Ustekinumab (Stelara)

Number: 0912

Policy

Aetna considers ustekinumab (Stelara) medically necessary for for the following indications, where the member has a documented negative TB testFootnotes^* (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 biologics, and repeated yearly for members with risk factors for TBFootnotes^** that are continuing therapy with biologics:

1. Crohn's disease

1. Active Crohn's disease

   Member is 18 years of age and older with moderate to severe active Crohn's disease, where active Crohn's disease is manifested by one or more of the following signs and symptoms, and Crohn's disease has remained active despite treatment with either 6-mercaptopurine, azathioprine, or corticosteroids (e.g., prednisone, methylprednisolone):

   1. Abdominal pain;
   2. Bleeding;
   3. Diarrhea;
   4. Extra-intestinal manifestations: arthritis or spondylitis;
   5. Internal fistulae;
   6. Intestinal obstruction;
   7. Megacolon;
   8. Perianal disease; or
   9. Weight loss

2. Fistulizing Crohn's disease

   Members 18 years of age and older and has fistulizing Crohn's disease for at least 3 months.

   Note: continuation criteria for either active or fistulizing Crohn's disease requires a documented diagnosis (as per above) and clinical documentation indicating there is disease stability or improvement.

2. For psoriasis and posoriatic arthritis indications, see CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators.

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 ustekinumab experimental and investigational for all other indications (other than Crohn's disease, psoriasis and psoriatic arthritis), including the following because its effectiveness for these indications has not been established:

• Alopecia areata
• Alzheimer disease
• Atopic dermatitis
• Behcet's syndrome
• Biliary cholangitis (also known as biliary cirrhosis)
• Cutaneous lupus erythematosus,
• 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,
• Ucerative colitis
• Uveitis.

Footnotes^* If the screening test is positive for active or latent TB, then TB treatment must begin prior to initiation of the biologic.  

Footnotes^** Risk factors for TB include: persons with close contact to people with infectious TB disease; persons who have recently emigrated from areas of the world with high rates of TB (e.g., Africa, Asia, Eastern Europe, Latin America, and Russia); children less than 5 years of age who have a positive TB test; groups with high rates of TB transmission (e.g., homeless persons, injection drug users, and persons with HIV infection); persons who work or reside with people who are at an increased risk for active TB (e.g., hospitals, long-term care facilities, correctional facilities, and homeless shelters) (CDC, 2012).

Note: There are several brands of targeted immune modulators on the market. There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  Enbrel (etanercept), Entyvio (vedolizumab), Inflectra (infliximab-dyyb), Otezla (apremilast), Remicade (infliximab), Renflexis (infliximab-abda)*, Simponi (golimumab), Simponi Aria (golimumab intravenous), Stelara (ustekinumab), Tremfya (guselkumab), Xeljanz and Xeljanz XR (tofacitinib) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna.  Consequently, because Actemra (tocilizumab), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab), Skyrizi (risankizumab-rzaa) and Tysabri (natalizumab) brands of targeted immune modulators are more costly than the least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, these brands of targeted immune modulator will be considered medically necessary only if the member has a contraindication, intolerance or incomplete response to the following numbers of trials of least cost brands of targeted immune modulators by indication:

• Ankylosing spondylitis – two least cost brands
• Crohn’s disease – one least cost brand (not including Renflexis) 
• Juvenile idiopathic arthritis – trial of Enbrel (etanercept)
• Plaque psoriasis – three least cost brands
• Psoriatic arthritis – three least cost brands
• Rheumatoid arthritis – three least cost brands
• Ulcerative colitis – one least cost brand (not including Renflexis)

Note that Cimzia (certolizumab), Cosentyx (secukinumab), Ilaris (canakinumab), Ilumya (tildakizumab-asmn), Kevzara (sarilumab), Olumiant (baricitinib), Siliq (brodalumab), and Taltz (ixekizumab) brands of targeted immune modulators do not require a trial of a least cost brand of targeted immune modulator; there may, however, be a higher copayment where these brands are covered under pharmacy plans with a tiered formulary. Please check benefit plan descriptions. If the least costly targeted immune modulators do not have the labeled indication (see Appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication. Also note that Renflexis is not a least cost brand for Crohn’s disease and ulcerative colitis indications.

Background

Ustekinumab (UST) is a human interleukin-12 and -23 antagonist indicated for the treatment of select moderately to severely active Crohn’s disease (CD) patients. 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.  The recommended dosing is listed in Appendix A.  Following IV dosing, a subcutaneous 90 mg dose is adinistered 8 weeks after the initial intravenous dose, then every 9 weeks thereafter.

Stelara is contraindicated in persons with hypersensitivity to ustekinumab or any of the excipients (Janssen Biotech, 2016).

In clinical trials, the most common adverse reactions from ustekinumab (Janssen Biotech, 2016) are:

• Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. 
• Crohn’s Disease, induction (≥3%): vomiting. 
• Crohn’s Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis.  

The prescribing information for ustekinumab (Janssen Biotech, 2016) includes the following warnings:

• Infections: Serious infections have occurred. Do not start ustekinumab during any clinically important active infection. If a serious infection or clinically significant infection develops, consider discontinuing ustekinumab until the infection resolves. 
• Theoretical Risk for Particular Infections: 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. 
• Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with ustekinumab. Initiate treatment of latent TB before administering ustekinumab.
• Malignancies: Ustekinumab may increase risk of malignancy. The safety of ustekinumab in patients with a history of or a known malignancy has not been evaluated.
• Hypersensitivity Reactions: Anaphylaxis or other clinically significant hypersensitivity reactions may occur. 
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): One case was reported. If suspected, treat promptly and discontinue ustekinumab.

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.

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.

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.

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 validated in future well-designed studies..

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.

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 (2017) 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.

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.

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 Experimental Indications:

There are clinical trials examining the use of ustekinumab for various diseases/conditions including Alzheimer disease, atopic dermatitis, axial spondyloarthritis, biliary cirrhosis, giant cell arteritis, graft versus host disease, sarcoidosis, systemic lupus erythematosus, ulcerative colitis, and uveitis.

Appendix

Crohn’s Disease Recommended Initial Adult Intravenous Dosage:

Table: Initial Adult Intravenous Dosage

Weight Range (kilogram)	Recommended Dosage
Up to 55 kg	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 Recommended Maintenance Adult Subcutaneous Dosage:

A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter.

Source: Janssen Biotech, 2016.

Table: Brands of Targeted Immune Modulators and FDA-approved Indications:

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Cytokine release syndrome (CRS)
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthrits 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	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 Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Plaque psoriasis Psoriatic arthritis
Remicade	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rituxan	rituximab	Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Plaque psoriasis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis
Taltz	ixekinumab	Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Rheumatoid arthritis Psoriatic arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Rheumatoid arthritis Psoriatic 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 "+" :
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
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)
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:
A18.54	Tuberculous iridocyclitis
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]
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
K51.00 - K51.919	Ulcerative colitis
K74.3 - K74.5	Biliary cirrhosis
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: