Ustekinumab (Stelara) [Medicare]

Number: 0912m

Commercial CPB  |  Medicare CPB

Medicare Part B Step Therapy Criteria

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

Stelara, for the indications listed below:

• Crohn’s Disease (CD)

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

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

• Plaque Psoriasis 

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

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

• Adult Psoriatic Arthritis (PsA)

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

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

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

Stelara, for the indications listed below:

• Crohn’s Disease (CD)

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

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

• Plaque Psoriasis 

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

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

• Adult Psoriatic Arthritis (PsA)

  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/Xeljanz XR
  2. Intolerable adverse event to Enbrel, Humira, or Xeljanz/Xeljanz XR
  3. Enbrel, Humira, or Xeljanz/Xeljanz XR is contraindicated for the member.

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

Stelara, for the indications listed below:

• Ulcerative Colitis (UC)

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

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

Policy

Note: Requires Precertification:

Precertification of ustekinumab (Stelara) is required of all Aetna participating providers and members in applicable plan designs. For precertification of ustekinumab, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (888) 267-3277.

1. Criteria for Initial Approval

   Aetna considers ustekinumab (Stelara) 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 DMARDs or targeted synthetic DMARDs associated with an increased risk of TB: 

   1. Moderately to severely active Crohn's disease (CD)

      1. For members who have previously received a biologic indicated for the treatment of Crohn’s disease; or
      2. For the treatment of moderately to severely active CD when the member has had an inadequate response, intolerance or contraindication to at least one conventional therapy option (see Appendix A); or
      3. For the treatment of fistulizing CD;

   2. Moderate to severe plaque psoriasis (PsO) or active psoriatic arthritis (PsA)

      When member meets criteria in CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators or CPB 0658m - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators [Medicare];

   3. Moderately to severely active ulcerative colitis (UC)

      1. For members who have previously received a biologic or targeted synthetic drug (e.g., Xeljanz) indicated for moderately to severely active ulcerative colitis; or
      2. For the treatment of moderately to severely active UC when the member has had an inadequate response, intolerance or contraindication to at least one conventional therapy option (See Appendix B).

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

2. Continuation of Therapy

   Aetna considers continuation of ustekinumab (Stelara) therapy medically necessary for the following indications: 

   1. Moderate to severe plaque psoriasis (PsO) or active psoriatic arthritis (PsA)

      See CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators or CPB 0658m - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators [Medicare];

   2. Moderately to severely active Crohn’s Disease (CD)

      1. For all 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 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. Endoscopic appearance of the mucosa; or
         7. Improvement on a disease activity scoring tool (e.g., Crohn’s Disease Activity Index [CDAI] score);

   3. Moderately to severely active ulcerative colitis

      1. For all members (including new members) who are using the requested medication for moderately to severely active ulcerative colitis and who achieve or maintain remission; or
      2. For all members (including new members) who are using the requested medication for moderately to severely active ulcerative colitis 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. Stool frequency; or
         2. Rectal bleeding; or
         3. Urgency of defecation; or
         4. C-reactive protein (CRP); or
         5. Fecal calprotectin (FC); or
         6. Endoscopic appearance of the mucosa; or
         7. Improvement on a disease activity scoring tool (e.g., Ulcerative Colitis Endoscopic Index of Severity [UCEIS], Mayo score).

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. 

See also:

• CPB 0249 Inflammatory Bowel Disease: Serologic Markers and Pharmacogenomic and Metabolic Assessment of Thiopurine Therapy
• CPB 0341 Infliximab or CPB 0341m Infliximab [Medicare]
• CPB 0655 Adalimumab (Humira)
• CPB 0761 - Certolizumab Pegol (Cimzia) or CPB 0761m - Certolizumab Pegol (Cimzia) [Medicare]
• CPB 0885 - Vedolizumab (Entyvio) or CPB 0885m - Vedolizumab (Entyvio) [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.

Stelara (ustekinumab) is available in the following dosage forms and strengths:

• Subcutaneous (SC) Injection

  • Injection: 45 mg/0.5 mL or 90 mg/mL in a single-dose prefilled syringe
  • Injection: 45 mg/0.5 mL in a single-dose vial
  • In pediatrics, it is recommended that subcutaneous Stelara be administered by a healthcare provider. If a physician determines that it is appropriate, a person may self-inject or a caregiver may inject Stelara after proper training in subcutaneous injection technique;
    
    

• Intravenous (IV) Infusion

  Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial.

Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage

A single intravenous (IV) infusion using weight-based dosing (see Table 1) 

Table 1: Initial IV Dosage of Stelara

Weight Range (kilograms)	Dosage Regimen
55 kg or less	260 mg (2 vials)
Greater than 55 kg to 85 kg	390 mg (3 vials)
Greater than 85 kg	520 mg (4 vials)

Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dosage

The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial IV dose, then every 8 weeks thereafter.

Psoriasis and Psoriatic Arthritis

For dosing recommendations on plaque psoriasis (PsO) or psoriatic arthritis (PsA), see CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators or CPB 0658m - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators [Medicare].

Source: Janssen Biotech, 2020

Experimental and Investigational

Aetna considers ustekinumab experimental and investigational for use with other targeted immune modulators (e.g., adalimumab (Humira), infliximab, apremilast (Otezla), or tofacitinib (Xeljanz)). 

Aetna considers combined ustekinumab and vedolizumab for the treatment of inflammatory bowel disease (IBD) experimental and investigational.

Aetna considers measurements of serum levels of ustekinumab and antibodies to ustekinumab (e.g., the Prometheus Anser UST test) experimental and investigational because the clinical value of these measurements for members receiving ustekinumab therapy has not been established.

Aetna considers ustekinumab experimental and investigational for all other indications, including any of the following, because its effectiveness for these indications has not been established (not an all-inclusive list):

• Alopecia areata
• Alzheimer disease
• Atopic dermatitis
• Behcet's syndrome
• Biliary cholangitis (also known as biliary cirrhosis)
• Chronic antibiotic-refractory pouchitis
• Cutaneous lupus erythematosus,
• Eosinophilic dermatoses
• Erythrodermic psoriasis
• Graft versus host disease
• Guttate psoriasis
• Hidradenitis suppurativa
• Large vessel vasculitis (e.g., giant cell arteritis and Takayasu arteritis)
• Lukocyte adhesion deficiency type 1
• Multiple sclerosis
• Pityriasis rubra pilaris
• Polymyalgia rheumatic
• Pyoderma gangrenosum
• Rheumatoid arthritis
• SAPHO syndrome
• Sarcoidosis
• Spondyloarthropathy
• Systemic lupus erythematosus,
• Uveitis.

Background

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

• Moderate to severe plaque psoriasis (PsO) in patients 6 years or older who are candidates for phototherapy or systemic therapy
• Active psoriatic arthritis (PsA) alone or in combination with methotrexate (MTX)
• Moderately to severely active Crohn’s disease (CD)
• Moderately to severely active ulcerative colitis (UC)

Ustekinumab, a human interleukin-12 and -23 antagonist, is available as Stelara (Janssen Biotech, Inc.). IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab, was shown to be protective (Janssen Biotech, 2020).

Labeled warnings and precautions include risk of infections, tuberculosis (TB), malignancies, hypersensitivity reactions, and noninfectious pneumonia. Serious infections from mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL-12/IL-23. Diagnostic tests for these infections should be considered as dictated by clinical circumstances. In addition, one case was reported for reversible posterior leukoencephalopathy syndrome. The most common adverse reactions included for those with psoriasis (≥3%) are nasopharyngitis, upper respiratory tract infection, headache, and fatigue; in Crohn’s disease, induction (≥3%), is vomiting; in Crohn’s disease, maintenance (≥3%), are nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis; in ulcerative colitis, induction (≥3%), is nasopharyngitis; and in ulcerative colitis, maintenance (≥3%), are nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea (Janssen Biotech, 2020).

The most common adverse reactions include the following:

• Psoriasis (3% or more): nasopharyngitis, upper respiratory tract infection, headache, and fatigue;
• Crohn’s Disease, induction (3% or more): vomiting;
• Crohn’s Disease, maintenance (3% or more): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis;
• Ulcerative colitis, induction (3% or more): nasopharyngitis;
• Ulcerative colitis, maintenance (3% or more): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea.

Alopecia Areata

Renert-Yuval and Guttman-Yassky (2017) stated that alopecia areata (AA) lacks FDA-approved therapeutics for extensive cases, which are associated with very poor rates of spontaneous hair regrowth and major psychological distress.  Current treatments for severe cases include broad immune-suppressants, which are associated with significant adverse effects, precluding long-term use, with rapid hair loss following treatment termination.  As a result of the extent of the disease in severe cases, topical contact sensitizers and intralesional treatments are of limited use.  The pathogenesis of AA is not yet fully understood, but recent investigations of the immune activation in AA skin reveal Th1/IFN-γ, as well as Th2, PDE4, IL-23, and IL-9 up-regulations.  Tissue analyses of both animal models and human lesions following broad-acting and cytokine-specific therapeutics (such as JAK inhibitors and ustekinumab, respectively) provided another opportunity for important insights into the pathogenesis of AA.  These investigators reviewed novel therapeutics that are undergoing clinical trials for AA, emphasizing the potential transformation of the clinical practice of AA, which is currently lacking.  Moreover, they noted that clinical trials of broad-acting T cell antagonists (JAK inhibitors, PDE4 inhibitor), Th2 antagonists (tralokinumab), and IL-23/IL-17 antagonist (ustekinumab) are ongoing.

Atopic Dermatitis

Khattri and associates (2017) noted that atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate-to-severe disease are limited.  In a double-blind, placebo-controlled phase-II clinical trial, these researchers evaluated the safety and effectiveness of ustekinumab in patients with moderate-to-severe AD.  A total of 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n = 16) or placebo (n = 17), with subsequent cross-over at 16 weeks, and last dose at 32 weeks.  Background therapy with mild topical steroids was allowed to promote retention.  Study end-points included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies.  The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary end-point) and 20 weeks compared to placebo, but the difference between groups was not significant.  The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32 weeks in the initial ustekinumab group.  Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen after 4 weeks of ustekinumab treatment (i.e., MMP12, IL-22, IL-13, IFN-γ, elafin/PI3, CXCL1 and CCL17; P<.05).  Epidermal responses (K16, terminal differentiation) showed faster (4 weeks) and long-term regulation (32 weeks) from baseline in the ustekinumab group.  No severe adverse events (AEs) were observed.  The authors concluded that ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound "placebo" effect, most likely due to background topical glucocorticoids and possibly insufficient dosing for AD.

Weiss and co-workers (2017) evaluated the immunologic effects of ustekinumab treatment on AD skin and correlated them with the effectiveness of this drug.  These researchers examined the course of 3 patients with severe AD who were administered 45-mg of subcutaneous ustekinumab over a period of 16 weeks.  Clinical scores and skin biopsy specimens, taken at baseline and at week 8, were used to assess changes in disease severity.  All 3 patients showed a gradual improvement of the disease, achieving a 50 % reduction in the Eczema Area and Severity Index (EASI) score by week 16.  Immunohistology of skin biopsy specimens revealed a significant decrease in the degree of epidermal hyperplasia/proliferation and the number of infiltrating dermal T cells, dendritic cells, and mast cells after treatment.  Using quantitative real-time polymerase chain reaction (PCR) of lesional skin, these researchers found a clear reduction of T-helper 2-/22-associated molecules after therapy.  The authors concluded that blocking IL-12/-23 p40 could be beneficial for a subgroup of patients with severely infiltrated AD.  Moreover, they stated that the small number of patients (n = 3) limited efficacy analysis and warrants prospective placebo-controlled studies in larger patient cohorts.

In a randomized, double-blind, placebo-controlled, phase-II clinical trial, Saeki and colleagues (2017) evaluated the safety and effectiveness of ustekinumab in patients with severe AD.  Patients (aged 20 to 65 years) with severe or very severe AD entered a 12-week, double-blind treatment period during which they received (1 : 1 : 1) ustekinumab 45-mg, 90-mg or placebo subcutaneous injections at weeks 0 and 4, with follow-up until week 24.  The primary efficacy end-point was percentage change from baseline in EASI score at week 12.  Major secondary efficacy end-points included the proportion of patients achieving EASI 50, EASI 75, Investigator's Global Assessment score 0 to 1, change from baseline Atopic Dermatitis Itch Scale and Dermatology Life Quality Index.  A total of 79 patients were randomized [ustekinumab 45-mg (n = 24), 90-mg (n = 28), placebo (n = 27)].  Ustekinumab treatment showed non-significant improvement in least square mean change from baseline EASI score at week 12 [45-mg: -38.2 %, 95 % CI: -21.02 to 19.51; p < 0.94 and 90-mg: -39.8 %, 95 % CI: -21.84 to 17.14; p < 0.81] versus placebo (-37.5 %).  A non-significant improvement in major secondary efficacy end-points was observed in both ustekinumab groups versus placebo.  The most common treatment-emergent AEs were nasopharyngitis and worsened AD (higher in placebo versus ustekinumab groups).  The authors concluded that ustekinumab 45-mg and 90-mg did not demonstrate meaningful effectiveness in Japanese patients with severe AD; the treatment was generally well-tolerated.

Behcet's Syndrome

Vitale and associates (2017) noted that Behcet's syndrome (BS) is a systemic inflammatory disorder characterized by a wide range of potential clinical manifestations with no gold-standard therapy.  However, the recent classification of BS at a crossroads between autoimmune and auto-inflammatory syndromes has paved the way to new further therapeutic opportunities in addition to anti-TNF agents.  These investigators provided a digest of all current experience and evidence about pharmacological agents recently described as having a role in the treatment of BS, including IL-1 inhibitors, tocilizumab, rituximab, alemtuzumab, ustekinumab, interferon (IFN)-alpha-2a, and apremilast.  IL-1 inhibitors currently represent the most studied agents among the latest treatment options for BS, proving to be effective, safe and with an acceptable retention on treatment.  However, since BS is a peculiar disorder with clinical features responding to certain treatments that in turn can worsen other manifestations, identifying new therapeutic options for patients unresponsive to the current drug armamentarium is of great relevance.  The authors noted that a number of agents have been studied in the past 10 years showing changing fortunes in some cases and promising results in others.

Biliary Cholangitis (Biliary Cirrhosis)

Floreani and Mangini (2018) noted that primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic liver disease that progresses slowly to end-stage liver disease.  The 1st Food and Drug Administration (FDA)-approved treatment for PBC was ursodeoxycholic acid (UDCA).  This treatment slows the progress of the disease, but about 30 to 40 % of patients fail to respond to UDCA.  A number of options are under investigation as 2nd-line treatment.  Obeticholic acid (OCA), a Farnesoid X receptor agonist, has been approved in May 2017 by the FDA for patients who are non-responders or intolerant to UDCA.  The results of a randomized, double-blind, phase-III clinical trial of OCA compared to placebo, showed that approximatively 50 % of patients reached a significant reduction in serum alkaline phosphatase, a marker predictive of disease progression, liver transplantation or death.  Other emerging therapies include: agents targeting fibrosis, inflammation, or immunological response.  Indeed, after 30 years of UDCA therapy as unique choice for PBC patients, a number of targets, derived from a deeper knowledge of the pathophysiology of the disease, has been discovered and they offer different and new therapeutic approaches that are now under evaluation; and ustekinumab was one of the keywords listed in the abstract of this study.

Chronic Antibiotic-Refractory Pouchitis

Ollech and colleagues (2019) noted that chronic antibiotic-refractory pouchitis (CARP) occurs in up to 15 % of patients with ulcerative colitis (UC) following proctocolectomy with ileal pouch-anal anastomosis (IPAA).  In a retrospective single-center study, these investigators examined the effectiveness of ustekinumab in the treatment of CARP.  This trial included UC patients with an IPAA, who subsequently developed CARP and received ustekinumab with standard CD dosing between 2016 and 2018.  Patients with CD of the pouch were excluded.  Demographic, clinical, and endoscopic data were collected.  Outcomes included a change in the endoscopic subscore of the Pouchitis Disease Activity Index (PDAI), change in the ulcerated surface area, clinical response, and the number of bowel movements per 24 hours.  A total of 24 patients with CARP were included for analysis.  Median follow-up time was 12.9 months (inter-quartile range [IQR] 7.9 to 16); 12 patients (50 %) had a clinical response with the median number of bowel movements within 24 hours decreasing from 8 (IQR, 5 to 12) to 6 (IQR, 5 to 8); p = 0.002; 13 patients had pouchoscopies available post-ustekinumab treatment.  In these patients, the median endoscopic subscore of the PDAI decreased from 5 (IQR, 3 to 6) to 4 (IQR, 2 to 5); p = 0.016.  Likewise, among these 13 patients, 9 (69 %) had an ulcerated surface area greater than 10 % before ustekinumab treatment; after treatment with ustekinumab, only 4 patients (31 %) still had an ulcerated surface area of greater than 10 %.  The authors concluded that this was the largest study of ustekinumab treatment for patients with CARP; ustekinumab therapy led to the improvement in clinical and endoscopic endpoints.  This was a small (n = 24), retrospective study; its findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Pouchitis: Management” (Shen, 2019) states that “Other agents have been used for treating chronic antibiotic refractory pouchitis, although data are limited.  Vedolizumab, an anti-integrin antibody, and ustekinumab, an anti-interleukin 12/23 antibody appear to be effective for some patients with chronic antibiotic refractory pouchitis (CARP)”.

Crohn's Disease

Sandborn et al (2008) performed a double-blind, cross-over trial of the clinical effects of UST in 104 patients with moderate-to-severe CD. Patients were given subcutaneous placebo at weeks 0-3, then UST at weeks 8-11; subcutaneous UST at weeks 0-3, then placebo at weeks 8-11; intravenous placebo at week 0, then UST at week 8; or intravenous UST at week 0, then placebo at week 8. Clinical rates for the combined groups given UST and placebo were 53% and 30% (p = .02), respectively at weeks 4 and 6, and 49% and 40% (p = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to UST was significantly greater than the group given placebo (p < .05) through week 8.  There was no increase in the number of adverse or serious adverse events in patients given UST through week 8 compared with placebo. Sandborn et al concluded that UST induced a clinical response in patients with moderate-to-severe CD, especially in patients previously given infliximab.

Toedter et al (2009) studied UST induction therapy in a placebo-controlled trial of patients with CD (n=104). Among study subjects receiving UST, 49% achieved clinical response at week 8 versus 40% for placebo (p=.34). Further, in a subgroup of patients previously treated with infliximab (n=49), 59% receiving UST had a clinical response versus 26% receiving placebo (p=.02). The investigators found that mean changes from baseline C-reactive protein (CRP) at week 8 in the primary group were -0.3 and -3.1 mg/l after treatments with placebo (n=43) and UST (n=46), respectively (p=.074) while in the infliximab-experienced subgroup, the mean changes were +2.0 (placebo, n=23) and -2.6 mg/l (UST, n=20) (p=.004). Toedter et al concluded that the potential benefit of UST in CD is supported by serum CRP reductions and that evidence suggests that increased systemic inflammation as manifested by higher baseline CRP values leads to larger treatment effects with UST, particularly in infliximab-experienced patients.

Sandborn et al (2012) evaluated UST in adults with moderate-to-severe CD that was resistant to anti-tumor necrosis factor (TNF) treatment. The investigators randomly assigned 526 patients to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0, with the primary endpoint being clinical response at 6 weeks. During the maintenance phase, 145 patients who had a response to UST at 6 weeks underwent a second randomization to receive subcutaneous injections of UST (90 mg) or placebo at weeks 8 and 16. The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of UST per kilogram, respectively, as compared with 23.5% for placebo (p=.005 for the comparison with the 6-mg group); the rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. The investigators found that maintenance therapy with UST resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, p=.03) and response (69.4% vs. 42.5%, p<.001) at 22 weeks compared to placebo. The investigators concluded that for patients with moderate-to-severe CD resistant to TNF antagonists there was an increased rate of response to induction with UST compared with placebo and that patients with an initial response to ustekinumab had significantly increased rates of response and remission with UST as maintenance therapy.

A 2015 Cochrane review reported that UST and briakinumab (ABT-874) are monoclonal antibodies that target the standard p40 subunit of the cytokines interleukin-12 and interleukin-23 (IL-12/23p40). In this review methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to induce clinical remission, defined as a CD activity index (CDAI) of < 150 points, while secondary outcomes included failure to induce clinical improvement, serious adverse events, and withdrawals due to adverse events. Clinical improvement was defined as decreases of > 70 or > 100 points in the CDAI from baseline with analysis on an intention-to-treat basis. Four randomized controlled trials (n = 955 patients) met their inclusion criteria. A low risk of bias was assigned to all studies. Two of these studies were ustekinumab studies (630 patients) and they were pooled despite differences in intravenous doses (i.e. 1mg/kg, 3 mg/kg, 4.5 mg/kg, and 6 mg/kg), however, the subcutaneous dose group was not included in the analysis, as it was unclear if subcutaneous was equivalent to intravenous dosing.  At Week 6, 85% (356/420) of UST patients failed to enter remission compared to 89% (142/159) of placebo patients (RR 0.94, 95% confidence interval [CI] 0.88 to 1.01). Subgroup analysis showed no statistically significant difference by dose, but there were statistically significant differences in clinical improvement between UST and placebo-treated patients. In the UST group, 55% (230/420) of patients failed to improve clinically with a 70-point decline in CDAI score compared to 72% (115/159) of placebo patients (RR 0.75, 95% CI 0.66 to 0.86). Subgroup analysis revealed significant differences compared to placebo for the 1 mg/kg, 4.5 mg/kg and 6 mg/kg dosage subgroups. Similarly for a 100-point decline in CDAI, 62% (262/420) of patients in the UST group failed to improve clinically compared to 78% (124/159) of placebo patients (RR 0.79, 95% CI 0.71 to 0.89). Subgroup analysis showed a significant difference compared to placebo for the 4.5 mg/kg dose group. GRADE analyses of the UST studies rated the overall quality of the evidence for the outcomes for clinical remission and clinical response as moderate. There were no statistically significant differences in the incidence of adverse events, serious adverse events or withdrawal due to adverse events. Sixty-seven percent (316/473) of UST patients developed at least one adverse event compared to 73% (135/184) of placebo patients (RR 0.92, 95% CI 0.83 to 1.03). The authors concluded that although they were uncertain about the efficacy ofUST for induction of remission, moderate quality evidence suggested that UST may be effective for induction of clinical improvement in patients with moderate  to severe CD (Khanna et al, 2015).

