An Atypical Presentation of Cytokine Release Syndrome With Signs of Arthritis During Treatment With Teplizumab in a Pediatric Patient Free

Teplizumab is an anti-CD3 monoclinal antibody that was recently approved by the U.S. Food and Drug Administration to delay the onset of clinical (stage 3) type 1 diabetes in those with stage 2 (preclinical with dysglycemia) type 1 diabetes (1,2). Common side effects that peak around day 5, as CD3 saturation is reached, include lymphopenia, rash, and fatigue (3). Rare major adverse effects include cytokine release syndrome (CRS) (typically including fever, nausea, headache, myalgia, arthralgia, and organ involvement), serious infections, and hypersensitivity reactions, including anaphylaxis, angioedema, and serum sickness (3).

Here, we describe an atypical reaction and our approach, with ultimate successful completion of therapy.

An 11-year-old boy with autoimmune hypothyroidism presented with stage 2 type 1 diabetes. He had elevated HbA_1c (5.9%, 41 mmol/mol), glutamic acid decarboxylase autoantibody (>250 IU/mL; normal is <5 IU/mL), and insulin autoantibody (2.3 units/mL; normal is <0.4 IU/mL). Family history was significant for autoimmune Graves disease, lupus, and vitiligo.

The patient started daily teplizumab infusions, with dosing per label, at Boston Children’s Hospital Outpatient Infusion Center, with recommended pretreatment medications acetaminophen and diphenhydramine. His clinical course proceeded as follows.

• On day 3, the patient reported fatigue and 7/10 knee pain, especially when walking downstairs. After infusion 3, he was febrile (38.7°C), tachycardic (114 bpm), and tachypneic, improving with additional acetaminophen, diphenhydramine, and 1 L 0.9% normal saline (NS). He then developed dyspnea and intermittent oxygen desaturation (91%), responding to albuterol. Subsequent infusions were given over 60 (instead of 30) min, concurrent with 1 L NS. On day 4, after infusion 4, he developed fever (38.3°C), rigors, and myalgias, improving with acetaminophen, diphenhydramine, famotidine, and NS. The infusion on day 5 was held; all symptoms improved. On days 6 and 7, premedications cetirizine and famotidine were added. He did well during infusions 5 and 6 but awoke with splotchy nonpruritic facial rash and hand swelling. Lymphopenia reached nadir on day 7.

• On day 8, the patient presented with fever (38.3°C); headache; nonpruritic erythematous rash on trunk, abdomen, and arms; facial swelling with periorbital edema; and knee and proximal interphalangeal and metacarpophalangeal joint pain. He had dorsal hand edema, erythema, and warmth but could fully extend and contract fingers with discomfort. Bilateral knees were hot to palpation with anterior erythema with no joint-line tenderness or stiffness, which overall is a concerning indication of arthritis. There were no mucosal lesions, pharyngeal swelling, wheezing, or hives. While this presentation is largely consistent with CRS (3), arthritis (as opposed to arthralgias) is not typical, leading us to explore alternate diagnoses. Notable laboratory values included low lymphocytes and elevated C-reactive protein and interleukins (Table 1). Together, evaluations were reassuring against severe CRS (normal liver enzymes), drug reaction with eosinophilia and systemic symptoms (no eosinophilia), and delayed drug reaction, i.e., Stevens-Johnson syndrome (no mucosal involvement). While unlikely given the early onset, we could not exclude serum sickness, as complement increases may lag. In decision-making between the family and providers, we proceeded with addition of twice-daily cetirizine and famotidine. While steroids present an effective treatment for CRS, we elected to avoid them due to unknown effects on teplizumab efficacy in the setting of mechanistic interactions on CD3 (4). After infusion 7, the patient developed rigors, 7/10 leg and abdominal pain, and tachycardia, improving with acetaminophen, cetirizine, and famotidine.

• On days 9–19, at the family’s request, the remaining infusions 8–14 were given with intermittent breaks. Except for persistent pronounced fatigue (compounded by heavy antihistamine use), he had no further adverse effects.

• One week after teplizumab treatment, he developed transient peeling of palms and soles. Six months after teplizumab treatment, his HbA_1c had decreased to 5.6% (31 mmol/mol).

Given the timing of symptoms, spontaneous resolution during subsequent infusions, and sustained normal complement, the observed reaction is consistent with an atypical presentation of grade 1 CRS including arthritis.

We report a previously unreported reaction to teplizumab and illustrate a possible management approach. Differentiating known, atypical, and unexpected reactions is critical to determining if treatment can continue or must be altered or stopped. Serum sickness, drug reaction with eosinophilia and systemic symptoms, or Stevens-Johnson syndrome would have required stopping therapy, likely limiting the effectiveness of teplizumab, whereas CRS is self-limited as CD3 saturation is reached (1). While severe CRS may warrant pausing infusions, discontinuation is only required with severe reactions, i.e., fivefold liver enzyme elevation (4). The diagnosis of atypical CRS allowed safe and tolerable completion of therapy with modified premedications and infusion schedule. Although not studied, the pharmacokinetics of teplizumab suggest that delayed completion, unlike reduced total exposure or steroids with unknown impact on efficacy (4), may retain efficacy for delaying the onset of clinical diabetes, but this aspect warrants additional future studies. This case also demonstrates the importance of completing pediatric infusions in a location where reactions can be treated promptly, as was needed for this patient (4).