Comparison of Early vs. Delayed Anakinra Treatment in Patients With Adult Onset Still's Disease and Effect on Clinical and Laboratory Outcomes

Abstract

Background: Aim of this study was to search for any difference in the outcome of patients with adult onset Still's disease (AOSD) treated with anakinra (ANK) in relation with the interval between disease onset and the start of anti-interleukin(IL)-1 treatment and according with the different lines of ANK treatment. Patients and Methods: One hundred and forty-one AOSD patients treated with ANK have been retrospectively assessed. Statistically significant differences (p < 0.05) were analyzed in the frequency of ANK effectiveness, primary or secondary inefficacy to ANK and rate of resolution of clinical and laboratory AOSD manifestations after 3, 6, and 12 months since ANK treatment according with different lines of treatment and different times between AOSD onset and start of ANK. Results: No significant differences were identified in the ANK effectiveness and frequency of primary or secondary inefficacy for patients starting ANK within 6 months (p = 0.19, p = 0.14, and p = 0.81, respectively) or 12 months (p = 0.37, p = 0.23, and p = 0.81, respectively) since AOSD onset compared with patients starting ANK thereafter; no significant differences were identified in ANK effectiveness and primary or secondary inefficacy according with different lines of ANK treatment (p = 0.06, p = 0.19, and p = 0.13, respectively). Patients starting ANK within 6 and 12 months since AOSD onset showed a significantly quicker decrease of erythrocyte sedimentation rate and C-reactive protein than observed among patients undergoing ANK treatment after 6 and 12 months. The number of swollen joints at the 3 month follow-up visit was significantly lower among patients undergoing ANK within 6 months since AOSD onset (p = 0.01), while no significance was identified at the 6 and 12 month assessments (p = 0.23 and p = 0.45, respectively). At the 3 and 6 month visits, the number of swollen joints was significantly higher among patients previously treated with conventional and biological disease modifying anti-rheumatic drugs (DMARDs) compared with those formerly treated only with conventional DMARDs (p < 0.017). Conclusions: Clinical and therapeutic outcomes are substantially independent of how early ANK treatment is started in AOSD patients. However, a faster ANK effectiveness in controlling systemic inflammation and resolving articular manifestations may be observed in patients benefiting from IL-1 inhibition as soon as after disease onset.

Keywords: adult onset Still's disease; anakinra; autoinflammatory diseases; innovative biotechnologies; interleukin-1; personalized medicine; systemic onset juvenile idiopathic arthritis; treat to target.

Figure 1

Radar graphics highlight the frequency of resolution of laboratory and clinical manifestations of adult onset Still's disease between patients starting anakinra (ANK) within the first 6 months since disease onset (<6 months) and those starting ANK thereafter (>6 months); (A–C) refer to the 3-month, 6-month and 12-month follow-up assessments, respectively. P-values were obtained by employing Chi square test. Alternatively, Fisher exact test was employed when expected frequencies were less than 5. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Figure 2

Radar graphics highlight the frequency of resolution of laboratory and clinical manifestations of adult onset Still's disease between patients starting anakinra (ANK) within the first 12 months since disease onset (<12 months) and those starting ANK thereafter (>12 months); (A–C) refer to the 3-month, 6-month and 12-month follow-up assessments, respectively. P-values were obtained by employing Chi square test. Alternatively, Fisher exact test was employed when expected frequencies were less than 5. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Figure 3

Radar graphics highlight the frequency of resolution of laboratory and clinical manifestations of adult onset Still's disease between: i) patients starting anakinra (ANK) before both conventional disease modifying anti-rheumatic drugs (cDMARDs) and other than anti-IL-1 biologic agents (ANK first); ii) patients treated with ANK after cDMARDs failure and before any other biologic agent (cDMARDs → ANK); and patients previously administered both cDMARDs and other biologics (cDMARDs → biologics → ANK). (A–C) refer to the 3-month, 6-month and 12-month follow-up assessments, respectively. P-values were obtained by employing Chi square test. Alternatively, Fisher exact test was employed when expected frequencies were less than 5. Significances at the post-hoc analysis: A = “ANK first” group vs. “cDMARDs → biologics → ANK” group; B = “cDMARDs → ANK” group vs. “cDMARDs → biologics → ANK” group. The sign “*” indicates a lack of significance at the Bonferroni correction (p>0.017).

Figure 4

Kaplan-Meier survival curves of anakinra (ANK) obtained by distinguishing: i) patients starting ANK during the first 6 months since onset of adult onset Still's disease (AOSD) and patients starting ANK thereafter (A); ii) patients starting ANK during the first 12 months since AOSD onset and patients starting ANK afterward (B); patients starting ANK before both conventional disease modifying anti-rheumatic drugs (cDMARDs) and biologics (soon after non steroidal anti-inflammatory drugs and/or corticosteroids, blue line) from patients treated with ANK after cDMARDs failure (green line) and patients previously administered both cDMARDs and other biologics (red line) (C). In order to focus attention to ANK efficacy, survival analysis excluded patients discontinuing ANK because of adverse events (25 cases), long-term disease remission (20 patients), lack/loss of compliance or other non-medical reasons (19 patients). One patient was also excluded owing to the lack of information about the overall treatment duration.