Khorrami et al (2016) assessed the effectiveness and safety of UST in refractory patients with CD in actual practice. The investigators recruited 116 consecutive patients with CD who were treated with subcutaneous UST between March 2010 and December 2014 were retrospectively included in a multicenter open-label study, with clinical response assessed after the loading doses, 6 months, 12 months, and last follow-up. Median follow-up was 10 months with an interquatile range of 5-21 months. Clinical response after loading UST was achieved in 97/116 (84%) patients while the clinical benefit at 6 months, 12 months, and at the end of the follow-up period was 76%, 64%, and 58%, respectively. Dose escalation was effective in 8 of 11 (73%) patients and perianal disease improved in 11 of 18 (61%) patients with active perianal fistulae. Adverse events, none of which required UST withdrawal, were reported in 11 (9.5%) patients. Khorrami et al concluded that subcutaneous ustekinumab is effective and safe in a high proportion  of patients with CD that were resistant to conventional immunosuppressant and antitumor necrosis factor drugs.

Sandborn et al (2016) stated that interleukins 12 & 23 are linked to the pathophysiology of CD, wherein the pro-inflammatory cytokines are blocked by UST. They conducted a phase 3 trial to study IV UST in these patients. The study included 741 patients with moderate to severe CD (CDAI 220-450) who had failed or were intolerant to at least 1 TNF antagonist. Study subjects were randomized 1:1 to a single dose of placebo, 130 mg of UST, or a weight-based, tiered UST dose.  The primary endpoint was clinical response at Week 6, with clinical response defined as reduction of CDAI score of more than 100 points. The study protocol also defined patients with a baseline CDAI between 220 and 248 points as having a clinical response with a CDAI score less than 150. At Week 8 patient were either transferred to a maintenance study or followed until Week 20.

Results of the study by Sandborn et al (2016) showed that Week 6 clinical response was observed in 33.7 % of subjects who received the 6 mg/kg UST dose and 34.3% of the 130 mg UST group versus 7.3% of the IV placebo group (p = .003 and .002, respectively). The investigators found that clinical remission occurred in 20.9% of the 6 mg/kg UST dose and 15.9% of the 130 mg UST dose, as compared with 7.3% of the placebo group (p < 0.001, p = 0.003). Clinical response at week 8 was seen in 37.8% of the 6 mg / kg UST dose group and 33.5% of the 130 mg UST group compared with 30.2% in the placebo group (p ≤ 0,001 for each experimental group compared with placebo). The IV UST groups both had results of induction doses significantly improve CDAI, IBDQ, CRP, fecal lactoferrin, and calprotectin as compared with the placebo group. It is of note that no malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST-treated patients through week 20. Sandborn et al concluded that among moderate to severe CD patients who are refractory to one or more TNF-antagonists, IV UST induced clinical response and remission and was well tolerated throughout induction.

Particularly in light of the results of the 2016 phase 3 study by Sandborn et al, the Food and Drug Adminstration has approved the use of ustekinumab for moderate to severe Crohn's disease.  

For adult outpatients with moderate to severe Crohn’s disease, guidelines from the American Gastroenterological Association  (AGA) recommend induction and maintenance therapy with anti–tumor necrosis factor–alpha agents or ustekinumab over no treatment (Feuerstein et al, 2021).

Cutaneous Lupus Erythematosus

Romero-Mate and colleagues (2017) reported on the case of a 52-year old woman with a 28-year history of disfiguring facial discoid lupus erythematosus(DLE), persistent despite both classical therapies and rituximab.  Ustekinumab 45-mg was started in combination with methotrexate and intralesional corticosteroids.  Methotrexate and intralesional corticosteroids were withdrawn 30 months later and ustekinumab maintained as monotherapy; 48 months later stable improvement was achieved without side effects.  The authors noted that only 9 patients with cutaneous lupus erythematosus (CLE) treated with ustekinumab had been reported to-date.  They concluded that ustekinumab could be a promising alternative in severe and recalcitrant cases of CLE.  These preliminary findings need to be validated in future well-designed studies.

Eosinophilic Dermatoses

Rozenblat and Ziv (2020) stated that eosinophilic dermatoses syndromes are rare diseases with a prominent eosinophilic infiltration mechanism.  These syndromes have several known treatments with limited success.  Several physicians world-wide suggested possible advantages of using specific biological drugs, which are different from eosinophil targeted biotherapies as treatments for eosinophilic dermatoses syndromes.  Others considered these drugs as possible triggers.  In a systematic review, these investigators examined the pros and cons of biological drugs as treatments and triggers of eosinophilic dermatoses.  Studies published in the last 30 years containing relevant key words were reviewed using PubMed and Medline.  Associations between infliximab, adalimumab, etanercept, TNF-alpha inhibitors and ustekinumab to eosinophilic dermatoses syndromes were reviewed.  The search revealed an association between 17 eosinophilic dermatoses patients and the drugs of interest.  Out of 5 Wells' syndrome cases, 4 patients had an outbreak of the disease following treatment and 1 improved by the treatment; 6 cases of eosinophilic fasciitis mostly had a positive reaction to the treatment.  More associations were found among 4 cases of Churg-Strauss syndrome, 1 case of granuloma faciale and 1 case of eosinophilic pustular folliculitis.  The authors concluded that TNF-alpha inhibitors and ustekinumab may have a role in the treatment of eosinophilic dermatosis syndromes.  These drugs may act as triggers among Wells' syndrome patients.  Moreover, these researchers stated that further investigation is needed.

Guttate Psoriasis

In a case-series study, Brummer and co-workers (2017) reported their findings on the use of ustekinumab for the treatment of patients with refractory guttate psoriasis (n = 6).  These researchers stated that the use of biologics for guttate psoriasis is not standard of care, as it is commonly self-limited, and biologics are intended for long-term control of chronic plaque psoriasis.  However, a phase-IIIb trial of patients with chronic plaque psoriasis comparing standard ustekinumab maintenance dosing (45 or 90 mg every 12 weeks) with extended tailored dosing (16, 20, and 24 week intervals) showed that some patients with chronic plaque psoriasis can remain clear/almost clear.  They noted that it is possible that after induction with ustekinumab, select patients with chronic plaque or chronic guttate psoriasis may obtain disease control with ustekinumab induction or intermittent dosing.  The authors stated that to-date, there is only 1 published case report of a chronic guttate psoriasis patient who was successfully treated with ustekinumab.  The authors presented 6 cases of recalcitrant guttate psoriasis successfully treated with ustekinumab.  However, they acknowledged the drawbacks of this series: small sample size (n = 6), lack of control group, and variable ustekinumab dosing used.  This was not a prospective clinical trial, and the researchers recognized the need for further clinical and laboratory studies to help elucidate the molecular mechanisms driving the pathogenesis of guttate psoriasis.  They noted that this limited case-series study provided evidence for the potential benefit of ustekinumab in the treatment of recalcitrant or chronic guttate psoriasis.

