rash </li></ul><ul><li>Pallor +, B/L pitting edema of lower limbs </li></ul><ul><li>Chest: dullness from 5 th ics downwards on Rt. and 3 rd ics downwards on Lt.; decreased B.S. on lt. inframammary region </li></ul><ul><li>CVS: S 1 + S 2 + M 0 </li></ul><ul><li>P/A: umbilicus everted, mild distension, soft, non tender, no organomegaly, shifting dullness +, fluid thrill – </li></ul><ul><li>Pigmented rash on lateral aspect of rt. thigh </li></ul>
  11. 11. Investigations CBC: TC 3500 N63L36M1;Hb 6.9gm%; PLT 42000/cumm ESR 72mm in 1 st hour Peripheral Smear: normocytic, normochromic to mildly hypochromic e mild anisocytosis. Plt reduced on smear Biochemistry: Urea 96mg/dl Cr 1.1mg/dl; Na 123meq/L, K 4meq/L Total protein: 4.3g/dl Albumin: 3.6g/dl Total Cholesterol 210 mg/dl HDL: 27mg/dl Triglycerides: 697mg/dl LDL could not be calculated. ANA , CRP, ASO, RA factor- negative Urine: pus 6-8/hpf, RBC plenty; Albumin 2 +, cast 0-2 24 hour urine volume: 350ml 24 hour urinary protein 2717mg. Urine C/S- insignificant bacteriuria Montoux test: no induration after 72 hrs Reticulocytes: 4% Albumin repeated after 2 weeks: 1.8mg/dl Anti-dsDNA by ELISA- positive (69.12 IU/ml) USG: B/L medicorenal disease B/L pleural effusion Minimal pericardial effusion. Ascites CXR: B/L pleural effusion Repeat Urine RMEs: persistent albumin, RBC and pus cells.
  12. 12. Diagnosis <ul><li>SLE with secondary Nephritic Syndrome with Culture proven UTI </li></ul><ul><li>Child was started on Steroid and diuretics. Antibiotics for UTI continued and she was closely monitored. </li></ul><ul><li>During the course of treatment, she got symptomatically better but ascites increased and her BP was also in a rising trend. </li></ul><ul><li>Due to parental wish and the need for specialist nephrologist expertise, she was referred to Kathmandu Nursing Home where she was continued with the same medication. </li></ul>
  13. 13. Clinical Presentation <ul><li>Skin manifestations </li></ul><ul><li>Renal disease </li></ul><ul><li>Neuropsychiatric </li></ul><ul><li>Arthritis </li></ul><ul><li>Cardiac </li></ul><ul><li>Respiratory </li></ul><ul><li>Haematology </li></ul><ul><li>Gastrointestinal </li></ul>
  14. 14. Muscles and bones <ul><li>Joint/muscle pain, myositis, proximal myopathy. </li></ul><ul><li>Any joint can be affected, but the most common spots are the hands, wrists, and knees. </li></ul><ul><li>Usually the same joints on both sides of the body are affected. </li></ul><ul><li>The pain can come and go, or it can be long lasting. </li></ul><ul><li>Non-erosive polyarthritis with periarticular and tendon involvement. </li></ul>
  15. 15. Skin manifestations <ul><li>Butterfly rash </li></ul><ul><li>Alopecia </li></ul><ul><li>Oral ulcers </li></ul><ul><li>Photosensitivity </li></ul>
  16. 16. Skin manifestations <ul><li>Discoid lupus </li></ul><ul><ul><li>Ears, cheeks, scalp, forehead, chest </li></ul></ul><ul><ul><li>3 stage rash – </li></ul></ul><ul><ul><ul><li>Erythema </li></ul></ul></ul><ul><ul><ul><li>Pigmented hyperkeratotic oedematous papules </li></ul></ul></ul><ul><ul><ul><li>Atrophic depressed lesions </li></ul></ul></ul><ul><li>Livedo reticularis (net-like rash) </li></ul><ul><li>Raynaud’s purpura </li></ul><ul><li>Urticaria </li></ul><ul><li>Conjunctivitis </li></ul><ul><li>Bullae </li></ul>
  17. 17. Renal <ul><li>Proteinuria </li></ul><ul><li>Casts </li></ul><ul><li>Oedema </li></ul><ul><li>Uraemia </li></ul><ul><li>Acute glomerulonephritis </li></ul>Mesangial proliferative lupus nephritis Advanced sclerosis lupus nephritis Membranous lupus nephritis
  18. 18. Neuropsychiatric <ul><li>Central Nervous System </li></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><li>Mood disorder </li></ul></ul><ul><ul><li>Cognitive dysfunction </li></ul></ul><ul><ul><li>Seizure disorder </li></ul></ul><ul><ul><li>Acute confusional state </li></ul></ul><ul><ul><li>Anxiety disorder </li></ul></ul><ul><ul><li>Cerebrovascular disease </li></ul></ul><ul><ul><li>Psychosis </li></ul></ul><ul><ul><li>Movement disorder </li></ul></ul><ul><ul><li>Demyelinating syndrome </li></ul></ul><ul><ul><li>Aseptic meningitis </li></ul></ul><ul><ul><li>Myelopathy </li></ul></ul><ul><li>Peripheral Nervous System </li></ul><ul><ul><li>GBS </li></ul></ul><ul><ul><li>Autonomic neuropathy </li></ul></ul><ul><ul><li>Mononeuropathy </li></ul></ul><ul><ul><li>Myasthenia gravis </li></ul></ul><ul><ul><li>Cranial neuropathy </li></ul></ul><ul><ul><li>Plexopathy </li></ul></ul><ul><ul><li>Polyneuropathy </li></ul></ul>Neuropsychiatric syndromes in SLE as defined by American College of Rheumatology
  19. 19. Respiratory <ul><li>Pleuritis (+/-Pleural effusion) </li></ul><ul><li>Acute pneumonitis </li></ul><ul><li>Chronic interstitial lung disease </li></ul><ul><li>Pulmonary haemorrhage </li></ul><ul><li>Pulmonary Oedema </li></ul><ul><li>Shrinking Lung Syndrome </li></ul><ul><li>Restrictive lung impairment with no respiratory symptoms </li></ul>
  20. 20. Cardiac
  21. 21. Cardiac <ul><li>Pericarditis (+/- effusion) </li></ul><ul><li>Myocarditis </li></ul><ul><li>Coronary Artery Disease </li></ul><ul><li>Libman-Sacks endocarditis </li></ul><ul><li>Valvular insufficiency </li></ul><ul><li>Cardiomegaly </li></ul><ul><li>Myocardial perfusion defects - IHD </li></ul>
  22. 22. Hematological <ul><li>Thrombocytopenia </li></ul><ul><li>Leucopenia </li></ul><ul><li>Lymphopenia </li></ul><ul><li>Anaemia due to chronic disease or secondary to Coomb’s positive haemolytic anaemia </li></ul><ul><li>INR, ESR increased </li></ul><ul><li>CRP normal, unless intercurrent infection. </li></ul>
  23. 23. Gastrointestinal <ul><li>Hepatosplenomegaly </li></ul><ul><li>Nausea and vomiting </li></ul>Constitutional <ul><li>Fatigue </li></ul><ul><li>Fever </li></ul><ul><li>Weight loss </li></ul><ul><li>Lymphadenopathy </li></ul>Ocular <ul><li>Retinopathy in upto 35% of cases </li></ul>
  24. 24. Diagnostic criteria <ul><li>Malar rash </li></ul><ul><li>Discoid lupus </li></ul><ul><li>Photosensitivity </li></ul><ul><li>Oral or nasal ulceration </li></ul><ul><li>Non-erosive arthritis </li></ul><ul><li>Serositis </li></ul><ul><li>Nephritis </li></ul><ul><li>Neurological </li></ul><ul><li>Haematological </li></ul><ul><li>Immunological </li></ul><ul><li>Anti-nuclear antibody </li></ul>Fixed erythema, flat or raised, over malar eminences, tending to spare nasolabial folds Erythematous raised patches of adherent keratotic scaling and follicular plugging. Atrophic scarring may be seen in older lesions. Skin rash as a result of unusual reaction to sunlight (UV rays) Oral or nasopharyngeal ulcers, usually painless, observed by a physician Non-erosive arthritis involving 2 or more peripheral joints, characterised by tenderness, swelling or effusion Pleuritis – pleuritic pain, rub heard or pleural effusion, or, Pericarditis – documented by ECG or rub or pericardial effusion Persistent proteinuria > 0.5g/day not > 3+. Cellular casts: red cell, haemoglobin, granular, tubular or mixed. Seizures or psychosis in the absence of offending drugs or metabolic derangement. Haemolytic anaemia with reticulocytes, or: Leucopenia < 4000/mm 3 on 2 or more occassions, or: Lymphopenia <1500/mm 3 on 2 or more occasions, or: Thrombocytopenia<100000/mm 3 in absence of offending drugs Anti-DNA antibody, or: Anti-Sm antibody, or: Anti-phospholipid antibodies: i. abnormal anticardiolipin antibody IgG or IgM; ii. Positive lupus anticoagulant; iii. False positive for syphilis for > 6 months Abnormal titre of ANA at any point in absence of drugs known to be associated with drug induced lupus 4 out of 11 criteria gives a 96% sensitivity and 96% specificity for SLE. Criteria do not all have to be present at a defined time and can be cumulative.
