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Aetna Aetna
Clinical Policy Bulletin:
Kineret (Anakinra)
Number: 0595


Policy

  1. Aetna considers Kineret (anakinra) medically necessary for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis in adults 18 years of age or older (see Note below). 

    Anakinra can be used alone or in combination with disease-modifying anti-rheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) blocking agents.

  2. Aetna considers Kineret (anakinra) medically necessary for neonatal-onset multisystem inflammatory disease (NOMID).

  3. Aetna considers Kineret (anakinra) medically necessary for members with adult-onset Still's disease when they have failed glucocorticoids, methotrexate and a TNF-alpha inhibitor,

  4. Aetna considers Kineret (anakinra) medically necessary for (i) members with systemic onset juvenile idiopathic arthritis with active systemic features and varying degrees of synovitis and who have failed to respond to systemic glucocorticoid monotherapy or non-steroidal anti-inflammatory drug (NSAID) monotherapy, and (ii) members with systemic onset juvenile idiopathic arthritis without active systemic features and with varying degrees of active synovitis, and who have failed intra-articular injection or NSAID monotherapy (for individuals with an active joint count (AJC) greater than 4) or have failed  methotrexate or leflunomide (for individuals with an AJC greater than 0).

  5. Note: This note applies to the use of anakinra for rheumatoid arthritis. There are several brands of targeted immune modulators on the market.  There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab), Simponi (golimumab), Simponi Aria (golimumab intravenous) and Stelara (ustekinumab) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna.  Consequently, because other brands (e.g., Actemra (tocilizumab), Cimzia (certolizumab), Kineret (anakinra), Otezla (apremilast), Orencia (abatacept), Rituxan (rituximab), and Xeljanz (tofacitinib)) of injectables are more costly than these least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, no other brands of targeted immune modulator will be considered medically necessary unless the member has a contraindication, intolerance or incomplete response to at least 2 of the least cost brands of targeted immune modulator: Enbrel, Humira, Remicade, Simponi, Simponi Aria, or Stelara, for the same medically necessary indication. If the least costly targeted immune modulator does not have the labeled indication (see appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication.

  6. Aetna considers anakinra experimental and investigational for persons with active infections because its safety in active infections has not been established.

  7. Aetna considers anakinra experimental and investigational for use in combination with TNF blocking agents (e.g., Enbrel (etanercept) or Remicade (infliximab)) because the safety and effectiveness of such combination therapy has not been established.

  8. Aetna considers anakinra experimental and investigational for all other indications, including any of the following diseases/disorders, because the safety and effectiveness of anakinra for these indications has not been established.

  • Ankylosing spondylitis
  • Anterior cruciate ligament injury
  • Diabetes mellitus (type 1 and type 2)
  • Fatigue associated with Sjogren's syndrome
  • Gout
  • Heart failure (prevention of heart failure after acute myocardial infarction)
  • Inflammatory bowel disease arthritis
  • Lupus arthritis
  • Myopathy/myositis
  • Osteoarthritis
  • Pyoderma gangraenosum
  • Reactive arthritis
  • Systemic lupus erythematosus.

See also CPB 0314 - Rituximab (Rituxan)CPB 0315 - Enbrel (Etanercept)CPB 0341 - Remicade (infliximab)CPB 0655 - Adalimumab (Humira)CPB 0720 - Abatacept (Orencia), and CPB 0810 - Gout.



Background

The U.S. Food and Drug Administration (FDA) approved Amgen Inc.’s Kineret (anakinra) for the treatment of moderately to severely active rheumatoid arthritis (RA) in adult patients who have failed 1 or more disease-modifying anti-rheumatic drugs (DMARDs).

Anakinra is indicated for use as monotherapy or in combination with other drugs except tumor necrosis factor (TNF)-blocking agents such as Enbrel (etanercept) or Remicade (infliximab).

Anakinra inhibits inflammation and pain by selectively blocking the protein interleukin-1, which is in excess in RA patients.  Interleukin-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses.  Interleukin-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption.  Anakinra blocks the biologic activity of interleukin-1 by competitively inhibiting interleukin-1 binding to the interleukin-1 type I receptor, which is expressed in a wide variety of tissues and organs.

The effectiveness of anakinra was evaluated in 3 randomized placebo-controlled clinical trials involving 1,392 adults (greater than or equal to18 years of age) with moderate to severe RA.  Patients assigned to anakinra had significant reductions in signs and symptoms of the disease compared to patients assigned to placebo. After 6 months of treatment, 38 % of anakinra-treated patients and 22 % of placebo-treated patients showed at least a 20 % improvement in the symptoms of disease, as assessed by the American College of Rheumatology response criteria.  The criteria include the number of swollen and tender joints, pain and a physician assessment of overall disease.

