Hereditary immunologic disorders caused by pyrin and cryopyrin

Hoffman, Hal M.

doi:10.1007/s11882-007-0049-4

Cited by 8 publications

(9 citation statements)

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“…Of note, relative to placebo, reduction in the disease signs and symptoms and reduction in the limitations of activities were observed with rilonacept treatment during both cold and warm periods. These results are consistent with the recent suggestion that FCAS patients have substantial underlying disease-related symptoms between disease exacerbations induced by exposure to cold temperatures (19).…”

Section: Discussionsupporting

confidence: 93%

Efficacy and safety of rilonacept (interleukin‐1 trap) in patients with cryopyrin‐associated periodic syndromes: Results from two sequential placebo‐controlled studies

Hoffman¹,

Throne²,

Amar³

et al. 2008

Arthritis & Rheumatism

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544

325

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Objective. To assess the efficacy and safety of rilonacept (Interleukin-1 [IL-1] Trap), a long-acting and potent inhibitor of IL-1, in patients with cryopyrinassociated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).Methods. Forty-seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6-week randomized double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score.Results. Forty-four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single-symptom disease flare days, single-symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, and C-reactive protein and serum amyloid A [SAA] levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions.Conclusion. Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.Cryopyrin-associated periodic syndromes (CAPS) are a group of inherited inflammatory disorClinicalTrials.gov identifier: NCT00288704.

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Section: Discussionsupporting

confidence: 93%

Efficacy and safety of rilonacept (interleukin‐1 trap) in patients with cryopyrin‐associated periodic syndromes: Results from two sequential placebo‐controlled studies

Hoffman¹,

Throne²,

Amar³

et al. 2008

Arthritis & Rheumatism

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544

325

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“…The conditions share common features of spontaneous generalized painful or pruritic erythematous rash, fever, and flulike symptoms of headache, fatigue, myalgia, arthralgia, and leukocytosis consistent with systemic inflammation (Table 1). The intensity of disease and associated disability is progressive from FCAS to MWS to NOMID 12 . Patients with FCAS may be relatively asymptomatic upon awakening, however, exposure to modest degrees of cooling temperature change (e.g., a cool breeze or air conditioning) will induce a significant systemic inflammatory reaction within hours.…”

Section: A New Directionmentioning

confidence: 99%

“…Patients with MWS experience inflammation more constitutively and a significant number (60%) develop sensorineural hearing loss due to inflammation in the inner ear 13 . A significant number (25%) also develop renal amyloidosis, which is the primary cause of death in MWS adults 12–14 . NOMID has severe onset in early infancy, and patients may have central nervous system inflammation causing seizures, developmental delay and visual impairment, as well as characteristic deformity/overgrowth of the distal femur, proximal tibia and patella 12 .…”

Section: A New Directionmentioning

confidence: 99%

“…A significant number (25%) also develop renal amyloidosis, which is the primary cause of death in MWS adults 12–14 . NOMID has severe onset in early infancy, and patients may have central nervous system inflammation causing seizures, developmental delay and visual impairment, as well as characteristic deformity/overgrowth of the distal femur, proximal tibia and patella 12 . For patients with FCAS and MWS, symptoms wax and wane, with flares triggered by exposure to cold in the case of FCAS and by other more random triggers, potentially including cold, exercise or stress, in MWS.…”

Section: A New Directionmentioning

confidence: 99%

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Rilonacept—CAPS and Beyond

Stahl¹,

Radin²,

Mellis³

2009

Annals of the New York Academy of Sciences

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Rilonacept is a dimeric fusion protein consisting of the extracellular domains of interleukin (IL)-1 type 1 receptor and IL-1 receptor accessory protein joined to the constant region (Fc) of human immunoglobulin G1. By incorporating both components of the IL-1 binding complex, rilonacept is able to tightly bind IL-1 with picomolar affinity. Although early clinical results in rheumatoid arthritis (RA) suggested that RA is not primarily an IL-1-driven disease, the discovery that the rare genetic conditions called cryopyrin-associated periodic syndromes (CAPS) were caused by overproduction of IL-1 led to clinical development and approval for these conditions. An assay that detects rilonacept:IL-1 complexes in plasma is helping to identify new indications, such as gout, in which IL-1 overproduction plays a key pathogenic role. The development of rilonacept for CAPS was achieved through collaboration between the pharmaceutical industry, academia, and government agencies, and demonstrates that knowledge gleaned in orphan indications can inform drug development for more common and heterogeneous diseases.

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“…They include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disorder (NOMID) (also known as chronic infantile neurologic cutaneous and articular syndrome [CINCA]). [1][2][3][4] CAPS are characterized by recurrent inflammation widely thought to be driven by an excessive production of interleukin-1 (IL-1) family member IL-1β, supported by patient response to IL-1β blocking therapies. [5][6][7][8] IL-1β binds to the IL-1 receptor I (IL-1RI) and signal transduction is facilitated by the recruitment of IL-1R-accessory protein (IL-1RI-AcP) ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS)

Gillespie

Mathews²,

McDermott

2010

JIR

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Cryopyrin-associated periodic syndromes (CAPS) are a subgroup of the hereditary periodic fever syndromes, which are rare autoinflammatory and inherited disorders, characterized by recurrent inflammation and varying degrees of severity. CAPS are thought to be driven by excessive production of interleukin-1β (IL-1β), through over-activation of the inflammasome by gain of function mutations in the gene encoding cryopyrin (NLRP3). This conclusion is supported by the remarkable efficacy of IL-1β blockade in these conditions. Rilonacept (Arcalyst TM ; Regeneron) is the first uS Food and Drug Administration-approved treatment for familial cold autoinflammatory syndrome and Muckle-Wells syndrome and the first in a new line of drugs designed for longer-acting IL-1 blockade. Rilonacept has been associated with a decrease in disease activity, high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) in the treatment of CAPS. The clinical safety and efficacy of rilonacept in CAPS and non-CAPS populations will be summarized in this review. Rilonacept is also beneficial for patients who tolerate injections poorly, due to an extended half-life over the unapproved CAPS treatment, anakinra, requiring weekly rather than daily self-administration. Other autoinflammatory disorders may also benefit from rilonacept treatment, with clinical trials in progress for systemic onset juvenile idiopathic arthritis, gout and familial mediterranean fever.

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Hereditary immunologic disorders caused by pyrin and cryopyrin

Cited by 8 publications

References 53 publications

Efficacy and safety of rilonacept (interleukin‐1 trap) in patients with cryopyrin‐associated periodic syndromes: Results from two sequential placebo‐controlled studies

Efficacy and safety of rilonacept (interleukin‐1 trap) in patients with cryopyrin‐associated periodic syndromes: Results from two sequential placebo‐controlled studies

Rilonacept—CAPS and Beyond

Rilonacept in the management of cryopyrin-associated periodic syndromes (CAPS)

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