Suspected Drug-Induced SLE, APLS and ANCA Vasculitis - PowerPoint Presentation

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Suspected Drug-Induced SLE, APLS and ANCA Vasculitis

Rheumatology winter clinical symposium 2019

Nina

narasimhalu

, md

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CASE PRESENTATION

33-year-old male presents with bilateral lower extremity edema, progressive

myalgias

, generalized weakness, periorbital swelling and rash for 2 weeks

Patient also reports history of progressive shortness of breath, which was evaluated 10 days prior to presentation at an outside hospital (work-up was incomplete since he left AMA), productive cough, sore throat and loss of appetite

Denies photosensitivity, pleurisy, hematuria, foaming/frothing of urine

Positive exposure to sick contacts (niece had upper respiratory tract symptoms)

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HISTORY

No past medical history

No prior surgeries

Allergy to Bactrim

Social history notable for tobacco (1/2 pack per day for 10 years), frequent intravenous heroin and methamphetamine use, skin popping

Last IVDU was 1 day prior to admission

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LABS in ED

WBC 7.2,

Hgb

9.7, platelets 97

Absolute lymphocytes 1.5, absolute neutrophils 5.1

Na 126, K 4.2, Cl 99, CO2 21, BUN 55, Cr 1.2, glucose 107, calcium 7.5

AlkP

53, AST 147, ALT 43,

Tbili

0.7, total protein 5.8, albumin 2.3

UA with 100 protein, moderate

Hgb

, 7 WBC, 4 RBC

CRP 5.1 mg/

dL

, ESR 59

INR 1.18

Lactic acid 1.0

Troponin 0.03

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PHYSICAL EXAM

T 98.1F, HR 122, RR 32, BP 111/65, 93%

General: Restless and uncomfortable.

HEENT: Periorbital edema bilaterally with overlying erythema.

Chest/CV: Diminished breath sounds. Tachycardic, regular rhythm.

Abd

: Normoactive bowel sounds. NT, ND.

Ext: 2+ edema of BLE extending above knees.

MSK: No active synovitis.

Skin: Dermatitis with flaking of skin of distal bilateral lower extremities. Erythematous maculopapular rash on anterior chest. Flaking of skin on scalp. Violaceous palpable and non-palpable macules on feet extending to toes with

retiform

pattern. Right lateral thigh with healing eschar vs non-draining wound. 

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RASH ON FEET

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IMAGING

CXR

:

Moderate cardiomegaly. No focal pulmonary consolidation. No large pleural effusion or gross PNX.

US BLE

:

No DVTs.

US

Abd

:

Mild HSM. Moderate pericardial effusion. Small bilateral pleural effusions.

TTE

:

Echo evidence of impending cardiac tamponade. Moderate pericardial effusion. Normal LVEF. RVSP 20.8mmHg. CT Chest: Mild to moderate pleural effusion on L with collapse of L lower lobe. Small to moderate pleural effusion on R. Prominent mediastinal LNs.

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Moderate pericardial effusion with small bilateral pleural effusions.

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CLINICAL COURSE

Pericardiocentesis

with removal of 650mL of serosanguinous fluid and placement of pericardial drain

 additional 1L drained

At this time, differential had included infectious etiology with post-nephrotic syndrome

Due to intermittent fevers, Infectious Disease service was consulted  infectious work-up remained negative  NO antibiotics

Skin biopsy of purpuric lesion on R foot concerning for

vaso

-occlusive process vs vasculitis

Nephrology was consulted as UPC 0.9  24-hour urine with 1.8g/24

At this point, there was a high index of suspicion for SLE

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CLINICAL COURSE CONTINUED

Increased work of breathing requiring

BiPAP

and

HiFloNC

Developed

pAF

and was started on amiodarone

Drop in

Hgb

7.3  6.6 with elevated

haptoglobin

and normal Tbili

Re-consulted ID due to fevers  repeat endocarditis and infectious work-up largely negative

Ended up starting antibiotics when sputum culture grew

Staph aureus

and

UCx

grew

E.

faecalis

At this point, labs were notable for

a positive ANA, low complements, +

Coomb’s

,

cytopenias

AND with patient’s

serositis

, renal insufficiency with proteinuria, patient met diagnostic criteria for SLE

After much discussion with family, decision made to begin

Solumedrol

125mg IV daily

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UPDATED RHEUMATOLOGY LABS

ANA 1:320 homogenous

dsDNA 1:2560

Histone 7.8 (+)

NEG Smith, RNP, SSA, SSB, Jo-1

C3 18.7, C4 7

p-ANCA 1:320 with MPO 63 and PR3 37

Cardiolipin

IgG 69, IgM 56, LAC weakly positive, Beta-2 IgG 119, IgM <5

Ferritin 2128

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CLINICAL COURSE

Worsening pulmonary edema and atrial fibrillation with RVR

 intubated for 2 days then extubated

Underwent thoracentesis with removal of 1L fluid

Now admitted to cocaine use too

Underwent renal biopsy to further elucidate etiology  SLE vs ANCA

Discharged home after biopsy on prednisone 60mg daily

Total hospitalization: 17 days

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PATHOLOGY of SKIN

FINAL DIAGNOSIS AFTER MICROSCOPY:

     SKIN, RIGHT LATERAL FOOT, PUNCH BIOPSY:   

     OCCLUSIVE VASCULOPATHY WITH VASCULAR NECROSIS (SEE COMMENT)

     PAS SPECIAL STAIN IS NEGATIVE FOR FUNGUS.

     Comment: Thrombotic vasculitis can be seen in patients taking

cocaine contaminated with levamisole and in autoimmune diseases

(lupus, antiphospholipid syndrome, anti-

cardiolipin

antibodies).

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SKIN BIOPSY PATHOLOGY

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SKIN BIOPSY

PATHOLOGY

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RENAL BIOPSY PATHOLOGY

UCLA FINAL DIAGNOSIS

KIDNEY, NATIVE (NEEDLE CORE BIOPSY):  

-     Focal proliferative glomerulonephritis with moderate activity including focal crescents (see COMMENT)

-     Acute tubular injury and

tubulointerstitial

inflammation, favor secondary to glomerulonephritis

-     Mild global glomerulosclerosis, no interstitial fibrosis/tubular atrophy, and moderate arterial sclerosis

-     No evidence for thrombotic

micrangiopathy

 

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RENAL BIOPSY IMMUNOFLUORESCENCE

Courtesy of UCLA

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RENAL BIOPSY PATHOLOGY

Courtesy of UCLA

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POST-HOSPITALIZATION

Returned 2 days after discharge for volume overload



hospitalized for 3 days for diuresis

Went to 1 post-hospitalization follow-up appointment, but no-showed 2 of his rheumatology follow-up appointments

Came back 2 months after initial hospitalization complaining of SOB and BLE swelling, had gone back to using IV drugs, including methamphetamine and heroin, had been off of prednisone x 1 month

 echocardiogram showed constrictive pericarditis  creatinine elevated, dsDNA > 5120, low complements  started on

Solumedrol

acutely then transitioned to prednisone upon discharge, also started on

Plaquenil

and

CellCept

500mg PO BID

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POST-HOSPITALIZATION COURSE

Returned 1 month after that discharge complaining of SOB, had started using intravenous heroin again



found to have multiple pulmonary emboli and bilateral thigh abscesses s/p I&Ds

Patient was restarted on a lower dose of prednisone to help support him through infection due to concern for adrenal insufficiency,

CellCept

was held, discharged home with antibiotics,

Plaquenil

and prednisone

Did not come to post-hospitalization Rheumatology appointment

Returned 5 months later and was admitted for 1 week

 had

Pseudomonas

and

S. pneumoniae

PNA and was receiving antibiotics but patient left AMA

Found to have new onset cardiomyopathy with EF 34% during this admission

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MOST RECENT HOSPITALIZATION

Patient had left against medical advice, but continued to feel unwell so he came back to the ED a few days later

…

Started on empiric antibiotics and heart failure therapy

Decompensated and briefly intubated for a day, creatinine steadily rising

Became hypoxic a few days later and was re-intubated

 had a bronchoscopy, which confirmed diffuse alveolar hemorrhage

Started on

Solumedrol

125mg q6h

Transfusion Medicine consulted for possible plasma exchange

Successfully extubated 3 days later and admitted to ongoing drug use

Had been clean for 3 months, but fell back into old habits 2-3 days before admission

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Diffuse bilateral ground glass opacities, smooth interlobular septal thickening, lower lobe predominant consolidative opacities.

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CLINICAL COURSE

Discharged to acute rehabilitation unit with a prednisone taper

Close outpatient follow-up appointment scheduled (within a few days)

If patient shows up, we can discuss immunosuppressive therapy options

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THE QUESTIONS THAT CAME UP …

Is patient’s underlying autoimmune disease (SLE, APLS and AAV) related to his drug use?

Isn’t drug-induced disease typically non-organ threatening?

Are his labs consistent with what we might see with drug-induced disease?

Could it be levamisole?

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LEVAMISOLE

Levamisole is an antihelminthic agent used in veterinary medicine

Removed from the US market in 2000 due to adverse effects

Popular adulterant of cocaine

Per DEA report, approximately 70% of cocaine contained levamisole in 2009

Has also been found with other illicit substances, such as heroin

Brunt, et al.

Casale

, et al.

Lee, et al.

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LEVAMISOLE and COCAINE

Looks similar to cocaine!

Can be used as a cutting or bulking agent

 can increase weight of sample  make drug appear purer

Unclear physiologic effect when both are combined

Theories include:

Prolong cocaine-induced euphoria via nicotinic acetylcholinergic effects on CNS?

Act as an indirect serotonin agonist?

Brunt, et al.

Lee, et al.

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HISTORY OF LEVAMISOLE

Was used as a DMARD for RA in the 1970s

Was used with 5-FU for colon cancer in the 1990s

Removed from US market in 2000 and Canadian market in 2003 due to reports of agranulocytosis

Lee, et al.

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MECHANISM OF ACTION

Immunomodulator

 increase macrophage chemotaxis and T-cell lymphocyte function

Stimulate neutrophil and monocyte chemotaxis  increase inflammatory responses

Up-regulate toll-like receptors

Enhance dendritic maturation and function of macrophages

Increased cytokine production (IL-1)

Metabolite

aminorex

exhibits amphetamine-like effects on dopamine and norepinephrine transporters

Acts as a central mediator in mice  changes metabolism of norepinephrine, serotonin and dopamine

Brunt, et al.

Lee, et al.

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LEVAMISOLE-TOXICITY

Can be characterized by the following:

Cutaneous manifestations:

Retiform

purpura

Hemorrhagic bullae

Necrosis

Commonly involves face, bilateral helixes, cheeks, nose

Case reports mention other areas of involvement throughout body

Vasculitis (with immune complex deposition) vs

pseudovasculitis

Lee, et al.

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OTHER SYMPTOMS of LEVAMISOLE-TOXICITY

Arthralgias

Large joints

Generalized fatigue and malaise

Constitutional symptoms

Renal failure

Pulmonary hemorrhage

Pulmonary HTN

Leukoencephalopathy

Brunt, et al.

Lee, et al.

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LAB ABNORMALITIES

Agranulocytosis*

Neutropenia, leukopenia

+ANA (in speckled pattern, most often)

+dsDNA, +LAC

Normal complements

+ANCA, +MPO > + PR3 (but can have both)

Anti-human elastase antibody

 sensitive and specific for levamisole-induced vasculitis

Brunt, et al.

Hennings

, et al.

Lee, et al.

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PATHOLOGY OF SPECIMENS

Skin biopsies:

LCV

TMA

Panniculitis

Necrosis

Renal biopsies:

Pauci

-immune focal necrotizing crescentic GN

Brunt, et al.

