Off-label use of anti-IL-1 drugs in rheumatic diseases

Abstract

Interleukin-1 (IL-1) plays a key role in the pathogenesis of different rheumatic diseases. There are now several agents available on the market capable of blocking IL-1. The proven effectiveness and excellent safety of these drugs makes them a possible therapeutic option in the treatment of IL-1 driven diseases, when previous therapies are contraindicated or ineffective. This article discusses the European wide off-label use of these drugs for the treatment of rheumatic diseases.

Keywords

anakinra anti IL-1 canakinumab off-label use rheumatic diseases

Introduction

Interleukin-1

IL-1 family is associated with innate immune responses, which occur in acute and chronic inflammatory conditions such as rheumatic diseases. IL-1 family is composed by seven pro-inflammatory molecules (IL-1α, IL-1β, IL-18, IL-33, e IL-36α, β e γ) and four anti-inflammatory ones (IL-1 receptor antagonist (IL-1RA), IL-36R antagonist (IL-36RA), IL-37 and IL-38). IL-1α and IL-1β have the greatest inflammatory activity. These Interleukins are encoded by two different genes and both bind the same receptor, therefore they result in the same biological activity. The receptor is IL-1 receptor type 1 (IL-1R), which recruits IL-1RAcP coreceptor, needed for signaling. IL-1α (also called alarmin) is present constitutively as a precursor in healthy individuals; it does not need to be synthesized or processed during a harmful event because it is biologically active and immediately available.^1,2 IL-1α is localized on epithelial cells of mucosa, skin, liver, kidneys, lungs, on platelets, endothelial cells and apoptotic bodies. The precursor IL-1α migrates on the cell surface activating its receptor placed on the adjacent cell.³ IL-1β is not constitutively expressed within the cells, compared to IL-1α. IL-1β is produced by hematopoietic cells (monocytes, tissue macrophages, dendritic cells) as a result of stimuli, such as microbial products activating toll-like receptors (TLR) or intracellular NODlike receptors (NLRs), and cytokines such as TNF, IL-1α and IL-1β itself, which is responsible for self-maintaining inflammation. IL-1β precursor is inactive and needs to be cleaved by caspase 1, a cysteine protease that transforms it into its active form. The same caspase is active only within the inflammasome, an intracellular protein complex activated by pathogenic stimuli such as Pathogen Associated Molecular Patterns (PAMPS) and Damage-Associated Molecular Patterns (DAMPS). Once transformed into its active form, IL-1β is released from the cells and binds to the IL-1R, triggering the inflammatory cascade. This process consists in the activation of genes related to inflammation, such as COX2 and PLA2, and causes the synthesis of PGE2, the recall of acquired immunity, and the development of systemic events such as fever.^2,3 Thus, IL-1α and IL-1β differ dramatically in their compartmentalization within the producing cell or in the microenvironment, possibly proving their different physiological roles; therefore, the non-redundant roles of IL-1α and IL-1β in inflammation underscore the importance of a treatment that targets both cytokines. Another IL-1 binds on the same receptor and competes with IL-1α and IL-1β; IL-1Ra, which acts as an inhibitor, blocks the inflammatory cascade downstream. IL-1Ra is expressed on all nucleated cells. The genetic disease DIRA syndrome, characterized by the loss of function of the IL-1RA, highlights the role of IL-1 in determining inflammation.^1,2

Anti-IL-1 drugs

Anti-IL-1 drugs are anakinra, canakinumab, rilonacept, gevokizumab; we discuss the off-label use only of the first two, the only ones approved in Europe.

Anakinra

Anakinra (Kineret) is the recombinant form of the natural IL-1antagonist. It prevents the link of IL-1α and IL-1β with IL-1R. Anakinra is administered subcutaneously on a daily basis. The drug is available in prefilled syringes of 100 mg per 0.67 mL, which allow for doses between 20 and 100 mg; its half-life is between 4 and 6 h, which makes the drug very manageable. A typical regimen is 100 mg subcutaneously (SC) each day.^4,5 Anakinra is currently approved in Italy to treat cryopyrin-associated periodic syndromes (CAPS), Adult Onset Still’s Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA), refractory Rheumatoid Arthritis (RA), and Family Mediterranean Fever (FMF). Its off-label use is widely supported.⁶

Canakinumab

Canakinumab (Ilaris) is a humanized monoclonal antibody with high affinity for IL-1β; its action is to prevent its link with IL-1R. It has a half-life of 26 days and has intracellular catabolism, with little or no bile and kidney excretion. The dosage varies depending on weight in patients <2 years and in patients with a low body weight; the highest dose is 4 mg/die up to a max of 300 mg every 4 weeks. It is approved in Italy for the treatment of CAPS, Tumor Necrosis Factor Receptor-associated Periodic Syndrome (TRAPS), Mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS), FMF, AOSD, sJIA, and Gout (the latter non-refundable by the National Health care Service).²

Retrospective studies have highlighted excellent safety profiles and tolerability of anti-IL-1 drugs. The adverse events emerged were mostly mild, such as reactions at the injection site, especially for anakinra, and an increased frequency of non-serious infections of the upper respiratory tract.^7,8 Off-label use is the use of drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration, when the previous treatment proved to be ineffective or contraindicated. We describe anti-IL-1 off-label use focusing only on those drugs allowed in Europe (Table 1).

Table 1.

Main studies dailing with off-label use of anakinra and canakinumab in rheumatic diseases.

Diseases	Studies	Drug	Efficacy	Safety
Microcrystals arthritis	Efficacy of anakinra in gouty arthritis: A retrospective study of 40 cases¹⁰ Anakinra for the treatment of acute gout flares: a randomized, double-blind, placebo-controlled, active-comparator, non-inferiority trial¹⁷ Efficacy of anakinra for refractory acute calcium pyrophosphate crystal arthritis¹⁹ Efficacy of anakinra in acute hydroxyapatite calcification-induced joint pain: A retrospective study of 23 cases²²	23 patients: ANA 100 mg for 3 days; 17 patients: ANA 100 mg > 3 days ANA 100 mg for 5 days versus treatment as usual ANA 100 mg for 3 days in five patients ANA 100 mg for 1–3 days	96% good response Anakinra was shown to be non-inferior to treatment as usual Four patients: rapid clinical response One patient: no response VAS pain score decreased rapidly. Size of calcifications not had significant change	Short-term use: one infectious event. Long term use: six infectious events One infectious event in the ANA group One injection-site skin reaction No adverse event
Behcet’s disease	Anakinra treatment in drug-resistant Behcet’s disease: a case series²⁵ Efficacy and safety profile of anti-interleukin-1 treatment in Behçet’s disease: a multicenter retrospective study²⁷ Inhibition of interleukin-1 by canakinumab as a successful mono-drug strategy for the treatment of refractory Behçet’s disease: A case series³²	ANA 100 mg/day (one patient 150 mg/day) 30 patients who received ANA 100 mg/day or CAN 150 mg every 6 to 8 weeks (with any therapeutic adjustments and shift) CAN 150 mg every 6 weeks	Eight of nine patients: rapid clinical improvement (one patient with 150 mg/die) Complete remission in the patients who received at least 12 months anti-IL-1 drugs (n = 13) complete resolution of symptoms	Three of nine patients: injection-site skin reaction ANA: 16% local cutaneous reactions; CAN: no adverse event No adverse event
Uveitis	Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet’s disease-related uveitis: a multicenter retrospective observational study³⁸ Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis⁴¹	ANA 100 mg/day; CAN 150 mg every 4, 6, or 8 weeks CAN 2 mg/kg/month	Significant reduction of intraocular flares and frequency of retinal vasculitis Rapid involvement of uveitis	No adverse event No adverse event
Scleritis	Efficacy of the IL-1 receptor antagonist, anakinra, for the treatment of diffuse anterior scleritis in rheumatoid arthritis. Report of two cases⁴³ Anakinra in the treatment of patients with refractory scleritis: A pilot study⁴⁴	ANA 100 mg/day ANA 100 mg/day	Remission of scleritis Clinical remission of the 90% of the patients at the end of the 19.4-months	No adverse event Four of Ten patients: injection-site skin reaction
Kawasaki Disease	The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: A retrospective cases series⁴⁸ Kawakinra: A phase Iia multicenter trial to assess the efficacy, and safety of anakinra in patients with intravenous immunoglobulin-resistant Kawasaki disease⁴⁹	ANA from 2 mg/kg/day to 8 mg/kg/day ANA 2–6 mg/kg/die	Reduction of fever, CRP; in 10/11 patients reduction in coronary dilation Reduction of clinical and biological inflammation and coronary dilatation	Well tolerated Three severe adverse events: anakinra overdose, MAS and increase of coronary dilatation. Others AE cytolytic hepatitis (two patients), hypereosinophilia (1), injection site reaction (1) and pancreatitis (1)
Schnitzler syndrome	Treatment of Schnitzler’s syndrome with anakinra: report of three cases and review of the literature⁵² Efficacy and safety of canakinumab in Schnitzler’s syndrome: a multi-center randomized placebo-controlled study⁵⁷	ANA 100 mg/day Single CAN 150 mg or placebo injections for 7 days, followed by a 16-week open-label phase with CAN on demand	Complete and lasting resolution of symptoms; not influence in the course of monoclonal gammopathy Clinical responses in CAN group, along with improvement of quality of life, reduction of CRP and SAA	No adverse event Three severe adverse events: hypertension (two patients), severe lumbago (1) 22 mild or moderate adverse events: infectious events, gastrointestinal complaints, non-specific pain, skin symptoms, osteochondrosis, asthma and weight gain
Erdheim-Chester disease	Favorable radiological outcome of skeletal Erdheim-Chester disease involvement with anakinra⁵⁹ Treating heart inflammation with interleukin-1 blockade in a case of Erdheim-Chester disease⁶²	ANA 100 mg/day ANA 100 mg/day	Complete clinical response. after 1 year: reduction in the uptake of radiopharmaceutical in the affected areas (PET-CT) Prompt reduction in pericardial effusion, inflammatory markers and general clinical improvement	No adverse event No adverse event
PFAPA	A case of resistant adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome responsive to anakinra⁶⁴ Canakinumab efficacy in refractory adult-onset PFAPA syndrome⁶⁶	ANA 100 mg/day CAN 150 mg every 8 weeks	Improvement of symptoms and decrease of CRP, ESR and SAA protein Improvement of the overall PFAPA symptoms	No adverse event No adverse event
CRMO/CNO	Anakinra in a cohort of children with chronic nonbacterial osteomyelitis⁶⁸ Efficacy of anti-IL-1 treatment in Majeed syndrome⁷⁰	ANA at a median dose of 2 mg/kg/day ANA 1.7 mg/kg/day and then CAN 4 mg/kg/4 weeks	After 6 months in 5/9 patients favorable clinical outcome (none o minimal PGA score). Dramatic clinical and laboratory improvement with both drugs	No adverse event No adverse event
TRAPS	Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome⁷⁶ On-demand treatment with anakinra: A treatment option for selected TRAPS patients⁷⁷	ANA 1.5 mg/kg/day ANA 2 mg/kg/day on demand (within 24 h of the first signs of an attack and for 5–7 days)	Clinical improvement, and reduction normalization of acute phase reagents Complete clinical remission and reduction of acute phase reagents	Few injection-site skin reaction Few injection-site skin reaction
MKD	On-demand anakinra treatment is effective in mevalonate kinase deficiency⁸¹ Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency⁸²	ANA 1 to 2 mg/kg/day for MA patients ANA on demand (100 mg/day or 1 mg/kg/day for 5–7 days) or continuous treatment for HIDS patients ANA 1 to 5 mg/kg/day CAN 2 to 7 mg/kg every 4 to 8 weeks	Partial remission in one MA patient complete remission in the HIDS patient with continuous treatment less intense and lasting attacks in HIDS patients with ANA on demand. Clinical improvement in the frequency and duration of attacks, reduction of CRP and SAA	Injection-site skin reaction; infectious events (n = 2) ANA and CAN: injection-site skin reaction, infectious event. ANA: hypothermia, shivers CAN: transient hepatitis
MAS	Anakinra treatment in macrophage activation syndrome: a single center experience and systemic review of literature⁸⁹ Refractory adult-onset still disease complicated by macrophage activation syndrome and acute myocarditis: A case report treated with high doses (8 mg/Kg/D) of Anakinra⁹³	ANA 2 mg/kg/day ANA 80 mg/kg/day	Rapid remission of symptoms and normalization of laboratory findings Clinical remission with complete normalization of cardiac function	Injection-site skin reaction (n = 1) Transient pancytopenia
Osteoarthritis	Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter, randomized, double-blind, placebo-controlled study¹⁰⁰ Open‑label use of anakinra (kineret) in the treatment of patients with osteoarthritis¹⁰³	Single dose IA of anakinra 50 mg, anakinra 150 mg or placebo ANA 30 mg IA for small joints of hands, or 50 to 100 mg IA for medium joints of wrists or ankles, or 150 to 200 mg IA for large joints of knees or shoulder. ANA 100 mg/day SC for 30 days for erosive OA	Only pain reduction with 150 mg of anakinra compared to placebo on day 4 Only four patients responded, especially those who received anakinra injections in large joints. Only one patient with erosive OA had a slight improvement on day 30	Well tolerated. Few cases of arthralgia, headache, infectious events, extremity pain Well tolerated
Rheumatoid arthritis	Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: Results of a 12-week, phase ii, dose-finding study¹⁰⁶	CAN 150 mg SC every 4 weeks, 300 mg SC every 2 weeks, a 600 mg IV loading dose of CAN followed by 300 mg SC every 2 weeks or placebo SC every 2 weeks	CA 150 mg SC every 4 weeks was effective to reach the primary endpoints (percentage of ACR 50 responders at 12 weeks significantly higher than placebo group). Higher doses of CAN did not result in higher efficacy	Few injection-site reactions, infectious events; elevations in transaminase (transient in most cases) with CAN 300 mg SC every 2 weeks and CAN 600 MG IV loading dose + 300 mg SC every 2 weeks
Ankylosing spondylitis	Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study¹⁰⁹	ANA 100 mg/day for 3 months	Improvements in disease activity, function and quality of life; reduction in inflammatory markers. More than half of the inflammatory lesions in basal MRI regressed or disappeared after 3 months	Few injection-site skin reactions, headache
Psoriatic arthritis	An open-label pilot study of the efficacy and safety of anakinra in patients with psoriatic arthritis refractory to or intolerant of methotrexate¹¹²	ANA 100 mg/day	Improvement of signs and symptoms in 9 out of 19 patients	Good safety profile, few injection-site skin reactions, rare infectious events
SLE	Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis¹¹⁴	ANA 100 mg/day	Subjective clinical response, reduction ECLAM score, and reduction in joint count and CRP after 12 weeks	Injection-site skin reaction, infectious events
Antiphospholipid antibodies syndrome	Disappearance of a strong triple positivity for antiphospholipid antibodies after treatment with anakinra¹¹⁶	ANA 100 mg/day	Disappearance of the strong positivity of aPLA	No adverse event
Sjogren asthenia and dry eye	Interleukin-1 inhibition and fatigue in primary Sjögren’s syndrome—a double blind, randomized clinical trial¹¹⁷	ANA 100 mg versus placebo	No reduction in significant asthenia. But more than a 50% reduction in post-hoc fatigue in a statistically higher number of patients treated with anakinra than in the placebo group	Injection-site skin reaction, infectious events
Polymyalgia rheumatica	A 2-week single-blind, randomized, three-arm proof of concept study of the effects of secukinumab (anti-IL-17 mAb), canakinumab (anti-IL-1 b mAb), or corticosteroids on initial disease activity scores in patients with PMR, followed by an open-label extension¹²⁰	Single dose (3 mg/kg/body weight) of either secukinumab or CAN, or daily oral prednisone	Only partial responses in patients treated with CAN	Well tolerated without Severe AEs or increased infections noted
Giant-cell arteritis	Interleukin-1 blockade in refractory giant cell arteritis¹²¹	ANA 100 mg/day	Improvement in inflammation biomarkers and/or in symptoms, as well as a disappearance of arterial inflammation in PET/CT of two out of three patients	Injection-site skin reaction
Urticarial vasculitis	Efficacy and safety of canakinumab in urticarial vasculitis: An open-label study¹²²	Single dose of CAN 300 mg SC	Improvement of symptoms, quality of life, inflammatory markers; not all patients had a complete symptom control	Well tolerated: 3 respiratory tract infections, one fever, and five laboratory abnormalities
Pericarditis	Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: The AIRTRIP Randomized Clinical Trial¹²⁵	ANA 2 mg/Kg/day SC up to 100 mg/day	Reduction of the risk of recurrence over a median of 14 months	Injection-site skin reactions, few cases of elevation of transaminase

ANA: anakinra; CAN: canakinumab; SC: subcutaneous; IA: intraarticular; IV: intravenous; AE: adverse event; CRP: C-reactive protein; SAA: serum amyloid A; ESR: erythrocyte sedimentation rate; PGA: patient global assessment; OA: oateoarthritis; ACR: American College of Rheumatology; ECLAM: European Consensus Lupus Activity Measurement; aPLA: antiphospholipid antibodies; PFAPA: periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis; CRMO/CNO: chronic recurrent multifocal osteomyelitis/chronic non-bacterial osteomyelitis; TRAPS: tumor necrosis factor receptor-associated periodic syndrome; MKD: mevalonate kinase deficiency; HIDS: hyperimmunoglobulin D syndrome; MA: mevalonic aciduria; MAS: macrophage activation syndrome; SLE: systemic lupus erythematosus.

Research strategy

PubMed and Google Scholar database were used to find articles treating European wide off-label use of anti-IL-1 for the treatment of rheumatic diseases, by using the terms “anakinra,” “canakinumab,” “anti interleukin-1 treatment,” “off-label,” “rheumatic diseases.” We excluded articles about rilonacept and gevokizumab because both drugs are not approved in Europe, and we only took into consideration articles written in English.

Microcrystal arthropathies

Gout

Monosodium urate crystals can activate the NLRP3 inflammasome with excessive release of IL-1β through monocytes in the blood and synovial fluid. A 10 patients pilot study first showed that anakinra, when administered for three consecutive days at 100 mg dose, was effective in symptomatic control of acute gout arthritis.⁹ A multicentric retrospective study confirmed the data. On the contrary, prolonged administration for the prevention of attacks was associated with an increased risk of infections, therefore not tolerated.¹⁰ Resistant tophaceous gout also responds to on demand administration of anakinra, in combination with sub-optimal doses of allopurinol, with faster steroids tapering.^11,12 There were excellent results in patients burdened by multiple comorbidities, whose gout attacks benefited from anakinra continuous treatment,¹³ and in complex hospitalized patients, thanks to the drug’s short half-life, rapidity of action and good tolerability.^14,15 Clinical improvements also occurred in patients with chronic kidney failure at the 4–5 stage and in patients with kidney transplantation.¹⁶ A randomized, double-blind, placebo-controlled, non-inferiority-related study highlighted the non-inferiority of anakinra in the treatment of gout exacerbations compared to conventional drugs (Colchicine, Naproxen, or Corticosteroids).¹⁷

Pseudogout

By acting on NALP3, inflammasome calcium pyrophosphate crystals increase IL-1β production, activating metalloproteinase, inhibiting collagen 2, and synthesizing proteoglycans in the cartilage matrix, thus promoting joint damage. Anakinra can be a highly valuable drug in the prevention of joint damage and in changing the outcome of this disease.^18,19 A patient with end-stage renal failure successfully responded to 100 mg of anakinra administered as a preventive therapy 3 days at week after each session of hemodialysis; after 8 months of follow-up, the patient did not show any serious episode of arthritis.²⁰

Hydroxyapatite crystal deposition disease

Acute inflammation is mainly due to crystals dissolution which also causes macrophages activation. Similarly to the gout and pseudogout, microcrystalline-induced inflammation involves mainly IL-1. The Inflammation is often self-limiting but can last up to 2 or 3 weeks with the need to take NSAIDs or glucocorticoids infiltration which may result insufficient, or contraindicated. An open study of five patients proved the effectiveness of anakinra in treating acute shoulder calcific periarthritis. Anakinra 100 mg was administered SC for three consecutive days with a prompt reduction in pain and inflammatory markers. Total crystals dissolution was not obtained, as the 6-week follow-up period was too short.²¹ A retrospective 23 patients study confirmed the effectiveness and speed of action of anakinra 100 mg on pain resolution, when administered 1–3 consecutive days.²²

Behcet’s disease

Behcet’s disease (BD) is a chronic multi-systemic inflammatory disease. It is characterized by the presence of recurrent oral and genital ulcers, skin lesions, and uveitis, a state of hypercoagulability, cerebral or gastrointestinal vasculitis. It shares some features with autoinflammatory diseases such as the lack of autoantibodies, recurrent episodes of inflammation, and mucocutaneous manifestations characterized by neutrophil infiltrations. It is characterized by an important activation of both innate and adaptive immunity. Many cytokines participate in the pathogenesis of the disease, among which IL-1 plays a key role, opening up new scenarios for Bechet’s disease’s treatment. Elevated IL-1β levels can be found in serum and synovial fluid of BD patients, although they do not correlate with the disease activity.²³ Botsios et al.²⁴ described the first case of multidrug resistant BD successfully treated with anakinra. Subsequently, a case series (nine patients with refractory BD) showed seven patients with rapid clinical improvement after 100 mg of daily anakinra, one responding to the dose of 150 mg, and another not responding. After an initial clinical remission, almost all patients showed exacerbations of the disease after a few months.²⁵ Anakinra was effective in inducing sacroiliitis resolution related to BD.²⁶ A retrospective study assessed the effectiveness of anakinra and canakinumab in 30 BD patients. Some patients who had a low response to daily administration of anakinra 100 mg, showed clinical improvement under a higher dose (150 mg), or by switching to canakinumab. Closer doses of canakinumab (150 mg every 6 weeks) also determined positive results if 150 mg every 8 weeks proved ineffective. Anakinra was partially effective in treating mucocutaneous lesions.²⁷ Anakinra was a safe treatment in a patient with refractory BD and latent tuberculosis.²⁸ A 2-step adaptive clinical trial concluded that a 200 mg/die dose of anakinra is partially effective in reducing oral and resistant genital ulcers.²⁹ Canakinumab demonstrated excellent results in various BD cases, after multiple failed therapies, including anakinra.^30–32 However, there were no encouraging results from canakinumab use in the control of neurological manifestations.³³ Anakinra appeared to be more effective in treating skin, joint, and intestinal mucosa, while canakinumab showed relevant efficacy in BD ocular involvement, evidently linked to different pharmacokinetics and cytochemical expression in the different organs.^34,35

Uveitis

IL-1 can have a pivotal role in inflammatory eye diseases such as uveitis. IL-1β produced in the retina by dendritic cells, macrophages, and neutrophils may be the protagonist of the local inflammatory process, and this would explain the great effectiveness of anti-IL-1 drugs.³⁶ Canakinumab has been successfully employed in a case of BD-related uveitis which was refractory to conventional treatment and anakinra. At the beginning of canakinumab therapy, a low-grade papillary bladder carcinoma was found and surgically excised. Canakinumab therapy continued once the excision led to a complete resolution of the symptoms and the absence of cancer recurrence was assured.³⁷ A multicenter retrospective study of 19 patients with refractory or long-standing BD-related uveitis showed that canakinumab and anakinra are both viable treatment options: after 12 months of follow-up there was a reduction in eye inflammations attacks and an improvement in retinal vasculitis, which allowed for a reduction in corticosteroid use. There were no differences in efficacy between the treatment with anti-IL-1 naive and the previously treated with anti-TNF. There was a higher rate of inflammatory flare in patients co-administered with DMARDS than in patients administered with anti-IL-1 in monotherapy. These results confirm the recent evidence indicating the role of IL-1β, produced by myeloid cells in the retina, in uveitis pathogenesis.³⁸ There were significant clinical improvements in BD uveitis with a longer duration of the disease.³⁹ Moreover, Anakinra and Canakinumab also showed excellent results in the treatment of Blau syndrome, a rare genetic disease characterized by triad arthritis, rash and uveitis.^40,41

Scleritis

Non-infectious scleritis refers to a wide spectrum of ocular conditions associated with a high risk of irreversible visual impairment and the potential to threaten the anatomical integrity of the eye. It often occurs in the context of systemic disorders such as RA, vasculitis or SLE. Therefore, early recognition and timely treatment are critical for a successful management of this sight-threatening condition. In this regard, refractory cases unresponsive to conventional Disease Modifying Antirheumatic Drugs (cDMARDs) may take advantage of biotechnologic agents that have revolutionized many rheumatic diseases. More in detail, encouraging results have been reported with anakinra.⁴² IL-1, together with other cytokines, is produced by the local inflammatory cell infiltrate, and it is involved in sclera damage. Anakinra was successful in two patients with anterior scleritis and RA resulting in a rapid response with the reduction of eye inflammation. However, the reduction of the dose caused symptoms reactivation in a patient, which resolved only after the restoration of the previous dose of anakinra.⁴³ A pilot study was carried out to evaluate the effectiveness of anakinra 100 mg daily in severe anterior refractory scleritis. Ten patients were enrolled, six of whom had scleritis associated with autoimmune and autoinflammatory diseases (Relapsing Polychondritis, BD, Psoriatic Arthritis, and RA). Ninety percent of the patients presented clinical remission at the end of the 19.4-months follow-up, corticosteroid therapy was reduced, immunosuppressants were discontinued (except in one case). Most patients responded after 1 month and only three patients experienced recurrence of scleritis which was successfully treated with corticosteroids. Only one patient was refractory to anakinra. In addition, patients with scleritis associated with systemic rheumatological diseases also showed improvement in extraocular symptoms.⁴⁴

Kawasaki disease

Kawasaki syndrome (KD) is a vasculitis of medium and small arteries, which characteristically affects coronary arteries generating ectasia or aneurysms in 15%–20% of untreated children and can lead to heart dysfunction and death. It is characterized by fever, skin rash, conjunctivitis, interest in the buccal mucosa and lips, lymphadenopathy. IL-1 recall inflammatory cells in the vasal walls in particular it facilitates the inflammatory infiltration, the smooth muscle cells proliferation and the myofibroblasts formation into the coronary arterial wall inducing endothelial damage, vasodilatation with subsequent aneurysm formation. Despite conventional therapies, a relapsed KD patient showed progressive cardiac deterioration and evolution to giant coronary artery aneurysm, which normalized after anakinra administration (1 mg/kg/die).⁴⁵ Two case reports documented the partial coronary aneurysms regression in KD after treatment with anakinra,⁴⁶ and another case reported the positive response in a 16-year-old KD.⁴⁷ Patients who started taking anakinra (variable dosage from 2 to 8 mg/kg/day) on average 15 days after the onset of the disease showed rapid clinical improvement: reduction of fever, C-reactive Protein (CRP), and 10/11 patients showed reduction in coronary dilation. The complete clinical and cardiac resolution verified in 6/10 patients.⁴⁸ A phase IIA multicenter trial assessing the effectiveness and safety of the 15-day anakinra immediately after the failure of IVIG treatment, found that when administered within the 2–6 mg/kg/die dose, anakinra is rapidly effective in reducing clinical and biological inflammation and coronary dilatation.⁴⁹

Schnitzler syndrome

Schnitzler syndrome is a rare inflammatory multisystemic disease with late onset, it is characterized by chronic urticaria and monoclonal gammopathy (often IgM), often associated with fever, myalgia and polyarthralgia, lymphadenopathies, and increased inflammatory markers. Patients have a higher risk of developing Waldenstrӧm macroglobulinemia and lymphoma. Clinical similarities with autoinflammatory diseases, the increase in proinflammatory cytokines such as IL-1 and the effectiveness of IL-1 blocking agents suggest the central role of IL-1 in the etiopathogenesis of this rare disease, which is not yet entirely known. Several case reports highlighted how anakinra induced remission of the disease.^50,51 It is also assumed that anakinra does not influence the course of monoclonal gammopathy.⁵² In a retrospective study 29 patients treated with anakinra responded significantly to treatment, with no loss of effectiveness after a median follow-up of 3-years of treatment ensuring steroids sparing. Cases of non-response to anakinra are rare and may be linked to a subtype of disease or even misdiagnosis.⁵³ Canakinumab has also been tested in three Schnitzler patients inducing prompt clinical benefit.⁵⁴ Vanderschueren and Knockaert describe a significant and long-lasting clinical and biological response, with the disappearance of fever, arthritis, skin rash, asthenia and reduction of CRP levels in a patient treated with canakinumab 150 mg every 8 weeks for 6 months. After discontinuation of the drug the disease reappeared, with its remission after the reintroduction of the drug.⁵⁵ An open study of eight patients, treated with canakinumab 150 mg every month for 6 months, confirmed the rapidly inducing clinical and biological remission of the disease, except for a single patient who had a relapse after the initial clinical remission. After the discontinuation of treatment, the patients experienced reactivation of symptoms.⁵⁶ A randomized phase 2, placebo-controlled, multicenter study on 20 patients to evaluate canakinumab effectiveness was carried out. At day 7, patients who received 150 mg had clinical responses unlike the placebo group, and these results, along with the improvement of quality of life and the reduction of CRP, continued up to 16 weeks with on demand administration.⁵⁷

Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis, characterized by fibro-inflammatory lesions in retroperitoneal, periureteral areas or in bone, determined by infiltration of macrophages CD68, CD1a-. It is a rare disease that manifests with bone pain, fever, asthenia, involvement of cardiocirculatory and central nervous systems. The etiopathogenesis is still unclear, but IL-1 and IL-6 seem to have a relevant role; in fact, the IL-1 signaling appears overstimulating in ECD. Two patients with ECDs had a rapid clinical and biological response after anakinra administration, with disappearance of fever and bone pain, and reduction of IL-1, IL-6 and CRP and the expression of the IL-1α on monocytes. Pulmonary fibrosis also partially regressed.⁵⁸ The radiological response in an ECD patient with refractory bone infiltration treated with anakinra was assessed: after 1 year of treatment, PET-CT showed a significant reduction in the uptake of radiopharmaceutical for the affected areas.⁵⁹ Two case reports highlighted the clinical and biological success of anakinra, with no significant improvement in radiological images.^60,61 Anakinra, thanks to its rapid action and excellent tolerance, was particularly suitable for this rapidly progressive condition; a patient with severe pericarditis, risk of cardiac buffering and secondary heart failure, refractory to NSAIDS, colchicine and pericardial window, showed prompt reduction in pericardial effusion, inflammatory markers and general clinical improvement after anakinra.⁶²

PFAPA

PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, cervical adenopathy) is an autoinflammatory disease, often with its onset in childhood. The etiopathogenesis remains unclear, but the disease is considered an inflammasome disorder, characterized by elevated production of IL-1β in PFAPA. Stojanov et al.⁶³ treated five patients with anakinra, with satisfactory results. Anakinra can be a valid option, especially in late-onset PFAPA.⁶⁴ Canakinumab also reduced adult disease activity, improving symptoms and biological reduction of inflammatory markers when anakinra was not effective⁶⁵ or lost its efficacy.⁶⁶ Child PFAPA attacks do not always respond to canakinumab. Higher or closer doses of canakinumab may be needed to control PFAPA attacks.⁶⁷

Chronic recurrent multifocal osteomyelitis/chronic non-bacterial osteomyelitis

Chronic Recurrent Multifocal Osteomyelitis/Chronic Non-Bacterial Osteomyelitis (CRMO/CNO) is a chronic inflammatory syndrome characterized by multiple sterile bone inflammation, very painful, that arises in childhood–adolescent age. The overactivation of innate immune systems with an abnormal production of IL-1β may be involved in pathogenesis, which still remains poorly understood. The effectiveness of anakinra was assessed in nine patients with CNO resistant to NSAIDs and bisphosphonates. Five out of nine patients reported a positive clinical response during 6 months of treatment at a median dose of 2 mg/kg/day.⁶⁸ Many authors argue that CRMO/CNO has a counterpart in adulthood, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis), in which positive responses were also described.⁶⁹ There are family monogenic forms of CNO: Majeed syndrome, PAPA syndrome, and DIRA syndrome. Satisfactory responses were observed under the administrations of anakinra and canakinumab also in these hereditary diseases.^70–74

Tumor necrosis factor receptor-associated periodic syndrome

TRAPS is a rare autoinflammatory dominant autosomal disease caused by the mutation of TNF type 1 receptor gene, characterized by recurrent fever, migrant myalgias, and painful skin lesions, often associated with abdominal pain, headaches, arthritis, and significant increase in inflammatory markers. The overactivation of TNF signaling is the protagonist of the excessive inflammation which characterized the disease, but a dysregulation of IL-1 production also seems to participate in pathogenesis. Case reports showed how anakinra promptly induced into remission refractory TRAPS.⁷⁵ Then a study conducted on five patients with severe form of TRAPS showed, already after 2 days of treatment, clinical improvement, and reduction of CRP levels, normalized within the first fortnight in all patients. At the end of the fortnight, therapy was suspended with exacerbation of the disease; anakinra was reintroduced inducing remission during the next 11 months of follow up.⁷⁶ Another study investigated the effects of on-demand anakinra on two TRAPS pediatric patients. The drug was administered within 24–48 h of the symptoms’ onset and it was continued for 5 days with rapid complete clinical remission and reduction of acute phase reagents in 24/48 H. After 2 years of treatment the number of attacks increased in one patient, requiring more lasting anakinra treatment, perhaps owed to the natural development of the disease rather than to the effectiveness of the drug.⁷⁷

Mevalonate kinase deficiency/hyperimmunoglobulin D syndrome

MKD is a rare autosomal recessive disease caused by the mutation of the MVK gene, which results in an altered isoprenoid and cholesterol production. IL-1 is involved in pathogenesis since the lack of isoprenoid products results in an increased production of IL-1β. It is an autoinflammatory disease and it includes a less severe form consisting of partial deficiency of Mevalonate Kinase or Hyperimmunoglobulinemia D with periodic fever (HIDS), and a more severe form with complete deficiency of Mevalonate Kinase, or Mevalonic Aciduria (MA).⁷⁸ Canakinumab is the only anti-IL-1 drug approved in Europe to treat this disease. Studies showed that Anakinra is able to reduce significantly the severity of fever attacks in refractory HIDS. Anakinra effectiveness was also assessed on demand in regressing fever attacks in patients with HIDS after vaccinations,^79,80 and in atypical MKD, with refractory erosive arthritis.⁸¹ A prospective study assessed the effects (1–2 mg/kg/day) of anakinra in patients with MKD; one of the two MA patients responded partially to continuous administration, 8/9 patients with HIDS chose to be treated on demand (in order to avoid daily injections on days free from symptoms), and only one chose continuous treatment. Patients receiving anakinra within 24 h of the onset of attacks, had less intense and shorter attacks. Continuous administration gave clinical remission for 7 months, after which the patient discontinued the drug due to its side effects.⁸² In a retrospective study anakinra (1–5 mg/kg/day) and canakinumab (2–7 mg/kg every 4–8 weeks) were administered in 11 patients (five received anakinra, two canakinumab, and four switched from anakinra to canakinumab). All patients experienced clinical improvements in the frequency and duration of attacks, with reduced CRP and Serum Amyloid A (SAA) protein. The complete clinical remission took place in one patient treated with anakinra and in three patients treated with canakinumab. Continuous drug administration, unlike on-demand administration, also led to a reduction in the frequency of attacks, as well as duration and intensity. Further research is necessary to assess the benefits of both strategies in preventing long-term complications such as amyloidosis.⁷⁸

Macrophage activation syndrome

Macrophage activation syndrome (MAS) is a hyperinflammation condition caused by excessive activation and proliferation of T lymphocytes and macrophages. This activation generates a cytokine storm, where IL-1 and IL-6 have a central role. The macrophages engulf normal hematopoietic cells and injure the organs in which they are located, for example liver, spleen, lymph nodes, and bone marrow. There are still many uncertainties concerning etiopathogenesis. This disease represents a dangerous complication of diseases such as SJIA and AOSD, but also SLE, KD^83,84; it is classified as hemophagocytic lymphohistiocytosis (HLH), secondary to rheumatic diseases. It manifests with fever, hepatosplenomegaly, progressive pancytopenia, coagulopathy, high increase in serum ferritin, encephalopathy, and even multi-organ failure. A bone marrow biopsy is often required to arrive at a clear diagnosis, since the clinical features are confused with those of sepsis.⁸⁴ Anakinra was successfully administered for the first time in a patient with cytophagic histiocytic panniculitis who developed HLH.⁸⁵ Conflicting data comes from a study affirming that anakinra can act as a potential trigger for the development of MAS, since a patient with SJIA developed MAS following anakinra treatment.⁸⁶ Out of 46 patients with SJIA treated with anakinra at doses of 1–2 mg/kg, five have developed MAS, which was controlled from higher doses of anakinra.⁸⁷ In a multicenter study evaluating the long-term effectiveness of anakinra in AOSD and SJIA, out of 137 patients only one developed MAS.⁸⁸ Anakinra and canakinumab are approved for the treatment of AOSD and SJIA, and they have proven effective on many patients with related MAS.^84,89 MAS also affects patients with SLE, although more rarely, and there is evidence that shows the effectiveness of anakinra in this condition.^90,91 More frequent dosing times are often necessary to reach the required efficacy,⁹² and sometimes higher doses of anakinra are essential to reduce hyperinflammation. Parisi et al.⁹³ described a patient with AOSD complicated by MAS and fulminant myocarditis who quickly responded to 400 mg/day of anakinra, after failed therapies such as steroids, cyclosporine and 100 mg/day of anakinra. In addition to the aforementioned SJIA case, canakinumab was also held responsible for the onset of MAS in a patient who developed AOSD 10 days after the second injection.⁹⁴ Other evidence declares that canakinumab does not increase the risk of MAS in patients under treatment for SJIA; it does not provide protection from MAS, although it induces clinical SJIA remission.⁹⁵ Shakoory et al.⁹⁶ reanalyzed data from phase III randomized trial about the effectiveness of anakinra in severe sepsis; in patients showing MAS characteristics anakinra led to an improvement in survival at 28 days compared to placebo. Hence, it is important to identify them in order to start immediately anti-IL-1 treatment. A recent retrospective study on sHLH/MAS patients associated with rheumatological diseases showed how anakinra reduces its mortality rate, especially when administered early.⁹⁷

Osteoarthritis

IL-1α and IL-1β are more expressed on cartilage and synovial fluid in osteoarthritis (OA); in particular IL-1β induces an increases production and activation of proteolytic enzymes, an inhibition of collagen and proteoglycan synthesis and an increase production of inflammatory mediators like cytokines, prostaglandins, nitric oxide which result in tissue damage.⁹⁸ Some studies showed both Intra Articular (IA) and Subcutaneous (SC) administration of anakinra in OA. In a double-blind, multicenter, prospective study Chevalier et al.⁹⁹ demonstrated that a single dose of 150 mg anakinra IA administered in 13 patients with knee OA was absolutely well tolerated. A later 170 patients study described no clinical benefit from 50 mg or 150 mg of anakinra IA compared to placebo in patients with knee OA, from baseline to week 4; only pain reduction was seen with 150 mg of anakinra compared to placebo on day 4.¹⁰⁰ Case reports showed a clinical improvement in patients with refractory erosive OA regarding overall pain and disability after 3 months of SC anakinra injections.^101,102 In a prospective study, 9 out of 11 patients received anakinra IA injections (an average of two over a 2–3 months period) and 2/11 patients with erosive polyosteoarthritis received anakinra 100 mg SC injections daily for 30 days. Only four patients responded, especially those who received anakinra injections in large joints, probably due to the major drug dose (150–200 mg than 100 mg) that can be administered in large joints. Only one patient with erosive polyarthritis had a slight improvement from SC administration of anakinra on day 30.¹⁰³ A post-hoc survey of a randomized placebo study dealing with the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) reported a reduction in the incidence of OA in patients treated with canakinumab.¹⁰⁴ Nevertheless some patients with erosive OA treated with a single injection of canakinumab SC did not report positive results.¹⁰⁵

