BOSTON—A few cases of serum sickness have been reported in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients treated with rituximab (Rituxan®, Genentech). The first case in a patient without an underlying autoimmune disorder raises the concern that this problem may be more common in RA patients than previously thought, although it may be missed because the symptoms resemble those of the underlying rheumatoid disease, according to Derrick J. Todd, MD, PhD, rheumatology fellow, and Simon M. Helfgott, MD, associate professor of rheumatology, at Brigham and Women's Hospital, in Boston. They report in The Journal of Rheumatology a case of rituximab-related serum sickness in a cancer patient.1

"With the increasing usage of rituximab in autoimmune conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), clinicians should be alert for serum sickness as a possible adverse reaction to treatment." —Derrick J. Todd, MD, PhD.
"Serum sickness remains a clinical diagnosis based on the triad of fevers, rash, and arthralgias occurring in the appropriate time frame following antigen exposure," Dr. Todd writes. "With the increasing usage of rituximab in autoimmune conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), clinicians should be alert for serum sickness as a possible adverse reaction to treatment."

Symptoms resemble some that commonly occur in rheumatoid disorders

Drs. Todd and Helfgott describe the case of a 68-year-old man with stage 2A mantle cell lymphoma who had sharp onset polyarthralgias and joint swelling 13 days after receiving  cyclophosphamide, vincristine, prednisone, and a 375 mg/m2 dose of of rituximab. They also reviewed the literature regarding rituximab-induced serum sickness. This is believed to be the first case of rituximab-induced serum sickness in a patient with a hematological malignancy.

The patient presented with a temperature of 100.8°F, as well as erythema, warmth, and effusion of the elbows, wrists, metacarpal phalangeal joints, and knees with reduced range of motion in these joints, as well as in the shoulders and hips; a "blanching, erythematous, macular rash" over his precordium and both ventral forearms also was present.

The patient was initially treated with intravenous antibiotics for suspected polyarticular septic arthritis and with indomethacin for pain control. Antibiotics were discontinued when blood and synovial fluid cultures yielded no organisms, and the patient was discharged on indomethacin. He returned 3 days later with persistent polyarthritis. Knee arthrocentesis yielded 100 cc of fluid with 297 WBC/mm3. When the symptoms did not resolve, the patient was started on 80 mg of intraarticular methylprednisolone and 20 mg/day of concurrent oral prednisone. His symptoms resolved within 24 hours, to the point where he was able to shovel snow within a day. Prednisone was tapered over a 4-week period, and at the time of this report, the patient has remained completely symptom-free for more than 4 months after completing steroid therapy.

The clinicians ruled out infectious, microcrystalline etiology, or other inflammatory causes for the man's illness. Specifically, there were no monosodium urate or calcium pyrophosphate dihydrate crystals in his synovial fluid.

Human antichimeric antibodies (HACA) were absent during the acute phase of illness. "Although HACA levels may be elevated in patients with monoclonal antibody-induced serum sickness, it is not diagnostic of the condition. HACA may have been undetectable because excessive amounts of antigen (ie, rituximab) consumed completely any HACA present. In addition, serum sickness does not occur in the majority of rituximab-treated patients who develop elevated HACA," the authors write.

 More common in autoimmunity than hematologic malignancies

Serum sickness has been seen in SLE, antiphospholipid antibody syndrome, immune idiopathic thrombocytopenia purpura (ITP), autoimmune polyneuropathy, and Sjögren's syndrome, according to Drs. Todd and Helfgott. Their literature review showed that rates of serum sickness ranged from 6% to 20% in patients receiving rituximab for pediatric chronic ITP or Sjögren's syndrome.

"It is conceivable that the altered immune responses to foreign antigens may predispose patients with autoimmunity to develop rituximab-induced serum sickness," the researchers speculate.

"We postulate that rituximab-induced serum sickness may be under recognized in patients with RA because of the clinical similarities between serum sickness and an exacerbation of RA," the study authors conclude.

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Reference

1. Todd DJ, Helfgott SM. Serum sickness following treatment with rituximab. J Rheumatol. 2007;34:430-433.