Suspected DrugInduced SLE APLS and ANCA Vasculitis RHEUMATOLOGY

Suspected Drug-Induced SLE, APLS and ANCA Vasculitis RHEUMATOLOGY WINTER CLINICAL SYMPOSIUM 2019 NINA NARASIMHALU, MD

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)

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

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, CO 2 21, BUN 55, Cr 1. 2, glucose 107, calcium 7. 5 Alk. P 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/d. L, ESR 59 INR 1. 18 Lactic acid 1. 0 Troponin 0. 03

PHYSICAL EXAM T 98. 1 F, 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 nonpalpable macules on feet extending to toes with retiform pattern. Right lateral thigh with healing eschar vs non-draining wound.

RASH ON FEET

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. 8 mm. Hg. 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.

Moderate pericardial effusion with small bilateral pleural effusions.

CLINICAL COURSE Pericardiocentesis with removal of 650 m. L of serosanguinous fluid and placement of pericardial drain additional 1 L 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. 8 g/24 At this point, there was a high index of suspicion for SLE

CLINICAL COURSE CONTINUED Increased work of breathing requiring Bi. PAP and Hi. Flo. NC Developed p. AF 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 125 mg IV daily

UPDATED RHEUMATOLOGY LABS ANA 1: 320 homogenous ds. DNA 1: 2560 Histone 7. 8 (+) NEG Smith, RNP, SSA, SSB, Jo-1 C 3 18. 7, C 4 7 p-ANCA 1: 320 with MPO 63 and PR 3 37 Cardiolipin Ig. G 69, Ig. M 56, LAC weakly positive, Beta-2 Ig. G 119, Ig. M <5 Ferritin 2128

CLINICAL COURSE Worsening pulmonary edema and atrial fibrillation with RVR intubated for 2 days then extubated Underwent thoracentesis with removal of 1 L fluid Now admitted to cocaine use too Underwent renal biopsy to further elucidate etiology SLE vs ANCA Discharged home after biopsy on prednisone 60 mg daily Total hospitalization: 17 days

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).

SKIN BIOPSY PATHOLOGY

SKIN BIOPSY PATHOLOGY

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

RENAL BIOPSY IMMUNOFLUORESCENCE Courtesy of UCLA

RENAL BIOPSY PATHOLOGY Courtesy of UCLA

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, ds. DNA > 5120, low complements started on Solumedrol acutely then transitioned to prednisone upon discharge, also started on Plaquenil and Cell. Cept 500 mg PO BID

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, Cell. Cept 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

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 125 mg q 6 h 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

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

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

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?

LEVAMISOLE Brunt, et al. Casale, et al. 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

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.

HISTORY OF LEVAMISOLE Lee, et al. Was used as a DMARD for RA in the 1970 s Was used with 5 -FU for colon cancer in the 1990 s Removed from US market in 2000 and Canadian market in 2003 due to reports of agranulocytosis

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.

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.

OTHER SYMPTOMS of LEVAMISOLETOXICITY Arthralgias Brunt, et al. Lee, et al. Large joints Generalized fatigue and malaise Constitutional symptoms Renal failure Pulmonary hemorrhage Pulmonary HTN Leukoencephalopathy

LAB ABNORMALITIES Agranulocytosis* Neutropenia, leukopenia +ANA (in speckled pattern, most often) +ds. DNA, +LAC Normal complements Brunt, et al. Hennings, et al. Lee, et al. +ANCA, +MPO > + PR 3 (but can have both) Anti-human elastase antibody sensitive and specific for levamisole-induced vasculitis

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 Brunt, et al. Lee, et al. 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?

PROGNOSIS OF LEVAMISOLEASSOCIATED DISEASE Generally good, but it depends on patient’s willingness to stop using drugs that contain the offending agent: Cocaine Heroin Rivera, et al. Striebich. 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

NOTABLY FOR OUR PATIENT His lupus anticoagulant, anti-cardiolipin Ig. G/Ig. M and beta-2 glycoprotein Ig. G/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?

TAKE HOME POINTS Broseus, et al. Brunt, et al. Lee, et al. 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 levamisoleinduced vasculitis

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

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.

REFERENCES Lee KC, Ladizinski B, Federman DG. Complications associated with use of levamisolecontaminated cocaine: an emerging public health challenge. Mayo Clin Proc. 2012 Jun; 87(6): 581 -6. Mc. Grath 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.