Serum Sickness/Serum Sickness–like Reactions Following Ocrelizumab Infusion in 2 Patients With Multiple Sclerosis

Ocrelizumab is an anti-CD20 monoclonal antibody (mAb) used to treat multiple sclerosis (MS). The most common adverse effects (AEs) reported in clinical trials and their open-label extensions include infusion reactions and infections.^1–3  Rare AEs such as neutropenia and drug reaction with eosinophilia and systemic symptoms (ie, DRESS) have been described in case reports.⁴  Serum sickness (SS) is a type III hypersensitivity reaction that can occur with mAb therapy.⁵  It is caused by antigen-antibody complex deposition with subsequent complement cascade activation and inflammation.⁶  Although SS has been reported with several mAbs, only 1 case has been previously reported with ocrelizumab.⁷ 

This case series presents 2 patients with MS who developed presumed SS following ocrelizumab infusion. Data were obtained from medical chart review and verified by the physician authors during clinical and video visits. Written informed consent to disclose was obtained from both patients. Our institution does not require ethical approval for reporting individual cases or case series involving 3 or fewer cases.

A man with primary progressive MS (PPMS), aged 45 years, was admitted to an outside hospital 2 weeks after his fifth ocrelizumab cycle for worsening sensory changes, lower extremity weakness, and arthralgias. He was given one 1000-mg dose of methylprednisolone for a suspected MS flare. Brain and cervical spine MRI showed 2 enhancing extra-axial nodules in the right occipital and frontal regions, consistent with meningiomas. Cerebrospinal fluid (CSF) analysis showed elevated protein (57 mg/dL) without pleocytosis; those results were in the context of a traumatic tap with an elevated red blood cell count of 6250/cumm. Blood and CSF studies showed no infections. Elevated C-reactive protein (CRP) and leukocytosis were noted (TABLE). CT with contrast of the chest, abdomen, and pelvis showed no infectious or inflammatory processes.

The patient was discharged but presented to our institution 4 days later with arthralgias, myalgias, and progressive, generalized weakness. He also complained of headaches, blurry vision, malaise, and fever. Imaging showed no new or enhancing demyelinating lesions; the meningiomas did not anatomically explain the neurological symptoms, which were deemed consistent with an MS pseudoflare. CSF analysis was repeated, demonstrating a now-normal protein level (20.6 mg/dL). Erythrocyte sedimentation rate (ESR), CRP, and complement levels were elevated; infectious workup (CSF and blood) was negative (Table). Urinalysis showed no hematuria, proteinuria, or casts.

He was started on prednisone for suspected SS (60 mg daily for 2 weeks, followed by a 10 mg daily taper). Symptoms significantly improved after 2 days. The decision was made to discontinue ocrelizumab infusions.

A woman with PPMS, aged 59 years, developed stiff, painful joints with unbearable abdominal pain 48 hours after her second ocrelizumab cycle. At an emergency department, her blood workup was unremarkable; she was given morphine and sent home. One day later, she presented again with severe abdominal pain, worsening arthralgias, generalized weakness with difficulty ambulating, and myalgias. Abdominal CT scan and ultrasound showed no acute process. She was admitted to an outside hospital due to uncontrolled pain.

Brain and spinal cord MRIs showed no gadolinium-enhancing lesions. Infectious workup was negative. ESR and total complement activity were elevated; electrolytes and metabolic panel were normal except for transaminitis, which was present at admission (Table).

Ketorolac injection dramatically improved her arthralgias and weakness. She was discharged on oral prednisone for suspected SS (60 mg daily for a week, followed by a 10 mg weekly taper). She returned to baseline within a few days. The decision was made to discontinue ocrelizumab infusions.

We describe 2 patients with arthralgias, myalgias, and generalized weakness after ocrelizumab infusion. After excluding infection and given the temporality following the infusion, SS was suspected. Steroids (and potent anti-inflammatory medications, in case 2) alleviated symptoms in both cases.

SS has been reported with rituximab, a chimeric anti-CD20 mAb used off-label for MS.⁸  As a fully humanized mAb, ocrelizumab purportedly has a reduced risk of inducing antibodies and thus SS; however, SS has been reported with other humanized mAbs given to treat MS, such as alemtuzumab and natalizumab.^5,9,10 

SS usually occurs 10 to 14 days after the first exposure to the causative antigen; however, a shorter onset within a few days can occur if a patient was previously sensitized to the antigen, as was true for the patient in our second case.⁸  Although the patient in the first case presented to the hospital 2 weeks following the infusion, which is later than expected for a previously sensitized individual, he had experienced slow worsening of symptoms prior to presentation, with an onset of symptoms within those 2 weeks, although the exact timing is uncertain.

Although fever, arthralgias, and rash constitute the classic triad of SS, neither patient exhibited rash. A systematic review of rituximab-induced SS reported that only 48.5% of cases presented with the full triad; therefore, not all triad components are necessary for diagnosis.⁸  Treatment of SS depends on symptom severity. As was true in our cases, nonsteroidal anti-inflammatory drugs, antihistamines, or corticosteroids may be used.⁶  In a systematic review of rituximab-induced SS, corticosteroids were most commonly used for treatment, and most patients had a full recovery, with a mean (SD) time to resolution of symptoms of 2.15 (1.34) days.⁸  This could explain why the patient in the first case did not feel improvement after only a single dose of steroid given at the outside hospital.

Infectious causes should be considered in such presentations, since ocrelizumab increases infection susceptibility.⁴  In particular, Lyme disease and viral infections, such as hepatitis and enteroviral infections, may have overlapping symptoms with SS.¹¹  Moreover, it is crucial to differentiate SS from MS relapse—although the latter is uncommon in ocrelizumab-treated patients—because the long-term treatment implications differ. In the context of systemic illness, the recrudescence of older MS symptoms, referable often to more than 1 central nervous system location and without new lesions on imaging, is typically thought to relate to the unmasking of deficits from old damage.

One limitation is that SS diagnosis remains clinical. Both patients had elevated inflammatory markers, but unlike the classically low complement levels seen in SS,¹¹  both exhibited elevated levels. Testing for antidrug antibodies was not done. Nevertheless, the rapid response to treatment and lack of alternative etiologies made SS the likely diagnosis. An SS-like reaction (SSLR), which has a clinical presentation similar to that of SS but without the association with significant immune complex formation, remains a plausible alternative diagnosis. Regardless, the treatment and management of both conditions are similar. Although the timing and evolution of symptoms experienced by the patient in the first case may be atypical for SS, in the absence of a more likely diagnosis, reporting of such cases is important to shed light on certain presentations that can rarely occur in clinical practice.

In conclusion, SS/SSLR is a rare AE following ocrelizumab infusion, and its diagnosis can be challenging. Longer experience with the medication is needed to further describe the presentation of ocrelizumab-induced SS/SSLR. Neurologists should be aware of its possibility in order to properly address it when it occurs.