Anakinra (Kineret)

Number: 0595

Brand Selection for Medically Necessary Indications

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Kineret (anakinra) is more costly to Aetna than other targeted immune modulators for certain indications. There is a lack of reliable evidence that Kineret is superior to the lower cost targeted immune modulators for the medically necessary indication listed below. Therefore, Aetna considers Kineret to be medically necessary only for members who have a contraindication, intolerance or ineffective response to the available equivalent alternative targeted immune modulators per criteria below:

Moderately to severely active rheumatoid arthritis (RA)

For the treatment of moderately to severely active RA, member has a contraindication, intolerance or ineffective response to all of the following available equivalent alternative targeted immune modulators (one-month trial each): Enbrel, Humira, Kevzara, Orencia, Rinvoq, and Xeljanz/Xeljanz XR.

Policy

Note: Requires Precertification.

Precertification of anakinra (Kineret) is required of all Aetna participating providers and members in applicable plan designs. For precertification of ravulizumab-cwvz, call (866) 752-7021, or fax (866) 267-3277.

1. Criteria for Initial Approval

   Aetna considers Kineret (anakinra) medically necessary for 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* within 6 months of initiating therapy for persons who are naive to biologic DMARDs or targeted synthetic DMARDs associated with an increased risk of TB, and repeated yearly for members with risk factorsFootnotes** for TB that are continuing therapy with biologics:

   1. Active systemic juvenile idiopathic arthritis (sJIA)

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

   2. Adult-onset Still's disease (AOSD)

      - when all of the following criteria are met:
      
      

      1. Member has had an inadequate response to a 3-month trial of methotrexate or corticosteroids or has intolerance or contraindication to methotrexate (see Appendix) and low dose corticosteroids; and
      2. Member will receive the requested medication concurrently with methotrexate or corticosteroids or has intolerance or contraindication to methotrexate (see Appendix) and low dose corticosteroids.
         

   3. Deficiency of interleukin-1 receptor antagonist (DIRA)

      - for treatment of genetically confirmed deficiency of interleukin-1 receptor antagonist (DIRA) due to IL1RN mutations.
      

   4. Gout and pseudogout flares 

      - for the management of flares for gout or pseudogout (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.

   5. 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 greater than or equal to 2, or C-reactive protein (CRP) greater than 10 mg/L.
         

   6. Moderately to Severely Active Rheumatoid Arthritis (RA)

      1. For members who have previously received a biologic or targeted synthetic DMARD (e.g., Rinvoq, Xeljanz) indicated for moderately to severely active rheumatoid arthritis; or
      2. For members with active RA when all of the following criteria are met:
         

         1. Member meets either of the following criteria:

            1. Member has been tested for either of the following biomarkers and the test was positive:

               1. Rheumatoid factor (RF); or
               2. Anti-cyclic citrullinated peptide (anti-CCP); or

            2. Member has been tested for all of the following biomarkers:

               1. RF; and
               2. Anti-CCP; and
               3. C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR); and
                  
         2. Member has experienced an inadequate response to at least a 3-month trial of methotrexate despite adequate dosing (i.e., titrated to 20 mg/week); or the member has an intolerance or contraindication to methotrexate (see Appendix); and
         3. Member has experienced an inadequate response to at least a 3-month trial of a biologic or a targeted synthetic DMARD (e.g., Rinvoq, Xeljanz) or has intolerance to a biologic or targeted synthetic DMARD.
            

   7. Multicentric Castleman's disease (CD)

      - for the treatment of multicentric Castleman’s disease when both of the following criteria are met:
      
      

      1. The requested medication will be used as a single-agent; and
      2. The disease has progressed following treatment of relapsed/refractory or progressive disease.

   8. Neonatal-onset multisystem inflammatory disease (NOMID)

      - for the treatment of cryopyrin-associated periodic syndromes (CAPS), including NOMID (also known as chronic infantile neurologic cutaneous and articular syndrome [CINCA]).

   9. Recurrent pericarditis

      - for the treatment of recurrent pericarditis for members who have failed a first-line therapy agent (i.e., colchicine).

   10. Schnitzler syndrome

       - for treatment when all of the following criteria are met:
       
       

       1. Member has an urticarial rash, monoclonal IgM (or IgG) gammopathy and at least 2 of the following signs and symptoms: fever, joint pain or inflammation, bone pain, palpable lymph nodes, enlargement of the liver or spleen, elevated numbers of white blood cells (leukocytosis), elevated red blood cell (erythrocyte) sedimentation rate or abnormalities on bone morphological study (e.g., increased bone density); and
       2. Other possible causes of the signs and symptoms have been ruled out, including but not limited to: hyperimmunoglobulin D syndrome, adult-onset Still disease, urticarial hypocomplementemic vasculitis, acquired C1 inhibitor deficiency and cryoglobulinemia.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections). 

2. Continuation of Therapy

   Aetna considers continuation of anakinra (Kineret) therapy medically necessary for the following indications:

   1. Adult-onset Still’s disease (AOSD) and active systemic juvenile idiopathic arthritis (sJIA)

      - for all members (including new members) who are using the requested medication for adult-onset Still’s disease or active systemic juvenile idiopathic arthritis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:
      
      

      1. Number of joints with active arthritis (e.g., swelling, pain, limitation of motion); or
      2. Number of joints with limitation of movement; or
      3. Functional ability; or
      4. Systemic symptoms (e.g., fevers, evanescent skin rashes).

   2. Moderately to severely active rheumatoid arthritis (RA)

      - for all members (including new members) who are using the requested medication for moderately to severely active rheumatoid arthritis and who achieve or maintain a positive clinical response as evidenced by disease activity improvement of at least 20% from baseline in tender joint count, swollen joint count, pain, or disability.
      
      

   3. Multicentric Castleman's disease

      - for continued treatment of multicentric Castleman’s disease in members requesting reauthorization who have not experienced disease progression or an unacceptable toxicity.
      
      

   4. Neonatal-onset multisystem inflammatory disease (NOMID)

      - for all members (including new members) who are using the requested medication for CAPS, including NOMID (also known as CINCA), and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:
      
      

      1. Fever; or
      2. Skin rash; or
      3. Joint pain and/or inflammation; or
      4. Central nervous system (CNS) symptoms (e.g., meningitis, headache, cerebral atrophy, uveitis, hearing loss); or
      5. Inflammatory markers (e.g., serum amyloid A [SAA], C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]).

   5. Recurrent pericarditis

      - for all members (including new members) who are using the requested medication for recurrent pericarditis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following:
      
      

      1. Pericarditic chest pain; or
      2. Pericardial rubs; or
      3. Electrocardiogram (ECG); or
      4. Pericardial effusion; or
      5. C-reactive protein (CRP).

   6. All other indications

      - for all members (including new members) who are using the requested medication for an indication outlined in Section I and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition.
      
      

Footnotes* If the screening test for TB is positive, there must be further testing to confirm there is no active disease. Do not administer the requested medication to members with active TB infection. If there is latent disease, TB treatment must be started before initiation of the requested medication. 

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).

Dosage and Administration

Note: Approvals may be subject to dosing limits in accordance with FDA-approved labeling, accepted compendia, and/or evidence-based practice guidelines. Below includes dosing recommendations as per the FDA-approved prescribing information.

Kineret (anakinra) is available as 100 mg/0.67 mL solution in a single-use prefilled syringe for subcutaneous injection. Graduated syringe allows for doses between 20 mg and 100 mg.

Active Rheumatoid Arthritis

The recommended dose of Kineret for the treatment of rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day. Physicians should consider a dose of 100 mg of Kineret administered every other day for RA persons who have severe renal insufficiency or end stage renal disease (defined as creatinine clearance < 30 mL/min, as estimated from serum creatinine levels).

Cryopyrin-Associated Periodic Syndromes (CAPS)

The recommended starting dose of Kineret is 1-2 mg/kg for NOMID. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation. Adjust doses in 0.5 to 1.0 mg/kg increments. Once daily administration is generally recommended, but the dose may be split into twice daily administrations. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.

Deficiency of Interleukin-1 Recepto Antagonist (DIRA)

The recommended starting dose of Kineret is 1-2 mg/kg daily for persons with DIRA. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation. Adjust doses in 0.5 to 1 mg/kg increments. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.

Source: Swedish Orphan Biovitrum (SOBI), 2020b

Experimental and Investigational

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

2. Aetna considers anakinra experimental and investigational for use in combination with TNF blocking agents (e.g., Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab) Remicade (infliximab), or Simponi (golimumab)) and other biologicals (e,.g., Orencia (abatacept)) because the safety and effectiveness of such combination therapy has not been established.

3. Aetna considers anakinra experimental and investigational for all other indications, including any of the following diseases/disorders (not an all-inclusive list), because the safety and effectiveness of anakinra for these indications has not been established:

   1. Ankylosing spondylitis
   2. Anterior cruciate ligament injury
   3. Behcet's disease
   4. Cerebral autoinflammatory disease (e.g., autoimmune encephalitis)
   5. Chronic fatigue syndrome
   6. Chronic non-bacterial osteomyelitis
   7. Colorectal cancer
   8. Diabetes mellitus (type 1 and type 2)
   9. Erdheim-Chester disease
   10. Familial Mediterranean fever
   11. Fatigue associated with Sjogren's syndrome
   12. Febrile infection-related epilepsy syndrome
   13. Focal and segmental glomerulosclerosis
   14. Heart failure (prevention of heart failure after acute myocardial infarction)
   15. Hemophagocytic lymphohistiocytosis
   16. Hidradenitis suppurativa
   17. Idiopathic recurrent pericarditis (anakinra as initial treatment)
   18. Inflammatory bowel disease
   19. Intestinal mucositis
   20. Kawasaki disease
   21. Lupus arthritis
   22. Myocarditis
   23. Myopathy/myositis
   24. Non-alcoholic steatohepatitis (NASH)
   25. Non-neuropathic hereditary familial amyloidosis
   26. Osteoarthritis
   27. Pustular psoriasis
   28. Pyoderma gangraenosum
   29. Reactive arthritis
   30. Sarcoidosis
   31. Scleritis (idiopathic or secondary to inflammatory disorders)
   32. Systemic amyloidosis
   33. Systemic lupus erythematosus (including recurrent fevers)
   34. Ulcerative colitis.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Moderately to severely active rheumatoid arthritis (RA)
• Cryopyrin-Associated Periodic Syndromes (CAPS), including Neonatal-Onset Multisystem Inflammatory Disease (NOMID)
• Deficiency of Interleukin-1 Receptor Antagonist (DIRA)

Compendial Uses

• Systemic juvenile idiopathic arthritis (sJIA)
• Adult-onset Still’s disease
• Multicentric Castleman’s disease
• Recurrent pericarditis
• Hyperimmunoglobulin D syndrome (HIDS) [Mevalonate Kinase Deficiency (MKD)]
• Schnitzler’s syndrome
• Gout and pseudogout (calcium pyrophosphate deposition

Anakinra is available as Kineret (Swedish Orphan Biovitrum AB). Anakinra is a recombinant, nonglycosylated form of the human interleukin 1 receptor antagonist (IL‐ IRa). Kineret (anakinra) acts similarly to the native interleukin‐1 receptor antagonist (IL‐1Ra). IL‐1Ra blocks effects of IL‐1 by competitively inhibiting the binding of IL‐1, specifically IL‐1alpha and IL‐1beta, to the interleukin‐1 type 1 receptor (IL‐1R1), which is expressed in a wide variety of tissues. IL‐1Ra is part of the feedback loop that is designed to balance the effects of inflammatory cytokines. Interleukin‐1 is one of the primary proinflammatory cytokines associated with rheumatoid arthritis, acting synergistically with tumor necrosis factor‐alpha (TNF‐alpha).

Kineret (anakinra) is approved by the U.S. Food and Drug Administration (FDA) for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed one or more disease modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents. Kineret is also approved for the treatment of Neonatal‐Onset Multisystem Inflammatory Disease (NOMID) and deficiency of Interleukin-1 receptor antagonist (DIRA).

Use of Anakinra for Persons with Active Infections

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.

Adult-Onset Still's Disease

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 non-steroidal anti-inflammatory drugs (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”.

Ankylosing Spondylitis, Inflammatory Bowel Disease and Reactive Arthritis

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".

Anterior Cruciate Ligament Injury

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.

Behcet’s Disease

Vitale and associates (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 crossroad 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 last decade 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.  However, the authors concluded that further studies are essential 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.

In an open-label, pilot study, Grayson and colleagues (2017) examined the effects of anakinra for the treatment of mucocutaneous manifestations in BD.  A total of 6 patients with BD and ongoing oral/genital ulcers for greater than or equal to 1 month were enrolled into an adaptive, 2-phase clinical trial and included in the analysis.  Study duration was 6 months with extension up to 16 months.  All were treated non-blinded with subcutaneous 100-mg anakinra daily with the option to escalate the dose to 200-mg in partial responders after 1 month and 300-mg after 6 months.  Patients recorded the number and severity of ulcers in daily diaries.  The primary outcome was remission defined as no ulcers on physical examination for 2 consecutive monthly visits between months 3 and 6.  Secondary outcomes included the number and severity of patient-reported ulcers, patient/physician global scores, and standardized disease activity scores; 2 of 6 patients achieved the primary outcome; 5 of 6 patients had improvement in the number and severity of ulcers.  Non-statistically significant improvements were seen in secondary outcomes.  Over the entire study, patients reported greater than or equal to 1 oral and greater than or equal to 1 genital ulcer on 665 (66 %) and 139 (14 %) days, respectively.  On anakinra 200-mg versus 100-mg, patients reported fewer days with oral ulcers (65 % versus 74 % of days, p = 0.01) and genital ulcers (10 % versus 22 % of days, p < 0.001) and milder oral ulcer severity (p < 0.001).  Increase of anakinra to 300-mg did not result in further improvements; AEs were notable for mild infections.  The authors concluded that anakinra at an optimal dose of 200-mg daily had an acceptable safety profile and was partially effective in the treatment of resistant oral and genital ulcers in BD.  These preliminary findings need to be validated by well-designed studies.

The drawbacks of this study included:

1. small sample size (n = 6),
2. the study was un-blinded, and
3. single-arm design. 

While there was a difference in degree of clinical response to anakinra among patients in this trial, the small sample size precluded identification of potential subsets of patients who may be more or less responsive to anakinra.  It also precluded a more thorough evaluation of potential confounders including concomitant medications and important lifestyle factors (e.g., smoking).

Furthermore, an UpToDate review on “Treatment of Behcet’s syndrome” (Smith and Yazici, 2017) states that “There are limited data available regarding the use of anakinra, tocilizumab, pentoxifylline, intravenous immune globulin, plasmapheresis, antibiotics, alemtuzumab (Campath 1-H), dapsone, antimalarials, rebamipide, hematopoietic stem cell transplantation (autologous, or derived from allogeneic bone marrow or umbilical cord blood), and granulocytapheresis”.

Castleman's Disease

The National Comprehensive Cancer Network's guideline on non-Hodgkin's lymphoma (NCCN, 2016) recommends anakinra as subsequent therapy as a single agent for multicentric Castleman's disease (CD) that has progressed following treatment of relapsed/refractory or progressive disease.

Cerebral Autoinflammatory Disease (e.g., Autoimmune Encephalitis)

Jang and colleagues (2018) stated that interest in autoimmune encephalitis has been growing since the discovery of various autoimmune antibodies, such as N-methyl D-aspartate receptors antibody and leucine-rich glioma-inactivated 1 antibody.  However, in contrast to autoimmune encephalitis associated with dysregulated adaptive immunity in the brain, the question of whether innate immunity-mediated autoinflammatory diseases exist in the brain has drawn much attention.  These investigators reported a patient with microglia-dominant acute autoinflammatory encephalitis successfully treated with anakinra.  In comparison to systemic autoinflammatory disease, the authors termed this encephalitis cerebral autoinflammatory disease.  These researchers concluded that the findings of this case suggested that anakinra could be utilized as a therapeutic option for clinically refractory encephalitis with microglia‐dominant neuroinflammation in the CNS.  In addition, they stated that further studies are needed with larger numbers of patients previously diagnosed with unspecified and otherwise refractory encephalitis to verify the extent of cerebral autoinflammation.

Chronic Fatigue Syndrome

In a randomized, placebo-controlled trial, Roerink and colleagues (2017) evaluated the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with chronic fatigue syndrome (CFS).  Patients, providers, and researchers were blinded to treatment assignment.  A total of 50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment were enrolled in this study.  Subjects were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50).  The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks.  Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 and 24 weeks.  At 4 weeks, 8 % (2 of 25) of anakinra recipients and 20 % (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons.  There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95 % CI: -4.1 to 7.2 points]) or the end of follow-up.  No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up; 1 patient in the anakinra group discontinued treatment because of an AE.  Patients in the anakinra group had more injection site reactions (68 % [17 of 25] versus 4 % [1 of 25]).  The authors concluded that peripheral IL-1 inhibition using anakinra for 4 weeks did not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue.

Chronic Non-Bacterial Osteomyelitis (CNO) / Chronic Recurrent Multifocal Osteomyelitis (CRMO)

Eleftheriou and colleagues (2010) stated that to-date there is no uniformly effective treatment for either chronic recurrent multifocal osteomyelitis (CRMO) or synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome.  These investigators reported on their clinical experience of using biologic therapy to treat children with these conditions.  They carried out a retrospective descriptive case series of 4 children with refractory disease treated with biologics.  Disease activity was assessed at pre-determined time-points (T = 0, T = 6 weeks and T = 12 months after the start of biologic therapy, and at latest follow-up) using a combination of clinical examination and radiological findings: a 10 cm pain and physician VAS; the Childhood Health Assessment Questionnaire as an assessment of disability; and changes in markers of systemic inflammation.  There was an initial improvement in all parameters assessed for all 3 children treated with TNF-alpha blockade, although the 3rd case had to discontinue the therapy due to a suspected (but unconfirmed) fungal skin infection.  Anakinra treatment alleviated the symptoms in the 4th patient at 6 weeks, but there was no sustained response to treatment at 1-year follow-up.  The authors presented their preliminary experience of using biological therapies to treat children with CRMO and SAPHO in conjunction with other immunosuppression.  Moreover, they stated that further studies are needed to establish the role of these therapies in refractory CRMO and SAPHO.

Rech and associates (2012) noted that Still's disease and CRMO are febrile rheumatic diseases of unknown etiology, which predominantly affect children but can also have their initial manifestation in adults.  Both can present as intermittent, relapsing episodes and are considered potential candidates within the expanding spectrum of auto-inflammatory disorders, although no genetic abnormalities have been described for either of them.  These researchers described a man with an initial manifestation of abacterial multi-focal osteitis at the age of 41.  During a relapsing-remitting course of his illness, he increasingly developed symptoms of adult-onset Still's disease (AOSD), and the diagnosis was established according to the Yamaguchi criteria.  When treated with anakinra, not only the acute symptoms disappeared promptly, but also the osteitis went into complete remission.  The authors concluded that to their knowledge, this was the first description of a simultaneous occurrence of these 2 manifestations of auto-inflammation in adulthood.

Hedrich and co-workers (2013) noted that sterile bone inflammation is the hallmark of auto-inflammatory bone disorders, including chronic non-bacterial osteomyelitis (CNO) with its most severe form CRMO.  Auto-inflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation.  Interestingly, auto-inflammatory bone disorders are associated with inflammation of the skin and/or the intestine.  In several monogenic auto-inflammatory bone disorders mutations in disease-causing genes have been reported.  However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear.  These investigators discussed the clinical presentation and molecular pathophysiology of human auto-inflammatory osteopathies and animal models with special focus on CNO/CRMO.  These researchers stated that patients with deficiency of IL-1 receptor antagonist (DIRA) rapidly responded to treatment anakinra.  However, response may be incomplete in patients with the 175 kb genomic deletion, suggesting a contribution of the adjacent genes to the pathophysiology of DIRA …  Patients with Majeed syndrome moderately responded to treatment with NSAIDs and corticosteroids.  The dyserythropoietic anemia, however, was not improved by treatment.  Recently, IL-1 blockade with anakinra (IL-1RA) and canakinumab (an IL-1β antibody) has been demonstrated effective.

Herlin et al (2013) described the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in 2 brothers with Majeed syndrome.  Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis.  Their bone disease and anemia were refractory to treatment with corticosteroids.  Both siblings had elevated pro-inflammatory cytokines in their serum, including TNF-α, however a trial of the TNF inhibitor etanercept resulted in no improvement; IL-1 inhibition with either anakinra or canakinumab resulted in dramatic clinical and laboratory improvement.  The authors concluded that the differential response to treatment with TNF-α or IL-1 blocking agents shed light into disease pathogenesis; it supported the hypothesis that Majeed syndrome is an IL-1β dependent auto-inflammatory disorder, and further underscored the importance of IL-1 in sterile bone inflammation.

Pardeo and colleagues (2017) reported the safety and efficacy of anakinra in patients with CNO, also known as CRMO, who were refractory to NSAID and bisphosphonates and/or glucocorticoids.  A total of 9 patients (6 females) with refractory CNO were treated with anakinra for at least 6 months.  These researchers recorded, at baseline and after 6 months of treatment, clinical and laboratory features, and number and distribution of bone lesions detected by 99mTc-MDP bone scintigraphy.  Disease activity was evaluated using a physician's global assessment (PGA).  At baseline, 9/9 patients had mild-to-severe PGA.  After 6 months of treatment, in 5 patients the PGA score was graded from none to minimal.  At baseline, erythrocyte sedimentation rate (ESR) and CRP were elevated in 8 out of 9 patients.  After 6 months, 5/9 patients had normalized CRP and ESR and in all except 1, CRP and ESR decreased.  Before starting anakinra, a total of 77 bone lesions were detected by bone scintigraphy.  After 6 months of treatment of the 77 lesions, 42 had resolved and 35 were stable.  In 7/9 patients, 20 new lesions appeared during treatment; 2 of these 7 patients were symptomatic.  At the last follow-up visit (median of 1.7 years, range of 0.8 to 2.8), 6/9 patients maintained a PGA graded as none to minimal.  The authors concluded that anakinra is a possible therapeutic alternative in patients with refractory CNO.  The practical significance of clinically silent bone lesions detected by bone scintigraphy remains to be established.

Zhao and associates (2018) developed standardized treatment regimens for CNO to enable comparative effectiveness treatment studies.  Virtual and face-to-face discussions and meetings were held within the CNO subgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA).  A literature search was conducted, and CARRA membership was surveyed to evaluate available treatment data and identify current treatment practices.  Nominal group technique was used to achieve consensus on treatment plans for CNO refractory to NSAID monotherapy and/or with active spinal lesions.  Three consensus treatment plans (CTPs) were developed for the first 12 months of therapy for CNO patients who were refractory to NSAID monotherapy and/or with active spinal lesions.  The 3 CTPs were methotrexate or sulfasalazine, TNF-alpha inhibitors with optional use of methotrexate, and bisphosphonates.  Short courses of glucocorticoids and continuation of NSAIDs were permitted for all regimens.  Consensus was achieved on these CTPs among CARRA members.  Consensus was also reached on subject eligibility criteria, initial evaluations that should be conducted prior to the initiation of CTPs, and data items to collect to assess treatment response.  The authors concluded that 3 consensus treatment plans were developed for pediatric patients with CNO refractory to NSAIDs and/or with active spinal lesions.  They stated that use of these CTPs will provide additional information on efficacy and will generate meaningful data for comparative effectiveness research in CNO.  Human IL-1 receptor antagonists (e.g., anakinra) are not listed as a therapeutic option.

Girschick and co-workers (2018) noted that CNO or CRMO is an auto-inflammatory disorder characterized by sterile bone osteolytic lesions.  These researchers evaluated the demographic data and clinical, instrumental and therapeutic features at baseline in a large series of CNO/CRMO patients enrolled in the Eurofever registry.  A web-based registry collected retrospective data on patients affected by CRMO/CNO.  Both pediatric and adult centers were involved.  Complete baseline information on 486 patients was available (176 male, 310 female).  The mean age of onset was 9.9 years.  Adult onset (greater than 18 years of age) was observed in 31 (6.3 %) patients.  The mean time from disease onset to final diagnosis was 1 year (range of 0 to 15); MRI was performed at baseline in 426 patients (88 %), revealing a mean number of 4.1 lesions.  More frequent manifestations not directly related to bone involvement were myalgia (12 %), mucocutaneous manifestations (5 % acne, 5 % palmoplantar pustulosis, 4 % psoriasis, 3 % papulo-pustular lesions, 2 % urticarial rash) and gastro-intestinal (GI) symptoms (8 %).  A total of 361 patients have been treated with NSAIDs, 112 with glucocorticoids, 61 with bisphosphonates, 58 with methotrexate (MTX), 47 with sulfasalazine (SSZ), 26 with anti-TNF and 4 with anakinra, with a variable response.  The authors concluded that this was the largest reported case series of CNO patients, showing that the range of associated clinical manifestations was rather heterogeneous.  The study confirmed that the disease usually presents with an early teenage onset, but it may also occur in adults, even in the absence of mucocutaneous manifestations.

Furthermore, an UpToDate review on “Periodic fever syndromes and other autoinflammatory diseases: An overview” (Nigrovic, 2019) states that “PAPA syndrome -- Glucocorticoids are standard treatment, although anti-tumor necrosis factor (TNF) therapy with etanercept, as well as IL-1 antagonism with anakinra, appears promising … NLRC4-activating mutations --  This patient responded well clinically to treatment with recombinant IL-1 receptor antagonist (anakinra) but continued to have subclinical abnormalities in laboratory markers of inflammation”.

Colorectal Cancer

Isambert and colleagues (2018) noted that in pre-clinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU).  In a single-arm, phase-II clinical trial, these researchers examined the activity and safety of 5-FU plus bevacizumab and anakinra in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy.  Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS).  Patients were treated with a simplified acid folinic plus 5-FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 mins every 2 weeks.  Anakinra (100 mg) was injected subcutaneously once-daily.  The primary end-point was the 2-month response rate determined upon CHOI criteria.  A total of 32 patients with mCRC were enrolled; 5 patients demonstrated response (CHOI criteria) and 22 patients had stable disease (SD) as the best 2-month overall response.  Median progression-free survival (PFS) and overall survival (OS) were 5.4 (95 % CI: 3.6 to 6.6) and 14.5 months (95 % CI: 9 to 20.6) respectively; 20 patients experienced grade 3 toxicity.  No grade 4 or 5 toxicity related to therapy occurred.  The most common grade 3 AEs were neutropenia in 8 (25 %) patients, digestive side effects in 7 (21.9 %) patients and hypertension in 6 (18.75 %) patients.  No treatment-related deaths or serious AEs were reported.  The authors concluded that 5-FU plus bevacizumab and anakinra had promising activity and a manageable safety profile, suggesting that this combination might become a potential therapeutic option for patients with refractory mCRC.

Combinational use of Anakinra and Tumor Necrosis Factor Blocking Agents

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 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.

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.

Cryopyrin-Associated Periodic Syndromes (CAPS)

Neven et al (2010) stated that cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases.  Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement.  CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin-1 (IL-1) processing.  Anakinra, an IL-1 receptor antagonist, has been shown to be an effective treatment; however, data on long-term efficacy and safety have been sparse.  These investigators evaluated the long-term safety and effectiveness of anakinra treatment in patients with NOMID/CINCA syndrome.  They retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007.  There were 10 patients with NOMID/CINCA syndrome who had been treated with anakinra.  The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years.  They had been followed-up for 26 to 42 months.  Sustained effectiveness in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved.  The dosage of anakinra required for effectiveness ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest.  Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment.  Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed.  No effect on over-growth arthropathy was observed.  Adverse events consisted of mild injection-site reactions.  The authors concluded that these findings indicated that anakinra treatment is effective over the long-term in NOMID/CINCA syndrome.  However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.

Kuemmerle-Deschner et al (2011) stated that Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive IL-1 release.  It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensori-neural deafness and amyloidosis.  The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1.  These researchers determined the short- and long-term safety and effectiveness of anakinra therapy in children and adults with severe MWS.  A single-center observational study was performed.  Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status.  The primary outcome was a score of less than 10 on the DAS for MWS at 2 weeks and at the last follow-up visit.  Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis.  A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range of 5 to 14 months).  The median follow-up was 11 months (range of 5 to 14 months).  Disease activity was significantly lower in all patients at 2 weeks (p = 0.0005).  Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients.  Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity.  Treatment was well-tolerated, and no serious adverse events were observed.  The authors concluded that anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term.  Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

Dhimolea (2011) noted that CAPS comprises a group of rare, but severe, inherited auto-inflammatory disorders associated with aberrant secretion of IL-1.  These distinct conditions of auto-inflammatory origin include MWS, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease (NOMID), which is also referred to as chronic infantile neurologic cutaneous and articular syndrome.  Recently, this group of diseases has been associated with mutations in the NLRP3 gene that encodes for the protein cryopyrin, a component of the inflammasome complex that regulates the maturation and secretion of inflammatory cytokine IL-1β.  Immune cells from patients with NOMID secrete higher levels of active IL-1β compared with monocytes from healthy subjects.  Over-production of IL-1 is believed to promote aberrant inflammatory response in CAPS patients.  The authors stated that evidence supporting the clinical value of IL-1β in CAPS has been provided from the complete response of patients after treatment with IL-1 blocking agents.

Sibley and colleagues (2012) stated that blocking IL-1 with anakinra in patients with the auto-inflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation.  However, the impact of long-term treatment has not been established.  This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID.  These researchers conducted a cohort study of 26 NOMID patients aged 0.80 to 42.17 years who were followed-up at the NIH and treated with anakinra 1-5 mg/kg/day for at least 36 months.  Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level.  Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated.  Sustained improvements in diary scores, parent's/patient's and physician's global scores of disease activity, parent's/patient's pain scores, and inflammatory markers were observed (all p < 0.001 at 36 and 60 months).  At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (p = 0.0026 and p = 0.0076, respectively), albumin levels, and opening pressures (p = 0.0012 and p < 0.001, respectively).  Most patients showed stable or improved hearing.  Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss.  Visual acuity and peripheral vision were stable.  Low optic nerve size correlated with poor visual field.  Bony lesions progressed.  Adverse events other than viral infections were rare, and all patients continued to receive the medication.  The authors concluded that these findings indicated that anakinra provided sustained effectiveness in the treatment of NOMID for up to 5 years, with the requirement of dose escalation.  Damage progression in the CNS, ear, and eye, but not bone, is preventable; anakinra was well-tolerated overall.

Miyamae (2012) stated that CAPS are a group of rare auto-inflammatory disorders; many cases of CAPS are caused by mutations in the NLRP3 gene.  In these conditions, IL-1 is over-produced, and this over-production plays a major role in disease onset and progression.  CAPS include 3 variants, ranging in order of increasing severity from familial cold auto-inflammatory syndrome, previously termed familial cold urticaria, through MWS, to CINCA syndrome, also known as NOMID.  Diagnosis of CAPS is initially based on clinical manifestations and medical history, and later confirmed genetically.  CAPS should be suspected when characteristic skin lesions, typical periodic fever episodes, bone/joint manifestations, and CNS involvement are recognized. The authors concluded that CAPS are life-long diseases, and early diagnosis and early treatment with IL-1-targeted therapies may improve prognosis.

Kone-Paut and Galeotti (2014) stated that CAPS is a very rare auto-inflammatory syndrome, which has recently served as a pure model of IL-1β-driven diseases.  CAPS is caused by mutations into the NLRP3 gene that encodes cryopyrin, which serves as a receptor of the innate immunity that senses danger signals and pathogens.  Constitutive activation of cryopyrin in CAPS leads to an excessive secretion of IL-1β. CAPS patients experience symptoms of systemic inflammation, intense fatigue and have poor quality of life.  In the most severe forms, they may develop serious organ damage such as visual and hearing impairment, neurological deterioration and renal insufficiency.  Anti-IL-1 drugs are effective in treating symptoms of almost all CAPS patients and have radically transformed their lives.  These investigators described the history of the “revival” of CAPS patients through anti-IL-1 treatments with a special focus on anakinra, the first drug used in cohorts with variable disease severity and number of patients.

Paccaud e al (2014) noted that chronic infantile neurological cutaneous articular (CINCA) syndrome, also called neonatal onset multisystem inflammatory disease (NOMID) is a chronic disease with early onset affecting mainly the central nervous system, bones and joints and may lead to permanent damage.  These researchers reported 2 preterm infants with severe CINCA syndrome treated by anti-IL-1 in the neonatal period, although, so far, no experience with this treatment in infants younger than 3 months of age has been reported.  A review of the literature was performed with focus on treatment and neonatal features of CINCA syndrome.  Two cases suspected to have CINCA syndrome were put on treatment with anakinra in the early neonatal period due to severe clinical presentation.  These investigators observed a rapid and persistent decline of clinical signs and systemic inflammation and good drug tolerance.  Diagnosis was confirmed in both cases by mutations in the NLRP3/CIAS1-gene coding for cryopyrin.  The authors concluded that they strongly suggested that specific treatment targeting IL-1 activity should be started early.  Being well-tolerated, it can be introduced already in neonates presenting clinical signs of severe CINCA syndrome in order to rapidly control inflammation and to prevent life-long disability.

Headley et al (2014) stated that Muckle-Wells syndrome (MWS) is a member of the CAPS family of auto-inflammatory diseases, originally described as a triad of urticaria, sensorineural deafness and amyloidosis.  Interleukin-1 blockade is a proven therapy for MWS.  In this study, the clinical, laboratory and genotypic characteristics of a novel kindred of 5 individuals with Muckle-Wells syndrome were described.  Response to IL-1 blockade therapy in the proband was evaluated.  All 5 affected family members experienced symptoms of multi-organ inflammation.  Lead time between symptom onset and diagnosis was approximately 30 years in the proband.  Fever was not a universal feature in all affected family members.  Anti-IL-1 therapy in the proband resulted in improvements in patient-reported symptoms, inflammatory markers, auditory acuity and reversal of her infertility.  Muckle-Wells syndrome is a rare, multi-system, auto-inflammatory syndrome; delay in diagnosis prevents effective treatment.

Satoh et al (2015) noted that the bioactive form of IL-1β, a key immunoregulatory and proinflammatory cytokine, is produced by the inflammasome -- a caspase-1 activating molecular platform -- in response to selected danger-associated molecular patterns and pathogen-associated molecular patterns.  Advances in understanding the role of IL-1β in inflammatory conditions has resulted in IL-1β becoming a therapeutic target for a number of inflammatory diseases beyond the rare monogenic autoinflammatory diseases characterized by aberrant inflammasome function and enhanced bioactive IL-1β production.  In the monogenic autoinflammatory diseases known as CAPS, neutralization of IL-1β results in a rapid and sustained reduction in disease severity without severe side effects

Furthermore, an UpToDate review on “Cryopyrin-associated periodic syndromes and related disorders” (Nigrovic, 2015) states that “Three clinically overlapping, interleukin-1-associated, autoinflammatory disorders are known collectively as the cryopyrin-associated periodic syndromes (CAPS) or cryopyrinopathies: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID, also known as chronic infantile neurologic cutaneous and articular [CINCA] syndrome) …. In patients with familial cold autoinflammatory syndrome (FCAS), treatment with the IL-1 receptor antagonist, anakinra, given subcutaneously on a daily basis can prevent cold-induced attacks and markedly reduce daily symptoms.  Among patients with renal secondary amyloidosis due to CAPS, anakinra has led to marked reductions in proteinuria and stabilization of serum creatinine.  Treatment with anakinra can also control systemic inflammation in MWS, potentially with an effect on amyloid risk mediated through normalization of levels of serum amyloid A protein.  The impact on hearing loss remains uncertain, but partial recovery has been reported.  In NOMID/CINCA, treatment with anakinra has improved signs and symptoms related to inflammation in some, but not all, cases.  Bone and joint abnormalities are less responsive to this agent”.

Diabetes Mellitus (Type 1 and Type 2)

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.

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.

DIRA (Deficiency of interleukin (IL)-1 Receptor Antagonist)

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare, autosomal-recessive, autoinflammatory condition caused by mutations affecting the IL1RN gene which encodes the endogenous IL-1 receptor antagonist. In persons with DIRA, the deficiency of IL-1Ra leads to unopposed action of IL-1 signaling, resulting in life-threatening systemic inflammation with skin and bone involvement (SOBI, 2020). DIRA presents in early infancy with a diffuse pustular skin rash, sterile osteomyelitis, and periostitis with articular pain in the setting of markedly elevated inflammatory markers without fever. Treatment with anakinra, a recombinant IL-1RA, has been found to result in marked improvement (Nigrovic, 2020c).

ter Haar et al (2010) noted that deficiency of IL-1 receptor antagonist (DIRA) is an autosomal recessive inherited inflammatory disease, characterized by pustular skin rash and characteristic osteolytic and hypertrophic bone lesions.  If left untreated, the disease may progress to a fatal sepsis with multiple organ failure.  The symptoms resulted from an uncontrolled activity of the pro-inflammatory cytokines IL-1 alpha and IL-1 beta, due to the genetic lacking of the natural antagonist, IL-1 receptor antagonist (IL-1RA).  Suppletion of the deficient protein induces rapid complete remission.  These researcher described 2 cases from 1 family, both female neonates, illustrated the fatal natural progression, as well as the course under suppletion of IL-1RA (anakinra).  Early recognition of this rare disorder can be life-saving.  

Minkis et al (2012) stated that DIRA is a recently described autoinflammatory syndrome of skin and bone caused by recessive mutations in the gene encoding the IL-1 receptor antagonist.  Few studies have been published regarding this debilitating condition.  Early identification is critical for targeted life-saving intervention.  These researchers reported on the case of a male infant, born to non-consanguineous Puerto Rican parents, was referred for management of a pustular eruption diagnosed as pustular psoriasis.  At 2 months of age, the infant developed a pustular eruption.  After extensive evaluation, he was confirmed to be homozygous for a 175-kb genomic deletion on chromosome 2 that includes the IL1RN gene, commonly found in Puerto Ricans.  Therapy with anakinra was initiated, with rapid clearance of skin lesions and resolution of systemic inflammation.  The authors concluded that recent identification of DIRA as a disease entity, compounded by the limited number of reported cases, made early identification difficult.  It is critical to consider this entity in the differential diagnosis of infantile pustulosis.  Targeted therapy with anakinra can be life-saving if initiated early. 

Altiok et al (2012) described a novel nonsense mutation in the IL1RN gene, associated with early intra-uterine onset, death and multi-organ involvement in a prematurely born baby.  The protein prediction model indicated that the novel Q119X mutation would result in a non-functional protein by impairing the ability of the IL-1Ra to bind and antagonize signaling through the IL-1R.  Since the disorder may mimic severe bacterial infections and the treatment with anakinra is life-saving, these researchers intended to raise awareness of the syndrome and the possibility of a founder mutation that may lead to the diagnosis of additional cases in Turkey.  The clinical suspicion of DIRA is critical to avoid improper management of the patients with antibiotics alone and death from multi-organ failure. 

Schnellbacher et al (2013) described a 3-month old infant who presented to the authors’ institution with DIRA, which consists of neutrophilic pustular dermatosis, periostitis, aseptic multi-focal osteomyelitis, and persistently high acute-phase reactants.  Skin findings promptly improved upon initiation of treatment with anakinra , and the bony lesions and systemic inflammation resolved with continued therapy.  

Sozeri et al (2018) noted that autoinflammatory diseases can cause severe inflammation in bone and skin such as neonatal-onset multi-system inflammatory disease (NOMID), Majeed syndrome, IL-36 receptor antagonist deficiency (DITRA) and DIRA syndrome.  These investigators reported on the case of a 5-year old boy who was admitted to the hospital with pustular skin lesions and fever in the 1st month of his life.  Molecular analysis of IL1RN gene revealed a single homozygous C nucleotide deletion at nucleotide position 396 (p.Thr133Profs*118).  The novel p.Thr133Profs*118 mutation found in the authors’ study caused frameshift mutation and as a result, the respective protein was most likely non-functional.  The patient, who received a variety of treatments for various preliminary diagnoses until the final diagnosis (DIRA), was treated with anakinra, and experienced significant clinical improvement.  

An UpToDate review on “Cryopyrin-associated periodic syndromes and related disorders” (Nigrovic, 2020a) states that “DIRA -- Treatment with nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and glucocorticoids was only partially effective.  As expected from the pathophysiology, anakinra, a recombinant human IL-1 receptor antagonist, was highly effective in most patients”.  

Furthermore, an UpToDate review on “Periodic fever syndromes and other autoinflammatory diseases: An overview” (Nigrovic, 2020b) states that “Deficiency of the interleukin-1 receptor antagonist (DIRA, also called osteomyelitis, sterile multifocal, with periostitis and pustulosis [OMPP], MIM #612852) is a syndrome that presents in early infancy with a diffuse pustular skin rash, sterile osteomyelitis, and periostitis with articular pain in the setting of markedly elevated inflammatory markers but no fever.  This rare, autosomal recessive condition is due to mutations in IL1RN, the gene encoding the interleukin-1 (IL-1) receptor antagonist (IL1RA).  Treatment with recombinant IL1RA, anakinra, results in marked improvement”.

In December 2020, the U.S. FDA approved supplemental Biologics License Application (sBLA) for Kineret (anakinra) for the treatment of deficiency of IL-1 receptor antagonist (DIRA). FDA approval was based a long-term natural history study that evaluated the safety and efficacy of anakinra in 9 DIRA patients (ages 1 month to 9 years at the start of anakinra treatment) who were treated with anakinra for up to 10 years. All patients had genetically confirmed DIRA. The starting dose of anakinra was 1 to 2 mg/kg/day in the 6 patients for which the dose was reported. The dose was then individually adjusted to reach a stable efficacious dose to control active inflammation. The highest anakinra dose studied was 7.5 mg/kg/day. At the last visit during the first anakinra treatment period, the dose ranged between 2.2 and 6.1 mg/kg/day. Inflammatory remission was defined as achievement of all of the following criteria: CRP ≤ 5 mg/L, no pustulosis, no inflammatory bone disease, and no concomitant glucocorticosteroid use. All 9 patients achieved inflammatory remission while on anakinra treatment (SOBI, 2020a, 2020b)

The most common adverse events in patients with DIRA were upper respiratory tract infections, rash, pyrexia, influenza-like illness and gastroenteritis. The safety profile observed in patients with DIRA treated with Kineret was consistent with the safety profile of Kineret use in patients with NOMID, a previously approved indication. There were no permanent discontinuations of Kineret due to adverse events (SOBI, 2020a, 2020b).

Erdheim-Chester Disease

Aouba and colleagues (2010) stated that the pathophysiology of Erdheim-Chester disease (ECD) remains largely unknown.  Its treatment is not codified and usually disappointing.  Interferon-alpha (IFN-α) therapy lacks efficacy for some life-threatening manifestations and has a poor tolerance profile.  Because interleukin (IL)-1Ra synthesis is naturally induced after stimulation by IFN-α, these researchers hypothesized that recombinant IL-1Ra (anakinra) might have some efficacy in ECD.  These investigators treated 2 patients who had poor tolerance or contraindication to IFN-α with anakinra as a rescue therapy and measured their serum CRP, IL-1β, IL-6, and monocytic membranous IL-1α (mIL-1α) levels before, under, and after therapy.  Another untreated ECD patient and 5 healthy subjects were enrolled as controls.  After treatment, fever and bone pains rapidly disappeared in both patients, as well as eyelid involvement in 1 patient.  Furthermore, retroperitoneal fibrosis completely or partially regressed, and CRP, IL-6, and mIL-1α levels decreased to within the normal and control range.  Beside injection-site reactions, no AE was reported.  The authors concluded that these findings supported a central role of the IL-1 network, which appeared to be over-stimulated in ECD.  Its specific blockade using anakinra thereby opens new pathophysiology and therapeutic perspectives in ECD. 

Aubert and associates (2013) noted that ECD is a rare non-Langerhans cell histiocytosis (LCD) characterized by infiltration of foamy CD68-positive but CD1a-negative macrophages and fibro-inflammatory lesions as retroperitoneal, periureteral areas or bones.  Interferon-α therapy has been used as treatment but it had variable efficiency and limited tolerance.  More recently, anakinra was used with success but no skeletal radiological improvement was recorded.  These investigators reported a case of anakinra in the treatment of refractory bones infiltration in ECD.  After 1 year of treatment, the positron emission tomography-computed tomography (PET/CT) showed an outstanding response of the skeletal involvement with clearly lower and smaller hyper-metabolism images. 

Adam and colleagues (2014) stated that ECD is a very rare histiocytic disease.  It represents one form of juvenile xanthogranuloma (JXG) in WHO classification of blood diseases.  The disease often causes B symptoms, skeletal pain and also may cause diabetes insipidus and retroperitoneal fibrosis.  Selection of therapy depends on published case reports and small clinical trials.  There are no recommendations for treatment based on randomized studies; IFN-α is probably the most commonly used drug for this disease.  Some remissions have been described after treatment.  However, long-term IFN-α application is needed which is associated with numerous side effects.  There are limited experiences with clabridine in this indication.  In PubMed Medline data-base, these investigators found 3 publications dedicated to description of treatment response following cladribine in ECD and other 7 papers evaluating effect of cladribine on JXG forms, mostly with positive outcome.  Based on these 10 publications these researchers chose cladribine as 1st-line treatment in their patient.  The treatment started in October 2009 with combination of subcutaneous 2-chlorodeoxyadenosine (Litak) 5 mg/m2 + intravenous (IV) cyclophosphamide 150 mg/m2 + IV dexamethasone 24 mg, 5 days consecutively.  These cycles were repeated monthly.  Mentioned formula was submitted 4 times and 3 times in limited application on day 1 to 3.  The reason of that was neutropenia grade-3.  All symptoms disappeared after treatment.  Only diabetes insipidus persisted because damage of pituitary stalk was irreversible.  Therapeutic effect was monitored by PET/CT imaging, initially every 6 months, later in 12-month intervals.  PET/CT imaging showed complete remission of disease and 4.5 years duration of remission after treatment.  The treatment was well-tolerated with no complications implying hospitalization.  Only mild thrombocytopenia and neutropenia remained after 4.5 years.  Based on this  case report and publications, the authors considered cladribine as appropriate 1st-line pharmacotherapy for ECD.  Therapeutic failure after 3 to 4 cycles may suggest other options (IFN-α, anakinra, vemurafenib). 

Adam and co-workers (2016) stated that ECD is a histiocytic neoplasm of diseases from the group of non-LCD, formed by infiltrates of foamy histiocytes.  These pathological histiocytes produce pro-inflammatory cytokines.  Thus, ECD is known as inflammatory histiocytary neoplasm.  The disease is accompanied by clinical symptoms of systemic inflammatory response.  Imaging examinations detect typical osteosclerotic changes affecting diaphyses and metaphyses of the lower long bones and fibrotic changes that affect the aorta wall and the vessels leading from it.  Also characteristic are peri-renal fibrotic changes spreading in the retroperitoneum.  They can cause serious complications -- hydronephrosis with all its consequences.  The therapy for this disease was not satisfactory in the previous years.  Conventional chemotherapy or glucocorticoids do not bring any substantial and long-term improvement.  Considering cytostatic drugs, only 2-chlorodeoxyadenosine (cladribine) is effective, though not in all patients.  These investigators had only reached complete remission through 2-chlorodeoxyadenosine in 1 of their 2 patients, which lasted more than 5 years, while cladribine in the same patient did effect the reduction of infiltrates into the CNS, it did not achieve abatement of the disease activity in other locations as shown by PET/CT with the application of the radio-pharmaceutical fluorodeoxyglucose (FDG).  Another effective medicine for patients with ECD is IFN-α.  However its long-term administration is associated with multiple AEs, thus, these researchers did not test it in the described patient.  The introduction of anakinra to therapy brought a new hope for these patients.  These investigators described the patient who has been treated with anakinra for more than 5 years.  The patient applied 1 ampoule of 100-mg subcutaneously per day.  This treatment completely removed systemic B symptoms, relieved bone pains and attained normalization of all findings that signaled systemic inflammatory response.  The treatment effect was regularly checked by CT imaging of the abdomen and by FDG-PET/CT examinations.  The retroperitoneal fibrotic changes gradually regressed during the 5 years of anakinra treatment.  Low-dose CT imaging that was part of the PET/CT examination, identified many osteosclerotic lesions in the skeleton, mainly in the legs, with an increased accumulation of 18F-FDG.  Osteosclerotic lesions remained well visible at repeated examinations.  Still during the 5-year period, the FDG accumulation in them decreased.  Anakinra treatment had a character of maintenance therapy.  The BRAFV600E mutation was not proven in the described patient, thus, these researchers did not test vemurafenib treatment.  The authors concluded that anakinra effected regression of fibrotic changes in the retroperitoneum and disappearance of B symptoms as well as decrease in FDG accumulation at FDG-PET/CT examination. 

Andre and Seebach (2017) noted that ECD is a rare multi-systemic non-LCD with about 500 reported cases.  Typical features include retroperitoneal and peri-renal fibrosis (hairy kidney), peri-aortitis with a coated aorta, osteosclerosis of the lower limbs, and sometimes exophthalmia or diabetes insipidus.  Histology is the cornerstone for diagnosis showing an infiltrate with foamy histiocytes and occasional multi-nucleated giant cells (Touton cells).  There is no standard treatment regimen, current options include corticosteroids, IFN-alpha, systemic chemotherapy, and radiation therapy; however, a better understanding of the pathophysiological mechanisms has allowed the emergence of novel targeted treatments such as vemurafenib, imatinib, and anakinra. 

Franconieri and colleagues (2018) noted that in ECD, the empirical single-dose (SD, 100 mg/day) anakinra sometimes induces only partial responses (PRs).   Since SD is usually well-tolerated, doubling the dose might improve response while maintaining an acceptable safety profile.  A retrospective analysis was performed of outcomes under double-dose (DD) of anakinra in 4 ECD patients who did not exhibit a complete response (CR) under SD treatment.  Bone, retroperitoneal, neurologic/orbital, peritoneal, pericardial, right atrium, and pleural involvements were recorded; CR, PR, stable disease, progressive disease (PD) and tolerance of DD were assessed.  SD treatment was a 2nd or 3rd line treatment in 3 patients after IFN-therapy failure; 2 patients, including 1 with a BRAF mutation, achieved a CR and 1 patient with a NRAS mutation achieved a PR with DD treatment.  The 4th patient, wild-type for both genes, did not respond to a 1st DD treatment, but then achieved CR under SD associated with a reduced dose of vemurafenib (960 mg/d).  Bone and retroperitoneal lesions partially improved on imaging with SD in all patients, but were further improved under DD with 2 patients achieving CR.  With SD treatment, 2 patients with right atrial masses showed sustained CR.  Under DD treatment, 2 patients with massive serositis refractory to SD, showed PR.  The authors concluded that DD improved the response to anakinra and led to 2 CRs and 1 PR in 3 out of 4 ECD patients, with minor and comparable side-effects to those of SD, while failures were essentially related to massive serositis.  These researchers stated that these findings suggested that the increased dose of anti-IL-1 drugs or their combination with anti-BRAF drugs may offer a synergic and optimal treatment option in refractory ECD.  BRAF and/or MEK inhibitors have or will likely proved their frequent efficacy in patients with corresponding mutations in prospective studies. Therefore, the strategic place of anti-cytokine therapy such as anakinra, which exhibits the most effect in ECD, remains to be specified considering the toxicity profiles of these targeted therapies and patients’ history of cutaneous neoplasm other than melanoma. 

Tomelleri et al (2018) stated that pericarditis is an inflammatory heart disease, which may be idiopathic or secondary to autoimmune or auto-inflammatory diseases and often leads to severe or life-threatening complications.  Colchicine and NSAIDs represent the mainstay of treatment, whereas use of corticosteroids is associated with recurrence of disease flares.  While effective and safe anti-inflammatory therapies remain an unmet clinical need, emerging clinical and experimental evidence points at a promising role of inhibition of the pro-inflammatory cytokine IL-1.  These researchers examined treatment with anakinra in a case of extremely severe pericarditis with cardiac tamponade and heart failure secondary to ECD.  A 62-year old man was admitted to the Emergency Department with severe pericardial effusion requiring the creation of a pleuro-pericardial window.  A whole-body contrast-enhanced CT pointed at a diagnosis of ECD with involvement of the heart and pericardium and of the retroperitoneal space.  Over the following days, an echocardiography (ECG) revealed a closure of the pleuro-pericardial window and a relapse of the pericardial effusion.  Treatment with anakinra was started at a standard subcutaneous dose of 100 mg/day.  After 2 days, these investigators observed a dramatic clinical improvement, an abrupt reduction of the inflammatory markers, and a reabsorption of the pericardial effusion.  Anakinra was maintained as monotherapy, and the patient remained asymptomatic in the absence of disease flares for the following year.  The authors concluded that recent studies pointed at inhibition of IL-1 activity as a therapeutic option for patients with refractory idiopathic recurrent pericarditis; and anakinra may also have a role in patients with pericarditis in the setting of systemic inflammatory disorders, such as ECD.  These researchers stated that confirmatory studies of IL-1 inhibition in ECD heart involvement are needed. 

Furthermore, an UpToDate review on “Erdheim-Chester disease” (Jacobsen, 2020) states that “IL-1-receptor antagonist (IL-1RA) production is stimulated by interferon alfa, and there are case reports of recombinant IL-1RA (anakinra, canakinumab) inducing responses in a small group of patients who could not tolerate interferon alfa”.

Familial Mediterranean Fever

Akgul et al (2013) stated that colchicine is the mainstay treatment for familial Mediterranean fever (FMF). However 5 % to 10 % of the patients with FMF are unresponsive or intolerant to colchicine.  Biologics are efficient in many rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, cryopyrin-associated periodic syndromes.  These researchers performed a systematic review to analyze patients with 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 efficacy and safety of biologics in FMF; 59 patients (32 female and 27 male) 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 years old).  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 efficacy of biologics in the treatment of patients with FMF.

Basaran et al (2015) evaluated and discussed treatment of pediatric FMF patients with anti-interleukin1 (IL-1) agents. Refractory or colchicine unresponsive FMF was described as severe and frequent attacks and/or having high acute phase reactance levels despite having a maximum dose of colchicine (2 mg/day).  Disease course, adverse effects, duration of follow-up, treatment protocols, responses to the therapies were discussed.  A total of 8 patients (6 male, 2 female) having refractory FMF were identified.  Mediterranean fever (MEFV) gene analyses revealed homozygous M694V mutations in 6 patients and heterozygote M694V mutations in 1 patient and no mutation in 1 patient.  They were all treated with anakinra and/or canakinumab.  The use of anti-IL-1 drugs was beneficial to all patients.  None of them had any severe adverse effects due to the therapy.  The authors concluded that anakinra and canakinumab were effective in patients refractory to colchicine treatment as shown both in this series and in the literature.  Therefore, they stated that controlled trials are needed to evaluate the safety and long-term efficacy of IL-1 targeting agents in colchicine resistant patients.

In a Cochrane review, Wu and colleagues (2015) evaluated the safety and effectiveness of interventions for reducing inflammation in people with FMF. They used detailed search strategies to search the following databases: CENTRAL; MEDLINE; Embase; Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure Database (CNKI); Wan Fang; and VIP.  In addition, they also searched the clinical trials registries including ClinicalTrials.gov, the International Standard Randomized Controlled Trial Number Register, the WHO International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry, as well as references listed in relevant reports.  Date of last search was May 21, 2014.  Randomized controlled studies of people with diagnosis of FMF, comparing active interventions (including colchicine, anakinra, rilonacept, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuard™ (a herbal dietary supplement) and non-steroidal anti-inflammatory drugs) with placebo or no treatment, or comparing active drugs to each other.  The authors independently selected studies, extracted data and assessed risk of bias.  They pooled data to present the risk ratio or mean difference with their 95 % CI.  They assessed overall evidence quality according to the GRADE approach.  These investigators included 4 randomized placebo-controlled studies with a total of 75 participants (aged 3 to 53 years); 3 were of cross-over and 1 of parallel design.  Two studies used the active intervention of oral colchicine (0.6 mg 3 times daily or 0.5 mg twice-daily), 1 study used oral ImmunoGuard™ and the 4th used rilonacept as a subcutaneous injection.  The duration of each study arm ranged from 1 to 3 months.  The 2 most recent studies were generally well-designed, except for an unclear risk of detection bias in 1 of these.  However, some inadequacy existed in the other 2 older studies, where each had an unclear risk of selection bias, a high risk of attrition bias, an unclear risk of reporting bias and a high risk of other potential bias (baseline characteristics such as mutation status and disease severity were not described); 1 of these studies additionally had an unclear risk of detection bias.  The authors aimed to report on the number of participants experiencing an attack, the timing of attacks, any adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack, but data were not available for all outcomes across all comparisons.  Based on 1 study (15 participants), there was a significant reduction in the number of people experiencing attacks at 3 months when colchicine was administered at a dose of 0.6 mg 3 times daily (14 % versus 100 %), risk ratio 0.21 (95 % CI: 0.05 to 0.95); however, the GRADE evidence quality was low.  Based on 2 further studies, there was no significant reduction in the number of participants experiencing attacks at 2 months when colchicine was administered at a dose of 0.5 mg twice-daily (22 participants) in people with FMF, or at 3 months when rilonacept was used in individuals who were colchicine-resistant or colchicine-intolerant (14 participants).  In the ImmunoGuard™ study (24 participants) acute phase response indicators (including erythrocyte sedimentation rate, white blood cell count and C-reactive protein) were not reduced after 1-month treatment.  The authors concluded that there were limited randomized controlled studies assessing interventions for people with FMF.  Based on the evidence, colchicine appears to reduce the number of people experiencing attacks; however, only a few low-quality randomized controlled studies contributed data for analysis.  They stated that further RCTs examining active interventions, not only colchicine, are necessary before a comprehensive conclusion regarding the efficacy and safety of interventions for reducing inflammation in familial Mediterranean fever can be drawn.

Furthermore, an UpToDate review on “Management of familial Mediterranean fever” (Goldfinger, 2016) states that “A few colchicine-resistant FMF patients have shown responsiveness to thalidomide (initial dose 100 mg daily), etanercept (25 mg subcutaneously twice weekly), infliximab, and anakinra (an interleukin-1 receptor antagonist) and rilonacept. However, the true efficacy and safety of treatment with biological agents remains uncertain because of the paucity of reports and absence of controlled trials”.

Fatigue Associated with Sjogren's Syndrome

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) hypothesized 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 analyzed 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.

Febrile Infection-Related Epilepsy Syndrome

Kenney-Jung and colleagues (2016) noted that febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited therapeutic options and an unclear etiology.  Anakinra is a recombinant version of the human IL-1 receptor antagonist used to treat auto-inflammatory disorders.  This is the 1st report of anakinra for the treatment of a child with super-refractory status epilepticus secondary to FIRES.  Anakinra was well-tolerated and effective.  Cerebral spinal fluid analysis revealed elevated levels of pro-inflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuro-inflammation in FIRES.  The authors noted that the findings, while promising, must be interpreted with caution.  It is difficult to determine precisely which therapy resulted in seizure control at a given time.  Increased electrographic seizures were at least in part controlled by escalating the midazolam infusion, but these effects were temporary, and seizures broke through despite unsustainable, extremely high doses of midazolam.  Only with the addition of anakinra were these investigators able to successfully decrease and wean the midazolam infusion.  Further, seizure control was maintained for 5 months after midazolam and the ketogenic diet had been discontinued, and only recurred when these researchers attempted to slowly wean anakinra.  The authors concluded that further studies are needed to evaluate anakinra effectiveness, dosing and time of intervention, and to further delineate disease etiology.

Focal and Segmental Glomerulosclerosis

Boehm and colleagues (2019) noted that focal and segmental glomerulosclerosis (FSGS) is a severe glomerulopathy that frequently leads to end stage renal disease (ESRD).  Only a subset of patients responds to current therapies, making it important to identify alternative therapeutic options.  Anakinra is beneficial in several diseases with renal involvement.  These researchers evaluated the potential of anakinra for FSGS treatment.  Molecular process models obtained from scientific literature data were used to build FSGS pathology and anakinra mechanism of action models by exploiting information on protein interactions.  These molecular models were compared by statistical interference analysis and expert based molecular signature matching.  Experimental validation was performed in adriamycin- and lipopolysaccharide (LPS)-induced nephropathy mouse models.  Interference analysis (containing 225 protein coding genes and 8 molecular process segments) of the FSGS molecular pathophysiology model with the drug mechanism of action of anakinra identified a statistically significant overlap with 43 shared molecular features that were enriched in pathways relevant in FSGS, such as plasminogen activating cascade, inflammation and apoptosis.  Expert adjudication of molecular signature matching, focusing on molecular process segments did not suggest a high therapeutic potential of anakinra in FSGS.  In line with this, experimental validation did not result in altered proteinuria or significant changes in expression of the FSGS-relevant genes COL1A1 and NPHS1.  The authors concluded that an integrated bioinformatic and experimental workflow showed that FSGS relevant molecular processes could be significantly affected by anakinra beyond the direct drug target IL-1 receptor type 1 (IL1R1) context; but might not counteract central pathophysiology processes in FSGS.  These researchers stated that anakinra is therefore not suggested for extended pre-clinical trials.

Gout

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.

Although the Prescribing Information for Kineret (anakinra) does not list gout as an FDA-approved indication, it is listed in Lexicomp and UpToDate, as an "off-label use" for the treatment of refractory gout flares. Becker and Gaffo (2019) state that anakinra (100 mg daily, administered subcutaneously) is the preferred IL-1 antagonist for use in a gout flare because of its short half-life of IL-1 blockade and its relatively modest cost compared with other alternative IL-1 inhibitors, such as canakinumab. The authors cite a randomized trial involving 88 patients with a crystal-proven gout flare who received anakinra (100 mg daily for five consecutive days) which resulted in similar degrees of benefit to usual antiinflammatory flare treatment (with either colchicine, oral glucocorticoids, or full-dose naproxen) with respect to magnitude of change in pain from baseline through days 2 to 4 of treatment, and anakinra resulted in comparable safety and improvements in pain, index joint swelling, and tenderness at day 5. However, the randomized trial did not follow patients long enough to evaluate the observation in prior reports that recurrent flares were not uncommon among anakinra-treated patients within one to six weeks after stopping therapy. The authors concluded that the short biologic half-life of anakinra, which mandates daily subcutaneous administration, makes anakinra an unlikely candidate for gout flare prophylaxis but may, in the case of gout flares, provide an advantage in safety, since blocking of IL-1 beta action is rapidly reversed when treatment with anakinra is discontinued. Becker and Gaffo (2019) recommend anakinra or 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.

Gout Flares Associated with Chronic Kidney Disease

Balasubramaniam and associates (2017) stated that acute gout occurs in people with chronic kidney disease (CKD), who are commonly older people with co-morbidities such as hypertension, heart disease and diabetes.  Potentially harmful treatments are administered to these vulnerable patients due to a lack of clear evidence.  Newly available treatment that targets a key inflammatory pathway in acute gout attacks provides an opportunity to undertake the first-ever trial specifically looking treating people with kidney disease.  These researchers described the protocol for a feasibility RCT comparing anakinra versus steroids in people with chronic kidney disease (the ASGARD Trial).  The ASGARD Trial is a 2-parallel group, double-blind, double-dummy multi-center RCT comparing subcutaneous anakinra 100 mg for 5 days against intramuscular methylprednisolone 120 mg.  The primary objective is to assess the feasibility of the trial design and procedures for a definitive RCT.  The specific aims are test recruitment and retention rates and willingness to be randomized; test eligibility criteria; collect and analyze outcome data to inform sample and power calculations for a trial of efficacy; collect economic data to inform a future economic evaluation estimating costs of treatment; and assess capacity of the project to scale up to a national multi-center trial.  These investigators will also gather qualitative insights from participants.  It aims to recruit 32 patients with a 1:1 randomization. Information from this feasibility study will help design a definitive trial and provide general information in designing acute gout studies.  The London-Central Ethics Committee approved the protocol; the results will be disseminated in peer-reviewed journals and at scientific conferences.

In a retrospective, multi-center, study, Loustau and colleagues (2018) examined the safety and efficacy of anakinra for the treatment of gout flares in patients with stage 4 to 5 CKD or renal transplantation.  This study included 3 academic centers with consecutive patients with stage 4 to 5 CKD or kidney transplantation who received anakinra for the treatment of acute gouty arthritis and completed at least one follow-up visit.  Efficacy, occurrence of infection, and renal function variations were recorded.  Of the 31 included patients (24 men, mean age of 72 ± 11 years), 25 were non-transplant subjects with stage 4 to 5 CKD (mean estimated glomerular filtration rate [GFR], MDRD formula (eGFR) 22.7 ± 6.5 ml/min/1.73 m2), and 6 had undergone kidney transplantation (mean eGFR 41.5 ± 22.8 ml/min/1.73 m2).  Median gout duration was 3.5 years, and the mean serum urate (SUA) level was 8.7 mg/dL; 21 (68 %) patients had tophi, and 21 had gout arthropathy.  Anakinra was effective in all patients (final VAS 10 and CRP level 10 mg/L); 10 patients (32 %) were anakinra-dependent (i.e., required prolonged treatment with anakinra).  A serious infection was recorded in only 1 patient, occurring 3 months after starting anakinra.  No significant variation in renal function was observed.  The authors concluded that anakinra may be a safe therapeutic option for gout patients with advanced CKD; further RCTs are needed to confirm these findings.

Heart Failure (Prevention of Heart Failure after Acute Myocardial Infarction)

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.

Van Tassell and colleagues (2017) hypothesized that administration of anakinra could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF.  These researchers randomly assigned 60 patients with reduced left ventricular ejection fraction (LVEF of less than 50 %) and elevated C-reactive protein levels (CRP of greater than 2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo.  Patients underwent measurement of peak oxygen consumption (Vo2 [ml/kg per minute]) and ventilatory efficiency (the VE/Vco2 slope).  Treatment with anakinra did not affect peak Vo2 or VE/Vco2 slope at 2 weeks.  At 12 weeks, patients continued on anakinra showed an improvement in peak Vo2 from 14.5 (10.5 to 16.6) ml/kg per minute to 16.1 (13.2 to 18.6) mL/kg per minute (p = 0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups.  The between-groups differences, however, were not statistically significant.  The incidence of death or re-hospitalization for HF at 24 weeks was 6 %, 31 %, and 30 %, in the anakinra 12-week, anakinra 2-week, and placebo groups, respectively (log-rank test p = 0.10).  The authors concluded that no change in peak Vo2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks.  They stated that additional larger studies are needed to validate the effects of prolonged anakinra on peak Vo2 and re-hospitalization for HF.

Hemophagocytic Lymphohistiocytosis

Wohlfarth and colleagues (2019) noted that hemophagocytic lymphohistiocytosis (HLH) causes multiple organ dysfunction frequently leading to ICU referral and/or death.  These investigators reported on a series of critically ill adult patients treated with a non-etoposide-based regimen including anakinra, IVIG, and/or corticosteroids (CS) for HLH.  A total of 8 adult (greater than or equal to 18 years) ICU patients having received treatment with anakinra ± IVIG ± CS for HLH between March 2014 and March 2016 at a large tertiary care university hospital were retrospectively analyzed.  Patients (median age of 38 years; range of 20 to 58 years; 4 men and 4 women) received anakinra together with IVIG (n = 7) and/or high-dose CS (n = 5) for suspected reactive HLH (median H-score of 214; range of 171 to 288); 7 (88 %) patients required vasopressors and invasive mechanical ventilation; and 6 (75 %) patients required renal replacement therapy (median Sequential Organ Failure Assessment [SOFA] score at HLH diagnosis: 9.5; range of 6 to 14); 6 patients showed a significant decline in the SOFA score at 1 and 2 weeks following treatment initiation (p = 0.03), and the remainder 2 patients experienced early death; 5 patients survived to ICU discharge, 4 of them could further be discharged from hospital (hospital survival rate: 50 %).  No overt treatment-related toxicity was noted.  The authors concluded that anakinra in combination with IVIG and/or CS resulted in a hospital survival rate of 50 % in 8 critically ill adult patients with HLH despite a vast degree of organ dysfunction and the need for aggressive ICU treatment.  Moreover, they stated that further research on non-etoposide-based treatment strategies for HLH in critically ill adults is needed.

Hidradenitis Suppurativa

In a double-blind, randomized, placebo-controlled, pilot study, Tzanetakou and colleagues (2016) examined the safety and effectiveness of anakinra in patients with hidradenitis suppurativa (HS).  This study had a 12-week treatment phase and a 12-week follow-up phase.  Participants were 20 patients with Hurley stage II or III HS.  Patients were randomized to receive injections from identical syringes containing placebo or anakinra subcutaneously once-daily for 12 weeks.  Peripheral blood mononuclear cells were isolated and stimulated for cytokine production before the beginning of treatment and at week 12 (the end of treatment) and week 24.  The primary end-point was the effect of anakinra on HS disease severity; secondary end-points were the time to a new exacerbation and the production of cytokines.  Among the 20 trial participants, 10 each were randomized to the group to receive anakinra or the placebo group.  The mean (SD) ages were 42.8 (13.8) and 36 (11.3) years in the anakinra and placebo groups, respectively.  The disease activity score was decreased at the end of treatment in 20 % (2 of 10) of the placebo arm compared with 67 % (6 of 9) of the anakinra arm (p = 0.04).  Hidradenitis suppurativa clinical response at 12 weeks was achieved in 30 % (3 of 10) of the placebo arm and in 78 % (7 of 9) of the anakinra arm (p = 0.04).  The production of interferon-gamma by peripheral blood mononuclear cells in the anakinra arm was decreased, and the production of IL-22 was increased.  The time to a new HS exacerbation was prolonged in the anakinra arm by log-rank test (log rank, 6.137; p = 0.01).  No serious AEs were reported.  The authors concluded that anakinra has the potential to be an effective and well-tolerated treatment for HS; inhibition of IL-1 is a promising treatment strategy.  The main drawback of this study was the small sample size (n = 20) owing to the fact that this was a pilot study. 

The European evidence-based guidelines on the treatment of HS (Gulliver et al, 2016) did not mention anakinra as a therapeutic option.

Andersen and Jemec (2017) noted that HS is not easily treated.  Although not uncommon, HS is often mis-diagnosed outside specialized clinics and inappropriately treated as a simple boil or abscess.  In recent years, guidelines have been developed on the basis of expert opinion and the available literature.  A multi-faceted approach is necessary as HS lesions include both inflammation (amenable to medical treatment) as well as fibrosis (amenable to surgery only).  The recommended anti-inflammatory therapies encompass both anti-microbials and regular anti-inflammatory drugs.  These investigators reviewed treatments with the following agents: clindamycin, tetracycline, rifampicin, ertapenem, dapsone, triamcinolone, infliximab, adalimumab, and anakinra.  The development of new medical treatments, however, is an ongoing effort, and important new data have been presented since the publication of the guideline.  The current approach to the management of fibrotic lesions is surgery.  It is important, as manifest fibrosis is generally not susceptible to medical treatment.  The authors also discussed minor excision, carbon dioxide-laser, and major surgery, and provided current evidence supporting their use.  A comprehensive 3-pronged approach with adjuvant therapy, medical therapy, and surgery is recommended.  The importance of adjuvant therapy, that is, pain management, wound care, and attention, was stressed.  The authors stated that adjuvant therapy not only plays a major role in patients' perception of a successful treatment but also is of practical importance to their coping and self-management.

Furthermore, an UpToDate review on “Hidradenitis suppurativa (acne inversa): Treatment” (Dahl, 2017) lists anakinra as an emerging therapy.  It states that “Ustekinumab and anakinra are newer therapies that may be of benefit for patients with severe and refractory HS/AI based upon limited data … Failure to respond to anakinra (100 mg per day) has been reported.  Additional data are needed to clarify the role of anakinra in HS/AI”.

Hydroxyapatite Calcification-Induced Joint Pain

Zufferey and colleagues (2019) noted that hydroxyapatite (HA) crystal calcifications in or around the joint can induce acute flares with severe pain.  A previous pilot study suggested that anakinra was effective. In a retrospective, observational study, these investigators attempted to confirm these results in a larger set of patients and to report on the long-term follow-up.  Flare was defined as acute pain for less than 10 days.  Calcification in or around a joint (rotator cuff: 15/23 patients) was confirmed by conventional radiography and/or US.   Anakinra 100-mg daily was administered subcutaneously for 1 to 3 consecutive days.  Clinical data collected before the injection and on days 3 and 21 included pain score on a VAS (0 to 10 cm) and CRP level.  When available, US baseline and follow-up findings were compared.  Long-term follow-up data were collected from patient charts and/or after a phone call.  A total of 23 patients (15 men, mean [SD] age of 58 [11] years) were included.  Baseline mean (SD) VAS pain was 7.7 (1) cm and CRP level was elevated in 50 % of the patients.  After therapy, mean (SD) VAS pain score decreased rapidly in the first 3 days to 1.6 (1.4) cm (p < 0.001) and remained stable for 3 weeks at 1.8 (2.1) cm; US assessment revealed decreased Doppler intensity but no significant change in size of calcifications.  No significant side effects were noted.  After long-term follow-up (median duration of 24 months), 50 % of the patients still had some chronic pain, but only 4 experienced acute relapses.  The authors concluded that the findings of this study suggested that anakinra may be an efficient therapeutic approach for acute HA flare, with a good safety profile.  Moreover, these researchers stated that RCTs are needed to better determine the place of this treatment in HA flare management.

The authors stated that this study had some important drawbacks due to the retrospective, observational design and the missing data for some of the evaluated parameters.  A RCT is needed to show that anakinra is definitively effective in acute HA flare.  Moreover, the drug has been tested in only very acute inflamed conditions, which does not prove that it can be useful in chronic or subacute pain syndromes associated with a calcific tendinopathy, with or without Doppler activity.  Finally, the potential future indication of anakinra as compared with other available therapeutic modalities needs to be better evaluated, including the cost-effectiveness.  Of note, the cost of this drug delivered for only 2 or 3 days is not much more than that for other treatments such as steroids or the cost for the rest, especially if future studies confirm that anakinra can shorten the duration of acute invalidating pain and loss of function.

Hyperimmunoglobulin D Syndrome

An UpToDate review on “Hyperimmunoglobulin D syndrome: Management” (Padeh and Rubinstein, 2019) states that “For patients who do not respond to either NSAIDs or glucocorticoids or who would benefit from a steroid-sparing agent and still want to continue treating episodes, we use the biologic anakinra, a short-acting anti-interleukin (IL) 1 agent”.

Idiopathic Recurrent Pericarditis

Lazaros and colleagues (2016) noted that accumulating evidence suggested idiopathic recurrent pericarditis as a disease of probable auto-inflammatory origin, thus anakinra could be of benefit.  In a systematic review, these investigators evaluated the safety and effectiveness of anakinra in this context.  Reports relevant to anakinra administration in patients with idiopathic recurrent pericarditis published up to October 2014 were searched in several databases.  All references found, upon initial assessment at title and abstract level for suitability, were consequently retrieved as full reports for further appraisal.  Among 12 citations retrieved, 9 reports (4 case series and 5 case reports with 34 patients, 20 men, mean age of 26.8 years) were assessed.  The mean disease duration was 31 months and the number of recurrences was 8.2.  Anakinra was generally administered as a daily subcutaneous injection of 100 mg or as a mean dose of 1.1 mg/kg/day in weight-adjusted regimens.  The mean full-dose duration was 9.2 months; CRP normalized within 7.1 days, and steroids were withdrawn within 62 days.  Dose tapering was adopted in 64.7 % of patients, leading to recurrence in 26 % of cases.  In a 28.3-month follow-up, 8 out of 34 patients (23.5 %) were disease-free without treatment, after having received anakinra for 10.4 months overall.  Anakinra was well-tolerated, with mild local reaction being reported in 44 % of patients.  The authors concluded that anakinra is a highly effective, rapidly acting, well-tolerated and steroid-sparing agent.  Recurrences after drug discontinuation are a matter of concern.  They stated that randomized trials are needed to confirm these findings and address the most effective treatment protocol.

Imazio and associates (2016) stated that recurrent pericarditis is one of the most common and troublesome complications after an episode of pericarditis, affecting 20 to 50 % of patients treated for pericarditis.  In most of these patients, the pericarditis remains idiopathic, although an immune-mediated (either autoimmune or auto-inflammatory) pathogenesis is often presumed.  The mainstay of therapy for recurrences is aspirin or NSAIDs, with the adjunct of colchicine.  Corticosteroids are a 2nd-line option to be considered for specific indications, such as connective tissue disease or pregnancy; contraindications or intolerance to aspirin, NSAIDs, and/or colchicine; or insufficient response to these medications.  Furthermore, corticosteroids can be added to NSAIDs and colchicine in patients with persistent symptoms.  In patients who do not respond adequately to any of these conventional therapies, alternative treatment options include azathioprine, IVIGs, and anakinra.  An improved understanding of how recurrent pericarditis develops after an initiating event is critical to prevent this complication, and further research is needed into the pathogenesis of recurrences.

Intestinal Mucositis

Ozcicek and colleagues (2020) stated that intestinal mucositis is an important problem in the patients receiving cancer treatment.  These investigators examined the effect of anakinra on methotrexate-induced small intestine mucositis in rats.  A total of 40 rats were divided into 4 groups with 10 in each group.  The healthy group (HG) and the methotrexate group (MTXG) were given distilled water, while the methotrexate+anakinra 50 (MTX+ANA50) and the methotrexate+anakinra 100 (MTX+ANA100) groups were intraperitoneally administered 50 and 100 mg/kg of anakinra.  After 1 hour, the MTXG, MTX+ANA50 and MTX+ANA100 groups were given oral methotrexate at a dose of 5 mg/kg.  This procedure was repeated once-daily for 7 days.  After the rats had been sacrificed, the small intestine tissue of rats were removed for the evaluation of biochemical markers, histopathological evaluation and gene expression analyze.  Statistical analyses of the data were performed using 1-way ANOVA.  Malondialdehyde (MDA), myeloperoxidase (MPO) and interleukin-6 (IL-6) levels were significantly higher, whereas total glutathione (tGSH) levels were significantly lower in MTXG (p < 0.001) compared to other groups.  MTX also increased IL-1β and TNF-α gene expression levels in MTXG (p < 0.001).  Inflammatory cell infiltration and damage to the villus were observed histopathologically in the MTXG group, whereas only mild inflammation was observed in the MTX+ANA100 group.  A dose of 100 mg/kg of anakinra prevented the increase of the biochemical markers and gene expression levels better than a dose of 50 mg/kg.  The authors concluded that intestinal mucositis caused by MTX may be prevented by co-administration of anakinra.

Juvenile Idiopathic Arthritis

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.

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).

Kawasaki Disease

Tremoulet et al (2016) noted that although Kawasaki disease (KD) is the most common cause of acquired heart disease in children and may result in coronary artery aneurysms (CAA) with an attendant risk of MI, there is no recommended therapy to halt progression of arterial wall damage and prevent aneurysm formation in the acute phase of the vasculitis. While intravenous immunoglobulin (IVIG) reduces the risk of CAA, up to 20 % of KD patients are IVIG resistant and have a higher risk for developing CAA.  The IL-1 pro-inflammatory pathway is up-regulated in children with acute KD and plays a critical role in the experimental animal model of KD.  Thus, IL-1 is a logical therapeutic target.  In a 2-center dose-escalation phase I/IIa clinical trial, these researchers determined the safety, tolerability, pharmacokinetics, and immunomodulatory effects of anakinra in acute KD patients with coronary artery abnormalities on the baseline echocardiogram.  A total of 30 acute KD patients of greater than or equal to 8 months old with a coronary artery Z score of greater than or equal to 3.0 in the right coronary artery and/or left anterior descending artery or an aneurysm will be recruited for this study.  Subjects will receive a 2- to 6-week course of anakinra by daily subcutaneous injection and will be assessed for resolution of inflammation and dose limiting toxicities (leukopenia, anaphylactoid reaction, or severe infection).  The authors concluded that the safety and tolerability of blocking both IL-1α and Il-1β by anakinra will be evaluated as a strategy to prevent or attenuate coronary artery damage in infants and children with acute KD.

Lupus Arthritis

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).

Myocarditis

Cavalli and colleagues (2017) noted that support measures currently represent the mainstay of treatment for fulminant myocarditis, while effective and safe anti-inflammatory therapies remain an unmet clinical need.  However, clinical and experimental evidence indicated that inhibition of the pro-inflammatory cytokine IL-1 is effective against both myocardial inflammation and contractile dysfunction.  These researchers evaluated treatment with the IL-1 receptor antagonist anakinra in a case of heart failure secondary to fulminant myocarditis.  A 65-year old man with T cell lymphoma developed fulminant myocarditis presenting with severe bi-ventricular failure and cardiogenic shock requiring admittance to the intensive care unit (ICU) and mechanical circulatory and respiratory support.  Specifically, acute heart failure and cardiogenic shock were initially treated with non-invasive ventilation and mechanical circulatory support with an intra-aortic balloon pump.  Nevertheless, cardiac function deteriorated further, and there were no signs of improvement.  Treatment with anakinra was started at a standard subcutaneous dose of 100 mg/day.  These investigators observed a dramatic clinical improvement within 24 hours of initiating anakinra.  Prompt, progressive amelioration of cardiac function allowed weaning from mechanical circulatory and respiratory support within 72 hours of anakinra administration.  Recent studies pointed at inhibition of IL-1 activity as an attractive therapeutic option for both myocardial inflammation and contractile dysfunction.  Furthermore, IL-1 receptor blockade with anakinra was characterized by an extremely rapid onset of action and remarkable safety and may thus be suitable for the treatment of patients critically ill with myocarditis.  The authors concluded that further studies of IL-1 blockade in myocarditis are needed to validate use in critically ill patients.  Specifically, prospective evaluation of a 2-week treatment course with anakinra 100-mg daily in addition to conventional life support measures may unequivocally assess the impact on acute and mid-term LVEF changes.  Additional outcome measures of interest include survival, requirements for and doses of conventional pharmacologic therapy, assessments of symptoms, and arrhythmias.

Myopathy/Myositis

Zong and colleagues (2014) 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.

Non-Alcoholic Steatohepatitis (NASH)

Jahn and colleagues (2016) stated that non-alcoholic fatty liver (NAFL) disease is defined by an accumulation of liver fat exceeding 5 % of its weight in the absence of significant alcoholic intake.  In 5 to 20 %, there is a progression from NAFL to non-alcoholic steatohepatitis (NASH).  Until now, it is not well-understood why only some patients develop NASH, and currently, no drugs are licensed for this indication.  Different T-cell populations such as T-regulatory, Th1 and Th17 cells play a central role in the immunopathogenesis of fatty liver disease and open the option of future IL-17-based therapeutics.  The inflammatory process underlying NASH is furthermore characterized by elevated expression of pro-inflammatory cytokines such as TNFα and IL-1β.  Anakinra, a recombinant version of IL-1Ra shows promising metabolic effects with improved hyperglycemia and beta-cell secretory function in a double-blind, placebo controlled, randomized trial in type 2 diabetic patients; but such studies are still in their preliminary stages for NASH.  They noted that several studies pointed out that bile acid farnesoid X receptor (FXR)-mediated signals (such as the enterohepatic hormone fibroblast growth factor 15/19) are involved in the regulation of triglyceride and glucose metabolism.  Recent clinical trials have revealed a beneficial impact of the FXR agonist obeticholic acid on body weight, insulin sensitivity and liver histology in patients with NASH.  The authors concluded that further potential novel therapeutic targets in NASH are currently in phase II clinical development.

Osteoarthritis

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.

Pustular Psoriasis

Cro and colleagues (2018) stated that palmo-plantar pustulosis (PPP) is a rare, chronic inflammatory skin disease.  It is known to affect QOL at a level comparable to that from major medical and psychiatric illness, yet current therapeutic options are remarkably limited.  Recent evidence however suggested that IL-1 blockade with anakinra will deliver therapeutic benefit in PPP.  Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) is a 2-staged, adaptive, double-blind, randomized placebo-controlled trial that aims to test the hypothesis that IL-1 blockade with anakinra will deliver therapeutic benefit in PPP.  During stage 1 a total of 24 patients will be randomized (1:1) to receive either placebo or anakinra.  The 2 candidate primary outcomes are fresh pustule count (across palms and soles) and the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score, recorded at baseline and at weeks 1, 4 and 8.  Analysis at the end of stage 1 will compare treatment arms to ensure sufficient efficacy and safety in order to progress to stage 2.  The primary outcome for stage 2 will also be identified following an assessment of the reliability and discriminative ability of fresh pustule count and PPPASI.  The trial is powered to detect efficacy and will recruit an additional 40 patients in stage 2 (n = 64 in total).  Analysis will follow the intention-to-treat (ITT) principle and analyze patients as randomized.  The authors stated that the findings of the trial will help to clarify the role of anakinra in the treatment of PPP.

Pyoderma Gangraenosum

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.

Recurrent Fevers in Systemic Lupus Erythematosus

Dein and colleagues (2018) stated that fever is a common manifestation in systemic lupus erythematosus (SLE) and may be associated with disease activity, but should be closely evaluated for infection, drug reaction, thromboembolism, malignancy, or other etiology.  These investigators presented the case of a 44-year old woman with SLE with periodic high fevers and elevated high-sensitivity CRP (hs-CRP) levels, treated with anakinra.  Following the birth of her 1st child, she developed frequent episodic fevers followed by multiple hospitalizations, approximately 2 to 3 times per year.  She was started on anakinra in September 2016 and had improvement of fevers and joint symptoms.  On 26-month follow-up, she had 1 episode of fever with bandemia requiring hospitalization but otherwise remained afebrile with a significant drop in CRP.  Anakinra was well-tolerable and safe due to a short half-life.  The authors concluded that anakinra may be a safe and effective treatment for recurrent fevers in SLE.

Recurrent Pericarditis

The European Society of Cardiology’s guidelines on pericardial diseases (2015) recommended anakinra among immunosuppressive options in corticosteroid-dependent recurrent pericarditis in patients not responsive to colchicine. 

A recent review (Lilly et al, 2015) recommended the use of anakinra for patients who have failed other therapies: For refractory pericarditis despite NSAID, colchicine, and glucocorticoid therapies, improved symptoms have been reported in small numbers of patients with the use of immunosuppressive agents (azathioprine or methotrexate), intravenous immunoglobulin, and the interleukin-1β receptor antagonist anakinra.2.

Furthermore, an UpToDate review on “Recurrent pericarditis” (Adler and Imazio, 2015) states that “Other immune therapy -- In patients who do not tolerate prednisone or the small number who do not respond adequately, another immunosuppressive agent should be added. The 2015 European Society of Cardiology guidelines recommend considering azathioprine or human intravenous immunoglobulins (IVIG) (400 to 500 mg IV for 5 days) or anakinra (1 to 2 mg/kg/day up to 100 mg/day for several months).  Emerging evidence supports the use of anakinra especially in corticosteroid-dependent patients.  In one retrospective review of 13 patients with recurrent pericarditis refractory to traditional therapy, all 13 patients had at least partial resolution of symptoms following treatment with anakinra, with 11 of 13 patients remaining symptom free and off of other therapies (NSAIDs, colchicine, and glucocorticoids) at median follow-up of 17 months.  Anakinra is generally well tolerated but it is expensive, and withdrawal is often followed by recurrences that may require the reintroduction of the drug.  Moreover, the best duration of therapy is unknown”.

Rheumatoid Arthritis

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).

The American College of Rheumatology (ACR) conducted a systematic review to synthesize the evidence for the benefits and harms of various treatment options. Their goal was to develop evidence-based, pharmacologic treatment guideline for rheumatoid arthritis. The 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis provided “strong” recommendations for established RA and symptomatic early RA.

For established RA, the guidelines state “if the disease activity is low, in patients who have never taken a DMARD, the recommendation is to use DMARD monotherapy (methotrexate preferred) over TNFi”. “If disease activity remains moderate or high despite DMARD monotherapy, the recommendation is to use combination traditional [conventional] DMARDs or add a TNFi or a non-TNF biologic or tofacitinib (all choices with or without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. Recommendations for patients with symptomatic early RA state that “if disease activity is low, in patients who have never taken a DMARD, use DMARD monotherapy (methotrexate preferred) over double or triple therapy”.  “If disease activity remains moderate or high despite DMARD monotherapy (with or without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with or without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. A strong recommendation means that the panel was confident that the desirable effects of following the recommendation outweigh the undesirable effects (or vice versa), so the course of action would apply to most patients, and only a small proportion would not want to follow the recommendation (Singh et al., 2016). 

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.

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 immune 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.

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.

Warnings and precautions include the following:

• In RA, discontinue use if serious infection develops. In Kineret‐treated NOMID patients. the risk of a NOMID flare when discontinuing Kineret treatment should be weighed against the potential risk of continued treatment. Do not initiate Kineret in patients with active infections.
• Use in combination with Tumor Necrosis Factor (TNF) blocking agents is not recommended.
• Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported.
• The impact of treatment with Kineret on active and/or chronic infections and the development of malignancies is not known.
• Live vaccines should not be given concurrently with Kineret.
• Neutrophil counts should be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly for 3 months, and thereafter quarterly for a period up to 1 year.

Sarcoidosis

Linger and colleagues (2016) anti-TNFα and anakinra are monoclonal antibodies against pro-inflammatory cytokines over-expressed in many systemic inflammatory diseases.  In Australia, they are registered for the treatment of several rheumatological, gastroenterological and dermatological indications.  Despite increasing observational evidence for their use in off-label indications, there is a paucity of outcome research from the Australian hospital sector.  These researchers describe the off-label use of anti-TNFα and anakinra at a tertiary referral hospital in Queensland, Australia and consideration of a drug register to inform future clinical decision-making.  They performed an in-depth retrospective chart audit of off-label treatment with anti-TNFα or anakinra at the Royal Brisbane and Women's Hospital from mid-2010 to mid-2014, linking demographic, phenotypic, pathology and outcome data with these drugs.  Off-label use was identified in 10 patients.  The most frequent indications were sarcoidosis and dermatological conditions; 3 patients required sequential therapy with a 2nd anti-TNFα (total responses = 13).  Complete response occurred in 46 %, partial response in 38 % and primary non-response in 8 %.  Response was unable to be determined in 8 %.  These investigators recorded 14 AEs (infections most common).  The authors concluded that these findings suggested that anti-TNFα may be beneficial for some off-label indications (e.g., sarcoidosis).  However, the observational design of this study (and pre-existing research) limited the ability to infer causality and generalize results.  They proposed the creation of a mandatory drug register to monitor off-label use.  They stated that while comparative effectiveness cannot be established without a matched placebo-arm, a register would enable some reporting on the effectiveness in rare diseases and identify infrequent but serious AEs.

Schnitzler Syndrome

Schnitzler syndrome is a rare disorder in adults characterized by recurrent febrile rash, bone and/or joint pain, enlarged lymph nodes, fatigue, leukocytosis and systemic inflammatory response (Lipsker, 2011). A monoclonal IgM component is present in all cases. Rituximab, intravenous immunoglobulins, and TNF-blocking agents are mostly ineffective. In contrast, the IL-1 receptor antagonist anakinra relieves all symptoms within hours after the first injection, and a marked and immediate response to anakinra is supportive of the diagnosis.

Scleritis

In a pilot study, Bottin and colleagues (2018) evaluated the safety and efficacy of anakinra for severe and refractory scleritis.  A total of 10 patients with severe (i.e., at least 2 ocular relapses per year despite treatment) and refractory [i.e., at least to 1 DMARD] scleritis were treated with anakinra (100 mg/day subcutaneously).  Scleritis was associated with inflammatory systemic diseases in 60 % of cases.  The remission rate defined the primary outcome; 90 % of patients were complete responders with a mean follow-up of 19.4 months after starting anakinra.  The corticosteroids daily dose decreased from 18.3 ± 4.1 mg to 4.2 ± 4.9 mg, (p < 0.05), at initiation of anakinra and at end of follow-up, respectively.  Associated immuno-suppressants were stopped in all cases except 1.  Side effects were observed in 4 patients who did not need anakinra withdrawal.  The authors concluded that the findings of this pilot study suggested the efficacy of anakinra in patients with refractory scleritis.

Systemic Amyloidosis

Nalcacioglu and colleagues (2018) stated that amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of unique protein fibrils.  The least common presentation of an amyloid deposition is as a discrete mass called amyloidoma or amyloid tumor.  These investigators reported a case of a soft tissue amyloidoma in the abdomen of a 16-year old girl who was diagnosed as having systemic amyloidosis.  A girl aged 16 years was referred to the authors’ hospital with a pre-diagnosis of a retroperitoneal mass documented with abdominal ultrasonography (US) and tomography.  A laboratory examination revealed nephrotic syndrome.  She underwent surgery for a complete resection of the lesion.  A histopathologic examination with Congo red and crystal violet dyes verified the diagnosis of amyloidoma.  An immuno-histochemical study for amyloid A protein was positive.  A renal biopsy was also compatible with AA amyloidosis.  A detailed search for the etiology of systemic amyloidosis revealed heterozygous mutation in the Mediterranean fever gene.  Treatment with colchicine and anakinra were started with the diagnosis of familial Mediterranean fever because the other causes of secondary amyloidosis were ruled out.  After 3 months of anakinra treatment, the laboratory findings returned to normal and excessive proteinuria disappeared.  In countries where FMF and other auto-inflammatory diseases are prevalent, systemic amyloidosis should be kept in mind in the differential diagnosis of children who present with nephrotic syndrome and abdominal mass.  The authors concluded that taking previously reported cases and this case together, it appeared that anti-IL-1 treatment represents a promising new approach in a subset of patients with systemic amyloidosis secondary to auto-inflammatory diseases.

Systemic Lupus Erythematosus

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.

Ulcerative Colitis

Kaly and colleagues (2019) noted that anakinra is a biological drug used in RA and several auto-inflammatory diseases.  Its main side effects are injection site reactions and increased infection rate.  These researchers presented the case of a 28-year old man with familial Mediterranean fever (FMF), whose disease went into remission on anakinra, with concomitant flare of his ulcerative colitis (UC).  The authors stated that to their knowledge, they reported the 5th published case of inflammatory bowel disease (IBD) exacerbation related to anakinra; in the present case, UC exacerbation in a patient with FMF.  These researchers stated that although there is some evidence that UC and FMF may have a shared pathogenesis pattern based on the inflammasome and IL-1b, treatment by IL-1 blockade might induce UC exacerbation.  They noted that anakinra is under evaluation for its efficacy in IBD; a short acting IL-1 blockade treatment would be preferred in a patient with FMF and concomitant IBD.

Appendix

Examples of Contraindications to Methotrexate

• Clinical diagnosis of alcohol use disorder, alcoholic liver disease or other chronic liver disease
• Breastfeeding
• Blood dyscrasias (e.g., thrombocytopenia, leukopenia, significant anemia) 
• Elevated liver transaminases
• History of intolerance or adverse event 
• Hypersensitivity
• Interstitial pneumonitis or clinically significant pulmonary fibrosis
• Myelodysplasia
• Pregnancy or currently planning pregnancy
• Renal impairment
• Significant drug interaction

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

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Cytokine release syndrome (CRS) Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
Arcalyst	rilonacept	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA)
Avsola	infliximab-axxq	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
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	Adult-onset Still's disease 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 Deficiency of interleukin-1 receptor antagonist (DIRA) Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behcet’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	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis Various subtypes of non-Hodgkin's lymphoma
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Juvenile idiopathic arthritis  Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Plaque psoriasis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis Ulcerative colitis
Taltz	ixekinumab	Ankylosing spondylitis or axial spondyloarthritis Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis Psoriatic arthritis
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:
71045 - 71048	Radiologic examination, chest
85651	Sedimentation rate, erythrocyte; non-automated
85652	Sedimentation rate, erythrocyte; automated
86140	C-reactive protein
86141	C-reactive protein; high sensitivity (hsCRP)
86200	Cyclic citrullinated peptide (CCP), antibody
86430	Rheumatoid factor; qualitative
86431	Rheumatoid factor; quantitative
86480	Tuberculosis test, cell mediated immunity antigen response measurement; gamma interferon
86481	Tuberculosis test, cell mediated immunity antigen response measurement; enumeration of gamma interferon – producing T cells in cell suspension
86580	Skin test; tuberculosis, intradermal
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
Anakinra (Kineret) – No specific code:
Other HCPCS codes related to the CPB:
Colchicine, Xeljanz - no specific code:
J1130	Injection, diclofenac sodium, 0.5 mg
J3245	Injection, tildrakizumab, 1 mg
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J8610	Methotrexate; oral, 2.5 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
ICD-10 codes covered if selection criteria are met:
D47.2	Monoclonal gammopathy [Schnitzler syndrome with documented monoclonal IgM gammopathy]
D47.Z2	Castleman's disease
I30.0 - I30.9	Acute pericarditis
M04.1	Periodic fever syndromes [hyperimmunoglobulin D syndrome]
M05.00 - M06.9	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]
M08.00 - M08.99	Juvenile arthritis
M1A.00x0 - M10.9	Gout
Q87.89	Other specified congenital malformation syndromes, not elsewhere classified [neonatal-onset multisystem inflammatory disease (NOMID)]
ICD-10 codes not covered for indications listed in the CPB:
A00.0 - B99.9	Infectious and parasitic diseases
C18.0 - C18.9	Malignant neoplasm of colon
C20	Malignant neoplasm of rectum
D76.1	Hemophagocytic lymphohistiocytosis
D76.1	Hemophagocytic lymphohistiocytosis
D86.0 - D86.9	Sarcoidosis
E08.00 - E13.9	Diabetes mellitus
E85.0 - E85.9	Amyloidosis
E88.89	Other specified metabolic disorders [Erdheim-Chester disease]
G04.81	Other encephalitis and encephalomyelitis [cerebral autoinflammatory disease]
G40.501 - G40.509	Epileptic seizures related to external causes [febrile infection-related epilepsy syndrome]
G72.41 - G72	Inflammatory and immune myopathies, NEC
G93.89	Other specified disorders of brain [cerebral autoinflammatory disease]
H15.00 - H15.099	Scleritis
I21.01 - I22.9	ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardinal infarction
I25.2	Old myocardial infarction
I40.0 - I40.9	Acute myocarditis
I50.1 - I50.9	Heart failure
I51.4	Myocarditis, unspecified
K50.00 - K50.919	Crohn's disease
K51.00 - K51.919	Ulcerative colitis
K75.81	Nonalcoholic steatohepatitis (NASH)
K92.81	Gastrointestinal mucositis (ulcerative) [intestinal mucositis]
L40.1	Generalized pustular psoriasis
L73.2	Hidradenitis suppurativa
L88	Pyoderma gangrenosum
M00.00 - M01.x9	Infectious arthropathies
M02.00 - M02.9	Postinfective and reactive arthropathies
M04.2 - M04.9	Autoinflammatory syndromes [except hyperimmunoglobulin D syndrome]
M15.0 - M19.93	Osteoarthritis
M30.3	Mucocutaneous lymph node syndrome
M32.0 - M32.9	Systemic lupus erythematosus (SLE)
M35.00 - M35.09	Sicca syndrome [Sjögren]
M35.2	Behcet's disease
M45.0 - M45.9	Ankylosing spondylitis
M60.0 - M60.9	Myositis
M79.10 - M79.18	Myalgia
M86.30 - M86.39	Chronic multifocal osteomyelitis
M86.40 - M86.49	Chronic osteomyelitis with draining sinus
M86.50 - M86.59	Other chronic hematogenous osteomyelitis
M86.60 - M86.69	Other chronic osteomyelitis
R53.81, R53.83	Other malaise and fatigue [associated with Sjögren's syndrome]
R53.82	Chronic fatigue, unspecified
R56.00 - R56.01	Febrile convulsions [febrile infection-related epilepsy syndrome]
S83.501A - S83.529S	Sprain of cruciate ligament of knee

The above policy is based on the following references: