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Abstract

Despite remarkable progress for management of moderate-to-severe IBD patients, there are significant rates of primary nonresponse, loss of response, and/or adverse events thereby necessitating additional treatment options. Additionally, the burden of intravenous administration or subcutaneous injection of biologics accompanied by associated high cost necessitate the development of alternative treatments. In recent years, remarkable research has focused on the development of oral small molecule agents. Fortunately, the rapidly growing number of targeted therapies with oral small molecule agents offer the advantage of ease of administration with the durable effectiveness and no downside of immunogenicity with relatively more safety profile compared to the FDA approved biologic agents with relatively lower cost in the management of patients with moderate-to-severe IBD. The purpose of this review article is to summarize available novel oral small molecule agents in treatment of patients with IBD. Two of the oral small molecule agents, tofacitinib and ozanimod were already approved by the FDA for patients with moderate-to-severe ulcerative colitis. We will not include other emerging therapeutic modalities such as microbiome targeted or stem cell therapies in this review.

Introduction

Inflammatory bowel disease (IBD) including ulcerative colitis and Crohn’s disease are chronic relapsing disorders of intestinal inflammation which leads to decreased quality of life, disability, and bowel damage resulting in hospitalizations and surgeries [1]. Several genetic models have been developed for the inflammatory cascade that leads to the chronic inflammation seen in IBD, but none of these models have been able to account for all the observed pathophysiologic features. This complexity is probably secondary to the intricate nature of IBD and an incomplete understanding of the interactions between the mucosal immune system and the intestinal microbiota [2]. The current goal of treatment is to achieve clinical, endoscopic and histologic remission of disease activity. Management of IBD is generally divided into induction and maintenance phases. These phases involve achieving remission of inflammation quickly usually over a 2-3 month period and then maintenance of that clinical and histologic remission beyond that point Table 1.

5-ASA acts as a topical anti-inflammatory agent that has efficacy within the lumen of the intestine [3]. Although its use is well established in ulcerative colitis, its efficacy in its effect in Crohn’s disease is not better than placebo. Mild-to-moderate ulcerative colitis can be managed with oral 5-ASA treatments, but is not effective for moderate-to-severe disease. Older treatments for moderate-to-severe IBD include steroids and thiopurines including azathioprine, mercaptopurine, and methotrexate Table 2. Despite the efficacy of prednisone in improving acute symptoms of IBD patients, they have not consistently demonstrated effectiveness in controlling histologic inflammation. In addition, side effects related to long term use of steroids can be debilitating including but not limited to insomnia, personality changes, acne, fatigue, and weight gain. Alternative agents such as the oral controlled ileal release budesonide have been developed. Budesonide is efficacious in the management of inflammation in the terminal ileum and right colon. This makes budesonide effective for short-term relief of symptoms for mild-to-moderate IBD but not a good long-term option. The efficacy of thiopurines to maintain medically induced remission as well as to prevent post-operative recurrence in IBD has been well established. In the SONIC trial, the mucosal healing rate in patients in clinical remission was not significantly different between the azathioprine and anti-TNF monotherapy arms (36% vs. 43%) [4]. Despite their effectiveness many patients elect to stop thiopurine therapy. Up to 40 percent of patients discontinued thiopurine therapy in the first 4 months of treatment due to intolerance or ineffectiveness [5]. In addition, there is no doubt that thiopurines safety profile is inferior as there is a significant risk of developing lymphoma and non-melanoma skin cancer [6]. No satisfactory management of IBD was achieved prior to the development of infliximab. Current recommendations for the management of IBD with biologics include the use of early therapy with a treat-to target strategy to achieve clinical remission, mucosal and histologic healing which ultimately decrease the risk of corticosteroid use, surgeries, hospitalizations and increases quality of life [7]. Available biologic agents include anti-tumor necrosis factor alpha (TNF-a) agents including infliximab, adalimumab, certolizumab, and golimumab; anti-integrin agents including vedolizumab and natalizumab; and anti-interleukin (IL) 12-23 agents such as ustekinumab. Unfortunately, despite remarkable progress in the management of moderate-to-severe IBD patients, there are significant rates of primary non-response, loss of response, and adverse events, thereby necessitating additional treatment options. Additionally, the burden of intravenous administration or subcutaneous injection accompanied by associated high cost necessitate the development of alternative treatments. In recent years, remarkable research has focused on the development of oral small molecule agents Table 3. Unlike antibodies that can develop with biologic agents, oral small molecule formulations do not carry the same risk of immunogenicity. Their molecular characteristics and size allow for a more convenient oral administration and avoids the potential development of anti-drug antibodies. The purpose of this review article is to summarize available novel oral small molecule agents in treatment of patients with IBD. Two of the oral small molecule agents, tofacitinib and ozanimod were already approved by the FDA for patients with moderate-to-severe ulcerative colitis. This review will not include other novel and emerging therapeutic modalities such as microbiome targeted or stem cell therapies.

JAK Inhibitors

One of the new treatment strategies that has been developed is the targeting of the Janus kinase (JAK) family of tyrosine kinases [8]. The functions of this family of tyrosine kinases is broad, but evidence suggests that innate and adaptive immune responses require JAK-STAT signaling to mediate several pathways of cytokine function. These agents inhibit cytokines in the inflammatory cascade such as IL-9, IL-12, IL-23 and interferon-gamma. Several studies have supported this hypothesis by demonstrating significant upregulation of JAK transcripts in intestinal mucosa of patients with active ulcerative colitis [9]. These facts make targeting the JAK-STAT an appealing therapeutic modality in IBD. This has led to the development and regulatory approval by the United States Food and Drug Administration (FDA) of therapies targeting the JAK pathway for the treatment of IBD [10]. One of those therapies is a non-specific pan-JAK inhibitor tofacitinib, which was approved by the FDA in 2018 for the treatment of patients with moderateto- severe ulcerative colitis. The Octave trial which included the phase 3 clinical trial that led to the regulatory approval of tofacitinib for the treatment of ulcerative colitis included patients randomly assigned to 10 mg of tofacitinib twice daily or placebo for 8 weeks. Clinical remission (determined to be a Mayo Clinic score of less than 2 and a rectal bleeding score of 0) at 8 weeks occurred in 18.5% of patients assigned to tofacitinib versus 8.2% of patients assigned to placebo (P = 0.007) [11]. The Octave sustain maintenance study re-randomized week 8 responders to receive 10 mg or 5 mg of maintenance tofacitinib twice daily or placebo for 52 weeks. Remission at 52 weeks was significantly higher in patients treated with 5 mg (34.3%) and 10 mg (40.6%) of tofacitinib than with placebo (11.1%; p<0.001 for both comparisons with placebo). Notably, tofacitinib has a rapid onset of induction and has shown to be effective in refractory anti-TNF exposed ulcerative colitis patients compared to placebo [12]. Similar studies in patients with Crohn’s disease failed to achieve primary and secondary endpoints though there were modest improvements in inflammatory markers; this was probably due to the study design and unusually high placebo response rate seen in the study [13]. Clearly more research in the use of tofacitinib is needed to elucidate its efficacy in patients with Crohn’s disease. This data makes tofacitinib an attractive treatment option for patients with moderate-to-severe ulcerative colitis. However, tofacitinib can inhibit the immune system to a degree that increases the risk of herpes zoster, serious bacterial infections, tuberculosis, and upper respiratory tract infections [14]. The safety committee of the European Medicines Agency performed a review of tofacitinib due to the concern for an increased risk of developing pulmonary embolisms [15]. Subsequently, the FDA released warnings about the risk of blood clots leading to a boxed warning. All patients irrespective of their risk factors for developing thromboembolism should be monitored for signs and symptoms of pulmonary emboli. Sudden death in patients using high doses of tofacitinib was seen in patients primarily with rheumatoid arthritis and not with inflammatory bowel disease [16,17]. Another important concern related to the use of tofacitinib is the increased risk of lymphoma and nonmelanoma skin malignancies [18]. In a recent study, 1455 patients receiving tofacitinib at a dose of 5 mg twice daily and 1456 patients receiving tofacitinib at a dose of 10 mg twice daily were compared to 1451 patients receiving a TNF inhibitor. Over a 4 year follow up period, incidences of cancer and major cardiovascular events were higher in patients receiving the combined tofacitinib doses (4.2% and 3.4%, respectively) than with a TNF-alpha inhibitor (2.9% and 2.5%) [19]. The hazard ratios were 1.33 for major cardiovascular events and 1.48 for cancer (particularly non-melanoma skin cancer); the non-inferiority of tofacitinib was not demonstrated. Rarely, gastrointestinal perforations can occur during tofacitinib therapy with data demonstrating and incidence of 0.2% [20]. It is important to remember that patients should be advised to reduce their dose of tofacitinib in half when combining treatment with cytochrome P450 inhibitors such as fluconazole and ketoconazole.

Selective JAK inhibitors have also been recently studied for the treatment of patients with IBD, including Crohn’s disease. Filgotinib, is a selective JAK inhibitor that was approved by the FDA for the treatment of rheumatoid arthritis. Filgotinib selectively targets the JAK1 cytokine at a 30-fold selectivity over JAK2. JAK2 inhibition is thought to lead to higher rates of anemia and thrombocytopenia through the interfering of erythropoietin and thrombopoietin and granulocyte-macrophage colony-stimulating factor which would make selective JAK1 inhibition an attractive option [21,22]. The phase II Fitzroy study demonstrated early clinical benefit of filgotinib in patients with Crohn’s disease. Fitzroy included patients with a disease activity score (CDAI) of 220-450 and confirmed endoscopically active Crohn’s disease. A total of 174 patient with moderate-to-severe active Crohn’s disease were randomly assigned to receive 200 mg of filgotinib daily or placebo for 10 weeks. Clinical remission (indicated as a CDAI score of <150) at 10 weeks was achieved in 47% of patients treated with filgotinib and 23% of patients who were given placebo (P = 0.0077). Endoscopic improvement at 10 weeks was not significantly different [23]. The phase II study, Divergence 2, examined the effect of filgotinib in patients with perianal fistulizing Crohn’s disease. Patients with a documented history or perianal fistulizing Crohn’s disease with at least one to two external openings with drainage previously treated with immunomodulators or anti-TNFs were randomly assigned to receive filgotinib 200 mg, 100 mg or placebo once daily for 24 weeks. The primary endpoint was fistula response with a reduction of greater than 1 from baseline in the number of fistulas and no fluid collections seen on MRI at week 24. Unfortunately, the study was not well powered as there was low recruitment rates due to the COVID-19 pandemic leading to a total of 57 participants. Results did demonstrate a numerically higher proportion of patients in the filgotinib 200 mg group (47%) versus the placebo group (25%) who achieved the primary endpoint [24]. Further studies with a large patient population will be required to further elucidate the efficacy of filgotinib in patients with fistulizing Crohn’s disease.

