More female (77.6%) than male (22.4%) patients with a mean age of about 57 years gave their consent to provide their clinical data for this noninterventional study. Ninety patients had been treated with rituximab and 106 with a second TNFα blocker. Comorbidity was present in 76.5% of the total population, most frequently musculoskeletal and cardiovascular disorders. However, the comorbidities, like other patient characteristics, were fairly equally distributed between both cohorts. An overview of the main demographic, clinical, and baseline characteristics is given in .
Demographic and disease-related characteristics at start of documentation (baseline)
The median observation plus treatment period was 197 days in the rituximab cohort and 189 days in the TNFα cohort. The most frequent reason for change of the first TNFα therapy was inadequate response in 79.1% of all patients and intolerable side effects in 11.2%.
Almost half of the patients (45.6%) were treated with two rituximab infusions at baseline without a second course during the observation period; 16 patients (17.8%) needed one or two further infusions after 3 months, and 42 patients (46.7%) needed one or two further infusions at 6 months. The majority of patients in the rituximab cohort (83.3%) were treated with rituximab together with methylprednisolone (median of 5 mg in the rituximab cohort and 7.5 mg in the TNFα cohort) plus analgesics plus antihistamines as indicated by the manufacturer. In the TNFα cohort, 47 (44.3%) patients received etanercept (50 mg subcutaneously weekly), 43 (40.6%) patients received adalimumab (40 mg subcutaneously every 2 weeks) and 16 (15.1%) patients were treated with infliximab (intravenous dose of 3 mg/kg at 0 weeks, 2 weeks, and 6 weeks, and thereafter every 8 weeks) as the second TNFα blocker.
Frequency and dosage of DMARD intake fluctuated slightly during the observational period. At baseline, 83.3% of patients treated with rituximab and 82.1% of patients treated with TNFα blockers received DMARDs concomitantly. These numbers decreased to 68.9% and 62.3% after 3 months and increased again to 81.1% and 77.4% after 6 months. Methotrexate was taken by 38%–48% of the patients in both cohorts throughout the observational period. Here, the frequency of patients with concomitant methotrexate therapy also decreased slightly at 3 months and increased again at the end of observation.
Although improvement was more pronounced under rituximab therapy compared to TNFα treatment in all variables, a statistically significant difference in the total population was only observed in the DAS28 total score (). Interestingly, the higher improvements in the rituximab cohort were only seen in patients seropositive for RF and/or anti-CCP, but not in seronegative patients.
Change in mean disease activity score-28 values between endpoint and baseline in all patients and subgroups.
An additional analysis investigated the influence of the inadequate first TNFα blocker on the outcome of the switch to rituximab or a second TNFα blocker (). If patients were pretreated with etanercept, marked cohort differences were seen in the total cohort as well as in all subgroups according to seropositivity, although the DAS28 changes were at a somewhat lower level compared to the total population (), especially in the TNFα subgroup. Significant cohort differences were already found at 3 months. In contrast, pretreatment with adalimumab was associated with an increased efficacy of rituximab, especially in anti-CCP-positive patients, but had no influence on the efficacy of the second TNFα blocker. The number of patients in the subgroup treated with infliximab was quite small and imbalanced between the two cohorts, and insufficient for subgroup analyses. The available data for all patients show no relevant differences between the two cohorts after pretreatment with infliximab.
Efficacy results depending on the first tumor necrosis factor-α inhibitor and seropositivity for rheumatoid factor and anti-cyclic citrullinated peptide: Disease Activity Score-28 change between baseline, 3 months, and 6 months
Comparisons of both cohorts regarding changes in tender joint counts ( and ) between baseline and end of observation revealed differences only in the subgroups of anti-CCP-positive patients (−5.28 [95% confidence interval: −6.78; −3.79] versus −3.06 [95% confidence interval: −4.28; −1.85], P = 0.024) and patients seropositive for both anti-CCP and RF (−5.49 [95% confidence interval: −7.21; −3.77] versus −2.85 [95% confidence interval: −4.05; −1.66], P = 0.013).
The mean absolute values of erythrocyte sedimentation rate, tender joint counts, swollen joint counts, and pain visual analog scale at baseline, 3 months posttreatment, and 6 months posttreatment.
Efficacy results: change from baseline to end of observation (196 patients)
For erythrocyte sedimentation rate, cohorts did not differ at the end of observation (); however, at 3 months there was a larger decrease under rituximab compared to the TNFα cohort (−11.2 [95% confidence interval: −15.61; −6.79] versus −4.03 [95% confidence interval: −9.10; 1.05], P = 0.037). A similar difference between both cohorts was observed in the RF-positive subgroup (−12.8 [95% confidence interval: −17.96; −7.64] versus −4.52 [95% confidence interval: −10.48; 1.45], P = 0.038), but not in the anti-CCP-positive subgroup (−9.69 [95% confidence interval: −14.88; −4.49] versus −4.51 [95% confidence interval: −11.71; 2.69], P = 0.239).
No cohort differences were found in other efficacy measures (swollen joint count, pain visual analog scale, C-reactive protein, Health Assessment Questionnaire). Data for swollen joint count and pain visual analog scale are presented in .
In the rituximab cohort, 30.0% (n = 27) of the patients showed good EULAR response, 47.8% (n = 43) of the patients showed moderate response, and 22.2% (n = 20) of the patients showed no response. In the TNFα blocker cohort, the proportion of patients that showed good, moderate, or no response was 15.1% (n = 16), 50.0% (n = 53), and 34.9% (n = 37), respectively. The cohort difference (P = 0.022, chi-squared test) was mainly due to a larger number of patients with good EULAR response (30.0% versus 15.1%) and a lower number of patients with no response in the rituximab cohort (22.2% versus 34.9%) (). For the RF-positive patients, the frequency distribution of response status was different between both cohorts (P = 0.023, chi-squared test). Furthermore, EULAR response was more favorable for rituximab than for the second TNFα blocker in the subgroup of anti-CCP-positive patients (P = 0.003, chi-squared test).
European league against Rheumatism response at observation endpoint in all groups.
Of the 247 patients available for safety analysis, seven (5.6% of 124) patients in the rituximab and five (4.1% of 123) patients in the TNFα blocker cohort suffered from at least one adverse drug reaction during the observation period. In total, 15 adverse drug reactions with a possible or definite relationship to the biologics occurred in the rituximab cohort, and six occurred in the TNFα cohort. With one exception (sinusitis), all adverse drug reactions were reported in female patients. Most frequently, patients developed skin disorders (in three patients of each cohort).
Infusion reactions occurred in three patients treated with rituximab; infusion was interrupted in one patient receiving rituximab (facial hypoesthesia of mild intensity). In another patient, the medication was stopped due to a moderate increase in liver function parameters. The third patient with infusion reactions suffered from infection, generalized pruritus, musculoskeletal pain, urticaria, eye swelling, and fatigue.
The number of adverse drug reactions documented was similar in both cohorts. In general, all were single incidents with no accumulation in a certain class of side effects. Only one patient treated with rituximab experienced an adverse drug reaction of severe intensity (nail dystrophy, dehydration, and anemia). All other reactions were of mild to moderate intensity and no action was taken with respect to the medication. In two patients, the outcome of the adverse drug reaction was reported as “unchanged” (one in either cohort); in all other patients the outcome was reported as “recovered.” No deaths or serious adverse reactions were reported during this observational study.