Systemic Lupus Erythematosus

Systemic Lupus ErythematosusAutoimmune diseaseOrgans and cells undergo damage mediated

by tissue-binding autoantibodies and immune complexes

90% are women of child-bearing yearsIn the US: 15-50 per 100,000

highest prevalence in African Americans

Pathogenesis(1) activation of innate immunity (dendritic

cells) by CpG DNA, DNA in immune complexes, and RNA in RNA/protein self-antigens;

(2) lowered activation thresholds of adaptive immunity cells (antigen-specific T and B lymphocytes);

(3) ineffective regulatory and inhibitory CD4+ and CD8+ T cells;

(4) reduced clearance of apoptotic cells and of immune complexes

The Case

E.G., 21 FemaleCame in with a chief complaint

of SEIZURES

The Case to manage

A diagnosed case of systemic lupus

erythematosus since December 2008

Initially presented withmalar rash, photosensitivity, arthralgia, hair

loss and oral ulcers, edema of both lower and upper extremities, weakness

-> was ANA (+)

The Case to manage

Maintained on

prednisone 10 mg once a day

hydrochloroquine 200 mg once a day

The Case to manage

Regular follow up in the OPD (Fammed and Rheuma)non-hypertensive

non-diabeticnon-asthmatic

The Case to manage

Currently pregnant

(PU 14 1/7 weeks AOG, G1P0)on follow-up at the PGH OB HRC, last seen February

17, 2010

The Case to manage

2 WEEKS PTA

(+) decreased appetite

(+) gradually increasing generalized body weakness

(-) interventions or consults

The Case to manage

4 DAYS PTA

generalized weakness now more prominent on both right upper and lower extremities(+) behavioral change (+) general decrease in activity (+) episodes of staring blankly into space(+) cough productive of whitish phlegm(+) febrile episodes (qualitative)(-) nasal congestion

The Case to manage

2 HOURS PTA

(-) rousability(+) seizure - upward rolling of the eyeballs, grinding of teeth and clenched fists (duration ~5 minutes)

-> Promptly rushed to PGH, hence this admission

General (+) fever, (-) nausea and vomiting, (+) weakness, (+) weight loss Integumentary (+) malar rash, (-) discoid rash,(-) hairloss Eyes (–) blurring of vision Ears (–) loss of hearing, tinnitus Nervous (–) dysphagia, dysphonia, seizures, dizziness, (+) headache prior Respiratory (+) cough, (+) exertional dyspnea, (-) colds Circulatory (–) chest pain, (-) bleeding Digestive (-) melena, (-) constipation, (-) diarrhea, (-) abdominal pain Urinary/ Reproductive System

(-) urinary incontinence, (-) polyuria/nocturia, dysuria (-) dribbling, (-) tea colored urine, (+) vaginal spotting (Feb 14, 2010)

Endocrine System(–) heat intolerance, (-) polyphagia, polydipsia, polyuria Joints (–) tremors, (+) joint pain

Review of Systems

PAST MEDICAL HISTORY (+) SLE, 2008 (-) HPN, DM, goiter, BA, PTB, Ca, (-) heart problems (-) allergy

FAMILY MEDICAL HISTORY(-) SLE, HPN, DM, goiter, BA, Ca, heart problems

PERSONAL/SOCIAL HISTORYPt lives with live-in partner, a college graduate (BA HRM), currently unemployed.Non-smoker, occasional alcoholic beverage drinker.(-) known exposure to chemicals, and radiation

OBSTETRIC HISTORYG1P0 LMP: October 9, 2009 , PU 14 1/7 weeks AOG by LUTZ

General Survey:

Pt is awake, with regard, responds to name calling, inconsistently follows commands, with no verbal output.