The Selection trial included two induction studies, a maintenance study, and a long- term extension study examining the efficacy of filgotinib in the treatment of moderate-to-severe ulcerative colitis. Adults with moderate-to-severe ulcerative colitis were randomized to filgotinib 200 mg, 100 mg or placebo once daily for 11 weeks. Patients who responded to selected treatment at week 10 were re-randomized to continue filgotinib or placebo for an additional 47 weeks. Clinical remission was evaluated at week 10 and 58. Filgotinib demonstrated clinical remission rates significantly improved over placebo (47% vs 23%) at 10 weeks. Secondary endpoints such as endoscopic remission, mucosal healing, and deep remission did achieve numerical improvement but failed to achieve statistical significance. At week 58 remission was achieved at a rate of 58% in the filgotinib group compared to placebo at 29.5%. These findings suggest that filgotinib is efficacious at inducing and maintaining remission in patients with ulcerative colitis. Due to the efficacy demonstrated by filgotinib regulatory approval for use in moderate-to-severe ulcerative colitis as well as Crohn’s disease is expected soon. The common side effects reported in patients taking filgotinib are quite similar to tofacitinib including but not limited to serious infections, herpes zoster, venous thrombosis, pulmonary embolism and gastrointestinal perforations [25,26]. It is of note that filgotinib was rejected for approval by the FDA in the treatment of rheumatoid arthritis on concerns of toxicity and reduced sperm count [27,28]. Two ongoing trials (MANTA and MANTA-Ray) are pending and will provide additional safety data on the matter in patients with IBD.

Another highly selective JAK inhibitor that was approved by the FDA for use in patients with rheumatoid arthritis, psoriatic arthritis, and atopic dermatitis and also has been studied for its potential benefit in IBD patients is upadacitinib. This molecule is even more selective for JAK1 then filgotinib and has been investigated in the Celest phase 2 trial [29,30]. Patients with ulcerative colitis who had been previously exposed to anti-TNFs were evaluated after 16 weeks for primary endpoints of clinical remission, which included a patient reported outcome of stool frequency and abdominal pain score. In the induction phase of the study, although a numerical benefit in clinical remission could be observed in the group on twice daily 6 mg upadacitinib, it did not demonstrate a statistical response over placebo. The phase II study showed that the clinical remission and endoscopic improvement were achieved better than placebo as well as reduction in inflammatory markers. Phase III clinical trials of upadacitinib are ongoing and will hopefully shed more light on its efficacy and risk profile. Upadacitinib has similar adverse events as seen with tofacitinib including major adverse cardiovascular events and serious infections [31]. Due to the concerns of significant adverse events with tofacitinib, filgotinib, and upadacitinib, the development of a more gut selective pan-JAK inhibitor has been investigated. TD-1473 is a pan-JAK inhibitor that has demonstrated such a gut selective effect on mice with in-vitro studies [32]. A Phase 2b/3 set of clinical trials is currently ongoing to assess the efficacy and safety of induction and maintenance therapy with TD-1473 in subjects with moderate-to-severe active ulcerative colitis. Preliminary results were promising in endoscopic improvement along with reduction in fecal calprotectin and CRP levels with TD-1473 compared to placebo. If its further effectiveness can be demonstrated with this pending trial it has the potential to limit severe systemic side-effects caused by other non-GI selective JAK inhibitors. TYK2 is one of the JAK-STAT family proteins that is involved in intracellular cytokine signaling and inhibition of which blocks IL-12, IL-23 and IFN [33]. The oral TYK2/JAK1 inhibitor is well tolerated and more selective than other JAK inhibitors potentially limiting toxicity. Two oral TYK2/JAK1 inhibitors, deucravacitinib and brepocitinib, are currently recruiting in phase II clinical trials for the treatment of moderate-to-severe ulcerative colitis and also, Crohn’s disease.

Sphingosine-1-Phosphate Receptor Modulators

Sphingosine 1- phosphate (S1P) receptors are G protein coupled receptors (S1P1-S1P5) that regulate the response and function of various cellular and organ systems including cell migration, proliferation, immune response, and trafficking of T and B lymphocytes from lymphoid organs [34,35]. Their role in the ability of immune cells to migrate to inflamed tissues has made them a potential new target of inhibition for the management of IBD. Ozanimod is a new oral small molecule agent that binds with high affinity to several S1P receptor subtypes leading to internalization of the receptor in targeted lymphocytes and prevention of lymphocyte trafficking [36]. Ozanimod was approved for the treatment of the patients with relapsing multiple sclerosis in 2020 and then for patients with moderate-to-severe ulcerative colitis in 2021 by the FDA. Sandborn et al performed a phase III double blind and placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderate-to-severe ulcerative colitis [37]. Patients were assigned to receive oral ozanimod 1 mg or placebo once daily and patients in a second cohort received open label ozanimod. They found that clinical remission was significantly higher in patients who received ozanimod than those who were on placebo (37% vs 18.5%, P<0.001). Clinical response was also significantly higher in the ozanimod group (60% vs 41%, P<0.001). The investigators found that rates of serious infection were equal in both groups. A few patients on ozanimod had higher rates of elevated liver transaminases. Adverse events have been reported with ozanimod treatment including herpes zoster, bradycardia, and elevation of liver enzymes, atrioventricular conduction delays and macula edema. Ozanimod is also being studied for the treatment of Crohn’s disease. In the phase II Stepstone study involving 69 patients with Crohn’s disease, 39.1% of patients who received ozinamod had clinical remission at week 12. There was no incidence of bradycardia or arrhythmias in these patients [38]. Phase III, placebo-controlled induction and maintenance studies of ozanimod are currently recruiting for moderate-to-severe Crohn’s disease. Etrasimod is another oral S1P receptor subtype 1 modulator which has demonstrated potential efficacy in the treatment of patients with IBD. In the phase II Elevate trial involving 156 patients with ulcerative colitis, those patients receiving a 2 mg dose of etrasimod demonstrated endoscopic improvement over placebo (41.8% vs 17.8%, P=0.003). Also, compared to placebo, the etrasimod 2 mg group had a higher rates histologic remission (19.5% vs 6.1%; p=0.03). Etrasimod adverse events were reported as minimal with a small group of patients developing a transient, asymptomatic, low grade atrioventricular block that resolved spontaneously. Amiselimod is an oral S1P receptor modulator with higher selectivity for S1PR1 than other S1P receptor modulators [39]. A phase II trial with this agent is pending in patients with active Crohn’s disease.

Anti-Adhesion Molecules

Migration of proinflammatory T cells into the gut facilitates inflammation that is characteristic of IBD [40]. Anti-adhesion agents that block lymphocyte trafficking to the gut are being investigated in patients with IBD. A variety of oral small molecules including alfa-4 integrin antagonists have been studied. AJM300 is an oral small molecule agent that targets alfa-4 integrin. A phase II study in 102 patients with moderate-to-severe ulcerative colitis showed higher rates of clinical response (62.7% vs 25.5%, p=0.0002), clinical remission (23.5% vs 3.9%, p= 0.0099) and mucosal healing (58.8% vs 29.4%) [41]. No major adverse events were reported. A phase III trial is ongoing with AJM300 in patients with ulcerative colitis. There is extensive research of other anti-adhesion agents in the treatment of inflammatory bowel disease.

Phosphodiesterase 4 Inhibitors

Phosphodiesterase 4 (PDE4) is part of a group of enzymes that catalyze the breakdown of cyclic adenosine monophosphate (cAMP). In inflammatory cells, PDE4 is the dominant enzyme responsible for this reaction and the resulting decrease in cAMP levels leads to an increase expression of proinflammatory factors. Thus, it has been postulated that if PDE4 were inhibited the resulting increase in cAMP levels would lead to the decreased expression of a number of proinflammatory factors including TNF-alfa, IL- 17, IL-23, and up-regulates anti-inflammatory IL-10 [42]. This makes PDE4 a potential target for the treatment of inflammatory disorders. Apremilast is an oral small molecule PDE4 inhibitor which has been approved by the FDA for the treatment of adults with psoriatic arthritis, plaque psoriasis, and Behcet’s disease. A recent phase II clinical trial demonstrated the clinical effectiveness of apremilast in the treatment of moderate-to-severe ulcerative colitis. The investigators performed a double-blind, placebocontrolled trial in patients with active ulcerative colitis who were either biologic naïve or had failed conventional therapies. Patients were randomly assigned to apremilast 30 mg twice daily, 40 mg twice daily, or placebo for 12 weeks. After which patients were then randomly assigned to receive apremilast 30 mg or 40 mg twice daily for an additional 40 weeks. Endoscopies were performed and biopsies were obtained at the initial encounter, week 12, and week 52 after initiation of the study. The primary endpoint for the study was clinical remission at week 12 (a Mayo score of 2 or less). The investigators found that clinical remission was achieved in the 30 mg apremilast group at a rate of 31.6% versus 12.1% of patients in the placebo group (P = 0.01) [43]. Both apremilast groups (the 30 mg and 40 mg groups) had similar improvement from baseline in Mayo score components. At week 52 clinical remission was achieved by 40.4% of patients. Endoscopic healing was achieved in 41.4% of patients in placebo compared to 73.7% in the 30 mg group (p< 0.0001). Moreover, both the 30 mg and 40 mg apremilast groups showed greater reduction in serum C-reactive protein and fecal calprotectin compared to placebo. In terms of safety, headache and nausea were found to be the most common side effect. One patient had an episode of acute pancreatitis but this was no attributed to the study drug. Currently, a phase III trial has not been registered for patients of ulcerative colitis or Crohn’s disease.

Anti-Tumor Necrosis Factor Agents

Anti-TNF agents were the first class of biologic medications approved for the treatment of patients with inflammatory bowel disease [44]. Limitations of this class of medications includes the intravenous or subcutaneous administration, infusion reactions, systemic side effects related to immunosuppression, and high cost [45]. An oral agent with a mechanism of action restricted to the gastrointestinal tract would be helpful to overcome some of these challenges of parenterally administered anti-TNF agents. AVX- 470 is an oral polyclonal immunoglobulin that inhibits TNF-alpha locally in the gastrointestinal tract, minimizing systemic exposure [46]. In a double blind, placebo-controlled trial, 37 patients with active ulcerative colitis received AVX-470 (0.2, 1.6, or 3.5 grams per day) or placebo for 4 weeks. Endoscopic activity was assessed pre and post treatment exposure.46 At all AVX-470 doses, 25.9% of patients achieved clinical response compared with 11.1% of those in the placebo group. Both groups were found to have similar adverse event rates without significant infectious reported.46 Further clinical trials evaluating the efficacy of AVX-470 are ongoing [47,48]. OPRX-106 is another oral anti-TNF agent which is currently undergoing evaluation for its efficacy in the treatment of inflammatory bowel disease [49]. In a phase II randomized open label clinical trial, 25 patients with ulcerative colitis who were administered OPRX-106 demonstrated clinical remission and mucosal healing with no major adverse events including immunogenicity. Initial studies with oral anti-TNF agents have shown promising results with the potential for enhanced safety and decreased immunogenicity. However, larger trials are needed to evaluate efficacy, safety and cost effectiveness.

Conclusion

Despite tremendous advancements in the field of treatments for IBD, there are significant rates of primary non-response, loss of response, adverse events and high cost thereby necessitating additional treatment options. Fortunately, the rapidly growing number of oral small molecule targeted therapies offers ease of administration with durable effectiveness, and an improved safety profile compared to the currently approved therapeutic agents.

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Over View of Gastro Intestinal Diseases in UAE 

Short Communication

One fifth of the population in UAE suffers from gastrointestinal diseases including obesity, reflux disease and fatty liver because of obesity, poor diets and close marriage, Acid reflux, ulcerative colitis and irritable bowel syndrome are increasing in recent years [1-3]. There are also a high number of sufferers of fatty liver, caused to a large extent by the excessive consumption of sugary drinks. Obesity is an issue that can affect the UAE’s development as a nation and needs to be managed immediately and effectively, vague discomfort is usually the only symptom of a fatty liver. Low fiber diets, lack of exercise and consuming large amounts of food and dairy products are responsible for the majority. Genetics combined with obesity are responsible for people suffering from many disorders. A case of fatty liver, if ignored, might escalate to an advanced liver problem later in life.

Increasing numbers of inflammatory bowel diseases specially in the young and more severe forms of Crohns disease. Increasing numbers of cancers especially colorectal cancers affecting younger populations. During our practice in UAE we came across many rare and unusual disease presentations that were missed because of either lack of awareness or failure to check detailed history including family history and proper physical examination. These diseases included: Celiac disease which affect 2.3% of the population, Inflammatory bowel diseases both ulcerative colitis & Crohns disease with obvious rise in Crohns disease, Studies on colorectal cancer showed that over 60% are discovered in an advanced stage and affecting younger populations and because of that the health authorities started the program to prevent, early detect colorectal cancer. Our initial study of over 6000 colonoscopies showed prevalence of polyps over 30% and colorectal cancer in about 1% of all colonoscopies,20% of colorectal cancers were below the age of 40 years. Many families with inherited colorectal cancers including Lynch syndrome were seen. Constipation is a real problem in UAE sometimes ending in severe disability and sometimes colectomies performed for some refractory cases. Missed diseases included over 10 cases of multiple auto immune IGG4 related diseases that presented as pancreaticobiliary manifestation or multiple auto immune diseases, pachymengitis & mesenteric panniculitis. Many cases of hyper elasticity syndromes associated with reflux disease & 10 cases of vascular compression syndromes mainly superior mesenteric artery syndrome [4-10]. 4 cases of Behcet disease with intestinal involvement, 3 cases of Cowden disease, 2 cases of tylosis with reflux disease and esophageal & colon cancers, 1 case of Gardner syndrome. 1 case of Chédiak–Higashi syndrome syndrome with albinism & colitis. We are running monthly meetings for these unusual presentations of common diseases and rare diseases in UAE. Awareness for young colleagues in all specialties is needed in these diseases [11].

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Acute Upper Gastrointestinal Bleeding (UGIB) In A Resource Limited Setting Highly Endemic for Viral Hepatitis B: Which Etiologies for Which Real Clinical Practices? 

Abstract

Aim : To determine the aetiologies of acute upper gastrointestinal bleeding (UGIB) in a setting highly endemic for hepatitis B and to describe actual clinical practices in a resource-limited setting.

Patients and methods: This study was conducted in two parts. The first part was retrospective from January 1st 2010, to December 31st 2019 on the epidemiological profile of UGIB and the second was a prospective study from December 1st 2017 to May 31st 2018 to evaluate, in a blinded experiment, the actual clinical practices in front of an acute UGIB at the emergency units in Yaounde (Cameroon), and included: recognizing UGIB, assessing for severity, taking emergency measures and prescribing emergency Eosogastroduodenal endoscopy (EGDE).

Results : During the retrospective period, 506 patients (prevalence of acute UGIB in the services 5.6%) were included of which 71.3% were men (sex ratio 2.5). The mean age was 49.9 +/- 8 years. Haematemesis was inaugural in 350 patients (69.1%), nonsteroidal anti-inflammatory drugs were the main risk factor in 297 (43.6%), in 78 (15.4%), this was a second episode. Clinical parameters showed initial instability in 435 patients (85.9%) and haemoglobin (Hb) was <7g/dl in 359 (83.4%). EGDE was performed in 203 patients (40.2%), the main causes of UGIB were lesions of portal hypertension in 111 (44.7%), followed by peptic ulcers in 108 (43.5%). Treatment was mainly medical. However, 94 patients (84.7%) with portal hypertension lesions received endoscopic treatment, mainly by injection of sclerosing agent (69.1%), as well as 13 (1.2%) with peptic ulcers, mainly by isolated injection of dilute adrenaline (1: 10,000) in 11 (84.6%). A total of 75 patients (14.8%) died. The second part concerned 74 patients admitted for acute UGIB at the emergency services of five hospitals in Yaounde. To recognize UGIB, a digital rectal examination was done in 43 patients (58.1%), no patient received a nasogastric tube. For assessment of severity, blood pressure was taken in 73 patients (98.6%), pulse rate in 61 (82.4%), respiratory rate in 17 (23%), saturation in 17 (23%), no patient had prognostic scores in their record. For resuscitation measures, 10 patients (13.5%) received a double peripheral venous line, 20 (27%) were filled with crystalloids, restrictive blood transfusion (Hb < 7 g /dl) was carried out in 24 out of 27 patients (88.9%), 9 (12.2%) received nasal oxygen therapy. EGDE was carried out in 43 patients (60.6%), all beyond 24 hours and none had a prognostic score (Forrest or Rockall).

Conclusion: Rupture of oesogastric varices plays a significant role in the occurrence of UGIB in areas with high hepatitis B endemicity, with exceptional severity and high mortality among young people. The lack of qualified human resources and insufficient technical facilities constitute a serious problem. Locally applicable protocols are needed. In the long term, eliminating viral hepatitis B and C should reduce the prevalence of UGIB

Keywords:Gastrointestinal Bleeding; Hepatitis B Virus; Portal Hypertension; Limited Resources; Endoscopy; Clinical Practice.

Background

Acute gastrointestinal bleeding is one of the major medical and surgical emergencies whose severity should never be underestimated [1]. In approximately 80% of cases, acute gastrointestinal bleeding is of high origin, i.e. the aetiology of the bleeding is located upstream of the duodenojejunal angle or Treitz angle [2]. Acute upper gastrointestinal bleeding (UGIB) is the most frequent emergency in hepato-gastroenterology and remains a major cause of mortality, despite improvements in technical facilities, the mortality rate remains stable at about 10-15% [1-4]. The UGIB is exteriorized in 66% of cases in the form of hematemesis and the aetiologies involved are varied [2,5-7]. In the West, the proportion of peptic ulcers is significantly high. Indeed, the most common causes of acute UGIB are non-varicose (80-90%) and include gastric and duodenal ulcers in 20-50% [2,3,5-7]. Contrarily, in sub-Saharan Africa, the proportion of portal hypertension lesions is significant [8,9]. The impact of chronic hepatitis B virus (HBV) infection in this highly endemic area is significant. In highly endemic countries, ≥8% HBsAg positivity, the HBV-related disease burden is due to liver cancer and cirrhosis in adulthood, responsible for portal hypertension. The majority (80%) of the world population lives in high- or intermediate-endemic areas [10]. The way to handle acute UGIB is well codified. Gastrointestinal bleeding must be recognised, its severity assessed, and blood loss compensated. Finally, the cause of the bleeding must be found and treated [1,2,7,11]. The diagnostic approach, non-specific measures to prevent or treat haemorrhagic shock and specific haemostasis measures according to the aetiology of UGIB are often not all implemented in resources limited countries and this has an impact on evolution and prognosis. Based on data collected in the files of patients admitted in emergency and those obtained following the daily clinical practice of emergency staff, the study aimed to highlight the epidemiology and actual management of acute UGIB in our context dominated by HBV infection and limited resources.

Methods

A retrospective collection of data contained in the files of patients admitted for acute UGIB at the Yaounde Central Hospital (Cameroon) between January 1st2010 and December 31st2019, was carried out. Located at the heart of the city of Yaounde, the Yaounde Central Hospital (YCH) was created in 1930. It is the largest public referral hospital in Cameroon with capacity of …. Beds that also acts as a teaching hospital. It houses several services including the Hepato-gastroenterology service with a capacity of 34 beds, three university specialists, four general practitioners and several permanent workers and residents. This service has an upper and lower gastrointestinal endoscopy room and endoscopy equipment. The variables recorded included: demographics (age, sex); clinical and biological characteristics (onset of UGIB, history of bleeding, physical parameters of bleeding severity, and haemoglobin levels on admission); Esogastroduodenal endoscopy (EGDE) findings; specific management of the cause of the bleeding and outcomes (Table1).

Table 1: Clinical and biological parameters of 506 patients admitted at the Yaounde Central hospital for a recognized acute UGIB.

Table 2: Main causes of acute UGIB at the Yaounde Central Hospital amongst 203 patients who had an EGD.

The second component, cross-sectional and observational blinded experiments, conducted from December 1st 2017 to May 31st 2018, assessed the diagnostic approach and actual management of patients admitted for acute UGIB in five hospitals of different categories (1st to 3rd) of the Cameroonian health pyramid, in the city of Yaounde. Twenty (20) doctors and 39 nurses in the emergency service who managed 74 patients admitted for acute UGIB were followed. The elements to take care of acute UGIB included recognition of acute UGIB by placing a nasogastric tube or performing a digital rectal exam; assessment of severity by clinical criteria (taking blood pressure (BP), pulse rate (PR), respiratory rate (RR) and room oxygen saturation (SPO2), Glasgow- Blatchford score; fluid resuscitation and transfusions (double venous line, crystalloids filling, proton pump inhibitors (PPI) or vasoactive treatment, oxygenation, restrictive blood transfusion (haemoglobin (Hb) <7 g/dl), hourly monitoring of vital signs and neurological status) and finally, the performance of EGDE and the Rockall and Forrest scores.

Statistical Analysis

Data was analysed using Statistical Package for Social Sciences (SSPS Inc, Chicago, Illinois, USA) version 23.0. Means ± standard deviation was used for quantitative variables; Categorical data was expressed as numbers and proportions. A p value of less than 0.05 was considered statistically significant.

Results

During the retrospective period, 506 patients (prevalence of acute UGIB in the services 5.6%) were included of which 361 men (71.3% and 145 women (28.7 %), given a 2.5 sex ratio. The mean age was 49.9+/- 8 years (maximum 14-96 years) and the peak of bleeding was in the 55-65-year age group. Haematemesis was the initial complaint in 350 patients (69.1%), non-steroidal antiinflammatory drugs (NSAIDs) constituted the most important risk factor in 297 patients (43.6%), in 78 (15.4%). This was a second episode. On admission, clinical parameters relevant to severity were systolic BP <100 mmHg in 122 patients (39.8%); HR >100 beats/ minutes in 435 (85.9%) and RR >20 cycles/minute in 435 (85.9%). Hb was <7g/dl in 359 patients (83.4%). EGDE was performed in 203 patients (40.2%), the major causes of bleeding were: portal hypertension lesions in 111 patients (44.7%) followed by peptic ulcers in 108 (43.5%). Treatment was mainly medical. However, 94 patients (84.7%) with portal hypertension lesions received endoscopic treatment, mainly by injection of sclerosing agent (69.1%), as well as 13 patients (1.2%) with peptic ulcers, mainly isolated injection of dilute adrenaline (1: 10,000) in 11 (84.6%). A total of 75 patients (14.8%) died during hospitalization (Table 2).

The second part concerned the assessment of care offered to 74 patients admitted for acute UGIB (mean age 55 years; sex ratio 2.1). For the recognition of bleeding, digital rectal examination was performed in 43 patients (58.1%) and no patient received nasogastric tube. Regarding the assessment of severity by clinical criteria, BP was taken in 73 patients (98.6%), HR in 61 (82.4%), and RR in 17 (23%), no patient had prognostic scores in the record, including the Glasgow-Blatchford score. Only 17 patients (23%) had SPO2 measurements. Regarding intensive care measures, only 10 patients (13.5%) received a double peripheral venous line, the majority of which was a small-bore venous line. Twenty patients (27%) were filled with crystalloids; restrictive blood transfusion was performed in 24 out of 27 patients (88.9%) with Hb < 7 g / dl. Only 9 patients (12.2%) received nasal oxygen therapy. EGDE was performed in 43 patients (60.6%), all beyond 24 hours after admission and none had a prognostic score after endoscopy (Forrest or Rockall).

Discussion

The study showed that acute UGIB is an emergency with exceptional severity in our environment, as mortality is very high at around 15%. In this study, it was found that acute UGIB affected two and a half times more men than women with a mean age of about 50 years. This is the case in studies conducted in Mali (sex ratio 2.78; mean age 47.45 years), and in Côte d’Ivoire (sex ratio 3.38; mean age 47 years) [8,12]. Indeed, in the sub-Saharan African region, the occurrence of acute UGIB often involves relatively young patients. This can be explained by the fact that the causes of bleeding are often dominated by portal hypertension lesions, especially in young patients, as reported in Mali in a rural area [8]. As opposed to sub-Saharan Africa, in the West, the age of onset of acute UGIB is higher than 70 years due to the use of NSAIDs in the elderly population. Of chronic NSAID users, 25% develop an ulcer, of which 2-4% are complicated by bleeding [2,7,13,14]. The male predominance is universal, and reverses in the West after the age of 80 years due to the higher life expectancy in the female population [2,4,6-9, 11,13,14].

As in several studies reported in literature, hematemesis was the most common initial clinical presentation [2,6,7,15,16]. This initial clinical presentation can be explained by the different lesions found on endoscopy. In fact, portal hypertension lesions, led by oesophageal varices, were the most frequent, alongside peptic ulcers. The frequency of the various aetiologies varies from one region to another [5,6,8]. Thus, in the sub-Saharan African region, several studies report very high frequencies of portal hypertension lesions. This is the case of the study by Diarra et al. in Mali in 2007 [8]. The authors reported a frequency of 55.2% in favour of ruptured oesophageal varices, far ahead of peptic ulcers which represented 16%. The frequency of portal hypertension lesions is also high in Burundi (28.2%) [16] and Gabon (29.5%) [17]. These various countries have liver diseases related to chronic HBV infection in common. Indeed, sub-Saharan African countries are located in a zone of high endemicity according to the World Health Organisation (WHO), i.e. the prevalence of hepatitis B is 8-20% of the general population [10]. Cirrhosis, which causes portal hypertension, is often the result of chronic HBV infection acquired at birth or in early childhood [18]. The annual incidence of varicose veins is approximately 5% [19]. UGIB from ruptured esophageal varices accounts for 70% of gastrointestinal bleeding in cirrhosis, with an estimated overall 2-year bleeding risk of 20% [19]. The aetiological approach to acute UGIB in high- and intermediate-endemic areas where the majority (80%) of the world population lives should therefore consider this high frequency of portal hypertension lesions and bleeding complications.

Regarding the severity of the bleeding, more than 85% of patients were initially unstable with clinical and laboratory signs of severity, despite the absence of Glasgow-Blatchford and Rockall scores in their records. This initial haemodynamic instability can be explained, on the one hand, by the causes of bleeding, in particular the rupture of oesogastric varices, which are exceptionally serious, but also, on the other hand, by the late arrival in hospital structures due to distance, cultural considerations or difficulties of mobility in our country.

Treatment was essentially medical. PPI treatment was most often initiated on admission, even if this treatment did not always fully comply with current recommendations in Europe and Asia [2,7,20,21]. Contrarily, in cases of suspected acute UGIB related to rupture oesogastric varices, vasoactive therapy to reduce portal blood flow was never initiated on admission, in line with international recommendations, including those adapted by the European Society of Gastrointestinal Endoscopy to be applicable to resource-limited settings, including some African countries [2,7,22-24]. Patients with bleeding peptic ulcers have rarely benefited from endoscopic haemostasis, unlike those with portal hypertension lesions. Late arrival at hospital would explain why in sub-Saharan Africa Forrest scores IIc and III, i.e. pigmented stain or clean base of the ulcer, are most frequently found [25]. For the Forrest classification guiding the choice of endoscopic treatment modality for ulcers, there is no endoscopic treatment for these scores [2,3,7,26]. The practice of injecting adrenaline alone instead of combined adrenaline and bipolar coagulation or endoclips was inappropriate. This could be explained by factors such as excessive procedure costs, insufficient training of practitioners and limited logistic equipment.

The mortality rate of upper GI bleeding varies between 2-10%, and is increased by the presence of associated diseases, but also rupture of oesogastric varices with a specific mortality rate of 15- 25% [2,27,28]. Because of the predominance of portal hypertension lesions in our series and the liver failure accompanying cirrhosis, mortality was high compared to other countries in the sub-region, 5% in Togo [15], 3.8% in Gabon [17] and 9.4% in Côte d’Ivoire [12]. On the other hand, it was close to the mortality found in Burundi, 22.9% [16]. The lack of primary prevention of varicose vein rupture could also explain this high mortality. However, this factor has not been studied (Table 3, 4).

Table 3: Specific treatment by medical and haemostatic endoscopy methods at the Yaounde Central.

Table 4: Evaluation of diagnostic approach and intial management of 74 patients admitted for acute UGIT in 5 emergency centres in Yaounde.

The quality of care is key to improving prognosis [2,3,7, 8,29- 31]. The actual care in the studied setting was assessed. The priority in the care of acute UGIB is to ensure haemodynamic stability with crystalloid or balanced infusions and possible transfusions [2- 5,29-31]. For this purpose, bleeding should be recognised either by nasogastric tube placement or by digital rectal examination. Also, the severity should be assessed by prognostic scores, in particular the Glasgow-Blatchford score (GBS), based on clinical and biological criteria, validated to identify low-risk patients with a sensitivity of 99% and a specificity of 32% [2,30,32]. From these recommendations, it was observed that the recognition of bleeding and the assessment of its severity were insufficient. Recording clinical parameters was neglected. Neither digital rectal examination nor nasogastric tube placement to aid diagnosis was rarely done if the patient was not present at the time of the blood loss. Oxygen therapy, even for initially unstable severe cases or cases with comorbidities, was often not effective. This may be due to the lack of oxygen in some hospitals or because of outdated or non-existent anaesthesia and intensive care equipment. The current guidelines, recommending a transfusion threshold of 7 g/dl [2,30,33,34], were met in about 90% of patients in this case. It should be noted that the Yaounde Central Hospital, which had the largest number of patients, has a certification for its blood bank. Treatment with venous PPI was started early in the majority of cases regardless of the suspected aetiology. Given the significant proportion of portal hypertension lesions, vasoactive drugs should be integrated into local protocols for the care of acute UGIB, since this is not currently the case. Helicobacter pylori testing and eradication is also not integrated into the care of acute UGIB in the setting. And yet, this is a validated approach [35]. Helicobacter pylori infection plays a major role in the development of ulcers in the studied environment, affecting approximately 70-80% of the population [36].

EGDE with or without endoscopic therapeutic procedures is an integral part of the care of UGIB and has been shown to improve patient outcomes in terms of morbidity and mortality [2,7,26,31]. However, the ideal time for its performance is unclear. Recommendations agree that it should be performed within 24 hours of admission [2,3,7,37]. Early endoscopy within 12 hours would not influence clinical outcomes, mortality, recurrence of bleeding or the need for surgery [20,31]. In our resource-limited environment, not only is there a shortage of qualified human resources, but there is also inadequate technical equipment. While it is accepted that an EGDE should be performed in every patient with acute UGIB, the rate of completion was only 40-60.6% in both study arms. This procedure is relatively expensive in relation to people’s income. Endoscopy was most often performed beyond 24 hours after admission. Thus, therapeutic endoscopic procedures were rare. If performed early, it seems to have an influence on hospital resources and costs, by identifying low-risk patients and allowing them to return home quickly [31,37]. This would be appropriate in our resource-limited environment.

Conclusion

Contrary to Western countries, ruptured oesogastric varices play an important role in the occurrence of gastrointestinal bleeding in areas with high hepatitis B endemicity. UGIB is exceptionally severe in these areas, as it has a high mortality. The lack of qualified human resources and insufficient technical facilities constitute a serious problem. For this reason, the improvement of clinical practice in relation to acute UIGB should consider the significance of portal hypertension lesions, on the one hand, and the limitation of resources on the other. Therefore, locally applicable protocols need to be devised. In the long term, the elimination of viral hepatitis B and C should considerably reduce the prevalence of UGIB. A multicentre study is therefore expected to establish protocols adapted to our health and limited resource settings.

What Is Known

a) 80% of gastrointestinal bleeding are upper. The most common causes of acute UGIB are non-variceal (80-90%) and include gastric and duodenal ulcers in 20-50%.

b) The age of onset of UGIB is around 70 years.

c) UGIB remains an important cause of morbidity and mortality.

The mortality rate has remained stable at around 10-15%.

d) The improvement of the prognosis depends on the care quality and treatment of acute UGIB is well codified.

e) The assessment of the severity of UGIB is based on prognostic scores, in particular the Glasgow-Blatchford score (GBS) which is based on clinical and biological criteria, validated to identify low-risk patients with a sensitivity of 99% and a specificity of 32%.

f) If acute UGIB is suspected in relation to rupture oesogastric varices, vasoactive therapy to reduce portal blood flow should be given as early as possible. In cases of suspected ulcerrelated UGIB, high-dose PPI therapy should be started early.

g) The priority in the care of acute UGIB is to ensure haemodynamic stability with crystalloid or balanced infusions and possible transfusions. Current guidelines recommend a transfusion threshold of 7 g/dl.

h) Helicobacter pylori testing and eradication is incorporated into the care of acute HDH.

i) It is accepted that an EGDE should be performed in all patients with acute UGIB. There is consensus that endoscopy should be performed within 24 hours of admission (12 hours in the case of portal hypertension related UGIB).

j) The Forrest classification guides the choice of endoscopic treatment modality for bleeding ulcers.

k) Haemostatic endoscopy is the first-line treatment for bleeding ulcers.

Relevance of the study

a) The causes of acute UGIB in areas of high hepatitis B endemicity are dominated by variceal bleeding in young patients.

b) The age of onset of UGIB is around 50 years.

c) The mortality rate is very high, around 15%.

d) The actual clinical practice is based on a non-codified care.

e) The prognostic scores of UGIB, notably those of Glasgow- Blatchford (GBS), Forrest and Rockall, are rarely used.

f) In case of suspected acute UGIB related to rupture oesogastric varices, vasoactive treatment is not often prescribed.

g) Not all emergency intensive care measures are followed, including oxygen therapy and monitoring.

h) Helicobacter pylori testing and eradication is not included in the care of acute UIGB.

i) The rate of completion of EGD is very low (40-61%) and it is done beyond the required 24 hours.

j) Haemostatic endoscopy is not the first-line treatment for bleeding ulcers, only in 1.2%.

Abbreviations and acronyms:

Upper gastrointestinal bleeding (UGIB); hepatitis B virus (HBV); HBV surface antigen (HBsAg); blood pressure (BP); pulse rate (PR), respiratory rate (RR); room oxygen saturation (SPO2), oesogastroduodenal endoscopy (EGDE); haemoglobin (Hb); proton pump inhibitors (PPIs); University of the Mountains (UdM); World Health Organisation (WHO); Institutional Ethics Committee of the University of the Mountains (CIE-UdM).

Declarations

a) Ethical considerations

We obtained ethical clearance from the Institutional Ethics Committee of the University of the Mountains (CIE-UdM) under the number No. 2018/149/UdM/PR/CIE of 19 March 2018.

b) Consent to publish

All authors gave their approval for publication.

c) Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

d) Competing interests

The authors declare no conflict of interest for this study.

e) Funding

The authors did not receive any fund for this study.

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