In clinical trials, anakinra was associated with a significantly greater incidence of serious infections (greater than 2 %) versus placebo (less than 1 %).  Therefore, the literature states anakinra should not be used in patients with active infections, and should be discontinued if the patient develops a serious infection.

The recommended dose of anakinra for the treatment of patients with RA is 100 mg/day administered daily by subcutaneous injection.  Higher doses did not result in a higher response.

A systematic review of the evidence for targeted immune modulators by the Drug Evaluation Review Project (Thaler, et al., 2012) found a lack of reliable evidence to determine the comparative effectiveness of anakinra to other targeted immue modulators for rheumatoid arthritis. The review stated that indirect comparisons of placebo-controlled randomized controlled trials suggest that etanercept is statistically significantly more efficacious than anakinra, infliximab, tocilizumab and adalimumab for rheumatoid arthritis. No statistically significant differences in efficacy could be detected among adalimumab, anakinra, infliximab, and tocilizumab for rheumatoid arthritis.

Anakinra should not be used with other TNF blockers (e.g., etanercept, infliximab).  Preliminary data has shown a higher rate of serious infection (7 %) and severe neutropenia (neutrophil count less than or equal to 1,000/mm3) (3 %) when anakinra was used with etanercept than when anakinra was used alone.

Patients receiving anakinra may experience a decrease in neutrophil counts.  In placebo-controlled studies, 8 % of patients receiving anakinra had decreases in neutrophil counts of at least 1 WHO toxicity grade compared with 2 % in the placebo control group.  Six anakinra-treated patients (0.3 %) experienced neutropenia (neutrophil count less than or equal to 1 x 106/mm3).  Therefore, the FDA-approved product labeling for anakinra recommends that neutrophil counts should be assessed prior to initiating anakinra treatment, and while receiving anakinra monthly for 3 months, and thereafter quarterly for a period up to 1 year.

In a randomized controlled study, Genovese et al (2004) studied the potential for additive or synergistic effects of combination therapy with etanercept and anakinra in 244 patients in whom RA was active despite methotrexate therapy.  Patients were treated with subcutaneous etanercept only (25 mg twice-weekly), full-dosage etanercept (25 mg twice-weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once-weekly) plus anakinra (100 mg/day) for 6 months.  Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk.  The authors concluded that combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.

There is some evidence from uncontrolled studies that juvenile RA may respond to anakinra (Lovell, 2004); controlled clinical studies are ongoing.

The U.S. Pharmacopoeial Convention (2003) concluded that "[t]here is insufficient data to establish the safety and efficacy of anakinra for the treatment of reactive arthritis, inflammatory bowel disease and ankylosing spondylitis."

Anakinra is being investigated in the treatment of severe refractory lupus arthritis.  Current available evidence is limited to case reports and small case series (Ostendorf et al, 2005; Moosig et al, 2004).

In a prospective, multi-center study, Chevalier et al (2005) examined the safety of intra-articular (IA) injections of anakinra in patients with knee osteoarthritis (OA).  Six doses of anakinra (0.05 to 150 mg) were considered, and the trial was double-blinded regarding the dose administered.  Patients with symptomatic knee OA and without synovial fluid effusion were included.  Acute inflammatory reaction (the primary endpoint defining intolerance) was recorded if pain increase over 30 mm on 100 mm visual analog scale and synovial fluid effusion occurred within 72 hours after the IA injection.  As a secondary aim, effectiveness was estimated (by total pain and Western Ontario and McMaster University OA functional index [WOMAC]) until the 3rd month.  One patient received 0.05 mg and 13 patients received 150 mg of anakinra.  No acute reaction occurred (1 patient experienced post-injection joint swelling with no pain) and the 150-mg dose was considered the maximum tolerated dose (intolerance level 0 %; confidence interval [CI]: 0 to 9.1 %).  A significant improvement was still observed until the 3rd month in the 13 patients who received 150 mg anakinra: pain improved by -20.4 +/- 23.3 mm (p = 0.008) and WOMAC global score by -19.5 +/- 20.1 (p = 0.005).  The authors concluded that IA injection of anakinra in patients with knee OA was well-tolerated and did not induce any acute inflammatory reaction.  The feasibility of such IA injections of anakinra opens a promising therapeutic perspective for patients with OA.

In a multi-center, double-blind, placebo-controlled study, Chevalier and colleagues (2009) evaluated the clinical response, safety, and tolerability of a single IA injection of anakinra in patients with symptomatic OA of the knee.  Patients with OA of the knee were randomized 2:1:2 to receive a single IA injection of placebo, 50-mg anakinra, or 150-mg anakinra in their symptomatic knee.  Patients were evaluated for 12 weeks post-injection.  The primary end point was the change in the WOMAC score from baseline to week 4.  Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs.  Pharmacokinetic parameters were assessed in a subset of patients.  Of 170 patients who enrolled, 160 (94 %) completed the study.  The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50-mg anakinra (p = 0.67) or 150-mg anakinra (p = 0.77).  Anakinra was well-tolerated.  No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported.  No clinically significant trends were noted in laboratory values or vital signs.  Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after IA injection was approximately 4 hours.  The authors concluded that anakinra was well-tolerated as a single 50-mg or 150-mg IA injection in patients with OA of the knee.  However, anakinra was not associated with improvements in OA symptoms compared with placebo.

In a double-blind, parallel-group, clinical study, Larsen and colleagues (2007) examined the effects of anakinra in patients with type 2 diabetes mellitus.  A total of 70 patients were randomly assigned into 2 groups: (i) 34 received 100 mg of subcutaneous anakinra once-daily for 13 weeks, and (ii) 36 received placebo.  At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine.  In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study.  The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers.  At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (p = 0.03); C-peptide secretion was enhanced (p = 0.05), and there were reductions in the ratio of pro-insulin to insulin (p = 0.005) and in levels of interleukin-6 (p < 0.001) and C-reactive protein (p = 0.002).  Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the 2 groups.  Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events.  The authors concluded that the findings of this study suggested that antagonism of interleukin-1 with anakinra has possible therapeutic potential in the treatment of type 2 diabetes mellitus.  They noted that further studies are needed to test higher doses of anakinra, to evaluate its long-term use, and to test interleukin-1 antagonists that have a prolonged half-life, with the aim of preventing beta-cell destruction and promoting beta-cell regeneration in type 2 diabetes.  The author of an accompanying editorial (Rothman, 2007) cautioned that although anakinra treatment led to a modest improvement in the control of glycemia, the maximal effect was at 4 weeks but with an upward trend in the glycated hemoglobin level at 13 weeks.  The editorialist also noted that, since the patients varied with respect to baseline blood glucose control and type of concomitant treatment, it is difficult to deduce the effectiveness of anakinra therapy in various stages of disease.

In a review on systemic lupus erythematosus, D'Cruz and colleagues (2007) noted that there is a range of new therapeutic approaches including biological agents (e.g., anakinra) that are being examined in animal studies or clinical trials.

Lequerre et al (2008) evaluated the safety and effectiveness of anakinra treatment in systemic-onset juvenile idiopathic arthritis (JIA).  Of the 20 patients, only 5 achieved American College of Rheumatology 50 % improvement in symptoms response criteria at 6 months.  Steroid dose had been decreased by 15 % to 78 % in 10 cases.

Gartlehner and colleagues (2008) stated that biologics are an important therapeutic option for treating patients with JIA.  In adults, they are associated with rare but severe adverse events such as serious infections and malignancies.  These researchers reviewed systematically the evidence on the safety and effectiveness of biologics for the treatment of JIA.  They limited evidence to prospective studies for effectiveness, but included retrospective observational evidence for safety.  Outcomes measures included clinical response, radiographical progression, quality of life, and adverse events.  One randomized controlled trial (RCT) and 11 uncontrolled prospective studies provided data on effectiveness; 3 additional studies assessed safety.  The only RCT and 6 uncontrolled trials support the general effectiveness of etanercept for the treatment of JIA.  Internal and external validity of these studies are limited.  The evidence on other biologic agents such as adalimumab, abatacept, anakinra, infliximab, rituximab, and tocilizumab is sparse or entirely missing.  Because of the lack of sound long-term safety data, evidence is insufficient to draw firm conclusions about the balance of risks and benefits of any biologic agent for the treatment of JIA.  Clinicians have to be aware of the lack of evidence supporting a long-term net benefit when considering biologics for patients with JIA.

Nigrovic and colleagues (2011) examined the safety and effectiveness of anakinra as first-line therapy for systemic JIA.  Patients with systemic JIA receiving anakinra as part of initial DMARD therapy were identified from 11 centers in 4 countries.  Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome.  Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22 %), while 67 % received corticosteroids and 33 % received additional DMARDs.  Outcomes were evaluated at a median follow-up interval of 14.5 months.  Fever and rash resolved within 1 month in greater than 95 % of patients, while C-reactive protein and ferritin normalized within this interval in greater than 80 % of patients.  Active arthritis persisted at 1 month in 39 % of patients, at 3 months in 27 %, and at greater than 6 months of follow-up in 11 %.  Approximately 60 % of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy.  Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age of 5.2 years versus 10.2 years; p = 0.004).  Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient.  Tachyphylaxis was not observed.  The authors concluded that anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90 % of patients during the interval examined.  These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.

Boerschmann et al (2010) reviewed 4 recent immuno-intervention trials in patients with type 1 diabetes mellitus (T1DM); (i) the Pre-POINT study is a primary prevention trial that will test whether vaccination with oral or nasal insulin can prevent the progression of islet autoimmunity and of T1DM in autoantibody-negative children who are genetically at high diabetes risk; (ii) the Cord Blood study is a tertiary trial that will investigate whether administration of autologous umbilical cord blood to children with T1DM can lead to regeneration of pancreatic islet insulin-producing beta-cells and improved blood glucose control; (iii) the GAD Vaccination study will test whether vaccination with alum-formulated rhGAD65 (recombinant human glutamic acid decarboxylate) can preserve beta-cell function in 320 children with newly diagnosed T1DM; and (iv) the AIDA study will test the beta-cell protective effect of interleukin-1 (IL-1) receptor antagonist anakinra in 80 patients with T1DM.

Moran and colleagues (2013) examined if canakinumab or anakinra improved β-cell function in recent-onset T1DM.  These researchers performed 2 randomized, placebo-controlled trials in 2 groups of patients with recent-onset T1DM 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 U.S. 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 carers 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 Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 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; 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 % 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 T1DM.

In a pilot study, Abbate et al (2010) tested the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after acute myocardial infarction (AMI).  A total of 10 patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion.  Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period.  The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging.  The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels.  A +2.0 ml/m(2) median increase (inter-quartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/m(2) median decrease (inter-quartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033).  The median difference was 5.2 ml/m(2).  On echocardiography, the median difference in the LVESVi change was 13.4 ml/m(2) (p = 0.006).  Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m(2), p = 0.033) and echocardiography (9.4 ml/m(2), p = 0.008).  The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022).  The authors concluded that in patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling.  They stated that if confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.

Wollina and Haroske (2011) discussed clinical observations as well as therapeutic interventions of pyoderma gangraenosum.  Pyoderma gangraenosum is one of the most common extra-intestinal manifestations of chronic inflammatory bowel disease.  In multi-variate analyses, pyoderma gangraenosum was significantly and independently associated with black African origin, familial history of ulcerative colitis, uninterrupted pancolitis as the initial location of inflammatory bowel disease, permanent stoma, eye involvement and erythema nodosum.  The treatment of choice for idiopathic pyoderma gangraenosum is systemic corticosteroids, but cyclosporine A, mycophenolate mofetil and TNF-alpha inhibitors have been successful to control pyoderma gangraenosum as second line or adjuvant options.  In addition, small studies have been published with successful therapeutic intervention using alefacept, visilizumab, or anakinra but controlled trials are warranted.

In a randomized controlled pilot study, Kraus et al (2012) evaluated the clinical effectiveness of intra-articular IL-1 receptor antagonist (IL-1Ra) for anterior cruciate ligament (ACL) tear.  A total of 11 patients with acute ACL tear confirmed by magnetic resonance imaging (MRI) were randomized to receive a single intra-articular injection of IL-1Ra (anakinra 150 mg, n = 6) or equal volume of saline placebo (1 ml, n = 5).  The double-blinded treatment was administered a mean 2 weeks after injury.  Synovial fluid (SF) (n = 9 patients) and sera (all patients) were available at baseline (prior to injection) and immediately prior to surgery (mean 35 days later) and analyzed for SF IL-1α, IL-1β, IL-1Ra and serum hyaluronan (HA), an indicator of synovial inflammation.  The primary outcome, standardized Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, was obtained at 0 (baseline), 4, and 14 days after injection.  Compared with placebo, the IL-1Ra group had substantially greater improvement in key outcomes over 14 days (KOOS pain, p = 0.001; activities of daily living, p = 0.0015; KOOS sports function, p = 0.0026; KOOS quality of life (QOL), p = 0.0048; and total KOOS, p < 0.0001).  There were no adverse reactions in either group.  SF IL-1α (p = 0.05) and serum HA (p = 0.03), but not IL-1β, or IL-1Ra, decreased significantly in the IL-1Ra but not the placebo-treated patients.  Compared with placebo, IL-1α was borderline significantly different in the IL-1Ra-treated group (p = 0.06).  The authors concluded that administered within the first month following severe knee injury, IL-1Ra reduced knee pain and improved function over a 2-week interval.  They stated that this promising proof of concept study provides a new paradigm for studies of acute joint injury and suggests that a larger follow-up study is warranted.

Fatigue is a major cause of disability in primary Sjogren's syndrome (pSS).  Fatigue has similarities with sickness behavior in animals; the latter mediated by pro-inflammatory cytokines, in particular IL-1, acting on neuronal brain cells.  Norheim et al (2012) hypothesised that IL-1 inhibition might improve fatigue in pSS patients.  These investigators examined the effects and safety of anakinra on fatigue.  A total of 26 pSS patients participated in a double-blind, placebo-controlled parallel group study.  Patients were randomized to receive either anakinra or a placebo for 4 weeks.  Fatigue was evaluated by a fatigue visual analog scale (VAS) and the Fatigue Severity Scale.  The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values.  Secondary outcome measures included evaluation of laboratory results and safety.  The proportion of patients in each group who experienced a 50 % reduction in fatigue was regarded as a post-hoc outcome.  All outcomes were measured at week 4.  There was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra.  However, 6 out of 12 patients on anakinra versus 1 out of 13 patients on the placebo reported a 50 % reduction in fatigue VAS (p = 0.03).  There were 2 serious adverse events in each group.  The authors concluded that this randomized, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint.  A 50 % reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint.  Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS.

Zong and colleagues (2013) performed a mechanistic study on the effect of anakinra in patients with refractory myositis and explored possible predictive biomarkers.  A total of 15 patients with refractory myositis were treated with anakinra for 12 months.  Clinical response was assessed by the 6-item core set measures of disease activity International Myositis Assessment and Clinical Studies (IMACS) and functional index (FI).  Repeated muscle biopsies were investigated for cellular infiltrates, IL-1α, IL-1β, IL-1Ra and major histocompatibility complex-class I by immunohistochemistry.  Serum levels of IL-1Ra and granulocyte colony-stimulating factor (G-CSF) were measured by ELISA.  T-cell phenotype and functional assays were investigated by multi-color flow cytometry.  Seven patients had clinical response according to IMACS, 4 of them also showed improved FI.  Responders had higher baseline extra-muscular score compared with non-responders.  In muscle biopsies, baseline CD163 macrophages and IL-1α expression were inversely correlated with muscle performance after 6 months treatment; all responders had IL-1Ra expression in the post-treatment biopsies but only 3/8 non-responders.  In serum, IL-1Ra levels were increased and G-CSF was decreased after 6 months treatment, but their levels and changes were not related to clinical response.  For T cells, an inverse correlation between baseline frequency of CD4 activated/memory T cells and decreased creatine kinase levels was observed.  Five of 6 patients demonstrated less IL-17A and more IFN-γ secreting CD4 T cells after 6 months treatment.  Moreover, anakinra reduced IL-17A secretion in-vitro.  The authors concluded that patients with myositis may respond to anakinra.  Extra-muscular score, muscle CD163 macrophages and IL-1α expression, blood CD4 activated/memory T cells might associate with anakinra treatment response.  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Treatment of recurrent and resistant dermatomyositis and polymyositis in adults” (Miller and Rudnicki, 2013) does not mention anakinra as a therapeutic option.

Nordstrom et al (2012) examined the effectiveness of anakinra versus (DMARD in refractory adult-onset Still's disease (AOSD).  In a 24-week study, 22 patients with AOSD taking prednisolone greater than or equal to 10 mg/day received anakinra (n = 12) or DMARD (n = 10).  The primary end-point was achievement of remission.  At 8 and 24 weeks, 7/12 and 6/12 receiving anakinra and 5/10 and 2/10 receiving DMARD achieved remission.  Anakinra induced greater improvement in physical health measured by Medical Outcomes Study Short-Form 36 (SF-36; p < 0.011).  During an open-label extension (OLE) of 28 weeks, 7/14 patients taking anakinra and 2/3 taking DMARD were in remission.  The authors concluded that anakinra induced more beneficial responses than DMARD in patients with AOSD and was favored in the OLE phase.

Giampietro et al (2013) stated that anakinra is effective in AOSD in the short-term, but little is known regarding its effectiveness over the long-term.  These researchers assessed the long-term safety and effectiveness of anakinra in AOSD.  A nationwide survey was conducted between 2009 and 2010 to identify AOSD patients treated with anakinra.  Collected data consisted of disease characteristics at diagnosis and at medication onset; anakinra efficacy, safety, and dose adaptation; and reasons for discontinuation, if applicable.  The study included 28 AOSD patients, with a mean age of 40.3 years, and a mean disease-duration at the start of anakinra of 9.3 years.  All patients had previously failed to respond to steroids and DMARDs.  All patients responded to anakinra, with a rapid and sustained decrease in steroid doses.  At the last follow-up (mean of 23 months), 16 patients were still being treated with anakinra: 4 had a partial response and 12 were in complete remission.  Twelve patients had discontinued anakinra: 2 due to an insufficient response, 4 due to an AOSD flare after a period of complete remission, 2 due to side effects, and 1 due to a desire for pregnancy.  In 3 patients, the drug discontinuation was possible because they achieved complete remission.  Six additional patients experienced anakinra dose tapering, with sustained remission in 2 and relapse in the others.  Anakinra was well-tolerated and adverse events were rated as mild.  The authors concluded that anakinra was consistently effective in AOSD and displayed good therapeutic maintenance.  Anakinra dose-tapering or discontinuation was associated with relapse in 50 % of the patients.

Iliou et al (2013) described the clinical manifestations, laboratory abnormalities and treatment of AOSD in Greek patients.  This was a retrospective observational study.  A total of 44 patients, diagnosed with AOSD, followed since 1985 up to June 2011, were included.  The disease course and treatment were recorded and compared to previously published studies; 21 males and 23 females were identified.  Mean age at diagnosis was 38.3 years.  The most common clinical manifestations were fever (100 %), arthralgias (97.7 %), arthritis (93.2 %), salmon-colored rash (84 %), myalgias (50 %) and sore throat (38.6 %).  Characteristic laboratory abnormalities were leucocytosis with neutrophilia (81.8 %), elevated C-reactive protein (100 %) and erythrocyte sedimentation rate (100 %).  Elevated liver enzymes and hyper-ferritinemia were found in 50 % and in 59 % of the patients, respectively.  Very high ferritin serum levels (greater than 5,000 μg/L) were found in 22.7 %.  Rheumatoid factor and anti-nuclear antibodies were negative in all patients.  Thirty patients (68.2 %) received NSAIDs or aspirin with or without corticosteroids.  Response to corticosteroids was common (58.9 %).  When this treatment was ineffective, a DMARD, usually methotrexate, was added with a response rate of 63.6 %.  Anakinra was used in cases resistant to conventional immunosuppressive treatment.  Ten out of 44 patients (22.7 %) were treated with anakinra and response was achieved in all of them.  The authors concluded that these results regarding clinical manifestations and laboratory abnormalities were similar to those of previous reports.  High ferritin serum levels were reported in all studies of AOSD and are considered as diagnostically valuable.  When treatment with corticosteroids and DMARDS had failed, biologic agents such as anakinra were successfully applied.

An UpToDate review on “Treatment of adult Still's disease” (Mandl, 2014) states that “Resistant to first TNF inhibitor -- We use a second TNF inhibitor (as is often done in RA) or another class of agent (usually anakinra) in patients who do not respond adequately to high-dose glucocorticoids, MTX, and four to eight weeks of treatment with a TNF inhibitor.  There are no comparative trials to indicate an advantage to one of these approaches in patients with ASD, and, in our experience, either of these strategies may be effective.  Tocilizumab is an alternative to anakinra, especially in patients with chronic articular disease that is difficult to control or with evidence of erosive joint changes on plain radiographs or by magnetic resonance imaging, given the evidence of its efficacy in RA.  However, there is less experience with this agent in ASD, and anakinra has a better adverse effect profile”.

The American College of Rheumatology’s update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis (Ringold et al, 2013) provided the following recommendations;

  • For systemic JIA with active systemic features and varying degrees of synovitis: Anakinra was recommended for patients with continued disease activity after treatment with systemic glucocorticoid monotherapy (level A) or NSAID monotherapy (level C).
  • For systemic JIA without active systemic features and with varying degrees of active synovitis: Anakinra was recommended as a therapeutic option for patients with an active joint count (AJC) greater than 4 following failed intra-articular injection or NSAID monotherapy (level B).  Use of anakinra was also recommended for patients with an AJC greater than 0 following treatment with (level B).

Appendix

Brand Name Generic Name FDA Labeled Indications
Actemra Tocilizumab

Juvenile idiopathic arthritis

Rheumatoid arthritis

Systemic juvenile idiopathic arthritis

Cimzia certolizumab

Crohn's disease

Psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Enbrel Etanercept

Ankylosing spondylitis

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthrits

Rheumatoid arthritis

Humira adalimumab

Ankylosing spondylitis

Crohn's disease

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Ulcerative colitis

Kineret anakinra Rheumatoid arthritis
Orencia abatacept

Juvenile idiopathic arthritis

Rheumatoid arthritis

Otezla apremilast Psoriatic arthritis
Remicade infliximab

Ankylosing spondylitis

Crohn's disease

Psoriatic arthritis

Plaque psoriasis

Rheumatoid arthritis

Ulcerative colitis

Rituxan rituximab Rheumatoid arthritis
Simponi golimumab

Ankylosing spondylitis

Psoriatic arthritis

Rheumatoid arthritis

Ulcerative colitis

Simponi Aria golimumab intravenous Rheumatoid arthritis
Stelara ustekinumab

Plaque psoriasis

Psoriatic arthritis

Xeljanz tofacitinib Rheumatoid arthritis
                                                                                 

 
CPT Codes / HCPCS Codes / ICD-9 Codes
There is no specific code for Kineret (Anakinra):
ICD-9 codes covered if selection criteria are met:
714.0 Rheumatoid arthritis [if the member has a contraindication, intolerance or incomplete response to at least 2 of the least cost brands of targeted immune modulators]
714.2 Other rheumatoid arthritis with visceral or systemic involvement [adult-onset Still's disease]
714.30 - 714.33 Juvenile chronic polyarthritis
759.89 Other specified congenital anomalies [neonatal-onset multisystem inflammatory disease (NOMID)]
ICD-9 codes not covered for indications listed in the CPB:
001.0 - 139.8 Infectious and parasitic diseases
249.00 - 250.93 Diabetes mellitus without mention of complication, type II or unspecified type, not stated as uncontrolled or uncontrolled
274.00 - 274.9 Gout
359.71 - 359.9 Inflammatory and immune myopathies, NEC
410.00 - 410.92 Acute myocardial infarction
412 Old myocardial infarction
428.0 - 428.9 Heart failure
556.0 - 556.9 Ulcerative colitis
686.01 Pyoderma gangrenosum
710.0 Systemic lupus erythematosus
710.2 Sicca syndrome [Sjögren's disease]
711.00 - 711.99 Arthropathy associated with infections
713.1 Arthropathy associated with gastrointestinal conditions other than infections
715.00 - 715.98 Osteoarthrosis and allied disorders
720.0 Ankylosing spondylitis
729.1 Myalgia and myositis, unspecified
780.79 Other malaise and fatigue [associated with Sjögren's syndrome]
844.2 Sprains and strains of cruciate ligament of knee


The above policy is based on the following references:
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  2. Hannum CH, Wilcox CJ, Arend WP, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990;343:336-340.
  3. Deleuran BW, Shu CQ, Field M, et al. Localization of interleukin-1 alpha, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis. Br J Rheumatol. 1992;31:801-809.
  4. Chomarat P, Vannier E, Dechanet J, et al. Balance of IL-1 receptor antagonist/IL-1B in rheumatoid synovium and its regulation by IL-4 and IL-10. J Immunol. 1995;154(3):1432-1439.
  5. Firestein GS, Boyle DL, Yu C, et al. Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum. 1994;37:644-652.
  6. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998;41:2196-2204.
  7. Pestell K. Anakinra for arthritis. Trends Pharmacol Sci. 2001;22(8):401.
  8. Amgen, Inc. Kineret™ (anakinra) (recombinant methionyl human interleukin-1 receptor antagonist). FDA Arthritis Advisory Committee Briefing Information. Rockville, MD: U.S. Food and Drug Administration (FDA); August 16, 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3779b1.htm. Accessed November 15, 2001.
  9. U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER). BLA STN 103950 Kineret (anakinra). Arthritis Drugs Advisory Committee Meeting Minutes. Rockville, MD: FDA, August 16, 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3779t1.pdf. Accessed November 15, 2001.
  10. National Horizon Scanning Centre (NHSC). Anakinra for rheumatoid arthritis -- horizon scanning review. Birmingham, UK: NHSC; 2001.
  11. Garces K. Anakinra: Interleukin-1 receptor antagonist therapy for rheumatoid arthritis. Issues in Emerging Health Technologies Issue 16. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2001.
  12. No authors listed. Anakinra (Kineret) for rheumatoid arthritis. Med Lett Drugs Ther. 2002;44(1124):18-19.
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  14. Hallegua DS, Weisman MH. Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases. Ann Rheum Dis. 2002;61(11):960-967.
  15. National Institute for Clinical Excellence (NICE). Anakinra for rheumatoid arthritis. Technology Appraisal 72. London, UK: NICE; November 2003.
  16. Genovese MC, Cohen S, Moreland L, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 2004;50(5):1412-1419.
  17. U.S. Pharmacopoeial Convention, Inc. Anakinra (systemic). In: USP DI - Volume 1: Drug Information for the Healthcare Professional. Greenwood Village, CO: Micromedex; revised September 5, 2003.
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  19. Haibel H, Rudwaleit M, Listing J, Sieper J. Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis. 2005;64(2):296-298.
  20. Ostendorf B, Iking-Konert C, Kurz K, et al. Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis. Ann Rheum Dis. 2005;64(4):630-633.
  21. Moosig F, Zeuner R, Renk C, Schroder JO. IL-1RA in refractory systemic lupus erythematosus. Lupus. 2004;13(8):605-606.
  22. Mertens MT, Singh JA. Anakinra for rheumatoid arthritis. Cochrane Database Syst Rev. 2009;(1):CD005121.
  23. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: An overview of Cochrane reviews. Cochrane Database Syst Rev. 2009;(4):CD007848.
  24. Clark W, Jobanputra P, Barton P, Burls A. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: A systematic review and economic analysis. Health Technol Assess. 2004;8(18):1-118.
  25. Chevalier X, Giraudeau B, Conrozier T, et al. Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: A multicenter study. J Rheumatol. 2005;32(7):1317-1323.
  26. Brandt J, Marzo-Ortega H, Emery P. Ankylosing spondylitis: New treatment modalities. Best Pract Res Clin Rheumatol. 2006;20(3):559-570.
  27. Iqbal I, Fleischmann R. Treatment of osteoarthritis with anakinra. Curr Rheumatol Rep. 2007;9(1):31-35.
  28. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517-1526.
  29. Rothman KI. Diabetes treatment -- bridging the divide. N Engl J Med. 2007;356(15):1499-1501.
  30. D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007;369(9561):587-596.
  31. Lequerre T, Quartier P, Rosellini D, et al; Société Francophone pour la Rhumatologie et les Maladies Inflammatoires en Pédiatrie (SOFREMIP); Club Rhumatismes et Inflammation (CRI). Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: Preliminary experience in France. Ann Rheum Dis. 2008;67(3):302-308.
  32. Gartlehner G, Hansen RA, Jonas BL, et al. Biologics for the treatment of juvenile idiopathic arthritis: A systematic review and critical analysis of the evidence. Clin Rheumatol. 2008;27(1):67-76.
  33. Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of anakinra in osteoarthritis of the knee: A multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2009;61(3):344-352.
  34. Boerschmann H, Walter M, Achenbach P, Ziegler AG. Survey of recent clinical trials of the prevention and immunointervention of type 1 diabetes mellitus. Dtsch Med Wochenschr. 2010;135(8):350-354.
  35. Abbate A, Kontos MC, Grizzard JD, et al; VCU-ART Investigators. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol. 2010;105(10):1371-1377.
  36. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: Report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63(2):545-555.
  37. Wollina U, Haroske G. Pyoderma gangraenosum. Curr Opin Rheumatol. 2011;23(1):50-56.
  38. Kraus VB, Birmingham J, Stabler TV, et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: A randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage. 2012;20(4):271-278.
  39. Norheim KB, Harboe E, Goransson LG, Omdal R. Interleukin-1 inhibition and fatigue in primary Sjogren's syndrome -- a double blind, randomised clinical trial. PLoS One. 2012;7(1):e30123.
  40. Thaler KJ, Gartlehner G, Kien C, et al. Targeted immune modulators. Drug Class Review. Final Update 3 Report. Produced by the RTI-UNC Evidence-based Practice Center, Cecil G. Sheps Center for Health Services Research, and the Drug Effectiveness Review Project, Oregon Evidence-based Practice Center. Portland, OR: Oregon Health & Science University; March 2012.
  41. Miller ML, Rudnicki SA. Treatment of recurrent and resistant dermatomyositis and polymyositis in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2013.
  42. Zong M, Dorph C, Dastmalchi M, et al. Anakinra treatment in patients with refractory inflammatory myopathies and possible predictive response biomarkers: A mechanistic study with 12 months follow-up. Ann Rheum Dis. 2013 Apr 26. [Epub ahead of print]
  43. Nordstrom D, Knight A, Luukkainen R, et al. Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still's disease. An open, randomized, multicenter study. J Rheumatol. 2012;39(10):2008-2011.
  44. Giampietro C, Ridene M, Lequerre T, et al; CRI (Club Rhumatismes et Inflammation). Anakinra in adult-onset Still's disease: Long-term treatment in patients resistant to conventional therapy. Arthritis Care Res (Hoboken). 2013;65(5):822-826.
  45. Iliou C, Papagoras C, Tsifetaki N, et al. Adult-onset Still's disease: Clinical, serological and therapeutic considerations. Clin Exp Rheumatol. 2013;31(1):47-52.
  46. Mandl LA. Treatment of adult Still's disease. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2014.
  47. Ringold S, Weiss PF, Beukelman T, et al; American College of Rheumatology. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Care Res (Hoboken). 2013;65(10):1551-1563.
  48. Moran A, Bundy B, Becker DJ, et al; AIDA Study Group. Interleukin-1 antagonism in type 1 diabetes of recent onset: Two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381(9881):1905-1915.


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