Conference Proceedings
 
Biological therapy in acute severe ulcerative colitis: Indian experience
 
Ajit Sood,1 Vandana Midha,2 Arshdeep Singh2
Departments of Gastroenterology1
and Medicine,2
DMC&H, Ludhiana - 141001,
India

Corresponding Author: Dr. Ajit Sood
Email: ajitsood10@gmail.com

Abstract

Biologicals have a well established role as rescue therapy in management of steroid refractory cases of Ulcerative colitis and Crohn’s disease. However, high cost and potential risk of infections like tuberculosis limits their use in developing countries. As there is paucity of data on the use of various biological agents from developing countries like India, we are reporting the limited Indian experience with the available agents. Infliximab has been used as a rescue therapy for severe refractory Ulcerative colitis while other agents have been used as a part of multicentre clinical trials.

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Inflammatory bowel disease is a polygenic, immune-mediated, chronic relapsing disease of the gastrointestinal tract. Ulcerative colitis (UC) and Crohn’s disease (CD) are the two major types of IBD. Ulcerative colitis is an immune-mediated mucosal disease that usually involves the rectum and extends proximally to involve a part or whole of the colon. IBD has become a global disease and the prevalence of IBD is on the rise in developing countries. Emergence of IBD in India has been attributed to the rapid modernization and westernization of the population.[1] The key question is the emergence of an autoimmune disorder in geographical areas which earlier bore the brunt of infectious diseases.

 Traditionally, the goals of treatment involved induction and maintenance of remission. Presently, other targets of management include improving quality of life, reduction in hospitalizations and avoidance of surgery. Apart from these, another important goal of therapy is mucosal healing. For many years the medical armamentarium of ulcerative colitis consisted of 5-aminosalicylates, corticosteroids and immunosuppressants. The recent introduction of biological agents that target key inflammatory molecules such as TNF alpha has transformed the medical management of ulcerative colitis.

 Corticosteroids are highly effective and act promptly in patients with moderate to severe UC. The disease, however, remains refractory in nearly 15-20% of patients. Medical rescue therapy based on agents like cyclosporine and biologicals has made it possible to avoid colectomy in a significant number of patients, although at the cost of expensive medications. As UC emerges in developing nations, there is a need to define the most appropriate treatment for these patients keeping in mind both the disease presentation and cost.

What are biologicals?

 A biological is a medicinal product such as a vaccine, blood component, allergenic somatic cell, tissue, recombinant therapeutic protein or living cell that is used as therapeutics to treat diseases. These include therapeutic proteins, DNA vaccines, monoclonal antibodies and fusion proteins.

Rationale of biological therapy in IBD

 The pathogenesis of ulcerative colitis is the interplay of genetic, microbial and environmental factors resulting in a deregulated immune response. Under normal situations, the intestinal mucosa is in a state of ‘controlled’ inflammation regulated by a delicate balance of proinflammatory (tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a key role in modulating inflammation.[3] Hence cytokines are a logical target for IBD therapy based on cytokine-specific inhibitors (Table 1). TNF-a is a key proinflammatory cytokine in patients with Crohn’s disease but is also found at increased concentrations in blood, colonic tissue and stool of patients with ulcerative colitis.



 Biological therapy of UC: Indian experience

 The requirement for biological therapy in India has been estimated to reach 10% for UC. Of the various biologicals available for UC, only infliximab is available in India. However, various biological therapies for UC have been used by different study groups with Indian participation. We discuss the Indian experience with these novel a gents.

 Infliximab

 The use of infliximab (IFX) in Indian UC patients was first reported by our team.[4] A retrospective analysis of 28 patients with severe steroid refractory UC treated with infliximab yielded an initial response in 86% patients thereby avoiding urgent colectomy. Infliximab had been used only for induction of remission (3 doses; 0, 2 and 6 weeks). Over a mean follow-up of two years 56% patients remained colectomy free. In addition to infliximab all patients had received azathioprine (2mg/kg).

 The short term efficacy of IFX treatment in this study was higher than prior controlled trails (ACT I and ACT II), yet comparable to few other studies. It was believed that variations in IFX responsiveness were possibly related to differences in study design, study populations and study end-points. The authors postulate the role of TNF-á genetic polymorphism in treatment responsiveness in Indian population. There were no significant safety issues as only mild shivering, transient sinus bradycardia and upper respiratory tract infections (responsive to oral antibiotics) were observed. Although, extension studies of ACT I and ACT II show beneficial ‘benefit-to-risk’ ratio, in developing countries like India high cost of biologicals precludes their long term use for sustaining remission. The authors believe that azathioprine may be successful in sustaining the clinical response achieved with IFX. Sriram et al[5] have also reported successful use of IFX in the management of toxic megacolon in a 48-year-old woman not responding to the routine measures and who had refused surgery.

 Basiliximab

 A multinational study analyzed the efficacy and safety of basiliximab (BSX) (anti-CD25) as a corticosteroid sensitizing agent in steroid refractory UC.[6] Multiple centers from India participated in this study. Though the drug was generally well tolerated with only mild to moderate gastrointestinal disturbances, it was found that BSX when added to corticosteroids, showed no greater efficacy than corticosteroids alone for all definite end-points in steroid refractory population.

Vedolizumab

 Vedolizumab (VDZ), an anti-a4â7 integrin antibody has also been studied in UC patients on corticosteroids in a multicenter study with Indian participation.[7] It was seen that vedolizumab is effective for both induction and maintenance therapy in patients with moderate to severe UC.

 Golimumab

 In a double-blind multinational study,[8] 1,064 adults with UC were randomly distributed into groups that were given golimumab in doses of 100 mg followed by 50 mg, 200 mg and then 100 mg or 400 mg and finally with 200 mg at 2 weeks intervals. The study suggested that treatment with subcutaneous golimumab induces clinical response, remission and increases quality of life in patients with active UC. The drug was well tolerated and the most commonly observed adverse events were headache and nasopharyngitis.

 Others

 There is paucity of data on Indian experience with other biological agents (natalizumab, adalimumab, etanercept, etc.) and there is scope for further evaluation and validation of newer biologicals/biosimilar therapies.

 Indications and contraindications of biologicals in IBD

 Based on available evidence and experience with biologicals in IBD, the Indian Society of Gastroenterology Task Force on IBD proposed the use of IFX in patients with refractory severe ulcerative colitis and as rescue therapy in fulminant ulcerative colitis (grade of recommendation: A, level of evidence: I).[9] Contraindications include active infection, septic arthritis in last 2 months, sepsis of prosthetic joint within last 12 months or indefinitely if joint remains in-situ, New York Heart Association (NYHA) grade 3 or 4 congestive cardiac failure (CCF), demyelinating disease, and patients with low immune status including HIV infected patients.[10]

 Challenges in use of biologicals

 Biologicals have well defined in various rheumatological diseases such as rheumatoid arthritis (RA), psoriatic arthritis, and spondyloarthropathies. Most of the experience with biologicals in India comes from their use in various rheumatological diseases. Since biologicals are not being currently used extensively for the management of UC, the challenges pertaining their use are based on the experience of rheumatologists.

 Opportunistic infections

 Reactivation of tuberculosis (TB): Biologicals inhibit migration of neutrophils, macrophages and T-cells into the affected tissues. One main disadvantage of the anti-TNF agents is that an underlying disease like TB may escape immune response. In a recent study by Grover et al[11] an interesting point was put forth. If we extrapolate US data to the Indian population, 1.1% of patients receiving IFX are expected to develop TB annually but unexpectedly high incidence of TB (21%) was encountered in the participants of this study. Another retrospective study examined patients of inflammatory arthritis treated with IFX who subsequently developed TB during follow-up. There were 10 cases of TB out of the 120 cases reviewed. Cases occurred from one month to one year after the last dose of IFX.[12] With etanercept therapy for RA there was reactivation of TB in 5% patients after one year of treatment.[13] Based on experience from hematology rituximab is not associated with increased risk of TB.

 Screening: All patients planned for biologics should be screened for active/latent TB. Screening should include a detailed history for prior TB, any antitubercular treatment received, and compliance to treatment. A thorough physical examination and chest radiograph are imperative. Interferon-gamma release assays are more specific to the presence of latent tuberculosis than the Mantoux test, which can react to previous BCG administration. The reliability of these screening methods has not been established in India.

 Prophylaxis: Latent TB is devoid of signs and symptoms. Patients with active TB should receive standard chemotherapy prior to initiation of anti-TNF agents. Prophylaxis is not recommended in patients with a past history of TB that has been adequately treated. These patients need close clinical follow-up and chest radiography every 3 months. Patients with a history of inadequate antitubercular treatment (ATT) or radiographic scarring without previous history of ATT should be offered prophylaxis. Recent data suggests that treatment of latent TB before starting anti-TNF therapy can reduce the risk of reactivation. British and American guidelines[14] recommend a 6-9 months course of daily isoniazid (INH) for latent TB. Twice weekly directly observed therapy (DOTS) can be substituted for daily therapy. Rifampicin can be instituted for 4 months in those intolerant to INH and those exposed to INHresistant strains. Ideally TNF blockers should be started after completing this treatment. However, if the clinical situation so warrants, anti TNF-a therapy can be initiated 1-2 months after the start of prophylaxis.[15] There are three potential concerns while using prophylaxis: toxicity, expense and in India, the fear of propagating INH resistance. But these concerns have been laid to rest by recent data from Mumbai[16] which highlighted the safety, efficacy and cost effectiveness of INH prophylaxis in the Indian patients with SLE. Another innovative strategy to decrease the incidence of TB is to avoid the loading dose of IFX.[17]

 Other serious infections

 Serious bacterial infections mainly upper respiratory tract infections have been observed in patients on anti-TNF therapy. Coccidiomycosis, histoplasmosis, invasive systemic fungal infections, septic arthritis, acute abscesses, osteomyelitis, reactivation of toxoplasmosis and listeriosis have also been reported.[18-21]

 Malignancies

 Trials indicate a two to six-fold increase in incidence of lymphomas in RA and psoriasis patients on biologicals.[22] Nonmelanoma skin cancers (squamous/basal cell carcinoma), development/recurrence of melanoma and precancerous skin lesions such as actinic keratosis and Bowen’s disease have also been noted in RA patients receiving anti-TNF therapy.[23] Use of etanercept in patients with Wegener’s granulomatosis resulted in increase in solid tumors.[24]

 Autoimmune syndromes

 Approximately 10% of the patients treated with TNF-alpha therapy develop antibodies to double stranded DNA (ds- DNA). Patients treated with TNF blocking agents may develop auto-antibodies including, anti-nuclear antibodies (ANA) and anti-cardiolipin antibodies (aCL). But the development of clinical lupus is rare. There is no increased risk of development of drug-induced lupus.[25]

 Neurological disease

 Cases of demyelinating syndromes, optic neuritis, transverse myelitis, multiple sclerosis, or Parkinson’s disease have been reported, more often with etanercept than with infliximab. All of these improve or disappear after the withdrawal of anti-TNF therapy.

 Hepatitis

 Anti-TNF agents can reactivate chronic viral hepatitis. Severe flares of chronic hepatitis B have been described. This is a major issue in India since the prevalence of hepatitis B and C is very high. The finding of hepatitis B reactivation in HBsAg positive patients by Esteve et al[26] emphasizes the need for careful monitoring of patients with viral hepatitis on IFX regimen. Antiviral therapy is recommended for all the patients requiring IFX who exhibit positive surface antigen with or without active viral replication. Hepatitis B vaccination should be routinely given to all patients of IBD at the time of diagnosis. In contrast, in an observational study on small number of HCV patients who used anti-TNF agents, there was no demonstrable increase in viral load.[27] In another controlled study of HCV patients where Etanercept was used on a background of IFN plus Ribavirin therapy, no effect on viral load was seen[28]. Regular follow-up and monitoring of liver function test (LFT) is advised

 Cardiovascular

 There is substantial evidence of TNFa involvement in the pathogenesis of cardiac failure. However, anti-TNF therapies have not benefitted patients with symptomatic heart failure. Rather high dose IFX is associated with increased risk of worsening heart failure and mortality.[29] Therefore patients with mild heart failure (NYHA class I and II) should be evaluated at baseline and closely monitored. NYHA class III and IV heart failure is a contraindication to anti-TNF therapy.[30]

 Antigenicity

 The development of antibodies to a therapeutic agent leads to adverse effects including immune-complex formation (serum sickness), hypersensitivity reactions and decreased therapeutic efficacy. There is a need to develop techniques for detection of such antibodies.

 Hematological disorders

 Pancytopenias have been reported with the use of biologicals and frequent monitoring of blood counts is recommended.

 Cost

 Cost remains a big question in India. For ulcerative colitis, only IFX is widely available in India. But it is being prescribed only to those who can afford the cost or have medical insurance. Pharmaco-economic studies are needed in future to avail maximum benefit from these drugs irrespective of the patient’s socioeconomic status.

 Conclusion

 The primary aim of treatment of IBD is not only to induce and maintain remission but also to achieve mucosal healing. The pharmacological management of IBD is constantly evolving. With the current treatment regimens based on 5-ASA, steroids and immunosuppressants there remains a therapeutic gap of 5-15% patients who need biologicals or alternative treatments such as colectomy. Despite biologicals being effective alternatives for IBD, there is little clinical data from India limiting their widespread use. A key future challenge is to define optimum, effective doses which prevent adverse events. Long term safety data will allow full assessment of risk-benefit ratio for every patient. Much more investigation is needed for this class of drugs.

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