Essay: Inflammatory bowel disease (IBD)

What is IBD?
Inflammatory bowel disease is a chronic disease which is dominated by inflammation in the gut. The inflammation is the result of an immune system defects inducing the production of adhesion molecules and inflammatory cytokines by specialized white blood cells called macrophages. (Katsanos et al, 2018). It is a life-long disease which can be treated but not cured. There are a vast number of treatments available which increase the overall quality of life, however treatments can be costly. Although immune system defects have been identified the exact cause of IBD is unknown. A combination of genetic susceptibility , environmental factors and altered gut microbiota are all linked to IBD. Genome-wide analysis has identified mutations in the NOD2 as an increase risk factor for IBD. The NOD2 plays a role in regulating the inflammation process and cell apoptosis. (Eckmann and Karin, 2005). Such advancements to identify specific environmental factors have not been made but studies exploring risk factors such as smoking, oral contraceptives, diet, breastfeeding, infections/vaccinations, antibiotics and childhood hygiene have been carried out, none have produced definite results. (Molodecky and Kaplan, 2010 ; Ogura et al, 2001). IBD can occur at any age but the majority of cases are diagnosed between the ages of 15 and 35. Crohn’s disease and ulcerative colitis are the major diseases which fall under the IBD title.
Prevalence:
IBD prevalence varies geographically with the number of cases and also the population growth rate significantly larger in western countries than in developing countries. (Tontini et al, 2015). Although incidence of IBD is stabilising in western countries, there has been an increase in the acceleration of incidence of IBD within developing countries which are have become industrialised over the past few decades. Although the incidence in these countries is still relatively low when compared to Europe and America the rate of increase in acceleration of incidence combined with the large population sizes of newly industrialised countries of India and China indicates that IBD is a global disease. The treatment of IBD in the western world has seen a large shift towards very effective biologic therapies in recent years. These biological therapies cost thousands of euro per patient per year which is a major limiting factor for healthcare systems and individuals in developing countries. The healthcare cost of IBD in Europe is estimated to be 4.6-5.6 billion euros a year .(Burisch et al, 2013). The incidence rates for CD in Europe is estimated to be 6.3 per 100,000 person-years and 9,8 per 100,000 person-years for UC. (Burisch and Munkholm, 2015; Van den Heuvel et al. 2017).
Diagnosis:
The diagnosis of IBD is based solely on invasive endoscopic, radiologic and histopathologic criteria. (Mitsuyama et al, 2016) . The majority of IBD patients can be categorized as having Crohn’s disease or Ulcerative colitis, however there is a small number, approx. 5% to 15% of cases who don’t meet the criteria for either. These patients are diagnosed with IBD type unclassified (IBDU). (Tontini et al, 2015). Both UC and CD are dominated by inflammation in the gut but the pattern of inflammation and how it appears differ. Although a large amount of the stage effector pathway of intestinal injury are similar in both UC and CD there is variance in some of the immune cell signaling and cytokines involved. Crohn’s disease affects the entire gastrointestinal tract discontinuously, it occurs in patches anywhere from the mouth to the perianal area. Type 1 Helper T cells have been identified as being involved in the pathogenesis of Crohn’s disease. The type 1 helper T-cell-mediated response is characterised by enhanced production of interferon-y(IFN-γ) and TNF-α. Interleukin-12(IL-12) and Interlukin-23(IL-13) control the differentiation of type 1 helper T-cells which TNFR2 receptors are expressed on. Ulcerative colitis affects the colon and only affects one block area rather than several patches along the tract like Crohn’s. The local response is less polarized in UC than in CD. It is characterised by cluster of differentiation 1 (CD1) natural killer t-cell production of interleukin-13 (IL-13). (Sanchez-Munoz et al. 2008). A modified TH2 cytosine is known to be involved. (de Lange and Barrett, 2015). Symptoms are rather similar between Crohn’s disease and Ulcerative colitis with diarrhea, abdominal pain, weight loss and fatigue are all reported. Bloody stool is more commonly reported in Ulcerative colitis.
Treatments
There are 5 medication categories for the treatment of IBD; Aminosalicylates, steroids, Immunomodulators, Antibiotics and Biologics. The two main aims of IBD therapies is firstly to achieve remission and then to maintain remission. Remission is defined as the reduction or complete absence of symptoms. IBD treatment is not one size fits all, treatment varies from one individual to another depending on the patient’s needs. IBD treatment is based on a traditional step-up plan where the patient is treated according to the severity of the symptoms.
Patients are placed on treatments based on disease severity, however there are flaws In the current system of defining the difference between mild, moderate and severe IBD. Systems often used in clinical trials for Ulcertaive colitis disease svereity calculation in patients include the Truelove and WItts Severity index and the Sutherland index. For Crohn’s disease the Crohn’s Disease activity index (CDAI), the Harvey Bradshaw Index and the Perianal Crohn’s disease Activity index are commonly used in clinical trail’s to access disease severeity and to monitor improvement.
The Trulove and Witts index is the most widely accepted index to desacribe Ulcerative colitis and is the most commonly used in clinical trials. Factors weighing on the diagnosis can be seen in include number of stools per day, precence of blood in stool, presence of fever, tachcardia level, presence of anemia which is deemed as less than 75% of normal haemoglobin concentration level in the blood and lastly Erthrpyte sedimentation rate which is the rate at which red blood cells sediment in a one hour period. (Wilhelm et al. 2017).
Truelove and Witts Severity Index for Ulcerative Colitis
Mild Severe
Number of stools per day <4 >6
Blood in stool +/- +
Fever – +
Tachcardia > 90 beats/min – +
Anaemia – +
ESR > 30mm/hour – +
ESR= erythrocyte sedimentation rate
-= symptom not present in patient
+= symptom is present in patient
*Moderate UC is described as symtoms between mild and severe
CDAI score is a commonly used score to determine the severity of Crohn’s in patients and it is influenced by a number of factors. Factors contributing to CDAI score include; number of liquid stools per 7 days, severity of abdominal pain, well-being on a weekly basis, complications present, abdominal mass presence and if the patient is consuminh anti-diarrheal medication. Each factor is assigned a different weighting score and the overall score allows the practioner to define the severity based on the total score. (Siegel et al. 2018; Peyrin-Biorulet et al. 2016)
Crohns Disease Activity Index Scoring
CDAI score
Remission <150
Mild 150-220
Moderate 220-450
Severe >450
Serum, genetic and mucosal markers can help divide UC and CD into sub-classes. There have been studies which have found correlation between the concentration of certain markers and the response of the patient with particular therapies. A high level of anti-neutrophil cytoplasmic antibodies can be associated with a subclass of UC patients but interestingly these high levels are also associated with non-response to anti-TNF therapy. (Taylor et al. 2001). Similarly an antibodies to the yeast Saccharomyces cerevisiae are associated with severe Crohn’s disease, defined by fibrostenotic and internal perforating disease in which minor-bowel surgery is needed. (Bilsborough et al. 2016). With studies showing this correlation there is a prospect of future treatment approach in which patients treatment is selected for is based on the sub-class in they fall into according to their there serum, genetic and mucosal markers.
In the past the first line of treatment for individuals with UC was treatment with
Aminosalicylates, steroids or immunosuppressants. Patients only escalated to more effective threapies when these lines had proven ineffective or they lost their response. These first line treatments were often ineffective at altering the course of the disease which is reflected in the high rate of surgery among patients. (Torres et al. 2017). There are multiple side effects associated with both short-term and long-term steroid therapy and it was found that many individuals experience disease recurrence upon discontinuation of use. The side-affects associated generally corelated with dose and duration of treatment. The side-affects coupled with the high number of patients who suffer from remission upon discontinuation of use associated with corticosteroids led to the development of Immunomodulators.
Antibiotics have been found to effective in the treatment of Crohn’s disease in some patients but there uses are very limited in the treatment of Ulcerative Colitis. (Podolsky, 2002). Standard treatment with Aminosalicylates, steroids or Immunomodulators is sufficient for remission induction in a large number of patients but only 50% of patients achieve sustained remission. These standard treatments were heavily relied on initially but with a mere 50% sustained remission rate and the numerous side-affects associated with them the reliance has been lifted and there has been a large increase in the number of patients treated with biologics in the past two decades. (Guo et al, 2013). The treatment goal of IBD has also evolved from aiming to control symptoms to now blocking the progression and interrupting the pathogenesis of the disease. With this the aim eveloved from achieving remission, which was reliant on clkincial symptoms, to achieveing deep remission which invloives clinical remsision, biomarker remission and mucosal healing.
These 3 treatments are regarded as the standard treatments in IBD however the high number of individuals which It is estimated that up to 70% of patients with Crohn’s disease undergo surgery.(20) Biologics started to be used Th17 cells identified in both ??—-22 Surgical treatment ??
WHAT ARE Antibodies ??
Different classes – heavy chain
Kappa lambda
IBD affects CELL WALL ETC
Antibody treatments
There is no exact definition of biologics as many different groups apply stricter required criteria for a drug to fall under the term. For the sake of this review the most generally accepted clinical trait for biologics will be accepted. This trait would be that biologics are produced within living systems. ***REWORD(Marrow and Felcone, 2004). The biologics market is continually growing, its global estimated worth in 2002 was $46 billion with that projected to rise to $390 billion by the year 2020, according to IMS institute for Healthcare Informatics. This increase in patients treated with biologics has reduced the number of surgeries required, extended the remission period and decreased hospitalization. A large proportion of Biological drugs are Antibodies. These Antibodies and particularly monoclonal antibodies targeting TNF alpha have proven to be specialists in IBD treatment. (Zheng et al. 2017).
In 1997, Targan et al. completed the first randomised control trial of anti-TNF treatment for Crohn’s disease. The anti-TNF used was infliximab and it was found to be effective at inducing and maintaining remission. (Targan et al. 1997). Since then IBD treatment has become more advanced with multiple antibodies targeting different pathways used to treat IBD. IBD has been revolutionised by the advancement of biologics in recent times, biologics have proven to be an effective therapy for inducing remission, maintaining remission and also prevention of long-term complications. For these reasons Monoclonal Antibody biologic therapies are now established as the most effective treatment therapies available however the costs of these therapies is a limiting factor.(Paramsothy et al., 2016). Biological therapies now include (1) monoclonal antibodies (mABs) that target TNF-α signalling which is a cytokine which plays a large role in the the inflammation processs in IBD, (2) mABs which target the α4β1(VLA-4) and the α4β7(LPAM) integrins which have both been identified as being involved in the extravasation of T-cells into the GI tract. (3) mABs which disrupt the IL12/23 pathways which play a role in the differentaiation of helper T-cells into type 1 helper T-cells.
Currently biologics are still all deemed as second-line therapies for when these first line treatments have failed but there have been studies to show early treatment with biologics may be more effective and beneficial for patients (studies of early tretamnet) . Until recently anti-TNF agents were the only remaining treatment option if treatment with coroticosteroids and immunomodulators had failed in patients with moderate-to-severe IBD. (Park and Jeen, 2018) With the advancement of biologic therapies came a clinical debate as to what was most effective treatment approach. Should patients treatment intensity be equal to their disease severity or should the traditional “step-up” approach be removed for a for a more modern approach in which patients were introduced to intensive treatments such as monoclonal antibody biologics from the onset rather than waiting on the increase in severity. (Stallmach et al, 2011) The goal of early intensive treatment is to avoid complications and to improve overall quality of life for patients. early intensive treatment could reduce the need for surgery and furthermore prevent bowel damage due to disease progression.
Drug Name Trade name Primary Target Administration FDA Approval EMA Approval Approved Biosimliars
(FDA) (EMA)
CD UC CD UC
Infliximab Remicade TNF Intravenous infusion over two-hour period 1998 2005 1999 2005 Inflectra (2016)(2013)
Renflexis (2017)
Flixabi ()(2016)
Remsima (NA)(2013)
Ixifi (2017)(NA)
Adalimumab Humira TNF Subcutaneously self-administered 2014 2012 2003 2003 Amjevita (2016)(2017)
Imraldi ()(2017)
Cyltezo (2017)(2017)
Hyrimoz (2018)()
Golimumab Simponi TNF Subcutaneously
self-administered NA 2013 2009 2009 No approved Biosimilars
Certolizumab Pegol Cimzia TNF Subcutaneously
self-administered 2008 NA NA NA No approved Biosimilars
Natalizumab Tysabri α4 Integrrin Intravenous-Infusion 2008 NA NA NA No approved Biosimilars
Vedolizumab Entyvio α4β7 Integrin 2014 2014 2014 2014 No approved Biosimilars
Ustekinumab Stelara IL-12/23 Initial Infusion, 2016 NA 2009 NA No approved Biosimilars
FDA-, FDA= Food and Drug Administration, EMA=, CD= Crohns Disease, UC= Ulcertaive Colitis , TNF= tumor necrosis factor EMA-, NA- Not Approved .
Anti-TNF-α
There a currently 4 approved Anti-TNF biologics; Infliximab, Adalimumab, Golumumab and Certollizumab. TNF stands for Tumor Necrosis Factor, it is a proinflammatory cytokine which has many biological roles such as in lipid metabolism, coagulation, insulin resistance and endothelial function. Cytokines are small peptide proteins which are produced by cells of the immune system. There are two forms of TNF-α; soluble TNF-α (sTNF) and transmembrane TNF-α (mTNF). mTNF-α is expressed by activated by macrophages and t-cells in inflamed mucosa. mTNF is a 26-kDa cytokine and it is the precursor of sTNF which is 17-kDa . The cleavage of sTNF from the cell surface of mTNF is carried out by TNF-α converting enzyme (TACE) and leads to sTNF being released. Both mTNF and sTNF are biologically active however sTNF has been found to be responsible for the majority of TNF-α induced responses. (Sedgaer and Mcdermott, 2014). There are two distinct receptors to which both TNF binds; TNF receptor 1 and TNF receptor 2. TNFR1 is 55-kDa receptor found on most cells where as TNFR2 is a 75-kDa receptor mainly found on endothelial and immune cells. (Aggarwal, 2003). mTNF has been found to have a higher binding affinity for TNFR2 than TNFR1. A study conducted by Komatsu et al in 2001 found serum concentrations of TNF-α to be 390-fold higher in IBD patients than in healthy donors. Another study conducted in 2007 by Spoettl et al. found a direct correlation between serum soluble TNF receptor I and II and disease activity in IBD patients. The binding of TNF initiates a cascade of events which are crucial in the pathogenesis of IBD. TNF disrupts the epithelial barrier, binds to receptors on the endothelium and is involved in the up regulation of the vascular cell adhesion molecule-1 (VCAM1), the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and E-selectin on the vascular endothelium of inflamed tissue. (Guo et al. 2013). The up regulation of these adhesion molecules leads to the migration of leukocytes to the inflammation site. The up regulation of the MAdCAM-1 expression levels has been linked with chronic inflammation in the small and large intestine of IBD patients. (Lawrance, 2014).
Fig3. Role of TNF in the pathogensis of IBD. (Neurath, 2014)
DESCRIBE DIAGRAM***
Anti-TNF-α biologics are monoclonal antibodies were initially thought to simply bind to the TNF-α and prevent it from interacting with TNF-α receptors on the cell surface and so reduce inflammation. (Lee et al. 2018) Further research has shown that anti TNF antibodies can induce monocyte and lymphocyte apoptosis, inhibit the up regulation of endothelium adhesion molecules like VCAM-1 and MAdCAM-1 and also restore the epithelial barrier. (Lugering et al. 2001). Infliximab is known as the first generation TNF agent as its success in IBD treatment lead to the introduction of a range of new anti-TNF agents. (Stallmach et al. 2010) . Although all of the anti-TNF agents work by interrupting the TNFα-TNFR interaction the new anti-TNF agents were developed and made with slight adjustments in an attempt to reduce the side effects associated and also to increase the overall half-life.
Infliximab is a chimeric monoclonal antibody which means it is not a fully human antibody. It is a purified, recombinant DNA-derived chimeric human-mouse IgG monoclonal antibody. It is 75% human and 25% murine. (Guo et al. 2013). It involves the generation of a murine anti-TNF hybridoma to produce human like antibodies. Infliximab is a chimeric monoclonal antibody and so human antichimeric antibody (HACA) formation can occur in the blood. This occurance has been associated with an increased risk of infusion reactions upon drug administration and reduced clinical efficacy. (Park and Jeen, 2015). The fab region of infliximab consists of both a heavy and a light chain while the Fc region consists of one heavy chain. The fab region which originates from mice binds to TNF. two domains that are composed of the constant region Fc and the variable region Fab, which binds to the antigen. The Fab region (VK and VH domains) that binds to TNF originates from mice, whereas the Fcγ1 isotope region is of human origin; the regions comprise approximately 25% and 75% of infliximab, respectively. The Fc region binds to both soluble and cellular membrane-bound TNF.
In contrast to this Adalimumab and Galimumab are fully human antibodies which are produced using Chinese Hamster ovary (CHO) cells. A 100% Human genetic sequence is designed and introduced into the CHO cells which then produces the antibody i.e. the genetic sequence does not contain any of the CHO DNA. An advantage Adalimumab and Galimumab share over infliximab is that they are fully human antibodies and so the patient is less likely to have a reaction upon administration. (Duomont et al. 2016). Mode of action ???
Certolizumab pegol varies greatly in comparison to the other anti-TNF antibodies. It is a PEGylated anti-TNFα agent. It consists of a human antigen-binding fragment (FAB) of a monoclonal antibody that targets TNFα attached to polyethylene glycol (PEG). (Goel and Stephens, 2010). The absence of the Fc region of the antibody means that Certolizumab pegol does not recruit effector cells and is not involved in fixation of complement which can lead to cell apoptosis. This attachment increased the half-life of the antibody. Infliximab, Adalimumab and Golimuab are all bivalent towards TNFα which can lead to the cross-linking of membrane bound TNFα resulting in polymeric biologic-ligan complexes. Certolizumab pegol differs to these agents in that it is univalent and therefore cannot cross-link. (Taylor, 2015). Mode of action ??
Although effective in most patients anti-TNF agents have been found to produce primary non-reponse in approx. 10-30%. (Roda et al. 2016). A number of gactors were suggested but the most interesting from a thereputic point of view was that in some patients TNF is not a major factor in development of inflammation. (Park and Jeen, 2018).
Anti-Integrins
Inflammation involves the transendothelial migration process of leukocytes to the site of inflammation. Leukocytes rely heavily on the interaction between their cell surface integrins and endothelial cell receptors, making the disruption of this interaction a treatment target for reduction of inflammation in IBD patients. (Lawrance, 2014). These cell surface integrins are heterodimeric receptors composed of α and β subunits. The two currently available anti-integrins are Vedolizumab and Natalizumab. Natalizumab targets the α4-intergin compoenent of the α4β7 and the α4β1 integrins . Vedolizumab binds exclusively to α4β7 integrins. The α4β1 is also known as very late antigen-4, or VLA-4 and the α4β7 integrin is also known lymphocyte Peyer’s patch adhesion molecule or LPAM-1 integrin. Natalizumab has not yet been approved in Europe and it has only been approved for the treatment moderate-severe Crohn’s disease in the US. The integrins which these agents target are expressed on the surface of leukocytes and they bind to vascular cell adhesion molecule-1 (VCAM1) and the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) cell surface receptors. (Yang et al. 1996). α4β1 also binds to certain forms of extreacallular-matrix (ECM) protein fibronectin and to osteopontin which results in further amplification of the inflammation response. Fibronectin is known to bind to TNF-α which promotes chemotaxis of monocytes. (Petrey and de la Motte, 2017).
The α4β1 integrin is an integrin which is expressed by intraepithelial T cells, dendritic cells and regulatory T cells. The α4β7 integrin is only expressed lymphocytes in the GI tract. This means anti-Integrins which target the α4β7 integrin are more specific to inflammation in the gut as this is only expressed on lymphocytes in the GI tract. (Lawrance, 2014; Yang et al. 1998).
Fig3. Leukocyte Migration interruption by Anti-Integrins
VCAM-1=vascular cell adhesion molecule-1, MAdCAM-1= mucosal addressin cell adhesion molecule-1
(A) Shows the migration of Leukocyte into the site of inflammation through the interactions of α4β7 and the α4β1 integrins and the VCAM-1 and MAdCAM-1 receptors. Leuckocyte migration leads to amplification of the inflammation
(B) With the introduction of Natalizumab and Vedolizumab the Leukocyte integrins cannot interact with the receptors and the leucocyte does not infiltrate.
(Lawrance, 2014)
Natalizumab was the first medication which disrupted the leukocyte migration process. It is a recombinant humanized monoclonal antibody. It is an Immunoglobin G4 antibody. Natalizumab was first released in US in 2004 for use in multiple sclerosis therapy but was removed 3 months later due to the development of three progressive multifocal leukoencephalopathy (PML) cases, two of which were CD patients. It was re-released in 2005 to be used in MS therapy before being approved in 2008 for the treatment of CD patients who had failed to respond to anti-TNF agents. (Armuzzi and Felice, 2013). Possible reason for this PML development is natalizumab binding to α4β1 integrins which inhibits t-cell homing to the brain. This PML development is not a risk with Vedolizumab due to it being specific antibody towards α4β7 integrins. (Neurath, 2017). The risk of developing PML has limited Natalizumabs use as an IBD therapy and the lack of more extensive studies has stalled Natalizumab FDA approval for UC and its EMA approval for both CD and UC.
Vedolizumab is like Natalizumab a humanized monoclonal antibody. Vedolizumab is an immunoglobin G1 antibody. It is manufactured using recombinant CHO cells which release the antibody into culture medium which is then purified.
mode of action
Clinical trials
Anti-Interleukin
CD4+ T cells play a vital role in the mediation of adaptive immunity but also play a role in autoimmunity. There are several distinctive populations of differentiated CD4 T cells; T helper (Th) 1, Th2, Th17 and regulatory T cells (T reg). A group of cytokines known as Interleukins play a key role in the differentiation process of an activated CD4+ T cell.
ROLE IN IBD ? enhancing immune reponse leading to inflammation etc….
In Th1 and Th2 development IL-12 and IL-4 cytokines play pivotal influencing roles. IL-12 is produced by activated inflammatory cells such as dendritic cells and phagocytes (macrophages and neutrophils), its presence is crucial in the differentiation of CD4+ T-cells into Th1 cells. These cells are activated by intracellular pathogens. Th1 cells produce interferon γ, TNF alpha and TNF beta. Interferon γ, also secreted by Natural killer in response to IL-12, stimulates further secretion of IL-12 by macrophages which stimulates further th1 differentiation. Th1 cells are involved in activating delayed hypersensitivity reactions. (Lafille, 1998; Galves, 2014).
In the presence of IL-4 CD4+ T-cells differentiated into Th2 cells. CD4+ and NK1.1+ cells are the initial source of IL-4. (Yoshimoto, 2018). Th2 cells produce IL-4, IL-5, IL-6, IL-13 and TNF alpha. Similarly to Interferon γ production by Th1 cells stimulating further Th1 differentiation, the production of IL-4 by Th2 cells stimulates further Th2 cell differentiation. Th2 cells trigger type 1 hypersensitivity reactions.
Th1 and Th2 cell differentiation is an antagonistic process. High levels of IL-4 or IL-6 will induce Th2 cell differentiation and block Th1 cell generation even in the presence of IL-12. The production of IL-10 by Th2 cells inhibits macrophage functions, one of which functions includes the production of IL-12. Simialrly interferon γ which is produced by Th1 cells blocks the proliferation of Th2 cells. Th1 and Th2 differentiation is considered mutually exclusive.(Lafille, 1998; Korn et al. 2009).
Initially IBD was thought to be primarily mediated by Th1 and Th2 cells. A third subset of T helper cells known as Th17 have recently been The Th17 seems to act as a back-up to Th1 and Th2 cells by dealing with pathogens of which they have not adequately dealt with. Th17 cells have also been noted to induce inflammation which makes them a key player on the pathogenesis of IBD. The differentiation of the naïve CD4+ t cell into Th17 requires TGF beta along with cytokines IL-6 and IL-23. (Korn et al. 2009).
Regulatory T-cells are a specialized set of T-cells which suppress immune response. They suppress the immune response through the inhibition of t-cell proliferation and cytokine production. (Kondĕlková et al. 2010). The differentiation of these cells is dependent on IL-2 and TGF-beta. The number of peripheral T-reg cells, the phenotype and function of these cells have been found to be significantly different in IBD patients than in healthy control patients.(Kullberg et al. 2005; Eastaff-Leung et al. 2010).
The major role of Interleukins in the amplification of T-helper cell differentiation and the subsequent amplification of the inflammation process makes them a primary antibody treatment targets in an attempt to squash the inflammation process and ultimately block the progression and interrupt the pathogenesis of the disease.
Fig4. Differentiation of Naïve CD4+ T-cell into Helper T-cells and the Cytokines involved .
IL= Interleukin, TH= Helper T cell, TGF= transforming growth factor, T reg= regulatory T cell, IFN=Interferon
Ustekinumab is a fully humanized IgG1 kappa (κ) monoclonal antibody which targets IL-12 and IL-23. It is the only approved antibody which targets IL-12 AND IL-23 for the treatment of Crohn’s disease. More specially it binds to the p40 subunit of IL-12 AND IL-23. Once bound Ustekinumab prevents IL-12 and L-23 from binding to the IL-12 β1 subunit of the IL-12 and IL-23 receptor complexes and so reduces the immune cell activation which leads to amplification of inflammation.
Ustekinumab was developed by Centocor research & development which is a division of division of Johnson & Johnson Pharmaceutical Research and Development. It was generated using human ig(hu-Ig) transgenic mice in which the four of the mouse Ig loci are replaced with human antibody transgenes. (Benson et al. 2011).
Ustekinumab is not yet approved for UC treatment however in November 2018 Janssen reported positive data from a Phase 3 trial known as the UNIFI study which aimed to evaluate the efficacy of ustekinumab induction and maintenance therapy in patients with moderate to severe UC. The study has so far shown that Ustekinumab is effective at enducing remission in patients with moderate-to severe UC when compared to the remission rates of those patients who received placebo. With trials producing such positive results its FDA and EMA approval for UC treatment looks imminent. Providing another effective therapeutic option for patients. (REFERENCE)??
Emerging Antibody Drugs for IBD treatment:
With the success of Vedolizumab further therapies targeting the translocation of lecuocytes have been developed aand are currentky being clicnically tested. Such antibodies include PF-00547659 which is an anti-MAsCAM1 antibody and Etrolisumab which is an anti-β7 integrin. (Vermiere et al. 2017; Vermiere et al. 2014).
There has been a large amount of research aimed towards developing new effective antibodies which target the proinflammatory cytokines in recent years. Antibodies which target IFNγ (Fontolizumab), IL-17A (Secunkinumab) and IL-13(anrukinzumab, tralokinumab) have been developed however clicnical trails have returned disappointing results. (Reinisch et al. 2006; Hueber et al. 2012; Lee et al. 2018; Maxwell et al. 2015).
Targetting Th17 ?? PF-00547659{Citation}
Issues aside from general side-effects of Individual antibodies ?
Immunogencity:
Immunogencity is the ability of foreign substance to provoke a specific immune response in the body. Most biopharmaceuticals induce immune response but in many cases the reposnse does not have clinically relevant consequences. Even the fully humanized Antibodies are immunogenic and there is the possibility of the antibody provoking an immune response although the risk is considerably lower than in chimeric antibodies. Antibodies are part of the immune response provoked by foreign molecules. The presence of antidrug antibodies produces by a patient’s immune system can alter the efficacy and safety of a drug. This response can sometimes cause unpredictable side effects and lead to loss of response. (Bendtzen, 2015). The immunogenicity of a particular drug is influenced by multiple factors, not all of which are fully understood yet. A simple switch to a biosimilar is not always an option as it is possible for these anti-drug antibodies to also recognise biosimilars of the drug and therefore inhibit the biosimilars to the same degree as the reference drug. (Ben Horin et al. 2016).
Solving Immunogencity problems with concomitant use of Immunomodulators and methotrexate ?? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974514/ PLAMETRA STUDY.
Pharmacokinetic Failures:
https://www.ncbi.nlm.nih.gov/pubmed/25724455/
Pharmokinetics refers to the absortion, distribution, metabolism, bioavailability and excretion involved in the passing of a drug through the body. These factors vary largely depending on the patients age, sex, age, body mass, disease severity. The chemical properties of the drug can also influence its Pharmokinetics. In terms of biosimilar development the biosimilar must have the same PK profile as its referende drug. (Rosen et al. 2015). Can be reason for loss of response .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389569/
Maintaining Remssion ??
Side affects ??
Only for Prescribed for moderate to severe disease.
Cost:
https://www.nature.com/articles/nrgastro.2015.135#ref55
Although extremely effective therapies, the cost of these antibody therapies is a major issue world-wide. The Costs of Inflamatory Bowel Disease in the Neatherlands (COIN) study found that the majority of the healthcare costs associated with IBD are largely due to the cost of medications like anti-TNF therapy and hospilitalization and surgery cost only account for a minor section of the total costs in the Neatherlands. (Valk et al. 2014).
In Treatment is rather expensive, the annual cost of treatment with Remicade for a single patient in the UK is approx. £12,500. This high cost has driven the demand for the development of biosimilars in recent years. The two currently approved biosimilars to Remicade; Inflectra and Remicade offer a cheaper route to treatment with the average selling price (ASP) per 100mg (excluding provider mark-up) of remicade $785.73, while the ASP of Infelctra and Renflexis, $649.98 and $656.64 respectively. In terms of annual tretatments cost per patient (cost per dose x average number of doses per year-6.5); Remicade-$21,067, Inflectra-$17,428, Renflexis $17,606. (22)CT-P13.
Biosimilar Development:
The rising prevelance of IBD globally and the impending patent expiary has led to the development and to the production of biosimilars. Biosimilars have the potential to reduce the healthcare costs of Biologics significantly. Patents have a term of 20 years from the date of filling out the form in both the United states and in Europe with an exclusivity period of up to 12-years, according to the Biologics Price and Competition Innovation Act of 2009. (Blackstone and Joseph, 2013). The first biosimilar was approved in the EU in 2006. According to the EMA Biosimilars are medicines which are similar to another already approved biological medicine in terms of structure, biological activity and efficacy, safety and immunogenicity profile. The biosimilar has minor differences in terms of their production methods and complex nature. These minor differences must not result in any variance in safety, purity or efficacy. If a biosimilar meets the strict criteria it receives approval from the EMA and FDA for all the indications the reference product has been approved for. (Danese et al. 2015) The reduced research, reduced development and simpler approval pathway associated with Biosimilars allows them to enter the market at a reduced costs when compared to their reference drug. According to the Institure for healthcare Informatics the average price of a biosimilar is approx. 30% lower than the price of the reference drug. (IMS, 2011). It was estimated that biosmilars have the potential to lead to a $44 billion reduction in direct spending omn biologics from 2014 to 2024.(Mulcahy et al. 2018).
The patent on Remicade was held Johnson & Johnson and expired in 2015 in Europe and in the US in 2018. The expiry allowed a host of Infliximab biosimilars to enter the market (Table1). These biosimilars received approval from the FDA and EMA in the years just previous to the patent expiry but marketing must be held until the patent has expired. Once the patent The patent on Humira which was held by AbbVie expired in Europe in 2018 and in the US in 2016. However in 2017 Abbievie won a patent ligation battle with Amgen which prevented them from marketing their biosimilar Amjevita in the US until 2023. This also meant that other Humira biosimilars could not be marketed until then (Table1). The patent on is expected to expire in 2021 in the EU and 2024 in the US while the patent on Simponi is expected to expire in 2024 in both the EU and the US. (GaBi Journal, 2018). The impending expiration of these patents opens the door for new biosimilars to be developed.
NEW EMA GUIDLINE PASSED AND FDA REDUCES COST OF APPROVAL – ONLY 1 CLINCIAL TRIAL NEEDED ??
The potential savings which accompany biosimilars is evident in the case of infliximab and its biosimilars
Savings to patients because of biosimilars ? There are a number of approved biosimilars; Inflectra, was approved by the FDA in 2016 and Renflexis, was approved by the FDA in 2017 which are both biosimilars to Infliximab, Amjevita and Cyltezo are biosimilars to Adalimumab. https://academic.oup.com/ecco-jcc/article/7/7/586/407523
Optimal Antibody Therapy ?
IBD treatment is not one “size” fits all so the optimal therapy is the therapy which best suits the patient. When choosing the optimal therapy a number of factors may be taken into account by both the physician and the patient. This include but are not limited to disease severity, disease history, previous treatments, treatment costs, administration….
There is currently very miminal study done on the direct head to head efficacy of these antibody treatments. Each approved antibody has in various studies proven effective and safe in inducing remission and also to some degree maintaining remission.
Of the anti-TNF agents Infliximab must be administered over a two-hour period where as Adalimumab, Golumumab and Certollizumab are all subcutaneously slef-admisntered which presumably would be the preference of the majority of patients although not all. These tretamnets again would only suggested by the physician if he/she deemed the patient capable of self-administration.
In the absence of head to head to head trials involving biologic agents, cost of treatments might act as a guide to the choice of treatment.