  25. 25. Useful Investigations <ul><li>General Investigations: </li></ul><ul><ul><li>TC, DC, Hb, PLT, ESR </li></ul></ul><ul><ul><li>Blood urea, Serum Creatinine </li></ul></ul><ul><ul><li>Urinalysis to check for protein, RBC and cellular casts </li></ul></ul><ul><ul><li>Spot urine test for Creatinine and protein concentration (normal protein:creatinine ratio <0.2) </li></ul></ul><ul><ul><li>24hrs Urine test for creatinine clearance and protein excretion. </li></ul></ul><ul><li>Tests of SLE disease activity: </li></ul><ul><ul><li>Anti-dsDNA, Complement determinations (C3, C4), CRP </li></ul></ul><ul><ul><li>Anti-nucleosome antibodies, anti-C1q antibodies </li></ul></ul>
  26. 26. Useful Investigations
  27. 27. Useful Investigations <ul><li>Renal biopsy indicated in: </li></ul><ul><ul><li>Any patient with SLE who has clinical or laboratory evidence of active nephritis, especially with the first episode of nephritis </li></ul></ul><ul><ul><li>Patients with recurrent episodes of nephritis </li></ul></ul>TO GUIDE TREATMENT ON USE OF POTENTIALLY TOXIC DRUGS TO PREDICT OUTCOME
  28. 28. International Society of Nephrology 2003 classification of lupus nephritis Chronic lesions and sclerosis Advanced sclerosing Class VI Predominantly nephrotic disease Membranous Class V >50% of glomeruli involved Diffuse proliferative Class IV <50% of glomeruli involved Focal proliferative Class III Hypercellular on light microscopy Mesangial proliferative Class II Normal light microscopy findings, abnormal electron microscopy findings Minimal mesangial Class I
  29. 29. Principles of Management <ul><li>Normalize renal function or, at least, prevent the progressive loss of renal function. Therapy differs depending on the pathologic lesion. </li></ul><ul><li>Strongly consider performing a renal biopsy in patients who present with lupus nephritis. </li></ul><ul><li>Assess activity and chronicity indices. </li></ul><ul><li>Treat extrarenal manifestations and other variables that may affect the kidneys. </li></ul>
  30. 30. Medications <ul><li>Corticosteroids </li></ul><ul><ul><li>if clinically significant renal disease. </li></ul></ul><ul><li>Immunosuppressive agents (cyclophosphamide, azathioprine, or mycophenolate mofetil) </li></ul><ul><ul><li>if aggressive proliferative renal lesions because they improve the renal outcome. </li></ul></ul><ul><ul><li>If the patient has an inadequate response or excessive sensitivity to corticosteroids. </li></ul></ul><ul><li>Hypertension: </li></ul><ul><ul><li>Angiotensin-converting enzyme (ACE) inhibitors </li></ul></ul><ul><ul><li>Angiotensin II receptor blockers (ARBs) if the patient has significant proteinuria, unless significant renal insufficiency is present. </li></ul></ul><ul><li>Hyperlipidemia </li></ul><ul><ul><li>Restrict fat intake </li></ul></ul><ul><ul><li>Use lipid-lowering therapy such as statins for hyperlipidemia secondary to nephrotic syndrome. </li></ul></ul>
  31. 31. Medications <ul><li>Restrict protein intake if renal function is significantly impaired. </li></ul><ul><li>Avoid nephrotoxic drugs like NSAIDs. Hydroxychloroquine can be used for pain relief. </li></ul><ul><li>Avoid pregnancy. </li></ul><ul><li>Prevent Infection. </li></ul><ul><li>Avoid sunlight exposure, use sunscreens. </li></ul><ul><li>Osteoporosis due to long term Corticosteroids </li></ul><ul><ul><li>Calcium supplementation </li></ul></ul><ul><ul><li>Bisphosphonate. </li></ul></ul>
  32. 32. Class specific Treatment <ul><ul><li>Class I: Minimal mesangial lupus nephritis require no specific therapy. </li></ul></ul><ul><ul><li>Class II: Mesangial proliferative lupus nephritis may require treatment if proteinuria is greater than 1000 mg/d. Consider prednisone in low-to-moderate doses (ie, 20-40 mg/d) for 1-3 months, with subsequent taper. </li></ul></ul>
  33. 33. Class specific Treatment <ul><ul><li>Classes III and IV: Patients with either focal or diffuse lupus nephritis are at high risk of progressing to end-stage renal disease and require aggressive therapy. </li></ul></ul><ul><ul><ul><ul><li>Administer prednisone 1 mg/kg/d for at least 4 weeks, depending on clinical response. Then, taper it gradually to a daily maintenance dose of 5-10 mg/d for approximately 2 years. In acutely ill patients, intravenous methylprednisolone of up to 1000 mg/d for 3 days may be used to initiate corticosteroid therapy. </li></ul></ul></ul></ul>
  34. 34. immunosuppressive drugs indication <ul><ul><ul><li>who do not respond to corticosteroids alone, </li></ul></ul></ul><ul><ul><ul><li>who have unacceptable toxicity to corticosteroids, </li></ul></ul></ul><ul><ul><ul><li>who have worsening renal function, </li></ul></ul></ul><ul><ul><ul><li>who have severe proliferative lesions, or </li></ul></ul></ul><ul><ul><ul><li>who have evidence of sclerosis on renal biopsy specimens. </li></ul></ul></ul>
  35. 35. Immunosuppressive regimen <ul><ul><ul><li>Both cyclophosphamide and azathioprine are effective for proliferative lupus nephritis, although cyclophosphamide is apparently more effective in preventing progression to end-stage renal disease. </li></ul></ul></ul><ul><ul><ul><li>Administer iv cyclophosphamide monthly for 6 months and every 2-3 months thereafter, depending on clinical response. The usual duration of therapy is 2-2.5 years. Reduce the dose if the creatinine clearance is less than 30 mL/min. Adjust the dose depending on the hematologic response. Gonadotropin-releasing hormone analog, leuprolide acetate, protects against ovarian failure. </li></ul></ul></ul><ul><ul><ul><li>Azathioprine can also be used as a second-line agent , with dose adjustments depending on hematologic response. </li></ul></ul></ul><ul><ul><ul><li>Mycophenolate mofetil is useful in patients with focal or diffuse lupus nephritis and has been to be at least effective as iv cyclophosphamide with less toxicity in patients with stable renal function . Can be used alone or sequentially after a 6-month course of iv cyclophosphamide. </li></ul></ul></ul>
  36. 36. Class specific Treatment <ul><ul><li>Class V: Prednisone for 1-3 months, followed by tapering for 1-2 years if a response occurs. If no response occurs, the drug is discontinued. </li></ul></ul><ul><ul><li>Immunosuppressive drugs are generally not used unless renal function worsens or a proliferative component is present on renal biopsy samples. </li></ul></ul><ul><ul><li>Azathioprine, cyclophosphamide, cyclosporine, and chlorambucil are effective in reducing proteinuria . </li></ul></ul><ul><ul><ul><li>Rituximab: monoclonal antibody that binds specifically to B cell surface antigen mediating B-cell lysis. </li></ul></ul></ul><ul><ul><ul><li>Infliximab: a TNF alpha antagonist, beneficial in lupus nephritis </li></ul></ul></ul><ul><ul><ul><li>Abetimus: reduces levels of anti-DNA antibodies however not effective in preventing flares of lupus nephritis. </li></ul></ul></ul>
  37. 37. Class specific Treatment <ul><li>End-stage renal disease </li></ul><ul><ul><li>Patients with end-stage renal disease need dialysis and are good candidates for kidney transplantation. </li></ul></ul><ul><ul><li>Hemodialysis superior to Peritoneal dialysis </li></ul></ul>
  38. 38. Surgical Care <ul><li>Ensure that the patient does not have active SLE disease at the time of transplantation. </li></ul><ul><li>In patients with SLE, reasons for a more severe outcome after transplantation include recurrent lupus nephritis and concomitant antiphospholipid antibody syndrome resulting in allograft loss. </li></ul>
  39. 39. Prognosis <ul><li>In 1950s: </li></ul><ul><ul><li>5 yr survival rate in case of lupus nephritis was 0% </li></ul></ul><ul><li>Recently: </li></ul><ul><ul><li>5 yr survival 85% </li></ul></ul><ul><ul><li>10 yr survival 73% </li></ul></ul><ul><li>In 1963: 2 yr survival rate 58% </li></ul><ul><li>1980-1990: 5 yr survival rate 85-93% </li></ul><ul><li>2004: J. Rheumatology </li></ul><ul><ul><li>5 yr survival rate 100% </li></ul></ul><ul><ul><li>10 yr survival rate 85.7% </li></ul></ul>
  40. 40. Prognosis <ul><li>Poor prognostic indicators </li></ul><ul><ul><li>Delay in treatment of more than 5 months from onset of nephritis </li></ul></ul><ul><ul><li>Young age at onset of nephritis </li></ul></ul><ul><ul><li>Male sex </li></ul></ul><ul><ul><li>Black racial background </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Nephrotic syndrome </li></ul></ul><ul><ul><li>Elevated creatinine level (>3 mg/dL) at presentation </li></ul></ul><ul><ul><li>Persistently elevated anti-dsDNA and low C3 and C4 levels </li></ul></ul><ul><ul><li>Renal biopsy findings showing diffuse lupus nephritis or high chronicity index </li></ul></ul>
  41. 41. Prognosis <ul><li>Excellent prognosis: Minimal mesangial lupus nephritis and mesangial proliferative lupus nephritis (ISN/RPS 2003 classes I and II) </li></ul><ul><li>Good prognosis: Focal lupus nephritis (ISN/RPS 2003 class III) </li></ul><ul><ul><li>only a minority of patients develop progressive renal failure. </li></ul></ul><ul><li>Fair prognosis </li></ul><ul><ul><li>Diffuse lupus nephritis (ISN/RPS 2003 class IV) </li></ul></ul><ul><ul><ul><li>a significant number of patients developing progressive renal failure. </li></ul></ul></ul><ul><ul><li>Membranous lupus nephritis (ISN/RPS 2003 class V) </li></ul></ul><ul><ul><ul><li>a significant number of patients developing progressive renal deterioration gradually over time. </li></ul></ul></ul>
  42. 42. Complications: <ul><li>Some degree of long term and often permanent organ dysfunction from either SLE or its treatment has been found in 88% of patients. </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Growth retardation </li></ul></ul><ul><ul><li>Chronic pulmonary impairment </li></ul></ul><ul><ul><li>Ocular abnormalities </li></ul></ul><ul><ul><li>Permanent renal damage </li></ul></ul><ul><ul><li>Neuropsychiatric symptoms </li></ul></ul><ul><ul><li>Musculoskeletal damange </li></ul></ul><ul><ul><li>Gonadal impairment </li></ul></ul>J. Rheumatology 1990
  43. 43. Summary: <ul><li>SLE is a potentially life-threatening disease, however pts can do well if the disease is recognized early and treated aggressively. </li></ul><ul><li>Renal disease is a major cause of morbidity and mortality in children with SLE. </li></ul><ul><li>The short and long term outcome have improved in recent years. </li></ul><ul><li>As pts survive longer, there is significant morbidity from the disease and its treatments and it is difficult to balance minimising permanent organ damage with side effects from potentially harmful drugs. </li></ul>
  44. 44. Thank you
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