intravenous immunoglobulin treatment to reduce inflammation in crohn's disease
Tomás McHugh TCD School of Medicine, Trinity College Dublin, College Green, Dublin 2
Crohn's Disease (CD) is a chronic, relapsing-remitting inflammatory bowel disease characterised by transmural granulomatous inflammation afflicting any part of the GI tract but typically including the terminal ileum. First-line therapies for CD include corticosteroids and 5-aminosalicylates. Depending depending on the individual case, methotrexate, surgery, and TNF-α inhibitors such as infliximab or adalimumab maybe added. Over time patients may become drug-resistant, leading to deterioration and repeated surgery.
IVIg therapy has the potential to treat these steroid and aminosalicylate resistant patients effectively. Overall, IVIg was shown to be an effective treatment for patients with relapse of CD. However, IVIg was not shown to maintain remission. Based on the evidence, IVIg may fit into a treatment algorithm for treatment of acute relapses of CD.
IVIg has been shown to be an excellent new treatment with few side-effects which has the potential to dramatically change how CD is treated. More research is needed, particularly randomised controlled trials to assess the clinical utility of IVIg. The ability to alleviate suffering in patients with Crohn’s disease using IVIg is potentially invaluable.
Crohn’s disease (CD) is a chronic, relapsing-remitting inflammatory bowel disease characterised by transmural granulomatous inflammation afflicting any part of the GI tract but typically including the terminal ileum. Symptoms of CD include diarrhoea, malaise, abdominal pain, weight loss, and vomiting. Extra-abdominal symptoms can include, arthritis, conjunctivitis, erythema nodosum and pyoderma gangrenosum.1 Signs include abdominal tenderness, skin tags, right iliac fossa mass and clubbing.
The key investigations to carry out in a patient with a CD-like presentation are: full blood count (FBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), stool microscopy culture sensitivities (MC&S), stool Clostridium difficile toxin (CDT), iron studies, folate, and vitamin b12 [2,3]. Other investigations include colonoscopy to visualize deep fissured ulcers. If the mucosa looks normal, a sigmoidoscopy with rectal biopsy may be done to detect microscopic granulomas. Traditionally, barium enemas were used to diagnose CD but these are now rarely done due to the widespread availability of colonoscopy [2,3].
CD is treated based on whether the patient is experiencing a mild attack or flare or a severe attack. In a mild attack the patient is symptomatic but systemically well. In a severe attack the patient is symptomatic and systemically ill. Mild attacks are treated with aminosalicylate and prednisolone. During severe attacks patients are admitted to hospital. They may be given IV fluids, IV steroids such as usually hydrocortisone, and may or may not receive aminosalicylate and antibiotics. If these treatments fail to cause remission then methotrexate or infliximab are used. Maintenance therapy usually includes aminosalicylate, azathioprine or infliximab. Tachyphylaxis and drug failure are common over time .
Surgery is necessary for 50 - 80% of CD patients mostly due to drug failure. Other surgical indications include obstruction, fistulae, abscess and perforation. Bowel resection and bowel rest with temporary ileostomy are the procedures of choice in CD . With multiple partial ileectomies there is a risk of short gut syndrome. This syndrome is characterized by not having enough functional small bowel for to absorb nutrients from the diet and typically occurs when gut length is < 250cm. This syndrome can lead to malabsorption of fat and essential vitamins (e.g. B12) [2,4].
Intravenous Immunoglobulin (IVIg) is a potential new effective treatment for CD. IVIg is a pooled blood product containing immunoglobulin G (IgG) from plasma of donors. IVIg suppresses various inflammatory mediators primarily by binding to the Fc receptors on phagocytes, B cells and parts of the complement system. This immunomodulating effect is used to treat diseases such as Kawasaki’s disease, idiopathic thrombocytopenic purpura (ITP), dermatomyositis, myasthenia gravis, and, in the near future, CD .
evidence for the effectiveness of IVIG Therapy in Cd
Treating CD is challenging as patients can become unresponsive to conventional therapy, develop infections after immunosuppression with steroids [4,6] and require repeated surgeries which can result in complications (e.g. short gut syndrome after resection) . In order to discover if IVIg is an effective treatment for patients with CD, a search was conducted for relevant research articles using the PubMed, Embase, and MEDLINE databases. The search terms used were “Crohn’s disease immunoglobulin” and “IVIg treatment for IBD”. The most up-to-date articles were selected which included several reviews [6,7] and two experimental studies [8,9]. Standard of care recommendations are made based upon the British Medical Journal Best Practice guidelines10 and on the National Institute for Health and Care Excellence guideline .
A study by Kazatchkine et al. concluded that IVIg has been shown to improve symptoms in patients who are steroid and aminosalicylate resistant . IVIg was also demonstrated to be effective at maintaining remission in medium-term length studies . A non-randomised, 20 patient trial comparing IVIg (specifically IgM, Pentaglobin) against steroid and aminosalicylates found that there was a greater improvement in symptoms (calculated by the CDAI) in the IVIg group .
Work by Chrissafidou et al. found that patients who are unresponsive to conventional treatments improved after administration of IVIg . In this study, improvement was described as a decrease of 3 or more points on the Harvey-Bradshaw index. The Harvey-Bradshaw index is a research tool to quantify symptoms of CD. This study also reported a 25% decreased in CRP, no hospitalization or surgeries and improvement in both symptoms and remission. The study concluded that IVIg is a safe and effective short-term treatment for CD .
In another study by Merkley et al, 19 steroid-resistant CD patients were treated with IVIg therapy of either Venimmun, Gamimun, Octagam (10g/day IV over 7 days) or Sandoglobin (72 - 90g IV over 8 - 10 days) . The IVIg was given in addition to standard treatment. The study found that all patients benefited from IVIg treatment in this timeframe. Additional benefit was also seen during the 4 weeks post-treatment where a total of 14 patients (73.7% of the group) achieved remission of disease. The study concluded IVIg to be effective in management of acute flares of CD but, did not recommend maintenance therapy with IVIg .
The results of the studies of treating patients with CD with IVIg therapy are promising. While the literature tends to support the use of IVIg in treating CD data from a large randomised control trial (RCT) is lacking. No such trial is currently in progess.
A possible reason for the lack of a controlled trial is that IVIg is an expensive therapy. A typical course of IVIg therapy can cost approximately $26,000 USD . Cost-effectiveness studies have not been completed for the use of IVIg in CD. Still, such studies have been completed for other diseases where the use of IVIg is more typical including, myasthenia gravis and chronic inflammatory demyelinating polyneuropathy (CIDP). In both studies [13,14], IVIg was not found to be cost-effective in treating these conditions compared to standard therapies.
The prohibitive cost has driven considerable investment into the development of new, cheaper TNF-α inhibitors such as adalimumab or golimumab. Demonstrating that IVIg therapy can reduce hospitalization or facilitate an earlier return to work could make treatment more economically viable. IVIg therapy in CD cannot be deemed cost-effective without such a study, and with the current economic climate and an increasing emphasis on cost per quality-adjusted-life-year (QALY) the question may remain unanswered in the near future.
Despite the cost, IVIg is an effective therapy and if it were widely available it would undoubtedly be used. An important consideration is the timing of use in CD patients. Currently, recommendations on IVIg use are not included in treatment guidelines for CD . The studies cited above suggest IVIg would be best used to manage acute relapses and flares. Still, further research must be done to recommend a treatment protocol.
IVIg is a new treatment with few side-effects which has the potential to change how CD is treated. More research is needed to discover where they will fit in in the treatment plan, its long-term effects on patients, and its cost-effectiveness. Finally, while preliminary research suggests that IVIg may represent an invaluable tool for CD patients, a randomized controlled trial is needed to clinically assess its effectiveness.
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