Rheumatology winter clinical symposium 2019 Nina narasimhalu md CASE PRESENTATION 33yearold male presents with bilateral lower extremity edema progressive myalgias generalized weakness periorbital swelling and rash for 2 weeks ID: 909026
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Slide1
Suspected Drug-Induced SLE, APLS and ANCA Vasculitis
Rheumatology winter clinical symposium 2019
Nina
narasimhalu
, md
Slide2CASE 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)
Slide3HISTORY
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
Slide4LABS 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
Slide5PHYSICAL 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.
Slide6RASH ON FEET
Slide7IMAGING
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.
Slide8Moderate pericardial effusion with small bilateral pleural effusions.
Slide9CLINICAL 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
Slide10CLINICAL 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
Slide11UPDATED 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
Slide12CLINICAL 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
Slide13PATHOLOGY 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).
Slide14SKIN BIOPSY PATHOLOGY
Slide15SKIN BIOPSY
PATHOLOGY
Slide16RENAL 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
RENAL BIOPSY IMMUNOFLUORESCENCE
Courtesy of UCLA
Slide18RENAL BIOPSY PATHOLOGY
Courtesy of UCLA
Slide19POST-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
Slide20POST-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
Slide21MOST 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
Slide22Diffuse bilateral ground glass opacities, smooth interlobular septal thickening, lower lobe predominant consolidative opacities.
Slide23CLINICAL 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
Slide24THE 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?
Slide25LEVAMISOLE
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.
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.
Slide27HISTORY 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.
Slide28MECHANISM 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.
Slide29LEVAMISOLE-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.
Slide30OTHER 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.
Slide31LAB 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.
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.
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.
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
.
Slide35NOTABLY 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?
Slide36TAKE 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.
Slide37ACKNOWLEDGMENTS
Patient provided verbal consent to present his case and emphatically agreed that “everyone should be aware of this!”
UCI Department of Rheumatology
Slide38REFERENCES
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
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Brunt TM, van den Berg J, Pennings E, Venhuis B.
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EM,
Casale
JF.
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Hennings
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Slide39REFERENCES
Lee KC,
Ladizinski
B,
Federman
DG.
Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge
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Clin
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HG,
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Weissmann
G.
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