Certolizumab Pegol (Cimzia) [Medicare]

Number: 0761m

Commercial CPB  |  Medicare CPB

 

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Medicare Part B Step Therapy Criteria

For Medicare Advantage Plans That Do Not Offer Prescription Drug Coverage (MA)

Cimzia, for the indications listed below:

• Rheumatoid arthritis
• Psoriatic arthritis
• Ankylosing spondylitis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Inflectra, Remicade, or Simponi Aria
  2. Intolerable adverse event to Inflectra, Remicade, or Simponi Aria
  3. Inflectra, Remicade, or Simponi Aria is contraindicated for the member

• Psoriasis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Inflectra or Remicade
  2. Intolerable adverse event to Inflectra or Remicade
  3. Inflectra or Remicade is contraindicated for the member

• Crohn's disease

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Entyvio, Inflectra, or Remicade
  2. Intolerable adverse event to Entyvio, Inflectra, or Remicade
  3. Entyvio, Inflectra or Remicade is contraindicated for the member.

For Medicare Advantage Plans That Offer Prescription Drug Coverage (MAPD)

Cimzia, for the indications listed below:

• Rheumatoid arthritis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel, Humira, Kevzara, Rinvoq, or Xeljanz/Xeljanz XR
  2. Intolerable adverse event to Enbrel, Humira, Kevzara, Rinvoq, or Xeljanz/Xeljanz XR
  3. Enbrel, Humira, Kevzara, Rinvoq, or Xeljanz/Xeljanz XR is contraindicated for the member

• Psoriatic arthritis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel, Humira, Otezla, Rinvoq, Skyrizi, or Xeljanz/Xeljanz XR
  2. Intolerable adverse event to Enbrel, Humira, Otezla, Rinvoq, Skyrizi, or Xeljanz/Xeljanz XR
  3. Enbrel, Humira, Otezla, Rinvoq, Skyrizi, or Xeljanz/Xeljanz XR is contraindicated for the member

• Psoriasis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel, Humira, Otezla, or Skyrizi
  2. Intolerable adverse event to Enbrel, Humira, Otezla, or Skyrizi
  3. Enbrel, Humira, Otezla, or Skyrizi is contraindicated for the member

• Ankylosing spondylitis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Enbrel, Humira, or Xeljanz/Xeljaz XR
  2. Intolerable adverse event to Enbrel, Humira, or Xeljanz/Xeljanz XR
  3. Enbrel, Humira, or Xeljanz/Xeljanz XR is contraindicated for the member

• Crohn's disease

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Humira or Skyrizi
  2. Intolerable adverse event to Humira or Skyrizi
  3. Humira or Skyrizi is contraindicated for the member.

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Policy

Note: Requires Precertification:

Precertification of certolizumab pegol (Cimzia) is required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 752-7021, or fax (888) 267-3277. For Medicare Part B plans, call (866) 503-0857 or fax (844) 268-7263.

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with one of the following:

   1. Rheumatoid arthritis, ankylosing spondylitis, or axial spondyloarthritis: rheumatologist;
   2. Psoriatic arthritis: rheumatologist or dermatologist;
   3. Crohn’s disease: gastroenterologist;
   4. Plaque psoriasis: dermatologist.

2. Criteria for Initial Approval

   Aetna considers certolizumab pegol (Cimzia) medically necessary for the following indications, where the member has a documented negative TB testFootnote1* (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray) within 6 months of initiating therapy for persons who are naive to biologic drugs or targeted synthetic drugs associated with an increased risk of TB:

   1. Rheumatoid arthritis (RA)

      1. For adult members who have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Xeljanz) indicated for moderately to severely active rheumatoid arthritis; or
      2. For adult members for treatment of moderately to severely 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 meets either of the following criteria:

            1. Member has experienced an inadequate response to at least a 3-month trial of methotrexate despite adequate dosing (i.e., titrated to at least 15 mg/week); or
            2. Member has an intolerance or contraindication to methotrexate (see Appendix);

   2. Psoriatic arthritis (PsA)

      1. For adult members have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Otezla) indicated for active psoriatic arthritis; or
      2. For adult members for treatment of active psoriatic arthritis when either of the following criteria is met:
         
         

         1. Member has mild to moderate disease and meets one of the following criteria:

            1. Member has had an inadequate response to methotrexate, leflunomide, or another conventional synthetic drug (e.g., sulfasalazine) administered at an adequate dose and duration; or
            2. Member has an intolerance or contraindication to methotrexate or leflunomide (see Appendix), or another conventional synthetic drug (e.g., sulfasalazine); or
            3. Member has enthesitis or predominantly axial disease; or

         2. Member has severe disease;

   3. Ankylosing spondylitis (AS) and axial spondyloarthritis (asSpA)

      1. For adult members who have previously received a biologic or targeted synthetic drug (e.g., Rinvoq, Xeljanz) indicated for active ankylosing spondylitis or active axial spondyloarthritis; or
      2. For adult members for treatment of active ankylosing spondylitis or active axial spondyloarthritis when any of the following criteria is met:
         
         
         1. Member has experienced an inadequate response to at least two non-steroidal anti-inflammatory drugs (NSAIDs); or
         2. Member has an intolerance or contraindication to two or more NSAIDs;

   4. Crohn’s disease (CD)

      1. For adult members who have previously received a biologic indicated for the treatment of moderately to severely active Crohn’s disease; or
      2. For adult members for treatment of moderately to severely active CD when either of the following criteria is met:
         
         
         1. Member has had an inadequate response to systemic corticosteroids, thiopurines (e.g., azathioprine, mercaptopurine), or methotrexate; or
         2. Member has an intolerance or contraindication to systemic corticosteroids, thiopurines (e.g., azathioprine, mercaptopurine), and methotrexate (see Appendix);

   5. Plaque psoriasis (PsO)

      1. For adult members who have previously received a biologic or targeted synthetic drug (e.g., Sotyktu, Otezla) indicated for the treatment of moderate to severe plaque psoriasis; or
      2. For adult members for treatment of moderate to severe plaque psoriasis when any of the following criteria is met:
         
         
         1. Crucial body areas (e.g., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected; or
         2. At least 10% of the body surface area (BSA) is affected; or
         3. At least 3% of body surface area (BSA) is affected and the member meets any of the following criteria:
            
            
            1. Member has had an inadequate response or intolerance to either phototherapy (e.g., UVB, PUVA) or pharmacologic treatment with methotrexate, cyclosporine, or acitretin; or
            2. Member has a clinical reason to avoid pharmacologic treatment with methotrexate, cyclosporine and acitretin (see Appendix).

