In a descriptive, prospective, longitudinal, open-label study, we included patients diagnosed as having RA, according to the 1987 criteria of the American College of Rheumatology,7 who were treated with TCZ in a routine clinical setting between March 2009 and July 2015. These patients were recruited from the outpatient clinics of Teaching Hospital Virgen de la Nieves in Granada, in southeastern Spain. Seventeen of these patients had participated in a clinical trial: 10 in ACT-SURE5 and 7 in JUST-ACT.

The study group was constituted by 85 adults (over 18 years of age) who had been diagnosed with RA, in whom biological therapy was indicated according to the recommendations of the European League Against Rheumatism (EULAR)2 and the Spanish Society of Rheumatology.8,9

Tocilizumab was administered intravenously at a dose of 8mg/kg body weight every 4 weeks. The TCZ dose was adjusted in agreement with the technical specifications. Optimization of the treatment was not done in any patient. All of the participants gave their informed consent. The study was performed in accordance with the ethical principles of the Declaration of Helsinki and those consistent with good clinical practice.

The baseline data of the patients (prior to starting treatment with TCZ) included: age, sex, disease duration, concomitant treatment with a DMARD, the number of biological agents used previously, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and blood parameters (hemoglobin, white blood cells, neutrophils and platelet count). The baseline serological findings for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies were also recorded. At 6, 12 and 24 months, the following variables were collected: tender and swollen joint counts, visual analog scale (VAS) provided by the patient to assess pain and their disease, VAS on the disease provided by the physician, and blood test to determine ESR, RF, CRP and anti-CCP.

The primary objective of the study was to assess the efficacy of TCZ in our patients. It was evaluated using an intention-to-treat analysis, completed by patients who had received 1 or more doses of TCZ. Those who withdrew from the study were considered non-responders in the efficacy analysis.

We calculated the percentage of patients who achieved a significant clinical improvement according to the EULAR response criteria (reduction of ≥0.6 units in the disease activity score of 28 joints [DAS28] and a DAS28 ≤5.1), low disease activity (DAS28 ≤3.2) and remission (DAS28 <2.6) at 6, 12 and 24 months. Likewise, the rates of low disease activity and of clinical remission according to the Clinical Disease Activity Index (CDAI), with a score of ≤2.8 for remission and ≤10 for low activity, were also determined. Similarly, to identify any clinical variable associated with a better response to treatment, we compared the efficacy of TCZ in 3 patient subgroups: patients positive for RF and/or anti-CCP with respect to those who were negative for both variables, patients receiving TCZ as monotherapy with respect to patients receiving a concomitant DMARD (mainly MTX), and patients who had received a previous biological therapy versus those who had received no prior biological therapy.

Safety was evaluated by means of reports of adverse events (AE) leading to the discontinuation of the drug in patients who had received at least 1 dose of TCZ.

Drug survival was assessed throughout the 2 years of treatment, and those recorded for the abovementioned subgroups were compared.

We provide a descriptive analysis, with the determination of measures of central tendency and of dispersion for the numerical variables; absolute and relative frequencies were calculated for the categorical variables. The normal distribution of the data was assessed using the Shapiro-Wilks test.

Bivariate analysis was performed to evaluate the relationship of a response or disease activity to the use of a concomitant DMARD, number of previous biological therapies, positivity for RF and/or anti-CCP and the rest of the characteristics measured. For continuous variables, Student's t test was used for independent samples, or Mann–Whitney U test for cases in which the distribution was not normal. For categorical variables, we utilized the Pearson chi-squared test or Fisher's exact test.

Moreover, we did an analysis of drug survival using Kaplan–Meier's method to study the time to the end of treatment. The probabilities of survival were calculated, together with the 95% confidence interval, as well as the means and medians. The log-rank test was utilized to compare the groups (in terms of concomitant DMARD, previous biological therapies and positivity for RF and/or anti-CCP).

In all of the analyses, a P<.05 was considered to indicate significance. The data were analyzed using the IBM SPSS Statistics 19 software package.

The study population included 85 patients, 72 (84.7%) of whom were women and 13 (15.3%) were men. They had a mean age of 54.92±11.36 years, a mean disease duration of 10.62±6.81 years, and a high disease activity (a mean DAS28 of 5.49±1.19 and mean CDAI of 26.96±13.12). Of the 85 patients, 38 received TCZ as monotherapy and 21 were taking TCZ as their first-line of treatment. The patients had previously received an average of 1.83±1.57 biological therapies and of 1.95±0.7 DMARD. Methotrexate was the most frequently associated DMARD (48.2%; n=41). In all, 68.7% of the patients were positive for RF and/or anti-CCP (Table 1).

Comparing the baseline DAS28-ESR score, improvements were observed at each time point to up to 24 months (Fig. 1A). The mean change in the DAS28 after 6 months ((ΔDAS28) was −2.7±1.61, from −2.8 ± 1.57 at 12 months and from −3.0±1.66 at 24 months.

Fig. 1.

(A) Mean Disease Activity Score 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at baseline visit and up to 2 years later. (B) Percentage of patients with DAS28 indicating low disease activity (≤3.2), remission (≤2.6) and European League Against Rheumatism (EULAR) response (decrease in DAS28 ≥0.6 and DAS28 ≤5.1) at 6, 12 and 24 months after beginning treatment with tocilizumab.

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According to the EULAR, response rates were achieved in 86.6% (n=71) of the patients at 6 months, 69.2% (n=54) at 12 months and in 55.7% (n=39) at 24 months. At 6 months, 67.1% of the patients had low disease activity, and 53.7% were in clinical remission according to the DAS28; these rates were 56.4/41% at 12 months and 47.1/37.1% at 24 months, respectively (Fig. 1B).

According to the CDAI, 14.3% achieved remission at 6 months, 9.5% at 12 months and 11.4% at 24 months; however, 58.4% had low activity according to the CDAI at 6 months, 54.1% at 12 months and 52.9% at 24 months.

A decrease was recorded in the biological variables (CRP 0.52±1.15 and ESR 12.63±12.99) at 6 months, whereas they remained at normal levels throughout the 24 months of follow-up.

Efficacy outcomes in the different patient subgroups are shown in Table 2.

When compared with patients receiving TCZ monotherapy, with respect to those who were taking combined therapy, it was observed that, of the 38 patients being treated with TCZ alone, 32 (84.2%) demonstrated EULAR response criteria at 6 months, 67.6% at 12 months and 53.1% at 24 months. This contrasts with the 82.9% at 6 months, 70.5% at 12 months and 57.9% at 24 months, of those patients who were receiving a concomitant DMARD, showing differences that were not statistically significant.

Likewise, 63.2% (24/38) of the patients receiving treatment with TCZ as monotherapy met the criteria for low activity according to the DAS28 at 6 months, as did 55.9% (19/34) at 12 months and 50% (16/32) at 24 months; among the patients with combined therapy, the rates were 66%, 56.8% and 44.7% at 6, 12, and 24 months, respectively.

There were no statistically significant differences with respect to the DAS28 remission rates between the patients taking TCZ monotherapy (55.2%, 38.2% and 40.6%, at 6, 12 and 24 months, respectively) and those receiving treatment with combined therapy (48.9%, 43.2% and 34.2%, at 6, 12 and 24 months).

At 6 months, only 10.5% of the patients with TCZ as monotherapy achieved remission according to the CDAI, with 14.7% at 12 months and 9.4% at 24 months; this compares with 14.9% at 6 months, 4.5% at 12 months and 13.2% at 24 months, among those receiving combined therapy.

We found no significant differences between the 2 groups in terms of the rates of low activity according to the CDAI (52.6%, 64.7% and 59.3% in patients receiving monotherapy, and 53.2%, 40.9% and 47.4% in those taking combined therapy, at 6, 12 and 24 months).

Of the patients who had received no previous biological treatment, 90.5% at 6 months, 70% at 12 months and 63.2% at 24 months, showed EULAR response criteria, and in those who had taken at least 1 previous biological agent, these rates were 81.3%, 68.9% and 52.9% at 6, 12 and 24 months, respectively, differences that did not reach statistical significance.

In all, 85.7% of the patients who were naïve to biological therapy had low activity rates, according to the DAS28 at 6 months, as did 65% at 12 months and 57.9% at 24 months. The rates of remission in terms of the DAS28 were 43.8% at 6 months of treatment in patients who had taken at least 1 biological DMARD previously, and were 36.2% at 12 months and 35.2% at 24 months. A comparison between these groups showed that the differences were statistically significant for the rates of low activity and for remission after 6 months of treatment (P=.028 and P=.041).

With regard to the rates of low activity and of remission according to the CDAI, the patients who had received no prior biological DMARD had higher rates throughout the study, although the differences were not statistically significant.

There were no differences between the patients who were positive for RF and/or anti-CCP with respect to those who were RF- and anti-CCP-negative in terms of the EULAR response, with regard to low activity or clinical remission, except in the rates of low activity according to the CDAI at 12 months, in which 62.7% of the patients positive for RF and/or anti-CCP had low activity according to the CDAI at 12 months (P=.006).

The safety outcomes that resulted in the discontinuation of the treatment are shown in Table 3.

In all, TCZ was interrupted in 16 patients due to AE. Infections were among the most frequent AE (n=5), as were reactions to the injection, which occurred in 5 patients. Two patients developed neutropenia, although the neutrophil count never fell below 500/mm,3 and 1 patient had an intestinal perforation. One patient developed an ovarian adenocarcinoma, and there was 1 death (a stroke) during the study, not related to the treatment.

In relation to the increase in liver enzymes and total cholesterol, it was not necessary to discontinue the administration of TCZ, since it was controlled either by adjusting the TCZ dose or with a specific treatment.

The retention rates with TCZ were 72.2% at 12 months and 61% at 24 months. The reasons for discontinuing the treatment were: lack of efficacy (16 patients, 48.5%), AE (16 patients, 48.5%) and other causes that do not include patients in remission (1 patient, 3%).

We found no statistically significant differences when comparing the rates of survival or the reasons for withdrawing from the treatment in the different subgroups of patients (Fig. 2).

Fig. 2.

Survival analysis using the Kaplan–Meier method. (A) Drug survival of TCZ during 24 months of treatment. (B) Survival of TCZ as monotherapy vs combined therapy. (C) Survival of TCZ in patients positive for RF and/or anti-CCP vs RF- and/or anti-CCP-negative patients. (D) Survival of TCZ in BT-naïve vs patients with previous BT. Anti-CCP, anti-cyclic citrullinated peptide antibodies; BT, biological therapy; DMARD, disease-modifying antirheumatic drug; RF, rheumatoid factor; TCZ, tocilizumab.

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The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).

The authors declare that they have followed the protocols of their work center on the publication of patient data.

The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.