Crohn’s Disease and Sarcoidosis
There are between 18,000 to 45,000 new cases of Crohn’s disease (CD), a subset of inflammatory bowel disease, each year in the United States. Crohn’s disease has a dual peak incidence often occurring between the ages of 20-30 and 60-70, with females being 20-30% more likely to develop CD than males. The signs and symptoms of CD are highly variable, but patients typically present with diarrhea and abdominal pain. Additional symptoms can include hematochezia, perirectal lesions, and perianal lesions.
Crohn’s disease is an inflammatory disease typically affecting the terminal ileum; however it may encompass any part of the gastrointestinal tract. The presence of TNFa, IL-2, and IL-10 leads to the inflammation of the gastrointestinal tract seen in CD. The inflammation of the gastrointestinal tract can cause edema, fibrosis, ulceration, mucosal thickening, narrowing of the intestinal lumen, and fistulas. Anemia and nutritional deficiencies due to bleeding in CD are common because of malabsorption, increased motility, and interactions between medications and nutrients. Additional complications include hepatobiliary, joint, ocular, dermatologic, coagulation, and metabolic disorders.
Treatment for CD focuses on inducing and maintaining remission, as well as improving the patients’ quality of life. Pharmacologic therapy includes anti-inflammatory drugs to induce remission of the disease, such as aminosalicylates (ASAs), immunosuppressive drugs, biologic agents, and antimicrobials for infection prevention. Nutritional support is also extremely important in CD as there are elevated levels of IL-6 and TNFa, which can lead to increased protein loss and muscle wasting. Enteral nutrition might help reduce intestinal cytokine levels, thereby reducing inflammation and improving the possibility of remission.
Aminosalicylates are the mainstay of treatment for mild-moderate CD. The mechanism of action of ASAs is unclear, but may involve reducing oxidative stress, interfering with TNFa, suppressing IL-1 production, and inhibiting inflammatory pathways. The downfall of ASAs is that they can be expensive, difficult, or unpleasant to administer, and this can lead to decreased adherence. Low- dose naltrexone is inexpensive, easy to administer, and has shown promising results in studies on its effects on CD. In a study using 4.5 mg/day of naltrexone, 89% of patients with active CD showed a response to LDN therapy, 67% achieved remission, and there was a statistically significant improvement in the inflammatory bowel disease questionnaire (IBDQ) and SF-36 quality of life surveys.17 Segal, MacDonald, and Chande18 reported that LDN therapy resulted in a statistically significant clinical response in adults, exhibited as a decrease of greater than 70 on the Crohn’s disease activity index (CDAI), as well as significant endoscopic response as evidenced by the greater than five-point drop in Crohn’s disease endoscopic index of severity (CDEIS).
Lie et al.19 conducted a study of LDN for the induction of remission in therapy-refractory inflammatory bowel disease (IBD) patients. This study also investigated if LDN has a direct modulatory effect on intestinal epithelial barrier function. A total of 47 IBD patients were enrolled (28 CD, 19 ulcerative colitis [UC]). All patients received 4.5 mg naltrexone daily, and self-assessed disease activity was recorded at 4, 8, and 12 weeks after initiation of LDN. Additionally, endoscopic evaluations, serum samples, and biopsies were collected. The effect of LDN on wound healing, cytokine production, and endoplasmic reticulum stress was also assessed. Thirty-five (74.5%) patients achieved a clinical response, defined as a decrease in disease activity within the first 4 weeks of LDN therapy lasting at least 4 weeks in total, with 25.5% of patients achieving a response of at least 3 months (8 CD, 4 UC). The remaining 48.9% of patients achieved short-lived improvements between 4 and 12 weeks (13 CD, 10 UC). Low-dose naltrexone improved epithelial barrier function by improving wound healing and decreasing endoplasmic reticulum stress levels. Cytokine levels were unaffected in the epithelial cells and serum collected from the IBD patients in this study. The authors concluded that naltrexone does not appear to positively impact inflammation through the modulation of intestinal epithelial cell cytokine production.
Raknes, Simonsen, and Smabrekke20 conducted a pharmacoepidemiologic study using the Norwegian prescription database to determine the effect of initiating LDN on the prescribing patterns of other medications used specifically in the treatment of inflammatory bowel disease. Medication dispensing was compared 2 years before and after the first LDN prescription was given. This study showed a reduction in a number of different medications for the treatment of CD and UC following the dispensing of an LDN prescription. The study authors note that LDN may have the potential to reduce polypharmacy in IBD patients, resulting in a reduction of both cost and adverse effects.
Overall, the anti-inflammatory, immune-modulatory effects of LDN seem to be beneficial in CD severity and remission, making it ideal as an adjunct to traditional treatment or as a monotherapy.
The symptoms of CD can often be debilitating and interfere with normal daily functioning of the affected patients, making any treatment that improves functioning valuable.
Sarcoidosis is another inflammatory disease often presenting with gastrointestinal involvement. The usual treatment for sarcoidosis consists of the long-term use of prednisone, immune- modulators, or infliximab. These treatment options have many undesirable side effects including an increased risk of infection and malignancies. Because of the similarities between CD and sarcoidosis, LDN has been investigated as a therapeutic option for symptom management. In a case study by Weinstock, Myers, and Shetty,21 LDN therapy improved fatigue, dyspnea, and parotitis when titrated from 1 mg up to 4.5 mg in a patient with a 39-year history of sarcoidosis.
