Infliximab is highly effective and relatively safe for the treatment of patients with rheumatoid arthritis (RA) in clinical trials.^1–,⁵ This prospective cohort study was undertaken to determine adverse events, in particular, infections in patients with RA treated with infliximab in daily clinical practice.

METHODS AND RESULTS

We treated 168 patients with RA between 1 April 2000 and 1 October 2002, 82% female, with a median disease duration of 10 years (range 1–49). Inclusion criteria were 28 joint count Disease Activity Score (DAS28) of >3.5 and failure of two disease modifying antirheumatic drugs, including methotrexate. Patients with heart failure or with a malignancy 5 years before screening were excluded. After the alert about tuberculosis,⁶ patients starting with infliximab treatment were screened for that disease.

All patients were treated with an initial infliximab dose of 3 mg/kg (weeks 0, 2, 6, and subsequently, every 8 weeks). When the response was insufficient—that is, a decrease in DAS28 <1.2 compared with baseline on two subsequent occasions, the dose could be increased to 7.5 mg/kg. The median duration of treatment was 0.86 years (range 0–2.5); the median number of infusions used was 7 (range 1–18). Methotrexate and prednisone were used by 92% and 50% of the patients, respectively.

Patients were systematically asked about events and, explicitly, about infections at each visit. All events occurring during the infliximab treatment period were interpreted as adverse events.

The most common mild adverse event was short lived headache. Early allergic reactions were seen in 12 patients (0.08/patient-year), but none developed severe cardiopulmonary problems. Some cases of heart failure (n = 2), neuropathy (n = 1), and malignancy (n = 2) were observed. Two patients died during the study, one of a cerebrovascular accident and one of unknown cause.

Patients frequently (43–57%, depending on the definition used) had infections, most commonly from the upper respiratory tract and the lower urinary tract (table 1⇓). One case of tuberculosis was seen. The number of clinically important infections was 0.59/patient-year, whereas serious infections were found in 0.08/patient-year.

Compared with patients receiving low dose infliximab, significantly (p<0.05) more patients with the increased dose had clinically important infections (including serious infections), but other adverse events, demographic characteristics, and drug use between the groups were comparable. After correction for treatment duration with infliximab, the rate of clinical infections was significantly higher in the group receiving the increased dose. However, after correction for treatment duration, clinically important infections were not significantly more common in the group receiving the increased dose.

DISCUSSION

Our study has shown that infection is the most common adverse event of infliximab treatment in daily practice. Clinical infections and clinically important infections were found more frequently in patients receiving high dose infliximab, without proven causality.

The occurrence of infections in our study is in the same range as that described in (randomised) clinical trials of infliximab.^1,3,5,7 However, the incidence of infection in our study was much higher than those described in a population based study of patients with RA not treated with infliximab, 64 versus 32 events per patient per year.⁸

There is evidence that a higher risk for infections occurs with a higher RA activity.⁹ It is reasonable to suppose that patients with a dose increase had greater disease activity than those treated with only low dose infliximab. We are unable to comment on whether the higher incidence of infections is associated with a high disease activity or with the strong immunosuppressive action of infliximab, or both.

In conclusion, infliximab can be used safely in daily clinical practice, but both doctors and patients should be aware of the (infection) risks, especially in patients receiving a higher dose (>3 mg/kg) of infliximab, in order to anticipate and minimise these risks.