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. 

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

2. 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) 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., Amevive (alefacept), Actemra (tocilizumab), Cimzia (certolizumab), Kineret (anakinra), 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 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.

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

4. 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.

5. 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.

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.

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.

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.

Appendix