Ustekinumab (Stelara™) (Centocor Ortho Biotech, Inc., Horsham, PA) is a human monoclonal antibody that binds to interleukin (IL)-12 and IL-23 cytokines involved in inflammatory and immune response. This document addresses the U.S. Food and Drug Administration (FDA) approved indications for ustekinumab, a biologic agent used for the treatment of moderate to severe plaque psoriasis in individuals 18 years of age or older.

Note: Please see the following documents for information concerning other biologic disease-modifying antirheumatic drugs (DMARDs) that may be used for the treatment of moderate to severe plaque psoriasis:

• CG-DRUG-26 Alefacept (Amevive^®)
• DRUG.00002 Tumor Necrosis Factor Antagonists

Medically Necessary:

Ustekinumab is considered medically necessary when the following criteria are met:

• Individual is 18 years of age or older with moderate to severe plaque psoriasis (Ps) with either of the following:
  1. Plaque Ps involving greater than five percent body surface area (BSA); or
  2. Plaque Ps involving less than or equal to five percent BSA involving sensitive areas or areas that significantly impact daily function (e.g. palms, soles of feet, head/neck, or genitalia); and

• Individual has failed to respond to, is intolerant of, or has a medical contraindication to phototherapy or other systemic therapy (e.g. acitretin, cyclosporine, or methotrexate).

Not Medically Necessary

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

1. Currently receiving other immunosuppressive therapy or phototherapy;
2. History of reversible posterior leukoencephalopathy syndrome (RPLS);
3. History of recurrent infection, current chronic infection, clinically important infection, or positive tuberculin skin test (TST) or a positive Centers for Disease Control (CDC)-recommended equivalent test.

Investigational and Not Medically Necessary

Ustekinumab is considered investigational and not medically necessary when criteria are not met and for all other indications, including, but not limited to treatment of Crohn's disease (CD), psoriatic arthritis (PsA), and relapsing-remitting multiple sclerosis (RRMS).

Ustekinumab for Moderate to Severe Plaque Psoriasis

Ustekinumab (Stelara™) is a fully human monoclonal antibody that selectively binds with high specificity and affinity to the cytokines IL-12 and IL-23, thereby suppressing IL-12 and IL-23-mediated inflammation associated with psoriasis. These cytokines are abundant in psoriasis skin and are thought to promote the accumulation of the psoriasis causing T-cells. In September 2009, the FDA approved ustekinumab for use in the treatment of individuals 18 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Comparative efficacy of ustekinumab to placebo is supported by two phase III, multicenter, randomized, double-blind, placebo-controlled trials, PHOENIX 1 and PHOENIX 2 (Leonardi, 2008; Papp, 2008). In these trials enrolling a total of 1996 subjects with moderate to severe plaque psoriasis, significantly more ustekinumab recipients (administered subcutaneous [SC] doses of 45 or 90 mgs as two injections, four weeks apart) than placebo recipients achieved a 75% improvement on the Psoriasis Area and Severity Index (PASI 75) score at 12 weeks. Other measures, including the Physician's Global Assessment (PGA) of clinical response at week 12, demonstrated efficacy of ustekinumab over placebo. Prolonged efficacy measured as psoriatic symptom control was maintained during ustekinumab maintenance therapy (administered once every 12 weeks) for up to 76 weeks; however, intensification of dosing to once every eight weeks with 90 mg ustekinumab may be necessary to elicit a full response in individuals who only partially respond to the initial regimen (PHOENIX 2) (Papp, 2008). Adverse events were generally similar across treatment and control groups, including infections, injection-site reactions, psychological disorders, and development of anti-ustekinumab antibodies. Studies are ongoing to assess the long term safety and efficacy profiles.  

