Review of Monoclonal Antibodies for the Treatment of Crohn’s Disease

AU-DOUNG, Phillip Lung Wai*; CHAN, Jason Chi Hin*; CHENG, Andrew Foon Yu*; LAU, Anna Pak Yan*; LEE, Dawn Kei Yan*; WU, Jason Tsun Singa*; SUN, Wai Yan Kiwi*#



Drugs & Therapeutics
HKPharm J Volume 30 (2), May-Aug-2023 (2023-12-21): P.43-52

ABSTRACT

Over the past 20 years, a rising prevalence of Crohn’s disease (CD) has been observed in Asian countries including Hong Kong. Apart from anti-TNF agents adalimumab and infliximab, some newer agents such as vedolizumab for anti-α4β7 integrin receptors, and ustekinumab for anti- interleukin (IL)-12 and anti-IL-23 are also available in Hong Kong. This review aims to summarize the four monoclonal antibodies (mABs): adalimumab, infliximab, ustekinumab and vedolizumab, in terms of indications, mechanisms of action, pharmacokinetics, dosing regimen, efficacy and adverse effects. The key clinical features of the mABs in treating CD are also discussed.

INTRODUCTION

Crohn’s disease (CD) is a type of inflammatory bowel disease (IBD) that was diagnosed by Dr. Burrill B. Crohn and team in 1932.(1) CD is characterized by chronic inflammation that can occur in any part of the mucosal area of the gastrointestinal tract. The presenting symptoms include diarrhea, abdominal pain, weight loss and fever.(2) The median onset time of CD is between the age of 20 and 30 years old, and with a peak at around 50 years old.(3)  The prevalence of CD is around 50 to 200 cases per 100,000 people globally.(4) In Hong Kong, the most recent registry showed that the local prevalence of CD is 18.6 cases per 100,000 people.(5)

 

The pathogenesis of CD involves a complicated mechanism between the innate and adaptive immune system. Gut microbiota is also described to have a role.(6) Conventional treatments include 5-aminosalicylates (5-ASA), corticosteroids, azathioprine or methotrexate that aim to delay the progression of CD.(7) Despite a lifelong therapy, the progression or relapse of CD still occur in most patients.  A meta-analysis showed the relapse rate in 1 year and 2 years was 38% and 52% respectively in patients who received anti-tumour necrosis factor (TNF) after CD remission.(8) The development of mABs aims to provide an alternative treatment option to overcome the high relapse rate.(9) Thus, it is important for healthcare professionals to acquire the knowledge of pharmacological treatment options for CD.

 

 

PATHOPHYSIOLOGY

CD is characterized by tissue inflammation that is triggered by the dysregulation of the innate and adaptive immune systems.(10) In the inflammation stage, more IL-34 is released in patients with CD via extracellular signal-regulated kinase (ERK)-mediated mechanism, therefore it increases TNF-α and IL-6 production.(11) In addition, CD4+ T cells are increased and lead to the production of type 1 T helper (TH1) and type 17 T helper (TH17) cells-associated proinflammatory cytokines, such as interferon (IFN)-γ, IL-12, IL-23 and TNF-α.(12, 13) For instance, IL-12 induces TH1 cell activity to further enhance the production of IFN-γ.(14) Excessive TH1 immune response is known to cause intestinal inflammation in CD. Furthermore, CD patients also have a high amount of IL-2 which binds to CD4+ T cells and activate the differentiation of plasma cells in the mucosa.(10) As a result, it triggers the activity of cytotoxic mediators on the intestinal mucosa and damages the epithelial cells.(15)

Good balance of gut microbiota in the intestinal tract can be key to control the inflammatory response.(10) A cohort study found that a higher percentage of dysbiosis occurs in patients with CD when compared to healthy individuals.(16)  It usually accompanied by excessive growth of Enterobacteriaceae (i.e. Salmonella, Shigella and Escherichia coli) that activates the inflammatory response in guts.(17)

Moreover, smoking is a risk factor of CD induction or deterioration as cigarettes affect colon mucus production and delay mucosal repairment in the guts.(18, 19)  Smoking also changes the autophagy-related gene ATG16L1 expression resulting in dysfunction of recognition, handling and clearance of invading pathogens.(20) Another risk factor is chronic use of high dose NSAIDs that inhibit COX1 and COX2 enzymes resulting in a high risk of intestinal ulcer.(21, 22) Genetic mutation is shown to contribute to the pathogenesis of CD. Nucleotide-binding oligomerization domain 2 (NOD2) mutation is found in one-third of the patients with CD, which the inhibitory effect on Toll-like receptor 2 (TLR2) is lost and causes the activation of inflammatory pathways via excessive TH1 responses.(23)

 

USE OF MONOCLONAL ANTIBODIES(mABs) IN CD

Corticosteroids, 5-ASA, azathioprine and methotrexate are the conventional treatments for CD. However, some patients are either not responding or intolerant to them.(24) With the advancement in the drug discovery, biologics (mABs) have been shown to be effective. (9) They are classified into anti-TNF agents (infliximab, adalimumab) and other selective agents such as anti-integrin (vedolizumab) and anti-IL agent (ustekinumab) (Table 1 and Table 2). As per the American Gastroenterological Association (AGA) 2021 guideline, these mABs are indicated for patients with moderate to severe CD.(25) In terms of safety, patients are required to screen for latent tuberculosis (TB) and hepatitis B virus before using mABs. Live vaccinations are generally not recommended in all mABs except vedolizumab, to prevent overacting immune response, patients should discuss with physicians the risk versus benefit of the live vaccination. Although mABs are effective in CD management, they are costly.(26) In Hong Kong, they are under the safety net at the Hospital Authority Drug formulary (Table 1).

The goal of CD therapy is divided into two aspects: inducing remission and preventing a relapse of CD.(27) Compared to the conventional regimens, there is no concrete consensus on the selection of first-line mABs. This is likely due to the limited head-to-head trials to compare the efficacy and safety between mABs.(9) Clinically, anti-TNF agents are considered as the first-line mABs treatment because of more evidence.(9) However, approximately two-third of patients experienced a recurrence of CD within 1 year post anti-TNF treatment.(28) Also, these patients tended not to have a good response to another anti-TNF agent after failing with one anti-TNF.(29)  AGA 2021 guideline emphasizes that selection of mABs should be based on patient’s conditions, such as history of failure to anti-TNF agents, allergic reaction any mABs, and screening results of    latent TB and hepatitis B virus.(25)   

 

 

INFLIXIMAB (Remicade®)

Approved Indication

Infliximab (Remicade®) is registered in Hong Kong since 2006 and is classified as P1S1S3 poison.(30) It is indicated for adult and pediatric patients with moderate to severe active CD.(31) 

 

Mechanism of Action

TNF-α is a key proinflammatory cytokine leading to CD. Overexpression of TNF-α amplifies the inflammatory process and causes the induction and perpetuation of intestinal inflammation.(32) Infliximab is a genetically engineered immunoglobulin 1 (IgG1) murine–human chimeric monoclonal antibody by binding to transmembrane and soluble forms of the protein and preventing the interaction between TNF-α and its receptor.(33) Other than the blockade of TNF, infliximab can inhibit the production of IL-1 and IL-6, which reduces leukocyte migration and adhesion molecule expression by the endothelial cells to help suppress inflammation.(34) The levels of soluble CD40L was elevated in plasma and surface CD40L was increased in platelets and T cells of CD patients. Infliximab also regulates the CD40L signaling pathway that contributes to the systemic anti-TNF-α action.(35)

Other than the known mechanisms of action of infliximab in humans, a recent study suggested that the efficacy of infliximab is correlated to the expression of Annexin A1 (AnxA1) on formyl peptide receptors (FRRs) by using dextran sulfate sodium colitis model in mice.(36) AnxA1 is a mediator produced by epithelial cells and mobilized to the membrane after the cell activation to trigger anti-inflammatory pathways of FRRs, which is a possible mechanism of infliximab.(36)

 

Evidence from Clinical Trials

A recent trial that recruited luminal CD patients with Asia background to show an increase of 60% remission rate by infliximab. The remission rate further increased to more than 90% in week 54 of infliximab.(37) Other than luminal CD patients, there was a prominent effect on the fistulizing CD patients as the remission rate reached 56.2%. Furthermore, the remission rate increased to 97.1% by week 54.(37) Only 6% of patients had serious adverse effects, such as severe infusion reactions (7 cases), serum sickness (2 cases), intra-abdominal abscess (2 cases), and active tuberculosis (2 cases).(37)

In pediatric CD patients,  a study conducted in Japan found that infliximab is effective in refractory cases when compared to cyclosporin and tacrolimus.(38) Upon remission, 54.7% and 69.6% of the pediatric CD patients can reduce or discontinue the dose of steroids, respectively.(38)

 

Dosing Regimen

The recommended dose is 5 mg/kg through intravenous (IV) injection at 0, 2, and 6 weeks and then started the maintenance dose at 5 mg/kg every 8 weeks for adult or pediatric patients with moderate or severe active CD or fistulizing CD.(31)

If adult patients showed partial response, infliximab can be increased to 10 mg/kg. However, if no response is observed by week 14, it should be discontinued and other treatment options should be considered.(31)

 

Adverse Drug Effects (ADRs)

Common ADRs include fever, shortness of breath, coughing and rash which may occur during the treatment in adult and pediatric patients.(31) It is more likely to increase the risk of infection, such as cytomegalovirus infection, re-activation of latent TB in adult patients.(37, 38)

 

Management of ADRs

Infusion related reactions (IRRs) to infliximab are common and acute that usually occur within 15 to 30 mins post-infusion.  The symptoms of IRRs include pruritus, urticaria, fever and bronchospasms.(39) There are four different types of IRRs: complement activation-related pseudo-allergy (CARPA), cytokine release syndrome, anaphylactoid reaction and immunoglobulin E-mediated anaphylaxis.(39)  CARPA and cytokine release syndrome are well described as IRRs, but the latter two syndromes are often considered as allergic reactions.(39) Physicians can prescribe prophylactic medications, such as prednisolone, hydrocortisone and antihistamine, to prevent the IRRs.(39)  However, if patient’s IRR symptoms exist despite the use of prophylactic medications, changing the regimen is needed, such as dosage adjustment and change of another class of drug.(40)

 

ADALIMUMAB (Humira®)

Approved Indication

Adalimumab (Humira®) is registered in Hong Kong since 2017 and is classified as P1S1S3 poison.(30)  It is available in single pen and prefilled syringe form for injection, and is indicated for moderate to severe active CD in adults and pediatric patients 6 years of age or above.(41)

 

Mechanism of Action

Adalimumab is a fully humanized IgG1 monoclonal antibody, which reduces the overexpression of TNF-α by blocking its receptors. Therefore, the associated proinflammatory signals is attenuated.(42) The Fc region of adalimumab can trigger M2-type wound-healing macrophages which may help to promote mucosal healing.(33) In addition, it induces antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). ADCC refers to the binding of Fc receptor to the target cells to trigger the killing action of the natural killer cells.(43) CDC refers to the antibodies binding to the target cells to activate the complement pathway for the killing action.(43)

 

Evidence from Clinical Trial

In the CHARM trial, around 40% of CD patients treated with adalimumab had remission in week 26. A similar percentage of remission remained in week 56, suggesting a good maintenance rate by adalimumab.(28) Also, patients treated with adalimumab had 64% reduction of hospitalization over a 12-month follow-up period.(44)  Patients who achieved steroid-free clinical remission increased from 22.3% to 50.0% over a prolonged period of 96 week.(45) Indeed, AGA (2021) guideline recommended that adalimumab can be administered with or without an immunomodulator for patients who have no response to the conventional pharmacological treatment.(25) Adalimumab is also effective for prophylactic therapy in patients with CD following surgical resection to prevent clinical recurrence. (46, 47)

 

Dosing Regimen

For adult patients, adalimumab 160mg is given subcutaneously (SC) on day 1 or split over 2 consecutive days, followed by 80mg SC on day 15 and then 40mg SC once every other week from day 29.(48)  

For pediatric patients ≥ 6 years old or less than 40kg, adalimumab 80mg SC is given on day 1, followed by 40mg SC on day 15 and then 20mg SC once every other week from day 29.(48)

For pediatric patients ≥ 6 years old and greater than 40kg, adult dosage of adalimumab is used.(48)

 

ADRs

The most frequent adverse effects are injection site reactions and dermatologic rashes. Other common side effects include headache, sinusitis and upper respiratory infection.(41) Adalimumab can increase the risk of infection, such as TB, invasive fungal infection leading to hospitalization as mentioned in the black box warning.(41) If occurs, immediate discontinuation of adalimumab is needed.(41) Case reports of lymphoma and malignancies in children and teenagers during the treatment of adalimumab are described.(49)

 

VEDOLIZUMAB (Entyvio®)

Approved Indication 

Vedolizumab (Entyvio®) is registered in Hong Kong since 2015 and is classified as P1S1S3 poison.(30) It is available in solution for infusion and is indicated for patients with active status of moderate to severe CD who are intolerant or have insufficient response to TNF-α blocker, or demonstrated dependence on corticosteroids.(50)

 

Mechanism of Action

Vedolizumab is a humanized α4β7 integrin monoclonal antibody.(50) It binds to the α4β7 integrin receptor to interfere the interaction with mucosal addressin cell adhesion molecules-1 (MAdCAM-1), resulting in alleviation of chronically inflamed gastrointestinal parenchymal tissue associated with CD. (51) Also, Vedolizumab prevents further inflammatory reaction by inhibiting the movement of memory T-lymphocytes across the endothelium into inflammatory gastrointestinal tissue.(51)

Evidence from Clinical Trials

The efficacy and safety of using vedolizumab in moderate-to-severely active CD were conducted in the GEMINI 2 phase 3 clinical trial.(52) The post-hoc analysis aimed to access the induction and maintenance phase of Asian and non-Asian patients who were treated with vedolizumab. The disposition of the Asian subgroup was separated into Cohort 1 included 51 patients, 34 were randomized to vedolizumab and 17 to placebo in the induction phase. Cohort 2 included 24 patients who were treated with vedolizumab on open-label. During the induction phase, approximately 15% of the patients in the vedolizumab group achieved remission compared to 0% in the placebo group at week 6.(52) The clinical remission and response rates were higher in vedolizumab compared to placebo. During the maintenance phase, patients with clinical response to vedolizumab during the induction phase were subsequently treated with vedolizumab every 8 weeks, every 4 weeks, or placebo for up to 52 weeks.(52) The clinical remission rate were 41.7%, 36.4% and 0% respectively; while enhanced clinical response rates indicated 41.7%, 63.6% and 42.9% respectively.(52) However, the limitation of the study is relatively small sample size in subgroup analysis.

Vedolizumab is effective in patients with history of failure with anti-TNF as the therapeutic benefits of vedolizumab were detectable in week 10.(53) GEMINI 2 trial showed that patients after receiving vedolizumab every 8 weeks, 83% [n=100/120] and 89% [n=62/70] of patients were in remission after 104 and 152 weeks, regardless of prior anti-TNF exposure.(52)

 

Dosing Regimen

For adults, the induction dose of vedolizumab is 300mg IV infusion over 30 minutes at 0, 2, and 6 weeks, and for maintenance, the same dose is administered once every 8 weeks thereafter.(50) Discontinuation of  vedolizumab is generally required in patients who show no therapeutic benefit by week 14.(50)

For pediatric patients, the safety and effectiveness of vedolizumab have not been analyzed.(50)

 

ADRs

The most common side effects include nasopharyngitis, headache, abdominal pain, arthralgia, upper respiratory tract infection and pain in extremities.(50) Monitoring any hypersensitivity signs and symptoms during and after infusion is recommended.(50) Infections may occur during treatment, infection-relate symptoms need to be recognized, such as fever, chills, muscle ache, cough, pain during urination and shortness of breath.(50) Vedolizumab should be withheld when a serious infection occurs.(50) Monitoring patients  for any worsening of neurological signs and symptoms is recommended to minimize the risk of progressive multifocal leukoencephalopathy (PML), a virus induced infection in the central nervous system (CNS) and is considered as a rare  but serious side effect reported in patients treated with another integrin receptor antagonist. A referral to neurologist should be made for suspect cases and permanent discontinuation of vedolizumab is needed if diagnosed with PML.(50)

 

USTEKINUMAB (Stelara®)

Approved Indication

Ustekinumab (Stelara®) is registered in Hong Kong since 2011 and is classified as P1S1S3 poison. It is available in solution for infusion and injection.(30) Ustekinumab is indicated for patients with moderate to severe CD who have history of failure or intolerance to corticosteroids or TNF blockers.(54)

 

Mechanism of Action

IL-12 and IL-23 are pro-inflammatory cytokines that are involved in the pathogenesis of CD by inducing intestinal inflammation.(55) Ustekinumab is a fully humanized IgG1 monoclonal antibody that selectively binds to the p40 subunit of IL-12 and IL-23, and thereby inhibiting the binding of the respective receptors on the T cells and NK cells surface. As a result, intestinal inflammation is attenuated. (56)

 

Evidence from Clinical Trials

Both UNITI-1 and UNITI-2 trials showed a larger remission rate in patients treated with 6 mg/kg of ustekinumab at week 8 when compared to the placebo controls (UNITI-1: 20.9%, UNITI-2: 40.2%, p<0.001).(57) Also the clinical response and health-related quality of life (HRQoL) measured by Inflammatory Bowel Disease Questionnaire (IBDQ) and 36-item short form health survey (SF-36) were significantly better in the treatment group of patients  (UNITI-1: 37,8%, UNITI-2: 57.9%, p<0.001).(57) Regarding the maintenance regimen, the rate of remaining remission at week 44 was significantly higher in patients with ustekinumab at 90 mg every 8 weeks (53.1%, p=0.005) and patients with ustekinumab at 90 mg every 12 weeks (48.8%, p=0.040) than the placebo groups.(57)

 

Dosing Regimen

The induction regimen is administered by IV infusion.(54) For patient whose body weight is <55kg, 55-85kg and >85kg, the dosage is 260mg, 390mg and 520mg respectively.(54, 57) The maintenance dose is injected at 90mg SC once every 8 weeks.(54)

For pediatric patients, the safety and effectiveness of ustekinumab have not been examined.(54)

 

ADRs

The common ADRs during the induction therapy were nasopharyngitis (up to 6.8%), arthralgia (up to 6.0%), pyrexia (up to 6.0%), nausea (up to 5.3%) and abdominal pain (up to 5.2%).(57)  A similar ADR profile was observed during the maintenance therapy.(57)

 

Rarely, patients treated with ustekinumab (up to 0.2%) developed non-melanoma skin cancer. Therefore, all patients receiving ustekinumab should be monitored for a new onset of skin abnormality.(54)
 

 

 

Table 1. Comparison of mABs for the treatment of CD

Monoclonal antibodies

Infliximab(31)

Adalimumab(41)

Vedolizumab(50)

Ustekinumab(54)

Brand name

Remicade®

Humira®

Entyvio®

Stelara®

Mechanism

TNF-α inhibitor

TNF-α inhibitor

α4β7 integrin receptor antagonist

Anti-IL-12 and IL-23 antagonist

Dosage form and strength in Hong Kong

100mg lyophilized powder per vial

Single use pen 40mg/0.8mL and 40mg/0.4mL single use prefilled syringe 40mg/0.8mL, 40 mg/0.4 mL, 20 mg/0.2 mL

300mg lyophilized powder per vial

130 mg/26mL (single dose vial), 45mg/0.5mL
 (Both pre-filled syringe and solution for injection)

90mg/1mL
 (Pre-filled syringe)

Indications

Moderate to severe Crohn’s disease

Route

IV

SC

IV

IV, SC*

Dosing regimen

Initial

Adult and Pediatric ≥ 6 years old:
 5 mg/kg at week 0, 2, 6
 
 

Adult and Pediatric ≥ 6 years old and ≥40kg:
160 mg on day 1 or 80mg on day 1 and 2,  followed by 80 mg on day 15

 

Pediatric
≥ 6 years old and 17kg to

< 40 kg:
80 mg on day 1, 40 mg on day 15

 

Adult:
 300 mg at week 0, 2, 6

 

A single IV infusion in weight-based dosage
 Adult ≤ 55kg:
 260 mg

Adult > 55 to 85kg:
 390 mg
 Adult > 85 kg:
 520 mg
 


 
 

Maintenance

Adult and Pediatric ≥ 6 years old:

5mg/kg Q8W

Adult and Pediatric ≥ 6 years old and ≥40kg: 
40 mg on day 29 and then
every other week


Pediatric
≥ 6 years old and 17kg to < 40 kg:

20 mg on day 29 and then

every other week

 

Adult:
 300 mg Q8W

 

 90mg at week 8* after initial infusion, then Q8W*

 

 

Pre-treatment screening

Screen for latent tuberculosis (TB) and hepatitis B virus before starting therapy

 

Vaccination

Live vaccines should not be given concurrently

Avoid the use of live vaccines during the therapy

Live vaccines may be administered concurrently only if the benefits outweigh the risks

Avoid the use of live vaccines during the therapy

Black-box warning

Serious infection and malignancy

No data

Most common adverse reactions

 

 Upper respiratory tract infection, infusion-related reactions, headache and abdominal pain

 Upper respiratory tract infection, injection site reactions, headache and rash

Infections, arthralgia, rash, pruritis and pain in extremities

 

vomiting, nasopharyngitis, injection site erythema and abdominal pain

Contraindications

 Moderate to severe heart failure (NYHA III and IV)

NA

NA

NA

Safety net(58)

Yes

Yes

Yes

Yes


 

Table 2. Pharmacokinetic profile of the mABs

Monoclonal antibodies

Infliximab(31)

Adalimumab(41)

 

Vedolizumab(50)

Ustekinumab(54)

Brand name

Remicade®

Humira®

 

Entyvio®

Stelara®

Mechanism

TNF-α inhibitor

TNF-α inhibitor

 

α4β7 integrin receptor antagonist

Anti- IL12 and IL-23 antagonist

Bioavailability

100%

64%

100%

100%

 

Elimination
Half-life (T1/2)

 

7.7~9.5 days

10-20 days

25 days

19 days

Steady-state trough level (Css trough)

No data

7 μg/mL

 

13.0 μg/mL

 

FDA: 2.5 μg /mL

EMA: 1.97 μg/mL

 

Clearance

No data

12 mL/hr

6.54 mL/hr

7.92 mL/hr

 


Monitoring parameters

IL-6 and CRP

CRP, MMP-1 and MMP-3

CBC

IL-12 and IL-23

 

 

 

IMMUNOGENICITY OF mABs

Anti-drug antibodies (ADAbs) can be developed in a patient’s body after receiving a specific mAB. (59) ADAbs is classified into neutralizing and non-neutralizing. Neutralizing ADAbs bind to the (Fab′)2 region of the mAB to reduce its therapeutic activity.(60) Non-neutralizing antibodies do not reduce therapeutic activity directly because they do not bind to the Fab region. However, they can affect the pharmacokinetics of mABs such as enhancing the clearance rate.(61)

A higher rate of ADAbs is found in patients who treated with infliximab when compared to adalimumab, vedolizumab and ustekinumab (2.9-60.8 % vs 0.3-35.0%, 1.0-4.1% and 0.7% respectively).(62) It is important to examine the levels of ADAbs periodically because the presence of ADAbs may result in the loss of response to mABs and treatment failure.(63) Moreover, ADAbs can increase the risk of infusion reactions.(64) Therefore, therapeutic drug monitoring (TDM) can be done to optimize the treatment outcomes.

 

FUTURE mABs DEVELOPMENT IN CD

The future development of mAB is in two main directions: 1.) New drug candidate with a novel mechanism of action and 2.) oral route of administration. For instance, Risankizumab binds to the p19 subunit of IL23 and which is currently in phase 2 clinical trials.(65) On the other hand, oral anti-TNF is also being investigated to test its effectiveness in rats. Using engineering technique, V565 combines with antibodies to resist protease enzyme, so that it is protected against the gastric environment for subsequent absorption.(66) Oral mABs will provide several advantages including no infusion-related hypersensitivity reaction, and reduced risk of opportunistic infections such as TB, as oral antibodies will not neutralize TNF systematically. Patient compliance should be improved with easy administration of the agent.(66)

Recently, V56B2 is a novel agent which consists of an IL23p19-specific domain antibody, engineered for intestinal protease resistance (V900), and combine with a TNFα-specific domain antibody (V565).(67) The preclinical results showed that V56B2 inhibited the production of TNF by decreasing the phosphorylation of p53, RSK-1 in ex vivo culture of colonic biopsies.(67)  

 

ROLE OF PHARMACISTS IN MANAGEMENT OF CD 

One of the roles of a pharmacist in the management of CD is to facilitate medication adherence for a good treatment response and prevent a relapse of the disease.(68, 69)  Indeed, 45% of CD patients self-reported to have poor adherence.(70) Pharmacists can enhance medication adherence by educating patients on the background of the disease, rationale and goal of the treatments during patient counselling.(71) Information leaflets and pills cards may also be given to improve adherence.(71)

Apart from medication adherence, pharmacists can also play a role in TDM. Dose intensification can recapture the therapeutic response for patients with low antidrug antibody against adalimumab. For patients with a high antidrug antibody level to adalimumab, switching to the same class infliximab can recapture the therapeutic response in proportion of patients.(72) The Asia-Pacific Working Group on IBD established a consensus statement and recommend checking the plasma concentration of anti-TNF regularly.(73) The recommended steady-state trough levels of infliximab and adalimumab are 3-7 µg/mL and 4-8 µg/mL respectively.(73) However, it should be noted that there is no standardized antibody cut-off level.(74) More clinical trials are warranted to determine the optimal steady-state trough concentration in Asian population.

As CD is a chronic inflammatory disease, chronic abdominal pain is often reported by the patients.(75) Pharmacists can suggest pain management and optimize the use of analgesics.(76)  First line treatments of pain relief include paracetamol and NSAIDs. Low dose of selective COX-2 inhibitors shows less adverse effect of gastrointestinal toxicity when compared to non-selective COX-2 inhibitors. However, cautious use of COX-2 inhibitors should be exercised due to its potential cardiovascular risks.(77) Long term use of opioid is discouraged because there is a risk of developing narcotic bowel syndrome, a side effect related to chronic use of opioid, characterized by unexplained abdominal pain and worsen with increasing opioid dose.(78) Opioid may also increase the risk of serious infection as it masks the early signs of infection.(79) Therefore, pharmacist should help monitor patients’ conditions and screen individuals who are at risk for opiate abuse.  

Regular monitoring the signs and symptoms of infections is important, as the use of mABs is associated with a risk of TB and hepatitis reactivation.(73) Antiviral treatment should be initiated for patients detected with positive HBV DNA prior to the use of mABs.(73) Prophylactic treatment should also be initiated for patients diagnosed with latent TB to prevent reactivation.(73) mAB is then initiated at least 3 to 4 weeks after the use of anti-TB medications.(73) Chest radiography and interferon gamma release assay (IGRA) should be performed every 6 months to 12 months to detect any active TB infection during the therapy.(73) Monitoring liver function for 6 to 9 months is also recommended after cessation of anti-TNF.(80)

 

 

CONCLUSION

 

Infliximab, adalimumab, vedolizumab and ustekinumab are the registered biologics in Hong Kong that indicate for moderate-to-severe CD. The selection of mABs depends mainly on patients’ conditions, including liver function, infection status, history of allergic adverse effects to mABs. Infliximab and adalimumab also suitable to pediatric patients who are ≥ 6 years old. All four mABs are of similar efficacy but associated with a higher cost than conventional treatments. Evidence from clinical trials and Asian consensus statement can help to guide healthcare professionals in prescribing mABs and monitoring parameters.

 

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21         Ananthakrishnan AN, Higuchi LM, Huang ES et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: a cohort study. Ann Intern Med 2012; 156 (5): 350-359.

22         Klein A, Eliakim R. Non Steroidal Anti-Inflammatory Drugs and Inflammatory Bowel Disease. Pharmaceuticals (Basel) 2010; 3 (4): 1084-1092.

23         Watanabe T, Kitani A, Murray PJ et al. NOD2 is a negative regulator of Toll-like receptor 2–mediated T helper type 1 responses. Nature Immunology 2004; 5 (8): 800-808.

24         Pagnini C, Pizarro TT, Cominelli F. Novel Pharmacological Therapy in Inflammatory Bowel Diseases: Beyond Anti-Tumor Necrosis Factor. Frontiers in Pharmacology 2019; 10 (671): 1-11.

25         Feuerstein JD, Ho EY, Shmidt E et al. AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology 2021; 160 (7): 2496-2508.

26         Park KT, Colletti RB, Rubin DT et al. Health Insurance Paid Costs and Drivers of Costs for Patients With Crohn's Disease in the United States. Am J Gastroenterol 2016; 111 (1): 15-23.

27         Gade AK, Douthit NT, Townsley E. Medical Management of Crohn's Disease. Cureus 2020; 12 (5): e8351-e8351.

28         Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 2007; 132 (1): 52-65.

29         Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146 (12): 829-838.

30         香港藥劑業及毒藥管理局. Search Drug Database. 2022. Accessed on  March 27, 2022 https://www.drugoffice.gov.hk/eps/drug/productDetail2/en/consumer/135766.

31         US FDA. REMICADE (infliximab) Lyophilized Concentrate for Injection for Intravenous Use 2013. Accessed on  March 27, 2022 https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf.

32         Cai Z, Wang S, Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front Med (Lausanne) 2021; 8: 765474.

33         Vos AC, Wildenberg ME, Duijvestein M et al. Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 2011; 140 (1): 221-230.

34         Monaco C, Nanchahal J, Taylor P et al. Anti-TNF therapy: past, present and future. Int Immunol 2015; 27 (1): 55-62.

35         Danese S, Sans M, Scaldaferri F et al. TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease. J Immunol 2006; 176 (4): 2617-2624.

36         de Paula-Silva M, da Rocha GHO, Broering MF et al. Formyl Peptide Receptors and Annexin A1: Complementary Mechanisms to Infliximab in Murine Experimental Colitis and Crohn's Disease. Front Immunol 2021; 12: 714138.

37         Choi CH, Song ID, Kim YH et al. Efficacy and Safety of Infliximab Therapy and Predictors of Response in Korean Patients with Crohn's Disease: A Nationwide, Multicenter Study. Yonsei Med J 2016; 57 (6): 1376-1385.

38         Hosoi K, Ohtsuka Y, Fujii T et al. Treatment with infliximab for pediatric Crohn's disease: Nationwide survey of Japan. J Gastroenterol Hepatol 2017; 32 (1): 114-119.

39         Gold SL, Cohen-Mekelburg S, Schneider Y et al. Premedication Use in Preventing Acute Infliximab Infusion Reactions in Patients with Inflammatory Bowel Disease: A Single Center Cohort Study. Inflammatory Bowel Diseases 2017; 23 (10): 1882-1889.

40         Strik AS, Wang YC, Ruff LE et al. Individualized Dosing of Therapeutic Monoclonal Antibodies-a Changing Treatment Paradigm? AAPS J 2018; 20 (6): 99.

41         US FDA. HUMIRA® (adalimumab) injection for subcutaneous use. 2018. Accessed on  March 27, 2022 https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s410lbl.pdf.

42         Adegbola SO, Sahnan K, Warusavitarne J et al. Anti-TNF Therapy in Crohn's Disease. Int J Mol Sci 2018; 19 (8).

43         Levin AD, Wildenberg ME, van den Brink GR. Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2016; 10 (8): 989-997.

44         Feagan BG, Panaccione R, Sandborn WJ et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn's disease: results from the CHARM study. Gastroenterology 2008; 135 (5): 1493-1499.

45         Panaccione R, Sandborn WJ, D’Haens G et al. Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn’s Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN/ADHERE Trials. Journal of Crohn's and Colitis 2018; 12 (8): 930-938.

46         Lichtenstein GR, Loftus EV, Isaacs KL et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Official journal of the American College of Gastroenterology | ACG 2018; 113 (4).

47         Nguyen GC, Loftus EV, Jr., Hirano I et al. American Gastroenterological Association Institute Guideline on the Management of Crohn's Disease After Surgical Resection. Gastroenterology 2017; 152 (1): 271-275.

48         Micromedex. Adalimumab. 2022. Accessed on  March 27, 2022 https://www-micromedexsolutions-com.easyaccess1.lib.cuhk.edu.hk/micromedex2/librarian/CS/4B64AD/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/B31F3C/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearch?SearchTerm=Adalimumab&fromInterSaltBase=true&UserMdxSearchTerm=%24userMdxSearchTerm&false=null&=null.

49         Lexicomp. Adalimumab. 2022. Accessed on  March 27, 2022, 2022 https://online-lexi-com.easyaccess1.lib.cuhk.edu.hk/lco/action/doc/retrieve/docid/multinat_f/4669705?cesid=6y4sH6jxoEI&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dhumira%26t%3Dname%26va%3Dhumira.

50         US FDA. ENTYVIO (vedolizumab) for injection for intravenous use. 2014. Accessed on  March 27, 2022 https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125476s000lbl.pdf.

51         Wyant T, Fedyk E, Abhyankar B. An Overview of the Mechanism of Action of the Monoclonal Antibody Vedolizumab. J Crohns Colitis 2016; 10 (12): 1437-1444.

52         Sandborn WJ, Feagan BG, Rutgeerts P et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013; 369 (8): 711-721.

53         Sands BE, Feagan BG, Rutgeerts P et al. Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 2014; 147 (3): 618-627.e613.

54         US FDA. STELARA® (ustekinumab) injection for subcutaneous or intravenous use. 2016. Accessed on  March 27, 2022 https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761044lbl.pdf.

55         Neurath MF. IL-23: a master regulator in Crohn disease. Nature Medicine 2007; 13 (1): 26-27.

56         Lamb YN, Duggan ST. Ustekinumab: A Review in Moderate to Severe Crohn's Disease. Drugs 2017; 77 (10): 1105-1114.

57         Feagan BG, Sandborn WJ, Gasink C et al. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. New England Journal of Medicine 2016; 375 (20): 1946-1960.

58         Hospital Authority. Self-financed Drugs Available for Purchase by Patients at HA Pharmacies. HA Drug Formulary Management. 2015. Accessed on  March 27, 2022 https://www.ha.org.hk/hadf/en-us/Updated-HA-Drug-Formulary/List-of-Self-financed-Items-to-be-sold-via-HA-pharmacies.html.

59         Vincent FB, Morand EF, Murphy K et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013; 72 (2): 165-178.

60         van Schie KA, Hart MH, de Groot ER et al. The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region. Ann Rheum Dis 2015; 74 (1): 311-314.

61         van der Laken CJ, Voskuyl AE, Roos JC et al. Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis 2007; 66 (2): 253-256.

62         Vermeire S, Gils A, Accossato P et al. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol 2018; 11: 1756283x17750355.

63         Reinhold I, Blümel S, Schreiner J et al. Clinical Relevance of Anti-TNF Antibody Trough Levels and Anti-Drug Antibodies in Treating Inflammatory Bowel Disease Patients. Inflammatory Intestinal Diseases 2021; 6 (1): 38-47.

64         Baert F, Noman M, Vermeire S et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003; 348 (7): 601-608.

65         Feagan BG, Panés J, Ferrante M et al. Risankizumab in patients with moderate to severe Crohn's disease: an open-label extension study. The Lancet Gastroenterology & Hepatology 2018; 3 (10): 671-680.

66         Griffiths OR, Landon J, Coxon RE et al. Inflammatory bowel disease and targeted oral anti-TNFα therapy. Adv Protein Chem Struct Biol 2020; 119: 157-198.

67         Roberts KJ, Cubitt MF, Carlton TM et al. Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease. Scientific Reports 2021; 11 (1): 19422.

68         Chan W, Chen A, Tiao D et al. Medication adherence in inflammatory bowel disease. Intest Res 2017; 15 (4): 434-445.

69         Bhat S, Farraye FA, Moss A. Roles of Clinical Pharmacists in Caring for Patients With Inflammatory Bowel Disease During COVID-19. Gastroenterology 2021; 160 (5): 1880.

70         Tiao DK, Chan W, Jeganathan J et al. Inflammatory Bowel Disease Pharmacist Adherence Counseling Improves Medication Adherence in Crohn's Disease and Ulcerative Colitis. Inflamm Bowel Dis 2017; 23 (8): 1257-1261.

71         Ashok K, Mathew A, Thomas A et al. Clinical Pharmacist’s Interventions on Medication Adherence and Knowledge of Inflammatory Bowel Disease Patients. Journal of Young Pharmacists 2017; 9: 381-385.

72         Morita Y, Imaeda H, Nishida A et al. Association between serum adalimumab concentrations and endoscopic disease activity in patients with Crohn's disease. J Gastroenterol Hepatol 2016; 31 (11): 1831-1836.

73         Ooi CJ, Hilmi I, Banerjee R et al. Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia. Intest Res 2019; 17 (3): 285-310.

74         Mak JW, Sung JJ. The Use of Biologics and Biosimilar in Asian patients with IBD: Are we ready? J Gastroenterol Hepatol 2019; 34 (8): 1269-1270.

75         Lönnfors S, Vermeire S, Greco M et al. IBD and health-related quality of life -- discovering the true impact. J Crohns Colitis 2014; 8 (10): 1281-1286.

76         Prasad SS, Duncanson K, Keely S et al. A Role for Primary Care Pharmacists in the Management of Inflammatory Bowel Disease? Lessons from Chronic Disease: A Systematic Review. Pharmacy (Basel) 2020; 8 (4): 204.

77         Bakshi N, Hart AL, Lee MC et al. Chronic pain in patients with inflammatory bowel disease. Pain 2021; 162 (10): 2466-2471.

78         Grunkemeier DM, Cassara JE, Dalton CB et al. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin Gastroenterol Hepatol 2007; 5 (10): 1126-1139; quiz 1121-1122.

79         Lichtenstein GR, Feagan BG, Cohen RD et al. Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry. Clin Gastroenterol Hepatol 2006; 4 (5): 621-630.

80         Leung WK, Ng SC, Chow DK et al. Use of biologics for inflammatory bowel disease in Hong Kong: consensus statement. Hong Kong Med J 2013; 19 (1): 61-68.

 

 

Questions for Pharmacy Central Continuing Education Committee Program

 

(Please be informed that this article and answer sheet will be available on PCCC website concurrently. Members may go to PCCC website(www.pccchk.com) to fill I their answers there.)

 

  1. Infusion related reactions (IRRs) are common adverse events associated with infliximab. Which of the following is not a prophylactic medication of IRRs?
    1. Prednisolone
    2. Paracetamol
    3. Ondansetron
    4. Chlorphenamine
  2. The side effects associated with ustekinumab include:
    1. Dyspnea
    2. Skin rash
    3. Increased risk of viral infections
    4. Nasopharyngitis     
  3. Which of the following maintenance regimen is calculated based on body weight?
    1. Infliximab
    2. Adalimumab
    3. Vedolizumab
    4. Ustekinumab
  4. How should an adult patient be advised in proper administration of adalimumab?
    1. It should be given subcutaneously soon after meal
    2. Pre-treatment screening is needed for those patients who have family history of hepatitis B infections
    3. It is administered every 2 weeks after the initial dose
    4. Annual FluMist (live attenuated intranasal influenza vaccine) can be recommended to the patients to prevent influenza infections
  5. A 62-year-old Chinese patient weighs 60 kg and has no known drug allergies, who do not have good response to infliximab at 10 mg/kg after 16 weeks of treatment. Which of the following is the most appropriate treatment options?
    1. Increase infliximab to 15 mg/kg IV
    2. Change to vedolizumab 300 mg IV
    3. Change to adalimumab 80 mg SC
    4. Continue IV infliximab at 10 mg/kg for another 14 weeks
  6. Which one of the following situations would preclude the patient from receiving ustekinumab?
    1. Hepatitis B surface antigen negative
    2. Hepatitis B surface antibody positive
    3. Pregnancy test negative
    4. Influenza PCR positive
  7. IPY is a 43-year-old male with CD, currently managed with adalimumab.  However, he was recently hospitalized for a flare up with severe diarrhoea.  Upon discharge, IPY expressed that he still prefers using self-injectable or oral drugs at home, instead of having to periodically return to the hospital for infusion.  Which one of the following drug options would you recommend?
    1. Infliximab
    2. Vedolizumab
    3. Ustekinumab
    4. Cyclosporine
  8. Which one of the following proinflammatory cytokines is the therapeutic target for the initial treatment of moderate to severe Crohn’s disease?
    1. IL12
    2. TNF-α
    3. IL23
    4. IFN-γ
  9. Which one of the following genetic mutations is commonly found in patients with Crohn’s disease, and may be linked with disease pathogenesis?
    1. NOD2
    2. TYK1
    3. KRAS g12c
    4. TP53
  10. Which one of the following mABs has the highest risk of developing human anti-chimeric antibodies (HACA) after use, which could reduce its efficacy towards CD treatment?
    1. Vedolizumab
    2. Infliximab
    3. Adalimumab
    4. Ustekinumab

 

Answers will be released in the next issue of HKPJ.

 

 

CE Questions Answer for 301(D&T)

Overview of the Drug Therapy of Psoriasis

1.D

2.C

3.C

4.D

5.C

6.A

7.D

8.D

9.B

10.D 


2023-12-21 於2021月03月11日

INTRODUCTION

Crohn’s disease (CD) is a type of inflammatory bowel disease (IBD) that was diagnosed by Dr. Burrill B. Crohn and team in 1932.(1) CD is characterized by chronic inflammation that can occur in any part of the mucosal area of the gastrointestinal tract. The presenting symptoms include diarrhea, abdominal pain, weight loss and fever.(2) The median onset time of CD is between the age of 20 and 30 years old, and with a peak at around 50 years old.(3)  The prevalence of CD is around 50 to 200 cases per 100,000 people globally.(4) In Hong Kong, the most recent registry showed that the local prevalence of CD is 18.6 cases per 100,000 people.(5)

 

The pathogenesis of CD involves a complicated mechanism between the innate and adaptive immune system. Gut microbiota is also described to have a role.(6) Conventional treatments include 5-aminosalicylates (5-ASA), corticosteroids, azathioprine or methotrexate that aim to delay the progression of CD.(7) Despite a lifelong therapy, the progression or relapse of CD still occur in most patients.  A meta-analysis showed the relapse rate in 1 year and 2 years was 38% and 52% respectively in patients who received anti-tumour necrosis factor (TNF) after CD remission.(8) The development of mABs aims to provide an alternative treatment option to overcome the high relapse rate.(9) Thus, it is important for healthcare professionals to acquire the knowledge of pharmacological treatment options for CD.

 

 

PATHOPHYSIOLOGY

CD is characterized by tissue inflammation that is triggered by the dysregulation of the innate and adaptive immune systems.(10) In the inflammation stage, more IL-34 is released in patients with CD via extracellular signal-regulated kinase (ERK)-mediated mechanism, therefore it increases TNF-α and IL-6 production.(11) In addition, CD4+ T cells are increased and lead to the production of type 1 T helper (TH1) and type 17 T helper (TH17) cells-associated proinflammatory cytokines, such as interferon (IFN)-γ, IL-12, IL-23 and TNF-α.(12, 13) For instance, IL-12 induces TH1 cell activity to further enhance the production of IFN-γ.(14) Excessive TH1 immune response is known to cause intestinal inflammation in CD. Furthermore, CD patients also have a high amount of IL-2 which binds to CD4+ T cells and activate the differentiation of plasma cells in the mucosa.(10) As a result, it triggers the activity of cytotoxic mediators on the intestinal mucosa and damages the epithelial cells.(15)

Good balance of gut microbiota in the intestinal tract can be key to control the inflammatory response.(10) A cohort study found that a higher percentage of dysbiosis occurs in patients with CD when compared to healthy individuals.(16)  It usually accompanied by excessive growth of Enterobacteriaceae (i.e. Salmonella, Shigella and Escherichia coli) that activates the inflammatory response in guts.(17)

Moreover, smoking is a risk factor of CD induction or deterioration as cigarettes affect colon mucus production and delay mucosal repairment in the guts.(18, 19)  Smoking also changes the autophagy-related gene ATG16L1 expression resulting in dysfunction of recognition, handling and clearance of invading pathogens.(20) Another risk factor is chronic use of high dose NSAIDs that inhibit COX1 and COX2 enzymes resulting in a high risk of intestinal ulcer.(21, 22) Genetic mutation is shown to contribute to the pathogenesis of CD. Nucleotide-binding oligomerization domain 2 (NOD2) mutation is found in one-third of the patients with CD, which the inhibitory effect on Toll-like receptor 2 (TLR2) is lost and causes the activation of inflammatory pathways via excessive TH1 responses.(23)

 

USE OF MONOCLONAL ANTIBODIES(mABs) IN CD

Corticosteroids, 5-ASA, azathioprine and methotrexate are the conventional treatments for CD. However, some patients are either not responding or intolerant to them.(24) With the advancement in the drug discovery, biologics (mABs) have been shown to be effective. (9) They are classified into anti-TNF agents (infliximab, adalimumab) and other selective agents such as anti-integrin (vedolizumab) and anti-IL agent (ustekinumab) (Table 1 and Table 2). As per the American Gastroenterological Association (AGA) 2021 guideline, these mABs are indicated for patients with moderate to severe CD.(25) In terms of safety, patients are required to screen for latent tuberculosis (TB) and hepatitis B virus before using mABs. Live vaccinations are generally not recommended in all mABs except vedolizumab, to prevent overacting immune response, patients should discuss with physicians the risk versus benefit of the live vaccination. Although mABs are effective in CD management, they are costly.(26) In Hong Kong, they are under the safety net at the Hospital Authority Drug formulary (Table 1).

The goal of CD therapy is divided into two aspects: inducing remission and preventing a relapse of CD.(27) Compared to the conventional regimens, there is no concrete consensus on the selection of first-line mABs. This is likely due to the limited head-to-head trials to compare the efficacy and safety between mABs.(9) Clinically, anti-TNF agents are considered as the first-line mABs treatment because of more evidence.(9) However, approximately two-third of patients experienced a recurrence of CD within 1 year post anti-TNF treatment.(28) Also, these patients tended not to have a good response to another anti-TNF agent after failing with one anti-TNF.(29)  AGA 2021 guideline emphasizes that selection of mABs should be based on patient’s conditions, such as history of failure to anti-TNF agents, allergic reaction any mABs, and screening results of    latent TB and hepatitis B virus.(25)   

 

 

INFLIXIMAB (Remicade®)

Approved Indication

Infliximab (Remicade®) is registered in Hong Kong since 2006 and is classified as P1S1S3 poison.(30) It is indicated for adult and pediatric patients with moderate to severe active CD.(31) 

 

Mechanism of Action

TNF-α is a key proinflammatory cytokine leading to CD. Overexpression of TNF-α amplifies the inflammatory process and causes the induction and perpetuation of intestinal inflammation.(32) Infliximab is a genetically engineered immunoglobulin 1 (IgG1) murine–human chimeric monoclonal antibody by binding to transmembrane and soluble forms of the protein and preventing the interaction between TNF-α and its receptor.(33) Other than the blockade of TNF, infliximab can inhibit the production of IL-1 and IL-6, which reduces leukocyte migration and adhesion molecule expression by the endothelial cells to help suppress inflammation.(34) The levels of soluble CD40L was elevated in plasma and surface CD40L was increased in platelets and T cells of CD patients. Infliximab also regulates the CD40L signaling pathway that contributes to the systemic anti-TNF-α action.(35)

Other than the known mechanisms of action of infliximab in humans, a recent study suggested that the efficacy of infliximab is correlated to the expression of Annexin A1 (AnxA1) on formyl peptide receptors (FRRs) by using dextran sulfate sodium colitis model in mice.(36) AnxA1 is a mediator produced by epithelial cells and mobilized to the membrane after the cell activation to trigger anti-inflammatory pathways of FRRs, which is a possible mechanism of infliximab.(36)

 

Evidence from Clinical Trials

A recent trial that recruited luminal CD patients with Asia background to show an increase of 60% remission rate by infliximab. The remission rate further increased to more than 90% in week 54 of infliximab.(37) Other than luminal CD patients, there was a prominent effect on the fistulizing CD patients as the remission rate reached 56.2%. Furthermore, the remission rate increased to 97.1% by week 54.(37) Only 6% of patients had serious adverse effects, such as severe infusion reactions (7 cases), serum sickness (2 cases), intra-abdominal abscess (2 cases), and active tuberculosis (2 cases).(37)

In pediatric CD patients,  a study conducted in Japan found that infliximab is effective in refractory cases when compared to cyclosporin and tacrolimus.(38) Upon remission, 54.7% and 69.6% of the pediatric CD patients can reduce or discontinue the dose of steroids, respectively.(38)

 

Dosing Regimen

The recommended dose is 5 mg/kg through intravenous (IV) injection at 0, 2, and 6 weeks and then started the maintenance dose at 5 mg/kg every 8 weeks for adult or pediatric patients with moderate or severe active CD or fistulizing CD.(31)

If adult patients showed partial response, infliximab can be increased to 10 mg/kg. However, if no response is observed by week 14, it should be discontinued and other treatment options should be considered.(31)

 

Adverse Drug Effects (ADRs)

Common ADRs include fever, shortness of breath, coughing and rash which may occur during the treatment in adult and pediatric patients.(31) It is more likely to increase the risk of infection, such as cytomegalovirus infection, re-activation of latent TB in adult patients.(37, 38)

 

Management of ADRs

Infusion related reactions (IRRs) to infliximab are common and acute that usually occur within 15 to 30 mins post-infusion.  The symptoms of IRRs include pruritus, urticaria, fever and bronchospasms.(39) There are four different types of IRRs: complement activation-related pseudo-allergy (CARPA), cytokine release syndrome, anaphylactoid reaction and immunoglobulin E-mediated anaphylaxis.(39)  CARPA and cytokine release syndrome are well described as IRRs, but the latter two syndromes are often considered as allergic reactions.(39) Physicians can prescribe prophylactic medications, such as prednisolone, hydrocortisone and antihistamine, to prevent the IRRs.(39)  However, if patient’s IRR symptoms exist despite the use of prophylactic medications, changing the regimen is needed, such as dosage adjustment and change of another class of drug.(40)

 

ADALIMUMAB (Humira®)

Approved Indication

Adalimumab (Humira®) is registered in Hong Kong since 2017 and is classified as P1S1S3 poison.(30)  It is available in single pen and prefilled syringe form for injection, and is indicated for moderate to severe active CD in adults and pediatric patients 6 years of age or above.(41)

 

Mechanism of Action

Adalimumab is a fully humanized IgG1 monoclonal antibody, which reduces the overexpression of TNF-α by blocking its receptors. Therefore, the associated proinflammatory signals is attenuated.(42) The Fc region of adalimumab can trigger M2-type wound-healing macrophages which may help to promote mucosal healing.(33) In addition, it induces antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). ADCC refers to the binding of Fc receptor to the target cells to trigger the killing action of the natural killer cells.(43) CDC refers to the antibodies binding to the target cells to activate the complement pathway for the killing action.(43)

 

Evidence from Clinical Trial

In the CHARM trial, around 40% of CD patients treated with adalimumab had remission in week 26. A similar percentage of remission remained in week 56, suggesting a good maintenance rate by adalimumab.(28) Also, patients treated with adalimumab had 64% reduction of hospitalization over a 12-month follow-up period.(44)  Patients who achieved steroid-free clinical remission increased from 22.3% to 50.0% over a prolonged period of 96 week.(45) Indeed, AGA (2021) guideline recommended that adalimumab can be administered with or without an immunomodulator for patients who have no response to the conventional pharmacological treatment.(25) Adalimumab is also effective for prophylactic therapy in patients with CD following surgical resection to prevent clinical recurrence. (46, 47)

 

Dosing Regimen

For adult patients, adalimumab 160mg is given subcutaneously (SC) on day 1 or split over 2 consecutive days, followed by 80mg SC on day 15 and then 40mg SC once every other week from day 29.(48)  

For pediatric patients ≥ 6 years old or less than 40kg, adalimumab 80mg SC is given on day 1, followed by 40mg SC on day 15 and then 20mg SC once every other week from day 29.(48)

For pediatric patients ≥ 6 years old and greater than 40kg, adult dosage of adalimumab is used.(48)

 

ADRs

The most frequent adverse effects are injection site reactions and dermatologic rashes. Other common side effects include headache, sinusitis and upper respiratory infection.(41) Adalimumab can increase the risk of infection, such as TB, invasive fungal infection leading to hospitalization as mentioned in the black box warning.(41) If occurs, immediate discontinuation of adalimumab is needed.(41) Case reports of lymphoma and malignancies in children and teenagers during the treatment of adalimumab are described.(49)

 

VEDOLIZUMAB (Entyvio®)

Approved Indication 

Vedolizumab (Entyvio®) is registered in Hong Kong since 2015 and is classified as P1S1S3 poison.(30) It is available in solution for infusion and is indicated for patients with active status of moderate to severe CD who are intolerant or have insufficient response to TNF-α blocker, or demonstrated dependence on corticosteroids.(50)

 

Mechanism of Action

Vedolizumab is a humanized α4β7 integrin monoclonal antibody.(50) It binds to the α4β7 integrin receptor to interfere the interaction with mucosal addressin cell adhesion molecules-1 (MAdCAM-1), resulting in alleviation of chronically inflamed gastrointestinal parenchymal tissue associated with CD. (51) Also, Vedolizumab prevents further inflammatory reaction by inhibiting the movement of memory T-lymphocytes across the endothelium into inflammatory gastrointestinal tissue.(51)

Evidence from Clinical Trials

The efficacy and safety of using vedolizumab in moderate-to-severely active CD were conducted in the GEMINI 2 phase 3 clinical trial.(52) The post-hoc analysis aimed to access the induction and maintenance phase of Asian and non-Asian patients who were treated with vedolizumab. The disposition of the Asian subgroup was separated into Cohort 1 included 51 patients, 34 were randomized to vedolizumab and 17 to placebo in the induction phase. Cohort 2 included 24 patients who were treated with vedolizumab on open-label. During the induction phase, approximately 15% of the patients in the vedolizumab group achieved remission compared to 0% in the placebo group at week 6.(52) The clinical remission and response rates were higher in vedolizumab compared to placebo. During the maintenance phase, patients with clinical response to vedolizumab during the induction phase were subsequently treated with vedolizumab every 8 weeks, every 4 weeks, or placebo for up to 52 weeks.(52) The clinical remission rate were 41.7%, 36.4% and 0% respectively; while enhanced clinical response rates indicated 41.7%, 63.6% and 42.9% respectively.(52) However, the limitation of the study is relatively small sample size in subgroup analysis.

Vedolizumab is effective in patients with history of failure with anti-TNF as the therapeutic benefits of vedolizumab were detectable in week 10.(53) GEMINI 2 trial showed that patients after receiving vedolizumab every 8 weeks, 83% [n=100/120] and 89% [n=62/70] of patients were in remission after 104 and 152 weeks, regardless of prior anti-TNF exposure.(52)

 

Dosing Regimen

For adults, the induction dose of vedolizumab is 300mg IV infusion over 30 minutes at 0, 2, and 6 weeks, and for maintenance, the same dose is administered once every 8 weeks thereafter.(50) Discontinuation of  vedolizumab is generally required in patients who show no therapeutic benefit by week 14.(50)

For pediatric patients, the safety and effectiveness of vedolizumab have not been analyzed.(50)

 

ADRs

The most common side effects include nasopharyngitis, headache, abdominal pain, arthralgia, upper respiratory tract infection and pain in extremities.(50) Monitoring any hypersensitivity signs and symptoms during and after infusion is recommended.(50) Infections may occur during treatment, infection-relate symptoms need to be recognized, such as fever, chills, muscle ache, cough, pain during urination and shortness of breath.(50) Vedolizumab should be withheld when a serious infection occurs.(50) Monitoring patients  for any worsening of neurological signs and symptoms is recommended to minimize the risk of progressive multifocal leukoencephalopathy (PML), a virus induced infection in the central nervous system (CNS) and is considered as a rare  but serious side effect reported in patients treated with another integrin receptor antagonist. A referral to neurologist should be made for suspect cases and permanent discontinuation of vedolizumab is needed if diagnosed with PML.(50)

 

USTEKINUMAB (Stelara®)

Approved Indication

Ustekinumab (Stelara®) is registered in Hong Kong since 2011 and is classified as P1S1S3 poison. It is available in solution for infusion and injection.(30) Ustekinumab is indicated for patients with moderate to severe CD who have history of failure or intolerance to corticosteroids or TNF blockers.(54)

 

Mechanism of Action

IL-12 and IL-23 are pro-inflammatory cytokines that are involved in the pathogenesis of CD by inducing intestinal inflammation.(55) Ustekinumab is a fully humanized IgG1 monoclonal antibody that selectively binds to the p40 subunit of IL-12 and IL-23, and thereby inhibiting the binding of the respective receptors on the T cells and NK cells surface. As a result, intestinal inflammation is attenuated. (56)

 

Evidence from Clinical Trials

Both UNITI-1 and UNITI-2 trials showed a larger remission rate in patients treated with 6 mg/kg of ustekinumab at week 8 when compared to the placebo controls (UNITI-1: 20.9%, UNITI-2: 40.2%, p<0.001).(57) Also the clinical response and health-related quality of life (HRQoL) measured by Inflammatory Bowel Disease Questionnaire (IBDQ) and 36-item short form health survey (SF-36) were significantly better in the treatment group of patients  (UNITI-1: 37,8%, UNITI-2: 57.9%, p<0.001).(57) Regarding the maintenance regimen, the rate of remaining remission at week 44 was significantly higher in patients with ustekinumab at 90 mg every 8 weeks (53.1%, p=0.005) and patients with ustekinumab at 90 mg every 12 weeks (48.8%, p=0.040) than the placebo groups.(57)

 

Dosing Regimen

The induction regimen is administered by IV infusion.(54) For patient whose body weight is <55kg, 55-85kg and >85kg, the dosage is 260mg, 390mg and 520mg respectively.(54, 57) The maintenance dose is injected at 90mg SC once every 8 weeks.(54)

For pediatric patients, the safety and effectiveness of ustekinumab have not been examined.(54)

 

ADRs

The common ADRs during the induction therapy were nasopharyngitis (up to 6.8%), arthralgia (up to 6.0%), pyrexia (up to 6.0%), nausea (up to 5.3%) and abdominal pain (up to 5.2%).(57)  A similar ADR profile was observed during the maintenance therapy.(57)

 

Rarely, patients treated with ustekinumab (up to 0.2%) developed non-melanoma skin cancer. Therefore, all patients receiving ustekinumab should be monitored for a new onset of skin abnormality.(54)
 

 

 

Table 1. Comparison of mABs for the treatment of CD

Monoclonal antibodies

Infliximab(31)

Adalimumab(41)

Vedolizumab(50)

Ustekinumab(54)

Brand name

Remicade®

Humira®

Entyvio®

Stelara®

Mechanism

TNF-α inhibitor

TNF-α inhibitor

α4β7 integrin receptor antagonist

Anti-IL-12 and IL-23 antagonist

Dosage form and strength in Hong Kong

100mg lyophilized powder per vial

Single use pen 40mg/0.8mL and 40mg/0.4mL single use prefilled syringe 40mg/0.8mL, 40 mg/0.4 mL, 20 mg/0.2 mL

300mg lyophilized powder per vial

130 mg/26mL (single dose vial), 45mg/0.5mL
 (Both pre-filled syringe and solution for injection)

90mg/1mL
 (Pre-filled syringe)

Indications

Moderate to severe Crohn’s disease

Route

IV

SC

IV

IV, SC*

Dosing regimen

Initial

Adult and Pediatric ≥ 6 years old:
 5 mg/kg at week 0, 2, 6
 
 

Adult and Pediatric ≥ 6 years old and ≥40kg:
160 mg on day 1 or 80mg on day 1 and 2,  followed by 80 mg on day 15

 

Pediatric
≥ 6 years old and 17kg to

< 40 kg:
80 mg on day 1, 40 mg on day 15

 

Adult:
 300 mg at week 0, 2, 6

 

A single IV infusion in weight-based dosage
 Adult ≤ 55kg:
 260 mg

Adult > 55 to 85kg:
 390 mg
 Adult > 85 kg:
 520 mg
 


 
 

Maintenance

Adult and Pediatric ≥ 6 years old:

5mg/kg Q8W

Adult and Pediatric ≥ 6 years old and ≥40kg: 
40 mg on day 29 and then
every other week


Pediatric
≥ 6 years old and 17kg to < 40 kg:

20 mg on day 29 and then

every other week

 

Adult:
 300 mg Q8W

 

 90mg at week 8* after initial infusion, then Q8W*

 

 

Pre-treatment screening

Screen for latent tuberculosis (TB) and hepatitis B virus before starting therapy

 

Vaccination

Live vaccines should not be given concurrently

Avoid the use of live vaccines during the therapy

Live vaccines may be administered concurrently only if the benefits outweigh the risks

Avoid the use of live vaccines during the therapy

Black-box warning

Serious infection and malignancy

No data

Most common adverse reactions

 

 Upper respiratory tract infection, infusion-related reactions, headache and abdominal pain

 Upper respiratory tract infection, injection site reactions, headache and rash

Infections, arthralgia, rash, pruritis and pain in extremities

 

vomiting, nasopharyngitis, injection site erythema and abdominal pain

Contraindications

 Moderate to severe heart failure (NYHA III and IV)

NA

NA

NA

Safety net(58)

Yes

Yes

Yes

Yes


 

Table 2. Pharmacokinetic profile of the mABs

Monoclonal antibodies

Infliximab(31)

Adalimumab(41)

 

Vedolizumab(50)

Ustekinumab(54)

Brand name

Remicade®

Humira®

 

Entyvio®

Stelara®

Mechanism

TNF-α inhibitor

TNF-α inhibitor

 

α4β7 integrin receptor antagonist

Anti- IL12 and IL-23 antagonist

Bioavailability

100%

64%

100%

100%

 

Elimination
Half-life (T1/2)

 

7.7~9.5 days

10-20 days

25 days

19 days

Steady-state trough level (Css trough)

No data

7 μg/mL

 

13.0 μg/mL

 

FDA: 2.5 μg /mL

EMA: 1.97 μg/mL

 

Clearance

No data

12 mL/hr

6.54 mL/hr

7.92 mL/hr

 


Monitoring parameters

IL-6 and CRP

CRP, MMP-1 and MMP-3

CBC

IL-12 and IL-23

 

 

 

IMMUNOGENICITY OF mABs

Anti-drug antibodies (ADAbs) can be developed in a patient’s body after receiving a specific mAB. (59) ADAbs is classified into neutralizing and non-neutralizing. Neutralizing ADAbs bind to the (Fab′)2 region of the mAB to reduce its therapeutic activity.(60) Non-neutralizing antibodies do not reduce therapeutic activity directly because they do not bind to the Fab region. However, they can affect the pharmacokinetics of mABs such as enhancing the clearance rate.(61)

A higher rate of ADAbs is found in patients who treated with infliximab when compared to adalimumab, vedolizumab and ustekinumab (2.9-60.8 % vs 0.3-35.0%, 1.0-4.1% and 0.7% respectively).(62) It is important to examine the levels of ADAbs periodically because the presence of ADAbs may result in the loss of response to mABs and treatment failure.(63) Moreover, ADAbs can increase the risk of infusion reactions.(64) Therefore, therapeutic drug monitoring (TDM) can be done to optimize the treatment outcomes.

 

FUTURE mABs DEVELOPMENT IN CD

The future development of mAB is in two main directions: 1.) New drug candidate with a novel mechanism of action and 2.) oral route of administration. For instance, Risankizumab binds to the p19 subunit of IL23 and which is currently in phase 2 clinical trials.(65) On the other hand, oral anti-TNF is also being investigated to test its effectiveness in rats. Using engineering technique, V565 combines with antibodies to resist protease enzyme, so that it is protected against the gastric environment for subsequent absorption.(66) Oral mABs will provide several advantages including no infusion-related hypersensitivity reaction, and reduced risk of opportunistic infections such as TB, as oral antibodies will not neutralize TNF systematically. Patient compliance should be improved with easy administration of the agent.(66)

Recently, V56B2 is a novel agent which consists of an IL23p19-specific domain antibody, engineered for intestinal protease resistance (V900), and combine with a TNFα-specific domain antibody (V565).(67) The preclinical results showed that V56B2 inhibited the production of TNF by decreasing the phosphorylation of p53, RSK-1 in ex vivo culture of colonic biopsies.(67)  

 

ROLE OF PHARMACISTS IN MANAGEMENT OF CD 

One of the roles of a pharmacist in the management of CD is to facilitate medication adherence for a good treatment response and prevent a relapse of the disease.(68, 69)  Indeed, 45% of CD patients self-reported to have poor adherence.(70) Pharmacists can enhance medication adherence by educating patients on the background of the disease, rationale and goal of the treatments during patient counselling.(71) Information leaflets and pills cards may also be given to improve adherence.(71)

Apart from medication adherence, pharmacists can also play a role in TDM. Dose intensification can recapture the therapeutic response for patients with low antidrug antibody against adalimumab. For patients with a high antidrug antibody level to adalimumab, switching to the same class infliximab can recapture the therapeutic response in proportion of patients.(72) The Asia-Pacific Working Group on IBD established a consensus statement and recommend checking the plasma concentration of anti-TNF regularly.(73) The recommended steady-state trough levels of infliximab and adalimumab are 3-7 µg/mL and 4-8 µg/mL respectively.(73) However, it should be noted that there is no standardized antibody cut-off level.(74) More clinical trials are warranted to determine the optimal steady-state trough concentration in Asian population.

As CD is a chronic inflammatory disease, chronic abdominal pain is often reported by the patients.(75) Pharmacists can suggest pain management and optimize the use of analgesics.(76)  First line treatments of pain relief include paracetamol and NSAIDs. Low dose of selective COX-2 inhibitors shows less adverse effect of gastrointestinal toxicity when compared to non-selective COX-2 inhibitors. However, cautious use of COX-2 inhibitors should be exercised due to its potential cardiovascular risks.(77) Long term use of opioid is discouraged because there is a risk of developing narcotic bowel syndrome, a side effect related to chronic use of opioid, characterized by unexplained abdominal pain and worsen with increasing opioid dose.(78) Opioid may also increase the risk of serious infection as it masks the early signs of infection.(79) Therefore, pharmacist should help monitor patients’ conditions and screen individuals who are at risk for opiate abuse.  

Regular monitoring the signs and symptoms of infections is important, as the use of mABs is associated with a risk of TB and hepatitis reactivation.(73) Antiviral treatment should be initiated for patients detected with positive HBV DNA prior to the use of mABs.(73) Prophylactic treatment should also be initiated for patients diagnosed with latent TB to prevent reactivation.(73) mAB is then initiated at least 3 to 4 weeks after the use of anti-TB medications.(73) Chest radiography and interferon gamma release assay (IGRA) should be performed every 6 months to 12 months to detect any active TB infection during the therapy.(73) Monitoring liver function for 6 to 9 months is also recommended after cessation of anti-TNF.(80)

 

 

CONCLUSION

 

Infliximab, adalimumab, vedolizumab and ustekinumab are the registered biologics in Hong Kong that indicate for moderate-to-severe CD. The selection of mABs depends mainly on patients’ conditions, including liver function, infection status, history of allergic adverse effects to mABs. Infliximab and adalimumab also suitable to pediatric patients who are ≥ 6 years old. All four mABs are of similar efficacy but associated with a higher cost than conventional treatments. Evidence from clinical trials and Asian consensus statement can help to guide healthcare professionals in prescribing mABs and monitoring parameters.

 

*School of Pharmacy, 8/F, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong

(#Corresponding author)

AU-DOUNG, Phillip Lung Wai is currently a year 4 Bachelor of Pharmacy student of The Chinese University of Hong Kong. His email address is phillipaudoung@link.cuhk.edu.hk.

CHAN, Jason Chi Hin is currently a year 4 Bachelor of Pharmacy student of The Chinese University of Hong Kong. His email address is 1155142302@link.cuhk.edu.hk.

CHENG, Andrew Foon Yu is currently a year 4 Bachelor of Pharmacy student of The Chinese University of Hong Kong. His email address is 1155126919@link.cuhk.edu.hk.

LAU, Anna Pak Yan is currently a year 4 Bachelor of Pharmacy student of The Chinese University of Hong Kong. Her email address is 1155143475@link.cuhk.edu.hk.

LEE, Dawn Kei Yan is currently a year 4 Bachelor of Pharmacy student of The Chinese University of Hong Kong. Her email address is dawnleekeiyan@gmail.com.

WU, Jason Tsun Sing is currently a year 4 Bachelor of Pharmacy student of The Chinese University of Hong Kong. His email address is 1155143854@link.cuhk.edu.hk.

SUN, Kiwi Wai Yan is a lecturer of School of Pharmacy, The Chinese University of Hong Kong. She is the corresponding author and her email address is kiwisun@cuhk.edu.hk.

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