I recently updated my understanding of treatments for crohns disease.

We currently believe there are two major chronic intestinal inflammatory disorders:  Crohn’s disease and ulcerative colitis. 

Ulcerative colitis is limited to the colon the superficial mucosa is inflamed, it usually “extends proximally in a contiguous manner, and can lead to ulcerations, severe bleeding, toxic megacolon, and fulminant colitis.” If the colon is removed because the disease is severe or uncontrollable, a person is usually cured. 

 

Crohn’s disease can affect any part of the digestive tract, often in a noncontiguous manner, and is characterized by transmural (Across the bowel wall) inflammation, that can lead to complications such as fibrotic strictures, fistulas, and abscesses. Ileal and colonic Crohn’s disease may represent distinct entities.

Current treatments include:

 aminosalicylates, glucocorticoids, and immunomodulators, as well as targeted biologic therapies—monoclonal antibodies-- that neutralize cytokines that promote inflammation (e.g., anti–tumor necrosis factor [TNF] antibodies)—remicade, humira and biosimilar drugs.

In people with crohn's disease:   

One third of patients do not have a response to initial treatment with tumor necrosis factor (TNF) antagonists Humira or Remicaid  (primary non-response)

Another one third has a transient response and requires dose escalation or a switch to another therapy (secondary non-response).

Patients with primary no-response are unlikely to benefit from another TNF antagonist. Patients with secondary non-response who switch to a second TNF antagonist are less likely to have a response than are patients who have not received a TNF antagonist.

Drug 2:  Preclinical studies have implicated interleukin-12 and interleukin-23 in the pathophysiology and pathogenesis of Crohn's disease. 

Ustekinumab, a fully human IgG_1κ monoclonal antibody, blocks the biologic activity of interleukin-12 and interleukin-23 through their common p40 subunit by inhibiting receptors for these two cytokines on T cells, natural killer cells, and antigen-presenting cells.  Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists were more likely to have a response to the monoclonal antibody ustekinumab as induction therapy than to placebo, but they were not more likely to have a remission.

Patients who had a response to ustekinumab as induction therapy had significantly increased rates of response and remission when ustekinumab was administered as maintenance therapy.

The proportions of patients who reached the primary end point were 34 to 39 % for 1, 3, and 6 mg of ustekinumab compared to 23.5% for placebo.

Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%) and response (69.4% vs. 42.5%) at 22 weeks.

Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance.

https://www.nejm.org/doi/full/10.1056/nejmoa1203572  October 18, 2012 N Engl J Med 2012

A study in the medical journal Lancet told of several hundred people with crohns who were injected with 600 or 1200 mg of risankizumab, a monoclonal antibody to Il 23.  The drug or placebo was given at 0, 4, and 8 weeks and the people were followed for 12 weeks.  The disease significantly improved in 40 to 45 percent of those who received the active medication and 20 to 29 percent of those receiving the placebo.

/https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00467-6/abstract

An oral drug that blocks Interleukin-23 should soon be available.  Il23 is one of the cytokines that fans-the-fire, that causes or worsens the chronic inflammation of the bowel in people like crohns. “Owing to its potency and stability in the gastrointestinal tract, this “macrocyclic peptide” is able to provide systemic interleukin-23 pathway blockade through oral administration.”  It has no name yet and is called JNJ-2113.  It was discovered by Protagonist Therapeutics of Newark California.  According to the company’s CEO its discovery was the result of “a 14-plus year journey leading to a proprietary technology platform.  It was developed by a highly specialized team of technical experts. They developed numerous ‘secret sauce’ recipes in the field of peptide therapeutics.” “

https://www.nejm.org/doi/full/10.1056/NEJMoa2308713

https://www.protagonist-inc.com/news/ceo-dinesh-patel-talks-culture-collaboration-and-courage 

Tofacitinib, an oral, pan-JAK inhibitor, was approved for patients with ulcerative colitis on the basis of three randomized, controlled trials they showed that this agent induced and maintained clinical remission, as well as mucosal healing, in patients with ulcerative colitis who did not have a response to conventional or anti–TNF-α therapy.

Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, as both induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn’s disease. Activation of signal transducers (STATs) that are mediated by Janus kinases (JAKs) in T cells play an important pathogenic role in Crohn’s disease.   Upadacitinib had a rapid onset of action, with a higher percentage of patients having a clinical response at week 2 and clinical remission at week 4 than with placebo. Maintenance of clinical remission at week 52 was more frequent in the upadacitinib groups than in the placebo group, and benefits with respect to endoscopic remission and quality of life were observed in both the induction and maintenance periods. Benefits were also observed for two important, frequent, and debilitating symptoms in patients with Crohn’s disease: fatigue (with the 45-mg induction dose and 30-mg maintenance dose) and extraintestinal manifestations (with the 30-mg maintenance dose) 

https://www.nejm.org/doi/full/10.1056/NEJMoa2212728  May 25, 2023 

There were 2 double blind Upadacitinib induction trials

1021 adults with moderate- severe crohns disease received 45 mg a day

502 who responded to induction therapy took 15-30 mg for 52 weeks. 

Clinical remission and endoscopic response at week 12 of induction and week 52 of maintenance. 

Clinical remission at 12 weeks:

50% vs 29% placebo first study

39% remission vs 21% placebo second study

Endoscopic response at 52 weeks 46% and 35% vs

13% and 4% with placebo

In another study clinical remission at week 52 ranged from

37% (15 mg) 48% and (30 mg) vs 15% with placebo

Endoscopic response 28 to 40 percent with drug and 7 % with placebo

Early studies suggested a heritable risk /that is greater for Crohn’s disease than for ulcerative colitis and a higher incidence of IBD in first-degree relatives of patients with IBD than in the general population.

Microbiota

Humans are colonized by trillions of viral, fungal, bacterial, and eukaryotic microbes, collectively referred to as the microbiome, which are present on all barrier surfaces. The gastrointestinal tract, particularly the distal ileum and colon, contains the largest number and greatest diversity of bacteria. Gut microbes exist in a mutually beneficial relationship with humans, established over many millennia, and play an essential role in maintaining health by metabolizing dietary components such as cellulose. Common gut bacteria and their products also have an essential role in the normal development and functioning of the immune system. The presence of these bacteria interferes with the ability of pathogens to colonize and invade the gut, in part because of competition for space and nutrients. Thus, when the integrity of the mucosal barrier is compromised, normally innocuous bacteria can become pathogenic by crossing the epithelium and eliciting an immune response and intestinal inflammation.

Studies have shown that both Crohn’s disease and ulcerative colitis are associated with reductions in the total number, diversity, and richness of microbial species. This raises the possibility that microbiota-based interventions, such as fecal microbiota transplantation, which has been shown to be beneficial in Clostridium difficile infection, might also be effective in IBD. In clinical trials, however, the efficacy of fecal transplants for the treatment of ulcerative colitis has been variable and I know of no studies in people with crohns.

Although natalizumab, a monoclonal antibody against α₄ integrins has been shown to induce and maintain clinical remission in patients with Crohn’s disease, its use has largely been abandoned outside the United States because of the risk of progressive multifocal leukoencephalopathy due to JC virus reactivation. Vedolizumab, a monoclonal antibody against α₄β₇ integrin was approved for the treatment of Crohn’s disease on the basis of its ability to induce clinical remission in both patients who have been exposed to anti–TNF-α therapy and those who have not been exposed.  Data on open-label mucosal healing are also available, but with no comparison group. The role of vedolizumab in the management of extraintestinal manifestations is less clear-cut. Published data from the post hoc GEMINI study and the prospective OBSERV-IBD study^\indicate that vedolizumab may be useful for patients who have Crohn’s disease with peripheral arthritis. In a case series, however, flares of arthritis, sacroiliitis, or both were reported with vedolizumab.

Vedolizumab (Millennium Pharmaceuticals), a humanized immunoglobulin G1 monoclonal antibody to α₄β₇ integrin, modulates gut, but not brain, lymphocyte trafficking and therefore should theoretically be less likely to confer a predisposition to PML. Results from phase 2 trials suggested a benefit in patients with inflammatory bowel disease. In one induction and maintenance trial of vedolizumab in patients with moderately to severely active Crohn's disease.

Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692

https://www.nejm.org/doi/full/10.1056/NEJMra2002697