Hidradenitis Suppurativa

Lee and Eisen (2015) stated that given the absence of significant improvement in the treatment of hidradenitis suppurativa (HS) with traditional medical and surgical therapies, biologics have piqued the interest of research investigators.  The effectiveness of biologics in the treatment of inflammatory conditions like psoriasis and rheumatoid arthritis (RA) is well-documented.  More recently, success with biologics has been demonstrated in atopic dermatitis, another dermatological condition associated with inflammatory states.  Researchers have begun to probe the utility of biologic agents in less prevalent conditions that feature inflammation as a key characteristic, namely, HS.  Five agents in particular adalimumab, anakinra, etanercept, infliximab, and ustekinumab, have been explored in the setting of HS.  The authors noted that results to-date put forward adalimumab and infliximab as biologic treatments that can safely be initiated with some expectant efficacy; other biologic agents require more rigorous examination before they can be added to the treatment armamentarium.

In a multi-center case-series study and systematic review, Montero-Vilchez and colleagues (2020) retrospectively examined the therapeutic outcomes of ustekinumab of patients with HS, and evaluated all published scientific evidence on its utilization in patients with HS.  These researchers examined the therapeutic outcomes of 10 patients with HS treated with ustekinumab and conducted a systematic review of published epidemiological studies on ustekinumab-treated patients with HS.  In the case-series study, an improvement in the Physician Global Assessment score was observed in 70 % (7/10) patients and an improvement in the Numerical Pain Rating Scale in 80 % (8/10).  In the systematic review, clinical improvement in disease severity was reported in 76 % (34/45) patients and symptomatic improvement in 84 % (38/45).  No severe ustekinumab-related AE was recorded.  The authors concluded that these findings suggested that ustekinumab may be a safe and effective therapeutic option for patients with HS who failed to respond to 1st-line therapies.

Romani and associates (2020) stated that adalimumab is the only approved biological therapy for HS.  The last published recommendations support the use of other off-label biologic therapies.  These investigators reported on a multi-centric, retrospective review of patients with HS treated with an ustekinumab dosing schedule of intravenous infusion adjusted by weight, followed by a subcutaneous maintenance dose of 90-mg every 8 weeks, as recently approved for Crohn's disease.  The minimal follow-up period required for inclusion was 16 weeks.  A total of 14 patients from 6 hospitals were included.  In 50 % of the treated patients, therapeutic outcomes, measured by means of the Hidradenitis Suppurativa Clinical Response (HiSCR) and decrease of Dermatology Life Quality Index (DLQI) and visual analog scale (VAS) of pain, were reached at week 16.  In 71.42 % of patients DLQI and VAS of pain improved, irrespective of achievement of HiSCR; 2 patients abandoned treatment due to lack of efficacy or patient preferences.  No ustekinumab-related adverse effects were reported.  The results were limited by the retrospective nature of the study, the short follow-up period (16 weeks), and the small patient number (n =14).  This therapeutic regime proved to be safe and showed moderate efficacy in treating HS with failure to previous biologic therapy.  The authors concluded that the efficacy of ustekinumab in HS should be tested in randomized controlled trials (RCTs).

Large Vessel Vasculitis and Polymyalgia Rheumatic

Hellmich (2016) noted that imaging methods, such as joint and color duplex sonography, magnetic resonance imaging (MRI) and positron emission tomography (PET) nowadays facilitate the diagnosis of polymyalgia rheumatica and large vessel vasculitis (LVV) and have now been included in the new classification criteria.  In patients with typical symptoms, color duplex sonography of the temporal artery can replace a biopsy of the temporal artery for the diagnosis of giant cell arteritis (GCA); however, the role of these methods for patient follow-up and assessment of prognosis is unclear.  Polymyalgia rheumatica is treated with glucocorticoids (GC) in an initial dosage of up to 20 mg/day.  In patients with LVV higher doses are needed for induction of remission.  Furthermore, the rate of relapse and GC-related AEs are higher in GCA and Takayasu arteritis (TA).  Thus, initial GC-sparing treatment with methotrexate or other immunosuppressants is recommended.  Recent studies showed an effectiveness of biologics.  Recent data of the placebo-controlled proof of concept trials showed that the IL-6 antagonist tocilizumab reduced GC requirements and relapse rates in patients with GCA and polymyalgia rheumatica.  Both ustekinumab and abatacept appeared to be effective in recent pilot trials for GCA.  Antibodies against TNF alpha were ineffective for polymyalgia rheumatica and GCA in placebo-controlled trials; but data from open label studies suggested some effectiveness in refractory TA.

Koster and colleagues (2016) reviewed advances in the management of GCA and TA focusing on recent developments in targeted biologic therapy.  The role of biologics in the treatment of LVV is expanding; TNF-alpha inhibitors appear to be effective in the treatment of TA but have little benefit in GCA.  Preliminary clinical trial data suggested that abatacept and tocilizumab reduce the risk of relapse in GCA.  Increasing observational evidence supported the use of iIL-6 inhibitors in TA.  Based on a small, open-label study, ustekinumab appeared safe and potentially effective for refractory GCA.  A possible role of B cell dysregulation may contribute to pathogenic mechanisms in LVV, but support for the use of B cell depleting therapy is limited.  The authors concluded that IL-6 inhibitors appeared effective in the treatment of refractory cases of LVV; however, utility in newly diagnosed immunosuppressive-naïve patients is less well established.  They stated that abatacept and ustekinumab are promising targets for therapy in LVV; but further investigation is needed before routine use is considered.

Roberts and Clifford (2017) stated that GCA is a large vessel vasculitis that may be associated with significant complications such as blindness, stroke, or aortic aneurysm and dissection in a subset of patients.  Given the serious side effects associated with prolonged courses of glucocorticoids and frequent relapses experienced when doses are tapered, increased efforts are being dedicated to the discovery of safer and more effective therapies to control this disease.  These investigators examined the role of glucocorticoid-sparing agents in the medical management of GCA with a special focus on the most recent evidence regarding the role of promising biologic agents (e.g., abatacept, tocilizumab, and ustekinumab) and other novel therapies.

Leukocyte Adhesion Deficiency Type 1

Moutsopoulos and co-workers (2017) reported on the case of a patient with leukocyte adhesion deficiency type 1 (LAD1) who had severe periodontitis and an intractable, deep, non-healing sacral wound.  These researchers had previously found a dominant IL-23-IL-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder.  Blockade of this pathway in mouse models had resulted in resolution of the immunopathologic condition.  These investigators treated the patient with ustekinumab, an antibody that binds the p40 subunit of IL-23 and IL-12 and thereby blocks the activity of these cytokines, inhibiting IL-23-dependent production of IL-17.  After 1 year of therapy, the patient had resolution of his inflammatory lesions without serious infections or adverse reactions.  Inhibition of IL-23 and IL-17 may have a role in the management of LAD1.  The authors stated that the dosing of ustekinumab that is normally used for psoriasis was effective in early complete blocking of IL-17 and related cytokines and chemokines in the gingiva for at least 3 weeks.  Whether a shorter treatment interval would have more clinical benefit is unclear.  Moreover, they stated that it is important to recall that skin-wound closure and complete epithelialization minimizes microbial stimulation; in contrast, the periodontal pocket is an open environment that is continuously subjected to a high level of microbial stimulation.  Thus, although a limited course of this targeted therapy might help in the treatment of a closable wound, LAD1 periodontitis is an ongoing process that is likely to require more long-term therapy.  The authors stated that treatment of additional patients with LAD1 is needed to help clarify the role of ustekinumab in the management of immunopathologic processes in LAD1 and the long-term safety of the drug in light of the underlying immunodeficiency in these patients.

Pityriasis Rubra Pilaris

Lwin and colleagues (2018) noted that pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which approximately 1 in 20 affected individuals show autosomal dominant inheritance.  In such cases, there may be gain-of-function mutations in CARD14, encoding caspase recruitment domain-containing protein 14 (CARD14) that activates the non-canonical nuclear factor-kappa B (NF-κB) pathway, thereby promoting cutaneous inflammation.  These investigators reported on the cases of a mother and son with PRP due to a new missense mutation in CARD14 and described the beneficial clinical effects of ustekinumab in both subjects.  A 49-year-old woman and her 20-year-old son had lifelong, generalized, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalized PRP.  Topical steroids, phototherapy and oral retinoids proved ineffective therapies.  Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single nucleotide transversion in exon 4, c.356T>G, resulting in the missense mutation, p.Met119Arg.  The authors reported that ustekinumab, at a dose of 45-mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing.  This report highlighted the therapeutic potential of biologics that down-regulate NF-kB signaling in familial PRP with mutations in CARD14.  These preliminary findings need to be validated in well-designed studies.

Pyoderma Gangrenosum

Guenova et al (2011) noted that IL-23 is involved in the pathogenesis of the chronic inflammatory Crohn disease.  Pyoderma gangrenosum (PG) is often associated with and can even be the first manifestation of this disease and has abundant neutrophilic infiltration.  Because IL-23 plays a critical role in driving inflammation associated with IL-17 production and especially neutrophil recruitment, these researches suspect that PG might be driven by a pathogenetic mechanism similar to that of inflammatory bowel diseases or psoriasis.  Tissue sample analysis showed highly elevated expression of IL-23 on both transcriptional and protein level in a recalcitrant PG lesion.  On the basis on these data, a treatment targeting the p40 subunit of the heterodimeric IL-23 with the monoclonal antibody ustekinumab was started.  Therapy with ustekinumab resulted in a significant decrease of IL-23 expression in PG and healing after 14 weeks of treatment.  No relapse occurred in a 6-month follow-up period.  The authors concluded that these findings provided evidence of an IL-23-dominated inflammatory infiltrate in PG.  This might specify a new concept for PG pathophysiology and suggests a possibility for using ustekinumab as a therapeutic agent in this disease.

Rheumatoid Arthritis

In a randomized phase-II clinical trial, Smolen and colleagues (2017) evaluated the safety and effectiveness of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy.  Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n = 55), ustekinumab 90-mg at weeks 0, 4 and every 8 weeks (n = 55), ustekinumab 90-mg at weeks 0, 4 and every 12 weeks (n = 55), guselkumab 50-mg at weeks 0, 4 and every 8 weeks (n = 55), or guselkumab 200-mg at weeks 0, 4 and every 8 weeks (n = 54) through week 28; all patients continued a stable dose of MTX (10 to 25 mg/week).  The primary end-point was the proportion of patients with at least a 20 % improvement in the American College of Rheumatology criteria (ACR 20) at week 28.  Safety was monitored through week 48.  At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6 %) or the combined guselkumab group (41.3 %) compared with placebo (40.0 %) (p = 0.101 and p = 0.877, respectively).  Through week 48, the proportions of patients with at least 1 AE were comparable among the treatment groups.  Infections were the most common type of AE.  The authors concluded that treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA.

SAPHO Syndrome

Firinu and colleagues (2016) stated that SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare autoimmune disease which, due to its clinical presentation and symptoms, is often mis-diagnosed and unrecognized.  Its main features are prominent inflammatory cutaneous and articular manifestations.  Treatments with immunosuppressive drugs have been used for the management of SAPHO with variable results.  To-date, the use of anti-TNF-alpha agents has proved to be an effective alternative to conventional treatment for unresponsive or refractory SAPHO cases.  TNF-alpha is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β, IL-6, and IL-8, involved in inflammation, acute-phase response induction, and chemotaxis. IL-1 inhibition strategies with anakinra have shown efficacy as 1st and 2nd lines of treatment.  These investigators described the main characteristics of biological drugs currently used for SAPHO syndrome.  They also described some of the promising therapeutic effects of ustekinumab after failure of multiple drugs including anti-TNF-alpha and anakinra.

Wendling and associates (2017) noted that treatment of SAPHO syndrome is not standardized, and in case of inadequate response to anti-inflammatory drugs, the use of anti-TNF or anti-IL-1 biologic treatments has been reported.  The IL-23/Th17 axis may be involved in SAPHO syndrome.  These investigators reported the findings of 6 courses of IL-23 and IL-17 targeted therapies (3 ustekinumab and 3 secukinumab) in patients with SAPHO syndrome unresponsive to previous treatments (conventional synthetic disease-modifying anti-rheumatic drugs [csDMARDs] and biological DMARDs [bDMARDs]).  With a mean treatment duration of 5.5 months, improvement of skin symptoms was noticed in 3 cases, 1 improvement with secukinumab and 2 remissions (1 with secukinumab, 1 with ustekinumab).  Regarding the rheumatic symptoms, no major improvement was observed under any of the 6 treatment courses.  No particular safety concerns were reported, except cases of paradoxical psoriasis flare in 1 under ustekinumab and the other case under secukinumab.  The effectiveness of ustekinumab in the treatment of SAPHO syndrome needs to be validated in well-designed studies.

Sarcoidosis

Monast and co-workers (2017) stated that the molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated.  Peripheral samples from sarcoidosis subjects who participated in a phase-II clinical trial of golimumab and ustekinumab were used to measure the whole blood transcriptome and levels of serum proteins.  Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement.  The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo.  These analyses revealed marked heterogeneity among the 3 sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway.  Conversely, enrichments of multiple pathways, including T cell receptor signaling, were similar among phenotypes.  These investigators also identified differences between treatment with golimumab and ustekinumab that may explain the differences in trends for clinical efficacy observed in the trial.  They found that molecular heterogeneity is associated with sarcoidosis in a manner that may be related to the extent of organ involvement.  They stated that these findings may help to explain the difficulty in identifying clinically effective sarcoidosis treatments and suggested hypotheses for improved therapeutic strategies.

Spondyloarthropathy

Her and Kavanaugh (2013) noted that inhibitors of TNF have demonstrated dramatic clinical efficacy in patients with spondyloarthropathy (SpA).  However, not all patients respond, and some patients who initially improve, subsequently lose response.  Therefore, there is still an unmet clinical need for additional therapies.  These researchers described the recent data on newer treatments for SpA patients.  Treatments targeting various cytokines, cell surface molecules, and signaling molecules have been assessed.  The effects of targeting B cells with rituximab, T-cell co-stimulation with abatacept, and interleukin (IL)-6 with tocilizumab have been disappointing in ankylosing spondylitis (AS).  Abatacept appears to have a modest effect in patients with psoriatic arthritis (PsA).  Targeting IL-17 with secukinumab, IL-12/23 with ustekinumab, and phosphodiesterase 4 (PDE4) with apremilast may prove to be promising treatments for SpA.  The authors concluded that there are several newer therapies that may emerge for SpA, particularly those targeting IL-17, IL-23/IL-12, and PDE4.

Ulcerative Colitis

Ulcerative colitis (UC) is a serious, chronic and progressive immune-mediated inflammatory disease of the large intestine, affecting approximately 910,000 people in the United States. Stelara (ustekinumab) targets the interleukin (IL)-12 and IL-23 cytokines which have been shown to play a role in inflammatory and immune responses (Janssen Phamaceutical, 2019). The efficacy of ustekinumab was evaluated in a pivotal study for the induction and maintenance therapy in patients with UC.

Ustekinumab was evaluated as 8-week induction therapy and 44-week maintenance therapy in two randomized, double-blind, placebo-controlled clinical studies [UC-1 and UC-2 (NCT02407236)] in 961 adult patients with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction study (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance study (UC-2) for a total of 52 weeks of therapy (Janssen Biotech, 2019). Sands et al. (2019) randomly assigned a total of 961 patients to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). The authors found that the percentage of patients who had clinical remission at week 8 among those who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than among patients who received placebo (5.3%) (p < 0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (p = 0.002 and p < 0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab, and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. The authors concluded that ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis.

On October 21, 2019, the FDA approved Stelara (ustekinumab) for the treatment of adult patients with moderately to severely active uclerative colitis. FDA approval was based on the pivotal Phase 3 UNIFI clinical trial [NCT02407236] which met its primary endpoint of clinical remission (Janssen Pharmaceutical, 2019).

Uveitis

Mugheddu and colleagues (2017) reported the first successful treatment of non-infectious uveitis with ustekinumab in a patient with severe concomitant psoriasis and psoriatic arthritis who failed to respond to conventional immune suppressants and with contraindications to TNF alpha inhibitors.  The effectiveness of ustekinumab in the treatment of non-infectious uveitis needs to be further investigated.

Sota and associates (2018) stated that intra-ocular inflammation is one of the more relevant complications of Behcet's disease (BD), which tends to respond poorly to different medications.  The ocular histopathologic changes are basically identical to those occurring in other organs and consist in a necrotizing leukocytoclastic obliterative vasculitis, which is probably immune complex-mediated and affects both arteries and veins of all sizes.  There are growing evidences showing the potential role of biologic agents other than TNF-alpha agents in the management of ocular-BD, which have been collected in this review, including IL-1 and IL-6 blockade, secukinumab, ustekinumab, daclizumab, rituximab, and alemtuzumab.  The authors concluded that further large studies are needed to fully elucidate and establish the effectiveness of these different agents in the refractory ocular manifestations of BD.

Furthermore, an UpToDate review on “Uveitis: Treatment” (Rosenbaum, 2017) does not mention ustekinumab as a therapeutic option.

Other Indications

Combined Ustekinumab and Vedolizumab for Inflammatory Bowel Disease

Ribaldone and colleagues (2019) noted that inflammatory bowel diseases (IBD) patients eligible for biological therapy represent a group with considerable disease burden and biologics only achieve 40 % clinical remission rates in responders after 1 year of therapy.  These researchers collected all the published data regarding patients treated with dual biological therapy with an anti-TNF, ustekinumab or vedolizumab, for a period of at least 3 months and pooled the data regarding the safety and effectiveness.  They carried out a Medline, and Web of Science search of all studies published in English until January 1, 2019.  These investigators included 7 studies with a total of 18 patients; 15 patients were treated with a combination of an anti-TNF and vedolizumab, 3 patients were treated with vedolizumab and ustekinumab; 56 % of patients were affected by CD and 50 % of patients were treated with an immunosuppressant drug or steroid too.  A clinical improvement was obtained in 100 % of patients, and an endoscopic improvement in 93 % of patients.  No serious AEs were reported.  The authors concluded that the use of dual biological therapy is an attractive therapeutic option and may be an opportunity to better tailor and personalize the therapies for patients.  Moreover, these researchers stated that further studies, as randomized control trials (RCTs), to provide comparative safety and efficacy endpoints of combination therapies, and to clarify potential advantages of combined biological therapies, are needed.

Measurement of Serum Levels of Ustekinumab and Antibodies to Ustekinumab

Hsu and colleagues (2014) stated that specific anti-drug antibodies (ADAs) against biological agents may be clinically significant and potentially alter a biological drug's treatment efficacy.  In a systematic review, these researchers determined the prevalence of ADAs against infliximab (IFX), etanercept (ETN), adalimumab (AdA), and ustekinumab in patients with psoriasis; examined if ADAs were associated with changes in drug efficacy; and examined the use of concomitant methotrexate to prevent ADA formation.  Through a systematic search using Medline and Embase from January 29, 1950 to March 29, 2013, these researchers identified 25 studies that met the inclusion criteria.  Of 7,969 patients with psoriasis, 950 tested positive for ADAs.  Antibodies against IFX, ETN, AdA, and ustekinumab were reported in 5.4 to 43.6 %, 0 to 18.3 %, 6 to 45 % and 3.8 to 6 % of patients, respectively.  Anti-IFX antibodies were associated with lower serum IFX concentrations in 3 studies, and decreased treatment response in 5 studies.  ADAs against ETN were non-neutralizing and not associated with any apparent effects on clinical response.  Anti-AdA antibodies were associated with lower serum AdA concentrations in 3 of 5 studies, and reduced clinical efficacy in 4 studies; 2 of 6 studies reported that anti-ustekinumab antibodies were associated with lower PASI responses, and 3 ustekinumab studies noted that most of these antibodies were neutralizing.  The authors concluded that although the use of concomitant methotrexate with biological agents to prevent ADA formation in other immune-mediated diseases is promising, their use in psoriasis is sparse.  Moreover, they stated that ADA development remains a challenge with biological therapies and therefore should be considered in patients with psoriasis who experience diminished treatment response. 

In a prospective, observational study, Chiu and associates (2015) examined the immunogenicity of ustekinumab and its clinical consequences in patients with psoriasis.  This trial enrolled 76 patients with plaque psoriasis who were treated with ustekinumab for a minimum of 7 months.  Blood samples were drawn just prior to scheduled ustekinumab injection during clinic visits.  Levels of anti-ustekinumab antibody (AUA) and serum ustekinumab concentration were measured respectively by radioimmunoassays (RIAs) and enzyme-linked immunoassays (ELISA), respectively, and correlated to clinical data and Psoriasis Area and Severity Index (PASI).  AUA was detected in 6.5 % of patients after a mean of 13 months of treatment.  Patients with positive AUA had significantly lower serum ustekinumab concentrations (0.01 versus 0.2 mg/L, p < 0.001) and lower PASI 50 response than patients without AUA (0 % versus 69 %, p = 0.004).  The percentage of AUA formation was comparable between patients who had failed previous AdA with or without anti-AdA antibodies (AAA) (14.3 % versus 12.5 %, p = 1.00).  However, a higher proportion of switchers without AAA obtaining PASI50 (71.4 % versus 37.5 %) and PASI75 response (42.9 % versus 12.5 %) within 7 months of ustekinumab treatment than with AAA although this difference did not reach statistical significance.  The authors concluded that these findings suggested that presence of AUA was significantly associated with treatment failure for ustekinumab, although limited by a small sample size.  Also, determining the presence of ADA to antecedent TNF-α antagonists may assist in choosing an optimized subsequent treatment modality achieving treatment success.  They stated that additional studies involving a larger sample size, longer follow-up, and serial sampling is needed to strengthen the conclusion; assessing the immunogenic status in psoriasis patients treated with ustekinumab may be a rational approach for further decision-making and might assist in choosing an optimized treatment modality for the individual patient. 

This study had several drawbacks, which included the observational cohort design and inadequate statistical power (less than 50 %) from small sample size of patient with AUA.  Furthermore, each patient’s blood sample was collected once during a clinic visit, although the timing of the collection was not uniform across all samples. 

The Prescribing Information does not mention measurement of serum ustekinumab levels or levels of antibodies to ustekinumab (Janssen Biotech, 2020).

It is also interesting to note that an UpToDate review on “Treatment of psoriasis in adults” (Feldman, 2019) states that “Further study is necessary to determine whether assessing serum levels of adalimumab during treatment will be useful for improving responses to therapy”.  Well-designed studies are needed to expand the existing evidence base to evaluate if therapeutic drug monitoring (e.g., using information provided by the Prometheus Anser UST test), would lead to changes in therapeutic interventions or other changes in disease management that ultimately improve patient health outcomes over the long-term.

Appendix

Appendix A: Examples of Conventional Therapy Options for CD

1. Mild to moderate disease - induction of remission:

   1. Oral budesonide
   2. Alternatives: metronidazole, ciprofloxacin, rifaximin

2. Mild to moderate disease - maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternatives: oral budesonide, methotrexate intramuscular (IM) or subcutaneous (SC), sulfasalazine

3. Moderate to severe disease - induction of remission:

   1. Prednisone, methylprednisolone intravenously (IV)
   2. Alternatives: methotrexate IM or SC

4. Moderate to severe disease - maintenance of remission:

1. Azathioprine, mercaptopurine
2. Alternative: methotrexate IM or SC

5. Perianal and fistulizing disease - induction of remission:

   Metronidazole ± ciprofloxacin, tacrolimus

6. Perianal and fistulizing disease - maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternative: methotrexate IM or SC

Appendix B: Examples of conventional therapy options for UC

1. Mild to moderate disease - induction of remission:

   1. Oral mesalamine (e.g., Asacol, Asacol HD, Lialda, Pentasa), balsalazide, olsalazine
   2. Rectal mesalamine (e.g., Canasa, Rowasa)
   3. Rectal hydrocortisone (e.g., Colocort, Cortifoam)
   4. Alternatives: prednisone, azathioprine, mercaptopurine, sulfasalazine

2. Mild to moderate disease - maintenance of remission:

   1. Oral mesalamine, balsalazide, olsalazine, rectal mesalamine
   2. Alternatives: azathioprine, mercaptopurine, sulfasalazine

3. Severe disease - induction of remission:

   1. Prednisone, hydrocortisone IV, methylprednisolone IV
   2. Alternatives: cyclosporine IV, tacrolimus, sulfasalazine

4. Severe disease – maintenance of remission:

   1. Azathioprine, mercaptopurine
   2. Alternative: sulfasalazine

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 Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis 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 Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Kevzara	sarilumab	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA) Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	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 Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Atopic dermatitis Psoriatic arthritis Rheumatoid arthritis
Rituxan	rituximab	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis Various subtypes of non-Hodgkin's lymphoma
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Plaque psoriasis 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

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:
Measurement of serum levels of ustekinumab and antibodies to ustekinumab - no specific code:
Other CPT codes related to the CPB :
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis
96369 - 96371	Subcutaneous infusion for therapy or prophylaxis (specify substance or drug)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
96409 - 96411	intravenous, push technique, single or initial, or each additional
96413 - 96417	Chemotherapy administration; intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J3357	Injection, ustekinumab, 1 mg
J3358	Ustekinumab, for intravenous injection, 1 mg
Other HCPCS codes related to the CPB:
J0717	Injection, certolizumab pegol 1 mg [not covered with Ustekinumab]
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1mg for intravenous use [not covered with Ustekinumab]
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J1745	Injection, infliximab, 10 mg [not covered with Ustekinumab]
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J3245	Injection, tildrakizumab, 1 mg
J3380	Injection, vedolizumab, 1 mg
J7506	Prednisone, oral, per 5 mg
J7509	Methylprednisolone, oral, per 4 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
ICD-10 codes covered if selection criteria are met:
K50.00 - K50.919	Crohn's disease (regional enteritis)
K51.00 - K51.919	Ulcerative colitis
L40.0 - L40.3, L40.5 - L40.9	Psoriasis [not covered for erythrodermic psoriasis]
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
Leukocyte adhesion deficiency type 1 - no specific code:
A15.0 - A15.9, A17.0 - A17.9, A18.01 - A18.89, A19.0 - A19.9	Tuberculosis [not covered for persons with active TB or untreated latent disease]
A36.89	Other diphtheritic complications [uveitis due to diptheria]
A50.39	Other late congenital syphilitic oculopathy [uveitis due to late congenital syphilis]
A51.43	Secondary syphilitic oculopathy [uveitis due to syphilis]
A52.71	Late syphilitic oculopathy [uveitis due to late syphilis]
A54.32	Gonococcal iridocyclitis
B02.32	Zoster iridocyclitis
B58.09	Other toxoplasma oculopathy [uveitis due to toxoplasmosis]
D72.1	Eosinophilia [eosinophilic dermatoses]
D86.0 - D86.9	Sarcoidosis
D89.810 - D89.813	Graft-versus-host disease
G30.0 - G30.9	Alzheimer's disease
G35	Multiple sclerosis
H20.00 - H20.9	Iridocyclitis
H44.131 - H44.139	Sympathetic uveitis
K74.3 - K74.5	Biliary cirrhosis
K91.850	Pouchitis [chronic antibiotic-refractory]
L20.0 - L20.9	Atopic dermatitis
L40.4	Guttate psoriasis
L44.0	Pityriasis rubra pilaris
L63.0 - L63.9	Alopecia areata
L73.2	Hidradenitis suppurativa
L88	Pyoderma gangrenosum
L93.1	Subacute cutaneous lupus erythematosus
M05.00 - M06.9	Rheumatoid arthritis
M31.4	Aortic arch syndrome [Takayasu]
M31.5 - M31.6	Giant cell arteritis
M32.0 - M32.9	Systemic lupus erythematosus
M35.2	Behcet's disease
M35.3	Polymyalgia rheumatica
M45.0 - M49.89	Spondyolpathies [spondyloarthropathy]
M86.30 - M86.39	Chronic multifocal osteomyelitis [SAPHO Syndrome]

The above policy is based on the following references: