Canakinumab (Ilaris)

Number: 0881

Policy

1. Aetna considers canakinumab (Ilaris) medically necessary for the following indications, where the member has a documented negative TB test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnotes for screening testing for TB^* within 6 months of initiating therapy for persons who are naive to biologics, and repeated yearly for members with risk factorsFootnotes for Risk factors for TB^** for TB that are continuing therapy with biologics:

   1. Periodic Fever Syndromes

      1. For treatment of cryopyrin-associated periodic syndromes (CAPS) when all of the following criteria are met:
         
         
         1. Member has a diagnosis of familial cold auto-inflammatory syndrome (FCAS) with classic signs and symptoms (i.e., recurrent, intermittent fever and rash that were often exacerbated by exposure to generalized cool ambient temperature) or Muckle-Wells syndrome (MWS) with classic signs and symptoms (i.e., chronic fever and rash of waxing and waning intensity, sometimes exacerbated by exposure to generalized cool ambient temperature); and
         2. Member has functional impairment limiting the activities of daily living.
            
      2. For treatment of tumor necrosis factor-receptor associated periodic syndrome (TRAPS) when all of the following criteria are met:
         
         
         1. Member has chronic or recurrent disease activity with active flares within the last 6 months; and
         2. Physician’s Global Assessment score greater than or equal to 2, or C-reactive protein (CRP) greater than 10 mg/L.
      3. For the treatment of hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD) when all of the following criteria are met:
         
         
         1. Member has had active flares within the last 6 months; and
         2. Physician's Global Assessment score greater than or equal to 2, or C-reactive protein (CRP) greater than 10 mg/L.
      4. For treatment of familial mediterranean fever (FMF) when all of the following criteria are met:
         
         
         1. Member has active disease with flares within the last 6 months; and 
         2. C-reactive protein (CRP) greater than 10 mg/L; and
         3. Member has had an inadequate response or intolerance to or has a contraindication to colchicine.
            

   2. Active Systemic Juvenile Idiopathic Arthritis (sJIA)

      1. For members who have received a biologic indicated for active systemic juvenile idiopathic arthritis; or
      2. For the treatment of active sJIA when any of the following criteria is met:
         
         
         1. Member has had an inadequate response to at least a 1-month trial of nonsteroidal anti-inflammatory drugs (NSAIDs); or
         2. Member has had an inadequate response to at least a 2-week trial of corticosteroids; or
         3. Member has had an inadequate response to at least a 3-month trial of methotrexate or leflunomide.
            

   3. Management of gout and pseudogout flares 

      (also known as calcium pyrophosphate deposition disease) when any of the following criteria is met: 
      
      

      1. Member has had an inadequate response or intolerance to maximum tolerated doses of non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and oral and injectable corticosteroid; or
      2. Member has a contraindication to NSAIDs and colchicine, and has a clinical reason to avoid repeated courses of corticosteroids.

2. Aetna considers continuation of canakinumab (Ilaris) therapy medically necessary for all members (including new members) who are using canakinumab for an indication outlined above and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition. 

3. Aetna considers concomitant use of canakinumab (Ilaris) with any other biologic DMARD (e.g., adalimumab, anakinra, rilonacept, etanercept, infliximab, tocilizumab) or targeted synthetic DMARD (e.g. tofacitinib) experimental and investigational because the effectiveness of this approach has not been established.

4. Aetna considers canakinumab experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

   • Acute coronary syndromes
   • Adult-onset Still's disease
   • Atherosclerosis
   • Behcet's disease
   • Breast cancer
   • Chronic obstructive pulmonary disease
   • Chronic spontaneous urticaria
   • Colorectal cancer
   • Diabetes (type 1 and type 2)
   • Dry eye
   • Heart failure
   • Hidradenitis suppurativa
   • IgG4-related sclerosing disease
   • Inflammatory dermatosis
   • Majeed syndrome
   • Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome)
   • Non-small cell lung cancer
   • Ocular diseases
   • Osteoarthritis
   • Osteomyelitis
   • Peripheral artery disease
   • Polymyalgia rheumatica
   • Pulmonary sarcoidosis
   • Pyoderma gangrenosum
   • Rheumatoid arthritis
   • Schnitzler syndrome
   • Yao syndrome (formerly named NOD2-associated auto-inflammatory disease)

Footnotes^*Canakinumab is contraindicated and considered not medically necessary for persons with active TB or untreated latent disease. If the screening test for TB is positive, there must be further testing to confirm there is no active disease. Do not administer canakinumab to persons with active TB infection. If there is latent disease, TB treatment must be started before initiation of canakinumab.

Footnotes^** Risk factors for TB include: persons with close contact to people with infectious TB disease; persons who have recently emigrated from areas of the world with high rates of TB (e.g., Africa, Asia, Eastern Europe, Latin America, and Russia); children less than 5 years of age who have a positive TB test; groups with high rates of TB transmission (e.g., homeless persons, injection drug users, and persons with HIV infection); persons who work or reside with people who are at an increased risk for active TB (e.g., hospitals, long-term care facilities, correctional facilities, and homeless shelters) (CDC, 2016).

See also CPB 0770 - Rilonacept (Arcalyst).

See also CPB 0810 - Gout.

Dosing Recommendations

Canakinumab is available as Ilaris supplied as a sterile, single-dose vial containing 150 mg of canakinumab lyophilized powder for reconstitution.

Cryopyrin-Associated Periodic Syndromes (CAPS)

• The recommended dose of Ilaris is 150 mg for persons with CAPS and have a body weight greater than 40 kg. For persons with body weight greater than or equal to 15 kg and less than or equal to 40 kg, the recommended dose is 2 mg/kg. For children (4 to 17 years) 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg.
• Ilaris is administered every eight weeks as a subcutaneous injection.

Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency (HIDS/MKD), and Familial Mediterranean Fever (FMF)

• The recommended dose of Ilaris for persons with TRAPS, HIDS/MKD, and FMF is based on body weight.
  
  
  • For persons with body weight less than or equal to 40 kg, the recommended dose is 2 mg/kg administered every 4 weeks. The dose can be increased to 4 mg/kg every 4 weeks if the clinical response is not adequate.
  • For persons with body weight greater than 40 kg, the recommended dose is 150 mg administered every 4 weeks. The dose can be increased to 300 mg every 4 weeks if the clinical response is not adequate.
    
    
• Ilaris is administered as a subcutaneous injection.

Systemic Juvenile Idiopathic Arthritis (SJIA)

• The recommended dose of Ilaris for persons with SJIA and with a body weight greater than or equal to 7.5 kg is 4 mg/kg (with a maximum of 300 mg) administered every 4 weeks.
• Ilaris is administered as a subcutaneous injection.

Source: Navartis, 2016

Background

Ilaris (canakinumab) is a recombinant human monoclonal anti‐human IL‐1βantibody of the IgG1/κisotype. Ilaris (canakinumab) binds to human IL‐1βand neutralizes its activity by blocking its interaction with IL‐1 receptors consequently decreasing or preventing inflammation. Canakinumab does not bind IL‐1αor IL‐1 receptor antagonist (IL‐1ra).

Ilaris (canakinumab) is U.S. Food and Drug Administration (FDA) approved for the following indications:

• Periodic Fever Syndromes:

  • Cryopyrin-Associated Periodic Syndromes (CAPS) - Ilaris is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).
  • Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) - Ilaris is indicated for the treatment of TRAPS in adult and pediatric patients.
  • Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) - Ilaris is indicated for the treatment of HIDS and MKD in adult and pediatric patients.
  • Familial Mediterranean Fever (FMF) - Ilaris is indicated for the treatment of FMF in adult and pediatric patients.
    
    

• Active Systemic Juvenile Idiopathic Arthritis (SJIA) - Ilaris is indicated for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older.

Compendial use includes treatment for gout and pseudogout (DRUGDEX, 2020; Richette et al, 2017).

Cryopyrinopathies, a group of rare autoinflammatory syndromes, are a distinct class of hereditary disorders of cytokine dysregulation with significant cutaneous features.  They include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystemic inflammatory disease (NOMID).  These syndromes were initially thought to be distinct disease entities despite some clinical similarities.  However, mutations of the same gene have since been found in all three cryopyrinopathies.  Thus, these diseases are not separate, but represent a continuum of phenotypes with FCAS being the mildest and NOMID being the most severe phenotype.  The gene in question, NLRP3 (nucleotide-binding domain, leucine rich family, pyrin domain containing, also known as CIAS1 and NALP3), encodes cryopyrin, which has led to the adoption of the term cryopyrin-associated periodic syndromes (CAPS) for this group of diseases.  Cryopyrin is an important mediator of inflammation and interleukin 1beta (IL-1b) processing.  Interleukin-1 acts as a messenger for the regulation of inflammatory responses, but in excess it can be harmful and has been shown to be key in the inflammation observed in patients with CAPS (Sinkai et al, 2008; Neven et al, 2008).

Cryopyrin-Associated Periodic Syndromes (CAPS)

Cryopyrin‐Associated Periodic Syndromes (CAPS) refer to rare genetic syndromes generally caused by mutations in the NLRP‐3 [Nucleotide‐binding domain, leucine rich family (NLR), pyrin domain containing 3] gene. In most cases, inflammation in CAPS is associated with mutations in the NLRP‐3 gene which encodes the protein cryopyrin. Cryopyrin regulates the protease caspase‐1 and controls the activation of interleukin‐1 beta (IL‐1ß. Mutations in NLRP‐3 result in overactive inflammasome resulting in excessive release of activated IL‐1ßthat drives inflammation. Ilaris binds to human IL‐1βand neutralizes its activity by blocking its interaction with IL‐1 receptors consequently decreasing or preventing inflammation.

Three related conditions make up the broader disease known as CAPS: Familial Cold Auto‐inflammatory Syndrome (FCAS), Muckle‐Wells Syndrome (MWS), and Neonatal‐Onset Multisystem Inflammatory Disease (NOMID). Clinical response may be less complete in patients with the most severe cryopyrinopathy, NOMID, despite dose escalation to 8 mg/kg every four weeks, which is double the conventional dose (Sibley, et al., 2015) 

Canakinumab (Ilaris) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 4 years of age and older. 

The approval of canakinumab by the FDA in June 2009 was based on a 3-part, 48-week double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS (Lachmann et al, 2009).  In part 1, 35 patients received 150 mg of canakinumab subcutaneously.  Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks.  After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least 2 more doses of canakinumab.  These investigators evaluated therapeutic responses using disease-activity scores and analysis of levels of CRP and SAA.  In part 1 of the study, 34 of the 35 patients (97 %) had a complete response to canakinumab.  Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission.  Disease flares occurred in 13 of the 16 patients (81 %) receiving placebo (p < 0.001).  At the end of part 2, median CRP and SAA values were normal (less than 10 mg/L for both measures) in patients receiving canakinumab; but were elevated in those receiving placebo (p < 0.001 and p = 0.002, respectively).  Of the 31 patients, 28 (90 %) completed part 3 in remission.  In part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (p = 0.03).  Two serious adverse events occurred during treatment with canakinumab: 1 case of urosepsis and an episode of vertigo.  The authors concluded that treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS.

Dhimolea (2010) stated that canakinumab was approved by the FDA for the treatment of FCAS and MWS, which are inflammatory diseases related to cryopyrinCAPS.  The drug is currently being evaluated for its potential in the treatment of chronic obstructive pulmonary disease, ocular diseases, rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis, as well as type 1 and type 2 diabetes.

Russo et al (2014) conducted a single-center observational study to determine the short- and long-term efficacy and safety of 8-weekly canakinumab therapy in children with CAPS in routine clinical practice. Study participants were assessed every 8 weeks at a dedicated clinic and standardized assessments were the 10-domains DAS for CAPS, acute phase reactants (APRs), physician's global assessment of disease activity, Child Health Assessment Questionnaire (CHAQ) and Child Health Questionnaire Parent Form 28 (CHQPF-28). The primary endpoint of clinical improvement was defined as a reduction of DAS score 8 weeks after commencing therapy and secondary endpoints included sustained clinical improvement in APRs, relapses, CHAQ score and CHQPF-28 score. Ten children with CAPS [eight Muckle-Wells syndrome (MWS), two chronic infantile cutaneous neurological articular (CINCA); median age 6.3 years] received 8-weekly canakinumab treatments at 2-8.7 mg/kg for a median of 21 months (range 12-31 months, with nine of 10 patients improving after the first dose: baseline median DAS of 7.5/20 decreased to 3.5/20 at 8 weeks (P = 0.04). This clinical improvement was sustained at a median follow-up of 21 months (range 12-31 months). It was noted that children with CINCA required higher doses of canakinumab than those with MWS. CHAQ and CHQ scores indicated improvement in functioning and health-related quality of life (HRQoL) and treatment was well tolerated, with no injection site reactions and no serious infections. The authors concluded that canakinumab, although costly, is a safe and effective treatment for CAPS in children, leading to sustained improvement in disease activity, serological markers, functional ability and HRQoL.