A head-to-head industry-sponsored, randomized active-control trial of 903 individuals evaluated the efficacy of ustekinumab compared to high-dose etanercept (Enbrel^®_, Immunex Corporation, Thousand Oaks, CA) in the treatment of moderate to severe psoriasis (Griffiths, 2010). The ACCEPT study evaluated either 45 mg or 90 mg of ustekinumab SC every 12 weeks compared to etanercept 50 mg SC twice weekly. The primary end point was the proportion of individuals with at least 75% improvement in the PASI at week 12, reported as significantly higher with 45 mg and 90 mg of ustekinumab compared to individuals who received etanercept (68% and 74% to 57%; p=.012 and p<0.001, respectively). Similarly, individuals who received 45 mg or 90 mg of ustekinumab compared to individuals who received etanercept (65% and 71% to 49%; p<0.001, both comparisons) had cleared or minimal disease according to the PGA. In the crossover portion of the trial, 48% of individuals who did not respond to etanercept had at least 75% improvement in the PASI in response to ustekinumab within 12 weeks. One or more adverse events occurred through week 12 in 66% and 69% of individuals who received 45 mg or 90 mg of ustekinumab, respectively compared to 70% who received etanercept. Safety patterns were similar before and after crossover from etanercept to ustekinumab.

Ustekinumab is approved for administration by a healthcare provider as 45 mg or 90 mg SC at week 0 and 4 then every 12 weeks. The higher dose is recommended for individuals weighing over 100 kg and the lower dose for those under 100 kg. In clinical trials, the 45 mg dose was found to be efficacious in subjects over 100 kg; however, the 90 mg dose improved efficacy.  

The American Academy of Dermatology (AAD) has approved a set of evidence-based guidelines, Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis (AAD, 2008), intended to assist physicians in managing the complexities of the treatment of individuals with psoriasis and psoriatic arthritis. The first guideline, Section 1: Overview of Psoriasis and Guidelines of Care for the Treatment of Psoriasis with Biologics (AAD, 2008) provides an overview of psoriasis classification, co-morbidities, assessment tools, and the use of biologics to treat psoriasis. The work group states that approximately 80% of individuals affected with psoriasis have mild to moderate disease, with 20% having moderate to severe psoriasis, defining the extent of body surface area (BSA) involvement as "affecting more than 5% of the BSA or affecting crucial body areas such as the hands, feet, face, or genitals." "The areas of involvement and types of psoriasis should be considered in evaluating severity of disease because the impact of these types of psoriasis may be quite substantial." Treatment planning for use of an FDA-approved biologic agent for moderate to severe plaque psoriasis considers this definition of BSA involvement with plaque psoriasis. In addition, for individuals with plaque psoriasis involving sensitive areas or areas that would significantly impact daily function (e.g. palms, soles of feet, head/neck, or genitalia), less than or equal to five percent of BSA involvement is considered as moderate to severe disease. Subsequent sections of the guidelines have been published, including Section 4: Guidelines of Care for the Management and Treatment of Psoriasis with Traditional Systemic Agents (Menter, 2009). This section reiterates that treatment planning should consider BSA criteria as recommended in the earlier guidelines. In addition, this section discusses in detail the "efficacy and safety, and offers recommendations for the use of the three most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin."  

Other Proposed Uses of Ustekinumab

Crohn's Disease

In a phase II/III, randomized, double-blind, crossover trial, Sandborn and colleagues (2008) assessed the clinical effects of ustekinumab for individuals (n=104) with moderate to severe Crohn's disease. In the crossover arm of the trial (population 1), individuals were given either SC placebo at weeks 0-3, then SC ustekinumab at weeks 8-11; SC ustekinumab at weeks 0-3, then placebo at weeks 8-11; intravenous (IV) placebo at week 0, then ustekinumab at week 8; or IV ustekinumab at week 0, then placebo at week 8. In the open-label phase, the effects of four weekly SC injections or one IV infusion of ustekinumab was evaluated in 27 individuals (population 2) who were primary or secondary nonresponders to infliximab (Remicade^®_, Centocor Ortho Biotech, Inc., Horsham, PA). In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (p=.02), respectively at weeks four and six, and 49% and 40% (p=.34), respectively at week eight. In a subgroup of 49 individuals who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (p<.05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in individuals given ustekinumab through week 8 compared with placebo. The investigators concluded that ustekinumab induced a clinical response in individuals with moderate-to-severe Crohn's disease, especially in individuals previously given infliximab. Further study is indicated in the form of larger, prospective trials evaluating the long-term effects of ustekinumab compared to placebo for the treatment of individuals with moderate to severe Crohn's disease.

Psoriatic Arthritis

A phase II, multicenter, randomized, double-blind, placebo-controlled, crossover trial (Gottlieb, 2009) evaluated the safety and efficacy of ustekinumab for psoriatic arthritis. Individuals with active psoriatic arthritis were randomized to receive ustekinumab (90 mg or 63 mg) every week for four weeks (week 0-3) followed by placebo at weeks 12 and 16 (n=76; Group 1) or placebo (weeks 0-3) and ustekinumab (63 mg) at weeks 12 and 16 (n=70; Group 2). The first 12 weeks of the study were placebo controlled. Masking was maintained to week 16, and individuals were followed up to week 36. The primary endpoint was American College of Rheumatology 20% improvement (ACR 20) response at week 12 with analysis by intention to treat. At week 12, 32 individuals (42%) in Group 1 and ten individuals (14%) in Group 2 achieved the primary endpoint (difference 28% [95% CI, 14.0-41.6]; p=0.0002). Of the 124 participants (85%) with psoriasis affecting 3% or more BSA, 33 of 63 (52%) in Group 1 and three of 55 (5%) in Group 2 had a 75% or greater improvement in PASI score at week 12 (46% [33.2-60.6]; p<0.0001). During the placebo-controlled period (weeks 0-12), adverse events occurred in 46 individuals (61%) in Group 1 and 44 individuals (63%) in Group 2. Serious adverse events were recorded in three Group 2 individuals (4%). The investigators concluded that ustekinumab was well tolerated and significantly reduced signs and symptoms of psoriatic arthritis and diminished skin lesions compared with placebo. However, larger studies of longer duration are needed to further determine the efficacy and safety of ustekinumab for the treatment of psoriatic arthritis.

Relapsing-Remitting Multiple Sclerosis

A phase II, multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial assessed the efficacy and safety of ustekinumab for individuals with relapsing-remitting multiple sclerosis (RRMS) (Segal, 2008). This trial (n=249 individuals) reported ustekinumab was generally well tolerated but found no clinical or radiologic improvement (i.e. a reduction in the cumulative number of gandolinium-enhancing T1-weighted lesions) in any treatment group compared with placebo controls. At week 37, adverse events occurred in 38 (78%) placebo-treated individuals and 170 (85%) ustekinumab-treated individuals, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated individual and six (3%) ustekinumab-treated individuals. Malignant diseases were reported in two individuals shortly after the initiation of ustekinumab treatment; both individuals were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. The advanced disease of the subjects in this study may have partially contributed to the lack of efficacy reported in the study results. Additional study, including a more limited subset of subjects with very early disease, is required to determine if ustekinumab may show a treatment effect in individuals with RRMS.

Description of Condition

Plaque Psoriasis

Psoriasis is a genetic, multi-system inflammatory disease characterized predominantly by chronic skin and joint manifestations, affecting approximately 2.2% of the United States population. Studies show that between 10-30% of individuals with psoriasis also develop psoriatic arthritis. The major manifestation of psoriasis is chronic inflammation of the skin, characterized by "disfiguring, scaling, and erythematous plaques that may be painful or often severely pruritis and may cause significant quality of like issues" (AAD, 2008). Plaque psoriasis is commonly located over the surfaces of the elbows, knees, scalp, and around or in the ears, navel, genitals or buttocks, but may appear elsewhere; it can be altered by environmental factors and may be associated with other inflammatory disorders such as psoriatic arthritis, inflammatory bowel disease, and coronary artery disease. Plaque psoriasis is a chronic disease that waxes and wanes during an individual's lifetime and is often modified by treatment initiation and cessation with few spontaneous remissions.

For individuals with chronic plaque psoriasis, key metrics for outcome assessment include improvement in the Psoriasis Area and Severity Index (PASI) as well as objective assessment of disease via the Physician Global Assessment (PGA). The PASI is a measure of overall psoriasis severity and coverage that assesses BSA and erythema, induration, and scaling. PASI is the metric commonly used in the clinical trials for psoriasis treatments, but is rarely used in clinical practice. Therefore, the AAD states that the physician generally uses subjective qualitative assessment of the severity of an individual's psoriasis by combining objective assessment of the BSA involvement, disease location, thickness, and symptoms, presence or absence of psoriatic arthritis with the subjective assessment of the physical, financial, and emotional impact of the diseases on the individual's life. Treatments available to help manage the symptoms of psoriasis include topical therapy (e.g. emollients or tar), phototherapy (e.g. psoralens in conjunction with ultraviolet A light [PUVA], narrowband and broadband ultraviolet B light [UVB]), systemic therapy (e.g. methotrexate, cyclosporine), and biologic DMARDs. 

Medical Management Information

Product Information Precautions and Warnings (Stelara™ Product Information, 2010)

• Serious infections have occurred including reactivation of latent infections. In particular, serious disseminated infections and fatal outcomes from mycobacteria (including nontuberculosis, environmental mycobacteria), salmonella and bacillus Calmette-Guerin (BCG) vaccinations have been reported in individuals genetically deficient in IL-12/IL-23.
  • Do not start ustekinumab during any clinically important active infection;
  • If a serious infection develops, stop ustekinumab until the infection resolves;
  • Consider diagnostic testing for infection (e.g. tissue culture, stool culture) as indicated by clinical circumstances
  • in an individual with a known genetic deficiency in IL-12/IL-23.

• Tuberculosis (TB) evaluation:
  • Evaluate an individual for TB prior to initiating treatment with ustekinumab;
  • Initiate treatment of latent TB prior to administering ustekinumab;
  • Do not administer ustekinumab to an individual with active TB.
• Risk of malignancy:
  • Ustekinumab may increase the risk of malignancy;
  • The safety of ustekinumab in individuals with a history of or known malignancy has not been evaluated.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
  • RPLS is a neurological disorder that can present as headache, seizures, confusion and visual disturbances and can progress to death;
  • A single case of RPLS was reported during the clinical trials that included 3,523 individuals;
  • RPLS is not associated with demyelination or a known infectious agent and is reversible;
  • If RPLS is suspected, ustekinumab should be discontinued and appropriate treatment administered.
• Immunizations:
  • Administer age-appropriate immunizations in accordance with current guidelines prior to initiating therapy with ustekinumab;
  • Live vaccines and BCG vaccines should not be given during treatment with ustekinumab;
  • BCG vaccines should not be given one year prior to initiating treatment or one year following discontinuation of treatment.
• Allergy immunotherapy:
  • Ustekinumab has not been evaluated in individuals who have undergone allergy immunotherapy;
  • Ustekinumab may decrease the protective effect of allergy immunotherapy and may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in individuals receiving or who have received allergy immunotherapy, particularly for anaphylaxis.
• Hypersensitivity reactions:
  • Serious allergic reactions, including angioedema and possible anaphylaxis, have been reported post marketing;
  • If an anaphylactic or other serious allergic reaction occurs, discontinue ustekinumab and institute appropriate therapy.
• Pregnant women and nursing mothers:
  • There are no studies of ustekinumab in pregnant women or nursing mothers;
  • Ustekinumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus;
  • The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. A decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
• Ustekinumab must be administered by a healthcare provider and is not approved for self-administration.

Drug Interactions

• Concomitant therapy:
  • The safety of concomitant use of ustekinumab with immunosuppressants or phototherapy has not been evaluated.
• Safety and efficacy of ustekinumab have not been evaluated beyond two years:
  • Drug interaction studies have not been conducted with ustekinumab;
  • Safety and effectiveness of ustekinumab in pediatric individuals have not been evaluated.
• Use with CYP450 substrates:
  • Upon initiation of ustekinumab in individuals who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect (e.g. for warfarin) or drug concentrations (e.g. for cyclosporine) and adjust the individual dose of the drug accordingly. 

Biologic 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-12 and IL-23, or by directly suppressing lymphocytes; includes the tumor necrosis factor (TNF) antagonists (inhibitors), abatacept, anakinra, rituximab, and ustekinumab.

Immunosuppressant drugs: A class of immunomodulatory drugs including 6-mercaptopurine (6-MP), azathioprine, cyclophosphamide, cyclosporine, methotrexate, and tacrolimus that reduce inflammation by affecting the immune system.

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 the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).

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

Psoriasis: A chronic autoimmune skin disease that is characterized by circumscribed red patches covered with white scales.

The following codes for treatments and procedures applicable to this document 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 document.  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. 

When services may be Medically Necessary when criteria are met: 

When services are Not Medically Necessary:
For situations described in the Position Statement section as not medically necessary. 

When services are Investigational and Not Medically Necessary:
When criteria are not met for the diagnosis indicated above, for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Rev Neurother. 2010; 10(5):791-809.
2. Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009; 373(9664):633-640.
3. Griffiths CE, Strober BE, van de Kerkhof P, et al. ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010; 362(2):118-128.
4. Lebwohl M, Papp K, Han C, et al. Ustekinumab improves health-related quality of life in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial. Br J Dermatol. 2010; 162(1):137-146. 
5. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008; 371(9625):1665-1674.
6. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008; 371(9625):1675-1684.
7. Robinson D Jr, Zhao N, Gathany T, et al. Health perceptions and clinical characteristics of relapsing-remitting multiple sclerosis patients: baseline data from an international clinical trail. Curr Med Res Opin. 2009; 25(5):1121-1130.
8. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2008; 135(4):1130-1141.
9. Segal BM, Constantinescu CS, Raychaudhuri A, et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008; 7(9):796-804.
10. Uhlenkhake EE, Feldman SR. Efficacy and safety of ustekinumab and etanercept for the treatment of psoriasis. Expert Opin Biol Ther. 2010; 10(7):1105-1112.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. American Academy of Dermatology (AAD). American Academy of Dermatology Association (AADA). Guidelines of care for management of psoriasis and psoriatic arthritis. May 2008. Available at: http://www.aad.org/research/guidelines/. Accessed on November 9, 2010.
2. Centers for Disease Control (CDC) and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010; 59(No. RR 5):1-28. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. Accessed on November 9, 2010.  
3. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009; 61(3):451-485.
4. Stelara™ [Product Information], Horsham, PA. Centocor Ortho Biotech, Inc.; October 2010. Available at: http://www.stelarainfo.com/pdf/PrescribingInformation.pdf. Accessed on January 4, 2010.
5. Ustekinumab. In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated May 21, 2010. Available at: http://www.thomsonhc.com. Accessed on November 9, 2010.

1. National Psoriasis Foundation (NPF). Available at: http://www.psoriasis.org/NetCommunity/Page.aspx?pid=322. Accessed on November 9, 2010.
2. U.S. National Library of Medicine. Psoriasis. Available at: http://www.nlm.nih.gov/medlineplus/psoriasis.html. Accessed on November 9, 2010.

Plaque Psoriasis
QuantiFERON-TB Gold Test (GFT-G)
QuantiFERON-TB Gold In-Tube Test (QFT-GIT)
Stelara™
T-SPOT.TB test (T-Spot)
Ustekinumab

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.