Secukinumab (Cosentyx)

Number: 0905

Table Of Contents

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

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses secukinumab (Cosentyx) for commercial medical plans. For Medicare criteria on intravenous Cosentyx, see Medicare Part B Criteria.

Note: Precertification of intravenous (IV) secukinumab (IV Cosentyx only) is required of all Aetna participating providers and members in applicable plan designs. For precertification of IV Cosentyx, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Site of Care Utilization Management Policy applies for commercial plans. For information on site of service for IV Cosentyx only, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Prescriber Specialties

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

   1. Plaque psoriasis: dermatologist;
   2. Psoriatic arthritis and hidradenitis suppurativa: rheumatologist or dermatologist;
   3. Ankylosing spondylitis, non-radiographic axial spondyloarthritis, and enthesitis-related arthritis: rheumatologist.

2. Criteria for Initial Approval

   Aetna considers secukinumab (Cosentyx) medically necessary for the following indications when criteria are met: 

   1. Plaque psoriasis (PsO)

      1. For members 6 years of age or older who have previously received a biologic or targeted synthetic drug (e.g., Sotyktu, Otezla) indicated for the treatment of moderate to severe plaque psoriasis; or
      2. For members 6 years of age or older for treatment of moderate to severe plaque psoriasis when any of the following criteria is met:
         
         
         1. Crucial body areas (e.g., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected; or
         2. At least 10% of the body surface area (BSA) is affected; or
         3. At least 3% of body surface area (BSA) is affected and the member meets any of the following criteria:
            
            
            1. Member has had an inadequate response or intolerance to either phototherapy (e.g., UVB, PUVA) or pharmacologic treatment with methotrexate, cyclosporine or acitretin; or
            2. Member has a clinical reason to avoid pharmacologic treatment with methotrexate, cyclosporine and acitretin (see Appendix);

   2. Psoriatic arthritis (PsA)

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

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

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

         2. Member has severe disease;
            

   3. Ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)

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

   4. Enthesitis-related arthritis (ERA)

      1. For members 4 years of age or older who have previously received a biologic for treatment of active-enthesitis related arthritis; or
      2. For members 4 years of age or older for treatment of active-enthesitis related arthritis when both of the following criteria are met:
          
         1. Member has active disease demonstrated by at least three active joints involved and at least one site of active enthesitis at baseline or documented by history; and
         2. Member meets either of the following:
            
            
            1. Member has had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs), sulfasalazine, or methotrexate; or
            2. Member has an intolerance or contraindication to NSAIDs, sulfasalazine (e.g., porphyria, intestinal or urinary obstruction), and methotrexate (see Appendix).

   5. Hidradenitis suppurativa

      1. For adult members who have previously received a biologic indicated for treatment of moderate to severe hidradenitis suppurativa; or
      2. For adult members for treatment of moderate to severe hidradenitis suppurativa when either of the following is met:
         
         
         1. Member has had an inadequate response to an oral antibiotic used for the treatment of hidradenitis suppurativa for at least 90 days (e.g., clindamycin, metronidazole, moxifloxacin, rifampin, tetracylines); or
         2. Member has an intolerance or contraindication to oral antibiotics used for the treatment of hidradenitis suppurativa.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of secukinumab (Cosentyx) therapy medically necessary for the following indications: 

   1. Plaque psoriasis (PsO)

      For all members 6 years of age or older (including new members) who are using secukinumab for moderate to severe plaque psoriasis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when either of the following is met:

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

   2. Psoriatic arthritis (PsA)

      For all members 2 years of age or oder (including new members) who are using secukinumab for psoriatic arthritis and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:

      1. Number of swollen joints; or
      2. Number of tender joints; or
      3. Dactylitis; or
      4. Enthesitis; or
      5. Axial disease; or
      6. Skin and/or nail involvement; or
      7. Functional status; or
      8. C-reactive protein (CRP);

   3. Ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)

      For all adult members (including new members) who are using secukinumab for ankylosing spondylitis or non-radiographic axial spondyloarthritis and who achieve or maintain 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. Functional status; or
      2. Total spinal pain; or
      3. Inflammation (e.g., morning stiffness); or
      4. Swollen joints; or
      5. Tender joints; or
      6. C-reactive protein (CRP);

   4. Enthesitis-related arthritis (ERA)

      For all members 4 years of age or older (including new members) who are using secukinumab for active-enthesitis related arthritis and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when there is improvement in any of the following from baseline:

      1. Number of flares; or
      2. Number of joints with active arthritis (e.g., swelling, pain); or
      3. Number of joints with limited movement; or
      4. Dactylitis; or
      5. Enthesitis;

   5. Hidradenitis suppurativa

      For all adult members (including new members) who are using secukinumab for moderate to severe hidradenitis suppurativa and who achieve or maintain a positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition when any of the following is met:

      1. Reduction in abscess and inflammatory nodule count from baseline
      2. Reduced formation of new sinus tracts and scarring
      3. Decrease in frequency of inflammatory lesions from baseline
      4. Reduction in pain from baseline
      5. Reduction in suppuration from baseline
      6. Improvement in frequency of relapses from baseline
      7. Improvement in quality of life from baseline
      8. Improvement on a disease severity assessment tool from baseline.

4. Other

   For all indications: Member has had a documented negative tuberculosis (TB) test (which can include a tuberculosis skin test [TST] or an interferon-release assay [IGRA]Footnote1* within 6 months of initiating therapy for persons who are naïve to biologic drugs or targeted synthetic drugs associated with an increased risk of TB.

   Footnote1* If the screening testing for TB is positive, there must be further testing to confirm there is no active disease (e.g., chest x-ray). 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.

   For all indications: Member cannot use the requested medication concomitantly with any other biologic drug or targeted synthetic drug for the same indication.

5. Related Policies

   1. CPB 0205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions
   2. CPB 0315 - Etanercept
   3. CPB 0341 - Infliximab
   4. CPB 0577 - Laser Treatment for Psoriasis and Other Selected Skin Conditions
   5. CPB 0655 - Adalimumab
   6. CPB 0720 - Abatacept (Orencia)
   7. CPB 0761 - Certolizumab Pegol (Cimzia)
   8. CPB 0790 - Golimumab (Simponi and Simponi Aria)
   9. CPB 0912 - Ustekinumab (Stelara)

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.

Secukinumab, branded as Cosentyx, is available in the following dosage forms and strengths: 

• Subcutaneous injection:

  Adults may self-administer Cosentyx. Pediatric persons should not self-administer Cosentyx. An adult caregiver should prepare and inject Cosentyx after proper training in subcutaneous injection technique.
  

  • 75 mg/0.5 mL solution in a single-dose prefilled syringe (for pediatrics)
  • 150 mg/mL solution in a single-use Sensoready pen and in a single-dose prefilled syringe
  • 300 mg/2 mL solution in a single-dose UnoReady pen and in a single-dose prefilled syringe
    
    

• Intravenous infusion:

  Intravenous infusion is only for use by a healthcare professional in a healthcare setting. Intravenous infusion may be administered only in adults with PsA, AS, and nr-axSPA.

  • 125 mg/5 mL solution in a single-dose vial.

Plaque Psoriasis (PsO)

Adults

The recommended dose is 300 mg administered by subcutaneous (SC) injection at Weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks. Each 300 mg dosage is given as one SC injection of 300 mg or as two SC injections of 150 mg. For some individuals, a dosage of 150 mg by SC injection at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter may be acceptable.

Pediatric persons 6 years of age and older

The recommended dosage is based on body weight and administered by SC injection at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter.

• For weight less than 50 kg (at time of dosing), the recommended dose is 75 mg
• For weight greater than or equal to 50 kg (at time of dosing), the recommended dose is 150 mg.

Psoriatic Arthritis (PsA)

Cosentyx may be administered with or without methotrexate.

Adults

Subcutaneous (SC) dosage:

• Adults with PsA and coexistent moderate to severe plaque psoriasis (PsO), use the dosing and administration recommendations for adults with PsO.
• For other adults with PsA, administer Cosentyx with or without a loading dosage by subcutaneous injection. The recommended dosage for adults with PsA:
  
  
  • With a loading dosage is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
  • Without a loading dosage is 150 mg every 4 weeks
  • If a person continues to have active PsA, consider increasing the dosage to 300 mg SC every 4 weeks. Each 300 mg dosage is given as one subcutaneous injection of 300 mg or as two subcutaneous injections of 150 mg.

Intravenous (IV) dosage:

The recommended IV dosages are:

• With a loading dosage: 6 mg/kg given at Week 0 as a loading dose, followed by 1.75 mg/kg every 4 weeks thereafter (max. maintenance dose 300 mg per infusion)
• Without a loading dosage: 1.75 mg/kg every 4 weeks (max. maintenance dose 300 mg per infusion).

Total doses exceeding 300 mg per infusion are not recommended for the 1.75 mg/kg maintenance dose in adults with PsA.

Pediatric persons 2 years and older

Subcutaneous (SC) dosage:

The recommended dose based on body weight is administered by SC injection at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter

• For weight greater than or equal to 15 kg and less than 50 kg the recommended dose is 75 mg
• For weight greater than or equal to 50 kg the recommended dose is 150 mg.

Ankylosing Spondylitis (AS)

Adults

Subcutaneous (SC) dosage:

Administer with or without a loading dosage.

The recommended dosages are:

• With a loading dosage: 150 mg at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
• Without a loading dosage: 150 mg every 4 weeks
• If a person continues to have active ankylosing spondylitis, consider a dosage of 300 mg every 4 weeks.

Intravenous (IV) dosage:

The recommended intravenous dosages are:

• With a loading dosage: 6 mg/kg given at Week 0 as a loading dose, followed by 1.75 mg/kg every 4 weeks thereafter (max. maintenance dose 300 mg per infusion).
• Without a loading dosage: 1.75 mg/kg every 4 weeks (max. maintenance dose 300 mg per infusion).

Total doses exceeding 300 mg per infusion are not recommended for the 1.75 mg/kg maintenance dose in persons with AS.

Non-Radiographic Axial Spondyloarthritis (nr-axSpA)

Adults

Subcutaneous (SC) dosage:

Administer with or without a loading dose. The recommended dosages are:

• With a loading dosage: 150 mg at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
• Without a loading dosage: 150 mg every 4 weeks.

Intravenous (IV) dosage:

The recommended intravenous dosages are:

• With a loading dosage: 6 mg/kg given at Week 0 as a loading dose, followed by 1.75 mg/kg every 4 weeks thereafter (max. maintenance dose 300 mg per infusion)
• Without a loading dosage: 1.75 mg/kg every 4 weeks (max. maintenance dose 300 mg per infusion).

Total doses exceeding 300 mg per infusion are not recommended for the 1.75 mg/kg maintenance dose in persons with nr-axSpA.

Enthesitis-Related Arthritis

Pediatric persons 4 years of age and older

Subcutaneous (SC) dosage:

Cosentyx is based on body weight and is administered by SC injection at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter. 

• For persons weighing greater than or equal to 15 kg and less than 50 kg the recommended dose is 75 mg
• For persons weighing greater than or equal to 50 kg the recommended dose is 150 mg.

Hidradenitis Suppurative

Adults

Subcutaneous (SC) dosage:

Recommended dosage is 300 mg administered by SC injection at Weeks 0, 1, 2, 3 and 4 and every 4 weeks thereafter. If a person does not adequately respond, consider increasing the
dosage to 300 mg every 2 weeks.

Source: Novartis, 2023

Experimental, Investigational, or Unproven

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

Aetna considers secukinumab experimental, investigational, or unproven for the treatment of the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Actinic granuloma
• Alopecia areata
• Alzheimer disease
• Atopic dermatitis
• Behcet's disease-related uveitis
• Diabetes mellitus type I
• Dry eye
• Erythrodermic psoriasis
• Granuloma annulare
• Granulomatous interstitial nephritis
• Hepatocellular carcinoma
• Ichthyoses
• Interstitial granulomatous dermatitis
• Non-infectious uveitis
• Palmoplantar psoriasis
• Papulopustular rosacea
• Parkinson's Disease
• Pityriasis rubra pilaris
• Pyoderma gangrenosum
• Rheumatoid arthritis
• SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome
• Vitiligo.

Aetna considers secukinumab gene therapy experimental, investigational, or unproven because its effectiveness has not been established.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
71045 – 71048	Radiologic examination, chest
86480 - 86481	Tuberculosis test, cell mediated immunity antigen response measurement
86580	Skin test; tuberculosis, intradermal
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96401, 96413 - 96415	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J3247	Injection, secukinumab, intravenous, 1 mg
HCPCS codes not covered for indications listed in the CPB:
Secukinumab Gene Therapy - no specific code:
Other HCPCS codes related to the CPB:
J0129	Injection, abatacept, 10 mg
J0135	Injection, adalimumab, 20 mg
J0717	Injection, certolizumab pegol 1 mg
J0736	Injection, clindamycin phosphate, 300 mg
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1 mg, for intravenous use
J1745	Injection, infliximab, 10 mg
J1836	Injection, metronidazole, 10 mg
J2280	Injection, moxifloxacin, 100 mg
J3245	Injection, tildrakizumab, 1 mg
J3262	Injection, Tocilizumab (Actemra), 1 mg
J3357	Injection, ustekinumab, 1 mg
J9311	Injection, rituximab 10 mg and hyaluronidase
J9312	Injection, rituximab, 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (ixifi), 10 mg
Q5115	Injection, rituximab-abbs, biosimilar, (Truxima), 10 mg
Q5119	Injection, rituximab-pvvr, biosimilar, (ruxience), 10 mg
Q5123	Injection, rituximab-arrx, biosimilar, (riabni), 10 mg
Q5131	Injection, adalimumab-aacf (idacio), biosimilar, 20 mg
Q5132	Injection, adalimumab-afzb (abrilada), biosimilar, 10 mg
Q5133	Injection, tocilizumab-bavi (tofidence), biosimilar, 1 mg
Q5135	Injection, tocilizumab-aazg (tyenne), biosimilar, 1 mg
ICD-10 codes covered if selection criteria are met:
L40.0	Psoriasis vulgaris [plaque psoriasis] [for members 6 years of age or older]
L40.50 – L40.59	Arthropathic psoriasis [for members 2 years of age or older]
L73.2	Hidradenitis suppurativa [for adult members]
M08.80 - M08.89	Other juvenile arthritis [enthesitis-related arthritis (ERA)] [for members 4 years of age or older]
M45.0 - M45.AB	Ankylosing spondylitis [for adult members]
ICD-10 codes not covered for indications listed in the CPB:
A15.0 - A19.9	Tuberculosis
C22.0	Liver cell carcinoma
E10.10 - E10.9	Type 1 diabetes mellitus
G20.A1 - G20.C	Parkinson's Disease
G30.0 - G30.9	Alzheimer's disease
H04.121 - H04.129	Dry eye syndrome
H20.041 - H20.049	Secondary noninfectious iridocyclitis
L20.0 - L20.9	Atopic dermatitis
L40.8	Other psoriasis [palmoplantar psoriasis]
L44.0	Pityriasis rubra pilaris
L57.5	Actinic granuloma
L63.0 - L63.9	Alopecia areata
L71.8	Other rosacea [papulopustular rosacea]
L80	Vitiligo
L88	Pyoderma gangrenosum
L92.0	Granuloma annulare
L92.9	Granulomatous disorder of the skin and subcutaneous tissue, unspecified [interstitial granulomatous dermatitis]
M05.00 - M05.9	Rheumatoid arthritis with rheumatoid factor
M35.2	Behcet's disease [uveitis]
M86.30	Chronic multifocal osteomyelitis, unspecified site [SAPHO]
N12	Tubulo-interstitial nephritis, not specified as acute or chronic [granulomatous interstitial nephritis]
Q80.0	Chronic multifocal osteomyelitis, unspecified site [SAPHO]
R76.11	Nonspecific reaction to tuberculin skin test without active tuberculosis

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Background

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

• Moderate to severe plaque psoriasis (PsO) in patients 6 years of age and older who are candidates for systemic therapy or phototherapy
• Adults with active psoriatic arthritis (PsA) in patients 2 years of age and older
• Adults with active ankylosing spondylitis (AS)
• Adults with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation
• Active enthesitis-related arthritis (ERA) in patients 4 years of age and older
• Adults with moderate to severe hidradenitis suppurativa (HS)

Secukinumab is available as Cosentyx (Novartis Pharmaceuticals Corporation). Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Secukinumab inhibits the release of proinflammatory cytokines and chemokines.

Labeled warnings and precautions for use of secukinumab (Cosentyx) include serious infections, tuberculosis (TB), inflammatory bowel disease, eczematous eruptions, and hypersensitivity reactions. Caution should be exercised when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection. If a serious infection develops, discontinue secukinumab until the infection resolves. Prior to initiating secukinumab, individuals are evaluated for tuberculosis (TB) infection. Do not administer secukinumab to persons with active TB infection. Initiate treatment of latent TB prior to administering secukinumab. Consider anti-TB therapy prior to initiation of secukinumab in persons with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Persons receiving secukinumab should be monitored closely for signs and symptoms of active TB during and after treatment. Cases of inflammatory bowel disease were observed in clinical trials, thus caution should be exercised when prescribing secukinumab. In addition, use of secukinumab increases risk of hypersensitivity reactions. If an anaphylactic reaction or other serious allergic reaction occurs, discontinue secukinumab immediately and initiate appropriate therapy (Novartis, 2023).

Most common adverse reactions (greater than 1%) are nasopharyngitis, diarrhea, and upper respiratory tract infection.

Ankylosing Spondylitis

Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterized by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. Secukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis. 

Baeten et al (2015) reported on two phase 3 trials of secukinumab in patients with active ankylosing spondylitis. In two double-blind trials, investigators randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16. In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.

In a phase II study, Baeten et al (2013) assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis. Investigators did a randomized double-blind proof-of-concept study at eight centers in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomization was done with a computer-generated block randomization list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. In this study, 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group.

Axial Spondyloarthritis

Yu and van Tubergen (2020a) state that axial spondyloarthritis (axSpA) is a potentially disabling inflammatory arthritis of the spine, usually presenting as chronic back pain. "It is often associated with one or more of several articular and periarticular extraspinal features, including synovitis, enthesitis, and dactylitis. It may also be associated with several nonarticular features; these include uveitis, psoriasis, and inflammatory bowel disease (IBD)". "Patients with axSpA can be classified as having either of two subtypes of axSpA: ankylosing spondylitis (AS, also termed radiographic axSpA) or nonradiographic axSpA (nr-axSpA). Patients with AS exhibit radiographic abnormalities consistent with sacroiliitis, but such findings are absent or minimal on plain radiography in nr-axSpA". nr-axSpA is referred to as being a part of the axSpA "spectrum", which also includes AS, in which joint damage is visible on x-ray, and nr-axSpA, where joint damage is generally not visible on x-ray (Novartis, 2020).

Initial drug therapy includes a nonsteroidal anti-inflammatory drug (NSAID) (e.g., naproxen, celecoxib, ibuprofen). In persons with symptoms due to active axial spondyloarthritis (SpA) and an inadequate response to initial therapy with two different NSAIDs used consecutively in an adequate dose for at least two to four weeks each, Yu and van Tubergen (2020b) recommend a tumor necrosis factor (TNF)-alpha inhibitor rather than continuing treatment with NSAIDs alone. In persons who have contraindications to the use of TNF inhibitors, treatment with an anti-IL-17 antibody, secukinumab or ixekizumab is recommended. 

In June 2020, Cosentyx (secukinumab) was U.S. FDA approved for the treatment of active non-radiographic axial spondyloarthritis (nr-axSpA), confirming Cosentyx efficacy in addressing the axial spondyloarthritis (axSpA) disease spectrum (Novartis, 2020). FDA approval was based on the efficacy and safety results from the PREVENT trial which showed a significant reduction in disease activity for patients treated with secukinumab versus placebo.

The PREVENT trial was a two-year randomized, double-blind, placebo-controlled, phase 3 study which evaluated the efficacy and safety of secukinumab in 555 patients (18 years of age and older) with active non-radiographic axial spondyloarthritis (nr-axSpA) and no evidence of radiographic changes in the sacroiliac joints that would meet the modified New York criteria for AS. Additional inclusion criteria were disease onset before 45 years of age, spinal pain rated as ≥40/100 on a visual analog scale (VAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4) and who had been taking at least two different NSAIDs at the highest dose up to 4 weeks prior to the start of the study. Patients may have previously taken a TNF inhibitor (not more than one) but had had an inadequate response. Patients also had to have objective signs of inflammation with a C-reactive protein (CRP) level above the upper limit of normal and/or evidence of sacroiliitis on MRI. Patients were treated with secukinumab 150 mg subcutaneous treatment with load (weeks 0, 1, 2, 3, and 4) or without a load (weeks 0 and 4) followed by the same dose every 4 weeks or placebo. In the double-blind period, patients (n = 555) received either placebo or secukinumab for 52 weeks. Starting Week 16, dose adjustment or addition of concomitant NSAIDs and DMARDs was permitted. Starting at Week 20, patients were allowed to switch to open-label secukinumab 150 mg monthly or other biologic at the discretion of the investigator and patient. The primary endpoint was at least 40% improvement in Assessment of Spondyloarthritis International Society (ASAS40) at Weeks 52. Secukinumab met the primary endpoints achieving statistically significant improvements versus placebo in the signs and symptoms of nr-axSpA. nr-axSpA patients treated with secukinumab showed improvement in both load and without load arms compared to placebo-treated patients at week 16 in health-related quality of life as measured by the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire. General health status and quality of life was assessed by the Short Form health survey (SF-36). At week 16, patients treated with secukinumab showed greater improvement from baseline in the SF-36 physical component summary (PCS) score and in the mental component summary (MCS) score10. The safety profile of secukinumab in the PREVENT trial was shown to be consistent with previous clinical trials. No new safety signals were detected (ClinicalTrials.gov Identifier: NCT02696031) (Novartis, 2020a, 2020b, 2021).

Enthesitis-Related Arthritis (ERA)

Enthesitis-related arthritis (ERA) is a condition classified as a type of juvenile idiopathic arthritis (JIA) that predominantly affects the joints and entheses of the lower extremities. ERA may eventually affect the sacroiliac joints and spine evolving to juvenile ankylosing spondylitis. The International League of Associations for Rheumatology (ILAR) classification criteria for ERA include the following:

• Sacroiliac joint tenderness and/or inflammatory spinal pain
• Presence of (human leukocyte antigen) HLA-B27
• Onset of arthritis in a male over 6 years of age
• Family history in at least one first-degree relative of ankylosing spondylitis, Enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, reactive arthritis, or acute anterior uveitis
• Acute anterior uveitis.

Children are excluded from this category if they have a first-degree relative with psoriasis, positive rheumatoid factor (RF), or systemic arthritis (Hahn, 2018; Klein-Gitelman, 2020).

In December 2021, the U.S. FDA approved Cosentyx for the treatment of active ERA in patients 4 years of age and older. FDA approval was based on data from the Phase III JUNIPERA study, which was a two-year, three-part, double-blind, placebo-controlled, randomized-withdrawal trial that enrolled 86 children and adolescents aged 2 to 18 years old with a confirmed diagnosis of ERA or juvenile psoriatic arthritis (JPsA) according to a modified ILAR classification criteria. The study consisted of an open-label portion (Part 1) followed by randomized withdrawal (Part 2) followed by open-label treatment (Part 3). In the study 67.6% of patients with JPsA, and 63.5% with ERA, were treated concomitantly with MTX. Patients were given a dose of 75 mg if weighing less than 50 kg, or 150 mg if weighing greater than or equal to 50 kg. The study's primary endpoint was time to flare in the treatment period 2 (Week 12 to Week 104). In children and adolescents aged 2 to 18 years old, the study demonstrated that patients with active JPsA (n = 34; mean age: 12.2) treated with Cosentyx had a longer time to flare, showing an 85% reduction in the risk of flare (p<0.001) versus placebo. The study also demonstrated that patients with active ERA (n = 52; mean age: 13.7) treated with Cosentyx had a significantly longer time to flare, showing a 53% reduction in the risk of flare versus placebo. Safety in this pediatric population was consistent with the known safety profile of Cosentyx for the treatment of plaque psoriasis, PsA, non-radiographic axial spondyloarthritis and ankylosing spondylitis (Novartis, 2021a, 2021b).

Plaque Psoriasis (PsO) and Psoriatic Arthritis (PsA)

The FDA has approved Cosentyx injection for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy (Novartis, 2015). Secukinumab (previously known as AIN457) is a human monoclonal antibody (mAb) that selectively binds to interleukin-17A (IL-17A) and inhibits its interaction with the IL-17 receptor. 

The Phase III clinical program included four placebo-controlled studies which examined secukinumab 300 mg and 150 mg in patients with moderate-to-severe plaque psoriasis (Novartis, 2015):

• Erasure - (Efficacy of response and safety of two fixed secukinumab regimens in psoriasis) was a randomized, double-blind, placebo-controlled, multicenter, parallel-group Phase III study involving 738 patients with moderate-to-severe plaque psoriasis.
• Fixture - (the full year investigative examination of secukinumab vs. etanercept using 2 dosing regimens to determine efficacy in psoriasis) was a randomized, double-blind, placebo and active controlled, multicenter, parallel-group Phase III study involving 1306 patients with moderate-to-severe plaque psoriasis.
• Feature - (First study of secukinumab in prefilled syringes in subjects with chronic plaqUe-type psoriasis response) was a randomized double-blind, placebo-controlled, multicenter, Phase III study involving 177 subjects with moderate-to-severe plaque psoriasis. In this study, prefilled syringes (PFS) were introduced into the Cosentyx clinical program.
• Juncture - (Judging the efficacy of secukinumab in patients with psoriasis using autoinjector: a clinical trial evaluating treatment results) was a double-blind, placebo-controlled, multicenter, Phase III study involving 182 subjects with moderate-to-severe plaque psoriasis. In this study, the autoinjector/pen (AI) was introduced into the Cosentyx clinical program.

In these studies, secukinumab met its primary endpoint and key secondary endpoints, including Psoriasis Area and Severity Index (PASI) 75 and 90 and Investigator's Global Assessment modified 2011 (IGA) 0/1 responses, showing significant skin clearance at Week 12 (Novartis, 2015). 

In placebo-controlled clinical trials, higher rates of common infections such as nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%) and mucocutaneous infections with candida (1.2% versus 0.3%) were observed with secukinumab compared with placebo (Novartis, 2015).  The incidence of some types of infections appeared to be dose-dependent in clinical studies. The labeling of Cosentyx recommends exercising caution when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should be discontinued until the infection resolves. 

The label recommends caution when prescribing secukinumab to patients with active Crohn's disease, as exacerbations of Crohn's disease, in some cases serious, were observed in secukinumab-treated patients during clinical trials (Novartis, 2015). The label recommends close monitoring of patients with active Crohn’s disease who are treated with secukinumab. 

Anaphylaxis and cases of urticaria occurred in secukinumab-treated patients in the clinical trials (Novartis, 2015).  The labeling recommends immediate discontinuation of secukinumab and initiation of appropriate therapy if an anaphylactic or other serious allergic reaction occurs. 

The label states that patients treated with secukinumab should not receive live vaccines (Novartis, 2015). Non-live vaccinations received during a course of secukinumab may not elicit an immune response sufficient to prevent disease. The labeling recommends completion of all age-appropriate immunizations prior to initiating therapy with secukinumab.

In a phase 3, double-blind, placebo-controlled study (McInnes, et al., 2015) undertaken at 76 centers in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42-13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25-13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14-4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. The investigators concluded that subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder.

McInnes, et al. (2014) evaluated the efficacy and safety of secukinumab in patients with psoriatic arthritis (PsA). Investigators randomly assigned (2:1) 42 patients with active PsA fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). ACR20 responses at week 6, the primary endpoint, were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. The investigators concluded that, although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. The investigators stated that secukinumab exhibited satisfactory safety.

Hidradenitis Suppurativa

1. the use of hospital-based study population, and
2. the lack of post-treatment assessment.

Thorlacius and colleagues (2018) stated that an inappropriate immunologic response to an unknown antigen has been suggested to play a role in the pathogenesis of HS.  Studies have identified elevated levels of several pro-inflammatory cytokines, including IL-17A and TNF-α, nominating these as possible therapeutic targets.  Secukinumab is an Il-17A monoclonal antibody, which binds to Il-17A and inhibits the cytokine interaction with the Il-17 receptors, inhibiting the inflammatory cascade.  These researchers reported on a case of a 47-year old man, with Hurley Stage III lesions at the neck, axillae, breasts, genital skin and buttocks, who had experienced only temporary benefit from different medical treatments over the years.  After 12 weeks of treatment with secukinumab the number of lesions reported by the patient within the period of the last 4 weeks was reduced from 23 to 7, pain visual analog scale (VAS) was reduced from 5 to 3 and pain/utility/handicap VAS was reduced from 7 to 4.  The authors concluded that these findings may be taken to imply that IL-17 blockade could provide a possible therapeutic approach in HS.

In October 2023, the FDA approved Cosentyx as a treatment option for adults with moderate to severe hidradenitis suppurativa (HS). FDA approval was based on two randomized, double-blind, placebo-controlled 52-week Phase 3 trials (SUNSHINE [NCT03713619] and SUNRISE [NCT03713632]) which found that a higher proportion of patients given subcutaneous injection of Cosentyx 300 mg either every two weeks or every four weeks achieved a Hidradenitis Suppurativa Clinical Response (HiSCR50) compared to placebo.

The SUNSHINE and SUNRISE trials, with combined enrollment of 1084 adult patients, assessed the efficacy and safety of secukinumab in the treatment of moderate to severe HS. The SUNSHINE trial evaluated 541 subjects and SUNRISE trial evaluated 543 subjects, of whom 13% and 11%, respectively, received concomitant stable dose of systemic antibiotics. In the trials, 24% and 23% of patients, respectively, were previously treated with a biologic (biologic-exposed patients) and discontinued the biologic agent for either lack of efficacy or intolerance. In both trials, patients were randomized to placebo or secukinumab 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3 and 4, followed by 300 mg every 2 weeks or every 4 weeks. At Week 16, patients who were randomized to placebo were reassigned to receive secukinumab 300 mg at Weeks 16, 17, 18, 19, and 20 followed by either secukinumab 300 mg every 2 weeks (Q2W) or every 4 weeks (Q4W). The primary endpoint in both trials was the proportion of patients who achieved a Hidradenitis Suppurativa Clinical Response (HiSCR50), defined as at least a 50% decrease in abscesses and inflammatory nodules (AN) count with no increase in the number of abscesses and/or in the number of draining fistulae relative to baseline, at Week 16. Trial outcomes found a greater proportion of patients randomized to secukinumab 300 mg dosed every four weeks (after standard weekly loading doses) achieved HiSCR50 compared with placebo in both SUNSHINE (41.3% vs 29.4%) and SUNRISE (42.5% vs 26.1% [p<0.05]) trials.  In both trials, the onset of action of secukinumab occurred as early as Week 2 and the efficacy progressively increased up to Week 16. 

Tuberculosis Screening

Per the Centers for Disease Control and Prevention (CDC), the tuberculin (TB) skin test (also called the Mantoux tuberculin skin test [TST]) and the TB blood test (also called interferon-gamma release assays or IGRAs) can be used to test for M. tuberculosis infection. Additional tests are required to confirm TB disease. "A posterior-anterior chest radiograph is used to detect chest abnormalities. Lesions may appear anywhere in the lungs and may differ in size, shape, density, and cavitation. These abnormalities may suggest TB, but cannot be used to definitively diagnose TB. However, a chest radiograph may be used to rule out the possibility of pulmonary TB in a person who has had a positive reaction to a TST or TB blood test and no symptoms of disease.

Other Indications

There are clinical trials regarding the use of secukinumab for the treatment of various diseases/conditions including alopecia areata, Alzheimer disease, atopic dermatitis, diabetes mellitus type-I, dry eye, hidradenitis suppurativa, ichthyoses, non-infectious uveitis, palmoplantar psoriasis, papulopustular rosacea, and rheumatoid arthritis.

Alopecia Areata

Ramot and associates (2018) noted that IL-17 has been implicated in the pathogenesis of a large number of inflammatory and autoimmune conditions, including skin disorders such as psoriasis. Recently, much data has accumulated on the possible role of IL-17 in the pathogenesis of alopecia areata (AA). In this review, the available information on the connection between AA and IL-17 is described. While IL-17 levels are consistently reported to be elevated in the serum and lesional skin of AA patients, there is no clear connection between IL-17 levels and disease severity or duration. Some evidence has suggested an association between IL-17 and an early-onset disease, although this awaits further confirmation. While there is enough information to support clinical trials with IL-17-targeted treatments, it is possible that they will be effective only in a subset of AA patients. Further studies are warranted to better delineate the exact role of IL-17 in AA pathogenesis.

Guttman-Yassky and colleagues (2018) stated that AA is a common form of non-scarring hair loss.  The pathogenesis of AA is believed to involve multiple inflammatory cytokines, including possibly IL-17A.  In a prospective, randomized, double-blinded pilot study, these researchers evaluated the safety and efficacy of the IL-17A antagonist secukinumab in AA.  A total of 11 subjects were treated with either secukinumab (n = 7) or placebo (n = 4) subcutaneously at weeks 0, 1, 2, 3, 4 and every 4 weeks thereafter until (inclusive of) week 20.  The primary end-point for the study was the percentage of patients achieving SALT50 at 24 weeks; 3 subjects out of 11 completed the study through the primary end-point, and thus, these investigators used the last observation carried forward method to analyze the missing data.  At the primary end-point or last completed observation, 0 % (0/7) of the secukinumab-treated subjects achieved a 50 % reduction in SALT score (SALT50), and likewise, 0 % (0/4) of the placebo-treated subjects achieved SALT50.  In the secukinumab group, 1 (14.3 %) subject had some hair regrowth, 1 (14.3 %) subject had worsening hair loss, and 5 (71.4 %) subjects had no change in response to treatment.  No adverse events (AEs) attributable to the study drug were observed.  The authors concluded that the lack of a therapeutic response to most of the treated patients suggested that the TH17/IL-17 axis likely has no pathogenic role in AA and an alternative therapeutic approach should be considered for this disease.  However, due to the low statistical power of this study, future studies may be needed to corroborate these findings.

Behcet's Disease-Related Uveitis

Sota and colleagues (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 anti-tumor necrosis factor-alpha (TNF-α) 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 tools in the refractory ocular manifestations of BD.

Erythrodermic Psoriasis

Weng and co-workers (2018) presented a case series on the use of secukinumab for the treatment of erythrodermic psoriasis (EP).  However, an UpToDate review on “Erythrodermic psoriasis in adults” (Hawkes and Duffin, 2018) states that “Small studies and case reports provide preliminary support for the use of newer biologic medications for the treatment of erythrodermic psoriasis, including ustekinumab, ixekizumab, secukinumab, and golimumab.  While these novel therapies represent a group of medications likely to be effective in the treatment of erythrodermic psoriasis, subsequent larger studies are necessary prior to a recommendation for the routine use of these therapies”.

Damiani and colleagues (2019) stated that EP is a dermatological emergency and its treatment with secukinumab is still controversial.  Furthermore, no data exist regarding the prognostic value of drug abuse in such a condition.  These researchers carried out a retrospective, multi-center, international, pilot study, enrolling a sample of EP patients (body surface area [BSA] > 90 %) who were treated with secukinumab (300 mg) during the study period from December 2015 to December 2018.  Demographics and clinical data were collected.  Drug abuses were screened and, specifically, smoking status (packages/year), cannabis use (application/week) and alcoholism-tested with the Alcohol Use Disorders Identification Test (AUDIT)-were assessed.  All patients were followed for up to 52 weeks.  These investigators enrolled 13 EP patients, 9 men, and 4 women, with a median age of 40 (28 to 52) years.  Patients naïve to biologic therapy were 3/13.  Regarding drug use, 7 patients had a medium-high risk of alcohol addiction, 3 used cannabis weekly, and 7 were smokers with a pack/year index of 295 (190 to 365).  The response rate to secukinumab was 10/13 patients with a median time to clearance of 3 weeks (1.5 to 3). No recurrences were registered in the 52-week follow-up and a PASI score of 90 was achieved.  The entire cohort of non-responders (n = 3) consumed at least 2 drugs of abuse (alcohol, smoking or cannabis).  Non-responders were switched to ustekinumab and obtained a PASI 100 in 24 weeks.  The authors concluded that although not conclusive, these preliminary findings in EP patients treated with secukinumab enlightened 2 presently unmet needs: the need of therapy-specific biomarkers/prognostic factors and the prevalence of drug use in EP.  These researchers stated that secukinumab may be a safe and effective treatment in EP, however, larger studies are needed to validate these findings.

Granuloma Annulare and Related Cutaneous, Granulomatous Conditions

Chen and associates (2019) stated that granuloma annulare (GA), a benign inflammatory skin disease, is considered a Th1-type delayed hypersensitivity reaction.  Localized GA is likely to resolve spontaneously, whereas disseminated GA (DGA) may persist for decades and can be resistant to treatment.  Biologics including TNF-α inhibitors have been proposed and utilized as salvage therapy for GA and other related diseases, actinic granuloma (AG), and interstitial granulomatous dermatitis (IGD).  These investigators carried out a systematic review using the combination of search terms "granuloma annulare", "interstitial granulomatous dermatitis", or "actinic granuloma" and either "biologics", "etanercept", "adalimumab", "infliximab", "ustekinumab", "ixekizumab", "secukinumab", "guselkumab", "golimumab", "brodalumab", "tildrakizumab" or "certolizumab" from 1970 to 2017.  Review of the literature revealed that 79.3 % of the patients with GA, IGD, or AG who had been treated with TNF-α inhibitor therapy showed a clinical response.  The authors concluded that TNF-α inhibitor therapy has been used to treat chronic GA, IGD, and AG that involved extensive BSA.  However, the literature is limited to case series lacking control groups.  These researchers stated that RCTs are needed to establish evidence-based treatment of GA and related cutaneous, granulomatous conditions.

Granulomatous Interstitial Nephritis

Sandys and associates (2018) stated that TNF-α inhibitors are frequently used for the treatment of immune-mediated diseases.  Conversely, cytokine therapy has the potential to paradoxically induce autoimmunity.  A number of case-reports have emerged concerning sarcoid-like granulomatosis secondary to TNF-α therapy, an adverse effect that typically affects the pulmonary and cutaneous systems.  Granulomatous interstitial nephritis (GIN) is a relatively unknown, relatively under-reported consequence of adalimumab therapy that can have important clinical implications.  The authors concluded that this was the 1st case-report of GIN secondary to anti-TNF-α therapy necessitating a prolonged period of dialysis and the 1st report demonstrating the successful use of secukinumab as an alternative immunomodulatory agent.

Hepato-Cellular Carcinoma

Xu and co-workers (2018) previously demonstrated that IL-17A is associated with the progression of hepato-cellular carcinoma (HCC).  However, its role in the invasion-metastasis cascade of HCC and the efficacy of IL-17A-targeting therapeutics in HCC remain largely unknown.  In this study, these researchers found that IL-17A promoted intra-hepatic and pulmonary metastases of HCC cells in an orthotopic implant model.  Moreover, the results showed that IL-17A induced epithelial-mesenchymal transition (EMT) and promoted HCC cell colonization in-vitro and in-vivo, and the role of IL-17A in invasion-metastasis was dependent on activation of the AKT pathway.  Remarkably, combined therapy using both secukinumab and sorafenib exhibited better inhibition on tumor growth and metastasis compared to sorafenib monotherapy.  Additionally, the combination of intra-tumoral IL-17A+ cells and E-cadherin predicted the outcome of patients with HCC at an early stage after hepatectomy based on tissue microarray and immunohistochemistry.  The authors concluded that these findings revealed that IL-17A induced early EMT and promoted late colonization of HCC metastasis by activating AKT signaling.  They stated that secukinumab is a promising candidate for clinical development in combination with sorafenib for the management of HCC.

Palmoplantar Psoriasis

In a double-blinded, randomized controlled trial (RCT), Gottlieb and colleagues (2017) evaluated the safety and effectiveness of secukinumab in patients with palmoplantar psoriasis.  A total of 205 participants were randomized in a 1:1:1 manner to secukinumab 300-mg, 150-mg, or placebo.  The primary end-point was Palmoplantar Investigator's Global Assessment (ppIGA) 0 (clear) or 1 (almost clear/minimal) response at week 16.  At week 16, the percentage of subjects who achieved clear or almost clear palms and soles (or ppIGA 0/1) with secukinumab 300-mg (33.3 %) and 150-mg (22.1 %) was superior to the percentage achieved with placebo (1.5 %, p < 0.001); ppPsoriasis Area Severity Index (ppPASI) was significantly reduced with secukinumab 300-mg (-54.5 %) and 150-mg (-35.3 %) compared with placebo (-4.0 %, p < 0.001).  Dermatology Life Quality Index (DLQI) 0/1 responses from subjects in the secukinumab groups were also significantly higher compared with placebo at week 16 (p < 0.01) and pain and function of palms and soles was markedly improved with secukinumab as measured by the palmoplantar Quality-of-Life Instrument.  Secukinumab 300-mg consistently showed the best outcomes.  The safety profile was favorable and similar to previous studies.  The authors concluded that in GESTURE, the largest RCT in palmoplantar psoriasis, secukinumab demonstrated the greatest efficacy to-date for treating difficult-to-treat psoriasis.  Moreover, these investigators stated that the findings of this study reinforced the difficult-to-treat nature of palmoplantar psoriasis compared with psoriasis on other locations of the body where higher rates of efficacy are more readily achieved.  Furthermore, it highlighted the need for more research given the paucity of RCTs dedicated to palmoplantar psoriasis to-date.  The main drawback of this study was the lack of active comparator. 

Parkinson's Disease

Sommer and associates (2018) noted that Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of mid-brain neurons (MBNs).  Recent evidence suggested contribution of the adaptive immune system in PD.  These investigators showed a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD.  Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in post-mortem PD brain tissues.  These researchers modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls.  After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by up-regulation of IL-17 receptor (IL-17R) and NFκB activation.  Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death.  The authors concluded that these findings indicated a critical role for IL-17-producing T lymphocytes in sporadic PD.

Pityriasis Rubra Pilaris

Gauci and colleagues (2016) stated that pityriasis rubra pilaris (PRP) is a heterogeneous inflammatory skin disease characterized by follicular papules, orange palmoplantar keratoderma, and erythematous scaly patches with islands of skin sparing.  Type II PRP is a rare, severe, chronic form of PRP presenting atypical features including long disease duration, palmoplantar keratoderma, ichthyosiform scaling, eczematous areas, and resistance to therapy.  These investigators reported on the case of a 33-year old woman with a childhood history of hydronephrosis secondary to vesico-ureteral reflux who had a 9-year history of erythroderma with confluent folliculo-centric erythematous scaly plaques, islands of sparing, orange palmoplantar hyperkeratosis, and eczematous lesions.  Previous unsuccessful treatments, given more than 3 months, included topical corticosteroids, acitretin, photochemotherapy, cyclosporine, methotrexate, infliximab, ustekinumab, intravenous immunoglobulin (IVIG), and omalizumab.  Prednisone was efficient, but the patient experienced relapse with less than 0.5 mg/kg/day.  The condition partially improved using cyclosporine (5 mg/kg/day) in association with 10-mg prednisone.  After informed consent, secukinumab was initiated in association with cyclosporine and 10-mg of prednisone.  The patient received 5 subcutaneous 300-mg weekly injections followed by once-monthly injections.  After 4 weeks, secukinumab allowed a significant and prompt clinical response and quality-of-life (QOL) improvement.  Psoriasis area and severity index and dermatologic life quality index score, respectively, decreased from 27.6 to 5.6 and from 30 to 15 after 4 injections.  Secukinumab was well-tolerated except an oral and esophageal candidiasis (treated with fluconazole for 14 days).  Secukinumab was highly effective on clinical symptoms and QOL, without recurrence of PRP lesions with a 6-month follow-up.  These researchers reported that secukinumab induced pruritus relief after 1 week of treatment and improvement of erythematous plaques and palmoplantar keratoderma after 2 weeks of treatment.  They stated that secukinumab could be considered an alternative therapeutic option for refractory type II PRP; further studies are needed to clarify the pathogenic role of IL-17 axis in PRP.

Pyoderma Gangrenosum

Moreno García and colleagues (2019) presented a case report on the use of secukinumab for the treatment of pyoderma gangrenosum.  However, an UpToDate review on “Pyoderma gangrenosum: Treatment and prognosis” (Schadt, 2018) does not mention secukinumab as a therapeutic option.

Rheumatoid Arthritis

In a phase-III, randomized, double-blind, active comparator- and placebo-controlled clinical trial, Blanco and colleagues (2017) evaluated the safety and effectiveness of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to or intolerance of TNF inhibitors.  A total of 551 patients were randomized (1:1:1:1) to receive intravenous secukinumab at a dose of 10 mg/kg (at baseline and weeks 2 and 4) followed by subcutaneous secukinumab at a dose of either 150-mg or 75-mg every 4 weeks or, alternatively, abatacept or placebo on the same dosing schedule.  The primary end-point was the proportion of patients achieving 20 % improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 24 in the secukinumab 150-mg or 75-mg treatment groups as compared with placebo.  Key secondary end-points included change from baseline to week 24 in the Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) and the Health Assessment Questionnaire disability index (HAQ DI), as well as the ACR 50 % improvement (ACR50) response rate at week 24.  The primary efficacy end-point was met in patients receiving 150 mg secukinumab, in whom the ACR20 response rate at week 24 was significantly higher than that in the placebo group.  The ACR20 response rates at week 24 were 30.7 % in patients receiving 150 mg secukinumab (p = 0.0305), 28.3 % in those receiving 75 mg secukinumab (p = 0.0916), and 42.8 % in those receiving abatacept, compared with 18.1 % in the placebo group.  A significant reduction in the DAS28-CRP was seen in patients treated with 150 mg secukinumab (p = 0.0495), but not in patients treated with 75 mg secukinumab.  Improvements in the HAQ DI and ACR50 response rates were not significant in the 2 secukinumab dose groups compared with the placebo group.  The overall safety profile was similar across all treatment groups.  The authors concluded that secukinumab at a dose of 150-mg resulted in improvement in signs and symptoms and reduced disease activity in patients with active RA who had an inadequate response to TNF inhibitors.  Improvements observed with abatacept were numerically higher than with secukinumab.  There were no new or unexpected safety signals with secukinumab in this study.

An UpToDate review on “Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy” (Cohen and Cannella, 2017) does not mention secukinumab as a therapeutic option.