Gout

Sundy (2010) discussed approved and emerging drugs used to treat hyperuricemia or the clinical manifestations of gout.  Results of several clinical trials provided new data on the safety and effectiveness of the approved urate-lowering drugs, allopurinol and febuxostat.  New recommendations have been presented on appropriate dosing of colchicine for acute gout flares and potential toxicities of combining colchicine with medications such as clarithromycin.  Emerging therapies, including pegloticase, the uricosuric agent RDEA596, and the IL-1 inhibitors, rilonacept and canakinumab, have shown promise in early and late phase clinical trials.  The author concluded that recent publications demonstrate an opportunity to use existing gout therapies more effectively in order to improve both safety and efefctiveness.  Emerging therapies for gout show promise for unmet needs in selected gout populations.

The American College of Rheumatology’s guidelines for management of gout (Khanna et al, 2012) noted that “Use of a biologic interleukin-1 (IL-1) inhibitor (anakinra 100 mg subcutaneously daily for 3 consecutive days; evidence B) or canakinumab 150 mg subcutaneously as an option for severe attacks of acute gouty arthritis refractory to other agents was graded as evidence A in the systematic review.  Given a lack of randomized studies for anakinra and the unclear risk/benefit ratio and lack of FDA approval for canakinumab at the time this was written, the authors, independent of TFP discussion, assessed the role of IL-1 inhibitor therapy in acute gout as uncertain”. The 2019 American College of Rheumatology Guidelines for the Management of Gout final publication of the updated guideline is anticipated in early 2020.

The Prescribing Information (Novartis, 2016) for Ilaris (canakinumab) does not list gout as an FDA-approved indication. According to Lexicomp and UpToDate, canakinumab has been trialed as an "off-label use" for the treatment of refractory gout flares. Canakinumab was approved in the European Union for treatment of patients with at least three gout flares annually that cannot be effectively managed with other anti-inflammatory treatment options. Becker and Gaffo (2019) cite two identically designed randomized trials (one in the U.S., one in Europe) comparing canakinumab (single dose of 150 mg subcutaneous (SC)) plus intramuscular (IM) placebo to triamcinolone acetonide (40 mg IM) plus placebo administered SC (total n=456). Those trials found that canakinumab administration resulted in a significantly greater reduction in mean 72-hour pain score using a 100 mm visual analog scale. Four patients receiving canakinumab required hospitalization for treatment of infections; however, none were found to be opportunistic. Other adverse events that were most common with canakinumab included low neutrophil counts and low platelet counts. Per Lexicomp, additional data may be necessary to further define the role of canakinumab in treatment of acute gout flares. Canakinumab has been approved in the European Union for use in patients with more than three gout flares annually that are refractory to treatment with alternative agents. Thus, Becker and Gaffo (2019) recommend canakinumab for patients who are unresponsive to any other available approach and who have frequent recurrent gout flares; however, the benefits for symptomatic relief need to be balanced with the potential for increased risk for serious infections.

Periodic Fever Syndromes

The FDA approved canakinumab to treat three additional types of Periodic Fever Syndromes: Tumor Necrosis Factor-Receptor Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) and Familial Mediterranean Fever (FMF) (Novartis, 2016). All three conditions plus CAPS are part of a group of rare autoinflammatory diseases called Periodic Fever Syndromes, which are also referred to as Hereditary Periodic Fevers (HPF). Periodic Fever Syndromes are a group of rare autoinflammatory diseases that cause disabling and persistent fevers which may be accompanied by joint pain, swelling, muscle pain and skin rashes with complications that can be life-threatening. The most common syndrome is FMF, which mainly affects people of Eastern Mediterranean ancestry. It affects 1 in 250 to 1 in 1,000 individuals in these populations, many of whom are children.

The FDA approvals are based on results from the pivotal Phase III CLUSTER study which showed rapid (at Day 15) and sustained disease control with Ilaris compared to placebo through 16 weeks, in patients with either TRAPS, HIDS/MKD or FMF (Novartis, 2016). The FDA granted Ilaris Breakthrough Therapy status and priority reviews for each of the three Periodic Fever Syndrome conditions.

Akgul et al (2013) performed a systematic review to analyze patients with familial Mediterranean fever (FMF), including juvenile patients who received treatment with biologics.  A MEDLINE search, including articles published in English language between 1990 and May 2012, was performed.  Patients who had Mediterranean fever variants but could not be classified as FMF according to Tel-Hashomer criteria were excluded.  There is no controlled trial on the safety and effectiveness of biologics in FMF.  A total of 59 (32 females and 27 males) patients with FMF who had been treated with biologics (infliximab, etanercept, adalimumab, anakinra, and canakinumab) were reported in 24 single reports and 7 case series.  There were 16 children and 43 adults (7- to 68-year olds).  Five patients were reported to have colchicine intolerance or had adverse events related to colchicine use, and the rest 54 were unresponsive to colchicine treatment.  The authors concluded that the current data are limited to case reports, and it is difficult to obtain a quantitative evaluation of response to biologic treatments.  However, on the basis of reported cases, biologic agents seem to be an alternative treatment for patients with FMF who are unresponsive or intolerant to colchicine therapy and seem to be safe.  Moreover, they stated that controlled studies are needed to better evaluate the safety and effectiveness of biologics in the treatment of patients with FMF.

Galeotti et al (2012) described the safety and effectiveness of IL-1-targeting drugs, anakinra and canakinumab, in patients with mevalonate kinase deficiency (MKD).  A questionnaire was sent to French pediatric and adult rheumatologists to retrospectively collect information on disease activity before and after treatment with IL-1 antagonists from genetically confirmed MKD patients.  The authors assessed the frequency of crises and their intensity using a 12-item clinical score built for the purpose of the study.  A total of 11 patients were included.  Anti-IL-1-targeting drugs were used continuously in all but 1 patient who received anakinra on demand.  Daily anakinra (9 patients) or canakinumab injections every 4 to 8 weeks (6 patients, in 4 cases following anakinra therapy) were associated with complete remission in 4 cases and partial remission in 7.  The median score during MKD attacks decreased from 7/12 before treatment to 3/12 after anakinra and 1/12 after canakinumab.  The number of days with fever during attacks decreased from 5 before treatment to 3 after anakinra and 2 after canakinumab.  Marked decrease of CRP and SAA protein were recorded.  Side effects were mild or moderate; they consisted of local pain and inflammation at injection site, infections and hepatic cytolysis.  The authors concluded that continuous IL-1 blockade brings substantial benefit to MKD patients.  Moreover, they stated that controlled trials are needed to further evaluate the clinical benefit and treatment modalities in these patients.

Systemic Juvenile Idiopathic Arthritis

Systemic juvenile idiopathic arthritis, previously referred to as Still's disease or systemic onset juvenile rheumatoid arthritis, is a subset of juvenile idiopathic arthritis.  Individuals with systemic juvenile idiopathic arthritis present with intermittent fever, rash, and arthritis.  Children with this illness comprise between 10 and 20 percent of all cases of JIA.  Children with systemic onset JIA require close supervision and careful monitoring as systemic complications, including drug reactions, macrophage activation syndrome, pericarditis, and other forms of internal organ involvement are more common in this subtype of JIA than in any other (Lehman, 2014).

Canakinumab received FDA approval for use in systemic juvenile idiopathic arthritis in patients age 2 years and older on May 9, 2014 (Novartis, 2013).

Ruperto et al (2012) assessed the safety and effectiveness of canakinumab for the treatment of systemic JIA in 2 trials.  In trial 1, these researchers randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; greater than or equal to 2 active joints; CRP, greater than 30 mg/L; and glucocorticoid dose, less than or equal to 1.0 mg/kg body weight/day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 m/kg) or placebo.  The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30 % or more in at least 3 of the 6 core criteria for JIA, worsening of more than 30 % in no more than 1 of the criteria, and resolution of fever.  In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo.  The primary outcome was time to flare of systemic JIA.  At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84 %], versus 4 of 41 [10 %] in the placebo group; p <0.001).  In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74 % of patients in the canakinumab group had no flare, versus 25 % in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; p = 0.003).  The average glucocorticoid dose was reduced from 0.34 to 0.05 mg/kg/day, and glucocorticoids were discontinued in 42 of 128 patients (33 %).  The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo.  The authors concluded that these 2 phase III studies showed the efficacy of canakinumab in systemic JIA with active systemic features.  The main drawback of the 2 studies was that patients without fever were excluded from participation.  In a subset of patients with systemic JIA, systemic symptoms eventually resolve while chronic arthritis continues.  Thus, the effectiveness of canakinumab in patients who have systemic JIA without fever cannot be deduced directly from these findings.  Furthermore, information on the safety of canakinumab in patients with systemic JIA is limited, given the short duration of exposure to placebo in both trials and the use of a withdrawal design.  The authors stated that longer-term safety data are needed.

Horneff (2013) noted that the development of biologics has markedly changed the treatment of JIA, specifically that complete control of the disease and remission has today become the main goal of treatment, including preventing long-term damage and disability. The author’s review included an overview of the current treatment options using biologics in JIA.  TNF inhibitors have emerged as the most commonly used biologics for the treatment of JIA. They were initially successful for the treatment of rheumatoid factor positive and negative polyarticular JIA, but have also been studied in patients with enthesitis-related arthritis, psoriatic arthritis, and extended olioarthritis, and approval of at least etanercept is expected. Second-line biologics are abatacept and tocilizumab. For systemic onset JIA, tocilizumab, and the IL-1 inhibitors anakinra and canakinumab have been successfully studied and in the treatment of JIA, biologics have emerged as potent drugs to control the disease. The author further noted that new advancements will be crucial for continued improvement in treatment options for JIA.

Otten et al (2013) conducted a systematic review of all available efficacy data from 11 randomized controlled trials performed in JIA with inclusion of biological agents.  If trials were comparable with regard to design and patients' characteristics related to treatment outcome an indirect between-drug comparison was conducted.  On the basis of the equality of the trials, 6 trials were grouped into two networks of evidence.  Network 1, which included withdrawal trials evaluating etanercept, adalimumab and abatacept in polyarticular course JIA, showed no significant differences in short-term efficacy based on indirect comparisons.  Network 2 indirectly compared trials with a parallel study design investigating anakinra, tocilizumab and canakinumab in SJIA and found no differences in comparative efficacy.  The authors concluded that due to the small number of trials and the observed differences between trials, no definite conclusions could be drawn regarding the comparative effectiveness of the indirectly compared biological agents.  They recommended that comparability of future trials be improved and noted that head-to-head trials are required to decide on the best biological treatment for JIA.

Experimental Indications

Previous and current clinical trials have examined the use of canakinumab in the treatment of various diseases/disorders including atherosclerosis, arthritis, breast cancer, chronic obstructive pulmonary disease, colorectal cancer, dry eye, neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome), non-small cell lung cancer, osteoarthritis, peripheral artery disease, polymyalgia rheumatica, pulmonary sarcoidosis, rheumatoid arthritis, as well as type 1 and type 2 diabetes.

Dinarello and colleagues (2012) noted that monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function.  This approach can therefore be effective in treating common conditions such as post-myocardial infarction (MI) heart failure, and trials targeting a broad spectrum of new indications are underway.  So far, 3 IL-1-targeted agents have been approved:

• the IL-1 receptor antagonist anakinra,
• the soluble decoy receptor rilonacept, and
• the neutralizing monoclonal anti-IL-1β antibody canakinumab.

In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.

Lipsker and Lenormand (2012) stated that anecdotal observations suggested that IL-1 antagonists may be effective for the treatment of patients with different types of inflammatory dermatological diseases.  These investigators reviewed the current evidence on the use of IL-1 antagonists in dermatology.  A Medline search was performed combining the keywords: "anakinra; canakinumab; rilonacept" and "skin; neutrophilic dermatoses; Sweet syndrome; pyoderma gangrenosum; hidradenitis suppurativa; Schnitzler syndrome; Still disease".  The precise dermatological phenotype of patients with IL-1 antagonist-responsive auto-inflammatory disorders was analysed in order to compare it to related complex disorders.  Double-blind randomized controlled trials have demonstrated the efficacy of these treatments in cryopyrinopathies with dermatological involvement including chronic infantile neurological cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold urticaria.  The authors stated that anakinra is the only treatment for Schnitzler syndrome that is almost constantly efficacious, even in refractory disease, as attested by numerous case reports.  It is also efficacious in the treatment of patients with adult-onset Still disease and systemic juvenile arthritis.  Neutrophilic dermatoses constitute the cutaneous hallmark of IL-1-responsive auto-inflammatory disorders, and neutrophilic dermatoses could thus form an indication for this treatment.  However, to-date, only 9 reports have been published showing efficiency in patients with Sweet syndrome, in 1 case of neutrophilic panniculitis, and in 2 cases of pustular psoriasis.  Anakinra appears less efficacious in patients with pyoderma gangrenosum.  The authors concluded that IL-1 antagonists are a first-line treatment in patients with Schnitzler syndrome and cryopyrinopathies.  They could become important alternatives in patients with acute and febrile neutrophilic dermatoses either unresponsive to or with contraindications to conventional treatments, but this requires confirmation by further clinical trials.

Atherosclerosis

Thompson et al (2013) noted that rupture or erosion of an unstable atherosclerotic plaque is the typical pathology and usual cause of acute coronary syndromes (ACS).  Despite detailed understanding of the processes of lipid accumulation, thinning of the fibrous cap, and inflammation leading to plaque instability, there are no strategies in clinical use that uniquely target the unstable plaque.  These investigators performed a critical review of recent publications on potential therapies that could be used to stabilize unstable plaque.  They searched PubMed, other literature databases, drug development sites, and clinical trial registries to retrieve clinical studies on anti-inflammatory and lipid-modulating therapies that could be used to stabilize unstable atherosclerotic plaque.  Multiple experimental targets involving lipid and inflammatory pathways have the potential to stabilize the plaque and expand the armamentarium against coronary artery disease.  Randomized clinical trials of darapladib, methotrexate, canakinumab, and colchicine are well advanced to establish if plaque stabilization is feasible and effective in patients with ACS.  The authors concluded that although there are still no agents in clinical use for plaque stabilization, there are important advances in understanding plaque instability and several encouraging approaches are being evaluated in phase III clinical trials.

Hassan (2018) noted that atherosclerosis is no longer considered solely a disorder of sub-intimal deposition of modified low-density lipoprotein (LDL) particles in the arterial wall.  Rather, it is known to be a chronic inflammatory disorder.  No evidence has shown that reducing vascular inflammation in the absence of concomitant lowering of lipoproteins levels reduces the rates of adverse cardiovascular (CV) events.  Canakinumab significantly reduced the rate of recurrent CV events in patients with prior MI in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS).  The author stated that canakinumab has no effect on CV or all-cause mortality, however it was associated with high incidence of fatal infections.  Thus, the net benefit needs to be properly addressed in future studies that evaluate the potential benefit of the anti-inflammatory therapies and whether it can change clinical practice in the near future.  The author concluded that the CANTOS study is an extremely exciting proof of concept clinical trial that opens up a new way of thinking about halting the progression of atherosclerosis and reducing residual CV risk.  However, considerably more research is needed for such anti-inflammatory therapies in order to change clinical practice and to reach the clinic.  The results of the ongoing Cardiovascular Inflammation Reduction Trial (CIRT) -- examining the efficacy and safety of low-dose methotrexate in patients with a previous MI who have diabetes or the metabolic syndrome -- are eagerly awaited.

Behcet's Disease

Vitale and colleagues (2016) stated that Behcet's disease (BD) is a systemic inflammatory disorder characterized by a protean clinical spectrum and an enigmatic pathogenesis.  After being classified as an autoimmune disorder, spondyloarthritis and vasculitis, today BD is considered at the cross-road between autoimmune and auto-inflammatory syndromes.  Many pathogenetic, clinical and therapeutic clues support this recent interpretation, enabling novel treatment choices such as IL-1 inhibition.  Thus, in the past 10 years the IL-1 receptor antagonist anakinra and the anti-IL-1β monoclonal antibody canakinumab were increasingly administered in BD patients resistant to standard therapies, leading to interesting results and intriguing new pathogenetic implications.  The authors concluded that further studies are needed to both establish how the innate and acquired immune systems interact in BD patients and identify the best way of administering anti-IL-1 agents with regard to dosage, interval of administration, and organ response.

Chronic Spontaneous Urticaria

Kocaturk and Zuberbier (2018) stated that symptomatic management of chronic spontaneous urticaria (CSU) basically depends on 2nd-generation H1 anti-histamines and omalizumab.  Omalizumab is a game changer in the management, but still there is a need for new targets and new biologics targeting new pathways in the treatment which will provide long-lasting remission, which will be given orally and which will be cheaper.  This review focused on new biologics that are underway of production or are already under use for different disorders but could be beneficial for the treatment of chronic urticaria.  The treatment targets are classified according to the cells which are involved in the pathogenesis of CSU.  Those are mast cells/basophils, B cells, T cells and eosinophils.  The treatments that are under clinical trials for CSU are anti-IgE treatments such as ligelizumab, molecules targeting intracellular signaling pathways such as spleen tyrosine kinase inhibitors (TKIs), surface inhibitory molecules such as siglec-8, anti-IL-1s such as canakinumab, Bruton kinase (BTK) inhibitors such as GDC-0853 and anti-IL-5s such as benralizumab and mepolizumab.  The authors concluded that ongoing clinical trials on new targets of treatment hold new hopes not only for a better care of the disease but also a better understanding of the pathomechanisms lying underneath.

Furthermore, an UpToDate review on “Chronic urticaria: Standard management and patient education” (Khan, 2018) does not mention canakinumab as a therapeutic option.

Diabetes

Ridker et al (2012) conducted a double-blind, multi-national phase IIb trial of 556 men and women with well-controlled diabetes mellitus and high cardiovascular risk who were randomly allocated to subcutaneous placebo or to subcutaneous canakinumab at doses of 5, 15, 50, or 150 mg monthly and followed over 4 months.  Compared with placebo, canakinumab had modest but non-significant effects on the change in hemoglobin A1c, glucose, and insulin levels.  No effects were seen for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non-high-density lipoprotein cholesterol, although triglyceride levels increased ≈approximately 10 % in the 50-mg (p = 0.02) and 150-mg (p = 0.03) groups.  By contrast, the median reductions in C-reactive protein at 4 months were 36.4 %, 53.0 %, 64.6 %, and 58.7 % for the 5-, 15-, 50-, and 150-mg canakinumab doses, respectively, compared with 4.7 % for placebo (all p values ≤ 0.02).  Similarly, the median reductions in interleukin-6 at 4 months across the canakinumab dose range tested were 23.9 %, 32.5 %, 47.9 %, and 44.5 %, respectively, compared with 2.9 % for placebo (all p ≤ 0.008), and the median reductions in fibrinogen at 4 months were 4.9 %, 11.7 %, 18.5 %, and 14.8 %, respectively, compared with 0.4 % for placebo (all p values ≤ 0.0001).  Effects were observed in women and men.  Clinical adverse events were similar in the canakinumab and placebo groups.  The authors concluded that canakinumab significantly reduced inflammation without major effect on low-density lipoprotein cholesterol or high-density lipoprotein cholesterol.  They stated that these phase II trial data supported the use of canakinumab as a potential therapeutic method to test directly the inflammatory hypothesis of atherosclerosis.

Moran et al (2013) examined if canakinumab or anakinra improved β-cell function in recent-onset type 1 diabetes.  These researchers performed 2 randomized, placebo-controlled trials in 2 groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0.2 nM.  Patients in the canakinumab trial were aged 6 to 45 years and those in the anakinra trial were aged 18 to 35 years.  Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe.  Participants were randomly assigned by computer-generated blocked randomization to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months.  Participants and care-givers were masked to treatment assignment.  The primary end-point was baseline-adjusted 2-hr area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial).  Analyses were by intention to treat.  Patients were enrolled in the canakinumab trial between November 12, 2010, and April 11, 2011, and in the anakinra trial between January 26, 2009, and May 25, 2011.  A total of 69 patients were randomly assigned to canakinumab (n = 47) or placebo (n = 22) monthly for 12 months and 69 were randomly assigned to anakinra (n = 35) or placebo (n = 34) daily for 9 months.  No interim analyses were done.  A total of 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses.  The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0.01 nmol/L (95 % confidence interval [CI]: -0.11 to 0.14; p = 0.86), and between the anakinra and the placebo groups at 9 months was 0.02 nmol/L (-0.09 to 0.15; p = 0.71).  The number and severity of adverse events did not differ between groups in the canakinumab trial.  In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p = 0.018), which was mainly because of a higher number of injection site reactions in the anakinra group.  The authors concluded that canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes.

Everett and colleagues (2018) tested the hypothesis that the IL-1β inhibitor canakinumab reduces incident diabetes.  These researchers randomized 10,061 patients with prior MI and high-sensitivity CRP (hsCRP) of greater than or equal to 2 mg/L to placebo or canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months.  They tested the effects of canakinumab on major CV events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry.  These researchers also evaluated the effect of canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA1c) in patients with and without established diabetes.  Of the participants, 4,057 (40.3 %) had baseline diabetes, 4,960 (49.3 %) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels.  Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003).  Canakinumab 150 mg as compared with placebo had similar magnitude effects on major CV event rates among those with diabetes (hazard ratio [HR]: 0.85; 95 % C]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95 % CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95 % CI: 0.49 to 1.35).  Despite large reductions in hsCRP and IL-6, canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84).  The HR comparing all canakinumab doses to placebo was 1.02 (95 % CI: 0.87 to 1.19; p = 0.82).  Canakinumab reduced HbA1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed.  The authors concluded that although IL-1β inhibition with canakinumab had similar effects on major CV events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes.

Hidradenitis Suppurativa

Tekin and co-workers (2017) reported on the case of a 27-year old nonsmoker, obese male who presented with a 5-year history of hidradenitis suppurativa resistant to multiple therapies including systemic (tetracycline and clindamycin for 5 months) and topical antibiotics and oral isotretinoin.  Medical history was insignificant except for hepato-steatosis and persistent elevation of transaminases contraindicating acitretin use.  Dermatological examination revealed inflammatory papulo-pustules and nodules, sinus tracts with malodorous discharge, and hypertrophic scars in the axillary and inguinal regions.  In addition, his scalp was covered with crusts roofing lakes of pus, leading to malodor.  He was diagnosed with hidradenitis suppurativa (Hurley stage III) and dissecting cellulitis of the scalp.  He did not have acne conglobata or pilonidal sinus and swab cultures from discharging lesions were negative.  Combination treatment with dapsone (150 mg/day) and intravenous infliximab (5 mg/kg per infusion) was initiated.  However, only slight improvement was observed after 8 infusions.  Based on previous reports of efficacy of IL-1 blockade, off-label treatment with subcutaneous canakinumab (150 mg, every 4 weeks) was started following an informed consent while continuing dapsone.  Subsequently, 3 canakinumab injections were administered, resulting in objective (measured by Sartorius score) and subjective worsening of the lesions.  The authors stated that considering its limitations, this report merely suggested that IL-1 blockade was not effective in every patient with hidradenitis suppurativa and should not be misinterpreted as an unjustifiable challenge to the overall effectiveness of this treatment approach documented in the literature.  These researchers stated that clinical studies that aim to identify which patients are most likely to benefit from blockade of TNF-α, IL-1, IL-17, or other potentially culprit pathways would be highly desirable.

IgG4-Related Sclerosing Disease

An UpToDate review on “Overview of IgG4-related disease” (Moutsopoulos et al, 2018) does not mention canakinumab as a therapeutic option.

Osteomyelitis

Moussa and associates (2016) reported the clinical manifestations, genetic testing results, magnetic resonance imaging (MRI) findings and biologics used in the management of non-bacterial osteomyelitis in their center.  These researchers conducted a retrospective review of medical records.  A previously proposed classification was implemented as follows: chronic recurrent multifocal osteomyelitis (CRMO), chronic non-bacterial osteomyelitis (CNBO) and acute non-bacterial osteomyelitis.  A total of 4 females and 3 males with a median age at presentation of 6 years (6 months to 14 years) presented with arthralgia (7/7), back pain (4/7), arthritis (4/7) and bone pain (2/7); 6 patients had CRMO and 1 patient had CNBO.  Genetic testing revealed an apparent homozygote p.S734L LPIN2 mutation in 2 siblings, a heterozygote p.M694V MEFV mutation in 1 patient with familial Mediterranean fever and heterozygote p.Q219H PSTPIPI variant of unknown significance in 1 patient.  The most common lesions on MRI involved the tibia (6/7), talar bones (5/7), fibula (4/7) and sacroiliac joints (4/7); 3 patients received infliximab; 2 were in remission after 2 and 5 years, and the 3rd was advanced after 5 years to canakinumab; 2 other patients received canakinumab first; 1 patient with Majeed syndrome and dys-erythropoietic anemia exhibited evidence of improvement, and 1 had partial improvement and was then treated with infliximab.  The authors concluded that non-bacterial osteomyelitis may co-exist with other auto-inflammatory diseases; MRI remains a favorable diagnostic tool and genetic testing may have a limited role in selected cases.  They stated that infliximab and canakinumab are associated with variable outcomes, and 6-week or less dosing intervals for both medications may be more effective.  The effectiveness of canakinumab in the treatment of osteomyelitis needs to be further investigated.

Pyoderma Gangrenosum

Partridge and colleagues (2018) noted that pyoderma gangrenosum (PG) is a neutrophilic dermatosis with substantial morbidity.  There is no consensus on gold-standard treatments.  These investigators reviewed the effectiveness of systemic therapy for PG.  They searched six databases for 24 systemic therapies for PG.  Primary outcomes were complete healing and clinical improvement; secondary outcomes were time to healing and adverse effects.  These researchers found 3,326 citations and 375 articles underwent full-text review; 41 studies met the inclusion criteria.  There were 704 participants in 26 retrospective cohort studies, 3 prospective cohort studies, 7 case series, 1 case-control study, 2 open-label trials and 2 randomized controlled trials (RCTs).  Systemic corticosteroids were the most studied (32 studies), followed by cyclosporine (21 studies), biologics (16 studies) and oral dapsone (11 studies).  One RCT (STOP-GAP, n = 121) showed that prednisolone and cyclosporine were similar: 15 to 20 % of patients showed complete healing at 6 weeks and 47 % at 6 months.  Another RCT (n = 30) found that infliximab was superior to placebo at 2 weeks (46 % versus 6 % response), with a 21 % complete healing rate at 6 weeks; 2 uncontrolled trials showed 60 % and 37 % healing within 4 months for canakinumab and infliximab, respectively; other data suggested that patients with concurrent inflammatory bowel disease may benefit from biologics.  The remaining studies were poor quality and had small sample sizes but supported the use of corticosteroids, cyclosporine and biologics.  The authors concluded that systemic corticosteroids, cyclosporine, infliximab and canakinumab had the most evidence in treating PG.  Moreover, they stated that current literature is limited to small and lower-quality studies with substantial heterogeneity.

Schnitzler Syndrome

Schnitzler's syndrome is an adult-onset autoinflammatory disease characterized by urticarial exanthema and monoclonal gammopathy accompanied by systemic symptoms such as fever, bone and muscle pain.

Krause et al (2017) assessed the effects of canakinumab on the clinical signs and symptoms of Schnitzler's syndrome. In this phase II, randomized placebo-controlled multi-center study, 20 patients with active disease enrolled in four German study centers. Patients were randomly assigned to receive single subcutaneous canakinumab 150 mg or placebo injections for 7 days, followed by a 16-week open-label phase with canakinumab injections upon confirmed relapse of symptoms. The primary endpoint was the proportion of patients with complete clinical response evaluated by physician global assessment at day 7. Key secondary endpoints included changes in patient-reported disease activity (Schnitzler activity score), inflammation markers (C-reactive protein [CRP], serum amyloid A [SAA]) and quality of life assessments (DLQI, SF-36). The proportion of patients with complete clinical response at day 7 was significantly higher (P = 0.001) in the canakinumab-treated group (n = 5/7) than the placebo group (n = 0/13). Levels of inflammation markers CRP and SAA and quality of life scores significantly reduced in canakinumab-treated but not in placebo-treated individuals. Positive effects continued up to 16 weeks. Adverse events were manageable and included respiratory tract infections, gastrointestinal symptoms and hypertension. The investigators concluded that canakinumab was effective in patients with Schnitzler's syndrome, and thus canakinumab may be further evaluated as a therapeutic option for this rare disease.

Vanderschueren and Knockaert (2013) tested canakinumab in patients with Schnitzler syndrome.  A patient with Schnitzler syndrome was treated with canakinumab, 150 mg subcutaneously injection every 8 weeks for 6 consecutive months.  Injections were resumed in case of a flare following discontinuation.  Canakinumab induced a swift and sustained clinical response, with disappearance of fever and arthralgias, near abolishment of fatigue and rash, and substantial reduction of CRP levels.  Interruption of canakinumab after four 8-weekly injections led to a flare 10 weeks after the last administration, which was countered as soon as canakinumab injections were resumed.  The patient remained in complete remission.  Canakinumab was well-tolerated.  No injection site reactions, other adverse events, or laboratory abnormalities were observed.  The authors concluded that canakinumab has potential for the treatment of Schnitzler syndrome.

Still's Disease (AOSD)

Giampietro and Fautrel (2012) stated that  IL-1β is emerging as a master mediator of adult-onset Still's disease (AOSD) pathogenesis.  This pleiotropic cytokine has a wide type of effects.  As a key mediator of innate immunity, it is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues, which are key AOSD manifestations.  The study of pro-inflammatory cytokines profiles in sera and pathological tissues of AOSD patients has shown elevated levels of IL-1β, these levels being highly correlated with disease activity and severity.  These experimental evidences as well as the analogy with other auto-inflammatory diseases that share with AOSD clinical and biological characteristics have suggested the blockade of IL-1β as a possible new therapeutic option for the AOSD, especially in conventional therapy resistant cases.  Anakinra, the first anti-IL-1 agent put on the market, has demonstrated capable to induce a rapid response sustained over time, especially in systemic forms, where anti-TNFα failed to control symptoms.  While a growing number of evidences supports the utilization of anakinra in AOSD, a new generation of anti-IL1β antagonists is developing.  Canakinumab and rilonacept could improve the management of this disease.

Kontzias and Efthimiou (2012) described the successful treatment of AOSD with canakinumab on patients refractory to anakinra and rilonacept.  In many cases the expected positive therapeutic effect of short-acting IL-1 inhibitors is transient or completely absent, leading to the hypothesis that their short half-life may be associated with incomplete IL-1 blockade, given the cyclic nature of the disease.  These investigators reported 2 cases of AOSD resistant to short-acting IL-1 blockade, which were subsequently treated with canakinumab.  A retrospective chart review was conducted of patients diagnosed with AOSD in the authors' regional referral center.  Response to treatment was assessed by its effect on the systemic symptoms (resolution of fever and rash), polyarthritis (using the disease activity score 28 -- CRP score), and the levels of serum ferritin.  Canakinumab demonstrated sustained efficacy in both patients as evidenced by clinical and laboratory parameters with minimal adverse reactions.  The authors concluded that this is the first documented report of successful use of canakinumab in AOSD patients refractory to traditional disease-modifying anti-rheumatic drugs and short- to moderate-acting IL-1 blockade. Moreover, they stated that prospective comparative studies are needed to validate canakinumab's safety and effectiveness in the treatment of AOSD.

Yao Syndrome

Yao and Shen (2017) noted that Yao syndrome, formerly named NOD2-associated auto-inflammatory disease, is a periodic disease characterized by fever, dermatitis, polyarthritis/leg swelling, and gastro-intestinal (GI) and sicca-like symptoms associated with specific NOD2 sequence variants.  These researchers evaluated the treatment and outcomes of the disease.  A total of 52 adult patients with auto-inflammatory disease phenotype were diagnosed with Yao syndrome and enrolled at the Cleveland Clinic between November 2009 and May 2015.  All patients were genotyped for the NOD2 variants, and systematically studied for treatment outcomes.  Among the 52 Yao syndrome patients, all were white, and 72 % were women.  The mean age at diagnosis was 38.0 ± 12.0 years, and the disease duration was 8.8 ± 5.8 years.  In the multi-organ disease, more common and typical manifestations were recurrent dermatitis and inflammatory arthritis with or without distal leg swelling besides recurrent fever.  It was genotypically associated with the NOD2 IVS8+158 or R702W.  Therapeutically, glucocorticoids markedly decreased the disease severity and duration of flares in 19 patients (36.6 %), sulfasalazine treatment achieved a significant symptomatic improvement in 22 (42 %) patients, and 3 patients received canakinumab or tocilizumab with benefits.  Prognostically, 13 % of the 52 patients had somewhat physical impairment, and there was no mortality during the follow-up.  Associated co-morbidities were fibromyalgia, asthma, renal stones, and ventricular hypertrophy.  The authors concluded that as a systemic disease, Yao syndrome uncommonly affects the solid internal organs, but it can be complicated with chronic pain syndrome and even disability.  Glucocorticoids or sulfasalazine may be considered as the 1st-line therapeutic option, and IL-1/IL-6 inhibitors may be tried for refractory cases.  The clinical value of canakinumab in the treatment of Yao syndrome needs to be further investigated.

Appendix

Table: Brands of Targeted Immune Modulators and FDA-approved Indications:

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Cytokine release syndrome (CRS)
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Entyvio	vedolizumab	Crohn's disease Ulcerative colitis
Humira	adalimumab	Ankylosing spondylitis Crohn's disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Uveitis
Ilaris	canakinumab	Periodic fever syndromes Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Inflectra	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Kevzara	sarilumab	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behçet’s Disease Plaque psoriasis Psoriatic arthritis
Remicade	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Rheumatoid arthritis
Rituxan	rituximab	Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Plaque psoriasis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis
Taltz	ixekinumab	Ankylosing spondylitis Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Rheumatoid arthritis Psoriatic arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J0638	Injection, canakinumab, 1 mg
HCPCS codes not covered for indications listed in the CPB:
J0135	Injection, adalimumab, 20 mg
J0717	Injection, certolizumab pegol, 1 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self administered)
J1438	Injection, etanercept, 25 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self administered)
J1602	Injection, golimumab, 1 mg, for intravenous use
J1745	Injection, infliximab, excludes biosimilar, 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
Other HCPCS codes related to the CPB:
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1 mg
J1130	Injection, diclofenac sodium, 0.5 mg
J1700	Injection, dexamethasone sodium phosphate, 1 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J2650	Injection, prednisolone acetate, up to 1 ml
J2793	Injection, rilonacept, 1 mg
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J3245	Injection, tildrakizumab, 1 mg
J3262	Injection, tocilizumab, 1 mg
J3300	Injection, triamcinolone acetonide, preservative free, 1 mg
J3301	Injection, triamcinolone acetonide, not otherwise specified, 10 mg
J3302	Injection, triamcinolone diacetate, per 5 mg
J3303	Injection, triamcinolone hexacetonide, per 5 mg
J7312	Injection, dexamethasone, intravitreal implant, 0.1 mg
J7509	Methylprednisolone, oral, per 4 mg
J7510	Prednisolone, oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J8540	Dexamethasone, oral, 0.25 mg
J8610	Methotrexate; oral, 2.5 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
Q5103	Injection, infliximab-dyyb, biosimilar, (inflectra), 10 mg
Q5104	Injection, infliximab-abda, biosimilar, (renflexis), 10 mg
ICD-10 codes covered if selection criteria are met :
E85.0	Non-neuropathic heredofamilial amyloidosis [Muckle-Wells syndrome (MWS)]
L50.2	Urticaria due to cold and heat [familial cold autoinflammatory syndrome (FCAS)]
M04.1	Periodic fever syndromes
M04.2	Cryopyrin-associated periodic syndromes [not covered for chronic infantile neurologic cutaneous, articular (CINCA) syndrome]
M04.8	Other autoinflammatory syndromes
M08.00 - M08.99	Juvenile arthritis
M1A.00x0 - M10.9	Gout
M11.20 - M11.29	Other chondrocalcinosis [pseudogout flares]
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
C18.0 - C18.9	Malignant neoplasm of colon
C34.00 - C34.929	Malignant neoplasm of bronchus and lung
C50.011 - C50.929	Malignant neoplasm of breast
D47.2	Monoclonal gammopathy [Schnitzler syndrome]
D86.0	Sarcoidosis of lung
E08.00 - E13.9	Diabetes mellitus
E88.89	Other specified metabolic disorders [Mevalonate kinase]
H00.001 - H59.89	Disorders of the eye and adnexa
I20.0	Unstable angina
I50.1 - I50.9	Heart failure
I70.0 - I70.92	Atherosclerosis
I73.00 - I73.9	Other peripheral vascular diseases
J40 - J47	Chronic lower respiratory diseases
L50.8	Other urticaria [chronic spontaneous urticaria]
L73.2	Hidradenitis suppurativa
L88	Pyoderma gangrenosum
L98.8	Other specified disorders of the skin and subcutaneous tissue [inflammatory]
M04.9	Autoinflammatory syndrome, unspecified [Yao syndrome]
M05.00 - M07.69, M11.011 - M11.19, M12.00 - M14.89	Rheumatoid arthritis and other inflammatory arthropathies
M15.0 - M19.93	Osteoarthritis
M35.2	Behcet's disease
M35.3	Polymyalgia rheumatica
M86.00 - M86.9	Osteomyelitis

The above policy is based on the following references: