A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study

Abstract

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis.Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults.Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016.Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0–2.0 mg/kg/day) among adults and 2–4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively).Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.

H-ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome

“…During MAS, the massive release/production of proinflammatory cytokines may induce H-ferritin expression by activation of specific transcription factors, such as ferritin 2 (FER2), which may in turn activate production of further proinflammatory cytokines, triggering a possible vicious loop [21][22][23][24][25][26]. In fact, we observed high H-ferritin in the BM of MAS patients and co-localization as well as a correlation between H-ferritin and IL-1b, a possibly therapeutic target in MAS and rheumatic diseases [27][28][29][30][31]. Furthermore, a specific receptor for H-ferritin on immune cells has also been reported [32].…”

“…The binding H-ferritin/TIM-2 may activate these immune cells, leading to subsequent pathogenic proinflammatory process [12,[18][19][20][21]. Taking together all these mechanisms, it is possible to speculate that the enhanced tissue expression of H-ferritin, via a vicious loop, may perpetuate the production of proinflammatory cytokines, possible therapeutic targets in MAS [16,17,22,23,27,28].…”

TNF receptor signalling in autoinflammatory diseases

“…Interestingly, the DUB, A20 also regulates the ubiquitin status of TRAF6 and therefore regulates activation of this pathway (33). (47) and the follow-up publication was in 2018 (48). The 2018 paper reported that significantly more patients receiving canakinumab had a complete response than the placebo group at week 16, and the risk of developing potentially fatal amyloidosis has been substantially reduced by the use IL-1 blockade in these patients.…”

Frontline Science: Reprogramming COX-2, 5-LOX, and CYP4A-mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis

“…Nonsteroidal anti‐inflammatory drugs (NSAIDs) are used as first‐line therapy to manage gouty arthritis, whereas the inevitable gastrointestinal or cardiovascular side effects restrict their utilization . Newly developed anti‐IL‐1 drugs appear to be highly effective, but present limitations such as high cost and hematopoietic disorders . Therefore, there is an urgent need to identify novel agents for gouty arthritis treatment.…”