Vital Signs: BP 100-110/60-70 HR 142 RR 40 Temp 38C

HEENT: (+) slight exophthalmos, anicteric sclerae, pink palpebral conjunctivae, (-) TPC, ANM, (-) NVE, (-) CLAD

Chest/Lungs: ECE, (+) bibasal and mid-field rhonchi, both lung fields

CVS: AP, DHS, tachycardic, regular rhythm, (-) murmurs

Abdomen: flat, normoactive bowel sounds, soft, (-) masses, (-) tenderness, liver edge not palpable

GU/IE: Deferred

Skin/Extremities:

FEP, PNB, (-) edema/cyanosis, (+) blanching erythematous rash over extremities

Physical Examination

Neuro Pt is awake, with regard, responds to name calling, inconsistently follows commands, with no verbal output, uncooperative. CN: I – not assessedII – pupils 2/2 EBRTL, primary gaze midline, (-) preferential gazeIII, IV, VI – (+) slight LR palsy, R; (+) visual threat, BV – brisk cornealsVII – (-) facial assymetryVIII – gross hearing intactIX, X – good gag and swallow XII – refuses to protrude tongue With spontaneous, purposeful movement of the extremities.Withdraws to pain, B ext. (-) Babinski (-) clonuspatient resists neck flexion.(-)dysmetria/dysdiadochokinesia(-) nystagmusMOTOR Strength: 3/5 on all extremities Sensory: WTP on all extremities

Physical Examination

Date 02/28 InterpGlucose 5.83 NBUN --Creatinine 72 NSodium 134 Sl lowPotassium 3.5 HypokalemiaChloride 100 Normal

Date 02/28 Protime Ctrl 12.4 Patient 9 Activity >1 INR 1

Date 02/28 Control 36.1 Patient 43.1 Px:Ctrl Ratio 1.19

Date Normal 2/28 WBC 4-11x109/L 14.1 LeucocytosisRBC 4-6x109/L 3.55 Low Hgb 120-180g/L 103 LowHct 0.370-0.540% 0.291 LowMCV 80-100fL 81.8 normalMCH 27-31pg 29.1 NormalMCHC 320-360g/L 356 NormalRDW-CV 11-16 L 15.2 LowPlatelets 2-4x1011/L CLUMPING then

94 Neut% 0.5-0.7 0.764 elevatedLymph% 0.2-0.5 0.197 nMono% 0.02-0.09 0.036 nEo% 0.0-0.06 0.002 nBaso% 0.0-0.02 0.001 N

Date Normal 02/28 FiO2 60 Temp Hb pH 7.35-7.45 7.429 PCO2 35-45mmHg 26.4 PO2 90-100mmHg 63.5 HCO3 22-28mEq/L 17.9 TCO2 Beb O2 sat’n 92.9

Date Normal 02/28 Color Yellow dark yellow Transparency Clear/hazy sl turbid SG 1.016-1.022 1.02 PH 4.6-6.5 6 Sugar (-) (-) Albumin (-) +++ RBC 0/0-2/hpf 1-2 WBC 0-2/0-5/hpf 15-25 Casts hyaline, coarse,

fine, granular, RBC, WBC, waxy

8-25 hyaline casts 0-2 waxy casts 2-4 coarse granular casts

Crystals Small amounts Epith cells Small amounts occasional Bacteria (-) 2+ Mucus thr Small amounts rare RBC morph

ECG2/28: sinus tachycardia, normal axis, low voltage complexes3/11: sinus tachycardia, normal axis, low voltage complexes3/12: sinus tachycardia, normal axis, low voltage complexes

Plasma K7.6

2D ECHO: concentric LVH with good wall motion and contractility, EF=73% minimal pericardial effusion, mild pulmo HPN, incidental finding of pleural effusion, mild TR, PR.

CRANIAL CT – enhanced: unremarkable

Systemic lupus erythematosus in activityt/c SLE cerebritis, myocarditist/c sec APASCommunity Acquired Pneumoniar/o SOL vs electrolyte imbalance vs CNS infection as cause of seizureAnemia of chronic diseaseComplicated UTI

Present Working Impression

Diagnosis

?

