DERBY, United Kingdom—Three more cases of severe neutropenia in patients treated with etanercept (Enbrel®, Amgen/Wyeth Pharmaceuticals) have sparked a recommendation that clinicians routinely monitor complete blood counts (CBC) in patients treated with the TNF-α inhibitor.

In the new report, published early online in Rheumatology, Drs. C. Wenham, K. Gadsby, and C. Deighton, all from the department of rheumatology at Derbyshire Royal Infirmary in the UK, described three cases of severe neutropenia (one of them septic) in patients treated with etanercept.¹

"Our first patient had no sepsis, but the second showed rapid and dramatic neutropenia, and though cultures were negative she behaved as if septic. The third patient had pre-existing neutropenia, and developed a dramatic and life-threatening infection with staphylococcal abscesses in a most unusual location. All three patients had normal bone marrow examinations, suggesting that the neutropenia may be due to peripheral consumption rather than a primary marrow disorder," Dr. Wenham wrote.

The three cases included

• 57-year-old woman with RA, intolerant of multiple DMARDs, with synovitis despite methotrexate and prednisolone, who became neutropenic 7 weeks after first dose of etanercept. She remained intermittently mildly neutropenic during first few months after switching to adalimumab (HumiraR, Abbott Laboratories), but currently has normal neutrophil count and good response to adalimumab.
• 50-year-old woman with RA intolerant of methotrexate, cyclosporin, and azathioprine, with previous cyclolsporin-induced neutropenia and asymptomatic neutropenias before taking DMARDs. She became neutropenic 17 days after first dose of etanercept. She was hospitalized and treated with intravenous tazocin and gentamicin for sore throat, mouth ulcers, and pyrexia, and required two doses of granulocyte-colony stimulating factor (G-CSF, filgastrim, NeupogenR, Amgen Inc) to raise neutrophil count to acceptable levels. She has been maintained on prednisolone.
• 61-year-old man with psoriatic arthritis had a history of neutropenia while taking methotrexate. He responded to etanercept but with persistent neutropenia, and 6 months later presented with weight loss and left upper quadrant pain, which proved to be multiple splenic abscesses caused by Staphylococcus aureus. Intravenous antibiotics were not effective, so he had an elective splenectomy, which was "complicated by postoperative sepsis and bleeding requiring repeat laparotomy and a 5-day ICU stay." He recovered completely.

A related case was reported in 2007 by Montane et al in a man with ankylosing spondylitis who became neutropenic after treatment with etanercept. The neutropenia recurred during two rechallenges with etanercept and again after an infusion of infliximab.²

Translating research into practice

Concern about this problem led another group of British researchers, Yazdani et al, to survey a population of 130 patients with being treated with TNF-inhibitors. They found that 16 of 130 patients had developed leucopenia or neutropenia, but none had developed any serious infections or required hospitalization.³ These researchers recommended both stringent eligibility criteria and "a robust monitoring system" for patients treated with these drugs. Dr. Wenham concurs, "We advise that all patients on anti-TNF agents should be monitored with regular full blood counts, with particular care for those with previously documented neutropenia."

MSK Report consulted Frederick Wolfe, MD, head of the National Data Bank for Rheumatic Diseases in Wichita, Kansas for help in putting this study into clinical perspective.

"Rare events occur. The issue is [are these] real clusters of events or just chance occurrences. In the National Data Bank for Rheumatic Diseases 0.16% of 4442 etanercept-treated patients reported leukopenia compared with 0.06% using infliximab, and 0.06% using celecoxib. On the other hand, 20.5% of 20,917 RA patients stated that they had a low WBC (3.2% of 169,000 observations) while [participating] in the National Data Bank." He noted that US physicians typically do obtain CBC regularly, but he also warned, "One has to be very careful not to over test."

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