Drug-induced hypersensitivity syndrome with myocardial involvement treated with tofacitinib.

Introduction

Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is a severe reaction to medications that presents with rash, fever, and lymphadenopathy. Patients typically have eosinophilia and end-organ damage, most commonly to the kidneys or liver. If the heart is involved, either hypersensitivity myocarditis or acute necrotizing eosinophilic myocarditis (ANEM) can occur; the former is often reversible, and the latter is usually fatal. DIHS can persist for months after drug withdrawal, and different organ systems can be affected at different times. Symptoms can persist for a year or more. DIHS is treated with high doses of corticosteroids, which may be administered for months.

DIHS is a type IV hypersensitivity reaction resulting in a T helper cell 2 (Th2)–predominant immune response with recruitment and activation of eosinophils. Interleukin 5 (IL-5), an eosinophil activator, and eosinophil chemokines, C-C motif chemokine ligand (CCL)17 and CCL22, are involved in DIHS and other eosinophilic disorders.2, 3, 4, 5, 6 In DIHS, other cytokines including IL-6, IL-10, and IL-13 are also thought to play a role in pathogenesis.7, 8 IL-5 blockers can be used to treat some eosinophilic disorders but these agents do not block these other pathogenic cytokines. However, all of these cytokines rely on the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway and can be simultaneously targeted using JAK inhibitors.

It is not known whether molecularly targeted small molecule inhibitors are effective or work rapidly enough to treat severe drug reactions such as DIHS. Here we report 2 consecutive patients with severe DIHS with myocardial involvement treated with the JAK inhibitor tofacitinib.

Patient 1

A 37-year-old woman developed an exanthematous rash, facial edema, fever, and lymphadenopathy 3 weeks after starting minocycline. She was found to have elevated transaminases and eosinophilia (1035 cells/μL). Her RegiSCAR score was 4 and DIHS was diagnosed (Fig 1; see Supplement). She was started on prednisone 80 mg once daily but had worsening eosinophilia (4024 cells/μL), increasing transaminase elevation, and creatine kinase elevation. Magnetic resonance imaging of multiple anatomic areas showed rhabdomyolysis, which can be observed in DIHS. Pulse methylprednisolone led to improvement, and the patient was transitioned to a prednisone taper. One month later, taking prednisone 40 mg daily, she became dyspneic and was found to have troponin elevation and biventricular heart failure with left ventricular ejection fraction (LVEF) less than 10%, consistent with ANEM (see Supplement). She was treated with an intra-aortic balloon pump, vasopressors, and pulse methylprednisolone. Her LVEF recovered, and she was transitioned to a prednisone taper plus cyclosporine. Given the life-threatening nature of her disease, similarities between DIHS and hypereosinophilic syndrome, and our experience treating hypereosinophilic syndrome with tofacitinib, tofacitinib 5 mg twice daily was also initiated.

Fig 1

Summary of clinical course in patient 1. Treatments before and after clinical DIHS flare are listed in the top panel. Doses of prednisone and cyclosporine are shown as milligram per kilogram per day. Doses of tofacitinib are milligrams per day and methotrexate milligrams per week. Methylprednisolone was given at 1 g daily for 3-5 days. Intravenous immunoglobulin (IVIG) was given at 2 g/kg divided over 5 days. Middle panel shows DIHS activity/disease flares (blue spikes), but are not to scale. Lower panel shows the most relevant clinical data during DIHS flares, including ejection fraction (EF) during and after recovery from the flare, when possible. Green highlight signifies an abnormal value. Asterisk signifies every other day. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; CNS, central nervous system; Creat, creatinine; Eos, eosinophils; n/a, data not available; Trop, troponin. Additional details for this case can be found in the Supplement.

While tapering prednisone (to 10 mg daily), diplopia, flaccid bilateral lower extremity weakness, and urinary retention developed, and DIHS flare involving the central nervous system was diagnosed. Other causes for her neurologic symptoms were evaluated and ruled out (Fig 1; see Supplement). She was treated with pulse methylprednisolone and intravenous immunoglobulin. She was discharged on prednisone, methotrexate, and tofacitinib, 5 mg twice daily.

She was stable for 4 weeks until tofacitinib was discontinued due to insurance issues. Nine days later, while taking prednisone, 40 mg daily, and methotrexate, she was admitted in cardiogenic shock with recurrent ANEM requiring intra-aortic balloon pump, vasopressors, and pulse methylprednisolone. Tofacitinib, 5 mg twice daily, was restarted. She had significant recovery of her LVEF and was discharged 2.5 weeks later on a prednisone taper, methotrexate, and tofacitinib, 5 mg twice daily.

She was stable for 10 months, and so tofacitinib was discontinued; at that time she was also taking prednisone, 10 mg every other day. Five months later she presented with fever and malaise (see Supplement). Laboratory evaluation showed peripheral eosinophilia (5,500 cells/μL). A relapse of DIHS (RegiSCAR score 6) was diagnosed, and she was treated with tofacitinib, 5 mg twice daily, monotherapy. Her symptoms resolved immediately, but because her peripheral eosinophil count was still 5,000 cells/μL after 3 days, the dose of tofacitinib was increased to 10 mg in the morning and 5 mg at night. By day 6 her eosinophil count normalized (600 cells/μL). She has continued on tofacitinib 15 mg daily for 23 months. Her cardiovascular function has nearly normalized, with recent LVEF of 44% and no evidence of heart failure.

Patient 2

A 31-year-old man was started on lamotrigine and 5 weeks later developed an exanthematous rash, facial swelling, fever, and lymphadenopathy. He was found to have peripheral eosinophilia (3000 cells/μL). RegiSCAR score was 5, consistent with DIHS. After a 3-week prednisone taper (starting at 60 mg daily), his peripheral eosinophil count continued to be elevated (approximately 1800 cells/μL on prednisone, 40 mg daily), and he developed new chest pain (Fig 2). Troponin was elevated, and echocardiogram and cardiac magnetic resonance imaging showed LVEF of 33%, regional wall motion abnormalities, and a delayed enhancement pattern consistent with myocarditis. DIHS-associated hypersensitivity myocarditis was diagnosed, and he was treated with pulse methylprednisolone, resulting in resolution of eosinophilia and clinical improvement. He was started on methotrexate and a prednisone taper.

Fig 2

Summary of clinical course in patient 2. Treatments before and after clinical DIHS flare are listed in the top panel. Doses of prednisone are shown as milligram per kilogram per day. Doses of tofacitinib are milligrams per day and methotrexate milligrams per week. Methylprednisolone was given at 1 g daily for 3 days. Middle panel shows DIHS activity/disease flares (blue spikes), but are not to scale. Lower panel shows the most relevant clinical data during DIHS flares, including ejection fraction (EF) during and after recovery from the flare, when possible. Green highlight signifies an abnormal value. Single asterisk signifies associated with wall motion abnormalities, double asterisk signifies trending upwards, and triple asterisk signifies associated with chest pain. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; CNS, central nervous system; Creat, creatinine; Eos, eosinophils; n/a, data not available; Trop, troponin.

Six weeks later, taking methotrexate and prednisone, 20 mg twice daily, the exanthematous eruption recurred. Tofacitinib, 5 mg twice daily, was started, and the dose of methotrexate was decreased. Over the next 8 weeks, prednisone was tapered and discontinued, together with methotrexate. He continued on tofacitinib monotherapy for 4 weeks without evidence of DIHS activity. Tofacitinib was discontinued, and 1 week later the rash and chest pain recurred (RegiSCAR score 3). Tofacitinib was restarted and the symptoms and rash remitted. Tofacitinib was continued for 5 months, at which time repeat imaging showed interval improvement in the delayed enhancement pattern and LVEF. Tofacitinib was continued for an additional 2 months and then discontinued without recurrence of disease.

Cytokine analysis in peripheral blood of patient 1

In patient 1, plasma was acquired during a DIHS flare (Fig 1, June 2017), just before reinitiation of tofacitinib monotherapy and then again after 24 hours and 5 days of treatment (see Supplement). IL-5, IL-6, and IL-13 were markedly elevated before initiation of tofacitinib, and within 24 hours of treatment, levels of these cytokines normalized (Fig 3). Other eosinophil chemokines including CCL1, CCL17, and CCL22 also normalized within 24 hours of tofacitinib (Fig 3). IL-10, IL-12, and C-X-C motif chemokine ligand 10 were also highly elevated and rapidly improved on therapy (not shown).

Fig 3

Cytokine measurements in patient 1. In patient 1, plasma was collected during a DIHS flare (Fig 1, June 2017) just prior to (baseline) reinitiation of tofacitinib and then again after 24 hours and 5 days of therapy. Each measurement was performed in duplicate. This analysis was not performed in patient 2. Measurement of cytokines described in the Supplement. *Ref indicates references ranges from ARUP laboratories.

Discussion

DIHS may have a protracted course and be lethal. The mainstay of treatment, corticosteroids, is sometimes insufficient. There are no guidelines for management of DIHS, and which steroid-sparing agents are preferable in patients with severe disease is not clear. JAK-STAT–dependent cytokines such as IL-5, IL-6, IL-10, and IL-13 play a role in DIHS pathogenesis and signal via the JAK-STAT pathway. We describe 2 cases of DIHS with cardiac involvement that responded to the JAK1/3 inhibitor, tofacitinib. Although the clinical courses in both cases are complicated, DIHS flares in both patients, including ANEM (which has a mortality rate >50%), appeared to respond well to tofacitinib treatment. In patient 1, a reduction in plasma levels of pathogenic cytokines such as IL-5 and IL-6 and chemokines such as CCL17 and CCL22 were observed within 24 hours of tofacitinib monotherapy. The rapid clinical and molecular responses, including normalization of organ function and eosinophil levels and reduction in levels of IL-5 and other pathogenic cytokines/chemokines in our patients, suggest that ;JAK inhibition should be further explored in the treatment of drug hypersensitivity reactions.

Table I

RegiSCAR scores and their associated diagnoses

Score	Diagnosis
−4 to 2	Not DRESS
2 to 3	Possible DRESS
4 to 5	Probable DRESS
5 to 9	“Definite” DRESS