Case report

We report a 20-year-old otherwise healthy Caucasian man, diagnosed with SJIA at the age of 15 years, after presenting with symptoms of quotidian fevers, evanescent rash, and polyarthritis. At that time he was started on canakinumab with subsequent resolution of symptoms without any complications. After 5 years of well-controlled disease, he developed 3 days of fever, joint pain, and petechial rash. The patient’s symptoms in combination with laboratory findings, including ferritin 6028 ng/mL, platelets 47×10^∧9/L, fibrinogen 117 mg/dL, aspartate aminotransferase (AST) 142 unit/L, were consistent with MAS.4 He was admitted and treated with intravenous methylprednisolone 1000 mg daily for 5 days and clinically stabilised, but his neutropenia, lymphopenia, thrombocytopaenia and hypofibrinogenaemia did not improve (figure 1). His CXCL9 levels returned at 34 638 pg/mL (reference range ≤647 pg/mL) so emapalumab was initiated twice weekly with rapid improvements in his cytopenias and hypofibrinogenemia.5 6 Given that this was his first MAS episode after years of well-controlled disease, a thorough workup was performed for MAS triggers. Bone marrow biopsy was performed showing increased numbers of CD8 positive T cells, scattered haemophagocytosis and no overt evidence of leukaemia or lymphoma. EBV serology showed negative IgG and IgM but quantitative PCR returned significantly elevated at 501 400 IU/mL, consistent with a primary EBV infection as trigger for his MAS episode. With the initiation of emapalumab, the patient was started on acyclovir and TMP/SMX for antiviral and antimicrobial prophylaxis. His labs continued to improve (figure 1) and he was discharged on emapalumab two times weekly, continued canakinumab every 4 weeks and prednisone 60 mg two times per day.

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Figure 1

Serial laboratory evaluation for patient from first episode of macrophage activation syndrome (MAS) through follow-up. Trend in ferritin, fibrinogen and platelet count in patient during and after hospitalisations for MAS. Treatments are shown above graph. Arrows represent intravenous methylprednisolone pulse therapy (1 g/day). Circles denote days of emapalumab infusion. TMP/SMX, trimethoprim/sulfamethoxazole.

Ten days after discharge and at the start of his third week of TMP/SMX, he developed fever and hypotension along with a diffuse erythematous rash on his neck, back, chest, arms and hands, as well as erythema of his conjunctiva with some facial swelling, while receiving emapalumab at our infusion centre. He was fluid resuscitated and further evaluated for causes of this acute decompensation. Comparison of labs before and after his TMP/SMX dose on the day of decompensation are shown in table 1 and demonstrate profound lymphopenia and thrombocytopaenia, worsening hyperferritinaemia and significantly elevated d-dimer. He was treated with empiric broad-spectrum intravenous antibiotics and simultaneously received intravenous methylprednisolone at 1000 mg daily × 3 days.

Differential diagnosis for his recurrent MAS included Steven-Johnson syndrome, sulfasalazine-induced 3-week syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), reactivation of EBV, or secondary infection. The timing and symptoms of his illness matched closely with that of both DRESS and sulfasalazine-induced 3-week syndrome, presenting approximately 3 weeks after starting TMP/SMX, a sulfasalazine-containing medication, and with symptoms of fever, rash, facial oedema, conjunctival oedema, haematological abnormalities and elevated transaminases.7–9 DRESS was considered given his symptoms; however, he only scored a 4 on the RegiSCAR scoring system for DRESS, and he did not fulfil Bocquet’s or the Japanese criteria.10 11 Bacterial and severe viral infections were ruled out with negative blood cultures and viral testing, and decreased EBV viral load. Unlike in many cases of sulfasalazine-induced 3-week syndrome and most DRESS, this patient did not manifest peripheral eosinophilia, but high-dose prednisone therapy may have prevented this typical response.

Treatment of sulfasalazine-induced 3-week syndrome and DRESS is discontinuation of the medication, so TMP/SMX was stopped, and prophylaxis was changed to intravenous pentamidine.7 As with his first episode of MAS, pulse steroids stabilised him clinically but did little to improve his lab abnormalities. Given his incomplete response to emapalumab, he was started on ruxolitinib, based on recent findings in a series of patients with EBV-driven MAS and secondary haemophagocytic lymphohistiocytosis (HLH).12 With this, he exhibited progressive improvement in his thrombocytopaenia and hypofibrinogenaemia (figure 1) and was discharged to complete a 28-day course of ruxolitinib and a tapering dose of prednisone. One month after his initial presentation of MAS, humoral response to EBV was checked with IgG titres and was positive. With known triggers for his episodes of MAS, genetic testing was not pursued.