Effectiveness and Safety of Local Adalimumab Injection in Patients With Fistulizing Perianal Crohn's Disease: A Pilot Study
ABSTRACT Various blockers of tumor necrosis factor-α are available for treatment of Crohn's disease. Randomized controlled trials have demonstrated the effects of systemic therapy with adalimumab, a fully humanized monoclonal antibody against tumor necrosis factor-α.
The aim of this study was to investigate the effectiveness and safety of local injection of adalimumab along the fistula in the treatment of perianal Crohn's disease.
This was a prospective, uncontrolled, open-label observational study performed at a university tertiary care center.
A total of 12 outpatients (9 women, 3 men) treated for fistulizing perianal Crohn's disease between 2009 and 2010 were enrolled. The mean age was 43.5 (range, 27-59) years. The fistula was classified as anovaginal in 3 patients, transsphincteric in 7 patients (low in 2, high in 5), and complex (multiple tracts) in 2 patients. Pikarsky's Perianal Crohn's Disease Activity Index was used to evaluate severity of the perianal disease.
Adalimumab was injected locally along the fistula tract and around the internal orifice every 2 weeks.
The primary end point of the study was the proportion of patients in whom complete or improved healing of fistulas was observed at follow-up, with improvement based on the number of daily changes of sanitary pads.
The median number of injections per patient was 7 (range, 4-16). The mean length of follow-up was 17.5 (range, 5-30) months; 75% of patients (9 of 12) reached complete cessation of fistula drainage, and 3 patients (25%), all with transsphincteric fistula, showed improvement. Comparison of overall follow-up scores on the Perianal Crohn's Disease Activity Index with baseline showed significant improvement (p = 0.002). No adverse side effects were noted.
The study was limited by its small sample size and by the absence of a control group.
This pilot study suggests that a high local concentration of adalimumab favors prompt and definitive healing of the fistulous tract in patients with perianal Crohn's disease. Future randomized trials with well-defined selection criteria are needed to determine the relative risks and benefits of available anti-TNF-α blockers (chimeric vs fully humanized) and the optimal mode of administration (systemic use vs local injection) in the treatment of fistulizing perianal Crohn's disease.
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ABSTRACT: Therapeutic antibodies provide important tools in the “medicine chest” of today’s clinician for the treatment of a range of disorders. Typically monoclonal or polyclonal antibodies are administered in large doses, either directly or indirectly into the circulation, via a systemic route which is well suited for disseminated ailments. Diseases confined within a specific localized tissue, however, may be treated more effectively and at reduced cost by a delivery system which targets directly the affected area. To explore the advantages of the local administration of antibodies, we reviewed current alternative, non-systemic delivery approaches which are in clinical use, being trialed or developed. These less conventional approaches comprise: (a) local injections, (b) topical and (c) peroral administration routes. Local delivery includes intra-ocular injections into the vitreal humor (i.e. Ranibizumab for age-related macular degeneration), subconjunctival injections (e.g. Bevacizumab for corneal neovascularization), intra-articular joint injections (i.e. anti-TNF alpha antibody for persistent inflammatory monoarthritis) and intratumoral or peritumoral injections (e.g. Ipilimumab for cancer). A range of other strategies, such as the local use of antibacterial antibodies, are also presented. Local injections of antibodies utilize doses which range from 1/10th to 1/100th of the required systemic dose therefore reducing both side-effects and treatment costs. In addition, any therapeutic antibody escaping from the local site of disease into the systemic circulation is immediately diluted within the large blood volume, further lowering the potential for unwanted effects. Needle-free topical application routes become an option when the condition is restricted locally to an external surface. The topical route may potentially be utilized in the form of eye drops for infections or corneal neovascularization or be applied to diseased skin for psoriasis, dermatitis, pyoderma gangrenosum, antibiotic resistant bacterial infections or ulcerated wounds. Diseases confined to the gastrointestinal tract can be targeted directly by applying antibody via the injection-free peroral route. The gastrointestinal tract is unusual in that its natural immuno-tolerant nature ensures the long-term safety of repeatedly ingesting heterologous antiserum or antibody materials. Without the stringent regulatory, purity and clean room requirements of manufacturing parenteral (injectable) antibodies, production costs are minimal, with the potential for more direct low-cost targeting of gastrointestinal diseases, especially with those caused by problematic antibiotic resistant or toxigenic bacteria (e.g. Clostridium difficile, Helicobacter pylori), viruses (e.g. rotavirus, norovirus) or inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease). Use of the oral route has previously been hindered by excessive antibody digestion within the gastrointestinal tract; however, this limitation may be overcome by intelligently applying one or more strategies (i.e. decoy proteins, masking therapeutic antibody cleavage sites, pH modulation, enzyme inhibition or encapsulation). These aspects are additionally discussed in this review and novel insights also provided. With the development of new applications via local injections, topical and peroral routes, it is envisaged that an extended range of ailments will increasingly fall within the clinical scope of therapeutic antibodies further expanding this market.Critical Reviews in Biotechnology 01/2015; DOI:10.3109/07388551.2014.992388 · 7.84 Impact Factor
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ABSTRACT: Inflammatory bowel disease (IBD) is a frequently occurring disease in young people, which is characterized by chronic inflammation of the gastrointestinal tract. The therapy of IBD is dominated by the administration of anti-inflammatory and immunosuppressive agents, which suppress the intestinal inflammatory burden and improve the disease-related symptoms. Present treatment strategies are characterized by a limited therapeutical efficacy and the occurrence of adverse drug reactions. The development of novel disease-targeted drug delivery strategies is preferable for a more effective therapy and thus demonstrates the potential to address unmet medical needs. This review gives an overview about drug delivery strategies for the treatment of IBD. Therefore, established intestine-targeting strategies for a selective drug release into the diseased part of the gastrointestinal tract will be presented, including prodrugs, and dosage forms with pH-/time-dependent drug release. Furthermore future-oriented disease-targeting strategies for a selective drug release into the intestinal inflammation will be described, including micro-/nanosized synthetic and biologic drug carriers. This novel therapeutic approach may enable a more effective anti-inflammatory treatment of IBD with reduced risks of adverse reactions. © Georg Thieme Verlag KG Stuttgart · New York.
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ABSTRACT: Perianal disease is one of the most disabling manifestations of Crohn's disease. A multidisciplinary approach of gastroenterologist, colorectal surgeon and radiologist is necessary for its management. A correct diagnosis, based on endoscopy, magnetic resonance imaging, endoanal ultrasound and examination under anesthesia, is crucial for perianal fistula treatment. Available medical and surgical therapies are discussed in this review, including new local treatment modalities that are under investigation.