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.

Keywords: anakinra; autoinflammatory disorders; canakinumab; interleukin (IL)-1; treatment.

Figure 1

On-label and off-label use of Anakinra (A) and Canakinumab (B). CAPS, Cryopyrin-Associated Periodic Syndrome; RA, rheumatoid arthritis; SOJA, Systemic Onset Juvenile Idiopathic Arthritis.

Figure 2

Use of concomitant therapies during IL-1 inhibition on the whole of treatment courses. DMARDs, disease modifying antirheumatic drugs; GCC, glucocorticosteroids; IL-1-INH, IL-1 inhibitors.

Figure 3

Use of concomitant therapies during IL-1 inhibition distinguishing by different indications. AOSD, Adult Onset Still's Disease; BD, Behçet's Disease; CAPS, Cryopyrin-Associated Periodic Syndrome; CRMO, Chronic Recurrent Multifocal Osteomyelitis; FMF, Familial Mediterranean Fever; IRAP, Idiopathic Recurrent Acute Pericarditis; RA, Rheumatoid Arthritis; SOJA, Systemic Onset Juvenile Idiopathic Arthritis; TRAPS, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome; USAID, Undifferentiated Systemic AutoInflammatory Disease.

Figure 4

Frequency of administration for different dosages employed with Anakinra (A) and Canakinumab (B).

Figure 5

First-line employment of Anakinra and Canakinumab in different indications differentiating between pediatric (A) and adult patients (B). AOSD, Adult Onset Still's Disease; BD, Behçet's Disease; CAPS, Cryopyrin-Associated Periodic Syndrome; CRMO, Chronic Recurrent Multifocal Osteomyelitis; FMF, Familial Mediterranean Fever; IRAP, Idiopathic Recurrent Acute Pericarditis; RA, Rheumatoid Arthritis; SOJA, Systemic Onset Juvenile Idiopathic Arthritis; TRAPS, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome; USAID, Undifferentiated Systemic AutoInflammatory Disease.

Figure 6

Amount of specific disease modifying antirheumatic drugs/corticosteroids (A) and biologic agents (B) previously administered. ABA, abatacept; ADA, adalimumab; AZA, azathioprine; COL, colchicine; CycA, cyclosporine A; CZP, certolizumab pegol; INX, infliximab; ETN, etanercept; GCC, glucocorticoids; GOL, golimumab; HCQ, hydroxychloroquine; LFN, leflunomide; MTX, methotrexate; RTX, rituximab; SSZ, sulfasalazine; TCZ, tocilizumab.

Figure 7

Frequency of disease modifying antirheumatic drugs (DMARDs) concomitantly administered with Anakinra (A) and Canakinumab (B). DMARDs, disease modifying antirheumatic drugs.

Figure 8

Frequency of adverse events in patients undergoing Anakinra.

Figure 9

Number of patients undergoing an increase or decrease of IL-1 INH dosage with related clinical outcome.

Figure 10

Reasons for discontinuation distinguishing between Anakinra (A) and Canakinumab (B).