Table 2.

Clinical trials and open label studies that report incidence of infections with use of rituximab in patients with rheumatoid arthritis

Type of study	Author, year [Ref.]	Patient characteristics	Immunosuppression	F/u of study duration	Comments	Outcome
Clinical trial	Lafyatis, 2009 [49]	Diffuse cutaneous systemic sclerosis	Rituximab	6 months	No significant infections were noted in this pilot study	Treatment with rituximab appeared to be safe and well tolerated among patients with dcSSc
Clinical trial	Genovese, 2009 [50]	Patients with advanced RA many of whom had previously been treated with multiple RA therapies, including biologicals prior to receiving rituximab, and then withdrew from clinical trials and subsequently received further biological therapy	Biological DMARD after rituximab treatment		In 185 patients who received rituximab plus another biological DMARD 13 SIEs (6.99 events/100 patient-years) occurred following rituximab, but prior to another biological DMARD. 10 SIEs (5.49 events/100 patient-years) occurred following another biological DMARD. SIEs were of typical type and severity for RA patients. No fatal or opportunistic infections	The size of the sample and limited follow-up restricts definitive conclusions about safety in B-cell depleted patients receiving additional biological DMARDs
DANCER RCT (phase IIB)	Emery, 2006 [51]	Patients with RA	MTX +/− rituximab	24 weeks	42/149 (28%) of patients who were treated with MTX developed infections and 2/149 (1%) developed serious infections. 50/142 (35%) of patients who were treated with MTX + rituximab (500 mg) developed infections and 0/142 (0%) developed serious infections. 67/192 (35%) of patients who were treated with MTX + rituximab (1000 mg) developed infections and 4/192 (2%) developed serious infections. Type and severity of infections were similar across all three treatment arms. The most common infections were respiratory tract infections, urinary tract infections, and nasopharyngitis. The overall rate of serious infections (events/100 patient-years) was 3.19 for MTX alone and 4.74 for rituximab 1000 mg	Of the 6 serious infections, 2 occurred in the MTX monotherapy group (1 each of pneumonia and respiratory tract infection) and 4 occurred in the rituximab 1000 mg group (2 cases of pyelonephritis and 1 case each of bronchitis and epiglottitis); all serious infections were reported to have resolved without sequelae
Phase IIA	Edwards, 2004 [52]	Patients with RA	MTX +/− rituximab, cyclophosphamide + rituximab	24 weeks	1/40 (3%) of patients who were treated with MTX developed serious infections. 2/40 (5%) of patients who were treated with rituximab (1000 mg) developed serious infections. 2/41 (5%) of patients who were treated with cyclophosphamide + rituximab (1000 mg) developed serious infections. 0/40 (0%) of patients who were treated with MTX + rituximab (1000 mg) developed serious infections. In total 4 patients who had received rituximab developed serious infections (2 had septic arthritis, 1 of whom also had Staphylococcus aureus-related septicemia; 1 had 2 episodes of Pseudomonas aeruginosa pneumonia; and 1 had bronchopneumonia)	One patient in the rituximab group with serious infection (bronchopneumonia) subsequently died, although death may have been related to concomitant ischemic/vascular heart disease
Phase IIA extension	Edwards, 2004 [52]	Patients with RA	MTX +/− rituximab, cyclophosphamide + rituximab	24 weeks	0/37 (0%) of patients who were treated with MTX developed serious infections. 1/38 (3%) of patients who were treated with rituximab (1000 mg) developed serious infections (1 case of gastroenteritis). 0/37 (0%) of patients who were treated with cyclophosphamide + rituximab (1000 mg) developed serious infections. 1/39 (3%) of patients who were treated with MTX + rituximab (1000 mg) developed serious infections (1 case of pyelonephritis)	NR
REFLEX RCT (phase III)	Cohen, 2006 [53]	Patients with RA	MTX +/− rituximab	24 weeks	79/209 (38%) of patients who were treated with MTX developed infections and 1/209 (3%) developed serious infections. 126/308 (41%) of patients who were treated with MTX + rituximab (1000mg) developed infections and 7/308 (2%) developed serious infections. The overall infection rate (events/100 patient-years) was slightly higher in placebo-treated patients (154.6) than in rituximab-treated patients (138.2). The most common infections observed in both groups were upper respiratory tract infections, nasopharyngitis, urinary tract infections, bronchitis, and sinusitis. Rates of serious infections were 3.7/100 patient-years for placebo and 5.2/100 patient-years for rituximab; no statistical comparison of this difference was reported	Of 7 serious infections that occurred in the rituximab-treated patients, 6 (1 case each of gastroenteritis, pyelonephritis, cat-bite infection, influenza, fever of unknown etiology, and de novo hepatitis B (HBV)) resolved without sequelae, while the other infection (gangrenous cellulitis) resulted in amputation of a toe
Open label trial	Keystone, 2007 [54]	Ongoing follow-up study of all patients enrolled in the three original clinical trials (2 phase II and 1 phase III) who had an incomplete response to or were intolerant of TNF inhibitors	Rituximab vs. control group		No evidence to date for any increase in the incidence of infections and serious infections, with all patients having received at least 2 courses of rituximab.25 Rates of infection (events/100 patient-years)were 83, 83, 80, and 88 for patients who had received 1, 2, 3, or 4 courses of rituximab, respectively; the corresponding rates for serious infections were 4.1, 4.6, 5.6, and 8.0 events/100 patient-years. Rates of infections and serious infections appear relatively stable with increasing courses of rituximab, however the extent of observation for patients receiving multiple courses of treatment is inevitably less than that for single-course treatment. Longer follow-up data is necessary. Irrespective of the number of courses of rituximab, serious infections occurred most often during the first 3months after administration and declined thereafter. Overall, 68 of 1039 patients (7%) in the all-exposure population experienced a total of 78 serious infections following treatment with rituximab. The most common infections reported were upper respiratory tract infection, nasopharyngitis, urinary tract infection, bronchitis, and sinusitis. No incidences of opportunistic infections or tuberculosis were observed. The serious infection rate after course 1 (5.1 per 100 patient-years) remained stable through additional courses. The proportion of patients with circulating IgM and IgG levels below the LLN increased with subsequent courses; however, serious infection rates in these patients (5.6 per 100 patient-years in patients with low IgM levels and 4.8 per 100 patient-years in patients with low IgG levels)were comparable with those in patients with immunoglobulin levels above the LLN (4.7 per 100 patient-years)	Three serious infections were fatal. Two occurred between course 1 and course 2; 1 patient had bronchopneumonia and a second patient had neutropenic sepsis following concomitant treatment with trimethoprim. The third infection-related fatality occurred after course 2, from septic shock in a 54-year-old female diabetic patient with a history of sepsis and recurrent urinary tract infections
Open label trial	Furst, 2007 [24]	Follow-up open label study on patients with RA	Rituximab vs. control group		From a total of 1053 patients who had been exposed to at least 1 course of rituximab (total drug exposure of 2438 patient-years), 702 patients reported at least 1 infection, the most common being upper respiratory infections (32%) and urinary tract infections (11%). Rates of serious infections for patients who had received 1, 2, 3, or 4 courses of rituximab were 5.4, 4.6, 6.3, and 5.4 events/100 patient-years, respectively
Open label trial	Furst, 2008 [25]	A 2-year follow-up of patients who participated in the phase IIA trial	Rituximab, MTX, MTX + rituximab, cyclophosphamide + rituximab	2 year follow-up	No significant differences in the rate of infections between the 4 treatment arms (MTX, rituximab, rituximab + cyclophosphamide, and rituximab + MTX)
Open label trial	Furst, 2010 [55]	Patients from both phase II studies	Rituximab vs. control group		Based on a total of 1669 patient-years of follow-up (145 patients had received at least 2 courses of rituximab), there was no evidence of an increase in the rate of infections compared with the data from the original phase II trials

DANCER, Dose-ranging Assessment International Clinical Evaluation of Rituximab in RA trial; dcSSc; diffuse cutaneous systemic sclerosis; DMARD, disease-modifying antirheumatic drug; F/u, follow-up; HBV, hepatitis B virus; LLN, lower limit of normal; MTX, methotrexate; NR, not reported; RA, rheumatoid arthritis; RCT, randomized controlled trial; REFLEX, Randomized Evaluation of Long-Term Efficacy of Rituximab trial; SIE, serious infection event; TNF, tumor necrosis factor.