In a randomized, double-blind, placebo-controlled phase-III clinical trial, Tahir and associates (2017) evaluated the safety and efficacy of secukinumab in patients with active RA who had an inadequate response to, or intolerance of TNF-inhibitors.  A total of 637 patients were randomized (1:1:1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule.  The primary end-point was the ACR20 at week 24.  Other pre-defined hierarchical end-points included HAQ-DI, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year.  The primary efficacy end-point was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2 % for both secukinumab dose groups (p = 0.0009) versus 19.6 % for placebo.  The improvements in secondary end-points were greater in the secukinumab dose groups versus placebo but did not meet statistical significance.  The overall safety profile was similar across all treatment groups.  The authors concluded that this phase-III clinical trial was the only study of IL-17A inhibition on structural progression in RA.  While there may have been a numerical trend for inhibition of structural progression the trial was hampered by high discontinuation rates and a very short placebo period.  In contrast to the good efficacy of IL-17A inhibition seen in psoriasis, psoriatic arthritis and ankylosing spondylitis, secukinumab was of lesser benefit in RA patients for whom TNF-inhibitor therapy has failed.  These investigators stated that given that multiple biologics with good efficacy are already available to these patients, further development of secukinumab for RA patients was not pursued.

In a phase-III, double-blind, double-dummy, placebo-controlled trial, Dokoupilova and colleagues (2018) examined the safety and efficacy of secukinumab in patients with RA who failed to respond to TNF-α inhibitors.  This study randomized (1:1:1) patients to subcutaneous secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks; ACR 20 response at week 24 was the primary end-point.  Secondary outcomes included the 28-joint DAS28-CRP, HAQ-DI, and ACR50 at week 24.  Long-term treatment was planned for 5 years.  ACR20 response rates at week 24 for the secukinumab 150 mg and 75 mg groups were not statistically superior to placebo.  None of the secondary end-points was met for either secukinumab dose.  Although not statistically significant, compared with placebo, numerically greater differences in least squares mean changes from baseline in HAQ-DI score and numerically higher ACR50 response rates were observed at week 24 in both secukinumab treatment groups.  No new or unexpected adverse events (AEs) were observed in this study compared with the large secukinumab safety database across psoriasis, psoriatic arthritis, ankylosing spondylitis, and other RA studies.  The authors concluded that given that other 2nd-line therapies have demonstrated efficacy in RA patients who failed to respond to TNF-α inhibitors, these findings suggested that IL-17A inhibition with secukinumab did not provide additional benefit to these patients.  This study further confirmed the well-characterized safety profile of secukinumab.

SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) Syndrome

Wendling and associates (2017) noted that SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome is a rare entity with skin and rheumatologic inflammatory presentation.  The treatment 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 results 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 DMARDs and biological DMARDs).  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 obvious 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.  These preliminary findings need to be validated by well-designed studies.

Secukinumab Gene Therapy

Fallah and colleagues (2020) noted that TNF-α, checkpoint inhibitors, and IL-17 are critical targets in inflammation and autoimmune diseases.  Monoclonal antibodies (mAbs) have a successful portfolio in the treatment of chronic diseases.  With the current progress in stem cells and gene therapy technologies, there is the promise of replacing costly mAbs production in bioreactors with a more direct and cost-effective production method inside the patient's cells.  These researchers examined the results of an investigational assessment of secukinumab gene therapy.  In this experimental study, the DNA sequence of the heavy and light chains of secukinumab antibodies were cloned in a lentiviral vector.  Human chorionic villous mesenchymal stem cells (CMSCs) were isolated and characterized.  After lentiviral packaging and titration, part of the recombinant viruses was used for transduction of the CMSCs and the other part were applied for systemic gene therapy.  The engineered stem cells and recombinant viruses were applied for ex-vivo and in-vivo gene therapy, respectively, in different groups of rat models.  In-vitro and in-vivo secukinumab expression was confirmed with quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and ELISA by considering the approved secukinumab as the standard reference.  Cell differentiation assays and flow cytometry of standard biomarkers confirmed the multipotency of the CMSCs.  Western blot and qRT-PCR confirmed in-vitro gene expression of secukinumab at both the mRNA and protein level.  ELISA testing of serum from treated rat models confirmed mAb over-expression for both in-vivo and ex-vivo gene therapies.  The authors concluded that in this study, a lentiviral-mediated ex-vivo and in-vivo gene therapy was developed to provide a moderate dose of secukinumab in rat models.  These researchers stated that biosimilar gene therapy is an attractive approach for the treatment of autoimmune disorders, cancers and other chronic diseases.

Vitiligo

Speeckaert and colleagues (2019) noted that multiple reports confirmed elevated circulating IL-17 levels and increased numbers of Th17 lymphocytes in patients with non-segmental vitiligo.  Additionally, melanocyte damaging characteristics have been ascribed to IL-17.  In a single-arm, pilot study, these researchers examined the use of secukinumab in active non-segmental vitiligo.  The large majority of patients developed additional skin de-pigmentations limiting further enrollment.  Overall, laboratory analysis revealed no change in secreted chemokines or Th subsets.  Th17 lymphocytes correlated with Th2, Th9, and Th22 cells while an inverse link with Th1 cells and serum sCD25 levels was observed.  In contrast, Th17.1 cells correlated positively with Th1 lymphocytes.  Confirmatory results were found in an independent group of patients with vitiligo showing a significant increase in Th17.1 and Th1 lymphocytes in progressive vitiligo patients compared to healthy controls, which was not found for Th17 cells.  The authors concluded that these findings did not support a direct pathogenic role of IL-17 or Th17 cells in vitiligo.  Nonetheless, a delicate Th17/Th17.1/Th1 balance appeared evident that changed markedly according to disease activity.  This may offer new therapeutic options by interfering with cytokines that drive differentiation of Th17 cells toward Th1.

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Appendix

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

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

Table: Brands of Targeted Immune Modulators and FDA-approved Indications (not an all-inclusive list)

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Coronavirus Disease 2019 (COVID-19) in hospitalized patients 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
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 Hidradenitis suppurativa 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 (for Humira biosimilars, see CPB 0655 - Adalimumab)	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 Gout flares Periodic fever syndromes  Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Kevzara	sarilumab	Polymyalgia rheumatica Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Deficiency of interleukin-1 receptor antagonist (DIRA) Rheumatoid arthritis
Olumiant	baricitinib	Alopecia areata COVID-19 in hospitalized adults Rheumatoid arthritis
Orencia	abatacept	Acute graft versus host disease Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behçet’s Disease Plaque psoriasis Psoriatic arthritis
Remicade (for Remicade biosimilars, see CPB 0341 - Infliximab)	infliximab	Ankylosing spondylitis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Ankylosing spondylitis or axial spondyloarthritis Atopic dermatitis Crohn's disease Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Rituxan (for Rituxan biosimilars, see CPB 0314 - Rituximab)	rituximab	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis Various subtypes of non-Hodgkin's lymphoma
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Crohn's disease Plaque psoriasis Psoriatic arthritis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis Ulcerative colitis
Taltz	ixekinumab	Ankylosing spondylitis or axial spondyloarthritis Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis Psoriatic arthritis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Ankylosing spondylitis Polyarticular course juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Xeljanz XR	tofacitinib, extended release	Ankylosing spondylitis Polyarticular course juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis

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References