Anakinra and related drugs targeting interleukin-1 in the treatment of cryopyrin-associated periodic syndromes

Figures & data

Table 1 Similarities and differences between CAPS with symptom progression from the mildest form to the most severe form of the disease

	FCAS	MWS	NOMID/CINCA
Severity	Low	Medium	High
Triggers	Cold-induced	None	None
Fever/rash	Usually daily symptoms	Variable symptoms (rare to daily)	Variable symptoms (rare fever, daily rash)
Joint involvement	Arthralgia	Arthralgia/arthritis	Arthralgia, arthritis, overgrowth arthropathy
Neurological involvement	None	None	Chronic aseptic meningitis (headache, mental retardation)
Eye involvement	Conjunctivitis	Conjunctivitis, uveitis	Uveitis, papillary edema, optic neuritis
Hearing loss	None	Frequent (60%)	Frequent (>60%)
Amyloidosis	No	Frequent (25%)	Frequent (25%)
Inheritance	Autosomal dominant	Autosomal dominant or de novo (rare)	De novo (typical) or autosomal dominant (rare)
Pathophysiology	Mutation in CIAS1 gene encoding for cryopyrin	Mutation in CIAS1 gene encoding for cryopyrin	Mutation in CIAS1 gene encoding for cryopyrin
Treatment	Anti-IL-1 therapy	Anti-IL-1 therapy	Anti-IL-1 therapy

Abbreviations: IL, interleukin; FCAS, familial cold autoinflammatory syndrome; MWS, Muckle–Wells syndrome; NOMID, neonatal onset multisystem inflammatory disease; CINCA, chronic infantile, neurological, cutaneous, articular syndrome; CAPS, cryopyrin-associated periodic syndromes.

Figure 1 Pathophysiology of CAPS. Activation of the NLRP3 inflammasome is triggered by exposure of immune cells to a variety of danger-associated molecular patterns and pathogen-associated molecular patterns. The leucine-rich repeat domain of the NLRP3 is thought to serve as an autoinhibitor by self-folding. The molecule spreads out, dimerizes, and associates through homotypic interaction with the ASC adaptor protein to mediate the proteolytic processing of pro-caspase 1 to caspase-1. The ASC protein also interacts with cryopyrin. When cryopyrin binds to ASC it can result in NFκB and caspase-1 activation. Once caspase-1 is activated, it results in cleavage of pro-IL-1β and pro-IL-18 into their mature forms IL-1β and IL-18, respectively, which is secreted by the immune cell. Thus, activated cryopyrin induces release of the active form, IL-1β.

Abbreviations: DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; IL, interleukin; ASC, apoptosis-associated speck-like protein; CAPS, cryopyrin-associated periodic syndromes; UVB, ultraviolet B; LRR, leucine-rich repeat; ATP, adenosine triphosphate.

Figure 2 Timeline highlighting use of anakinra in various disease states.

Abbreviations: CAPS, cryopyrin-associated periodic syndromes; DMARDs, disease-modifying antirheumatic drugs; US FDA, US Food and Drug Administration; FMF, familial Mediterranean fever; HIDS, hyper-IgD syndrome; STEMI, ST elevation myocardial infarction; NOMID, neonatal onset multisystem inflammatory disease; MWS, Muckle–Wells syndrome.

Table 2 Examples of conditions treated by anakinra

Inflammatory diseases

Gout and pseudogout

Type 2 diabetes

Pustular psoriasis

Sjögren’s syndrome

Joint, bone, and muscle diseases

Rheumatoid arthritis

Ankylosing spondylitis

Erosive osteoarthritis of the hand

Osteomyelitis

Hereditary systemic autoinflammatory disease

Cryopyrin-associated periodic syndrome

Hyper-IgD syndrome

Familial Mediterranean fever

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis

System inflammatory diseases

Systemic juvenile idiopathic arthritis

Adult onset Still’s disease

Schnitzler syndrome

Behçet’s disease

Synovitis, acne, pustulosis, hyperostosis, osteitis

Table 3 Diseases showing positive effects of treatment with anakinra

Reference	Disease state	Study design	Year	Patients (n)	Mean follow-up	Dose of anakinra	Response/outcome	Time to response	Adverse effects
Lequerre et al^Citation42	Juvenile idiopathic arthritis	Placebo-controlled, randomized, controlled	2008	20	15 months (range 2–27 months)	1–2 mg/kg/day	15 patients (93% response to systemic symptoms), steroid reduction in 45%	<1 week	Pain at injection site 90%, 1 kala-azar, 4 viral infections, 2 transient headaches
Larsen et al^Citation43	Type 2 diabetes	Placebo-controlled, double-blind	2007	70 (34 anakinra, 36 placebo)	13 weeks	100 mg daily	The glycated hemoglobin level was reduced by 46% in drug group versus placebo group; ratio of proinsulin to insulin was markedly lower in the anakinra group	13 weeks	Injection site reactions, nausea, URI, UTI
Wendling et al^Citation44	SAPHO syndrome	Case study	2012	6	1 month	100 mg daily	Reduction of pain visual analog scale, improvement in disease activity assessment, reduction in inflammation, reduction in analgesics and NSAIDS	1 month	Injection site reaction
Rigante et al^Citation45	Hyper-IgD syndrome/periodic fever syndrome	Case study	2006	1	18 months	1 mg/kg/day	Frequency and severity of fever attacks were reduced	18 months	Injection site reaction
Tan et al^Citation46	Ankylosing spondylitis	Open-label study	2004	9	3 months	100 mg daily	Improvement in Bath AS functional index, disease activity index and quality of life, improvement in inflammatory markers, back pain. and MRI (axial enthesitis and osteitis)	3 months	Injection site reactions and initial transient mild headaches
Botsios et al^Citation47	Behçet’s disease	Case report	2008	1	20 months	100 mg daily	Remission in fever, improvement in oral and genital ulcers, no evidence of thrombophlebitis or decrease in inflammatory markers	7–10 days	None
Bacconnier et al^Citation48	Osteoarthritis of the hand	Case series	2009	3	3 months	100 mg daily	Improvement in pain, and global handicap. NSAIDs were withdrawn in all patients	3 months	Unknown
Stankovic Stojanovic et al^Citation49	Familial Mediterranean fever	Case study	2012	4	6–18 months	100 mg daily	Complete remission of attacks, partial effect on constitutional symptoms, normalization of CRP levels	2 weeks to 3 months	Slight neutropenia
Nordstrom et al^Citation50	Adult onset Still’s disease	Open, randomized, multicenter study	2012	22	8 weeks and 6 months	100 mg daily	Normalization of CRP and ferritin and reduction/discontinuation of corticosteroids. Significant improvements in physical health	2 weeks to 6 months	Flu-like symptoms, diarrhea, and myalgias
Ghosh et al^Citation51	Acute gouty arthritis	Retrospective chart review	2013	26	Unknown	100 mg daily	Complete resolution of symptoms (pain, swelling, erythema, warmth)	5–10 days	None

Abbreviations: AS, ankylosing spondylitis; CRP, C-reactive protein; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs; URI, upper respiratory infection; UTI, urinary tract infection; SAPHO, synovitis, acne, pustulosis, hyperostosis, osteitis.

LequerreTQuartierPRoselliniDInterleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in FranceAnn Rheum Dis200867330230817947302

 PubMed Web of Science ®Google Scholar

LarsenCMFaulenbachMVaagAInterleukin-1-receptor antagonist in type 2 diabetes mellitusN Engl J Med2007356151517152617429083

 PubMed Web of Science ®Google Scholar

WendlingDPratiCAubinFAnakinra treatment of SAPHO syndrome: short-term results of an open studyAnn Rheum Dis20127161098110022219141

 PubMed Web of Science ®Google Scholar

RiganteDAnsuiniVBertoniBTreatment with anakinra in the hyperimmunoglobulinemia D/periodic fever syndromeRheumatol Int20062719710016871408

 PubMed Web of Science ®Google Scholar

TanALMarzo-OrtegaHO’ConnorPFraserAEmeryPMcGonagleDEfficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging studyAnn Rheum Dis20046391041104515066864

 PubMed Web of Science ®Google Scholar

BotsiosCSfrisoPFurlanAPunziLDinarelloCAResistant Behcet disease responsive to anakinraAnn Intern Med2008149428428618711165

 PubMed Web of Science ®Google Scholar

BacconnierLJorgensenCFabreSErosive osteoarthritis of the hand: clinical experience with anakinraAnn Rheum Dis20096861078107919435727

 PubMed Web of Science ®Google Scholar

Stankovic StojanovicKDelmasYTorresPUDramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failureNephrol Dial Transplant20122751898190121931121

 PubMed Web of Science ®Google Scholar

NordstromDKnightALuukkainenRBeneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still’s disease. An open, randomized, multicenter studyJ Rheumatol201239102008201122859346

 PubMed Web of Science ®Google Scholar

GhoshPChoMRawatGSimkinPAGardnerGCTreatment of acute gouty arthritis in complex hospitalized patients with anakinraArthritis Care Res (Hoboken)20136581381138423650178

 PubMed Web of Science ®Google Scholar