Systemic Lupus Erythematosus

Slide 1: Systemic Lupus Erythematosus Sheelendra Shakya Dept. of Pediatrics, KMCTH

Slide 2: Introduction 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. 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.

Slide 3: Topics of Discussion Pathogenesis  Clinical presentation  Diagnosis  Useful investigations  Lupus nephritis  Treatment  Prognosis 

Slide 4: Pathogenesis Fundamental defect is a failure of the  regulatory mechanisms that sustain self- tolerance. Anti-bodies identified against  Nuclear components  Cytoplasmic components  Cell surface antigens of blood elements incl.  phospholipids

Slide 5: Pathogenesis Genetic factors  Hormonal Influences  Environmental Triggers  Immune Dysregulation 

Slide 6: Pathogenesis

Slide 7: Pathogenesis Most visceral lesions are mediated by  immune complexes (Type III hypersensitivity) Autoantibodies against red cells, white cells  and platelets mediate their effects via Type II hypersensitivity. In tissues, nuclei of damaged cells react with  ANAs, lose their chromatin pattern, and become homogeneous, to produce LE bodies.

Slide 8: Case study Swastika Maharjan  8yrs/F from Baneshwor  DOA: 065.1.3  c/o puffiness of face,  swelling of lower limbs, oral ulcer and skin rash, fever since 3 days. 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. On follow up, antibiotics changed, Urine albumin +++; Diuretics  continued. After 12 days of stopping diuretics, swelling reappeared. Diagnosed  as Nephrotic Syndrome e culture proven UTI. Treated with Ofloxacin.

Slide 9: HPI 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. Also h/o fever, multiple oral ulcers and  skin rashes, more on face and few on CRP >6mg/dl, the thigh, erythematous, macular, non Urine RME : RBC and pus itching e h/o decreased urine output. plenty, albumin + Occassional c/o joint pains. TC8400cumm No h/o SOB, photosensitivity, burning  N82L17M1 micturition. Hb 13gm% ESR 52mm in 1st hr

Slide 10: O/E Ill looking, oral ulcers, facial  puffiness, malar rash Pallor +, B/L pitting edema of  lower limbs Chest: dullness from 5th ics  downwards on Rt. and 3rd ics downwards on Lt.; decreased B.S. on lt. inframammary region CVS: S1+ S2+ M0  P/A: umbilicus everted, mild  distension, soft, non tender, no organomegaly, shifting dullness +, fluid thrill – Pigmented rash on lateral  aspect of rt. thigh

Slide 11: Investigations CBC:TC 3500 N63L36M1;Hb 6.9gm%; PLT 42000/cumm Montoux test: no induration after 72 hrs ESR 72mm in 1st hour Reticulocytes: 4% Peripheral Smear: normocytic, Albumin repeated after 2 weeks: normochromic to mildly hypochromic e 1.8mg/dl mild anisocytosis. Plt reduced on smear Anti-dsDNA by ELISA- Biochemistry: Urea 96mg/dl Cr 1.1mg/dl; positive (69.12 IU/ml) Na 123meq/L, K 4meq/L Total protein: 4.3g/dl USG: Albumin: 3.6g/dl B/L medicorenal disease Total Cholesterol 210 mg/dl B/L pleural effusion HDL: 27mg/dl Minimal pericardial effusion. Triglycerides: 697mg/dl Ascites LDL could not be calculated. ANA , CRP, ASO, RA factor- negative CXR: Urine: pus 6-8/hpf, RBC plenty; Albumin 2 +, cast 0-2 B/L pleural effusion 24 hour urine volume: 350ml 24 hour urinary protein 2717mg. Repeat Urine RMEs: persistent Urine C/S- insignificant bacteriuria albumin, RBC and pus cells.

Slide 12: Diagnosis SLE with secondary Nephritic Syndrome  with Culture proven UTI Child was started on Steroid and diuretics. Antibiotics for UTI  continued and she was closely monitored. During the course of treatment, she got symptomatically better  but ascites increased and her BP was also in a rising trend. 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.

Slide 13: Clinical Presentation Skin manifestations  Renal disease  Neuropsychiatric  Arthritis  Cardiac  Respiratory  Haematology  Gastrointestinal 

Slide 14: Muscles and bones Joint/muscle pain, myositis,  proximal myopathy. Any joint can be affected, but the  most common spots are the hands, wrists, and knees. Usually the same joints on both  sides of the body are affected. The pain can come and go, or it  can be long lasting. Non-erosive polyarthritis with  periarticular and tendon involvement.

Slide 15: Skin manifestations Butterfly rash  Alopecia  Oral ulcers  Photosensitivity 

Slide 16: Skin manifestations Discoid lupus  Ears, cheeks, scalp, forehead, chest  3 stage rash –   Erythema  Pigmented hyperkeratotic oedematous papules  Atrophic depressed lesions Livedo reticularis (net-like rash)  Raynaud’s purpura  Urticaria  Conjunctivitis  Bullae 

Slide 17: Renal Proteinuria  Casts  Oedema  Uraemia  Acute glomerulonephritis  Mesangial proliferative lupus nephritis Membranous lupus nephritis Advanced sclerosis lupus nephritis

Slide 18: Neuropsychiatric Central Nervous System Peripheral Nervous System   Headache GBS   Mood disorder Autonomic neuropathy   Cognitive dysfunction Mononeuropathy   Seizure disorder Myasthenia gravis   Acute confusional state Cranial neuropathy   Anxiety disorder Plexopathy   Cerebrovascular disease Polyneuropathy   Psychosis  Movement disorder  Demyelinating syndrome  Neuropsychiatric syndromes Aseptic meningitis  in SLE as defined by American Myelopathy  College of Rheumatology

Slide 19: Respiratory Pleuritis (+/-Pleural effusion)  Acute pneumonitis  Chronic interstitial lung disease  Pulmonary haemorrhage  Pulmonary Oedema  Shrinking Lung Syndrome  Restrictive lung impairment with no  respiratory symptoms

Slide 20: Cardiac

Slide 21: Cardiac Pericarditis (+/- effusion)  Myocarditis  Coronary Artery Disease  Libman-Sacks endocarditis  Valvular insufficiency  Cardiomegaly  Myocardial perfusion  defects - IHD

Slide 22: Hematological Thrombocytopenia  Leucopenia  Lymphopenia  Anaemia due to chronic  disease or secondary to Coomb’s positive haemolytic anaemia INR, ESR increased  CRP normal, unless  intercurrent infection.

Slide 23: Constitutional Fatigue  Fever  Weight loss  Lymphadenopathy  Gastrointestinal Ocular Hepatosplenomegaly Retinopathy   in upto 35% Nausea and vomiting  of cases

Slide 24: Diagnostic criteria Fixed erythema, flat or Malar rash  raised, over malar Erythematous raised Discoid lupus  eminences, tending to Skin rash adherent patches ofas a result of Photosensitivity  spare nasolabial and keratoticreaction folds scaling to Oral or nasal ulceration unusual  Oral or (UV rays) follicular plugging. sunlight Non-erosive arthritis  nasopharyngeal Non-erosive arthritis Atrophic scarring may Haemolyticantibody, or: a 96% Anti-DNA 11in oldergives 4 out of usually with ulcers, anaemia specificity criteria Serositis Pleuritis or:or more involving– pleuritic pain, 2 be seen and 96%  sensitivity reticulocytes, observed Anti-Sm antibody, or: painless, joints, 3 peripheral lesions. or pleural Nephritis for SLE.  rub heard4000/mm Leucopenia < not all have onbe or Anti-phospholipid antibodies: by a physicianby to 2 Criteria do proteinuria > Persistent characterised Neurological more occassions,Pericarditis – Seizures or, psychosis at effusion, a defined time in  i. abnormal anticardiolipin and or: Abnormalor > of ANA present at notswelling 0.5g/day titre 3+. 3 tenderness, antibody IgG or IgM;ECG or documented ofred cell, by Lymphopenia <1500/mm on 2 or Haematological can be cumulative. the absenceabsence of  Cellular casts: any point in or effusion anticoagulant; more occasions, or: or ii. Positivepericardial effusion rub or lupus granular, offending drugs be Immunological haemoglobin,to drugs known  Thrombocytopenia<100000/mm3> iii. False positive for syphilis for in metabolic derangement. 6 months or mixed. tubular Anti-nuclear antibody absence of offending drug associated with drugs  induced lupus

Slide 25: Useful Investigations General Investigations:  TC, DC, Hb, PLT, ESR  Blood urea, Serum Creatinine  Urinalysis to check for protein, RBC and cellular casts  Spot urine test for Creatinine and protein concentration  (normal protein:creatinine ratio <0.2) 24hrs Urine test for creatinine clearance and protein  excretion. Tests of SLE disease activity:  Anti-dsDNA, Complement determinations (C3, C4), CRP  Anti-nucleosome antibodies, anti-C1q antibodies 

Slide 26: Useful Investigations

Slide 27: Useful Investigations Renal biopsy indicated in:  Any patient with SLE who has clinical or laboratory  evidence of active nephritis, especially with the first episode of nephritis Patients with recurrent episodes of nephritis  TO GUIDE TREATMENT ON USE OF POTENTIALLY TOXIC DRUGS TO PREDICT OUTCOME

Slide 28: International Society of Nephrology 2003 classification of lupus nephritis Class I Minimal mesangial Normal light microscopy findings, abnormal electron microscopy findings Class II Mesangial proliferative Hypercellular on light microscopy Class III Focal proliferative <50% of glomeruli involved Class IV Diffuse proliferative >50% of glomeruli involved Class V Membranous Predominantly nephrotic disease Class VI Advanced sclerosing Chronic lesions and sclerosis

Slide 29: Principles of Management Normalize renal function or, at least, prevent  the progressive loss of renal function. Therapy differs depending on the pathologic lesion. Strongly consider performing a renal biopsy  in patients who present with lupus nephritis. Assess activity and chronicity indices.  Treat extrarenal manifestations and other  variables that may affect the kidneys.

Slide 30: Medications Corticosteroids  if clinically significant renal disease.  Immunosuppressive agents (cyclophosphamide, azathioprine, or  mycophenolate mofetil) if aggressive proliferative renal lesions because they improve the  renal outcome. If the patient has an inadequate response or excessive sensitivity to  corticosteroids. Hypertension:  Angiotensin-converting enzyme (ACE) inhibitors  Angiotensin II receptor blockers (ARBs) if the patient has significant  proteinuria, unless significant renal insufficiency is present. Hyperlipidemia  Restrict fat intake  Use lipid-lowering therapy such as statins for hyperlipidemia  secondary to nephrotic syndrome.

Slide 31: Medications Restrict protein intake if renal function is significantly  impaired. Avoid nephrotoxic drugs like NSAIDs.  Hydroxychloroquine can be used for pain relief. Avoid pregnancy.  Prevent Infection.  Avoid sunlight exposure, use sunscreens.  Osteoporosis due to long term Corticosteroids  Calcium supplementation  Bisphosphonate. 

Slide 32: Class specific Treatment Class I: Minimal mesangial lupus nephritis require  no specific therapy. 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.

Slide 33: Class specific Treatment 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. 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.

Slide 34: immunosuppressive drugs indication who do not respond to corticosteroids  alone,  who have unacceptable toxicity to corticosteroids,  who have worsening renal function,  who have severe proliferative lesions, or  who have evidence of sclerosis on renal biopsy specimens.

Slide 35: Immunosuppressive regimen Both cyclophosphamide and azathioprine are effective for  proliferative lupus nephritis, although cyclophosphamide is apparently more effective in preventing progression to end-stage renal disease. 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. Azathioprine can also be used as a second-line agent, with dose  adjustments depending on hematologic response. 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.

Slide 36: Class specific Treatment 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. Immunosuppressive drugs are generally not used  unless renal function worsens or a proliferative component is present on renal biopsy samples. Azathioprine, cyclophosphamide, cyclosporine, and  chlorambucil are effective in reducing proteinuria. Rituximab: monoclonal antibody that binds specifically to B  cell surface antigen mediating B-cell lysis. Infliximab: a TNF alpha antagonist, beneficial in lupus  nephritis Abetimus: reduces levels of anti-DNA antibodies however  not effective in preventing flares of lupus nephritis.

Slide 37: Class specific Treatment End-stage renal disease  Patients with end-stage renal disease need dialysis  and are good candidates for kidney transplantation. Hemodialysis superior to Peritoneal dialysis 

Slide 38: Surgical Care Ensure that the patient does not have active  SLE disease at the time of transplantation. 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.

Slide 39: Prognosis In 1950s:  5 yr survival rate in case of lupus nephritis was 0%  Recently:  5 yr survival 85%  10 yr survival 73%  In 1963: 2 yr survival rate 58%  1980-1990: 5 yr survival rate 85-93%  2004: J. Rheumatology  5 yr survival rate 100%  10 yr survival rate 85.7% 

Slide 40: Prognosis Poor prognostic indicators  Delay in treatment of more than 5 months from onset of  nephritis Young age at onset of nephritis  Male sex  Black racial background  Hypertension  Nephrotic syndrome  Elevated creatinine level (>3 mg/dL) at presentation  Persistently elevated anti-dsDNA and low C3 and C4 levels  Renal biopsy findings showing diffuse lupus nephritis or high  chronicity index

Slide 41: Prognosis Excellent prognosis: Minimal mesangial lupus nephritis and  mesangial proliferative lupus nephritis (ISN/RPS 2003 classes I and II) Good prognosis: Focal lupus nephritis (ISN/RPS 2003 class III)   only a minority of patients develop progressive renal failure. Fair prognosis   Diffuse lupus nephritis (ISN/RPS 2003 class IV) a significant number of patients developing progressive renal failure.  Membranous lupus nephritis (ISN/RPS 2003 class V)  a significant number of patients developing progressive renal  deterioration gradually over time.

Slide 42: Complications: Some degree of long term and often permanent  organ dysfunction from either SLE or its treatment has been found in 88% of patients. Hypertension  Growth retardation  Chronic pulmonary impairment  Ocular abnormalities  Permanent renal damage  Neuropsychiatric symptoms  Musculoskeletal damange  Gonadal impairment  J. Rheumatology 1990

Slide 43: Summary: SLE is a potentially life-threatening disease, however pts can do  well if the disease is recognized early and treated aggressively. Renal disease is a major cause of morbidity and mortality in  children with SLE. The short and long term outcome have improved in recent years.  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.