Clinical UM Guideline

 

Subject: Tumor Necrosis Factor Antagonists
Guideline #: CG-DRUG-65 Publish Date:    06/28/2018
Status: New Last Review Date:    11/02/2017

Description

This document addresses the indications for a class of biologic immunosuppressive agents known as tumor necrosis factor (TNF) antagonists (inhibitors), that target specific pathways of the immune system and either enhance or inhibit immune response.

The U.S. Food and Drug Administration (FDA) has approved the following TNF antagonists for use in specific indications:

Note: For additional information on review of clinically equivalent cost effective criteria for products addressed in CG-DRUG-65, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.

Note: Please refer to CG-DRUG-64 FDA-Approved Biosimilar Products for additional information on clinical criteria for review of a biosimilar product to an already FDA-approved TNF antagonist (a biological product, known as the reference product) addressed in CG-DRUG-65.

Clinical Indications

I.  Infliximab

Medically Necessary:

Infliximab is considered medically necessary when criteria are met for any of the following indications:

  1. Crohn’s disease when the following criteria are met:
    1. Individual is 6 years of age or older; and
    2. Individual has fistulizing or moderately to severely active Crohn’s disease which has previously responded to therapy with infliximab; or
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as 5-Aminosalicylic acid products, sulfasalazine, systemic corticosteroids, or immunosuppressive drugs) and infliximab is used for one of the following:
      1. To reduce signs or symptoms in an individual with moderately to severely active Crohn’s disease; or
      2. To induce or maintain clinical remission in an individual with moderately to severely active Crohn’s disease; or
    4. To reduce the number of draining enterocutaneous or rectovaginal fistulas in an individual with fistulizing Crohn’s disease of at least 3 months duration.
  2. Ulcerative colitis when each of the following criteria are met:
    1. Individual is 6 years of age or older with moderately to severely active ulcerative colitis; and
    2. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as 5-Aminosalicylic acid products, sulfasalazine, systemic corticosteroids, or immunosuppressive drugs) and infliximab is used for one of the following:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical remission and mucosal healing.
  3. Rheumatoid arthritis when each of the following criteria are met:
    1. Individual is 18 years of age or older with moderately to severely active rheumatoid arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To inhibit the progression of structural damage; or
      4. To improve physical function; and
    3. Infliximab is given in combination with methotrexate or with another immunosuppressive agent if the individual is intolerant to methotrexate; and
    4. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic disease modifying anti-rheumatic drugs (DMARDs).
  4. Ankylosing spondylitis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active ankylosing spondylitis; and
    2. Agent is used to reduce signs or symptoms of the disease; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as nonsteroidal anti-inflammatory drugs [NSAIDs] or nonbiologic DMARDs).
  5. Psoriatic arthritis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active psoriatic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To inhibit the progression of structural damage; or
      4. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as nonbiologic DMARDs).
  6. Plaque psoriasis when each of the following criteria are met:
    1. Individual is 18 years of age or older with chronic moderate to severe (that is, extensive or disabling) plaque psoriasis with either of the following:
      1. Plaque psoriasis involving greater than 5% body surface area; or
      2. Plaque psoriasis involving less than or equal to 5% body surface area involving sensitive areas or areas that significantly impact daily function (such as palms, soles of feet, head/neck, or genitalia); and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to phototherapy or other systemic therapy (such as acitretin, cyclosporine, or methotrexate).
  7. Juvenile idiopathic arthritis when each of the following criteria are met:
    1. Individual is 2 years of age or older with moderately to severely active juvenile idiopathic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.
  8. Non-infectious uveitis when each of the following criteria are met:
    1. Individual has chronic, recurrent, treatment-refractory or vision-threatening disease; and
    2. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as corticosteroids or immunosuppressive drugs [for example, azathioprine, cyclosporine, or methotrexate]).

Not Medically Necessary:

Infliximab is considered not medically necessary for an individual with any of the following:

  1. In combination with other TNF antagonists; or
  2. In combination with tofacitinib citrate (Xeljanz®, Pfizer Inc., New York, NY); or
  3. In combination with the following non-TNF immunomodulator drugs: abatacept (Orencia®, Bristol-Myers Squibb Company, Princeton, NJ), anakinra (Kineret®, Amgen, Thousand Oaks, CA), or tocilizumab (Actemra, Genentech, Inc., Roche USA, South San Francisco, CA); or
  4. Tuberculosis, invasive fungal infection, other active serious infections, or a history of recurrent infections; or
  5. Individual has not had a tuberculin skin test or Centers for Disease Control and Prevention (CDC)-recommended equivalent to evaluate for latent tuberculosis prior to initiating infliximab.

Note: The clinician should consider the status of an individual with moderate or severe heart failure - New York Heart Association (NYHA) Functional Class III-IV before initiating treatment with infliximab at doses greater than 5mg/kg.

Infliximab is considered not medically necessary when the criteria are not met and for all other indications, including, but not limited to treatment of asthma, chronic obstructive pulmonary disease, disc-herniation-induced sciatica, hairy cell leukemia, graft-versus-host disease, hidradenitis suppurativa, acute Kawasaki disease, neurosarcoidosis, sarcoidosis, Still’s disease, Sjogren’s syndrome, Takayasu arteritis, and Wegener’s granulomatosis.

II.  Etanercept

Medically Necessary:

Etanercept is considered medically necessary when criteria are met for any of the following indications:

  1. Rheumatoid arthritis when each the following criteria are met:
    1. Individual is 18 years of age or older with moderately to severely active rheumatoid arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To inhibit the progression of structural damage; or
      4. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.
  2. Ankylosing spondylitis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active ankylosing spondylitis; and
    2. Agent is used to reduce signs or symptoms of the disease; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as NSAIDs or nonbiologic DMARDs).
  3. Juvenile idiopathic arthritis when each of the following criteria are met:
    1. Individual is 2 years of age or older with moderately to severely active juvenile idiopathic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.
  4. Psoriatic arthritis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active psoriatic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To inhibit the progression of structural damage; or
      4. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as nonbiologic DMARDs).
  5. Plaque psoriasis when each of the following criteria are met:
    1. Individual is 4 years of age or older with chronic moderate to severe (that is, extensive or disabling) plaque psoriasis with either of the following:
      1. Plaque psoriasis involving greater than 5% body surface area; or
      2. Plaque psoriasis involving less than or equal to 5% body surface area involving sensitive areas or areas that significantly impact daily function (such as palms, soles of feet, head/neck, or genitalia); and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to phototherapy or other systemic therapy (such as acitretin, cyclosporine, or methotrexate).

Not Medically Necessary:

Etanercept is considered not medically necessary for an individual with any of the following: 

  1. In combination with other TNF antagonists; or
  2. In combination with tofacitinib citrate; or
  3. In combination with the following non-TNF immunomodulator drugs: abatacept, anakinra or cyclophosphamides; or
  4. Tuberculosis, invasive fungal infection, other active serious infections, or a history of recurrent infections; or
  5. Individual has not had a tuberculin skin test or a CDC-recommended equivalent to evaluate for latent tuberculosis prior to initiating etanercept.

Etanercept is considered not medically necessary when the criteria are not met and for all other indications, including, but not limited to treatment of asthma, disc-herniation-induced radiculopathy or sciatica, graft-versus-host disease, inclusion-body myositis, inflammatory bowel disease, hidradenitis suppurativa, sarcoidosis, septic shock, Sjogren’s syndrome, and Wegener’s granulomatosis.

III.  Adalimumab

Medically Necessary:

Adalimumab is considered medically necessary when criteria are met for any of the following indications:

  1. Crohn’s disease when each of the following criteria are met:
    1. Individual is 6 years of age or older with moderately to severely active Crohn’s disease; and
    2. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as 5-Aminosalicylic acid products, sulfasalazine, systemic corticosteroids, or immunosuppressants), or has lost response to or is intolerant to infliximab, and adalimumab is used for one of the following:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical remission.
  2. Ulcerative colitis when each of the following criteria are met:
    1. Individual is 18 years of age or older with moderately to severely active ulcerative colitis; and
    2. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as 5-Aminosalicylic acid products, sulfasalazine, systemic corticosteroids, or immunosuppressive drugs), and adalimumab is used for one of the following:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical remission.
  3. Rheumatoid arthritis when each of the following criteria are met:
    1. Individual is 18 years of age or older with moderately to severely active rheumatoid arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To inhibit the progression of structural damage; or
      4. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.
  4. Ankylosing spondylitis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active ankylosing spondylitis; and
    2. Agent is used to reduce signs or symptoms of the disease; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as NSAIDs or nonbiologic DMARDs).
  5. Juvenile idiopathic arthritis when each of the following criteria are met:
    1. Individual is 2 years of age or older with moderately to severely active juvenile idiopathic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.
  6. Psoriatic arthritis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active psoriatic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To inhibit the progression of structural damage; or
      4. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as nonbiologic DMARDs).
  7. Plaque psoriasis when each of the following criteria are met:
    1. Individual is 18 years of age or older with chronic moderate to severe (that is, extensive or disabling) plaque psoriasis with either of the following:
      1. Plaque psoriasis involving greater than 5% body surface area; or
      2. Plaque psoriasis involving less than or equal to 5% body surface area involving sensitive areas or areas that significantly impact daily function (such as fingernails, palms, soles of feet, head/neck, or genitalia); and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to phototherapy or other systemic therapy (such as acitretin, cyclosporine, or methotrexate).
  8. Non-infectious uveitis when each of the following criteria are met:
    1. Individual has chronic, recurrent, treatment-refractory or vision-threatening disease; and
    2. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as corticosteroids or immunosuppressive drugs [for example, azathioprine, cyclosporine, or methotrexate]).
  9. Hidradenitis suppurativa when each of the following criteria are met:
    1. Individual is 18 years of age or older; and
    2. Individual has moderate to severe hidradenitis suppurativa (Hurley stage II or Hurley stage III disease); and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as oral antibiotics).

Not Medically Necessary:

Adalimumab is considered not medically necessary for an individual with any of the following:

  1. In combination with other TNF antagonists; or
  2. In combination with tofacitinib citrate; or
  3. In combination with the following non-TNF immunomodulator drugs: abatacept or anakinra; or
  4. Tuberculosis, invasive fungal infection, other active serious infections, or a history of recurrent infections; or
  5. Individual has not had a tuberculin skin test or CDC-recommended equivalent to evaluate for latent-tuberculosis prior to initiating adalimumab.

Adalimumab is considered not medically necessary when the criteria are not met and for all other indications.

IV. Certolizumab pegol

Medically Necessary:

Certolizumab pegol is considered medically necessary when criteria are met for any of the following indications:

  1. Crohn’s disease when each of the following criteria are met:
    1. Individual is 18 years of age or older with moderately to severely active Crohn’s disease; and
    2. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as 5-Aminosalicylic acid products, systemic corticosteroids, or immunosuppressants) and certolizumab pegol is used for one of the following:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response.
  2. Rheumatoid arthritis when each of the following criteria are met:
    1. Individual is 18 years of age or older with moderately to severely active rheumatoid arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.
  3. Ankylosing spondylitis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active ankylosing spondylitis; and
    2. Agent is used to reduce signs or symptoms of the disease; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as NSAIDs or nonbiologic DMARDs).
  4. Psoriatic arthritis when each of the following criteria are met:
    1. Individual is 18 years of age or older with active psoriatic arthritis; and
    2. Agent is used for any of the following reasons:
      1. To reduce signs or symptoms; or
      2. To induce or maintain clinical response; or
      3. To improve physical function; and
    3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as nonbiologic DMARDs).

Not Medically Necessary:

Certolizumab pegol is considered not medically necessary for an individual with any of the following:

  1. In combination with other TNF antagonists; or
  2. In combination with tofacitinib citrate; or
  3. In combination with the following non-TNF immunomodulator drugs: abatacept, anakinra, natalizumab (Tysabri®, Biogen Idec Inc., Cambridge, MA; Elan Pharmaceuticals, Inc., San Diego, CA), or rituximab (Rituxan®, Genentech, Inc., Roche USA, South San Francisco, CA); or
  4. Tuberculosis, invasive fungal infection, other active serious infections, or a history of recurrent infections; or
  5. Individual has not had a tuberculin skin test or CDC-recommended equivalent to evaluate for latent tuberculosis prior to initiating certolizumab pegol.

Certolizumab pegol is considered not medically necessary when the criteria are not met and for all other indications.

V.  Golimumab (Simponi and Simponi Aria)

Medically Necessary:

  1. Golimumab (Simponi) is considered medically necessary for individuals when criteria are met for any of the following indications:
    1. Ulcerative colitis when each of the following criteria are met:
      1. Individual is 18 years of age or older with moderately to severely active ulcerative colitis; and
      2. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as 6-mercaptopurine, azathioprine, oral aminosalicylates, or oral corticosteroids), or has demonstrated dependence on corticosteroids, and golimumab is used for one of the following:
        1. To reduce signs or symptoms; or
        2. To induce or maintain clinical remission and mucosal healing.
    2. Ankylosing spondylitis when each of the following criteria are met:
      1. Individual is 18 years of age or older with active ankylosing spondylitis; and
      2. Is being used to reduce signs or symptoms of the disease; and
      3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as NSAIDs or nonbiologic DMARDs).
    3. Psoriatic arthritis when each of the following criteria are met:
      1. Individual is 18 years of age or older with active psoriatic arthritis; and
      2. Agent is used for any of the following reasons:
        1. To reduce signs or symptoms; or
        2. To induce or maintain clinical response; or
        3. To improve physical function; and
      3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as nonbiologic DMARDs).
    4. Rheumatoid arthritis when each of the following criteria are met:
      1. Individual is 18 years of age or older with moderately to severely active rheumatoid arthritis; and
      2. Agent is used for any of the following reasons:
        1. To reduce signs or symptoms; or
        2. To induce or maintain clinical response; or
        3. To improve physical function; and
      3. Golimumab is given in combination with methotrexate or with another immunosuppressive agent if the individual is intolerant to methotrexate; and
      4. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.
  2. Golimumab (Simponi Aria) is considered medically necessary when criteria are met for the following indications:
    1. Ankylosing spondylitis when each of the following criteria are met:
      1. Individual is 18 years of age or older with active ankylosing spondylitis; and
      2. Is being used to reduce signs or symptoms of the disease; and
      3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as NSAIDs or nonbiologic DMARDs).
    2. Psoriatic arthritis when each of the following criteria are met:
      1. Individual is 18 years of age or older with active psoriatic arthritis; and
      2. Agent is used for any of the following reasons:
        1. To reduce signs or symptoms; or
        2. To induce or maintain clinical response; or
        3. To improve physical function; and
      3. Individual has failed to respond to, is intolerant of, or has a medical contraindication to conventional therapy (such as NSAIDs or nonbiologic DMARDs).
    3. Rheumatoid arthritis when each of the following criteria are met:
      1. Individual is 18 years of age or older with moderately to severely active rheumatoid arthritis; and
      2. Agent is used for any of the following reasons:
        1. To reduce signs or symptoms; or
        2. To induce or maintain clinical response; or
        3. To improve physical function; and
      3. Golimumab is given in combination with methotrexate or with another immunosuppressive agent if the individual is intolerant to methotrexate; and
      4. Individual has failed to respond to, is intolerant of, or has a medical contraindication to one or more nonbiologic DMARDs.

Not Medically Necessary:

Golimumab is considered not medically necessary for an individual with any of the following:

  1. In combination with other TNF antagonists; or
  2. In combination with tofacitinib citrate; or
  3. In combination with the following non-TNF immunomodulator drugs: abatacept or anakinra; or
  4. Tuberculosis, invasive fungal infections, other active serious infections, or a history of recurrent infections; or
  5. Individual has not had a tuberculin skin test or CDC-recommended equivalent to evaluate for latent tuberculosis prior to initiating golimumab.

Golimumab is considered not medically necessary when the criteria are not met and for all other indications.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Note: See also CG-DRUG-64 for descriptions of biosimilar drugs and clinically equivalent cost effective agent status.

HCPCS

 

J0135

Injection, adalimumab, 20 mg [Humira]

J0717

Injection, certolizumab pegol, 1 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered) [Cimzia]

J1438

Injection, etanercept; 25 mg (when drug administered under the direct supervision of a physician, not for use when drug is self-administered) [Enbrel]

J1602

Injection, golimumab, 1 mg, for intravenous use [Simponi Aria]

J1745

Injection, infliximab, excludes biosimilar, 10 mg [Remicade]

J3590

Unclassified biologics [no specific code for golimumab (Simponi), etanercept-szzs (Erelzi), adalimumab-atto (Amjevita), adalimumab-adbm (Cyltezo), or infliximab-qbtx (Ixifi)]

Q5103

Injection, infliximab-dyyb, biosimilar, (Inflectra), 10 mg

Q5104

Injection, infliximab-abda, biosimilar, (Renflexis), 10 mg

S9359

Home infusion therapy, antitumor necrosis factor intravenous therapy; (e.g., Infliximab); per diem

 

 

ICD-10 Diagnosis

 

H20.00-H20.9

Iridocyclitis [Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

H44.111-H44.119

Panuveitis [Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

H44.131-H44.139

Sympathetic uveitis [Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

K50.00-K50.919

Crohn’s disease (regional enteritis) [Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Cimzia, Ixifi]

K51.00-K51.919

Ulcerative colitis [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Simponi, Ixifi]

K60.4

Rectal fistula [Remicade, Inflectra, Renflexis, Ixifi]

L40.0

Psoriasis vulgaris (plaque psoriasis) [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

L40.1

Generalized pustular psoriasis [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

L40.2

Acrodermatitis continua [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

L40.3

Pustolosis palmaris et plantaris [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

L40.4

Guttate psoriasis [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

L40.50-L40.59

Arthropathic psoriasis [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Simponi, Simponi Aria, Cimzia, Ixifi]

L40.8-L40.9

Psoriasis, other and unspecified [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Ixifi]

L73.2

Hidradenitis suppurativa [Humira, Amjevita, Cyltezo]

M05.00-M05.9

Rheumatoid arthritis with rheumatoid factor [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Cimzia, Simponi, Simponi Aria, Ixifi]

M06.00-M06.09

Rheumatoid arthritis without rheumatoid factor [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Cimzia, Simponi, Simponi Aria, Ixifi]

M06.80-M06.89

Other specified rheumatoid arthritis [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Cimzia, Simponi, Simponi Aria, Ixifi]

M06.9

Rheumatoid arthritis, unspecified [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Humira, Amjevita, Cyltezo, Cimzia, Simponi, Simponi Aria, Ixifi]

M08.00-M08.09

Unspecified juvenile rheumatoid arthritis [Enbrel, Erelzi, Humira, Amjevita, Cyltezo, Remicade, Inflectra, Renflexis, Ixifi]

M08.20-M08.29

Juvenile rheumatoid arthritis with systemic onset [Enbrel, Erelzi, Humira, Amjevita, Cyltezo, Remicade, Inflectra, Renflexis, Ixifi]

M08.3

Juvenile rheumatoid polyarthritis (seronegative) [Enbrel, Erelzi, Humira, Amjevita, Cyltezo, Remicade, Inflectra, Renflexis, Ixifi]

M08.40-M08.48

Pauciarticular juvenile rheumatoid arthritis [Enbrel, Erelzi, Humira. Amjevita, Cyltezo, Remicade, Inflectra, Renflexis, Ixifi]

M08.80-M08.99

Other or unspecified juvenile arthritis [Enbrel, Erelzi, Humira, Amjevita, Cyltezo, Remicade, Inflectra, Renflexis, Ixifi]

M35.2

Behçet’s disease [related uveitis; Remicade, Inflectra, Renflexis, Ixifi, Humira, Amjevita, Cyltezo]

M45.0-M45.9

Ankylosing spondylitis [Enbrel, Erelzi, Remicade, Inflectra, Renflexis, Ixifi, Humira, Amjevita, Cyltezo, Simponi, Simponi Aria, Cimzia]

N82.3

Fistula of vagina to large intestine (rectovaginal fistula) [Remicade, Inflectra, Renflexis, Ixifi]

Discussion/General Information

Infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi and Simponi Aria) belong to a class of drugs known as tumor necrosis factor (TNF or TNF-α) antagonists (inhibitors). TNF antagonists are designed to neutralize inflammatory cytokines that mediate joint damage and destruction due to its activities on many cells in the joints as well as effects on other organs and body systems. TNF antagonists are biologic DMARDs approved by the FDA for use in specific indications. These indications, along with the clinical study data, are included on the current FDA-approved product information (PI) label for each agent.

Considerations for Use of TNF Antagonists

Ankylosing Spondylitis

The American College of Rheumatology, in conjunction with the Spondylitis Association of America and the Spondyloarthritis Research and Treatment Network (Ward, 2015) has published recommendations for both pharmacologic and non-pharmacologic treatment of ankylosing spondylitis and non-radiographic spondyloarthritis, including treatment of individuals with active or stable disease (pharmacologic and rehabilitation) and treatment of those with ankylosing spondylitis and specific impairments or comorbidities (for example, acute iritis, advanced hip arthritis, severe kyphosis, and inflammatory bowel disease). The recommendations also address the treatment of individuals with non-radiographic axial spondyloarthritis and education and preventive care recommendations for ankylosing spondylitis and spondyloarthritis. For treatment of an individual with active ankylosing spondylitis, strong recommendations include use of NSAIDs, TNF antagonists when activity persists despite NSAID treatment, and no use of systemic glucocorticoids; non-pharmacologic treatments include use of physical therapy and hip arthroplasty in individuals with advanced hip arthritis. The recommendations did not include preference for use of a particular TNF antagonist, except in individuals with concomitant inflammatory bowel disease or recurrent iritis (use adalimumab or infliximab). Treatment with TNF antagonists is conditionally recommended in individuals with active non-radiographic axial spondyloarthritis despite treatment with NSAIDs.

Inflammatory Bowel Disease: Crohn’s Disease and Ulcerative Colitis

The American College of Gastroenterology (Lichtenstein, 2009) practice guidelines for the management of Crohn’s disease includes therapeutic recommendations for use of biologic agents in adults. Anti-TNF agents (adalimumab, certolizumab pegol, and infliximab) are efficacious in individuals who have moderately to severely active Crohn’s disease despite complete and adequate treatment with corticosteroids and immunosuppressive drugs. Infliximab monotherapy and combined with azathioprine is more efficacious than azathioprine in the treatment of individuals who have failed first-line therapy with mesalamine and/or corticosteroids. Monotherapy with biologics may be reasonable due to increased safety risks with combination therapy. Adalimumab, certolizumab pegol, and infliximab may be used as alternative to steroids in selected individuals in whom steroids may be contraindicated or not desired. Nonsuppurative chronic fistulization or perianal fissuring is treated medically with infliximab, antibiotics, or immunosuppressive drugs.

The American College of Gastroenterology practice guidelines for ulcerative colitis in adults (Kornbluth, 2010), includes recommendations for the diagnosis, assessment and management of mild-moderate distal colitis, maintenance of remission in distal disease, and management of mild-moderate extensive colitis (active disease) with infliximab. Infliximab may be used in the treatment of severe ulcerative colitis if hospitalization is not urgent and the individual is refractory to maximal oral treatment with prednisone, oral aminosalicylates, and topical medications. Infliximab may also be effective in avoiding colectomy in individuals failing to respond to intravenous steroids, but long-term efficacy in this setting is unknown.

Juvenile Idiopathic Arthritis

The American College of Rheumatology guidelines for the treatment of juvenile idiopathic arthritis include recommendations for use of nonbiologic DMARDs and biologic DMARDs in the treatment of systemic juvenile idiopathic arthritis (Ringold, 2013). The guidelines also address features of macrophage activation syndrome (MAS) and recommendations for tuberculosis screening in children with systemic idiopathic juvenile arthritis on biologics. To date, the FDA has not approved the use of any TNF antagonist for the treatment of systemic idiopathic juvenile arthritis; however, for children with active systemic features and varying degrees of synovitis, the guideline state that a TNF antagonist (adalimumab, etanercept, infliximab) may be considered as an option following initial therapy (and continued disease activity), with anakinra (Kineret), glucocorticoid monotherapy (oral or intravenous), NSAIDs, or methotrexate or leflunomide. For children without active systemic features and varying degrees of synovitis, a TNF antagonist may be considered as an option following initial therapy (and continued disease activity) with methotrexate or leflunomide, NSAID monotherapy, or intra-articular glucocorticoid injections. In summary, the goal of therapy for systemic juvenile idiopathic arthritis is similar to therapies for other categories of juvenile idiopathic arthritis, focusing on the prompt control of active inflammation and symptoms, and the prevention of a number of disease-and/or treatment-related morbidities such as growth disturbances, joint damage, and functional limitations.

Psoriasis and Psoriatic Arthritis

The American Academy of Dermatology published clinical guidelines in 2008 that include recommendations for use of TNF antagonists in the management of psoriasis and psoriatic arthritis. These recommendations preclude the FDA approval of other non-TNF drugs (that is, apremilast, brodalumab, ixekizumab, secukinumab, and ustekinumab) for these conditions. In general, the guideline emphasizes the treatment options must be individualized to the needs of each individual, taking into account treatment efficacy, side effects, availability, ease of administration, comorbid conditions, and family history. For those individuals with more extensive or moderate to severe disease, defined as body surface area (BSA) involvement “affecting more than 5% of the BSA or affecting crucial body areas such as the hands, feet, face, or genitals” or plaque psoriasis involving sensitive areas or areas that would significantly impact daily function (such as palms, soles of feet, head/neck, or genitalia), less than or equal to 5% of BSA involvement is considered as moderate to severe disease. The guideline recommends the following treatments (along with adjunctive topical agents): 1) first-line therapy (if available) with targeted ultraviolet B light therapy (UVB), with or without methotrexate/acetretin or topical psoralen plus ultraviolet light (PUVA); or 2) first line therapy with methotrexate, cyclosporine, acitretin, TNF antagonists (that is, adalimumab, etanercept, or infliximab), with or without methotrexate or ustekinumab. For adults with psoriasis (that is, greater than 5% BSA) with concurrent psoriatic arthritis, the guideline recommends first-line therapy with single agent adalimumab, etanercept, infliximab, golimumab, or methotrexate, or a TNF antagonist in combination with methotrexate.

Rheumatoid Arthritis

An Agency for Healthcare Research and Quality comparative effectiveness review on rheumatoid arthritis drug therapy found that comparative studies on biologic DMARDs, including the TNF antagonists, are limited (Donahue, 2012). While there are many observational comparative studies and mixed treatment comparisons, studies have not provided sufficient evidence to determine optimal strategies for use of biologic DMARDs, including when to begin biologic DMARDs and in what drug therapy combinations. Superiority of any biologic DMARD, including TNF antagonists, over others could not be determined due to lack of head-to-head, randomized comparative trials.

The American College of Rheumatology published guidelines for the treatment of rheumatoid arthritis (Singh, 2015) include guidance on DMARDS, biologic agents, tofacitinib, and glucocorticoids in established and early rheumatoid arthritis. Recommendations were issued on using a “treat-to-target approach,” discontinuing and tapering medications, and the use of DMARDS and biologic agents for individuals with high-risk comorbidities such as serious infections, hepatitis, congestive heart failure, and malignancy. The guidelines states “treatment recommendations apply to common clinical situations, since the panel considered issues common to most patients, not exceptions.” A strong recommendation for use of a specific treatment “indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa).” A conditional recommendation “denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences.” Concerning the use of TNF inhibitors (antagonists) for early disease, defined as greater than 6 months with moderate or high disease activity despite monotherapy with a DMARD, the guideline recommends use of combination DMARDs or use of a TNF inhibitor or a non-TNF inhibitor biologic (all options are with or without methotrexate and given in no particular order of preference) rather than continuing DMARD monotherapy alone (Recommendation: strong; Level of evidence: low). For established disease, defined as greater than 6 months with moderate or high disease activity despite DMARD monotherapy including methotrexate, the guideline strongly recommends using combination DMARDs or adding a TNF inhibitor 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. Biologic therapy should be used in combination with methotrexate over biologic monotherapy, when possible, due to its superior efficacy (Recommendation: strong; Level of evidence: moderate to very low). For individuals treated with a TNF inhibitor and worsening congestive heart failure while on the TNF inhibitor, the guideline conditionally recommends switching to combination DMARD therapy, a non-TNF biologic, or tofacitinib rather than a different TNF inhibitor.

Infliximab (Remicade)

Infliximab has received FDA approval for the treatment of adults with moderately to severely active rheumatoid arthritis (in combination with methotrexate) (Lipsky, 2000; Maini, 1999), active ankylosing spondylitis (van der Heijde, 2005), active psoriatic arthritis (Antoni, 2005; Kavanaugh, 2006), chronic moderate to severe plaque psoriasis (Gottlieb, 2004; Reich, 2005), adult (Rutgeerts, 2005) and pediatric ulcerative colitis (Hyams, 2010) and adult and pediatric Crohn’s disease and fistulizing Crohn’s disease (Baldassano, 2003; Borrelli, 2004; de Ridder, 2004; Hanauer, 2002; Kugathasan, 2000; Sands, 2004).

Off-Label Indications for Infliximab

Dose Escalation to Maintain Remission in Pediatric Crohn’s Disease

Because the incidence of pediatric onset Crohn’s disease is increasing and recent reports confirm that the disease has a more aggressive presentation and poorer prognosis than adult onset Crohn’s disease (Van Limbergen, 2008), pediatric gastroenterologists recognize that a sustained remission can prevent rapid progression from uncomplicated to complicated Crohn’s disease, and that the benefits of a sustained remission outweigh the risks associated with the use of infliximab. Furthermore, there does not appear to be an increased risk of adverse events associated with dose escalation. Therefore, if a child with Crohn’s disease responds and then loses response, consideration may be given to increase infliximab dosing to 10 mg/kg or increase the frequency of administration from every 8 weeks to every 6 weeks thereafter.

Juvenile Idiopathic Arthritis

A multicenter, randomized, double-blind, placebo-controlled study of 122 children with symptomatic polyarticular juvenile idiopathic arthritis despite prior methotrexate therapy found favorable results in those who received infliximab compared to placebo. At Week 16, after the crossover from placebo to infliximab 6 mg/kg when all participants were receiving infliximab, an American College of Rheumatology (ACR) Pedi 30 response was achieved in 73% of all participants; and, by Week 52, ACR Pedi 50 and ACR Pedi 70 responses were 69.6% and 51.8%, respectively (Ruperto, 2007). In an open-label extension (weeks 52-204) study, 78 of 122 (64%) of children received infliximab 3-6 mg/kg every 8 weeks plus methotrexate. Infliximab was generally well tolerated. Infusion reactions occurred in 32% (25 of 78) of the children, with a higher incidence in children positive for antibodies to infliximab (58%, 15 of 26). At week 204, the proportions of children achieving the ACR Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively.

Beukelman and colleagues (2012) performed a cross-sectional analysis of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry for current and prior DMARD use in children with juvenile idiopathic arthritis representing the majority of pediatric rheumatology centers from all major geographic regions of the United States. Medication use for children with systemic juvenile idiopathic arthritis was analyzed separately from the other categories of juvenile idiopathic arthritis. Of the 2748 identified children with juvenile idiopathic arthritis with median disease duration of 3.9 years, 1246 (45%) children had used a biologic DMARD, and TNF antagonists were used by 96% of all biologic users. Overall, there were 304 children with a history of uveitis and most received treatment with methotrexate (88%), and many received TNF antagonists (57%). Children with uveitis who received TNF antagonists were much more likely to receive adalimumab, infliximab, or golimumab compared to those who received TNF antagonists and did not have uveitis. Among children without systemic arthritis, biologic DMARD use was most strongly associated with rheumatoid factor positive (RF+) polyarthritis and uveitis. The CARRA Registry analysis summarized that infliximab was used by a significant proportion of children with juvenile idiopathic arthritis, including those without uveitis or inflammatory bowel disease, despite the lack of FDA approval for this indication. Numerous observational studies support this usage pattern, though no randomized studies have been reported. “These TNF inhibitor usage patterns suggest that pediatric rheumatologists do not rely solely on the results of controlled clinical trials or FDA-approved labeling when making treatment decisions for children with JIA” (Beukelman, 2012).

In summary, considering the available peer-reviewed medical literature, recommendations of the American College of Rheumatology (Ringold, 2013), and views of relevant medical specialists practicing in pediatrics and pediatric rheumatology, the use of infliximab is standard therapy for the treatment of moderately to severely active juvenile idiopathic arthritis and juvenile idiopathic arthritis-associated uveitis.

Non-Infectious Uveitis

Infliximab may be a treatment option when conservative therapy fails (for example, corticosteroids and azathioprine) for non-infectious uveitis. The evidence in the peer-reviewed medical literature for use of infliximab in non-infectious uveitis includes, but is not limited to, case series and small open-label prospective and retrospective studies (Ardoin, 2007; Foeldvari, 2007; Kahn, 2006; Niccoli, 2007; Saurenmann, 2007; Suhler, 2009; Tognon, 2007; Tugal-Tutkun, 2005; Tynjala, 2007). Studies of juvenile idiopathic arthritis-associated uveitis have reported that infliximab is an effective, well-tolerated therapeutic agent that resulted in a reduction in symptoms or control of ocular inflammation in individuals with chronic, medically refractory uveitis. In addition to infliximab-induced remission, some individuals were able to reduce or discontinue corticosteroid and other immunosuppressive therapy. Some individuals with active uveitis who had previously failed other treatments, responded to infliximab better than etanercept in controlling inflammation (Tynjala, 2007) and improving visual acuity, glaucoma and complications rates (Saurenmann, 2007). Tynjala and colleagues (2007) reported findings during the 2-year follow-up where “the frequency of long-term complications of uveitis seemed to increase despite decreased ocular inflammatory activity.”

Cantini and colleagues (2012) evaluated the long-term efficacy of infliximab in a single center prospective study of 50 individuals with Behcet's disease-associated uveitis (n=36) and idiopathic posterior uveitis (n=14) refractory to at least one immunosuppressive drug. With a mean follow-up duration of 36.8 months, the authors reported improved vision in both eyes. None of the participants had worsening visual acuity and new onset ocular complications. Complete response was recorded in 34 of 50 (68%) participants with idiopathic posterior uveitis and partial response in 11 of 50 (22%) participants.

Kruh and colleagues (2013) retrospectively studied 88 subjects with refractory non-infectious uveitis treated with infliximab and other immunomodulator medications. Complete remission was achieved in 81.8% of subjects and at 44 weeks, 75% achieved complete remission while off corticosteroids. Only 5 subjects were able to be tapered off infliximab and the authors questioned if infliximab-free remission is a realistic goal. While the authors noted that side effects were “well-tolerated in most cases,” 17 subjects (19.3%) had to discontinue infliximab due to serious side effects.

An Expert Panel convened by the American Uveitis Society performed a systemic review of the literature regarding anti-TNF drugs for the treatment of oculatory inflammatory disorders (Levy-Clarke, 2014). Recommendations were made based on the Grading of Recommendations Assessment, Development and Evaluation methodology (GRADE system) that rates the body of evidence as either of good, moderate or insufficient quality. The recommendation is considered either “strong” or “discretionary.” The document noted good-quality evidence and a strong recommendation for infliximab for treatment of uveitis associated with Behcet’s disease, ankylosing spondylitis, inflammatory bowel disease or psoriatic arthritis, and discretionary recommendations based on lower quality evidence for uveitis associated with sarcoidosis, birdshot chorioretinitis or posterior uveitis.

Other Off-Label Uses of Infliximab

Sarcoidosis

Sarcoidosis is a systemic granulomatous disease of undetermined etiology. The evidence in the peer-reviewed medical literature for the efficacy and safety of infliximab in the treatment of chronic, steroid-resistant sarcoidosis, including cardiac, cutaneous (lupus pernio), intestinal, neurological/nervous system, and pulmonary manifestations consists of small case series, case reports (Pereira, 2011; Santos, 2010), small retrospective studies (Hostettler, 2012) and several small prospective studies. The largest prospective study was a phase II, multicenter, randomized, double-blind, placebo-controlled study assessing the safety and efficacy of infliximab in 138 individuals with chronic pulmonary sarcoidosis (Baughman, 2006; Rossman, 2006). Participants received infliximab 3 mg/kg (n=46), 5 mg/kg (n=47) or placebo (n=45) every 6 weeks (after a loading period) through Week 24 and were followed through Week 52. There was a statistically significant improvement in percentage predicted forced vital capacity (FVC) of 2.5% in the combined infliximab treatment group at Week 24 of therapy, but a treatment benefit was not demonstrated in endpoints of improvement in scores on a respiratory questionnaire (total score), 6-minute walk distance, or Borg’s CR10 dyspnea score. The results did not differ significantly between infliximab doses. A limitation of this study includes the potential for selection bias, as investigators may have opted to administer infliximab in an open label fashion to participants with severe or progressive disease, thereby biasing enrollment of subjects with milder disease. Another potential limitation is the short 24-week duration of therapy.

The current peer-reviewed medical literature is lacking in prospective studies demonstrating the safety and prolonged clinical benefit of infliximab in the treatment of sarcoidosis and its clinical manifestations. The FDA has not approved infliximab for use in the treatment of sarcoidosis or manifestations of the condition. There are, however, case reports and single case studies in the peer-reviewed medical literature documenting the occurrence of TNF antagonist agent-induced sarcoidosis and sarcoid-related conditions, either during or immediately following the use of infliximab for the treatment of conditions such as, rheumatoid arthritis, and psoriatic arthritis (Clementine, 2009; Daien, 2009; Dhaille, 2010).

Heart Failure

A phase II, double-blind, placebo-controlled, pilot study of  subjects with stable NYHA class III or IV congestive heart failure (left ventricular ejection fraction equal to or less than 35%) reported that short-term use of infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of individuals with this chronic condition (Chung, 2003).

Hidradenitis Suppurativa

Grant and colleagues (2011) assessed the efficacy and safety of infliximab therapy for individuals with moderate to severe hidradenitis suppurativa in a randomized, double-blind, placebo-controlled crossover trial. Study subjects (n=38) received infliximab (n=15) or placebo (n=23) during an 8-week double-blind treatment phase, followed by an open-label phase where subjects taking placebo were allowed to crossover to infliximab and an observational phase. The primary treatment efficacy was based on Hidradenitis Severity (HS) Severity Index. Secondary endpoints included DLQI, visual analog scale (VAS) score, and Physician Global Assessment (PGA) scores. Laboratory outcomes assessed inflammatory markers of erythrocyte sedimentation rate and C-reactive protein. In the infliximab treatment group, 73% participated through week 22 when they received their last infusion; 20% (n=3) continued through the observational phase to week 52. The investigators found that more participants in the infliximab group than in the placebo group showed a 50% or greater decrease from baseline HS Severity Index score. In addition, statistically and clinically significant improvement from baseline was observed at week 8 in DLQI score, VAS score, erythrocyte sedimentation rate, and C-reactive protein compared with placebo. Participants in the placebo group treated with infliximab after week 8 (crossover) responded similarly to the original infliximab group; however, 9 participants (60%) withdrew consent between weeks 22 and 52 (observational phase) to continue infliximab therapy outside of the trial. No unexpected serious adverse events were observed. Limitations of this study include treatment of participants by a single physician at a single center, lack of intention to treat analysis, a significant number of participants did not return after their last infusion (making an evaluation of time to relapse difficult), and the high withdrawal rate.

Rambhatla and colleagues (2012) conducted a systematic review of the effectiveness of various modalities to treat hidradenitis suppurativa, identifying use of infliximab in eight studies assigned grade C (consensus guidelines, usual practice, expert opinion, or case series) due to small sample sizes of 15 participants or fewer and a case series study design. Two small studies were identified that reported adverse effects or a lack of efficacy of infliximab (Fardet, 2007; Usmani, 2007). Subsequent systematic reviews evaluated the use of TNF antagonists in hidradenitis suppurativa (Blok, 2013; van Rappard, 2013). Based on data from observational case studies, moderate to good response rates were observed in 82% of individuals treated with infliximab; however, evidence quality was moderate to low overall and differed among the agents, making direct comparisons difficult.

Summary of Other Off-Label Uses of Infliximab

Infliximab has been studied as a single agent or in combination therapy with short-term outcomes reported in observational case reports, uncontrolled case series, small, open-label prospective pilot studies and randomized controlled trials for other conditions including advanced renal cell carcinoma (Larkin, 2010), asthma (Erin, 2006), Behcet’s disease (including entero- and neuro-Behcet’s disease, but excluding Behcet’s-associated uveitis) (Borhani Haghighi, 2011; Iwata, 2009; Kikuchi, 2008), chronic obstructive pulmonary disease (Rennard, 2007), chronic recurrent gonarthritis (van der Bijl, 2009), cutaneous systemic sclerosis (Denton, 2009), disc herniation-induced sciatica (Korhonen, 2006), discoid lupus erythematosus (Jessop, 2009), erythrodermic psoriasis (Rosenbach, 2010), graft-versus-host disease (Couriel, 2009), Kawasaki disease (Tremoulet, 2014), orbital inflammatory disease (such as, orbital myositis) (Bennion, 2012; Culver, 2008; Garrity, 2004), pelvic pain associated with endometriosis (Lu, 2010), pityriasis rubra pilaris (Gemmeke, 2010), polymyalgia rheumatica (Hernandez-Rodríguez, 2009), pyoderma gangrenosum (Brooklyn, 2006), refractory diabetic macular edema (Sfikakis, 2010; Wu, 2011), Still’s disease, Sjogren syndrome (Mariette, 2004), systemic lupus erythematosus (Aringer, 2009), Takayasu arteritis (Hoffman, 2004), and Wegener’s granulomatosis (Bartolucci, 2002). The FDA has not approved use of infliximab for any of these conditions.

Etanercept (Enbrel)

Etanercept has received FDA approval for the treatment of adults with moderately to severely active rheumatoid arthritis (Genovese, 2002; Johnsen, 2006; Keystone, 2004; Klareskog, 2006), active psoriatic arthritis (Mease, 2006), and active ankylosing spondylitis (van der Heijde, 2006a); individuals 4 years of age or older with chronic moderate to severe plaque psoriasis (Leonardi, 2003; Paller, 2008; Paller, 2016); and, children 2 years of age or older with moderately to severely active polyarticular juvenile idiopathic arthritis (Lovell, 2000).

Off-Label Indication for Etanercept: Juvenile Idiopathic Arthritis (Other than Polyarticular Juvenile Idiopathic Arthritis)

As discussed earlier in this document, Beukelman and colleagues (2012) performed a cross-sectional analysis of the CARRA Registry for current and prior DMARD use in children with juvenile idiopathic arthritis. Among 1026 children without systemic arthritis who received TNF antagonists, 92% had also received nonbiologic DMARDs. Etanercept was the most commonly used TNF antagonist (81%) among all children with juvenile idiopathic arthritis, most likely because it was the first TNF antagonist studied and approved by the FDA for the treatment of juvenile idiopathic arthritis.

The long-term safety and efficacy of etanercept alone or in combination with methotrexate was evaluated in children with selected categories of juvenile idiopathic arthritis (Giannini, 2009). In this phase IV, open-label, nonrandomized multicenter registry, participants ages 2 through 18 with RF-positive or RF-negative polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, or extended oligoarthritis received methotrexate alone, etanercept alone, or etanercept plus methotrexate for 3 years. The results suggested that etanercept or etanercept plus methotrexate had an acceptable safety and effectiveness profile in select children with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis.

In summary, considering the available peer-reviewed medical literature, recommendations of the American College of Rheumatology (Ringold, 2013), and views of relevant medical specialists practicing in pediatrics and pediatric rheumatology, the use of etanercept has become standard therapy for the treatment of all types of moderately to severely active juvenile idiopathic arthritis, including oligoarthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis.

Other Off-Label Uses of Etanercept

Wegener’s Granulomatosis

Etanercept has been evaluated for the management of Wegener’s granulomatosis and is designated as an orphan drug by the FDA for this use (AHFS, 2011). In a randomized, placebo-controlled study of subjects with Wegener’s granulomatosis (n=180), the rates of sustained remission, sustained periods of low level disease activity, and time needed to achieve these measures in subjects receiving etanercept in combination with standard therapy (glucocorticoids plus cyclophosphamide or methotrexate) were similar to those who received standard therapy alone. Additionally, disease flares did not differ significantly between the groups. In addition, solid malignant tumors developed in a significant group (p=0.01) of these etanercept-treated subjects, (n=6 of 89) versus placebo group (n=0) (Stone, 2006; Wegener's Granulomatosis Etanercept Trial (WGET) Research Group, 2005). According to the AHFS (2011), based on results of this study and the increased incidence of malignancy, some clinicians state that use of etanercept in regimens to induce or maintain remissions in Wegener’s granulomatosis is not justified.

Non-Infectious Uveitis

In a systematic review of anti-TNF factors for the treatment of uveitis, Corder-Coma and colleagues (2013) identified two randomized, placebo-controlled studies of etanercept; neither study reported positive outcomes. The review concluded that there was strong evidence that etanercept was ineffective in the treatment of uveitis. Similarly, an expert panel convened by the American Uveitis Society did not provide any strong recommendations for etanercept for treatment of uveitis and indicated a strong recommendation against etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (Levy-Clarke 2014). Additionally, this document indicated that either infliximab or etanercept are strongly recommended in preference to etanercept for the treatment of oculatory inflammatory disease, noting that use of etanercept has been associated with the development of uveitis in individuals with juvenile idiopathic arthritis and “sarcoid-like” syndromes.

Hidradenitis Suppurativa

Two small phase II clinical trials evaluated the safety and effectiveness of etanercept for the treatment of hidradenitis suppurativa. The results of these studies were conflicting; one study reported improvement in disease activity without adverse events at Week 12 and Week 24 (Giamarellos-Bourboulis, 2008) whereas the other study failed to show statistically significant improvement in PGA scores when baseline scores were compared with Week 12 scores (Lee, 2009). A follow-up single-center, randomized, prospective, double-blind, placebo-controlled trial of 20 subjects also failed to show a significant treatment effect following 24 weeks of etanercept for hidradenitis suppurativa (Adams, 2010).

Summary of Other Off-Label Uses of Etanercept

Etanercept has been studied as treatment for acute Kawasaki disease (Choueiter, 2010), asthma (mild to moderate disease; corticosteroid-refractory) (Morjaria, 2008), disc-herniation-induced radiculopathy or sciatica (Cohen, 2009; Okoro, 2010), discoid lupus erythematosus (Jessop, 2009), graft-versus-host disease (Alousi, 2009); heart failure (Mann, 2004); inclusion-body myositis (Barohn, 2006), myelodysplastic syndrome (Scott, 2010), pemphigus vulgaris (Fiorentino, 2011), polymyalgia rheumatica (Kreiner, 2010), septic shock (Fisher, 1996), and Sjogrens syndrome (Sankar, 2004). While some of these studies report positive outcomes on the clinical manifestations of these diseases, the FDA has not approved use of etanercept for any of these conditions.

Adalimumab (Humira)

Adalimumab has received FDA approval for the treatment of adults with moderately to severely active rheumatoid arthritis (Weinblatt, 2006), active psoriatic arthritis (Gladman, 2007; Mease, 2005), chronic moderate to severe plaque psoriasis (Gordon, 2006; Menter, 2008), including use in moderate to severe fingernail plaque psoriasis (Elewski, 2017; Humira PI, 2017), active ankylosing spondylitis (van der Heijde, 2006b), pediatric (Hyams, 2012) and adult moderately to severely active Crohn’s disease (Hanauer, 2006; Sandborn, 2004; Sandborn, 2007a; Sandborn, 2007b), moderately to severely active ulcerative colitis (Sandborn, 2012), moderate to severe hidradenitis suppurativa (HS) (Kimball, 2016), non-infectious intermediate, posterior and panuveitis (Jaffe, 2016; Nguyen, 2016), and children 2 years of age or older with moderately to severely active polyarticular juvenile idiopathic arthritis (Kingsbury, 2014; Lovell, 2008).

Off-Label Indications for Adalimumab: Juvenile Idiopathic Arthritis (Other than Polyarticular Juvenile Idiopathic Arthritis) and Pediatric non-Infectious Uveitis

As discussed earlier in this document, Beukelman and colleagues (2012) performed a cross-sectional analysis of the CARRA Registry for current and prior DMARD use in children with juvenile idiopathic arthritis and non-infectious uveitis. Among all children with juvenile idiopathic arthritis, 45% (1246) received a biologic DMARD throughout their course of treatment. TNF antagonists were used by 96% of all biologic users, with adalimumab use at 32% for pediatric juvenile idiopathic arthritis. Overall, there were 304 children (11%) in the registry with a history of uveitis, most received treatment with methotrexate (88%), and many received TNF antagonists (57%). Children with uveitis who received TNF antagonists were much more likely to receive adalimumab, infliximab, or golimumab compared to those who received TNF antagonists and did not have uveitis (OR 10, 95% CI, 6.7-16).The authors noted that TNF antagonists are used more among children with uveitis and this medication usage pattern is supported by observational studies (Biester, 2007), concluding that “…TNF inhibitor usage patterns suggest that pediatric rheumatologists do not rely solely on the results of controlled clinical trials or FDA-approved labeling when making treatment decisions for children with JIA” (Beukelman, 2012).

Dick and colleagues (2017) performed a multicenter, double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active juvenile idiopathic arthritis-associated uveitis. A total of 90 children taking a stable dose of methotrexate were randomly assigned to receive either adalimumab (n=60; age 9.07 ± 3.94 years) in doses according to body weight or placebo (n=30; age 8.56 ± 3.79 years), administered subcutaneously every 2 weeks. All participants were followed for up to 2 years. The primary endpoint was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria. Nine participants (15%) in the adalimumab group and 7 (23%) in the placebo group discontinued the trial intervention for reasons other than treatment failure; 7 participants in the adalimumab group and 6 in the placebo group agreed to subsequent follow-up. In the intention-to-treat analysis of the primary endpoint, the addition of adalimumab to methotrexate significantly delayed the time to treatment failure, as compared with placebo (HR, 0.25; 95% CI, 0.12 to 0.49; p<0.0001 by log-rank test). During the 18-month trial, the median time to treatment failure was not reached in the adalimumab group and was 24.1 weeks (95% CI, 12.4 to 81.0) in the placebo group. Treatment failure occurred in a significantly lower percentage of participants in the adalimumab group than in the placebo group (n=16 participants [27%] vs. 18 [60%]; relative risk, 0.40; 95% CI, 0.22 to 0.73; p=0.002). A total of 588 adverse events, including minor infections (including nasopharyngitis, viral infection, and tonsillitis) and respiratory disorders (including cough, oropharyngeal pain) were reported in 53 (88%) participants in the adalimumab group; 103 adverse events were reported in 25 (83%) participants in the placebo group. Serious adverse events reported as “a flare of uveitis that resulted in hospitalization and treatment” occurred in 1 participant (n=1 event) in the adalimumab group and 2 participants (n=3 events) in the placebo group. The study follow-up period was too short to detect serious events such as cancers and demyelinating diseases. In conclusion, despite the higher incidence of adverse and serious adverse events in adalimumab-treated participants than in the placebo group, adalimumab in combination with methotrexate was an effective therapy in children and adolescents with juvenile idiopathic arthritis-associated uveitis.

In summary, considering the evidence in the peer-reviewed medical literature, recommendations of the American College of Rheumatology (Ringold, 2013), the CARRA registry (Beukelman, 2012), and views of relevant medical specialists practicing in pediatrics and pediatric rheumatology, the use of adalimumab has become standard therapy for the treatment of moderately to severely active juvenile idiopathic arthritis and non-infectious uveitis in children.

Other Off-Label Uses of Adalimumab

Use of adalimumab has been studied in case reports, uncontrolled case series, a retrospective uncontrolled chart review, small, open-label or uncontrolled phase I and II studies, and a small, randomized, double-blind, controlled trial with short-term treatment outcomes for treatment of other conditions including acute and severe sciatica due to lumbar disc degeneration (Genevay, 2010), ANCA-associated systemic vasculitis (Laurino, 2010), intravitreal injections in refractory diabetic macular edema (Wu, 2011), pediatric Crohn’s disease unresponsive to infliximab (Rosh, 2009), focal segmental glomerulosclerosis (Peyser, 2010), and orbital inflammatory disease (for example, orbital myositis, a rare extra-intestinal manifestation of inflammatory bowel disease) (Adams, 2005; Hernandez-Garfella, 2011; Verma, 2013). The FDA has not approved use of adalimumab for any of these conditions.

Certolizumab pegol (Cimzia)

Certolizumab pegol has received FDA approval for the treatment of adults for the following indications: active ankylosing spondylitis (Landewe, 2014), reducing signs and symptoms of moderately to severely active Crohn’s disease and maintaining response in individuals who have had an inadequate response to conventional therapy (Sandborn, 2007; Schreiber, 2007), moderately to severely active rheumatoid arthritis (Fleischmann, 2009; Keystone, 2008; Smolen, 2009), and active psoriatic arthritis (Mease, 2014; van der Heijde, 2014).

Golimumab (Simponi and Simponi Aria)

Golimumab (Simponi [subcutaneous golimumab]) has received FDA approval for the treatment of adults with active ankylosing spondylitis (Inman, 2008), active psoriatic arthritis (Kavanaugh, 2009), moderately to severely active adult rheumatoid arthritis (in combination with methotrexate) (Keystone, 2013), and to induce and maintain clinical response and remission in moderately to severely active ulcerative colitis (Sandborn 2014a; Sandborn 2014b). Golimumab (Simponi Aria [intravenous]) has received FDA approval for the treatment of adults with active ankylosing spondylitis (Simponi Aria PI, 2017; NCT02186873), active psoriatic arthritis (Kavanaugh, 2017), and for moderately to severely active adult rheumatoid arthritis (in combination with methotrexate) (Weinblatt, 2013).

Off-Label Uses of Golimumab

The safety and efficacy of golimumab in the treatment of plaque psoriasis has not been established (Simponi PI, 2017). The FDA has not approved the use of golimumab for this indication despite study subjects reporting some improvement in skin manifestations in a clinical trial of adults with moderately to severely active PsA (Kavanaugh, 2009).

The treatment effect of golimumab was studied in subjects (n=309) with uncontrolled, severe persistent asthma despite high-dose inhaled corticosteroids and long-acting beta-2 agonists (Wenzel, 2009). Subjects were randomized to receive monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. The results showed no significant differences were observed for a change in percent-predicted FEV1 or severe exacerbations through week 24; in addition, 2.6% of subjects treated with placebo versus 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively.

FDA Boxed Warnings and Product Information (PI) for TNF Antagonists

The PI label for each TNF antagonist includes the following boxed warning.

Note: Cimzia PI (2017), Enbrel PI (2017), Humira PI (2017), Remicade PI (2017), Simponi PI (2017), and Simponi Aria PI (2017) are referred to collectively as [TNF antagonists]).

Warning: Risk of Serious Infections (Full Prescribing Information)

Warning: Malignancy (Full Prescribing Information)

Additional Boxed Warning: Malignancy: (Humira PI, 2017; Remicade PI, 2017; Simponi Aria PI, 2017):

Additional precautions and warnings, drug interactions, contraindications for use, and screening recommendations for use of each TNF antagonist agent are available on the current PI labels.

Definitions

5-Aminosalicylic acid (5-ASA) products: A class of anti-inflammatory drugs used to treat bowel inflammation, diarrhea, rectal bleeding, and abdominal pain in Crohn’s disease and ulcerative colitis; includes mesalamine or mesalamine converting products such as balsalazide, olsalazine, and sulfasalazine.

Biologic disease modifying anti-rheumatic drugs (DMARDs): A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing IL-1ß, IL-6, IL-12 and/or IL-23, IL-17A, IL-1Ra, or by directly suppressing lymphocytes.

Conventional therapy: Treatments that are widely accepted and practiced by the medical community.

Corticosteroids (systemic): A class of drugs, also referred to as glucocorticoids, which reduce inflammation and are synthetic derivatives of the natural steroid, cortisol, which is produced by the adrenal glands; includes prednisone, methylprednisone, and hydrocortisone.

Disease modifying anti-rheumatic drugs (DMARDs): A variety of drugs that work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.

Fistulizing: The formation of an abnormal passage from one epithelialized surface to another.

Hidradenitis suppurativa (HS): A chronic, inflammatory disease affecting sweat glands known as apocrine glands. The extent of the disease in tissue is classified by the Hurley staging system for HS (Scheinfeld, 2014):

Immunomodulator drugs: A class of drugs that modifies or influences the immune system.

Immunosuppressive drugs: A subclass of immunomodulator drugs that reduce inflammation by affecting the immune system; includes 6-mercaptopurine (6-MP), azathioprine, cyclophosphamide, cyclosporine, methotrexate, and tacrolimus; also referred to as immunosuppressant drugs.

Induction: Treatment designed as a first step toward treatment of a given condition.

Interferon gamma (IFN-γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include:

Monoclonal antibody: Monoclonal antibodies are produced by a single clone of cells and are of exceptional purity and specificity.

Nonbiologic disease modifying antirheumatic drugs (DMARDs): A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown; includes azathioprine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds, penicillamine, and sulfasalazine.

Nonsteroidal anti-inflammatory drugs (NSAIDs): A class of drugs used to treat pain, redness, swelling, and inflammation from conditions including different types of arthritis; includes over-the-counter (OTC) and prescription medicines, such as celecoxib, diclofenac, ibuprofen, indomethacin, meloxicam, naproxen, sulindac, tolmetin, and valdecoxib.

Orbital inflammatory disease (OID): Inflammatory diseases that affect some or all of the structures contained within the orbit external to the globe of the eye, occur as a part of an initial symptom complex, and can complicate many systemic inflammatory disorders such as Graves' disease, Wegener's granulomatosis, sarcoidosis, vasculitis, Crohn’s disease, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, and scleroderma. Other causes of orbital inflammatory disease, such as idiopathic orbital inflammation (formerly known as "orbital pseudotumor"), orbital myositis, and Tolosa-Hunt syndrome frequently involve systemic immunosuppression.

Refractory disease: Illness or disease that is unresponsive to conventional treatment.

Tumor necrosis factor (TNF or TNF-α): A protein manufactured by white blood cells to stimulate and activate the immune system in response to infection or cancer; also referred to as tumor necrosis factor alpha. Overproduction of this protein can lead to diseases, such as arthritis or psoriasis, where the immune system acts against healthy tissues.

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Websites for Additional Information
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Index

Tumor necrosis factor antagonist

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

 

03/29/2018

Updated Coding section with 04/01/2018 HCPCS changes; added Q5103, Q5104; removed Q5102 (deleted 03/31/18).

New

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development. Moved content of DRUG.00002 Tumor Necrosis Factor Antagonists to new clinical utilization management guideline document with the same title. Added MN criteria and coding for FDA approved use of intravenous golimumab (Simponi Aria) in adults with active ankylosing spondylitis or active psoriatic arthritis when criteria are met.