- Jay Shah, MD Internal Medicine Resident

Maine Medical Center

Heuristic decision making "When you hear hoofbeats, think of

horses not zebras". ~ Dr. Theodore Woodward, professor at the

University of Maryland School of Medicine in 1940s

Overview Case Presentation

History, Physical & Data Build a Differential Diagnosis Additional test results and data Update our Differential Diagnosis Clinical Pearls

Case Presentation Mr. F. D. - 50 y/o man Setting

PCP office, being transferred to Emergency Department / Hospital admission

Chief Complaint Fever, malaise, fatigue, diffuse body aches and

dyspnea for 1 week

Recent History & HPI Last 2 years – Swelling of wrist and ankles,

tendonopathy and polyarthralgia. Imaging studies:

MR of the right shoulder, MR left knee, XR pelvis, XR left wrist and XR right ankle – Degenerative arthorpathy

MR of the left wrist - synovitis PCP referred to rheumatologist

ANA + (no titer reported) with elevated anti-RNP Negative: HLAB27, RF anti-CCP and normal CRP.

Patient used ibuprofen 800mg TID PRN with mild symptomatic relief, and was started on sulfasalazine DR 500mg daily, up titrating gradually every 3-5 days to 500mg BID to 1000mg BID for seronegative spondyloarthropathy.

History of Present Illness 4 weeks ago

Sulfasalazine initiated, 500mg – 1000mg/d 3 weeks ago

Began to experience “flu-like” symptoms, fevers 102, malaise, diffuse body aches, fatigue, dyspnea and occasional chest palpitations.

Held sulfasalazine for a week with resolution of symptoms.

1 week ago Restarted sulfasalazine for a day Recurrence of his previous symptoms with increased

malaise, myalgias and exertional dyspnea lasting for a week with bed rest the first four days.

Patient then presented to PCP office for evaluation

Other Clinical History Past Medical History

Anxiety, insomnia, migraine, seronegative spondyloarthropathy

Past Surgical History Right rotator cuff surgery, 2 years ago

Medications Buspirone 10mg BID, quetiapine 50mg qHS,

sumatriptan 25mg PRN, Ibuprofen PRN and sulfasalazine 500mg.

No Known allergies

Family and Social History FH:

Father- CV disease and stroke SH:

Non smoker Glass of wine with dinner – none in last week No illicit drug use Married, monogamous relationship and owns

a bagel store. Exercise ~30min everyday

Physical Exam VS: 36.8 ℃, Pulse 77, BP 113/76, RR 20 with O2

97%. Appears stated age, mild distress. Lungs were clear to auscultation bilaterally Cardiac examination showed normal rate and

regular rhythm with systolic murmur, grade 2/6, heard lower left sternal border. No JVD. No edema in extremities.

Musculoskeletal examination was unremarkable for joint swelling or synovitis.

Skin examination negative rashes or lesions

Data Na 138, K 4, Cl 102, Bicarb 23, BUN 14,

Creatinine 1.02, Glucose 98, Calcium 8.8, Albumin 3.3, Bilirubin 0.5, AST 33, ALT 32 Troponin T 3.93 Cholesterol 156, TG 77, HDL 34, LDL 107 PT 36 ESR 55 and CRP 46.5.

Differential Diagnosis ???

Echocardiogram

Management Medications:

Aspirin 81mg Clopidogrel load 600mg Atorvastatin 80mg Heparin gtt

Coronary Catheterization

Moderate coronary artery disease involving right coronary artery and proximal left anterior descending artery, coronary artery dissection in circumflex artery and right coronary artery demonstrating signs of healed dissection versus vasculitis changes.

Coronary Catheterization

Moderate coronary artery disease involving right coronary artery and proximal left anterior descending artery, coronary artery dissection in circumflex artery and right coronary artery demonstrating signs of healed dissection versus vasculitis changes.

Cardiac MRI

Cardiac MRI

Cardiac MRI

Cardiac MRI

Microvascular transmural infarction

Epicardial surface at the junction of anteroseptal and inferoseptal segment at basal level, anterior mid-cavity level and anteriorly along with subtle subendocardial enhancement of the anteroseptal segment at the mid cavity level

Cardiac MRI

Cardiac MRI

Cardiac MRI

Cardiac MRI

Cardiac MRI

Cardiac MRI

Cardiac MRI

Cardiac MRI

Endomyocardial Biopsy

Management CT Chest Abdomen Pelvis

Bilateral PE and ?Renal infarction Started on warfarin

Hypercoaguable Work Up Repeat ANA (-) but RNP (+) SPEP - ↑ CRP and alpha-2 zone suggesting

a reactive process. G20210A mutation in prothrombin gene

and Factor V R506Q (Leiden) mutation – (-).

Mildly high cardiolipin antibody IgM 14.0 (normal ≤12 MPL) with (-) cardiolipin antibody IgG and IgA

Diagnosis Sulfasalazine induced myocarditis with

coronary vasculitis vs spontaneous coronary artery dissection

Myocarditis Inflammation of the myocardium 1-10 cases per 100,000 WHO/ISFC: Diagnosis by established histological

(Dallas criteria), immunological, and immunohistochemical criteria

Most patient do not undergo endomyocardial biopsy Heart failure in combination with acute disease (<2 weeks,

class I) or LV dilatation (<3 months, class I). Positive RV biopsy 0-80%

Cardiac MRI Inflammatory hyperemia and edema, necrosis/scar,

contractile dysfunction, and accompanying pericardial effusion

Signs and Symptoms Mild symptoms:

Fever, sweats, chills, dyspnea, flu-like illness Other symptoms:

Arthralgia, malaise or pharyngitis, tonsillitis or upper respiratory tract infection

Palpitations, syncope, AV block Heart failure & Arrhythmia ○ Rapidly progressive/fatal

Unique Presentations Acute rheumatic fever

Usually affects heart in 50-90%; associated signs, such as erythema marginatum, polyarthralgia, chorea, subcutaneous nodules (Jones criteria)

Giant cell myocarditis Sustained ventricular tachycardia in rapidly progressive

heart failure Sarcoid myocarditis

Lymphadenopathy, also with arrhythmias, sarcoid involvement in other organs (up to 70%)

Peripartum cardiomyopathy Heart failure developing in the last month of pregnancy or

within 5 months following delivery Hypersensitive/eosinophilic myocarditis

Pruritic maculopapular rash, history of using offending drug

Eosinophilic myocarditis Presence of infiltrates

rich in macrophages and eosinophils

Myocyte necrosis is usually absent, and scattered poorly formed granulomas can be seen.

Cardiac function may improve or normalize when the offending drug is withheld

Sulfasalazine Sulfa drug class Combination of salicylate and sulfa

antibiotic / sulfonamide by Azole bond

Sulfasalazine

Sulfasalazine Rheumatoid arthritis 70s years ago Juvenile idiopathic arthritis Ankylosing spondylitis Psoriatic arthritis Ulcerative colitis

Sulfasalazine – Common Side Effects Nausea Adominal discomfort (improve over time) Mouth sores, itching, liver function abn,

pulmonary problems Folate supplementation recommended

Photosensitivity Rare: agranulocytosis, hypospermia, case

reports - myocarditis

Sulfasalzine/Mesalamine induced Myocarditis & Coronary Vasculitis Literature Review 1980:

Mesalamine and it’s prodrug (Sulfasalazine and Balsalazide)

Indication UC, seronegative and

seropositive spondyloarthropathy

~20 cases of mesalamine cardiac toxicity reported in Pubmed

~ 30 adverse events reported to FDA (FAERS)

Cardiotoxicity Mechanism Unclear Hypersensitivity reaction rather than a

cytotoxic effect. Humoral-mediated hypersensitivity in

which antibodies formed against mesalamine cross-react with cardiac tissue causing inflammation.

Most cases of mesalamine-induced cardiovascular toxicity occur 2–4 weeks after the initial exposure to the drug, although presentation may be delayed in the setting of concomitant steroid administration.

Resolution of symptoms generally occurs within one week of drug discontinuation.

Drug induced myocarditis - Prognosis Varied presentation

Improvement post discontinuation of drug Gradual progression to heart failure Fulminant heart failure

Spontaneous Coronary Artery Dissection Younger, Peripartum woman Connective tissue disorders Vasculitidies Exercise

An Unfinished Story… 1.5 months later

Normal echocardiogram, no wall motion abnormalities and normal EF

2 months later Exercise stress test 12mins, normal

4.5 months later Warfarin discontinued (Indication: PE)

5 months later Dyspnea, Chest discomfort, repeat echo

with global hypokinesis and mobile apical thrombus

Repeat diagnostic cath with mild-mod non obstructive CAD, no dissection noted

An Unfinished Story… 5 months later

Restarted warfarin therapy 8 months later

Echocardiogram - Normal LV function, Inferior wall hypokinesis, No clot in LA

Acknowledgement Dr. Douglas Sawyer Dr. Sanjeev Francis Dr. Jennifer Hillstrom Dr. Brain Daikh Dr. Mehdi Gheshlagi Dr. Steve Hayes Maine Chapter ACP Warene Eldridge

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Summary Points & Questions Sulfasalazine,

mesalamine-derivative, associated with rare cardiac adverse effect – myocarditis, vasculitis.