Hennings

, et al.

Lee, et al.

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PHARMACOKINETICS of LEVAMISOLE

Cocaine remains in urine for 48-72 hours

Hard to necessarily tie cocaine use and levamisole together

Levamisole quickly absorbed with short half-life (5.5-6 hours)

Extensively metabolized in the liver

Highest concentrations of levamisole found in blood and lung tissue

Women affected more than men?

Brunt, et al.

Lee, et al.

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PROGNOSIS OF LEVAMISOLE-ASSOCIATED DISEASE

Generally good, but it depends on patient’s willingness to stop using drugs that contain the offending agent:

Cocaine

Heroin

Sometimes, it is necessary to use immunosuppressive therapy such as high-dose steroids, Cytoxan or MMF

Plasmapheresis has been used too in severe cases

Plaquenil

for skin and joint-related disease

Rivera, et al.

Striebich

.

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NOTABLY FOR OUR PATIENT

His lupus anticoagulant, anti-

cardiolipin

IgG/IgM and beta-2 glycoprotein IgG/M are now negative and his pulmonary emboli have resolved

But in light of continued drug use, do we continue with anti-coagulation? Did being clean for 3 months prior to relapse have any effect on his

serologies

?

Systemic Lupus Erythematosus in 6 Male Cocaine Users at Bellevue Hospital

by Rivera et. al discussed an interesting topic:

Can we learn more about disease pathogenesis of SLE in men who abuse cocaine?

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TAKE HOME POINTS

Not only is levamisole being used to adulterate

cocaine

, but it is also found in

heroin

!

Levamisole has been associated with SLE, APLS and ANCA-vasculitis

Cocaine is not only adulterated with levamisole, but diltiazem too, which is another cause of drug-induced SLE

Heroin can also be adulterated with

griseofulvin

, which has been associated with drug-induced SLE

Anti-elastase antibody

is both sensitive and specific for levamisole-induced vasculitis

Broseus

, et al.

Brunt, et al.

Lee, et al.

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ACKNOWLEDGMENTS

Patient provided verbal consent to present his case and emphatically agreed that “everyone should be aware of this!”

UCI Department of Rheumatology

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REFERENCES

Borchers

AT, Keen CL, Gershwin ME. Drug-induced lupus. Ann N Y

Acad

Sci. 2007 Jun;1108:166-82.

Broséus

J, Gentile N,

Esseiva

P.

The cutting of cocaine and heroin: A critical review

. Forensic

Sci

Int. 2016 May;262:73-83.

Brunt TM, van den Berg J, Pennings E, Venhuis B.

Adverse effects of levamisole in cocaine users: a review and risk assessment. Arch

Toxicol

.

2017 Jun;91(6):2303-2313.

Casale

EM,

Casale

JF.

Identification of levamisole and lidocaine acetylation reaction impurities found in illicit cocaine exhibits

. Microgram J. 2011; 8(1):16-23.

Hennings

C, Miller J.

Illicit drugs: What dermatologists need to know

. J Am

Acad

Dermatol

. 2013 Jul;69(1):135-42.

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REFERENCES

Lee KC,

Ladizinski

B,

Federman

DG.

Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge

. Mayo

Clin

Proc. 2012 Jun;87(6):581-6.

McGrath MM, Isakova T,

Rennke

HG,

Mottola AM, Laliberte KA, Niles JL. Contaminated cocaine and

antineutrophil

cytoplasmic antibody-associated disease.

Clin

J Am

Soc

Nephrol

. 2011 Dec;6(12):2799-805.

Rivera TL, Belmont HM,

Weissmann

G.

Systemic lupus erythematosus in 6 male cocaine users at Bellevue hospital

. J

Rheumatol

. 2009 Dec;36(12):2854-5.

Striebich

, C. Chapter 17:

Drug Induced Lupus

. 

Rheumatology Secrets

. Sterling G. West.

Philidelphia

: Elsevier/Mosby, 2015. 137-140.