Serum sickness and severe angioedema following rituximab therapy in RA

Abstract

Dear Editor, Rituximab is being used frequently in rheumatology, particularly in patients with rheumatoid arthritis (RA), systemic vasculitis and systemic lupus erythematosus (SLE). It is a chimeric monoclonal antibody to CD20 antigen expressed on B-cell precursors and mature B-cells. Infusion-related reactions such as fever, rigors and chills are seen in up to 85% of treated patients.1 Reactions tend to be more severe during the first infusion with onset usually within 30–120 min.2 Fortunately, the risk of such a reaction falls significantly after the first episode.3 Serum sickness with the use of rituximab in 22 patients has been reported in the English literature so far.4-9 These patients had either a hematological malignancy or an autoimmune condition. Surprisingly, serum sickness has not been reported in RA. We describe the first reported case of serum sickness following rituximab infusion in a patient with RA. A 60-year-old woman with seropositive RA for 14 years, presented with a history of increased pain and swelling in the left ankle and right knee for one and a half months. She was unable to bear weight on the left ankle and used to limp. For the past 2 years, she had been taking a combination of intramuscular methotrexate 12.5 mg weekly, hydroxychloroquine 200 mg once daily, leflunomide 20 mg once daily and sulphasalazine 1000 mg twice daily. She had also received intra-articular injection of methylprednisolone into the left ankle and right knee in the previous month without much relief. One and a half years ago, the patient had received two doses of rituximab 500 mg each in another hospital without significant benefit. Examination revealed that the left ankle and right knee were swollen and tender. There was no deformity in any joint. The Disease Activity Score (DAS28) was 6.04. Investigations showed an Hb 10.6 g/dL, white blood cell count 6400/mm3, erythrocyte sedimentation rate of 81 mm/h, creatinine 0.9 mg/dL, rheumatoid factor 44.2 units/mL and anti-cyclic citrullinated protein 114 units/mL. Antinuclear antibody was negative. Since the patient was unable to tolerate higher doses of methotrexate because of severe nausea, and the disease was refractory, it was decided to explore biological therapy. As she had received a subtherapeutic dose of rituximab previously, we wondered if a full dose would have achieved the goal. Therefore, she was administered 1000 mg of rituximab intravenously over 4 h. She was premedicated with methylprednisolone 100 mg and pheniramine 25 mg. Six days later, she developed an erythematous, urticarial rash over the feet, hands and face. In addition, she developed pain and swelling in the shoulders (previously never involved) and high-grade fever up to 39°C. The right knee became acutely swollen. There was no hematuria. A diagnosis of serum sickness syndrome was made in view of the triad of fever, arthritis and erythematous rash following a drug exposure. The patient was treated with one intramuscular dose of methylprednisolone 80 mg and oral levocetirizine. There was resolution of symptoms within 3 days. Since the serum sickness subsided promptly, it was considered appropriate to go ahead with the second infusion of rituximab on day 15. After informed consent, the second dose of rituximab was carefully started, observing the standard protocol of premedication and slow rate of infusion. Within minutes, the patient developed swelling of lips and periorbital regions as well as choking sensation. Although blood pressure was normal, she developed tachycardia (100 beats/min). There was no wheezing in the chest. Rituximab infusion was abandoned and adrenaline 0.5 mL (1 : 1000) was injected intravenously. In the next hour the reaction subsided almost completely but heart rate increased to 125 beats/min before returning to normal. Electrocardiogram showed only sinus tachycardia. It is possible this was in keeping with a type 1 immunoglobulin E (IgE) mediated hypersensitivity reaction which should preclude any further use of the drug in this patient. Six months later, the patient was started on etanercept 50 mg subcutaneously per week in combination with weekly methotrexate. There was an excellent response with a DAS28 of 2.5 after 4 weeks. Serum sickness is a type 3 hypersensitivity reaction, which comprises a triad of fever, rash and arthralgias occurring in the appropriate timeframe, usually 10–14 days following primary antigen exposure or within a few days of secondary antigen exposure. Overt arthritis can develop with increased inflammatory markers and decreased C3 level.10 Rituximab causes this syndrome more in patients with autoimmune conditions than in hematological malignancies.9 Typically, it is a self-limiting illness and steroids provide rapid and complete relief of symptoms.11 Altered immune response to foreign antigens is involved in the pathogenesis. In RA, it may be under-recognized because of the clinical similarities between serum sickness and an exacerbation of RA. The lesson learnt from the present case is that rituximab should not be re-administered to those who develop an episode of rituximab-induced serum sickness.