Systemic ManifestationsSeverity varies from mild and intermittent to

severe and fulminantExacerbations interspersed with periods of

relative quiescencePermanent complete remissions (absence of

symptoms with no treatment) – rareSystemic symptoms, particularly fatigue and

myalgias/arthralgias – present most of the timeSevere systemic illness requiring

glucocorticoid therapy can occur with fever, prostration, weight loss, and anemia with or without other organ-targeted manifestations.

Musculoskeletal

Cutaneousdiscoid lupus erythematosus (DLE), systemic

rash, subacute cutaneous lupus erythematosus (SCLE), or "other"

Hematologic

Normochromic, normocytic anemiaLymphopenia, not granulocytopenia

RenalDangerous proliferative forms of glomerular

damage (ISN III, IV)microscopic hematuria and proteinuria

(>500mg/24h)One half develop nephrotic syndromeMost develop hypertension

Vascular OcclusionsIncreased prevalence of TIA, CVD, MI

Increased in patients with antibodies to phospholipids (aPL)

Associated with hypercoagulability and acute thrombotic events

Accelerated atherosclerosisCharacteristics associated with increased risk for

atherosclerosis include older age, hypertension, dyslipidemia, dysfunctional proinflammatory high-density lipoproteins, repeated high scores for disease activity, high cumulative or daily doses of glucocorticoids, and high levels of homocysteine.

Neurologic

SLE or not?Diffuse process of vascular occlusive disease?

Cardiopulmonary

GastrointestinalAutoimmune peritonitis and/or intestinal

vasculitisInc in AST and ALT

OcularSicca syndromeNonspecific conjunctivitisRetinal vasculitis and optic neuritis – threaten

vision

Lab Tests(1) to establish or rule out the diagnosis;(2) to follow the course of disease,

particularly to suggest that a flare is occurring or organ damage is developing; and

(3) to identify adverse effects of therapies

Tests for AntibodiesANA – positive in >95% usually at the onset of

symptomsAnti-dsDNA – specific

Increases in titers herald a flare, particularly nephritis or vasculitis

Anti-Sm – specificUsually does not correlate with disease activity

aPL – not specific for SLEClassification criterionIdentify patients with increased risk for

venous/arterial clotting, thrombocytopenia, and fetal loss

ELISA for anticardiolipinInternationally standardized

Phospholipid-based activated prothrombin time (dilute Russell venom viper test)sensitive

Anti-RoNot used for diagnosticsIncreased risk for neonatal lupus, sicca

syndrome, and SCLE

Standard Tests for DiagnosisCBCPlatelet countUrinalysis

Tests for Disease CourseHb levelsPlatelet countU/ASerum crea/albuminAnti-DNAC3Activated complement productsIFN-inducible genesSoluble IL-2Urinary adiponectin or monocyte chemotactic

protein 1

Treatment(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 approaches to preventing complications of disease and its treatments

Non-life Threatening DiseaseNSAIDs – analgesic/anti-inflammatory

For arthritis and arthralgiasIncreased risk for NSAID-induced aseptic

meningitis, elevated serum transaminases, HPN, renal dysfunction

May increase MIAntimalarials (hydroxychloroquine, chloroquine,

quinacrine) – reduce dermatitis, arthritis, fatigueReduces the number of disease flaresReduce accrual of tissue damage over timeRetinal toxicity

Low-dose systemic glucocorticoids

Life-threatening Diseasesystemic glucocorticoids

(0.5–2 mg/kg per day PO or 1000 mg of methylprednisolone sodium succinate IV daily for 3 days followed by 0.5–1 mg/kg of daily prednisone or equivalent

4–6 weeks of these doses.Maintenance dose: 5 -10 mg of prednisone or

equivalent per day or 10-20 mg every other day.

May add cytotoxic/immunosuppressive drugs

CyclophosphamideAlkylating agentFor patients with ISN gr III or IV, reduced

progression and improves survival500-750 mg/m2 IV, monthly for 3-6 monthsOvarian failure – GnRH agonist prior to each doseDuration of therapy

(1) once monthly IV for 6 months followed by 2 more years of quarterly doses,

(2) for 12 weeks followed by azathioprine(3) for 6 months followed by azathioprine or

mycophenolate.

Mycophenolate mofetilrelatively lymphocyte-specific inhibitor of

inosine monophosphatase and therefore of purine synthesis

Safer in maintaining improvement after a 6-month induction phase

Azathioprine – slower to influence responsea purine analogue and cycle-specific

antimetaboliteSlower to influence responseContraindicated in patients with homozygous

deficiency of TMPT enzyme

ChlorambucilAlkylating agentHigher risk of irreversible bone marrow

suppressionMethotrexate

Folinic acid antagonistFor arthritis and dermatitis but not in life-

threateningLeflunomide

Relatively lymphocyte-specific pyrimidine antagonist

CyclosporineInhibits production of IL-2 and T-lymphocyte

fxns

Pregnancy and LupusRate of fetal loss is increased

Higher in mothers with high disease activityAntiphospholipid antibodiesnephritisShould be controlled with

prednisone/prednisolone11-dehydrogenase 2 in placenta

Adverse effects on offspring: low birth weight, CNS developmental abnormalities, predilection toward metabolic syndrome

Flares of SLE uncommon during pregnancy often easily treatedmost common symptoms of these flares include arthritis,

rashes, and fatigue.increases the risk of

spontaneous abortion intrauterine fetal death, Preeclampsia intrauterine growth retardation, preterm birth.

Prognoses best when SLE is quiescent for at least 6 months before the pregnancy and when the mother's underlying renal function is stable and normal or near normal.

SLE in Pregnancy

+ aPL x 2 and prior fetal lossesHeparin plus low-dose aspirin

Anti-RoAssoc with neonatal lupus (rash and congenital

heart block)

Poor maternal outcomes – active nephritis or irreversible organ damage

Lupus and Antiphospholipid Antibody Syndromevenous or arterial clotting, and/or repeated

fetal losses, and at least two positive tests for aPL have APS

Target INR of 2-2.5 (1 epi of venous clotting)INR 3-3.5 (recurring clots or arterial clotting)

Microvascular Thrombotic CrisisThrombotic Thrombocytopenic PurpuraHemolytic Uremic Syndrome

High mortality rateYoung, with lupus nephritis

Labs: identification of schistocytes on PBS, elevated LDH

Tx: plasma exchange or extensive plasmapheresis

Lupus Dermatitisminimize exposure to ultraviolet lightsunscreens with a sun protection factor of at

least 15Topical glucocorticoids and antimalarialsSystemic retinoic acidIn therapy resistant: topical tacrolimus,

systemic dapsone, or thalidomide

Preventive TherapiesVaccinationsSuppressing recurrent UTIPrevention of osteoporosisControl of hypertensionManagement of hyperglycemia, dyslipidemia,

and obesity

Prognosis Survival

95% at 5 years 90% at 10 years 78 at 20 years

In poor countries – glucocorticoid is the sole therapy, worse prognosis

Poor prognosis High serum crea[>124 mol/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 aPL male sex ethnicity (African American, Hispanic, and mestizo heritage)

PrognosisDisability is common25% may experience remissionsLeading cause of death in 1st decade –

systemic disease activity, renal failure, infections, thromboembolic

THANK YOU!

END…

02/28/2010 DEM received GCS 5 E2V1M2

BP 100/70, HR 88, RR 18; CBG 163

given Diazepam 5 mg IV

intubated with note of yellowish secretions per ET tube

GCS 10, E4V1M5 bilateral rhonchi, (+) Babinski, left and decorticate posturing, right.

A> PU 14 1/7 weeks AOG, G1P0; SLE not in activity, t/c SLE cerebritis. Referred to POD.

02/28/2010 PODS> received stuporous, E2V1M5, intubated

vitals: BP 120/80, HR 110, RR 24, T 38.4C. (-) malar rash, no oral ulcers, (+) rhonchi BLF,tachycardic, regular rate and rhythm, (-) murmurs, pupils sluggishly reactive to light, (+) babinski bilateral, (+) doll’s eye

02/28/2010 PODA> SLE in activity

t/c SLE cerebritist/c pneumonia in the ICH, PU 15 1/7 weeks AOG by LUTZ.

P> IVF: D5NR1L x 10Piperacillin Tazobactam 4.5 g IVq8, Hydrocortisone 200 mg IV after Pip-tazo

load Diazepam 5 mg IV for frank seizures,Paracetamol 300mg IV q4 for T>38C. hooked to a mechanical ventilator. Referred to OB.

02/28/2010 OB Examined

benefits of MPPT treatment was deemed to supercede risks

MPPT treatment allowed to start

02/28/2010 RHEUMA

S> awake but with (-) verbal output and regardBP 120/80, HR 118, RR 20, (+) crackles BLF, tachycardic with S3 gallop,no lateralizing signs.

A> SLE in activity, (cerebritis, myocarditis), t/c APAS, CAP, r/o SOL, electrolyte imbalance, CNS infection

02/28/2010 RHEUMA

P> Recommended MPPT regimen: 500mg methylprednisolone + 250cc D5W x 6

D1 500mg methylprednisolone + 250cc D5W x 4 D2 500mg methylprednisolone + 250cc D5W x 4, D3

02/28/201010 :30 AM – patient was extubated by MICU senior prior to admission to MICU.

11: 00 AM – admitted at MICU, bed 5

02/28/2010 (1st MICU day, 1st hospital day) received awake with no verbal output

BP 100/70, HR 132, RR 24 rhonchi on bilateral lung fields.

put on O2 support via nasal cannulaMedications:

1. Pip-tazo 4.5 gm IV q8 2. Hydrocortisone 100 mg IV q8

3. Omeprazole 40 mg tab 1 tab OD 4. CaCO3 1 tab OD

5. NAC 200 mg sachet, 1 sachet + 50 cc water TID 6. Salbutamol neb Q6.

Feeding started via NGT.

03/01/2010 2D echo results: concentric LVH with good wall motion and contractility, EF=73% minimal pericardial effusion, mild pulmo HPN, incidental finding of pleural effusion, mild TR, PR.

Cardio service no longer highly considering myocarditis.

Neuro: diazepam 5mg IV for frank seizures, leviteracetam 500mg tab 1 tab BID.

Rheuma: SLE activity in the patient are cerebritis, nephritis and serositis (due to pericardial and pleural effusion seen on 2D echo). Plan for MPPT therapy, to hold hydroscortisone while on MPPT.

03/02/2010dyspneic episodes not relieved by nebulization but not associated with desaturation.

Breath sounds were noted to be harsher.

She was given Furosemide 40mg and there was noted improvement in dyspnea.

03/03/04Patient awake, conversant, comfortable in bed, still with dyspneic episodes and harsh breath sounds on chest PE.

new labs: Urine CS – No growth after 2 days; ET CS – moderately heavy growth of S. aureus (sensitive to Clindamycin, Erythromycin, Gentamicin, Ofloxacin resistant to penicillin.

03/03/04

NEURO: S> blurring of vision, OS>OD. Still with no recurrence of seizure, (-) headache, vomiting, LOC.

O> Oriented to time and place, neurologic PE: normal. Motor strength: from 4/5 to 5/5 on all extremities.

P> Patient referred to Ophtha for the BOV. Clindamycin discontinued on the basis of sufficient coverage by Pip-tazo as recommended by IDS,

03/04/2010S> (-) seizures, vomiting, headache, LOC (+) mild DOB

O> BP 100-120/70-80, HR 130-140, RR 24-40 38.2CHBS, and occasional crackles and rhonchi on bilateral lung fields. fever Tachycardic, normal rhythm, no murmurs.

A> SLE in activity (nephritis, serositis, hematologic, t/c cerebritis, NPSLE); pneumonia in the ICH, r/o APAS, UTI, PU 15 4/7 wks AOG by EUTZ, NIL.

03/04/2010OB-GYN cleared pt for CT scan. Fetal biometry and viability recommended

03/04/2010OPHTHA: VA 20/25 (near vision chart), eoms full and equal, tonometry soft OU. ; Slit beam: AC formed, cornea looks clear, lens look clear, (-) dye uptake. ; On indirect fundoscopy, clear media, distinct disc borders, CD ratio 0.3, AV 2:3, (+) exudates on vessels, (-) hemorrhages, retina attached.

t/c SLE retinopathy, OU.good VA

Patient’s serum K found to be 2.9, correction started for a K deficit of 222. Oral KCl 30cc q8 x 5.

03/05/2010O> dyspneic, tachycardic, tachypneic. (+) harsh breath sounds, crackles and rhonchi all over both lung fields. Hemoglobin decreased from 81 to 78. Crea 100 Mg 0.89 Na 144 K 2.9. P> for BT with 2 units pRBC.

3:00 PM, the pt was referred for DOB -> nebulized with 1 neb salbutaol, given 40 mg furosemide IV.

03/05/2010

3:35 PM, the pt was persistently dyspneic with 02 saturation decreasing from 95 -> 87 -> 84%. Pt was intubated ET size 7.5, level 21. Subsequently hooked to mech vent with the following settings: AC mode, FiO2 100%, BUR 16, IFR 60, PEEP 5, TV 450cc. (+) copious whitish to yellowish secretion per ET. : BP 100-120/70-80, HR 160s, RR 20 CAB, O2 sat 100%.

Pt was also sent to radio for CT scan after intubation. Cranial CT scan results: Unremarkable.

03/09/10Patient was referred for desaturation, noted to be dyspneic. Suction was done, found to have mucus plug, and ET out. Patient was reintubated with ET size 7.5, level 20, tolerated very well, hooked to MV with settings: AC mode FiO2 40%, BUR 16, IFR 60 PEEP 5, TV 450 cc (+) copious whitish secretions per ET.Patient became persistently tachypneic (30s): MV settings were adjusted as follows: SIMV, FiO2 35%, TV 400, BUR 12, PEEP 5, I:E 1:2.

03/10/10Patient’s K was low at 2.7. This was corrected with 60 mEqs K x 1L pNSS x 10H x 3 cycles.There was also note of harsh breath sounds despite regular suctioning, along with a spike in temperature, on ave 39C, which remained constant throughout the day, sepsis was a strong consideration so a shift of antibiotic medication from Pip-Tazo to Meropenem was ordered to provide wider and stronger coverage of nosocomial pathogens

03/11/10Patient arrested and was revived after 7 minutes, 2 epinephrine ampoules were given. Post ACLS: BP 110/70, HR 136, O2 sat 100%, ECE, CBS. Suctioning was done with no resistance and minimal brownish secretions per ET. Possible cause of code: NFA secondary to Hypokalemia, r/o PE. MICU ROD then changed MV settings to: AC mode FIO2 100%, BUR 16, IFR 60, PEEP 5, TV 400cc. She was also given Heparin 3600 ‘u’ as IV bolus then started on Heparin drip: 10000 ‘u’ heparin + enough pNSS to make 100cc in a soluset to run for 7cc/hr.

03/11/10Post-code, she was E1V1M1. Also on PE, there was note of an S3 gallop.Post-code ECG showed ST, NA, low voltage complexes.Her ECG at 9am had similar findings: ST, NA, low voltage complexes.Electrolytes were obtained revealing high K at 7.7 so KCl drip was discontinued.

03/11/10She had a complete abortion at 1pm and was immediately seen by the OB service, there was no uterine atony. Stat Hgb and Hct were 61 and 0.148 respectively, and she had hypotensive episodes (lowest 70/50) and was immediately given 500cc fast drip of pNSS and so 2’u’ pRBC were processed as quickly as possible. She also had Dopamine on standby, 400mg in 250cc D5W, to run at 38cc/hr max, to be down titrated by 2cc/hr until it reaches 10cc/hr if BP remains above 90/60.Her PWI was revised to: