Post on 27-Jul-2020
- 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
References 1. Querol-Fernandez, J.C. and G. Isasti, [Mesalamine-induced myocarditis]. Med Clin (Barc), 2016. 146(2): p. e7-8. 2. Nair, A.G. and R.R. Cross, Mesalamine-induced myopericarditis in a paediatric patient with Crohn's disease. Cardiol Young, 2015. 25(4): p. 783-6. 3. Jeremic, I., et al., Fatal sulfasalazine-induced eosinophilic myocarditis in a patient with periodic fever syndrome. Med Princ Pract, 2015. 24(2): p. 195-7. 4. Baker, W.L., et al., Cardiac MRI-confirmed mesalamine-induced myocarditis. BMJ Case Rep, 2015. 2015. 5. Varnavas, V.C., et al., Recurrent lymphocytic myocarditis in a young male with ulcerative colitis. Eur J Med Res, 2014. 19: p. 11. 6. Sabatini, T., et al., Recurrence of myocarditis after mesalazine treatment for ulcerative colitis: a case report. Inflamm Bowel Dis, 2013. 19(3): p. E46-8. 7. Mitoff, P.R., et al., Giant cell myocarditis in a patient with a spondyloarthropathy after a drug hypersensitivity reaction. Can J Cardiol, 2013. 29(9): p. 1138 e7-8. 8. Galvao Braga, C., et al., Mesalamine-induced myocarditis following diagnosis of Crohn's disease: a case report. Rev Port Cardiol, 2013. 32(9): p. 717-20. 9. Liu, Y., et al., Myocarditis due to mesalamine treatment in a patient with Crohn's disease in China. Turk J Gastroenterol, 2012. 23(3): p. 304-6. 10. Daoulah, A., et al., Acute myocardial infarction in a 56-year-old female patient treated with sulfasalazine. Am J Emerg Med, 2012. 30(4): p. 638 e1-3. 11. Perez-Colon, E., et al., Mesalamine-induced myocarditis and coronary vasculitis in a pediatric ulcerative colitis patient: a case report. Case Rep Pediatr, 2011. 2011: p. 524364. 12. Merceron, O., et al., Mesalamine-induced myocarditis. Cardiol Res Pract, 2010. 2010. 13. Freeman, H.J. and B. Salh, Recurrent myopericarditis with extensive ulcerative colitis. Can J Cardiol, 2010. 26(10): p. 549-50. 14. Kounis, G.N., et al., Comment: Mesalamine-associated hypersensitivity myocarditis in ulcerative colitis and the Kounis syndrome. Ann Pharmacother, 2009. 43(2): p. 393-4. 15. Garcia-Ferrer, L., J. Estornell, and V. Palanca, Myocarditis by mesalazine with cardiac magnetic resonance imaging. Eur Heart J, 2009. 30(8): p. 1015. 16. Cooper, L.T., Jr., Myocarditis. N Engl J Med, 2009. 360(15): p. 1526-38. 17. Stelts, S., et al., Mesalamine-associated hypersensitivity myocarditis in ulcerative colitis. Ann Pharmacother, 2008. 42(6): p. 904-5. 18. Robertson, E., et al., Balsalazide-induced myocarditis. Int J Cardiol, 2008. 130(3): p. e121-2. 19. Lau, G., C. Kwan, and S.M. Chong, The 3-week sulphasalazine syndrome strikes again. Forensic Sci Int, 2001. 122(2-3): p. 79-84. 20. Marteau, P., et al., Adverse events in patients treated with 5-aminosalicyclic acid: 1993-1994 pharmacovigilance report for Pentasa in France. Aliment Pharmacol Ther, 1996. 10(6): p. 949-56. 21. Kristensen, K.S., et al., Fatal myocarditis associated with mesalazine. Lancet, 1990. 335(8689): p. 605. 22. Agnholt, J., et al., Cardiac hypersensitivity to 5-aminosalicylic acid. Lancet, 1989. 1(8647): p. 1135. 23. Drug Insight: aminosalicylates for the treatment of IBD. http://www.nature.com/nrgastro/journal/v4/n3/fig_tab/ncpgasthep0696_F2.html Cardiac Magnetic Resonance Assessment of Myocarditis. http://circimaging.ahajournals.org/content/6/5/833.full#T1
Summary Points & Questions Sulfasalazine,
mesalamine-derivative, associated with rare cardiac adverse effect – myocarditis, vasculitis.