Description 
Certolizumab pegol (Cimzia^®) is one of five commercially available tumor necrosis factor (TNF) alpha inhibitors available, not counting biosimilars as separate products, in the United States. It was FDA approved for Crohn's disease in April 2008, for rheumatoid arthritis (RA) in May 2009, for psoriatic arthritis (PsA) in September 2013, and for ankylosing spondylitis (AS) in October 2013. Tumor necrosis factor, a proinflammatory cytokine, initiates the body’s defense response to local injury by stimulating the production of inflammatory mediators and signaling immune cells. TNF may augment host defense mechanisms when in low concentration, but large amounts of TNF can lead to excessive inflammation and tissue deterioration. In rheumatoid arthritis, activated T-cells migrate into the synovial lining of the joint where TNF is released and joint destruction begins. The intestinal mucosa from patients with Crohn’s disease or ulcerative colitis has been associated with high levels of TNF as compared to healthy individuals; a similar elevation in TNF has been demonstrated in patients with psoriasis.

Biological agents exhibiting antagonistic properties for TNF bind to the cytokine with a high affinity and prevent TNF binding to receptors on immune, inflammatory, and endothelial cells. TNF-inhibitors may exert action using a variety of biologic activities that may be agent-specific or synergistic with other immunosuppressive agents. Interestingly, many individuals initially non-responsive or intolerant of one TNF-inhibitor have responded when switched to a different agent within the class. However, the TNF-alpha inhibitors as a class are considered to have similar efficacy and safety for the majority of indications. Research in this area is imperative in understanding and identifying potential risks and adverse effects associated with use. Combined data from randomized, controlled trials and safety registries have raised concerns that TNF-inhibitors increase the risk of infections and malignancies; although, some studies have found no increased risk as compared to the frequency of infections and malignancies observed in a population predisposed to an immune-mediated inflammatory disease.

In 2015, the American College of Rheumatology (ACR) published an updated guideline for the treatment of rheumatoid arthritis (RA). The guidelines support the use of a TNFi (e.g., certolizumab pegol) in the following scenarios: (1) patients with early RA if disease activity remains moderate or high despite DMARD monotherapy (with or without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with or without methotrexate (MTX), in no particular order of preference); (2) patients with early RA if disease activity remains moderate or high despite DMARDs, use a TNFi over tofacitinib, (3) patients with established RA if disease activity remains moderate or high despite DMARD monotherapy, use combination traditional DMARDS or add a TNFi or a non-TNF biologic or tofacitinib (all choices with or without MTX, in no particular order of preference); and (4) patients with established RA if disease activity remains moderate or high despite TNFi therapy in patients who are currently not on DMARDs, add one or two DMARDs to TNFI therapy rather than continuation TNFi therapy alone. The avoidance of TNFi therapy and use of alternatives is recommended in certain high-risk conditions([i.e., congestive heart failure, hepatitis C infection and not receiving or requiring antiviral treatment, lymphoproliferative disorders, previously treated or untreated skin cancer, and previous serious infection).

In the 2015 TACIT pragmatic, non-inferiority, randomized controlled trial, 205 persons with established moderate to severe RA received either an anti-TNF biologic with one DMARD (e.g., methotrexate), or conventional DMARD therapy titrated upward to include combination therapy. Most persons in the DMARD group eventually received 2 or 3 DMARDs in combination (e.g., methotrexate + leflunomide). The DMARD group was shown to be non-inferior to the anti-TNF group for the primary outcome of disability measured by a patient-recorded health assessment questionnaire at 12 months with a numerical advantage towards the DMARD group. Further supporting use of combination DMARD therapy, the 2-year follow-up of the SWEFOT trial (438 persons with methotrexate-refractory RA) showed no difference in utility or QALY gain over 21 months when comparing methotrexate + infliximab vs. methotrexate + sulfasalazine + hydroxychloroquine.

While methotrexate must be avoided in women who are pregnant or trying to become pregnant, sulfasalazine has adequate data supporting safe use (pregnancy Category B), and is consider a preferred DMARD when given with folic acid if treatment is clinically necessary. Hydroxychloroquine, cyclosporine, and anti-TNF biologics are also considered to be low-risk options during pregnancy.

Policy 
Coverage of Cimzia is provided when the criteria below are met and there has been a trial and failure of preferred therapy.

Cimzia is considered MEDICALLY NECESSARY to treat the following conditions in adults: 

• Moderate to severe Crohn's disease
  • Trial and failure, contraindication, or intolerance to ONE of the following conventional therapies: 6-mercaptopurine (Purinethol) Azathioprine (Imuran) Corticosteroids (e.g., prednisone, methylprednisolone) Methotrexate (Rheumatrex, Trexall)
• Active Ankylosing spondylitis
  • Trial and failure, contraindication, or intolerance to two NSAIDs
• Axial spondylarthritis
  • Trial and failure, contraindication, or intolerance to two NSAIDs
  • Patient has objective signs of inflammation (e.g., C-reactive protein [CRP] levels above the upper limit of normal and/or sacroiliitis on magnetic resonance imaging [MRI], indicative of inflammatory disease, but without definitive radiographic evidence of structural damage on sacroiliac joints.
• Moderate to severe psoriatric arthritis
• plaque psoriasis
• rheumatoid arthritis
  • Trial and failure, contraindication or intolerance to one non-biologic DMARD [e.g., Rheumatrex/Trexall (methotrexate), Arava (leflunomide), Azulfidine (sulfasalazine)

Testing for tuberculosis must be done prior to initiation of Cimzia.   

CONTINUATION OF THERAPY

• Documentation of positive clinical response to therapy for all diagnosis.
• Documentation of positive clinical response to therapy as evidenced by ONE of the following for plaque psoriasis: 
  • Reduction the body surface area (BSA) involvement from baseline 
  • Improvement in symptoms (e.g., pruritus, inflammation) from baseline  

References

1. Buchner AM, Blonski W, Lichtenstein GR. Update on the management of Crohn’s disease. Curr Gastroenterol Rep 2011;13:465-74.
2. Callhoff J, Sieper J, Weiß A, et al. Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis. 2015 Jun;74(6):1241-8.
3. Cimzia (certolizumab pegol) [package insert]. UCB Pharma Inc., Smyrna (GA): May 2016.
4. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at: www.clinicalpharmacilogy-ip.com. Accessed 8/8/17.
5. Coates LC, Kavanaugh A, Mease PJ et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis: Treatment Recommendations for Psoriatic Arthritis 2015. Arthritis Rheumatol 2016;68:1060–71.
6. FDA Orphan Drug Designations and Approvals [Internet]. Washington, D.C. [cited 2017 August 8]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/.
7. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016 Mar;75(3):499-510.
8. Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008 May;58(5):851-64. doi: 10.1016/j.jaad.2008.02.040
9. Graudal N, Hubeck-Graudal T, Tarp S, et al. Effect of combination therapy on joint destruction in rheumatoid arthritis: a network meta-analysis of randomized controlled trials. PLoS One. 2014 Sep 22;9(9):e106408.
10. Kornbluth A, Sachar DB, et al. Erratum: ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010;105:500-23.
11. Krause ML, Amin A, and Makol A. Use of DMARDs and biologics during pregnancy and lactation in rheumatoid arthritis: what the rheumatologist needs to know. Ther Adv Musculoskelet Dis. 2014 Oct; 6(5): 169–184.
12. Kroon FP, van der Burg LR, Ramiro S, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis). Cochrane Database Syst Rev. 2015 Jul 17;7:CD010952.
13. Lichtenstein GR, Hanauer SB, Sanborn WJ, et al. Management of crohn’s disease in adults. Am J Gastroenterol 2009;104(2):465-83.
14. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008 May;58(5):826-50.
15. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol 2011;65:137-74.
16. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 8/8/17.
17. Nast A, Gisondi P, Ormerod AD, et al. European S3-Guidelines on the systemic treatment of psoriasis vulgaris--Update 2015--Short version--EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol. 2015 Dec;29(12):2277-94.
18. Rahimi R, Nikfar S, Rezaie A, et al. Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis. Reprod. Toxicol;2008:25,271–275.
19. Rudwaleit M, van der Heijde D, Landewé R, et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis. 2011 Jan;70(1):25-31.
20. Scott DL, Ibrahim F, Farewell V, et al. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial. BMJ. 2015 Mar 13;350:h1046.
21. Scott DL, Kinglsey GH. Tumor necrosis factor inhibitors in rheumatoid arthritis. N Engl J Med 2006;355:704-12.
22. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016 Jan;68(1):1-25.
23. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017 Jun;76(6):960-977.
24. Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanism of action: a comprehensive review. Pharmacol Ther 2008;117:244-79.
25. van der Heijde D, Ramiro S, Landewé R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017 Jun;76(6):978-991.
26. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012 May 5;379(9827):1712-20

 Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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