Other diseases

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Alongside TNFα, the dysregulation of IL-1β plays an important role in pathogenesis by fueling inflammatory processes that result in synovial pannus formation, cartilage destruction, and bone erosion. In fact, elevated levels of IL-1β were detected in synovial fluid of RA patients. In a 12-week, phase II, dose-finding study Canakinumab showed excellent results in patients with active RA despite maximum tolerated doses of MTX. The SC dose of 150 mg every 4 weeks was effective to reach the primary endpoints with a percentage of ACR 50 responders at 12 weeks significantly higher than the placebo group. Higher doses of canakinumab (600 mg intravenous -IV- plus 300 mg SC every 4 weeks, or 300 mg SC every 2 weeks) did not result in higher efficacy.¹⁰⁶ These results were also confirmed in another study in which 150 mg SC of canakinumab improved ACR 50, unlike higher doses or more frequent administrations which did not lead to more benefit. Total canakinumab and IL-1β measurements were compared with serum markers (CRP) and clinical outcomes (ACR 20, 50, 70). Therefore, it could be assumed that the lack of a clear dose-effect characterization could be due to the limited role of IL-1β in RA pathogenesis compared to the role of other cytokines, such as TNFα and IL-6. Indeed, it is also possible that therapy led to differential up-or down-regulation of receptors and soluble receptors, including IL-1 type 2 decoy receptor which is involved in regulation of IL-1β activity, thereby resulting in paradoxical effects.¹⁰⁷ A case report showed how canakinumab administration, after failure of previous treatments (MTX, Leflunomide, anti-TNFα, anti-CD20, and Anakinra), brought the disease into remission in a girl with rapidly destructive RA.¹⁰⁸

Ankylosing spondylitis

Ankylosing spondylitis (AS) is the prototype of spondyloarthritis, characterized mainly by enthesitis/osteitis. The IL-1 is overexpressed in AS patients, and it contributes to the inflammatory state amplification and to joint damage by stimulating macrophage and osteoclast activity, and fibroblast proliferation. An open label study of nine patients with active AS refractory to NSAIDs highlighted how anakinra 100 mg SC for 3 months led to significant improvements in disease activity (BASDAI), function (BASFI) and quality of life (ASQoL), as well as a reduction in inflammatory markers. In addition, more than half of the inflammatory lesions in basal MRI regressed or disappeared after 3 months.¹⁰⁹ However, the encouraging clinical, biochemical and radiologic success observed in the first months was not confirmed by long-term data.^110,111

Psoriatic arthritis

It is an inflammatory chronic disease that involves skin and joints. Alongside TNF, IL-1 also participates in the pathogenesis of the disease by inducing chronic inflammation. There is little data on anti-IL-1 use in Psoriatic Arthritis (PA); in a pilot study 9 out of 19 PA patients responded to anakinra therapy. However, the clinical benefit received by 30% of the patients should be not underestimated. Thus, larger randomized controlled trials could better define the role of Anakinra in PA.¹¹²

Systemic lupus erythematosus (SLE)

Despite the paucity of data on IL-1 inhibition in SLE, its pivotal role in the inflammatory cascade may provide the biologic rationale for the use of IL-1 blockers, at least in certain areas such as articular/musculoskeletal involvement. Three patients refractory to conventional treatment received anakinra. The drug was effective in lupus arthritis, while there were no improvements in myositis.¹¹³ Another study on active polyarthritis secondary to SLE revealed, after 3 months of 100 mg/day anakinra, subjective clinical response, reduction of European Consensus Lupus Activity Measurement (ECLAM) score, and a reduction in joint count and CRP in all its four patients. The clinical response was short-lived in two patients, one patient showed remission after treatment and another continued the treatment.¹¹⁴ The drug was also effective on general symptoms; a patient with increased CRP and recurrent fever, after anakinra treatment, had no more fever and CRP significantly decreased during a follow up of 26 months.¹¹⁵

Antiphospholipid antibodies syndrome

A patient with primary aPLA syndrome, after treatment with anakinra 100 mg daily for the onset of relapsed pericarditis refractory to conventional therapies, showed symptoms of improvement after 2 weeks and the disappearance of the strong positivity of aPLA too, confirmed repeatedly during quarterly follow-up. The physiopathogenetic mechanism that binds the IL-1 blockage to the disappearance of above autoantibodies remains poorly understood. The hypothesis is that blocking the activity of IL-1 could determine an increase in regulatory T-cells which can suppress the production of autoantibodies by B-cells, containing the production of antiphospholipid antibodies (aPLA) too.¹¹⁶

Sjogren asthenia and dry eye

A randomized, double-blind, placebo-controlled study was conducted to assess the effectiveness of anakinra on asthenia in Sjogren’s syndrome. The hypothesis that IL-1 could participate, at the level of the central nervous system, in the genesis of asthenia associated with Sjogren’s syndrome, moved the basis of this study. Although there was no reduction in significant asthenia after anti-IL-1 treatment, there was more than a 50% reduction in post-hoc fatigue in a statistically higher number of patients treated with anakinra than in the placebo group.¹¹⁷ A study documented the effectiveness of topical treatment with anakinra 2.5% in patients with Dry Eye Syndrome, pointing out the role of IL-1 which recalls and activates inflammatory cells, stimulates the production of other cytokines and thus participates to the production of ocular surface inflammation.¹¹⁸ A subsequent randomized, double-controlled, placebo-controlled study showed no positive results after a single intravenous dose of canakinumab in patients with dry eye.¹¹⁹

Polymyalgia rheumatica

The role of IL-1 and its blockage with IL-1 inhibitors is poorly understood. A single-blinded, double-dummy, randomized, active-controlled, parallel-group study was conducted to assess the effects of canakinumab compared to prednisone in patients with newly onset untreated polymyalgia rheumatica. Patients treated with prednisone had quick and meaningful responses to pain, and one patient got a full response, while patients treated with canakinumab had only partial responses. However, patients treated with biologics switched to glucocorticoids, requiring reduced doses.¹²⁰

Giant-cell arteritis (GCA)

IL-1β is highly expressed in inflamed arterial walls of patients with giant cell arteritis and may contribute to the pathogenesis of this disease; in addition, GCA patients showed high levels of IL-1. Case reports showed the positive response of two out of three patients refractory to multiple therapies. Anakinra yielded improvements in inflammation biomarkers and/or in symptoms, as well as a disappearance of arterial inflammation in PET/CT in two of the three patients; it also had steroid sparing effect.¹²¹

Urticarial vasculitis

Urticarial Vasculitis is a chronic disease characterized by recurrent attacks of urticaria and histopathological leukocytoclastic vasculitis. Often, the lesions are joined with burden, pain or pruritus, but also joint pain, gastrointestinal and pulmonary involvement. The use of IL-1 inhibitors is based on the hypothesis that IL-1 participates in the vascular inflammation process. In a refractory patient with non-complementary Urticarial Vasculitis (NUV), after 2 weeks of daily anakinra treatment, the symptoms resolved. It was decided to administer anakinra on alternate days, with the reappearance of urticaria and fever; so daily therapy was restored with lasting remission; disappearance of fever, urticaria, and reduction of inflammatory markers.¹²² Canakinumab was studied on 10 patients with NUV assessing its effects on symptoms, quality of life, inflammatory markers. All factors improved after administration of a single dose of canakinumab, although not all patients had a complete symptom control.¹²³

Pericarditis

Pericarditis is a debilitating condition that results from profound inflammation of the pericardial tissue. Between 10% and 15% of first episodes of acute pericarditis are followed by several episodes refractory to conventional therapy (high-dose non-steroidal anti-inflammatory drugs, colchicine, and systemic corticosteroids, each associated with potentially severe toxicities too). The causes of pericarditis vary widely and most cases are considered idiopathic recurrent pericarditis (IRP). Anakinra was highly effective in treating IRP.^124–126 Its impressive effectiveness is due to the autoinflammatory pathogenesis, in which IL-1 (in particular IL-1β) plays a pivotal role. Pericarditis is initiated by an irritant itself or by the release of necrotic cellular debris and then amplified through the activation of the Nod-like receptor 3 (NLRP3) inflammasome. This process leads to the intensification of the inflammatory response through the release of mature IL-1β.¹²⁷ The presence of pro-inflammatory cytokines in the pericardial fluid supports this hypothesis. Moreover, IRP can be associated with a procession of symptoms such as fever, myalgias, arthralgias, polyserositis, increased inflammatory markers, with a remitting chronic trend similar to those of autoinflammatory diseases, like FMF and TRAPS. The effectiveness of anti-IL-1 drugs in treating pericarditis associated with autoinflammatory and autoimmune rheumatic diseases is well known.^128,129

The use of anakinra and canakinumab has also been considered in other diseases such as urticarial,^130–132 suppurative hidradenitis,^133–138 pyoderma gangrenosum,^139–147 panniculite neutrophila,¹⁴⁸ sweet syndrome.^149,150

Conclusions

Anti-IL-1 drugs are successfully used off-label in a wide variety of rheumatological diseases, suggesting the important role of IL-1 in their pathogenesis. Off-label prescription is crucial in clinical settings when therapies are limited or research is scarce. The problems arising from the use of off-label drugs in clinical practice are the difficulty to define the optimal dosage or the duration of treatment, the patient population, as well as the high costs. Therefore, since the majority of these are low-prevalence diseases, it would be necessary to obtain evidence from multicenter national and international studies in order to assess their effectiveness and safety.

Footnotes

Acknowledgements

We thank Eva Trotta for her writing and language assistance.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This paper has been published with the financial support of the Department of Medical and Surgical Sciences of the University of Foggia.

Presentation

The content of the manuscript has never been presented in professional meetings.

ORCID iDs

Silvia Stefania

Ripalta Colia

References

Garlanda

Dinarello

Mantovani

(2013) The interleukin-1 family: Back to the future. Immunity 39(6): 1003–1018.

Marotto

Batticciotto

Ceribelli

, et al. (2019) The journey of canakinumab; on- and off-label indications. Beyond Rheumatology 1(1): 22–30.

Dinarello

Simon

van der Meer

JWM

(2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Reviews Drug Discovery 11(8): 633–652.

Cvetkovic

Keating

(2002) Anakinra. BioDrugs 16(4): 303–311.

Ruscitti

Masedu

Alvaro

, et al. (2019) Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial. PLoS Medicine 16(9): 1–22.

Lyseng-Williamson

(2018) Anakinra in Still’s disease: A profile of its use. Drugs & Therapy Perspectives 34(12): 543–553.

Vitale

Insalaco

Sfriso

, et al. (2016) 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. Frontiers in Pharmacology 7: 380.

Sota

Vitale

Insalaco

, et al. (2018) Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: A nationwide multicenter retrospective observational study. Clinical Rheumatology 37(8): 2233–2240.

De Smedt

Revaz

, et al. (2007) A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Research & Therapy 9(2): R28.

10.

Ottaviani

Moltó

, et al. (2013) Efficacy of anakinra in gouty arthritis: A retrospective study of 40 cases. Arthritis Research & Therapy 15(5): R123.

11.

Avram

Duarte

Santos

, et al. (2015) Identifying patient candidates for IL-1 inhibition: Lessons from real-world cases. Joint Bone Spine 82(Suppl. 1): eS17–eS29.

12.

Van Wabeke

Dhondt

Peene

, et al. (2017) Anakinra in resistant gout: A case report. Acta Clinica Belgica 72(4): 293–295.

13.

McGonagle

Tan

Shankaranarayana

, et al. (2007) Management of treatment resistant inflammation of acute on chronic tophaceous gout with anakinra. Annals of the Rheumatic Diseases 66(12): 1683–1684.

14.

Aouba

Deshayes

Frenzel

, et al. (2015) Efficacy of anakinra for various types of crystal-induced arthritis in complex hospitalized patients: A case series and review of the literature. Mediators of Inflammation 2015: 1–7.

15.

Thueringer

Doll

Gertner

(2015) Anakinra for the treatment of acute severe gout in critically ill patients. Seminars in Arthritis and Rheumatism 45(1): 81–85.

16.

Loustau

Rosine

Forien

, et al. (2018) Effectiveness and safety of anakinra in gout patients with stage 4–5 chronic kidney disease or kidney transplantation: A multicentre, retrospective study. Joint Bone Spine 85(6): 755–760.

17.

Janssen

Oude Voshaar

MAH

Vonkeman

, et al. (2019) Anakinra for the treatment of acute gout flares: A randomized, double-blind, placebo-controlled, active-comparator, non-inferiority trial. Rheumatology 58(8): 1344–1352.

18.

McGonagle

Tan

Madden

, et al. (2008) Successful treatment of resistant pseudogout with anakinra. Arthritis & Rheumatism 58(2): 631–633.

19.

Moltó

Richette

, et al. (2012) Efficacy of anakinra for refractory acute calcium pyrophosphate crystal arthritis. Joint Bone Spine 79(6): 621–623.

20.

Announ

Palmer

Guerne

, et al. (2009) Anakinra is a possible alternative in the treatment and prevention of acute attacks of pseudogout in end-stage renal failure. Joint Bone Spine 76(4): 424–426.

21.

Zufferey

(2013) A pilot study of IL-1 inhibition in acute calcific periarthritis of the shoulder. Annals of the Rheumatic Diseases 72(3): 465–467.

22.

Zufferey

Valcov

Thomas

, et al. (2019) Efficacy of anakinra in acute hydroxyapatite calcification-induced joint pain: A retrospective study of 23 cases. Joint Bone Spine 86(1): 83–88.

23.

Rotondo

Lopalco

Iannone

, et al. (2015) Mucocutaneous involvement in Behçet’s disease: How systemic treatment has changed in the last decades and future perspectives. Mediators of inflammation 2015: 451675.

24.

Botsios

Sfriso

Furlan

, et al. (2008) Resistant Behçet disease responsive to anakinra. Annals of Internal Medicine 149(4): 284–286.

25.

Cantarini

Vitale

Scalini

, et al. (2015) Anakinra treatment in drug-resistant Behcet’s disease: A case series. Clinical Rheumatology 34(7): 1293–1301.

26.

Caso

Rigante

Vitale

, et al. (2014) Efficacy of anakinra in refractory Behçet’s disease sacroiliitis. Clinical and Experimental Rheumatology 32(4 Suppl. 84): S171.

27.

Emmi

Talarico

Lopalco

, et al. (2016) Efficacy and safety profile of anti-interleukin-1 treatment in Behçet’s disease: A multicenter retrospective study. Clinical Rheumatology 35(5): 1281–1286.

28.

Emmi

Silvestri

Squatrito

, et al. (2017) Long-term efficacy and safety of anakinra in a patient with Behçet’s disease and concomitant tuberculosis infection. International Journal of Dermatology 56(2): 218–220.

29.

Grayson

Yazici

Merideth

, et al. (2017) Treatment of mucocutaneous manifestations in Behçet’s disease with anakinra: A pilot open-label study. Arthritis Research & Therapy 19(1): 69.

30.

Cantarini

Vitale

Borri

, et al. (2012) Successful use of canakinumab in a patient with resistant Behçet’s disease. Clinical and Experimental Rheumatology 30(3 Suppl. 72): S115.

31.

Pagnini

Bondi

Simonini

, et al. (2015) Successful treatment with canakinumab of a paediatric patient with resistant Behçet’s disease. Rheumatology 2015; 54(7): 1327–1328.

32.

Vitale

Rigante

Caso

, et al. (2014) Inhibition of interleukin-1 by Canakinumab as a successful mono-drug strategy for the treatment of refractory Behçet’s disease: A case series. Dermatology 2014; 228(3): 211–214.

33.

Vitale

Rigante

Caso

, et al. (2017) Interleukin-1 blockade in neuro-Behçet’s disease: A case-based reflection. International Journal of Rheumatic Diseases 20(8): 1046–1049.

34.

Emmi

Silvestri

Ciucciarelli

, et al. (2014) Reply: Anti-IL1 blocking agents in drug-resistant Behçet’s syndrome: Our Little case series. Clinical and Experimental Rheumatology 32(4 Suppl. 84): S172.

35.

Ugurlu

Ucar

Seyahi

, et al. (2012) Canakinumab in a patient with juvenile Behçet’s syndrome with refractory eye disease. Annals of the Rheumatic Diseases 71(9): 1589–1591.

36.

Fabiani

Sota

Tosi

, et al. (2017) The emerging role of interleukin (IL)-1 in the pathogenesis and treatment of inflammatory and degenerative eye diseases. Clinical Rheumatology 36(10): 2307–2318.

37.

Orlando

Vitale

Rigante

, et al. (2017) Long-term efficacy and safety of the interleukin-1 inhibitors anakinra and canakinumab in refractory Behçet disease uveitis and concomitant bladder papillary carcinoma Behçet. Internal Medicine Journal 47(9): 1086–1088.

38.

Fabiani

Vitale

Emmi

, et al. (2017) Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet’s disease-related uveitis: A multicenter retrospective observational study. Clinical Rheumatology 36(1): 191–197.

39.

Fabiani

Vitale

Rigante

, et al. (2020) The presence of Uveitis is associated with a sustained response to the Interleukin (IL)-1 inhibitors anakinra and canakinumab in Behçet’s disease. Ocular Immunology and Inflammation 28(2): 298–304.

40.

Aróstegui

Arnal

Merino

, et al. (2007) NOD2 gene-associated pediatric granulomatous arthritis: Clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis & Rheumatism 56(11): 3805–3813.

41.

Simonini

Caputo

, et al. (2013) Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis. Arthritis & Rheumatism 65(2): 513–518.

42.

Fabiani

Sota

Sainz-de-la-Maza

, et al. (2020) New potential weapons for refractory scleritis in the era of targeted therapy. Mediators of inflammation 2020: 8294560.

43.

Botsios

Sfriso

Ostuni

, et al. (2007) Efficacy of the IL-1 receptor antagonist, anakinra, for the treatment of diffuse anterior scleritis in rheumatoid arthritis. Report of two cases. Rheumatology 46(6): 1042–1043.

44.

Bottin

Fel

Butel

, et al. (2018) Anakinra in the treatment of patients with refractory scleritis: A pilot study. Ocular Immunology and Inflammation 26(6): 915–920.

45.

Cohen

Tacke

Straver

, et al. (2012) A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation. Annals of the Rheumatic Diseases 71(12): 2059–2061.

46.

Guillaume

Reumaux

Dubos

(2018) Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary artery aneurysm. Cardiology in the Young 28(5): 739–742.

47.

Blonz

Lacroix

Benbrik

, et al. (2020) Severe late-onset Kawasaki disease successfully treated with anakinra. Journal of Clinical Rheumatology 26(2): e42–e43.

48.

Kone-Paut

Cimaz

Herberg

, et al. (2018) The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: A retrospective cases series. Autoimmunity Reviews 17(8): 768–774.

49.

Koné-Paut

Tellier

Lambert

, et al. (2019) Kawakinra: A phase Iia multicenter trial to assess the efficacy, and safety of anakinra in patients with intravenous immunoglobulin-resistant Kawasaki disease. Annals of the Rheumatic Diseases 78: 148–149.

50.

Dybowski

Sepp

Bergerhausen

, et al. (2008) Successful use of anakinra to treat refractory Schnitzler’s syndrome. Clinical and Experimental Rheumatology 26(2): 354–357.

51.

Besada

Nossent

(2010) Dramatic response to IL1-RA treatment in longstanding multidrug resistant Schnitzler’s syndrome: A case report and literature review. Clinical Rheumatology 29(5): 567–571.

52.

Gran

Midtvedt

Haug

, et al. (2011) Treatment of Schnitzler’s syndrome with anakinra: Report of three cases and review of the literature. Scandinavian Journal of Rheumatology 40(1): 74–79.

53.

Néel

Henry

Barbarot

, et al. (2014) Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler’s syndrome: A french multicenter study. Autoimmunity Reviews 13(10): 1035–1041.

54.

de Koning

Schalkwijk

van der Meer

JWM

, et al. (2011) Successful canakinumab treatment identifies IL-1β as a pivotal mediator in Schnitzler syndrome. Journal of Allergy and Clinical Immunology 128(6): 1352–1354.

55.

Vanderschueren

Knockaert

(2013) Canakinumab in Schnitzler syndrome. Seminars in Arthritis and Rheumatism 42(4): 413–416.

56.

de Koning

Schalkwijk

van der Ven-jongekrijg

, et al. (2013) Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler’s syndrome. Annals of the Rheumatic Diseases 72(10): 1634–1638.

57.

Krause

Tsianakas

Wagner

, et al. (2017) Efficacy and safety of canakinumab in Schnitzler’s syndrome: A multi-center randomized placebo-controlled study. Journal of Allergy and Clinical Immunology 139(4): 1311–1320.

58.

Aouba

Georgin-Lavialle

Pagnoux

, et al. (2010) Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease. Blood 116(20): 4070–4076.

59.

Aubert

Aouba

Deshayes

, et al. (2013) Favorable radiological outcome of skeletal Erdheim-Chester disease involvement with anakinra. Joint Bone Spine 80(2): 206–207.

60.

Tran

Pariente

Lecron

, et al. (2011) Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs. Arthritis & Rheumatism 63(12): 4031–4032.

61.

Courcoul

Vignot

Chapurlat

(2014) Successful treatment of Erdheim-Chester disease by interleukin-1 receptor antagonist protein. Joint Bone Spine 81(2): 175–177.

62.

Tomelleri

Cavalli

De Luca

, et al. (2018) Treating heart inflammation with interleukin-1 blockade in a case of Erdheim-Chester disease. Frontiers in Immunology 9: 1233.

63.

Stojanov

Lapidus

Chitkara

, et al. (2011) Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proceedings of the National Academy of Sciences 108(17): 7148–7153.

64.

Cantarini

Vitale

Galeazzi

, et al. (2012) A case of resistant adult-onset periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome responsive to anakinra. Clinical and Experimental Rheumatology 30(4): 593.

65.

Kortus-Götze

Hoyer

(2015) Anti-IL1ß-monoclonal antibody in two adult patients with PFAPA Syndrome - a single centre experience. Pediatric Rheumatology 13(Suppl. 1): P135.

66.

Lopalco

Rigante

Vitale

, et al. (2015) Canakinumab efficacy in refractory adult-onset PFAPA syndrome. International Journal of Rheumatic Diseases 20(8): 1050–1051.

67.

Soylu

Yıldız

Torun Bayram

, et al. (2021) IL-1β blockade in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: Case-based review. Rheumatology International 41(1): 183–188.

68.

Pardeo

Marafon

Messia

, et al. (2017) Anakinra in a cohort of children with chronic nonbacterial osteomyelitis. The Journal of Rheumatology 44(8): 1231–1238.

69.

Colina

Pizzirani

Khodeir

, et al. (2010) Dysregulation of P2X7 receptor-inflammasome axis in SAPHO syndrome: Successful treatment with anakinra. Rheumatology 49(7): 1416–1418.

70.

Herlin

Fiirgaard

Bjerre

, et al. (2013) Efficacy of anti-IL-1 treatment in Majeed syndrome. Annals of the Rheumatic Diseases 72(3): 410–413.

71.

Glerup

Fiirgaard

Host

, et al. (2016) Canakinumab monotherapy for the treatment of majeed syndrome. Five-year experience [abstract]. Arthritis & Rheumatology 68(Suppl. 10).

72.

Dierselhuis

Frenkel

Wulffraat

, et al. (2005) Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology 44(3): 406–408.

73.

Fernandez

MIG

Montesinos

Vidal

, et al. (2017) PAPA syndrome with latent tuberculosis successfully treated with canakinumab. Pediatric Rheumatology 15(Suppl. 1): 44.

74.

Schnellbacher

Ciocca

Menendez

, et al. (2013) Deficiency of interleukin-1 receptor antagonist responsive to anakinra. Pediatric Dermatology 30(6): 758–760.

75.

Sacré

Brihaye

Lidove

, et al. (2008) Dramatic improvement following interleukin 1beta blockade in tumor necrosis factor receptor-1-associated syndrome (TRAPS) resistant to anti-TNF-alpha therapy. The Journal of Rheumatology 35(2): 357–358.

76.

Gattorno

Pelagatti

Meini

, et al. (2008) Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis & Rheumatism 58(5): 1516–1520.

77.

Grimwood

Despert

Jeru

, et al. (2015) On-demand treatment with anakinra: A treatment option for selected TRAPS patients. Rheumatology 54(9): 1749–1751.

78.

Galeotti

Meinzer

Quartier

, et al. (2012) Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology 51(10): 1855–1859.

79.

Bodar

van der Hilst

JCH

Drenth

JPH

, et al. (2005) Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: Introducing a vaccination provocation model. The Netherlands Journal of Medicine 63(7): 260–264.

80.

Rigante

Ansuini

Bertoni

, et al. (2006) Treatment with anakinra in the hyperimmunoglobulinemia D/periodic fever syndrome. Rheumatology International 27(1): 97–100.

81.

Lequerré

Vittecoq

Pouplin

, et al. (2007) Mevalonate kinase deficiency syndrome with structural damage responsive to anakinra. Rheumatology 46(12): 1860–1862.

82.

Bodar

Kuijk

Drenth

JPH

, et al. (2011) On-demand anakinra treatment is effective in mevalonate kinase deficiency. Annals of the Rheumatic Diseases 70(12): 2155–2158.

83.

Shafferman

Birmingham

Cron

(2014) High dose anakinra for treatment of severe neonatal Kawasaki disease: A case report. Pediatric Rheumatology 12(1): 26.

84.

Grom

Horne

De Benedetti

(2016) Macrophage activation syndrome in the era of biologic therapy. Nature Reviews Rheumatology 12(5): 259–268.

85.

Behrens

Kreiger

Cherian

, et al. (2006) Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis. The Journal of Rheumatology 33(10): 2081–2084.

86.

Lurati

Terruzzi

Salmaso

(2005) Macrophage activation syndrome (MAS) during anti-IL1 receptor therapy (anakinra) in a patient affected by systemic onset idiopathic juvenile arthritis (soJIA): A report and review of the literature. Pediatric Rheumatology Online Journal 3: 79–85.

87.

Nigrovic

Mannion

Prince

FHM

, et al. (2011) Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: Report of forty-six patients from an international multicenter series. Arthritis & Rheumatism 63(2): 545–555.

88.

Sota

Rigante

Ruscitti

, et al. (2019) Anakinra drug retention rate and predictive factors of long-term response in systemic juvenile idiopathic arthritis and adult onset still disease. Frontiers in Pharmacology 10: 918.

89.

Sönmez

Demir

Bilginer

, et al. (2018) Anakinra treatment in macrophage activation syndrome: A single center experience and systemic review of literature. Clinical Rheumatology 37(12): 3329–3335.

90.

Young

Sharara

Townsend

, et al. (2017) A case of macrophage activation syndrome complicating severe systemic lupus erythematosus. Chest 152(4): A895.

91.

Tayer-Shifman

Ben-Chetrit

(2013) Refractory macrophage activation syndrome in a patient with SLE and APLA syndrome - Successful use of PET-CT and Anakinra in its diagnosis and treatment. Modern Rheumatology 25(6): 954–957.

92.

Kahn

Cron

(2013) Higher-dose anakinra is effective in a case of medically refractory macrophage activation syndrome. The Journal of Rheumatology 40(5): 743–744.

93.

Parisi

Paglionico

Varriano

, et al. (2017) Refractory adult-onset still disease complicated by macrophage activation syndrome and acute myocarditis: A case report treated with high doses (8mg/Kg/D) of Anakinra. Medicine (Baltimore) 96(24): E6656.

94.

Banse

Vittecoq

Benhamou

, et al. (2013) Reactive macrophage activation syndrome possibly triggered by canakinumab in a patient with adult-onset Still’s disease. Joint Bone Spine 80(6): 653–655.

95.

Grom

Ilowite

Pascual

, et al. (2016) Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis & Rheumatology 68(1): 218–228.

96.

Shakoory

Carcillo

Chatham

, et al. (2016) Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of the macrophage activation syndrome: Re-analysis of a prior Phase III trial. Critical Care Medicine 44(2): 275–281.

97.

Eloseily

Weiser

Crayne

, et al. (2020) Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis & Rheumatology 72(2): 326–334.

98.

Ghouri

Conaghan

(2019) Treating osteoarthritis pain : Recent approaches using pharmacological therapies. Clinical and Experimental Rheumatology 120(5): 124–129.

99.

Chevalier

Giraudeau

Conrozier

, et al. (2005) Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: A multicenter study. The Journal of Rheumatology 32(7): 1317–1323.

100.

Chevalier

Goupille

Beaulieu

, et al. (2009) Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter, randomized, double-blind, placebo-controlled study. Arthritis Care & Research 61(3): 344–352.

101.

Bacconier

Jorgensen

Fabre

(2009) Erosive osteoarthritis of the hand : Clinical experience with anakinra. Annals of the Rheumatic Diseases 68(6): 1078–1079.

102.

Varan

Babaoglu

Atas

, et al. (2021) Response to anakinra in 3 patients with erosive osteoarthritis. Journal of Clinical Rheumatology 27(2): e52–e53.

103.

Scoville

Dickson

(2017) Open‑label use of Anakinra (Kineret) in the treatment of patients with osteoarthritis. Indian Journal of Rheumatology 12(1): 17–22.

104.

Schieker

Mindeholm

Praestgaard

, et al. (2018) Interleukin-1b inhibition with canakinumab associates with reduced rates of total hip and knee replacement (THR/TKR) and osteoarthritis (OA) symptoms: Exploratory results from the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS). Arthritis & Rheumatology 70(Suppl. 10).

105.

Carroll

(2015) Canakinumab in the treatment of erosive hand osteoarthritis: A case series. Journal of Case Reports and Studies 3(5): 503.

106.

Alten

Gomez-Reino

Durez

, et al. (2011) Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: Results of a 12-week, phase II, dose-finding study. BMC Musculoskeletal Disorders 12: 153.

107.

Ait-Oudhia

Lowe

Mager

(2012) Bridging clinical outcomes of canakinumab treatment in patients with rheumatoid arthritis with a population model of IL-1β kinetics. CPT: Pharmacometrics & Systems Pharmacology 1(9): e5.

108.

Marketos

Bournazos

Ioakimidis

(2018) Canakinumab for refractory RA: A case report. Mediterranean Journal of Rheumatology 29(3): 170–172.

109.

Tan

Connor

Fraser

, et al. (2004) Efficacy of anakinra in active ankylosing spondylitis: A clinical and magnetic resonance imaging study. Annals of the Rheumatic Diseases 63(9): 1041–1045.

110.

Bennett

Tan

Coates

, et al. (2008) Sustained response to anakinra in ankylosing spondylitis. Rheumatology 47(2): 223–224.

111.

Haibel

Rudwaleit

Listing

, et al. (2005) Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Annals of the Rheumatic Diseases 64(2): 296–298.

112.

Jung

Hellmann

Hoheisel

, et al. (2010) An open-label pilot study of the efficacy and safety of anakinra in patients with psoriatic arthritis refractory to or intolerant of methotrexate (MTX). Clinical Rheumatology 29(10): 1169–1173.

113.

Moosig

Zeuner

Renk

, et al. (2004) IL-1RA in refractory systemic lupus erythematosus. Lupus 13(8): 605–606.

114.

Ostendorf

Iking-Konert

Kurz

, et al. (2005) Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis. Annals of the Rheumatic Diseases 64(4): 630–633.

115.

Dein

Ingolia

Connolly

, et al. (2018) Anakinra for recurrent fevers in systemic lupus erythematosus. Cureus 10(12): e3782.

116.

Arnaud

Soulier

Gris

(2019) Disappearance of a strong triple positivity for antiphospholipid antibodies after treatment with anakinra. Haematologica 104(2): e83–e84.

117.

Norheim

Harboe

Gøransson

, et al. (2012) Interleukin-1 inhibition and fatigue in primary sjögren’s syndrome - a double blind, randomised clinical trial. PLoS One 7(1): e30123.

118.

Amparo

Dastjerdi

Okanobo

, et al. (2013) Topical interleukin 1 receptor antagonist for treatment of dry eye disease: A randomized clinical trial. JAMA Ophthalmology 131(16): 715–723.

119.

Grosskreutz

Hockey

Serra

, et al. (2015) Dry eye signs and symptoms persist during systemic neutralization of IL-1β by canakinumab or IL-17A by secukinumab. Cornea 34(12): 1551–1556.

120.

Matteson

Dasgupta

Schmidt

, et al. (2014) A 2-week single-blind, randomized, 3-arm proof of concept study of the effects of secukinumab (anti-IL-17 mAb), canakinumab (anti-IL-1 b mAb), or corticosteroids on initial disease activity scores in patients with PMR, followed by an open-label extension to assess satefy and effect duration: 885 [abstract]. Arthritis and Rheumatology 66.

121.

Stirnemann

JÔ

Liozon

, et al. (2014) Interleukin-1 blockade in refractory giant cell arteritis. Joint Bone Spine 81(1): 76–78.

122.

Botsios

Sfriso

Punzi

, et al. (2007) Non-complementaemic urticarial vasculitis: Successful treatment with the IL-1 receptor antagonist, anakinra. Scandinavian Journal of Rheumatology 36(3): 236–237.

123.

Krause

Mahamed

Weller

, et al. (2013) Efficacy and safety of canakinumab in urticarial vasculitis: An open-label study. Journal of Allergy and Clinical Immunology 132(3): 751–754.

124.

Brucato

Emmi

Cantarini

, et al. (2018) Management of idiopathic recurrent pericarditis in adults and in children: A role for IL‑1 receptor antagonism. Internal and Emergency Medicine 13(4): 475–489.

125.

Brucato

Imazio

Gattorno

, et al. (2016) Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: The AIRTRIP Randomized Clinical Trial. JAMA 316(18): 1906–1912.

126.

de Oliveira Correia

dos

Santos

Barbetta

de Almeida

JPCL

, et al. (2020) Anakinra in recurrent pericarditis: Current evidence on clinical use, effectiveness, and safety. Journal of Cardiovascular Pharmacology 76(1): 42–49.

127.

Baskar

Klein

Zeft

(2016) The use of IL-1 receptor antagonist (anakinra) in idiopathic recurrent pericarditis: A narrative review. Cardiology Research and Practice 2016: 7840724.

128.

Cantarini

Lucherini

Cimaz

, et al. (2010) Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clinical and Experimental Rheumatology 28(5): 802.

129.

Kougkas

Fanouriakis

Papalopoulos

, et al. (2018) Canakinumab for recurrent rheumatic disease associated-pericarditis: A case series with long- term follow-up. Rheumatology 57: 1494–1495.

130.

Lenormand

Lipsker

(2012) Efficiency of interleukin-1 blockade in refractory delayed-pressure urticaria. Annals of Internal Medicine 157(8): 599–600.

131.

Bodar

Simon

De Visser

, et al. (2009) Complete remission of severe idiopathic cold urticaria on interleukin-1 receptor antagonist (anakinra). The Netherlands Journal of Medicine 67(9): 302–305.

132.

Lipsker

(2013) Neutrophilic urticaria with systemic inflammation identical to neutrophilic urticarial dermatosis. JAMA Dermatology 149(10): 1244–1245.

133.

Zarchi

Dufour

Jemec

GBE

(2013) Successful treatment of severe hidradenitis suppurativa with anakinra. JAMA Dermatology 149(10):1192–1194.

134.

Houriet

Jafari

SMS

Thomi

, et al. (2017) Canakinumab for severe hidradenitis suppurativa: Preliminary experience in 2 cases. JAMA Dermatology 153(11): 1195–1197.

135.

Leslie

Tripathi

Nguyen

, et al. (2014) An open-label study of anakinra for the treatment of moderate to severe hidradenitis suppurativa. Journal of the American Academy of Dermatology 70(2): 243–251.

136.

Tzanetakou

Kanni

Giatrakou

, et al. (2016) Safety and efficacy of anakinra in severe hidradenitis suppurativa a randomized clinical trial. JAMA Dermatology 152(1): 52–59.

137.

Van Der Zee

Prens

(2013) Failure of anti-interleukin-1 therapy in severe hidradenitis suppurativa: A case report. Dermatology 226(2): 97–100.

138.

Menis

Maroñas-Jiménez

Delgado-Marquez

, et al. (2015) Two cases of severe hidradenitis suppurativa with failure of anakinra therapy. The British Journal of Dermatology 172(3): 810–811.

139.

Kolios

AGA

Maul

Meier

, et al. (2015) Canakinumab in adults with steroid-refractory pyoderma gangrenosum. The British Journal of Dermatology 173(5): 1216–1223.

140.

Acquitter

Plantin

Kupfer

, et al. (2015) Anakinra improves pyoderma gangrenosum in psoriatic arthritis: A case report. Annals of Internal Medicine 163(1): 70–71.

141.

Brenner

Ruzicka

Plewig

, et al. (2009) Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. The British Journal of Dermatology 161(5): 1199–1201.

142.

Geusau

Mothes-Luksch

Nahavandi

, et al. (2013) Identification of a homozygous PSTPIP1 mutation in a patient with a PAPA-like syndrome responding to canakinumab treatment. JAMA Dermatology 149(2): 209–215.

143.

Jaeger

Andres

Grosber

, et al. (2013) Pyoderma gangrenosum and concomitant hidradenitis suppurativa – rapid response to canakinumab (anti-IL-1β). European Journal of Dermatology 23(3): 408–410.

144.

Leuenberger

Berner

Di Lucca

, et al. (2016) PASS syndrome: An IL-1-driven autoinflammatory disease. Dermatology 232(2): 254–258.

145.

Jennings

Molloy

Quinlan

, et al. (2017) Treatment of pyoderma gangrenosum, acne, suppurative hidradenitis (PASH) with weight-based anakinra dosing in a Hepatitis B carrier. International Journal of Dermatology 56(6): e128–e129.

146.

Lin

Hegarty

Lin

, et al. (2011) Failure of anakinra treatment of pyoderma gangrenosum in an IBD patient and relevance to the PSTPIP1 gene. Inflammatory Bowel Diseases 17(6): E41–E42

147.

Sun

Jolly

, et al. (2017) Non-response to interleukin-1 antagonist canakinumab in two patients with refractory pyoderma gangrenosum and hidradenitis suppurativa. The Journal of Clinical and Aesthetic Dermatology 10(9): 36–38.

148.

Lipsker

Perrigouard

Foubert

, et al. (2010) Anakinra for difficult-to-treat neutrophilic panniculitis: Il-1 blockade as a promising treatment option for neutrophil-mediated inflammatory skin disease. Dermatology 220(3): 264–267.

149.

Passaro

Cerrito

Giovinale

, et al. (2013) Anakinra for sweet syndrome treatment. Pediatric Rheumatology 11(Suppl. 1): A217.

150.

Shahid

Kalayanamitra

Patel

, et al. (2019) Refractory sweet syndrome treated with anakinra. Cureus 11(4): e4536.