Biotechnological Agents for Patients With Tumor Necrosis Factor Receptor Associated Periodic Syndrome-Therapeutic Outcome and Predictors of Response: Real-Life Data From the AIDA Network

Abstract

Objective: To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response. Methods: Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers. Results: A total of 55 biological courses with anakinra (n = 26), canakinumab (n = 16), anti-TNF-α agents (n = 10), and tocilizumab (n = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbations was 458.2 flare/100 patients-year during the 12 months prior to the start of biologic treatment and 65.7 flare/100 patients-years during the first 12 months of therapy (p < 0.0001). The median duration of attacks was 5.00 (IQR = 10.50) days at the start of biologics and 1.00 (IQR = 0.00) days at the 12-month assessment (p < 0.0001). Likewise, a significant reduction was observed in the Autoinflammatory Disease Activity Index during the study period (p < 0.0001). A significant corticosteroid sparing effect was observed as early as the first 12 months of treatment both in the number of patients requiring corticosteroids (p = 0.025) and in the dosages employed (p < 0.0001). A significant reduction was identified in the erythrocyte sedimentation rate (p < 0.0001), C reactive protein (p < 0.0001), serum amyloid A (p < 0.0001), and in the 24-h proteinuria dosage during follow-up (p = 0.001). A relapsing-remitting disease course (OR = 0.027, C.I. 0.001-0.841, p = 0.040) and the frequency of relapses at the start of biologics (OR = 0.363, C.I. 0.301-0.953, p = 0.034) were significantly associated with a complete response. No serious adverse events were observed. Conclusions: Treatment with biologic agents is highly effective in controlling clinical and laboratory TRAPS manifestations. Patients with a relapsing-remitting course and a lower frequency of flares at the start of treatment show more likely a complete response to biologic agents.

Keywords: biologic therapy; interleukin-1 inhibitors; personalized medicine; tocilizumab; tumor necrosis factor inhibitors; tumor necrosis factor receptor-associated periodic syndrome.

Conflict of interest statement

LD has received consultation honoraria from SOBI, Novartis, Pfizer, Abbvie, Amgen, Biogen, Celltrion, and Roche outside of the present work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Vitale, Obici, Cattalini, Lopalco, Merlini, Ricco, Soriano, La Torre, Verrecchia, Insalaco, Dagna, Jaber, Montin, Emmi, Ciarcia, Barneschi, Parronchi, Ruscitti, Maggio, Viapiana, Sota, Gaggiano, Giacomelli, Sicignano, Manna, Renieri, Lo Rizzo, Frediani, Rigante and Cantarini.

Figures

Figure 1

Posology strategies employed at the start of treatment and at the last assessment in the 55 treatment courses considered in the present study. The “On-label” posology for canakinumab corresponded to 150 mg/4 weeks (or 2 mg/Kg/4 weeks) to increase to 300 mg/4 weeks (or 4 mg/Kg/4 weeks) in case of unsatisfactory response to the former attempt. The “Posology usually used for patients with rheumatoid arthritis” along with the “on-label use in rheumatoid arthritis” were meant as 100 mg/day for anakinra, 50 mg/week for etanercept, 40 mg every other week for adalimumab, 3 mg/kg every 8 weeks for infliximab, 162 mg/week for tocilizumab. The 4 patients aged <16 years at the start of anakinra received the posology of 2–4 mg/Kg/day, which is considered “on-label” for patients with cryopyrinopathies, and were included in the group “Posology usually used for patients with rheumatoid arthritis.” TNF, tumor necrosis factor; n, number of patients (and of treatment courses).

Figure 2

Autoinflammatory disease activity index (AIDAI) recorded at the start of treatment courses (baseline) and during the following visits. Statistical differences resulting from pairwise comparisons between different follow-up visits were provided to better detail the overall significance (p < 0.0001). Of note, statistical analysis on AIDAI changes was restricted to 18 patients (22 treatment courses) starting treatments after 2014, year of the AIDAI publication. Error bars refer to one standard deviation.

Figure 3

Details about 24 h proteinuria in six patients (eight biologic courses) presenting with pathologic proteinuria (i.e., >150 mg/24 h) at the start of biologic treatments (baseline), after 12 months and at the last assessment. The numbers added in the histograms indicate the median of the 24 h proteinuria values found in the eight biologic courses at the three time-points.

Figure 4

Laboratory inflammatory markers observed at the start of treatment courses (baseline) and during the following visits. Graphics are referred to (A) erythrocyte sedimentation rate (ESR); (B) C-reactive protein (CRP); (C) serum amyloid A (SAA). Error bars refer to one standard error.

Figure 5

Details about corticosteroid administration. (A) Patients taking corticosteroids at the start of biologic treatments (baseline) and at the following visits; the decrease is statistically significant (p = 0.025). The numbers contained in the histograms refer to the specific number of patients taking corticosteroids at the corresponding visit. (B) Median daily corticosteroid dosage (as prednisone or equivalent) among patients already treated with corticosteroids at the different follow-up visits; the decrease is statistically significant (p < 0.0001). Statistical differences regarding the daily corticosteroid dosage between different follow-up visits have also been provided in the figure.; error bars in (B) refer to one standard deviation.

Figure 6

Use of corticosteroids in specific subgroups of patients. Number of patients requiring the use of corticosteroids at the different time-points, distinguishing biologic treatment courses according to: (A) the age at TRAPS onset (adult vs. pediatric onset); (B) penetrance of mutations (high- vs. low-penetrance) and (C) the line of biologic agents (first line vs. second or more line). As also reported in the text, the number of patients discontinuing corticosteroids was statistically significant higher in adult-onset TRAPS patients when compared to pediatric-onset patients at 3-month (p = 0.01) and 6-month (p = 0.02) assessments. Conversely, neither statistically significant difference was observed according to the different age at onset at the 12-month visit nor between subjects carrying low-penetrance and high-penetrance mutations or based on the biologic treatment line at the 3, 6, and 12-month assessments.

Figure 7

Reasons for biologic discontinuation. Graphical representation of reasons leading to biologic treatment discontinuation. As better explained in the text (Cause of biologic withdrawal and safety concerns), the term “Others” includes a patient experiencing the onset of inflammatory bowel disease during canakinumab treatment and a patient experiencing paradoxical flares after infliximab administrations.

Figure 8

Long-term drug retention rate of biologic treatment courses. Kaplan-Meier survival curve describing the overall drug retention rate assessed on 55 treatment courses. Time 0” corresponds to the start of biologic courses and the “event” represents the discontinuation of therapy because of primary or secondary inefficacy, adverse events, or lack of compliance.