GI in the Immunocompromised Host: GI in the Immunocompromised Host: Checkpoint Drugs

0:00Welcome to Board Pearls. This is episode four of four, the last episode of the GI in the Immunocompromised Host chapter, in the Special Populations and Acute or Supportive Care module. This episode is the immune checkpoint inhibitor toxicities of the gut and liver. The first patient is a man with melanoma and bloody diarrhea. His case shows which drugs cause checkpoint colitis most often and when, what's excluded before steroids, how stool frequency sets the grade and the treatment, why seventy-two hours is the decision point, how the choice is made between infliximab and vedolizumab, and why one drug class can be restarted while the other can't. The second patient is a woman with kidney cancer and high transaminases. Her case shows how checkpoint hepatitis is confirmed and graded, how its biopsy differs from autoimmune hepatitis, why infliximab is forbidden in the liver and what replaces it, and which other immune-related events, including a lipase rise, do and don't need treatment.

0:58Here's the first patient. A sixty-four-year-old man with metastatic melanoma has had two infusions of ipilimumab plus nivolumab, the second three weeks ago. For four days he's had eight to nine stools a day above baseline, with cramping and some blood, and he's lightheaded and has been admitted. He hasn't had steroids.

1:18He most likely has checkpoint inhibitor colitis, immune-mediated injury of the colon caused by his cancer immunotherapy. Checkpoint inhibitors block cytotoxic T-lymphocyte antigen four, CTLA-4, as ipilimumab and tremelimumab do, or programmed death one, PD-1, and its ligand, PD-L1, as nivolumab, pembrolizumab, cemiplimab, atezolizumab, and durvalumab do. Releasing those brakes turns T cells against the tumor, and also against the patient's own tissues, and the gastrointestinal, GI, tract is among the organs most often affected.

1:57His regimen and timing make the diagnosis more likely. Anti-CTLA-4 monotherapy causes severe colitis several times more often than anti-PD-1 monotherapy, and the combination of ipilimumab and nivolumab has the highest rate, about twelve percent for grade three to four colitis. Colitis typically starts after the first or second ipilimumab infusion, at four to ten weeks, or three to six months into anti-PD-1 monotherapy, although cases more than a year after the last dose are reported. He's on the combination, after his second infusion, so checkpoint colitis leads his differential, but it isn't confirmed until the mimics are excluded.

2:37Before he gets steroids, infection is excluded, because steroids would worsen it. The diagnosis rests on the drug exposure, the exclusion of infectious mimics, and endoscopy with biopsies. Clostridioides difficile is tested in every patient before steroids are escalated. Cytomegalovirus, CMV, polymerase chain reaction, PCR, in blood and tissue is added once a patient has received corticosteroids or biologics, because CMV reactivation is the main superinfection that mimics treatment failure. He hasn't had steroids, so C. difficile testing is his essential step, and it's negative.

3:16His endoscopy confirms the diagnosis and predicts how hard it will be to treat. Findings range from normal-looking mucosa with inflammation only on biopsy, to erythema, granularity, friability, and ulceration, with deep ulcers in severe disease. Ulcers deeper than two millimeters or larger than one centimeter, and extensive pancolitis, predict steroid failure and the need for a biologic. Biopsies show neutrophilic cryptitis, crypt abscesses, more intraepithelial lymphocytes, and prominent crypt apoptosis, more apoptosis than in idiopathic inflammatory bowel disease and overlapping the pattern of graft-versus-host disease from episode two. His sigmoidoscopy shows friable mucosa with several ulcers over one centimeter, and his biopsies show cryptitis with apoptosis, so he's likely to need a biologic, which is known before his first steroid dose.

4:11His grade sets his treatment, and it's measured by stool frequency above his own baseline under the Common Terminology Criteria for Adverse Events. Grade one is fewer than four stools a day above baseline, grade two is four to six, and grade three to four is seven or more, or hospitalization, or hemodynamic instability. With eight to nine extra stools a day and admission, he's grade three.

4:36Treatment deepens with the depth of the T-cell injury. Grade one gets loperamide and oral hydration, and the checkpoint inhibitor continues under monitoring. Grade two holds the drug and adds oral budesonide, nine milligrams daily, or oral prednisone, one milligram per kilogram, escalating if there's no response in seventy-two hours. Grade three to four needs intravenous methylprednisolone, one to two milligrams per kilogram per day, and anti-CTLA-4 is permanently discontinued. So he starts intravenous methylprednisolone, and his ipilimumab is stopped for good.

5:10His response is judged at seventy-two hours. Without a response by then, a biologic is added, infliximab five to ten milligrams per kilogram or vedolizumab three hundred milligrams. The window matches the time steroids take to induce lymphocyte apoptosis, so waiting longer only delays the drug that will work. At seventy-two hours he still has seven stools a day, so he needs a biologic now, not another week of steroids.

5:36The choice of biologic depends on three things. Infliximab acts faster, within days, and has the largest evidence base. Vedolizumab is gut-selective, blocking alpha-four-beta-seven integrin from binding MAdCAM-1 on gut endothelium, and it's preferred when there's concurrent liver injury or a reason to avoid anti-tumor necrosis factor, TNF, therapy. And CMV reactivation is more likely with infliximab, whose systemic TNF blockade suppresses the cellular immunity that keeps latent CMV in check, while vedolizumab acts only in the gut and leaves systemic anti-CMV immunity intact. That's why CMV PCR is checked before infliximab in anyone who has already had steroids.

6:23After three days of steroids, his CMV PCR is negative and his liver tests are normal, so he gets infliximab, five milligrams per kilogram, often as a single dose repeated at two weeks if symptoms persist. Vedolizumab, when it's chosen, is given at weeks zero, two, and six. Had his liver enzymes been rising from checkpoint hepatitis, vedolizumab would have been the choice, because infliximab is contraindicated in that setting, as the second patient shows.

6:51For disease that fails both biologics, fecal microbiota transplantation, tofacitinib, ustekinumab, and mycophenolate have been used in case series, and surgery is reserved for perforation, fulminant colitis, or refractory hemorrhage. He responds to infliximab, and his stools return to baseline over the next week.

7:12Whether his immunotherapy can restart depends on the drug class and his grade. After grade one to two colitis, re-challenge with the same class is generally safe once the patient is back to grade one or below, and a normal fecal calprotectin or mucosal healing on repeat sigmoidoscopy supports it. After grade three to four colitis, anti-CTLA-4 is never restarted, but switching to anti-PD-1 monotherapy can be considered with careful counseling.

7:40The difference lies in where each drug acts. Anti-CTLA-4 acts at T-cell priming in the lymph nodes, producing broad, durable activation that reliably recurs on re-exposure. Anti-PD-1 acts at the effector stage in tissue, more focally, so anti-PD-1 alone often doesn't reproduce colitis that the earlier anti-CTLA-4 exposure set off. His ipilimumab is gone for good, but once he's recovered with a normal calprotectin, nivolumab alone can be considered after a careful conversation. His colitis ends one of his two drugs, not necessarily his immunotherapy.

8:19Checkpoint colitis doesn't always look like colitis. A seventy-year-old woman with lung cancer, on pembrolizumab for five months, has five watery, non-bloody stools a day above baseline, a negative C. difficile test, and a grossly normal colonoscopy. A pattern like microscopic colitis is increasingly recognized, particularly with anti-PD-1 agents: the colon looks normal, but biopsies show a lymphocytic or collagenous infiltrate. It's treated with open-capsule budesonide, nine milligrams daily, with consideration of holding the inhibitor. Her biopsies show a lymphocytic infiltrate that skipping biopsies would have missed, and at grade two she starts budesonide with her pembrolizumab held.

9:00Checkpoint inhibitors can also inflame the small bowel without the colon, an enteritis whose biopsies show a lymphocytic infiltrate, more apoptosis, and sometimes villous blunting. Chapter eleven covers its pattern, and it's managed with the same grading as colitis.

9:15Now the liver. A fifty-six-year-old woman with metastatic renal cell carcinoma started ipilimumab plus nivolumab nine weeks ago and feels well. Routine labs show an alanine aminotransferase, ALT, twelve times the upper limit of normal, an aspartate aminotransferase, AST, nearly as high, and a bilirubin one point two times normal, all normal a month ago. She takes no new medications and drinks little.

9:42She most likely has checkpoint inhibitor hepatitis, and her timing and regimen are typical. It affects a few percent of patients on anti-CTLA-4 or anti-PD-1 monotherapy and up to eighteen percent on ipilimumab plus nivolumab, usually six to fourteen weeks after starting, with a median of eight to twelve. It's most often an asymptomatic transaminase rise found on surveillance labs, occasionally with jaundice, and rarely fulminant, which is why liver tests are checked routinely during treatment rather than waiting for symptoms.

10:14Her other causes still have to be excluded. The pattern is usually hepatocellular, with an R value above five, though cholestatic and mixed patterns occur. The workup excludes hepatitis A, B, C, and E and reactivation of hepatitis B; drug-induced injury, including over-the-counter and herbal products; autoimmune hepatitis; and alcohol. About a third of patients have another immune-related adverse event at the same time, a third have fever, and a third have rash. Her pattern is hepatocellular, her serologies, including hepatitis B, are negative, and when asked about supplements by name, since a herbal tea may not seem like medicine, she takes none.

11:00She doesn't need a biopsy, because the context is clear and other causes are excluded, but its findings explain how checkpoint hepatitis differs from autoimmune hepatitis. Biopsy, used in steroid-refractory or atypical cases, shows a panlobular hepatitis with mild portal lymphocytic or histiocytic inflammation. The key difference from autoimmune hepatitis is the absence of plasma cells. Lymphocytic cholangitis appears in about half, granulomas are more common with anti-CTLA-4, autoantibodies are usually negative or low-titer, and immunoglobulin G, IgG, is usually normal, all unlike classical autoimmune hepatitis from chapter twenty. Her autoantibodies are negative and her IgG is normal. Dense plasma cells, a high IgG, and positive autoantibodies would point instead to classical autoimmune hepatitis.

11:52Her grade is set by both ALT and bilirubin, whichever is worse. Grade one is an ALT under three times the upper limit with a bilirubin under one and a half times, and the inhibitor continues with weekly labs. Grade two is an ALT three to five times or a bilirubin one and a half to three times, and the drug is held, with oral prednisone, half to one milligram per kilogram, considered if it persists. Grade three is an ALT five to twenty times or a bilirubin three to ten times, and the inhibitor is permanently discontinued, with intravenous methylprednisolone, one to two milligrams per kilogram per day. Grade four is an ALT over twenty times, a bilirubin over ten times, or decompensation, with permanent discontinuation, intravenous methylprednisolone two milligrams per kilogram per day, and mycophenolate if there's no response in seventy-two hours.

12:46Her ALT of twelve times normal makes her grade three despite a barely raised bilirubin, so her immunotherapy is permanently stopped and she starts intravenous methylprednisolone. Once her liver tests improve, the taper runs over four to six weeks, because a rapid taper drives relapse.

13:04If her steroids fail, the most important rule of checkpoint hepatitis applies: infliximab is contraindicated. Infliximab can itself cause idiosyncratic immune-mediated liver injury with autoimmune features, and it can reactivate hepatitis B, so in a liver already under immune attack it risks adding injury rather than resolving it. That liver toxicity doesn't arise in the colon, which is why infliximab is the first second-line agent for colitis and forbidden for hepatitis.

13:33Mycophenolate mofetil replaces it, one gram twice daily, sometimes raised to one and a half grams twice daily. It inhibits inosine monophosphate dehydrogenase, suppressing lymphocyte proliferation without infliximab's liver toxicity. Tocilizumab, an anti-interleukin-6 receptor antibody, eight milligrams per kilogram intravenously, is third-line, because interleukin-6 drives hepatic inflammation in refractory disease, and azathioprine or tacrolimus have been used in case series, borrowing their role in autoimmune hepatitis. If her ALT is still climbing after seventy-two hours of steroids, she gets mycophenolate, then tocilizumab if needed.

14:14Her grade also decides whether she can be re-challenged. Same-class re-challenge is considered after grade one to two hepatitis once the patient is back to grade one or below, but it's generally avoided after grade three to four hepatic events, because recurrence is common and re-exposure risks worse injury. After her grade three hepatitis, her checkpoint inhibitors stay stopped and her oncologist discusses other options. That differs from the man with grade three colitis, in whom nivolumab alone could still be considered.

14:45Her liver injury could also take a cholestatic form. A pattern resembling sclerosing cholangitis, often with anti-PD-1 agents, presents with cholestatic liver tests, strictures and beading of the bile ducts on magnetic resonance cholangiopancreatography, MRCP, and lymphocytic cholangitis on biopsy. It responds less well to steroids than the parenchymal form, because the main injury is cholestasis from inflamed bile ducts, which steroids only partly modulate and can't relieve mechanically. Ursodeoxycholic acid is added, because it enriches the bile acid pool with hydrophilic bile acids that protect cholangiocytes, the same reason it's used in primary biliary cholangitis, PBC, and primary sclerosing cholangitis, PSC. The course is more chronic, and the standard algorithm works incompletely. A rising alkaline phosphatase with beaded ducts on MRCP would add ursodeoxycholic acid to her steroids, with a slower, less complete response expected.

15:44Because the T-cell activation behind her hepatitis is system-wide, her combination therapy can injure other organs at the same time. Checkpoint pancreatitis is rare, about one to two percent, and an asymptomatic lipase rise without imaging changes or clinical pancreatitis is more common and needs no steroids, which are reserved for symptomatic pancreatitis with an imaging correlate. So a lipase three times normal with no pain and a normal computed tomography, CT, scan is left alone. The long-term consequences of pancreatic injury are exocrine insufficiency and brittle diabetes from cumulative beta-cell damage, so fat malabsorption and unstable glucose are watched long after an event settles.

16:26Checkpoint gastritis, focal and erosive or diffuse, can mimic Helicobacter pylori or autoimmune gastritis at endoscopy and is treated with a proton pump inhibitor and a steroid taper, as is the uncommon checkpoint esophagitis. Endocrine events, thyroiditis, hypophysitis, and adrenalitis, need hormone replacement, and they often occur alongside GI events, so finding one prompts checking thyroid and other hormone levels.

16:55Here are the traps the boards set in these patients. Starting steroids without testing for C. difficile. Forgetting CMV in a patient who's already had steroids, especially before infliximab. Skipping biopsies because the colon looks normal. Continuing the inhibitor in grade two colitis, or using oral steroids for grade three to four. Waiting past seventy-two hours to add a biologic. Using infliximab when checkpoint hepatitis is also present. Re-challenging with anti-CTLA-4 after grade three to four colitis. And assuming severe colitis ends all immunotherapy.

17:31For hepatitis and the other events, the traps are these. Waiting for symptoms instead of following routine liver tests. Forgetting hepatitis B reactivation, supplements, and alcohol. Calling it autoimmune hepatitis despite absent plasma cells and a normal IgG. Grading by bilirubin alone when the ALT is high. Tapering steroids too fast. Giving infliximab for steroid-refractory checkpoint hepatitis. Re-challenging after grade three to four hepatitis. Missing the cholangitic variant and its need for ursodeoxycholic acid. And giving steroids for an asymptomatic lipase rise.

18:13So, start to finish. Anti-CTLA-4 causes severe colitis more often than anti-PD-1, and the combination most of all, usually after the first or second ipilimumab dose. C. difficile is tested first, and CMV in patients who've had steroids. The grade comes from stool frequency above baseline. Grade one gets loperamide and the drug continues. Grade two holds the drug and adds budesonide or prednisone. Grade three to four gets intravenous methylprednisolone and ends CTLA-4 blockade permanently, with infliximab or vedolizumab added if there's no response at seventy-two hours, and vedolizumab chosen when the liver is also injured. A lymphocytic or collagenous pattern under normal-looking mucosa responds to budesonide. Anti-PD-1 can sometimes be restarted after recovery, but anti-CTLA-4 can't after grade three or four.

19:07Checkpoint hepatitis is usually an asymptomatic transaminase rise six to fourteen weeks into treatment, most often with combination therapy. Viral hepatitis, including hepatitis B reactivation, drugs, supplements, alcohol, and autoimmune hepatitis are excluded. The grade comes from ALT and bilirubin: the drug continues at grade one, is held at grade two, and stops permanently with intravenous steroids at grades three and four, tapered over four to six weeks. If steroids fail, mycophenolate is added, never infliximab. The cholangitic variant adds ursodeoxycholic acid, an asymptomatic lipase rise is left alone, and endocrine events are looked for alongside.

19:50That completes chapter thirty-four. Chapter thirty-five is GI disease in pregnancy.

19:57For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode four of four of chapter thirty-four, and I'll see you in the next one.