Secukinumab


Article Author:
Shamma Aboobacker


Article Editor:
Ahmad Al Aboud


Editors In Chief:
Sisira Reddy
Joseph Nahas


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Richard Ciresi
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
3/27/2019 12:08:47 AM

Indications

Secukinumab is a novel biologic agent that specifically targets interleukin-17 (IL-17) involved in a pathological process. It is a fully human monoclonal antibody. Recent literature refers to secukinumab as ‘a new kid on the block.’ Many clinical trials have demonstrated its efficacy for management of plaque psoriasis in 2015, psoriatic arthritis and ankylosing spondylitis in 2016. Additionally, the drug has a commendable safety profile.[1]

FDA approved indications:

  1. Moderate to severe psoriasis
  2. Hypertrophic palmoplantar psoriasis
  3. Generalized pustular psoriasis
  4. Psoriatic arthritis
  5. Ankylosing spondylitis

Off-label uses[1][2][3][4]:

  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Familial Mediterranean fever
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Psoriasis – Clinical studies have labeled secukinumab suitable as first-line therapy for moderate to severe cases of active, stable disease, hypertrophic palmoplantar psoriasis and generalized pustular psoriasis in adult patients. In cases of prior failure to systemic therapies, contraindications, or intolerability to systemic agents, the drug is an acceptable choice for the initiation of biologic therapy.

Psoriatic arthritis – For active disease not responding to systemic agents in adult patients, secukinumab is prescribable as first-line therapy.

Ankylosing spondylitis – For active disease not responding to systemic agents or moderate-to-severe disease in adult patients are indications for secukinumab.[1]

Mechanism of Action

Interleukin-17 is a proinflammatory cytokine released by T-helper-17 (Th17) cells. Under the action of interleukin-6 and transforming growth factor-ß, CD4 T cells differentiate into Th17 cells and furthermore induce expression of interleukin-23 receptors (IL-23R) and IL-17. Apart from T-cells, mast cells and neutrophils also secrete IL-17.

Interleukin-17 encompasses a group of cytokines, IL-17A to IL-17F, with IL-17A being the key effector cytokine. Furthermore, IL-17A is described to be 10-30 more potent than IL-17F displaying a greater affinity to the interleukin-17 receptor (IL-17R).

The efferent pathway from binding to IL7R involves secretion of chemokines (CCL20, CXCL1m CXCL8) that augments the inflammatory response while activating the innate immune system. The known effects of IL-17 become amplified by other cytokines such as tumor necrosis factor-a.[5]

Another effect of IL-17 is seemingly contradictory being a stimulator of cancer cell invasion while promoting T-cell mediated tumor rejection. The significance is unknown due to lack of evidence confirming a carcinogenic or protective.[6]

The basic notion behind the use of biologics is to block the disease process at a very early stage, being more specific and reducing the side effects of therapy. Secukinumab specifically targets IL-17A, thereby blocking its binding with IL-17R and expression of cytokines. This blockade normalizes the inflammatory processes and thus combats epidermal hyperproliferation, T-cell infiltration and excessive expression of pathogenic genes.[5]

Administration

Secukinumab comes formulated as lyophilized powder of 150 mg in a vial, prefilled syringe or a sensory ready pen that requires storage at a cool temperature (2-8 °C).[7]

Prior to administration, the pen or prefilled syringe must be kept aside for 20-30 mins until it reaches room temperature. Product reconstitution is with 10 ml sterile distilled water following which gentle stirring is performed to dissolve the powder and kept aside for 10 mins. The solution must be inspected to be free of residual particles or discoloration and must administration must follow promptly.

Administration of secukinumab should be by a specialist physician while performing routine monitoring of the disease. It is given subcutaneously at sites such as upper arm, thigh, abdomen while avoiding sites of previous injection or tender, bruised, inflamed, indurated or lesional skin.

The pharmacokinetic profile of the drug is such that it will attain peak concentrations after 5-6 days and a two-fold increase achieved after monthly dosing that becomes stable after 20 weeks. The average bioavailability is 73% while the distribution is primarily peripheral thereby increasing its specificity. The half-life is 27 days with its elimination being dose and time-dependent.[5]  

FDA approved indications with dosages[8]:

  • Psoriasis – 300 mg subcutaneous injection at weeks 0, 1, 2, 3, 4, and every four weeks thereafter.
  • Psoriatic arthritis – Two regimens may be followed; with or without the loading dose.

With loading dose; 150 mg given subcutaneously at weeks 0, 1, 2, 3, and 4: followed by a dose every four weeks.

Without loading dose; 150 mg via subcutaneous route at intervals of 4 weeks.

In case of no response, up-dosing to 300 mg is an option.

  • Ankylosing spondylitis - Two regimens may be followed; with and without a loading dose.

With loading dose; 150 mg given subcutaneously at weeks 0,1,2,3, and 4: followed by a dose every four weeks.

Without loading dose; 150 mg via subcutaneous route at intervals of 4 weeks.

In case of no response, up-dosing to 300 mg is an option.

Intravenous dosing of 300 mg at 3-week intervals followed by a maintenance dosing of 3 mg/kg every four weeks showed long-term efficacy.

Adverse Effects

Secukinumab has a favorable safety profile; however, the following adverse effects have been reported[1][2][9]:

  • Nasopharyngitis
  • Diarrhea
  • Upper respiratory tract infection
  • Inflammatory bowel disease and Exacerbation of Crohn’s disease
  • Urticaria and Anaphylaxis
  • Headache
  • Pruritus
  • Hypertension
  • Arthralgia and back pain
  • Cough
  • Rhinorrhea
  • Injection site reaction
  • Infections –
  • Pyoderma
  • Candidiasis
  • Malignancies –
  • Nonmelanoma skin cancer (basal cell carcinoma, squamous cell carcinoma)
  • Melanoma
  • Bladder cancer
  • Thyroid cancer
  • Neutropenia

Contraindications

The absolute contraindications for the use of biologics are the presence of active infections, more importantly, latent or active tuberculosis, hepatitis B, C and HIV, and hypersensitivity to secukinumab or latex.

Other contraindications include:

  • PUVA sessions
  • Premalignant conditions
  • Demyelinating disease
  • Optic neuritis
  • Multiple sclerosis
  • Children
  • Pregnancy and lactation
  • Congestive heart failure
  • Fever
  • Jaundice or marked liver enzyme elevations[10]

Pregnancy – As an IgG1 molecule, secukinumab could cross the placenta, but mostly in the third trimester. Studies do not indicate harmful effects of secukinumab concerning pregnancy or fetal development. However, a precautionary measure is to avoid use in pregnancy.

Monitoring

Baseline Monitoring

  • Complete blood count and Hemogram
  • Erythrocyte sedimentation rate or C-reactive protein
  • Liver function test
  • Renal function test and urinalysis
  • Serum electrolytes
  • Anti-nuclear and anti-dsDNA antibodies
  • Screening for hepatitis and HIV infection
  • Chest x-ray
  • Tuberculin skin testing or Quantiferon Gold test
  • Pregnancy test in females of childbearing age

If indicated – Serology for varicella zoster and measles.         

Ongoing Monitoring

Evaluation of response to treatment is measurable by respective assessment scores, i.e., Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) at three months initially and subsequently every six months.

Complete blood count and hemogram repeated at three months and every six months after that     

Liver function test, renal function test, serum electrolytes, and urinalysis evaluations should be at three months and every six months after.[10][11]

Toxicity

The safety profile of secukinumab leaves it highly recommendable. Since secukinumab interferes with the normal immune process, it enhances the risk of infections including staphylococcal and candidal, however mild disease results and not disseminated.

Concerning pregnancy, a few studies have outlined pregnancy occurring while on secukinumab therapy with no congenital anomalies or risk of abortion and thereby strict contraception is not the stated case. However, studies mention potential deleterious effects if taken during the third trimester due to placental transfer, and therefore the drug should be withdrawn or considered contraindicated in pregnancy and lactation.

Another possible toxic effect is the carcinogenic potential, with existing reports of malignancies such as non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma), melanoma, bladder cancer, and thyroid cancer.[1]

Enhancing Healthcare Team Outcomes

The common notion related to biologic therapy is the necessity for lifelong or long-term therapy, the failure of which can lead to incomplete resolution or recurrences. With secukinumab, relapses and recurrences are less frequent and can are preventable with a maintenance regime of fixed interval dosing. In addition, following patient education by an interprofessional team of a nurse, pharmacist, and physician, subsequent doses can be self-administered thereby increasing patient compliance and adherence.[5]

Patient on active secukinumab therapy should avoid live vaccines, and contact with infectious agents due to the markedly depressed immunity that can lead to infection. Furthermore, the administration of non-live vaccines is also discouraged due to the unlikelihood of mounting a desired immune response.[10]   

In the likelihood of a history of latent or active tuberculosis with no confirmation of complete therapy or recent travel to a country with a high prevalence of tuberculosis may warrant a course of empiric anti-tubercular therapy.


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Secukinumab - Questions

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Which of the following cytokines is targeted by secukinumab?



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Which of the following regarding secukinumab is false?



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What is the adult dose of secukinumab for psoriasis?



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A 40-year-old man undergoing dialysis developed bullous eruptions with 12.5 mg of methotrexate for moderate-to-severe psoriasis. Which of the following treatments is the most suitable treatment for this patient?



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Which of the followings is not an approved FDA indication for secukinumab?



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Secukinumab - References

References

Koenders MI,van den Berg WB, Secukinumab for rheumatology: development and its potential place in therapy. Drug design, development and therapy. 2016     [PubMed]
Armstrong AW,Papp K,Kircik L, Secukinumab: Review of Clinical Evidence from the Pivotal Studies ERASURE, FIXTURE, and CLEAR. The Journal of clinical and aesthetic dermatology. 2016 Jun     [PubMed]
Baker KF,Isaacs JD, Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Annals of the rheumatic diseases. 2018 Feb     [PubMed]
Patel DD,Lee DM,Kolbinger F,Antoni C, Effect of IL-17A blockade with secukinumab in autoimmune diseases. Annals of the rheumatic diseases. 2013 Apr     [PubMed]
Frieder J,Kivelevitch D,Menter A, Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Therapeutic advances in chronic disease. 2018 Jan     [PubMed]
Kryczek I,Wu K,Zhao E,Wei S,Vatan L,Szeliga W,Huang E,Greenson J,Chang A,Roliński J,Radwan P,Fang J,Wang G,Zou W, IL-17 regulatory T cells in the microenvironments of chronic inflammation and cancer. Journal of immunology (Baltimore, Md. : 1950). 2011 Apr 1     [PubMed]
Garnock-Jones KP, Secukinumab: a review in moderate to severe plaque psoriasis. American journal of clinical dermatology. 2015 Aug     [PubMed]
Ordenes-Cavieres G,Andino-Navarrete R, Secukinumab for plaque psoriasis. Medwave. 2018 Nov 30     [PubMed]
Armstrong AW,Vender R,Kircik L, Secukinumab in the Treatment of Palmoplantar, Nail, Scalp, and Pustular Psoriasis. The Journal of clinical and aesthetic dermatology. 2016 Jun     [PubMed]
Smith CH,Jabbar-Lopez ZK,Yiu ZZ,Bale T,Burden AD,Coates LC,Cruickshank M,Hadoke T,MacMahon E,Murphy R,Nelson-Piercy C,Owen CM,Parslew R,Peleva E,Pottinger E,Samarasekera EJ,Stoddart J,Strudwicke C,Venning VA,Warren RB,Exton LS,Mohd Mustapa MF, British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017. The British journal of dermatology. 2017 Sep     [PubMed]
Smith BJ,Nuccio BC,Graves KY,McMillan VM, Preparing patients for biologic medications for dermatologic and rheumatic diseases. JAAPA : official journal of the American Academy of Physician Assistants. 2018 Jun     [PubMed]

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