Interleukin-1 Inhibitors Form

Overview Clinical criteria Overview Coding Document history References This document addresses the use of interleukin-1 (IL-1) inhibitors which block IL-1β signaling, thereby reducing the effects of overactive inflammasone which is a crucial mediator of autoinflammatory conditions. Indications are drug-specific but IL-1 inhibitors are approved for the treatment of cryopyrin-associated periodic syndromes (CAPS), rheumatoid arthritis, systemic juvenile idiopathic arthritis, familial Mediterranean fever (FMF), Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), tumor necrosis factor receptor associated periodic syndrome (TRAPS), and other conditions as appropriate. Agents addressed in this clinical guideline include: • Arcalyst (rilonacept) • Ilaris (canakinumab) • Kineret (anakinra) Rheumatoid Arthritis: The American College of Rheumatology (ACR) guidelines recommend disease-modifying antirheumatic drug (DMARD) monotherapy as first-line treatment in individuals with RA with moderate to high disease activity. Methotrexate (MTX) monotherapy, titrated to a dose of at least 15 mg, is recommended over hydroxychloroquine, sulfasalazine, and leflunomide. Methotrexate monotherapy is also recommended over monotherapy with biologics (TNFi, IL-6 inhibitors, abatacept) or JAK inhibitors. For individuals taking maximally tolerated doses MTX who are not at target, the addition of a biologic or JAK inhibitor is recommended.
Non-TNFi biologics or JAK inhibitors are conditionally recommended over TNFi in individuals with heart failure. Anakinra was not included in these guidelines due to infrequent use.
Juvenile Idiopathic Arthritis: The American College of Rheumatology (ACR) guidelines provide recommendations for juvenile idiopathic arthritis, including systemic disease (SJIA) and JIA with polyarthritis (PJIA). SJIA is an autoinflammatory condition marked by intermittent fever, rash, and arthritis. PJIA is marked by the presence of more than four affected joints in the first six months of illness.
For SJIA, NSAIDs or glucocorticoids are conditionally recommended as initial monotherapy, depending on whether macrophage activation syndrome (MAS) is present or not. IL-1 inhibitors (anakinra or canakinumab), or tocilizumab are also conditionally recommended as initial therapy or to achieve inactive disease, with no preferred agent. For SJIA without MAS, IL-1 inhibitors (anakinra or canakinumab) and tocilizumab are strongly recommended for inadequate response to or intolerance of NSAIDs and/or glucocorticoids (ACR 2021). For children with active polyarthritis, biologic therapy including TNFi, abatacept, or tocilizumab +/- DMARD is recommended following initial DMARD therapy (preferably methotrexate) (ACR 2019). Adult-onset Still’s Disease (AOSD) describes SJIA when the condition begins after the patient’s 16th birthday. Though only canakinumab has been specifically FDA approved for AOSD, other agents used for SJIA may be useful in clinical practice.
CAPS and DIRA: Cryopyrin-associated periodic syndromes (CAPS) are rare, clinically overlapping, IL-1 associated, autoinflammatory conditions and 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 (CINCA) syndrome]. Individuals with FCAS, when exposed to generalized cold, experience a systemic inflammatory response including fever, urticarial rash, and substantial arthralgias. MWS is characterized by progressive sensorineural hearing loss, secondary amyloidosis with nephropathy, and intermittent episodes of fever, headache, urticarial rash, and arthralgia. NOMID is the most severe CAPS with a multitude of symptoms that develop at or near the time of birth and may result in premature death or secondary amyloidosis as a result of chronic inflammation. IL-1 inhibitors play a central role in the treatment of CAPS. Deficiency of Interleukin-1 Receptor Antagonist (DIRA) is a distinct but related extremely rare autoinflammatory disease found in neonates. The most common characteristics of DIRA include sterile multifocal osteomyelitis, periostitis and neutrophilic pustulosis and may also include periarticular swelling, oral mucosal lesions and vasculitis. DIRA typically presents between birth and 2 months postpartum and is diagnosed through homozygous germline mutations in IL1RN gene. If untreated, DIRA can lead to multiorgan failure and death. There are currently two medications indicated for DIRA, Aracalyst (rilonacept) and Kineret (anakinra).
FMF, HIDS/MKD, and TRAPS: Familial Mediterranean fever (FMF), Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), and Tumor necrosis factor receptor associated periodic syndrome (TRAPS) are autoinflammatory conditions 1

characterized by recurrent fever episodes with variable skin, joint, and serosal involvement. Colchicine is the standard first-line therapy for FMF while there is no standard first-line treatment for HIDS/MKD or TRAPS. Ilaris (canakinumab) is approved for the treatment of FMF, HIDS/MKD, and TRAPS. Recurrent Pericarditis (RP): Acute pericarditis refers to inflammation of the pericardial sac caused by infection, malignancy, or autoimmune disorder, with most cases being idiopathic. Symptoms may return after initial attack, especially in cases with an autoimmune origin, but exact recurrence rates are unknown. Treatment of Recurrent Pericarditis (RP) may include NSAIDS, colchicine, or glucocorticoid therapy. Arcalyst is FDA approved for treatment of recurrent pericarditis and for reduction in the risk of recurrence.
Gout: The 2020 American College of Rheumatology (ACR) guidelines were published prior to the approval of Ilaris for gout flares. Guidelines recommend oral colchicine, NSAIDs or glucocorticoids as appropriate first-line therapy for gout flares over IL-1 inhibitors. For individuals for whom other anti-inflammatory therapies are poorly tolerated or contraindicated, guidelines conditionally recommend using IL-1 inhibition over no therapy. Canakinumab was recently approved by the FDA for the symptomatic treatment of adult patients with gout flares in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate.
Clinical Criteria When a drug is being reviewed for coverage under a member’s medical benefit plan or is otherwise subject to clinical review (including prior authorization), the following criteria will be used to determine whether the drug meets any applicable medical necessity requirements for the intended/prescribed purpose. Arcalyst (rilonacept) Initial requests for Arcalyst (rilonacept) may be approved for the following: I. Cryopyrin-associated periodic syndromes (CAPS) when each of the following criteria are met: A. Individual is 12 years of age or older with either of the following cryopyrin-associated periodic syndromes:

2. Muckle-Wells syndrome; Familial cold autoinflammatory syndromes; OR OR II. Deficiency of Interleukin-1 Receptor Antagonist (DIRA) when each of the following criteria are met: A. Individual weighs at least 10 kilograms; AND B. DIRA is confirmed through IL1RN mutations; AND C. Disease is in remission from previous anakinra (Kineret) treatment; OR III. Recurrent Pericarditis (RP) when each of the following criteria are met: A. B. Individual is 12 years of age or older using for treatment of RP or reduction in risk of recurrence; AND Individual has a history of at least two pericarditis episodes (i.e. presents with at least the third episode) (Klein 2021).
   Continuation requests for Arcalyst (rilonacept) may be approved if the following criteria are met:
   I. II. Individual has been receiving and is maintained on a stable dose of Arcalyst; AND There is clinically significant improvement or stabilization in clinical signs and symptoms of disease.
   Requests for Arcalyst (rilonacept) may not be approved for the following: I. II. III. In combination with topical or oral JAK inhibitors, ozanimod, etrasimod, deucravacitinib, or any of the following biologic immunomodulators: TNF antagonists, IL-23 inhibitors, IL-17 inhibitors, vedolizumab, ustekinumab, abatacept, other IL-1 inhibitors, IL-6 inhibitors, rituximab, or natalizumab; OR Tuberculosis, other active serious infections, or a history of recurrent infections [repeat TB testing is not required for ongoing therapy]; OR If initiating therapy, individual has not had a tuberculin skin test (TST) or a Centers for Disease Control (CDC-) and Prevention -recommended equivalent to evaluate for latent tuberculosis (unless switching therapy from another targeted immune modulator and no new risk factors); OR IV. When the above criteria are not met and for all other indications. Ilaris (canakinumab) Initial requests for Ilaris (canakinumab) may be approved for the following: I. Cryopyrin-associated periodic syndromes (CAPS) when each of the following criteria are met: A. Individual is 4 years of age or older with either of the following cryopyrin-associated periodic syndromes:
3. Familial cold autoinflammatory syndromes; OR

4. Muckle-Wells syndrome; 2

   OR II. OR III. OR IV. OR V. OR VI. Familial Mediterranean fever (FMF) when each of the following criteria are met: A. Individual has active type 1 FMF disease with genetic confirmation of the diagnosis (MEFV gene exon 10 mutation) (De Benedetti 2018); AND Individual has confirmed recurrent, active disease (defined as at least one flare per month); AND Individual has failed to respond to or is intolerant of colchicine therapy; B. C. Hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD) when each of the following criteria are met: Individual has HIDS with genetic confirmation of the diagnosis by deoxyribonucleic acid (DNA) analysis or enzymatic A. studies (for example, mutations in the MVK gene or markedly reduced mevalonate kinase activity); AND Individual has confirmed prior history of greater than or equal to three febrile acute flares within a 6-month period when not receiving prophylactic treatment; B. Tumor necrosis factor receptor associated periodic syndrome (TRAPS) when each of the following criteria are met: A. B. Individual has TRAPS with genetic confirmation of the diagnosis (TNFRSF1A gene mutation) (De Benedetti 2018); AND Individual has chronic or recurrent disease activity (defined as six flares in a 12-month period); Still’s disease (Adult-onset Still’s Disease [AOSD] or Systemic juvenile idiopathic arthritis [SJIA]) when the following is met: A. Individual is 2 years of age or older with Still’s Disease as either ASOD or SJIA; Gout flares when each of the following criteria are met: A. B. Individual 18 years of age or older and is using Ilaris for symptomatic treatment of a gout flare; AND Individual meets either of the following:

5. Individual has had an inadequate response to both nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine; OR Individual has a contraindication to or is intolerant of both NSAIDs and colchicine; AND

   2. C. Repeated courses of corticosteroids are not appropriate for the individual; AND D. If individual has received a prior administration of Ilaris for a gout flare, there is a least a 12-week interval between treatments. Approval duration for gout flares: Treatment of one flare (one 150 mg subcutaneous administration). Continuation requests for Ilaris (canakinumab) may be approved if the following criteria are met:
      I. II. Individual has been receiving and is maintained on a stable dose of Ilaris; AND There is clinically significant improvement or stabilization in clinical signs and symptoms of disease. Requests for Ilaris (canakinumab) may not be approved for the following: I. II. III. In combination with topical or oral JAK inhibitors, ozanimod, etrasimod, deucravacitinib, or any of the following biologic immunomodulators: TNF antagonists, IL-23 inhibitors, IL-17 inhibitors, vedolizumab, ustekinumab, abatacept, other IL-1 inhibitors, IL-6 inhibitors, rituximab, or natalizumab; OR Tuberculosis, other active serious infections, or a history of recurrent infections [repeat TB testing not required for ongoing therapy]; OR If initiating therapy, individual has not had a tuberculin skin test (TST) or a Centers for Disease Control (CDC-) and Prevention -recommended equivalent to evaluate for latent tuberculosis (unless switching therapy from another targeted immune modulator and no new risk factors); OR IV. When the above criteria are not met and for all other indications. Kineret (anakinra) Initial requests for Kineret (anakinra) may be approved for if the following: I. OR II. OR III. Rheumatoid Arthritis (RA) when each of the following criteria are met: A. B. C. Individual is 18 years of age or older with moderate to severe RA; AND Individual has had an inadequate response to methotrexate titrated to maximally tolerated dose (ACR 2021); OR If methotrexate is not tolerated, individual has had an inadequate response to, or is intolerant of other conventional therapy (sulfasalazine, leflunomide, or hydroxychloroquine); OR Individual has a contraindication to methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine;
      D. Individual has a diagnosis of deficiency of interleukin-1 receptor antagonist (DIRA), confirmed through IL1RN mutations; Individual has a diagnosis of treatment-naïve or refractory (DP B IIa) neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological cutaneous and articular (CINCA) syndrome; 3

   OR IV. V. OR VI. VII. OR VIII. IX. OR X. Individual has a diagnosis of multicentric Castleman’s Disease (MCD) (NCCN 2A); AND Disease has progressed following treatment of relapsed/refractory or progressive disease;
   Individual has a diagnosis of Chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome CRS (NCCN 2A); AND CRS is refractory to steroids and anti-IL-6 therapy; Individual has a diagnosis of Erdheim-Chester Disease (NCCN 2A); AND Individual is using anakinra as a single agent;
   Still’s disease (Adult-onset Still’s Disease [AOSD] or Systemic juvenile idiopathic arthritis (SJIA) when the following is met (ACR 2021): A. Individual is 2 years of age or older with Still’s Disease as either AOSD or SJIA.
   Continuation requests for Kineret (anakinra) may be approved if the following criteria are met:
   I. II. Individual has been receiving and is maintained on a stable dose of Kineret; AND There is clinically significant improvement or stabilization in clinical signs and symptoms of disease. Requests for Kineret (anakinra) may not be approved for the following: I. II. III. In combination with topical or oral JAK inhibitors, ozanimod, etrasimod, deucravacitinib, or any of the following biologic immunomodulators: TNF antagonists, IL-23 inhibitors, IL-17 inhibitors, vedolizumab, ustekinumab, abatacept, other IL-1 inhibitors, IL-6 inhibitors, rituximab, or natalizumab; OR Tuberculosis, other active serious infections, or a history of recurrent infections [repeat TB testing not required for ongoing therapy]; OR If initiating therapy, individual has not had a tuberculin skin test (TST) or Centers for Disease Control (CDC) and Prevention - recommended equivalent to evaluate for latent tuberculosis (unless switching therapy from another targeted immune modulator and no new risk factors); OR IV. When the above criteria are not met and for all other indication. Quantity Limits Arcalyst (rilonacept) Quantity Limit
   Arcalyst 160 mg/2 mL (220 mg) single-use vial 4 vials per 28 days Drug Limit Override Criteria Initiation of therapy for Familial Cold Auto-inflammatory Syndrome (FCAS) or Muckle-Wells Syndrome (MWS): May approve 1 (one) additional vial (160 mg/2 mL) in the first 28 days (4 weeks) of treatment.

   • For the treatment of deficiency of interleukin-1 receptor antagonist (DIRA): May approve up to 8 vials per 28 days. Ilaris (canakinumab) Quantity Limit
     Drug Ilaris (canakinumab) 150 mg/mL (180 mg) single use vial 2 vials per 28 days Indicates FDA maximum dosing to accommodate Still’s Disease, TRAPS, HIDS/MKD, and FMF indications. Kineret (anakinra) Quantity Limit
     Drug Limit Limit Kineret (anakinra) 100 mg/0.67 mL prefilled syringe 1 prefilled syringe per day Override Criteria For the treatment of neonatal-onset multisystem inflammatory disease (NOMID) or deficiency of interleukin-1 receptor antagonist (DIRA): May approve up to 8 mg/kg/day Coding The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement 4
   
   

   policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. HCPCS
   J2793 J0638 J3490 J3590 ICD-10 Diagnosis D47.Z2 I31.9 M04.2 M04.1 M04.8 Injection, rilonacept, 1 mg [Arcalyst] Injection, canakinumab, 1 mg [Ilaris] Unclassified drugs [when specified as anakinra (Kineret)] Unclassified drugs and biologics [when specified as anakinra (Kineret)] Castleman disease [Kineret] Disease of pericardium, unspecified Cryopyrin-associated periodic syndromes [Arcalyst, Ilaris, (Kineret)] Periodic fever syndromes (TRAPS) [Ilaris] Deficiency of interleukin 1 receptor antagonist [DIRA] M05.00-M05.9 Rheumatoid arthritis with rheumatoid factor [Kineret] M06.00-M06.09 Rheumatoid arthritis without rheumatoid factor[Kineret] M06.1 M06.4 Adult-onset Still's disease Inflammatory polyarthropathy [Kineret] M06.80-M06.89 M06.9 Other specified rheumatoid arthritis [Kineret] Rheumatoid arthritis, unspecified [Kineret] M08.00-M08.3 Juvenile rheumatoid arthritis [Kineret, Ilaris] M08.80-M08.89 Other juvenile arthritis M10.00-M10.9 Gout Document History Revised: 11/17/2023