Key Points
- best options for treatment are:
- management with diet, rest, exercise, mind control
- genetic therapies - customized gene modifications tailored to the patient - only working to get to trials now
- steroids are only a temporary treatment ( not more than 14 days )
- biologics as defined now can create significant risks through immunity suppression
- surgery is challenging and is effective at best for 5 to 10 years at which point patient has larger problems with smaller digestive tract
- more
To Do List
References
| Reference_description_with_linked_URLs__________________________ | Notes__________________________________________________________________ |
|---|---|
| https://www.fiercebiotech.com/biotech/sangamo-taps-mogrify- for-off-shelf-car-treg-project | Sangamo bought TXCell and is working on CART solutions for Crohns treatments - no details yet on trials |
Key Concepts
Sangamo - future is gene therapies for IBD, etc
https://investor.sangamo.com/static-files/e29a38f9-b55b-49c0-b9e5-5240c2165cfd
worth a quick read to compare to what doctors say
Genetic studies of Crohn's disease: Past, present and future - 2014
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075408/
The exact causes of Crohn's disease are unknown, though it is likely to involve a disrupted immunological response to gut microbiota in genetically susceptible individuals [2]. There is currently no known cure and disease is managed by a combination of immune-suppressing medications, dietary changes or surgery.
Potential Value Opportunities
Guide to Clinical Trials for Crohns
https://policylab.us/clinical-trials/crohns-disease/
start as assessment
This site finds local trials
List of trials within 100 miles of Mansfield
https://antidote.me/match/search/results/d3fa7cd5-c7cf-450e-bc81-b862cede9a87/1
Mayo Clinic Crohns Trials
https://www.mayo.edu/research/clinical-trials/diseases-conditions/crohn%27s-disease
Information on Crohns Clinical Trials in summary - not specific treatments
https://www.gastrojournal.org/article/S0016-5085(19)41240-7/fulltext
Other Stuff
Adjuvant Treatment of Crohn's Disease with Traditional Chinese Medicine: A Meta-Analysis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425422/
The meta-analysis indicated that treatment with Traditional Chinese Medicine ( TCM ) and Western Medicine (WM) was significantly superior compared to treatment with WM alone with regard to total effective rate, remission maintenance rate, reduction of C-reactive protein (CRP), reduction of erythrocyte sedimentation rate (ESR), clinical score reduction, and reduction of adverse events.
Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281334/
how granulomas form in Crohns
Inflammatory granuloma formation
Unlike infectious granulomas, the impetus for inflammatory granuloma formation is unclear. In the prototypical granulomatous diseases of sarcoidosis and Crohn’s disease (CD), cytokine stimulation leads to macrophage migration into a site of inflammation (5, 6). These macrophages produce tumor necrosis factor α (TNF-α), which recruits additional macrophages and lymphocytes to the area (6). It is hypothesized that M1 (pro-inflammatory) macrophages, activated by Toll-like receptor (TLR) ligands and interferon (IFN)-γ produced by Th1 cells, predominate in the acute granulomatous process. Over time, the lesion undergoes tissue remodeling and becomes increasingly fibrotic, which is marked by a shift in macrophage polarity towards an M2 (remodeling/fibrosing) subtype (7, 8). Macrophages develop into epithelioid cells which eventually coalesce into multinucleated giant cells that secrete potent cytokines, including TNF-α, interleukin (IL)-1 and tumor growth factor-β (9, 10). These inflammatory factors attract CD4+ helper T cells, which help to further organize the granuloma. Th1 cells are particularly responsive to stimulation by IFN-γ and IL-12, and once recruited to the site of inflammation, they secrete IL-2 to stimulate T-cell proliferation, as well as additional IFN-γ which perpetuates macrophage activation and amplifies macrophage TNF-α secretion (6). As the granuloma matures, T-cell polarity shifts towards Th2 predominance, which is believed to contribute to increased fibrosis (9).
Taken together, these observations suggest that altered B-cell behavior may contribute to granuloma formation and granulomatous inflammation.
PLCγ2-associated antibody deficiency and immune dysregulation
PLAID is an autosomal dominant condition with a broad constellation of clinical and laboratory features (62). It is characterized universally by cold urticaria, together with antibody deficiency and immune dysregulation manifesting as susceptibility to recurrent infection, atopic disease, autoimmunity and cutaneous granulomatous inflammation. Many clinical features of PLAID correspond to abnormalities of specific immune cells that signal through PLCγ2, such as cold urticaria (mast cells), antibody deficiency (B cells), autoimmunity (NK and B cells) and susceptibility to infection (NK and B cells). Signaling abnormalities in macrophages and neutrophils may also contribute to the pathogenesis of granulomatosis in PLAID (63).
Potential Challenges
Crohn's disease study identifies genetic variant with potential to personalize treatment
https://www.sciencedaily.com/releases/2019/10/191007100427.htm
A genetic variant carried by 40% of the population explains why some patients develop antibodies against the anti-TNF drugs, infliximab and adalimumab and lose response. The authors conclude that a further trial is required to confirm that genetic testing prior to treatment will reduce the rate of treatment failure by facilitating the most effective choice of therapy for individual patients. The research is part of a program of work committed to finding the right drug for the right patient first time
Anti-tumour necrosis factor (TNF) drugs, infliximab and adalimumab, are used to treat patients with moderate to severe Crohn's disease and ulcerative colitis when other treatments have not worked. Also known as biological medicines, these drugs work by blocking TNF, a protein which drives persistent gut inflammation. Introduced in the 1990s, anti-TNF drugs now rank in the top five by drug spend in the NHS.
Candidate Solutions
2020 Crohns Information
Crohns and Colitis Foundation
https://www.crohnsandcolitis.com/crohns/disease-treatment
Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/crohns-disease/diagnosis-treatment/drc-20353309
Good article overall
Crohn's clinical trials
This is a long list - visit the web site - here are SOME
Search Results 1-10 of 36 for Crohn's disease
- Results filtered:
- Study status: Open/Status Unknown
Trial of Specific Carbohydrate and Mediterranean Diets to Induce Remission of Crohn's Disease
Rochester, MN
An Extension Study of Oral Ozanimod for Moderately-to-Severely Active Crohn's Disease
La Crosse, WI
A Study of Oral Ozanimod as Induction Therapy for Moderately to Severely Active Crohn's Disease
La Crosse, WI
A Study of Adult Allogeneic Expanded Adipose-derived Stem Cells (eASC) for the Treatment of Complex Perianal Fistula(s) in Patients With Crohn's Disease
Jacksonville, FL
Filgotinib in the Induction and Maintenance of Remission in Adults With Moderately to Severely Active Crohn's Disease
Rochester, MN
Stem Cell Coated Fistula Plug in Patients With Crohn's RVF
Rochester, MN, Rochester, MN
A Study of Oral Ozanimod as Maintenance Therapy for Moderately-to-Severely Active Crohn's Disease
La Crosse, WI
A Study to Assess the Efficacy and Safety of Risankizumab in Subjects With Moderately to Severely Active Crohn's Disease Who Failed Prior Biologic Treatment
Rochester, MN, Rochester, MN
A Study to Evaluate the Effectiveness and Safety of Oral OPS-2071 in Subjects With Crohn's Disease Showing Symptoms of Active Inflammation
Rochester, MN
A Study to Evaluate the Effectiveness and Safety of Triple Combination Therapy in High Risk Crohn's Disease (CD)
Scottsdale/Phoenix, AZ
Webmd.com
The goals for treatment are:
- to reduce inflammation
- to relieve symptoms of pain, diarrhea, and bleeding
- to eliminate nutritional deficiencies
Treatment might involve drugs, nutritional supplements, surgery, or a combination of these therapies. Treatment choices depend upon where the disease is located and how severe it is. They also depend on the complications associated with the disease and the way the person has responded in the past to treatment when symptoms recurred.
Healthline.com
https://www.healthline.com/health/crohns-disease/medications
Medscape.com - emerging IBD treatments
https://www.medscape.com/viewarticle/922125
Updates on the treatment of Crohn's disease, including potentially practice-changing results from a phase 3 trial of an adalimumab biosimilar, will be in the spotlight at the upcoming Advances in Inflammatory Bowel Diseases (AIBD) 2019 in Orlando.
"Biosimilars have the potential to lower societal costs and increase access" for people with immune-mediated inflammatory diseases, including Crohn's, said Stephen Hanauer, MD, from Northwestern University in Chicago, who is cochair of the conference.
He and his colleagues compared the adalimumab biosimilar BI 695501 (Boehringer Ingelheim) with adalimumab (Humira, AbbVie) in close to 150 adults who had moderate or severe active Crohn's disease for at least 4 months.
Crohns and Covid-19 treatment options
search
medicalnewstoday.com
https://www.medicalnewstoday.com/articles/crohns-and-covid-19#risk-factors
However, some treatments for Crohn’s may modify or suppress the immune system, which may increase a person’s risk. These drugs include:
- steroids, such as prednisone, methylprednisolone, and hydrocortisone
- immunomodulators, such as methotrexate, azathioprine, and 6-mercaptopurine
- JAK inhibitor drugs, such as tofacitinib
- anti-TNF biologic drugs, such as infliximab, golimumab, and adalimumab
- other biologics, such as vedolizumab and ustekinumab
People who take immunosuppressive medications may be at an increased risk of infections and serious complications from infections. However, people taking these medications should not stop taking them unless it is under the direct guidance of a doctor.
Other treatments, including the drug mesalamine (or mesalazine), do not suppress the immune system. Research in The Lancet Gastroenterology & Hepatology notes that mesalamine should not increase the risk of infection and that people taking this drug should continue to do so.
However, researchers do not recommend that doctors make new prescriptions or increase the dosages of drugs that modify the immune system during the pandemic.
Importantly, people who are taking immunosuppressant drugs should not stop taking the drugs unless a doctor specifically tells them to do so.
Suddenly stopping a medication may result in a flare-up of symptoms, which may put extra stress on the immune system. A person should check with a doctor and follow their specific instructions.
COVID prevention methods
There are a number of general prevention methods that apply to all, including people with Crohn’s. General prevention tips include:
- washing the hands regularly, using warm water and soap and lathering for at least 20 seconds
- using hand sanitizer containing at least 60% alcohol when soap is not available
- avoiding touching the mouth, eyes, or nose with unwashed hands
- avoiding close contact with people who are ill in any way
- practicing physical distancing to help reduce the impact of the virus — this involves staying at least 6 feet away from other people while in public
- disinfecting surfaces and objects in the home that see regular use
- using a tissue to cover the mouth and nose while sneezing and then disposing of the tissue immediately afterward
Additionally, anyone with symptoms of any sickness, even common illnesses such as a cold or the flu, should stay home.
uchicagomedicine.org
is it Crohns or Covid?
We haven't seen enough IBD patients who've developed COVID-19 to know whether these patients have different types of symptoms but for patients with IBD, having digestive symptoms could be confused for activation of IBD. The unique concern here is to distinguish between someone who is having a relapse of their IBD, compared to someone who might be having symptoms of an infection. We're working hard with our patients and performing additional research to figure this out.
Patients with inflammatory bowel disease who develop COVID-19 will have the same symptoms as the general population of patients who don't have IBD: fever, cough, respiratory symptoms (shortness of breath) or new onset diarrhea. Let your doctor know right away if you develop some of these symptoms or if you're worried that you might have developed COVID-19.
It may be hard to tell the difference between a flare up and COVID-19 infection because their symptoms can be similar. Loss of appetite, abdominal discomfort, more frequent bowel movements or loose stools are symptoms of both conditions.
We have testing options that do not require an in-person visit. These simple tests can help identify the cause of your symptoms.
We have treatments available that are safe to start even while this pandemic is going on. There's guidance that we've developed and published that will give people more information about which treatments to use and when to use them. If a patient has more severe inflammatory bowel disease, the usual treatments we use for IBD are safe and appropriate to be used in this setting. Patients shouldn't ignore their IBD symptoms or any other digestive symptoms. Keep in touch with your physician to get it back under control quickly. The last thing we want is for patients to be living with these symptoms and afraid to notify their doctor or come to the clinic.
Tuning the immune system
Patients who have Crohn's disease and ulcerative colitis have a chronic condition in which the immune system of the intestines is overactive. The goal of IBD treatment is not to immune suppress the patient, but rather to modify their overactive immune system so it’s under better control. We don't think of our IBD patients at baseline as being immune suppressed. In fact, it's the opposite. When we treat them effectively, we turn down the overactive immune system just enough so their body takes over, and we minimize their risk for infections.
What to do
Being on immune therapies for inflammatory bowel disease may increase the risk for some viral infections, but based on the information we have so far, we have not seen an increased risk of contracting COVID-19 in patients who are on the standard IBD therapies. Of the Crohn’s and ulcerative colitis patients we have seen who developed COVID-19, their course and recovery is exactly like what we're seeing in the general population. Our general message to patients right now is to stay on your existing therapies and stay in remission. If you have any concerns, please make an appointment with your doctor and have a conversation about whether there might be any adjustments to be made.
If you have been diagnosed with COVID-19, based on the treatments you're on, you may need to stop your therapy for a couple weeks. I don't recommend that you stop your medicines without talking to your doctor first. Based on an international registry of IBD patients who developed COVID-19, there does not appear to be an increased risk overall in patients with IBD developing COVID-19 or having a different set of outcomes. Most IBD patients who develop COVID-19 won't require hospitalization, but if they get sicker or develop more shortness of breath, it is important to know that we're here to help.
Which IBD medications suppress the immune system? Is it safe to take these medications?
The medications we used to treat inflammatory bowel disease include a variety of therapies that work by different mechanisms or target different parts of our immune system. Sometimes we recommend immune modulator therapies called thiopurines or azathioprine and 6MP, or another medicine called methotrexate.
More recently, we have a variety of biological therapies which target different components of the immune system. A class of therapies called anti-TNF treatments focus on an inflammatory protein called TNF or tumor necrosis factor, which is elevated whenever somebody has an infection or overactive immune response. Anti-TNF drugs such as Remicade, Humira, Cimzia or Simponi are recommended to be continued at the current time.
Another drug called Entyvio targets the white blood cells that might be on their way to the bowel, blocking them from getting out of the blood vessels into the intestines. This is a more selective therapy in that it only works on the intestinal immune system, and therefore, the risk for infection might be lower than with anti-TNF and other treatments.
Lastly, we use a treatment known as Stelara, which targets two other inflammatory proteins that tend to be elevated only where there is inflammation in your body. This is a more selective treatment, but it still works on the entire body.
The goal of these therapies is not to suppress the immune system so patients are more susceptible to infections, but rather, to control the overactive inflammation of the bowel and let the body heal itself.
The general message regarding all of these therapies is that if you are in remission and the treatment you're on is working for your Crohn's disease and ulcerative colitis, you should stay on that therapy during the COVID-19 pandemic. We recommend that you continue to communicate with your health care team about any additional changes that might be necessary. For most patients, we are not recommending that they stop treatments. It is important to remember that these treatments are keeping your IBD under control. If the IBD becomes active, we may recommend corticosteroids like prednisone, however they can increase your risk of infections. This is why we want our patients to do their best to stay in remission.
Healio.com
AGA guidance for Crohn's patients with COVID
The American Gastroenterological Association issued new guidance for the clinical management of patients with inflammatory bowel disease during the COVID-19 pandemic.
“While the COVID-19 pandemic is a global health emergency, patients with IBD have particular concerns for their risk for infection and management of their medical therapies,” the AGA said in a release. “This clinical practice update incorporates the emerging understanding of COVID-19 and summarizes available guidance for patients with IBD and the providers who take care of them.”
“Despite the potential for increased exposure to SARS-CoV-2, the limited available data and expert opinion suggest that patients with IBD do not appear to have a baseline increased risk of infection with SARS-CoV-2 or development of COVID-19,” they wrote. “It is unclear whether inflammation of the bowel per se is a risk for infection with SARS-CoV-2, but it is sensible that patients with IBD should maintain remission in order to reduce the risk of relapse and need for more intense medical therapy or hospitalization.”
What are the outcomes if a patient with IBD develops COVID-19?
As with many aspects of COVID-19, the data needed to answer this question are limited.
“It is too early to make definitive conclusions, but of 164 patients reported to the registry at the time of this writing, patients with severe IBD and COVID-19 (reported as Physician’s Global Assessment) are more likely to be hospitalized related to their IBD or COVID-19 (or both),” Rubin and colleagues wrote. “We anticipate more robust data in the upcoming one to two months as the cases worldwide grow.”
The SECURE-IBD international registry was established to collect more information on how IBD and COVID-19 might interact. Part of the AGA guidance is to ask physicians to submit cases of IBD and confirmed COVID-19 to the registry.
What to do if you have COVID-19?
If a patient with IBD tests positive for SARS-CoV-2, thiopurines, methotrexate and tofacitinib should be temporarily held, Rubin and colleagues wrote. Biologic therapies should also be held. If symptoms of COVID-19 have not yet manifested, biologic dosing can be delayed for 2 weeks while monitoring for symptoms.
Thelancet.com
https://www.thelancet.com/journals/langas/article/PIIS2468-1253(20)30121-7/fulltext
Patients with COVID and Crohns in Wuhan
Between Jan 31 and March 30, 20 (6%) patients required medical management of disease flare, which was treated preferentially with exclusive enteral nutrition for Crohn's disease (n=15) and steroids (n=18), with a median time to review of 1·3 days (IQR 1·0-2·3).
On Jan 3, 2020, we temporarily ceased infliximab infusions and immunosuppressive treatment for all patients, in accordance with national Chinese Society of Gastroenterology guidelines,
altering treatment to 5-aminosalicylic acid (37 patients) or thalidomide (43 patients; with 25 patients receiving both medications) depending on the patients' condition. On Jan 3, we sent educational and instructional alerts and messages to the online IBD groups of our outpatients via WeChat, with all patients responding to our alerts (table). Within 3 days, most patients reported that they maintained good hand hygiene, sought medical assistance online rather than in person, and kept track of fever and respiratory symptoms; all confirmed notification of our information for self-prevention and all patients kept up to date on official news on COVID-19 (table). Most patients decreased the time they spent outside the home, wore masks when outside, and purchased masks for storage; most patients were very satisfied with our team's work (table).
By Jan 13, most patients with IBD in our hospital were discharged, IBD clinics were closed, and routine, non-urgent medical care was moved online. We published online recommended guidelines and precautions for prevention of COVID-19 in the IBD population.
Practiceupdate.com
- This consensus document discusses the treatment of IBD and the concerns with using immune-modifying therapies to control IBD considering the COVID-19 pandemic. The International Organization for the Study of Inflammatory Bowel Diseases utilized the RAND/UCLA method to address the appropriateness of medical decisions and interventions. The panel agreed that IBD did not increase the risk of SARS-CoV-2 infection or developing COVID-19 and that it is safe for patients to continue to attend infusion centers as long as the center has appropriate screening protocols. The group agreed that it is appropriate to decrease or stop prednisone to prevent COVID-19 but not to reduce or stop other IBD therapies. Other scenarios were also presented and voted upon by members.
- Clinicians should take into consideration these recommendations in developing individual management plans for their patients with IBD.
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