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

3. Continuation of Therapy 

   Aetna considers continuation of certolizumab pegol (Cimzia) therapy medically necessary for the following indications:

   1. Rheumatoid arthritis (RA)

      For all adult 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;

   2. Psoriatic arthritis (PsA)

      For all adult members (including new members) who are using the requested medication for psoriatic 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 swollen joints; or
      2. Number of tender joints; or
      3. Dactylitis; or
      4. Enthesitis; or
      5. Axial disease; or
      6. Skin and/or nail involvement;

   3. Ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA)

      For all adult members (including new members) who are using the requested medication for active ankylosing spondylitis or active axial spondyloarthritis and who achieve or maintain a positive clinical response with the requested medication 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. Functional status; or
      2. Total spinal pain; or
      3. Inflammation (e.g., morning stiffness);

   4. Crohn's disease (CD)

      1. For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease and who achieve or maintain remission; or
      2. For all adult members (including new members) who are using the requested medication for moderately to severely active Crohn’s disease 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. Abdominal pain or tenderness; or
         2. Diarrhea; or
         3. Body weight; or
         4. Abdominal mass; or
         5. Hematocrit; or
         6. Appearance of the mucosa on endoscopy, computed tomography enterography (CTE), or magnetic resonance enterography (MRE); or
         7. Improvement on a disease activity scoring tool (e.g., Crohn’s Disease Activity Index [CDAI] score);

   5. Plaque psoriasis (PsO)

      For all adult members (including new members) who are using the requested medication for moderate to severe plaque psoriasis 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 any of the following is met:

      1. Reduction in body surface area (BSA) affected from baseline; or
      2. Improvement in signs and symptoms from baseline (e.g., itching, redness, flaking, scaling, burning, cracking, pain).

   Footnote1* 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. 

4. Related Policies

   1. CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions
   2. CPB 0314 - Rituximab or CPB 0314m - Rituximab [Medicare]
   3. CPB 0315 - Etanercept
   4. CPB 0341 - Infliximab or CPB 0341m - Infliximab [Medicare]
   5. CPB 0577 - Laser Treatment for Psoriasis and Other Selected Skin Conditions
   6. CPB 0655 - Adalimumab
   7. CPB 0720 - Abatacept (Orencia) or CPB 0720m - Abatacept (Orencia) [Medicare]
   8. CPB 0790 - Golimumab (Simponi and Simponi Aria) or CPB 0790m - Golimumab (Simponi and Simponi Aria) [Medicare]
   9. CPB 0905 - Secukinumab (Cosentyx)
   10. CPB 0912 - Ustekinumab (Stelara) or CPB 0912m - Ustekinumab (Stelara) [Medicare]

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.

Certolizumab is available as Cimzia 200 mg lyophilized powder for reconstitution in a single‐use vial and 200 mg/mL in a single‐use prefilled glass syringe. Cimzia (certolizumab) is intended for subcutaneous administration as directed by the prescribing physician. Cimzia Lyophilized powder should be prepared and administered by a health care professional. After proper training in subcutaneous injection technique, a person may self-inject with the Cimzia prefilled syringe if a physician determines that it is appropriate.

Ankylosing Spondylitis

The recommended dose of Cimzia for adults with ankylosing spondylitis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks.

Axial Spondyloarthritis

The recommended dose of Cimzia for adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation is 400 mg (given as two subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks.

Crohn's Disease (CD)

The recommended initial adult dose of Cimzia for Crohn’s Disease is 400 mg (given as two subcutaneous injections of 200 mg) initially, and at Weeks 2 and 4. In persons who obtain a clinical response, the recommended maintenance regimen is 400 mg every 4 weeks.

Plaque Psoriasis (PsO)

The recommended dose of Cimzia for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy is 400 mg (given as two subcutaneous injections of 200 mg each) every other week. For some persons (with body weight less than or equal to 90 kg), a dose of 400 mg (given as two subcutaneous injections of 200 mg each) initially and at Weeks 2 and 4, followed by 200 mg every other week may be considered.

Psoriatic Arthritis (PsA)

The recommended dose of Cimzia for adults with psoriatic arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered.

Rheumatoid Arthritis (RA)

The recommended dose of Cimzia for adults with rheumatoid arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered.

Source: UCB, 2019

Experimental and Investigational

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

2. Aetna considers measurements of certolizumab level and certolizumab antibody level experimental and investigational for individuals who are on certolizumab therapy because the clinical value of this approach has not been established.

3. Aetna considers certolizumab pegol experimental and investigational for all other indications (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:

   • Behcet's disease
   • Ocular inflammation/uveitis
   • Sarcoidosis.

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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 "+":
CPT codes not covered for indications listed in the CPB:
Measurements of certolizumab level and certolizumab antibody level - no specific code:
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
96401	Chemotherapy administration, subcutaneous
HCPCS codes covered if selection criteria are met:
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)
Other HCPCS codes related to the CPB:
J0135	Injection, adalimumab, 20 mg
J0702	Injection, betamethasone acetate and betamethasone sodium phosphate, per 3 mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1 mg, for intravenous use
J1628	Injection, guselkumab, 1 mg
J1700	Injection, hydrocortisone acetate, up to 25 mg (i. e., Hydrocortone acetate)
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg (i.e., Hydrocortone phosphate)
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg (i.e., Solu-Cortef)
J1745	Injection infliximab, 10 mg
J3245	Injection, tildrakizumab, 1 mg
J8610	Methotrexate, oral, 2.5 mg
J2650	Injection, prednisolone acetate, up to 1 ml (i.e., Key-Pred 25, Key-Pred 50, Predcor-25, Predcor-50, Predoject 50, Predalone-50, Predicort-50)
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg (i.e., Solu-Medrol)
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg (i.e., Solu-Medrol)
J3301	Injection, triamcinolone acetonide, not otherwise specified, per 10 mg (i.e., Kenalog)
J3302	Injection, triamcinolone diacetate, per 5 mg (i.e., Aristocort)
J3303	Injection, triamcinolone hexacetonide, per 5 mg (i.e., Aristospan)
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7509	Methylprednisolone, oral, per 4 mg
J7510	Prednisolone, oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J8540	Dexamethasone, oral, 0.25 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
S0108	Mercaptopurine, oral 50 mg
ICD-10 codes covered if selection criteria are met:
K50.00 - K50.919	Crohn's disease [regional enteritis]
L40.0 - L40.9	Psoriasis
M05.00 - M05.09	Felty's syndrome
M05.20 - M06.09 M06.20 - M06.29 M06.80 - M06.9	Rheumatoid arthritis
M45.0 - M45.AB	Ankylosing spondylitis
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D86.0 - D86.9	Sarcoidosis
H20.9	Unspecified iridocyclitis [uveitis NOS]
M35.2	Behcet's disease

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Background

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

• Reducing signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy
• Treatment of adults with moderately to severely active rheumatoid arthritis
• Treatment of adult patients with active psoriatic arthritis
• Treatment of adults with active ankylosing spondylitis
• Treatment of adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation
• Treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy

Certolizumab pegol is available as Cimzia (UCB, Inc., Smyrna, GA) which is a pegylated form of anti‐tumor necrosis factor‐alpha (anti‐TNFα). Certolizumab pegol has a high-affinity for human TNF-alpha and selectively targets TNF-alpha in inflamed tissue. Pegylation allows for subcutaneous dosing every four weeks. Certain inflammatory processes involve the overproduction of TNFα by the immune system. TNFα is one of the agents implicated in the auto‐immune response leading to conditions such as Crohn’s disease, rheumatoid arthritis, and psoriasis. Cimzia is an antibody that binds to circulating TNFα, thus diminishing the effects of this molecule in the inflammatory process. In vitro studies show that certolizumab is more potent and binds with greater affinity to TNFα than adalimumab and infliximab. Cimzia does not contain the Fc region and therefore does not activate the complement pathway or cause cell‐mediated cytotoxicity.

Cimzia carries a Black Box Warning for serious infections and malignancy. These include:

• Increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens
• Cimzia should be discontinued if a patient develops a serious infection or sepsis
• Perform test for latent TB; if positive, start treatment for TB prior to starting Cimzia
• Monitor all patients for active TB during treatment, even if initial latent TB test is negative
• Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which Cimzia is a member.
• Cimzia is not indicated for use in pediatric patients.

In addition to risk of serious infection and malignancies, other labeled warnings and precautions include the following:

• New onset or worsening congestive heart failure
• Hypersensitivity reactions
• Hepatitis B virus reactivation
• Exacerbation or new onset demyelinating disease 
• Hematological reactions (including leukopenia, pancytopenia and thrombocytopenia)
• Increased risk of serious infections when Cimzia is used concomitantly with anakinra, abatacept, rituximab and natalizumab; thus, concomitant use with these drugs are not recommended
• Lupus-like syndrome
• Avoid use with live vaccines.

Most common adverse reactions (≥7%) include upper respiratory tract infection, rash, and urinary tract infection.

Ankylosing Spondylitis and Axial Spondyloarthritis

Spondyloarthritis is a term used to include a group of arthritis-associated conditions. One of the associated conditions include axial spndyloarthritis (axSpA), which is a potentially disabling inflammatory arthritis that typically affects the spine; however, may also affect joints in the arms and legs. Symptoms typically begin before the age of 45. Those with axSpA can be further classified into 2 subtypes such as ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA). Individuals affected by AS exhibit radiographic abnormalities consistent with sacrolitis, whereas, findings are absent or minimal on plain radiography for those with nr-axSpA. Individuals with nr-axSpA may have evidence of active inflammation of the sacroiliac (SI) joints on MRI findings (e.g., bone marrow edema of the joints). The diagnosis of axSpA, including AS and nr-axSpA, should be considered in persons with continuous chronic back pain prior to age 45, Per UpToDate, "there is no single historical feature, physical finding, laboratory test, or imaging study with sufficient specificity by itself to establish the diagnosis without the presence of additional abnormalities. Thus, the presence of a combination of features together with the exclusion of other diagnoses that may explain such symptoms or findings is necessary to arrive at an accurate diagnosis" (Yu and van Tubergen, 2018a).

Machado et al (2013) noted that biological agents directed against TNF represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non-steroidal anti-inflammatory drugs.  To evaluate the safety and effectiveness of the anti-TNF agents adalimumab, certolizumab, etanercept, golimumab, and infliximab for the treatment of ankylosing spondylitis, these researchers performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the Embase, Medline, Cochrane Controlled Trials Register and LILACS databases (September 2012), manual literature search, and the gray literature.  Study selections and data collection were performed by 2 independent reviewers, with disagreements solved by a 3rd reviewer.  The following outcomes were evaluated: ASAS 20 response, disease activity, physical function, vertebral mobility, adverse events, and withdraws.  The meta-analysis was performed using the Review Manager 5.1 software by applying the random effects model.  A total of 18 studies were included in this review.  No study of certolizumab was included.  Patients treated with anti-TNF agents were more likely to display an ASAS 20 response after 12/14 weeks (RR 2.21; 95 % confidence interval [CI]: 1.91; to 2.56) and 24 weeks (RR 2.68; 95 % CI: 2.06 to 3.48) compared with controls, which was also true for several other efficacy outcomes.  Meta-analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks.  The authors concluded that adalimumab, etanercept, golimumab, and infliximab can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis.  Moreover, they stated that safety outcomes deserve further study, especially with respect to long-term follow-ups.

The FDA has approved Cimzia for adults with ankylosing spondylitis (UCB, 2013)  The approval of Cimzia for adults with active ankylosing spondylitis was based on a phase 3, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Cimzia in patients with active axial spondyloarthritis, in which the majority had ankylosing spondylitis 

In the efficacy and safety study of certolizumab, patients with active axial spondyloarthritis were randomized (1:1:1) to receive certolizumab 200 mg every two weeks, 400 mg every four weeks or placebo (UCB, 2013). There were a total of 325 patients in the study, of which 178 had ankylosing spondylitis. All patients received a loading dose with certolizumab or placebo at weeks 0, 2 and 4. The primary efficacy variable, the proportion of patients achieving an ASAS20 response rate at week 12, was met with clinical and statistical significance in both dosing arms versus placebo. 

A greater proportion of ankylosing spondylitis patients treated with certolizumab 200 mg every two weeks or 400 mg every four weeks achieved ASAS20 response at week 12, compared with ankylosing spondylitis patients treated with placebo (UCB, 2013). Responses were similar in patients receiving certolizumab 200 mg every two weeks and 400 mg every four weeks. 

In this study, adverse events occurred in 70.4% of patients in the certolizumab group (combined dose) compared to 62.6% of patients in the placebo group (UCB, 2013). Serious adverse events occurred in 4.7% of patients in both the certollizumab group (combined dose) and in the placebo group. According to the manufacturer, the safety profile for patients with ankylosing spondylitis treated with certolizumab was similar to the safety profile seen in patients with rheumatoid arthritis and in patients with previous experience with certolizumab.

On March 28, 2019, the FDA announced the approval of Cimzia (certolizumab pegol) injection for the treatment of adults with non-radiographic axial spondyloarthritis (nr-axSpA) who have objective signs of inflammation. Nr-axSpA is a type of inflammatory arthritis that causes inflammation in the spine and other symptoms in which there is no visible damage seen on x-rays, thus, referred to as non-radiographic. FDA approval was based on outcomes from a phase 3, multi-center, double-blind, placebo-controlled 52-week study (C-AXSPAND) that randomized 317 adult patients with objective signs of inflammation indicated by elevated CRP levels, and/or sacrolitis on MRI. Patients received either Cimzia (400 mg at weeks 0, 2, and 4 followed by 200 mg every 2 weeks) or placebo plus other medications, which included NSAIDs, corticosteroids, analgesics and slow-acting anti-rheumatic drugs.The primary endpoint of the study was met, with 47.2% of patients treated with Cimzia demonstrating major improvement response in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) at week 52, compared to 7.0% of patients treated with placebo. The secondary endpoint of the study was also met, with 47.8% of Cimzia-treated patients achieving a 40% improvement in Ankylosing Spondylitis Assessment Score (ASAS40) compared to 11.4% of placebo-treated patients at week 12. Furthermore, the safety profile was found to be similar to the safety profile seen in patients with RA and previous experience with Cimzia. The study investigators concluded that their results indicate that remission in nr-axSpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond non-biologic therapy (Deodhar et al. 2019; FDA, 2019).

UpToDate recommends adding a tumor necrosis factor (TNF)-alpha inhibitor for patients with active axial SpA symptoms and have had an inadequate response to initial therapy with at least two NSAIDs consecutively rather than treatment with NSAIDs alone. TNF inhibitors (e.g., subcutaneous adalimumab) is an acceptable treatment option (Yu and van Tubergen, 2019b).

Behcet's Disease

Lopalco and colleagues (2017) described their experience with certolizumab pegol (CZP) in patients with Behcet's disease (BD) refractory to standardized therapies and previous biologic agents.  Retrieved data including demographic characteristics, clinical manifestations, and previous treatments were collected in 3 different specialized rheumatologic units in Italy.  In order to evaluate disease activity, the BD current activity form (BDCAF) has been used before starting CZP therapy and at each visit during treatment.  A total of 13 BD patients (mean age of 42.6 ± 8.8 years) with a disease duration of 8.80 ± 6.9 years, underwent CZP treatment for 6.92 ± 3.52 months; 6 patients (46.15 %) experienced a worsening of symptoms after 4.16 ± 1.21 months, whereas a satisfactory response was achieved in 7 patients (53.84 %) who were still on CZP therapy at the last follow-up visit (after 9.28 ± 3.03 months of treatment).  The mean decrease of BDCAF between the first and last visit was 0.308 ± 1.84 without reaching significant difference (mean of 8.3 ± 1.3 and 8 ± 2.08, respectively; p= 0.51).  During the whole study period, CZP was well-tolerated in all patients except for 1 who developed a generalized cutaneous reaction after the 3rd administration.  The authors concluded that these findings suggested that despite an improvement of clinical manifestations has been observed in more than 50 % of the patients, it is not possible to draw firm conclusions about the effectiveness of CZP in BD and further studies with larger cohorts of patients are needed.  Whether the increase of CZP dosage may ensure a better clinical response remains an unsolved issue that needs to be considered.

Crohn's Disease

Crohn's disease is a chronic, inflammatory bowel disease that affects more than 1 million people worldwide.  It has no cure and its cause is unknown.  Crohn's disease can cause diarrhea, fever, rectal bleeding, malnutrition, narrowing of the intestinal tract, obstructions, abscesses, cramping, and abdominal pain. It also can lead to fistulas (abnormal connections) leading from the intestine to the skin or internal organs.

In April 2008, the U.S. Food and Drug Administration (FDA) approved certolizumab pegol for adults with moderately-to-severely active Crohn's disease who have not responded to conventional therapies.  The approval of certolizumab pegol was based on safety and efficacy data from clinical trials in more than 1,500 patients with Crohn's disease.

The Pegylated Antibody Fragment Evaluation in Crohn's Disease: Safety and Efficacy (PRECiSE) program enrolled more than 1,300 patients in 4 trials and evaluated the safety and efficacy of certolizumab pegol.  The PRECiSE 1 and PRECiSE 2 studies were 26-week trials that evaluated induction and short-term maintenance of remission.  Outcome data from the PRECiSE 3 and PRECiSE 4 studies, designed to evaluate long-term maintenance of remission, have not yet been published.

The PRECiSE 1 trial, a placebo-controlled phase IIII study, stratified patients (n = 662) according to baseline levels of C-reactive protein (CRP).  Patients were randomly assigned to receive either 400 mg of certolizumab pegol or placebo subcutaneously at weeks 0, 2, and 4 and then every 4 weeks.  Primary endpoints were the induction of a response at week 6 and a response at both weeks 6 and 26.  Among patients with a baseline CRP level of at least 10 mg per liter, 37 % of patients in the certolizumab group had a response at week 6, as compared with 26 % in the placebo group.  At both weeks 6 and 26, the corresponding values were 22 % and 12 %, respectively.  In the overall population, response rates at week 6 were 35 % in the certolizumab group and 27 % in the placebo group; at both weeks 6 and 26, the response rates were 23 % and 16 %, respectively.  At weeks 6 and 26, the rates of remission in the 2 groups did not differ significantly.  Serious adverse events were reported in 10 % of patients in the certolizumab group and 7 % of those in the placebo group; serious infections were reported in 2 % and less than 1 %, respectively.  In the certolizumab group, antibodies to the drug developed in 8 % of patients, and anti-nuclear antibodies developed in 2 %.  The authors concluded that in patients with moderate-to-severe Crohn's disease, induction and maintenance therapy with certolizumab pegol was associated with a modest improvement in response rates, as compared with placebo, but with no significant improvement in remission rates (Sandborn et al, 2007).

The PRECiSE 2 trial, a placebo-controlled study, evaluated the efficacy of certolizumab pegol maintenance therapy in adults (n = 668) with moderate-to-severe Crohn's disease.  Certolizumab pegol (400 mg) was administered subcutaneously at weeks 0, 2, and 4 as induction therapy.  Patients with a clinical response (defined as reduction of at least 100 from the baseline score on the Crohn's Disease Activity Index [CDAI]) at week 6 were stratified according to their baseline CRP level and were randomly assigned to receive 400 mg of certolizumab pegol or placebo every 4 weeks through week 24, with follow-up through week 26.  Among patients with a response to induction therapy at week 6 (n = 428 or 64 %), the response was maintained through week 26 in 62 % of patients with a baseline CRP level of at least 10 mg per liter (the primary endpoint) who were receiving certolizumab pegol (versus 34 % of those receiving placebo) and in 63 % of patients in the intention-to-treat population who were receiving certolizumab pegol (versus 36 % receiving placebo).  Among patients with a response to induction therapy at week 6, remission (defined by a CDAI score of 150) at week 26 was achieved in 48 % of patients in the certolizumab group and 29 % of those in the placebo group.  The use of immunosuppressants, corticosteroids, and previous treatment with infliximab were not demonstrated to affect the response rate.  Serious infections, including one case of pulmonary tuberculosis, occurred in 3 % of patients receiving certolizumab pegol and in less than 1 % of patients receiving placebo.  Anti-nuclear antibodies developed in 8 % of the patients in the certolizumab group; antibodies against certolizumab pegol developed in 9 % of all patients who entered the induction phase.  The authors concluded that patients with moderate-to-severe Crohn's disease who had a response to induction therapy with 400 mg of certolizumab pegol were more likely to have a maintained response and a remission at 26 weeks with continued certolizumab pegol treatment than with a switch to placebo.

A Cochrane systematic review (2008) evaluated the evidence of the effectiveness of TNF-alpha blocking agents in the maintenance of remission in patients with Crohn's disease.  Randomized controlled trials involving patients greater than 18 years of age with Crohn's disease who had a clinical response or clinical remission with a TNF-alpha blocking agent, or patients with Crohn's disease in remission but unable to wean from corticosteroids, who were then randomized to maintenance of remission with a TNF-alpha blocking agent or placebo were selected for review.  Nine studies met all inclusion criteria.  Four different anti-TNF-alpha agents were evaluated (infliximab in 3 studies, CDP571 in 3 studies, adalimumab in 2 studies, and certolizumab in 1 study).  The authors reported that infliximab, adalimumab, and certolizumab maintained clinical remission, clinical response, had corticosteroid-sparing effects, and maintained fistula healing in patients with Crohn's disease.  There was no evidence to support the use of CDP571 for the maintenance of remission in Crohn's disease.  No comparative trials have evaluated the relative efficacy of these agents.  Adverse events were similar in the infliximab, adalimumab, and certolizumab groups compared with placebo, but study size and duration generally were insufficient to allow an adequate assessment of serious adverse events associated with long-term use.

In the Crohn's Disease Study Group, Rutgeerts et al (2008) reported the health-related quality of life (HRQoL) of patients with moderately-to-severely active Crohn's disease (n = 292) who received subcutaneous certolizumab pegol.  Patients with moderately-to-severely active Crohn's disease (n = 292) received subcutaneous certolizumab pegol 100, 200, or 400 mg or placebo at weeks 0, 4, and 8.  A post hoc analysis of the intent-to-treat population (290 patients with HRQoL data) assessed HRQoL by evaluating patients' responses to the self-administered inflammatory bowel disease questionnaire (IBDQ) at baseline and weeks 2, 4, 6, 8, 10, and 12.  Patients receiving certolizumab pegol 400 mg at weeks 0, 4, and 8 demonstrated, via their IBDQ total score, significantly greater improvement in HRQoL from baseline to week 12 and at all other time points compared with placebo.  In addition, HRQoL improved over time in all certolizumab pegol groups, irrespective of baseline CRP levels.  Emotional well-being improved throughout the study for patients receiving certolizumab pegol 400 mg.  This improvement was significantly greater than for patients receiving placebo at all time points.  In addition, systemic symptoms improved more in patients receiving certolizumab pegol 400 mg than in those receiving placebo at weeks 4, 8, 10, and 12 and approached statistical significance at week 2.  The authors concluded that certolizumab pegol 400 mg improved health-related quality of life in patients with moderate-to-severe Crohn's disease.

A review of the evidence for targeted immunomodulators by the Drug Effectiveness Review Project (DERP) (Thaler, et al., 2012) identified no head-to-head trials providing direct evidence on the comparative efficacy of targeted immune modulators for Crohn’s disease. The review found that the general efficacy of certolizumab pegol, adalimumab, infliximab, and natalizumab for the treatment of moderate to severe Crohn’s disease was supported by several good to fair randomized controlled trials and meta-analyses including 6901 patients. In efficacy trials 26% to 57% of patients treated with targeted immune modulators achieved a Crohn’s Disease Activity Index remission (CDAI <150), compared with 12% to 30% of patients on placebo.

Plaque Psoriasis 

On May 29, 2018, the U.S. Food and Drug Administration (FDA) approved the biologic Cimzia (certolizumab pegol) for the treatment of adults with psoriasis who are eligible for systemic therapy or phototherapy. Certolizumab is already approved in moderately to severely active Crohn’s disease, moderately to severely active rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis. Certolizumab is a recombinant, humanized antibody Fab' fragment that binds to and blocks human TNFα, a key pro-inflammatory cytokine with a central role in inflammatory processes. A potential advantage of certolizumab pegol is minimal transfer across the placenta; unlike other anti-TNF biologics, certolizumab pegol does not bind the neonatal Fc receptor because it does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.

FDA approval of certolizumab in adult plaque psoriasis was based on three multicenter, randomized, double-blind studies (CIMPASI-1 [NCT02326298], CIMPASI-2 [NCT02326272], and CIMPACT [NCT02346240]) that enrolled subjects 18 years of age or older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had a Physician Global Assessment (PGA) of 3 or greater (“moderate”) on a 5-category scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score 12 or greater, and body surface area (BSA) involvement of 10% or more.

Gottlieb et al (2018) stated certolizumab pegol, the only Fc-free, PEGylated anti-tumor necrosis factor biologic, demonstrated clinically meaningful improvements suggestive of a positive risk-benefit balance in phase 2 studies in adults with moderate-to-severe chronic plaque psoriasis. The authors assessed certolizumab (CZP) efficacy and safety versus placebo in two phase 3 studies (CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272)). Of 587 participants screened for both studies, 234 were randomized in CIMPASI-1 and 227 were randomized in CIMPASI-2. At the baseline visit, patients were assigned to subcutaneous treatment with CZP 400 mg every 2 weeks, CZP 200 mg every 2 weeks (after loading dose of CZP 400 mg at weeks 0, 2, and 4), or placebo every 2 weeks until week 16 (initial treatment period) according to the randomization schedule produced by an independent biostatistician (2:2:1, stratified by site). Studies CIMPASI-1 and CIMPASI-2 assessed the co-primary endpoints of the proportion of patients who achieved a 75% reduction in Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment of “clear” or “almost clear” (PGA of 0/1 ) with at least a 2-point improvement at Week 16. Secondary endpoints included week-16 PASI 90 responder rate, change in Dermatology Life Quality Index (DLQI) between baseline and week 16, and PASI 75 and PGA 0/1 responder rates at week 48. Other efficacy variables included PASI 90 responder rate at week 48 and PASI 100 (100% reduction in PASI from baseline PASI) and DLQI 0/1 (no/small impact of psoriasis on patient's quality of life) responder rates at week 16 and week 48. Safety was assessed via treatment-emergent adverse events (TEAEs). Eligible patients were 18 years of age or older with plaque psoriasis for at least 6 months with baseline PASI 12 or greater, body surface area affected 10% or more, and a Physician's Global Assessment (PGA) 3 or greater on a 5-point scale. All participants were candidates for systemic therapy, phototherapy, or photochemotherapy.

At week 16, significantly higher PASI 75 responder rates were observed for CZP 400 mg (CIMPASI-1, 75.8%; CIMPASI-2, 82.6%) and CZP 200 mg (CIMPASI-1, 66.5%; CIMPASI-2, 81.4%) than placebo (CIMPASI-1, 6.5%; CIMPASI-2, 11.6%; P < .0001 for all), and responses were maintained through week 48 for both CZP doses. At week 16, significantly higher PGA 0/1 responder rates were observed for CZP 400 mg (CIMPASI-1, 57.9%; CIMPASI-2, 71.6%) and CZP 200 mg (CIMPASI-1, 47.0%; CIMPASI-2, 66.8%) than placebo (CIMPASI-1, 4.2%; CIMPASI-2, 2.0%; P < .0001 for all); responses were maintained through week 48 for both CZP doses. No unexpected safety signals were identified. The safety profile was consistent with the therapeutic class. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection. The limitations of this trial were that there was no active comparator arm and patients were excluded from the study for having a history of primary failure to biologic therapy. In addition, sample sizes are smaller than other phase 3 psoriasis trials, making it difficult to discern whether observed study variations are simply a consequence of patient numbers. The authors concluded that treatment with either certolizumab 400 mg or 200 mg every 2 weeks was associated with significant and clinically meaningful improvements in moderate-to-severe psoriasis. The 400-mg dose could provide additional clinical benefit.

Lebwohl et al (2018) assessed the safety and efficacy of certolizumab (CZP) in adults with moderate-to-severe chronic plaque psoriasis in a phase 3, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled study, followed by a placebo-controlled maintenance period and open-label follow-up period (CIMPACT; NCT02346240). During the initial period, 559 patients were randomized 3:3:1:3 (stratified by site) to CZP 400 mg every 2 weeks or CZP 200 mg every 2 weeks (after 400-mg loading doses at weeks 0, 2, and 4) for 16 weeks, placebo every 2 weeks for 16 weeks, or etanercept 50 mg twice weekly for 12 weeks. At week 16, patients in the CZP-treatment groups achieving a PASI 75 (≥75% reduction in the Psoriasis Area and Severity Index [PASI] from baseline) were re-randomized (2:2:1): from CZP 400 mg every 2 weeks to CZP 400 mg every 2 weeks, CZP 200 mg every 2 weeks, or placebo; and from CZP 200 mg every 2 weeks to CZP 400 mg every 4 weeks, CZP 200 mg every 2 weeks, or placebo for the 32-week maintenance period. Placebo-treated PASI 75 responders continued placebo for the maintenance period, and etanercept-treated PASI 75 responders, after a 4-week washout, were re-randomized (2:1) to CZP 200 mg every 2 weeks (after 400 mg loading doses at weeks 16, 18, and 20) or placebo. PASI 75 nonresponders at week 16 entered an escape arm and received treatment with CZP 400 mg every 2 weeks. Patients who were rerandomized and were PASI 50 nonresponders (had a <50% reduction in PASI from baseline PASI) at any visit during the maintenance period and patients who completed the double-blind maintenance period entered the open-label safety extension, which was ongoing at the time of publication, and received CZP 400 mg every 2 weeks. The primary efficacy endpoint was PASI 75 responder rate for both CZP doses versus placebo at week 12. Secondary efficacy endpoints were PASI 75 responder rate versus placebo at week 16; PGA 0/1 responder rate (clear/almost clear with ≥2-point improvement from baseline PGA score) versus placebo at weeks 12 and 16; PASI 90 responder rate versus placebo at weeks 12 and 16; PASI 75 responder rate versus etanercept at week 12; and PASI 75 responder rates at week 48 for patients achieving PASI 75 at week 16. Safety was assessed by treatment-emergent adverse events (TEAEs). Eligible patients were 18 years of age or older with plaque psoriasis for at least 6 months with baseline PASI 12 or greater, body surface area affected 10% or more, and a Physician's Global Assessment (PGA) 3 or greater on a 5-point scale. All participants were candidates for systemic therapy, phototherapy, or photochemotherapy.

By week 12, PASI 75 responder rate was significantly greater for CZP-treated patients versus placebo-treated patients (66.7% CZP 400 mg, p<00001; 61.3% CZP 200 mg, p<00001; 5.0% placebo). Differences were evident between the drug groups and the placebo group as early as week 4 and increased through week 16. At week 12, CZP 400 mg was superior and CZP 200 mg was non-inferior to etanercept for PASI 75 responder rate (66.7% CZP 400 mg, p=0.0152; 61.3% CZP 200 mg, p=0.1523; 53.5% Etanercept). Similar trends occurred for PGA 0/1 and PASI 90 responder rates for both doses of CZP versus placebo. All endpoints were significantly greater for certolizumab versus placebo with the greatest response seen with 400 mg. No new safety signals were observed. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection. The limitation for this study was that etanercept was administered by un-blinded study staff or self-administered, but efficacy assessments were performed by a blinded assessor. The authors concluded that both certolizumab regimens improved psoriasis symptoms, with a greater response seen with the higher dose. 

Psoriatic Arthritis

Rozenblit and Lebwohl (2009) stated that the prevalence of psoriasis is estimated to be 2.2 % in the United States, and 6 to 39 % of patients with psoriasis also develop psoriatic arthritis.  New advances have been made in developing treatment options.  A new human TNF-alpha antibody, golimumab, has been shown to significantly improve symptoms of psoriatic arthritis.  In addition, clinical trials of certolizumab pegol show promising results for treating rheumatoid arthritis and suggest that it may be applicable for treating psoriasis and psoriatic arthritis in the future.  New biological therapies also include antibodies to interleukin-12 and interleukin-23.  Phase II studies suggest that ustekinumab is effective in alleviating symptoms of psoriasis and psoriatic arthritis.  However, longer studies with radiographical evaluation will be required before their impact on joint destruction can be assessed.  In a review on the treatment of peripheral arthritis in psoriatic arthritis, Soriano and Rosa (2009) noted that among new drugs, evidence of efficacy has already been published with regard to golimumab and ustekimumab; results are forthcoming from trials with abatacept, certolizumab pegol, and rituximab.  Furthermore, Farhi and Dupin (2009) stated that new biological therapies under investigation in the treatment of psoriasis include certolizumab, golimumab, and ustekinumab.

Certolizumab has been approved by the FDA for use in adults with active psoriatic arthritis (UCB, 2013). FDA approval of Cimzia for active psoriatic arthritis was based on data from the RAPIDTM-PsA study, an ongoing, phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of certolizumab pegol in 409 patients with active and progressive adult onset psoriatic arthritis. Patients received a loading dose of certolizumab 400 mg at weeks 0, 2 and 4 or placebo, followed by either certolizumab 200 mg every other week, certolizumab 400 mg every 4 weeks, or placebo every other week.  Patients were evaluated for signs and symptoms of psoriatic arthritis using the ACR20 response at week 12 and for structural damage using the modified Total Sharp Score (mTSS) at week 24. 

ACR20, 50, and 70 response rates at weeks 12 and 24 were higher for each certolizumab dose group relative to placebo (UCB, 2013). Patients treated with certolizumab 200 mg every other week demonstrated greater reduction in radiographic progression compared with placebo-treated patients at week 24, as measured by change from baseline in total modified mTSS Score. Patients treated with certolizumab 400 mg every four weeks did not demonstrate greater inhibition of radiographic progression at week 24, compared with placebo-treated patients. Treatment with certolizumab also resulted in improvement in skin manifestations in patients with psoriatic arthritis. However, the safety and efficacy of certolizumab in the treatment of patients with plaque psoriasis has not been established.

Adverse events occurred in 62% of patients in the certolizumab group (combined dose) compared to 68% of patients in the placebo group (UCB, 2013). Serious adverse events occurred in 7% of patients in the certolizumab group (combined dose) compared to 4% of patients in the placebo group. According to the manufacturer, the safety profile for patients with psoriatic arthritis treated with certolizumab was similar to the safety profile seen in patients with rheumatoid arthritis and in patients with previous experience with certolizumab.

Rheumatoid Arthritis

Certolizumab pegol was approved by the FDA on April 24, 2009 for adults with moderately-to-severely active RA.  It can be administered as combination therapy with methotrexate (MTX) or as monotherapy.  The recommended dose for patients with moderately-to-severely active RA is 400 mg initially and at weeks 2 and 4, followed by 200 mg every other week.  For maintenance dosing, 400 mg every 4 weeks can be considered.  It is self-administered by subcutaneous injection.  According to the prescribing information, certolizumab pegol should not be used in combination with biological disease-modifying antirheumatic drugs (DMARDs) or other TNF blocker therapies.

The FDA approval of Cimzia for RA was based on data from 4 multi-center placebo-controlled phase III trials, involving more than 2,300 patients aged 18 years or older with moderately-to-severely active RA.  Patients who received certolizumab pegol together with MTX, experienced a significant reduction in the signs and symptoms of RA at week 24 with some showing clinical responses within 1 to 2 weeks, compared with MTX alone.  Additionally, radiographic data showed certolizumab pegol, together with MTX, inhibited progression of joint damage, with a significantly smaller change from baseline in modified Total Sharp Score (TSS) at 24 and 52 weeks of treatment, compared with MTX alone (p < 0.001).

The DERP review (Thaler, et al., 2012) found good to fair evidence from meta-analyses and large randomized controlled trials that certolizumab pegol, abatacept, adalimumab, anakinra, etanercept, golimumab, infliximab, rituximab, and tocilizumab are statistically significantly more efficacious than placebo for the treatment of rheumatoid arthritis. The review stated that data were too heterogeneous to conduct indirect comparisons of certolizumab pegol with other targeted immune modulators for rheumatoid arthritis.

Keystone et al (2008) evaluated the safety and effectiveness of 2 dosage regimens of certolizumab pegol as adjunctive therapy to MTX in patients with active RA who had an inadequate response to MTX therapy alone.  In this 52-week, phase III, multi-center, randomized, double-blind, placebo-controlled, parallel-group trial, 982 patients were randomized 2:2:1 to receive treatment with 400 mg of certolizumab pegol as an initial dosage and at weeks 2 and 4, with a subsequent dosage of 200 mg or 400 mg given every 2 weeks, plus MTX, or placebo plus MTX.  Co-primary endpoints were the response rate at week 24 according to the American College of Rheumatology 20 % criteria for improvement (ACR20) and the mean change from baseline in the modified TSS at week 52.  At week 24, ACR20 response rates using non-responder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8 % and 60.8 %, respectively, as compared with 13.6 % for the placebo group.  Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 (p < 0.001).  At week 52, mean radiographic progression from baseline was reduced in patients treated with 200 mg of certolizumab pegol (0.4 Sharp units) or 400 mg (0.2 Sharp units) as compared with that in placebo-treated patients (2.8 Sharp units) (p < 0.001 by rank analysis).  Improvements in all ACR core set of disease activity measures, including physical function, were observed by week 1 with both certolizumab pegol dosage regimens.  Most adverse events were mild or moderate.  The authors concluded that 200 mg or 400 mg of certolizumab pegol plus MTX resulted in a rapid and sustained reduction in RA signs and symptoms, inhibited the progression of structural joint damage, and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX.

Smolen et al (2009) reported the safety and efficacy of certolizumab pegol plus MTX in a randomized controlled trial (RAPID 2 study).  Patients (n = 619) were randomized 2:2:1 to 400 mg of certolizumab pegol at weeks 0, 2 and 4 followed by 200 mg or 400 mg of certolizumab pegol plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks.  The primary endpoint was ACR20 response at week 24.  Secondary endpoints included ACR50 and ACR70 responses, change from baseline in modified TSS Score, ACR core set variables and physical function.  The authors reported that significantly more patients in the 200 mg and 400 mg certolizumab pegol groups achieved an ACR20 response versus placebo (p < or = 0.001); rates were 57.3 %, 57.6 % and 8.7 %, respectively.  Certolizumab pegol significantly inhibited radiographic progression; mean changes from baseline in modified TSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p < or = 0.01).  Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in the Disability Index of the Health Assessment Questionnaire (HAQ DI) at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p < or = 0.001).  Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events.  Five patients developed tuberculosis.  The authors concluded that certolizumab pegol plus MTX were more efficacious than placebo plus MTX.

Fleischmann et al (2009) evaluated the safety and efficacy of certolizumab pegol in a randomized, double-blind, placebo-controlled study (FAST4WARD study) in RA patients (n = 220) previously failing one or more DMARDs.  Patients were randomized 1:1 to receive 400 mg of subcutaneous certolizumab pegol (n = 111) or placebo (n = 109) every 4 weeks.  The primary endpoint was the ACR20 response at week 24.  Secondary endpoints included ACR50/70 response, ACR component scores, 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 (DAS28(ESR)3), patient-reported outcomes (including physical function, HRQoL, pain and fatigue) and safety.  At week 24, the ACR20 response rates were 45.5 % for 400 mg of certolizumab pegol every 4 weeks versus 9.3 % for placebo (p < 0.001).  Differences for certolizumab pegol versus placebo in the ACR20 response were statistically significant as early as week 1 through week 24 (p < 0.001).  Significant improvements in ACR50, ACR components, DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study.  Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported.  The authors concluded that 400 mg of certolizumab pegol monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing one or more DMARDs compared with placebo, and demonstrated an acceptable safety profile.

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 our without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with our 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).

Uveitis

Rifkin et al (2013) discussed the differences in the mechanism of action, route of administration, indication, and effectiveness of TNF inhibitors used in the treatment of ocular inflammation.  A review of the literature in the PubMed, Medline, and Cochrane databases was conducted to identify clinical trials, comparative studies, case series, and case reports describing the use of tumor necrosis factor inhibitors in uveitis therapy.  The search was limited to primary reports published in English with human subjects from 1990 to the present, yielding 5,238 manuscripts.  In addition, referenced articles from the initial searches were hand searched to identify additional relevant reports.  After title and abstract selection, duplicate elimination, and manual search, a total of 69 papers were selected for analysis.  Exclusion criteria included review articles and case reports on the effectiveness of adalimumab, etanercept, and infliximab.  Manuscripts with fewer than 20 study subjects were excluded if other larger studies existed on the use of the same drug for a particular indication.  Studies with less than 6 months of patient follow-up were also excluded, except in the case where no other data were available.  Articles meeting these criteria were then reviewed by the 3 authors for inclusion in this review.  Tumor necrosis factor inhibitors have been shown to decrease inflammation associated with a number of rheumatologic conditions.  Three of the 5 commercially available TNF inhibitors – adalimumab, etanercept, and infliximab -- have been studied for their effectiveness in treatment of ocular inflammation.  Etanercept appears to be inadequate in controlling ocular inflammation and is not recommended for the treatment of uveitis.  Adalimumab and infliximab, however, have shown encouraging results in multiple trials.  Serious potential side effects such as infection, including re-activation of latent tuberculosis, malignancy, and demyelinating disease, may limit the use of TNF inhibitors in uveitis.  Proper screening of patients prior to initiating these therapies may decrease these risks.  The authors concluded that early success with adalimumab and infliximab has paved the way for new TNF inhibitors and other corticosteroid-sparing drugs to emerge in the treatment of ocular inflammation.  They stated that future studies are on the horizon to determine the long-term safety and effectiveness of newer TNF inhibitors such as certolizumab and golimumab.

Sanchez-Cano et al (2013) stated that TNF-alpha plays a central role in both the inflammatory response and that of the immune system.  Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropathies, inflammatory bowel disease, and psoriasis.  Nonetheless, theoretically, some other autoimmune disorders may benefit from these agents.  These investigators reviewed these off-label uses of anti-TNF blockers in 3 common conditions:

1. Behcet's disease,
2. sarcoidosis, and
3. non-infectious uveitis.

They noted that due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review was mainly based on case reports and case series. 

Measurements of Certolizumab Level and Certolizumab Antibody Level

Gehin and colleagues (2019) identified a therapeutic target interval for certolizumab pegol drug levels and examined the influence of anti-drug antibodies (ADAs) in patients with inflammatory joint diseases (IJDs).  Certolizumab pegol and ADA levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with IJDs (116 axSpA, 91 RA, and 61 PsA) in the NOR-DMARD study.  Therapeutic response was defined by ASDAS clinically important improvement in axSpA, European League Against Rheumatism (EULAR) good/moderate response in RA, and improvement in 28-joint DAS of greater than or equal to 0.6 in PsA.  Serum drug levels and ADAs were analyzed using automated in-house assays.  Certolizumab pegol serum levels varied considerably between individuals (median inter-quartile range [IQR] 32.9 (17.3 to 43.9) mg/L).  Certolizumab pegol level of greater than or equal to 20 mg/L was associated with therapeutic response for the total IJD population, with odds ratio (OR) 2.3 (95 % CI: 1.2 to 4.5, p = 0.01) and OR 1.9 (95 % CI: 1.0 to 3.5, p = 0.05) after 3 and 6 months of treatment, respectively.  For individual diagnoses, this association was most consistent for axSpA, with OR 3.4 (95 % CI: 1.0 to 11.1, p < 0.05) and OR 3.3 (95 % CI: 1.0 to 10.8, p < 0.05), respectively.  Certolizumab pegol level of greater than 40 mg/L was not associated with any additional benefit for any of the diagnoses; ADAs were detected in 6.1 % (19/310) of samples and were associated with low certolizumab pegol levels (p < 0.01).  The authors concluded that serum certolizumab pegol levels of 20 to 40 mg/L were associated with therapeutic response in IJDs.  These researchers stated that this study was the 1st to show this association in axSpA and PsA patients.  They stated that these findings suggested a possible benefit of therapeutic drug monitoring  (TDM)in patients with IJD on certolizumab pegol treatment; however, the clinical significance of tailoring TNF inhibitor (TNFi) treatment in IJDs by TDM should be further examined in randomized controlled trials (RCTs).  Moreover, these researchers stated that the lack of data on body weight and of more extensive joint counts in PsA patients was a drawback of this study.

Mehta and Manson (2020) noted that TNFis have revolutionized the management of RA, however despite considerable progress, only a small proportion of patients maintain long-term clinical response.  Selection of, and switching between, biologics is mainly empirical, experiential, and not evidence-based.  Most biopharmaceutical proteins (BP) could induce an immune response against the foreign protein component.  Immunogenicity and the development of anti-drug antibodies (ADAs) is considered one of the main reasons for loss of therapeutic efficacy (secondary failure).  ADAs may neutralize and/or promote clearance of circulating BP with resultant low serum drug levels, loss of clinical response, poor drug survival and adverse events (AEs), such as infusion reactions.  ADA identification is technically difficult and not standardized, making interpretation of immunogenicity data from published clinical studies challenging.  Trough TNFi drug levels correlate with clinical outcomes, exhibiting a "concentration-response" relationship.  Measurement of ADA and drug levels may improve patient care and improve cost-effectiveness of BP use.  However, in the absence of clinically-validated, reliable assays and consensus guidelines, TDM and immunogenicity testing have not been widely adopted in routine clinical practice in rheumatology.  These researchers stated that prospective, longitudinal studies of BP-naïve patients may provide mechanistic information and address a critical unanswered question -- why BPs are immunogenic in some patients, but tolerogenic in others.  Prediction of immunogenicity may allow mitigation and management strategies to be implemented to prevent or minimize the generation of ADAs.  Other strategies to personalize biologic selection, include pharmacogenetic testing to identify genetic factors that may predict lack of response to, or toxicities from, TNFi.  These investigators stated that further research is needed to develop standardized, clinically-validated assays for both drug and ADA testing.  These tests could then be incorporated into evidence-based guidelines to optimize treatment-decisions along the patient pathway: for patients with active disease about to start treatment, not responding to treatment (primary or secondary failure) or for those in remission, to permit drug tapering strategies.  Taken together this may help to improve the safety profile, long-term efficacy, and cost-effectiveness of BPs.

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Appendix

Examples of Clinical Reasons to Avoid Pharmacologic Treatment with Methotrexate, Cyclosporine, Acitretin, or Leflunomide

1. Clinical diagnosis of alcohol use disorder, alcoholic liver disease or other chronic liver disease
2. Drug interaction
3. Risk of treatment-related toxicity
4. Pregnancy or currently planning pregnancy
5. Breastfeeding
6. Significant comorbidity prohibits use of systemic agents (e.g., liver or kidney disease, blood dyscrasias, uncontrolled hypertension)
7. Hypersensitivity
8. History of intolerance or adverse event
   

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) Recurrent pericarditis
Avsola	infliximab-axxq	Ankylosing spondylitis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis or axial spondyloarthritis Enthesitis-related arthritis 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 Plaque psoriasis Psoriatic arthritis 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	Alopecia areata COVID-19 in hospitalized adults Rheumatoid arthritis
Orencia	abatacept	Acute graft versus host disease 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 Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Ankylosing spondylitis Atopic dermatitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
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	Crohn's disease Plaque psoriasis Psoriatic arthritis
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	Ankylosing Spondylitis Polyarticular Course Juvenile Idiopathic Arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Ankylosing Spondylitis Polyarticular Course Juvenile Idiopathic Arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis

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References