Second-Line Treatments for Autoimmune Hepatitis

A recent retrospective study (C Efe et al. Clin Gastroenterol Hepatol 2017; 15: 1950-6) examined both mycophenolate mofetil (MMF, n=121) and tacrolimus (TAC, n=80) as second-line therapies for autoimmnue hepatitis with a median followup of 62 months. Patients were divided into two groups. The first group (n=108) had a complete response to steroids/azathioprine but had side effects.  The second group (n=93) were nonresponders to steroids/azathioprine. Overall, the cohort examined patients as young as 7 years and as old as 76 years.

Key findings:

  • No significant difference in complete response noted in 69.4% of MMF-treated compared with 72.4% in TAC-treated patients.
  • In group 1 patients (responders to azathioprine), MMF and TAC maintained biochemical remission in 91.9% and 94.1% respectively.
  • In group 2 (prior nonresponders), TAC-treated patients had a complete response rate of 56.5% compared with 34% for MMF-treated patients (P=.029).
  • Liver-related deaths and transplantation occurred with similar rates: MMF 13.2% compared with TAC 10.3%.  With each treatment, 10 patients withdrew from treatment due to side effects.

My take: In this study, both agents were effective in those who changed due to side effects.  However, tacrolimus-treated patients had a higher response among prior nonresponders.

Related blog posts:

Bright Angel Trail, Grand Canyon

 

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IBD Short Takes -Fall 2017

From ImproveCareNow: Real-World Experience with Adalimumab

An excerpt:

A total of 174 children and adolescents were treated with adalimumab as their first anti-TNF therapy…The mean age at the time of Crohn’s disease diagnosis was 13 years and, on average, they started adalimumab at 14.5 years of age…

  • At 3 months after adalimumab was started, all 174 were still on the medication, and 69-71% were in steroid-free remission
  • At 6 months after adalimumab was started, of the 174 who had a clinic visit, 95% were still on the medication, and 75-77% were in steroid-free remission
  • At 12 months after adalimumab was started, of the 154 who had a clinic visit, 94% were still on the medication, and 79-80% were in steroid-free remission
  • At 24 months after adalimumab was started, of the 71 who had a clinic visit, 97% were still on the medication, and 91-94% were in steroid-free remission
  • At 36 months after adalimumab was started, of the 39 who had a clinic visit, 80-86% were still on the medication, and 81-86% were in steroid-free remission

No positive or negative effect on remission was seen with concomitant immunomodulator therapy. However, the number of patients studied during the retrospective analysis is too small to detect all but the greatest impact of this approach.

EC Maxwell et al. JPGN 2017; 65: 299-305  CHOP experience with diverting ileostomy for severe IBD (2000-2014).

  • In this retrospective study, a diverting ileostomy in 24 patients had improvement: 71% –>22% on chronic steroids, improved growth, hemoglobin, blood transfusion and hospitalization.
  • 10 patients underwent subsequent colectomy, 7 had successful reanastomosis, and 7 remain diverted.
  • Diversion allowed a definitive diagnosis in 7 subjects (initially 13 patients were considered IBD-U).
  • Surgical complications were common (n=13 in 7 subjects) and included stoma obstruction, stoma prolapse, and resection of ischemic bowel.
  • One notable feature regarding this cohort was that 50% were 5 or younger when diagnosed with IBD.
  • The authors conclude that a diverting ileostomy can induce clinical stability and allow time to clarify diagnosis.

A Assa et al. JPGN 2017; 65: 293-98. In this study involving findings from 234 patients extracted from the ImageKids database (prospective multicenter cohort), the authors found that pediatric patients with perianal Crohn’s disease have a greater inflammatory burden; however, this was driven mainly by those who had fistulizing disease.

L Lian et al. Clin Gastroenterol Hepatol 2017; 15: 1226-31. This retrospective study from the Cleveland Clinic compared outcomes of endoscopic balloon dilation (EBD) (n=176) or surgery (n=131) for Crohn’s disease-related strictures (1998-2013). Patients who had EBD had an “average time to surgery delayed by 6.45 years.” Immediate success rate for EBD was 91.3%; the perforation rate was 1.1%.. Ultimately, 52% of patients who had EBD required surgery.  Earlier surgery lowered the risk of further surgery but also was associated with significant perioperative complications. In the operative group, 8.8% of patients experienced complications, mainly intra-abdominal abscesses and enterocutaneous fistula. Thus, in the right hands and with careful selection, EBD may be useful.

I Lawrance et al. Clin Gastroenterol Hepatol 2017; 15: 1248-55. This study reported the results of 11 patients who received rectal tacrolimus for resistant ulcerative proctitis. Dosing: The concentration of tacrolimus was 0.5 mg/mL and 3 mL was administered twice a day.Clinical response, using the Mayo Clinic score, was achieved in 73% of tacrolimus subjects compared with 10% (n=1) of placebo-treated subjects.  Mucosal healing at week 8 was noted in 73% of tacrolimus-treated patients, as well.

Soapes Creek Trail

NASPGHAN Postgraduate Course 2014 -Intestinal Inflammation

This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Link: PG Course Syllabus – FINAL (entire syllabus)

The speakers reviewed a lot of IBD material (both at the postgraduate course and at the meeting); much of it has been has been covered in previous blog posts:

Early Onset Inflammatory Bowel Disease –Scott Snapper (Boston Children’s Hospital) pg 170 in Syllabus

  • If one has a 1st degree relative with Crohn’s disease: 26-fold increased risk for IBD compared with 8-fold increased risk if 1st degree relative has ulcerative colitis
  • 30% of children have one or more family members with IBD
  • Concordance rate much greater in monozygotic vs dizygotic twins: 10-15% in UC and 25-30% in Crohn’s with monozygotic

Infantile IBD (age <2 years)

  • Often isolated colonic disease
  • Severe course – refractory to multiple immunosuppressant medications, often requiring surgery, occasionally fatal
  • > 40 % with one or more family members with IBD
  • 25% with infantile IBD have this as their first manifestation of underlying immunodeficiency (pg 174): IPEX, CGD, NEMO, Wiscott-Aldrich, XIAP, common variable immunodeficiency
  • NEOPICS: interNational Early Onset Pediatric IBD Cohort Study. Expanded to 80 Centers (250 scientists) on 5 continents with access to over 1000 VEO-IBD patients
  • IL10 Receptor defect results in infantile onset IBD. Hematopoietic stem cell therapy can be curative. Increased risk of B-cell lymphomas.
  • NCF2 variant (NADPH Oxidase Gene) found in 4% of   (n=11/268)
  • TTC7A mutations (identified by whole exome sequencing) cause apoptotic enterocolitis, intestinal atresias, and SCID (severe combined immunodeficiency) –may not benefit by stem cell transplantation
  • Immune workup for VEO-IBD: immunoglobulins, DHR for CGD, lymphocyte subsets. If negative, further genetic testing (candidate gene testing &/or exome sequencing)

Surgery in Crohn’s Disease –Jason Frischer (Cincinnati Children’s)

  • 28% of CD patients need surgery within 10 years of CD diagnosis; 5.7% within one year.
  • Reviewed principles: conserve bowel, reserved for complications/does not cure Crohn’s disease, strictures can be treated without resection.

Perioperative care

  • Preop-“no answer with regard to biologics,” steroids are detrimental (goal <20 mg of prednisone).  Biologics may increase risk of infections (could be related to specific level) but this is unclear.
  • Postop: thromboprophylaxis

Surgical problems (JPGN 2013; 57: 394 NASPGHAN Guidelines): Abscess, Fistula, Stricture

  • Abscess: percutaneously drain abscess if >2 cm and can remove drain when having less than 10 mL/day. Surgery reserved if refractory to conservative treatment –?timing
  • Strictures: steroids to minimize acute inflammation.  Stricturolplasty rare in pediatrics –used only in those without fistulas. Most common stricturolplasty: Heineke-Mikulicz.
  • In Crohn’s patients at Cincinnati children’s who have undergone ileostomy, long-term only 46% able to have intestinal continuity

Crohn’s and UC What to do when antiTNF isn’t working? –Athos Bousvaros (Boston Children’s) pg 190 in Syllabus

Off-label IBD drugs in children for medically-refractory disease.

Potential Rescue treatments

  •  Calcineurin inhibitors for UC (eg. tacrolimus, cyclosporine)
  •  Thalidomide for Crohn disease
  •  Natalizumab for Crohn disease –>not being used anymore. PML risk
  •  Vedolizumab for Crohn disease and UC
  •  Ustekinumab for Crohn disease
  •  Tofacitinib for UC

Before off-label drugs:

  • Optimize TNF: Make sure the diagnosis is right (eg. exclude CGD), Minimize risk of loss of response (combination therapy, optimize dose, scheduled infusions)
  • Consider surgery -strictures, ulcerative colitis, limited disease

Data for tacrolimus from Boston. n=46. (Watson et al, IBD Journal 2011).  Used most frequently with severe UC.

Data for thalidomide –31 of 49 achieved remission. Lazzerini et al, JAMA. 2013;310(20):2164‐2173.  Side effects -birth defects, neuropathy.  STEPS program.

Data for vedolizumab. Feagan et al NEJM 2013; 369:699.  Remission (in the responders) for ulcerative colitis at 52 weeks:

  • 45% of patients getting vedolizumab monthly
  • 42% of patients getting it every other month
  • 16% of patients randomized to placebo

For Crohns’ disease , Vedolizumab also works in Crohn’s disease, but it takes time (Sands et al: Gastroenterology 2014 147:618‐627)

Off-label does not equate to experimental! pg 199:

FDA Statement: The FD&C Act does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such “unapproved” or, more precisely, “unlabeled” uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.

 

“Luminitis:” When Inflammation is Not IBD (Microscopic Colitides) –Robbyn Sockolow (Weill Cornell Medical School) pg 180 in Syllabus

Microscopic Colitis -pediatric prevalence unknown (JPGN 2013;57:557-561). Nonbloody diarrhea with normal-appearance grossly.

  • Lymphocytic Colitis (>20 intraepithelial lymphocytes/100 colonocytes) -Normal crypt architecture
  • Collagenous Colitis -Thick layer (up to 30 micrometers) of collagen in the tissue and increased lymphocytes in colon

Eosinophilic colitis

  • At-risk groups?  Infants & post-transplant patients (tacrolimus trigger?) (Saeed et al Pediatr Transplantation 2006: 10: 730–735)
  • Associated with food allergy, IBD, autoimmune diseases
  • Elevated serum IgE.

 

 

Once Daily Tacrolimus for Liver Transplant Recipients

A recent study shows that once daily tacrolimus can be effective in patients who have been stable following liver transplantation (LT) (Liver Transplantation 2013; 19: 529-33).

In this retrospective, single center study with 394 adult LT patients, the authors examined the results of conversion to once daily dosing of tacrolimus.  Patient demographics noted an mean age of 53 years & mean time post-transplant was 74 months.

Criteria for conversion:

  1. At least 6 months posttransplant
  2. No rejection in >3 months
  3. Tacrolimus bid was changed to the same total daily dose at once a day and then modified based on levels.

Results after a 24 month followup:

  • 358 of 394 were able to maintain once a day dosing. 6 patients had been converted to cyclosporine, 14 patients had stopped all calcineurin inhibitors, 16 patients had returned to BID dosing.
  • Acute rejection episode was noted in 7 patients
  • Mean serum tacrolimus trough decreased after conversion from 6.1 to 4.9 ng/mL

Take-home message:

Once daily tacrolimus appears to be a reasonable strategy for stable LT patients.  It is possible that once daily administration will improve adherence.

Related blog links:

Tacrolimus for Refractory Crohn’s Disease

While tacrolimus has been considered a potential option for refractory Crohn’s, data on its usage are sparse, mostly small retrospective studies.  Another small retrospective study from the Mayo clinic provides data from their experience with 24 adult patients who were treated with tacrolimus for a median of 4 months (Inflamm Bowel Dis 2013; 19: 1107-11).

17 (71%) of study participants were female and their median age was 38 years.  18 (75%) had ileocolonic disease.  All patients were either intolerant or unresponsive to at least one anti-TNFα agent.  Most patients received concurrent therapy: thiopurines (58%), methotrexate (8%) and antibiotics (46%).

Results:

  • 67% responded to tacrolimus and 21% achieved a steroid-free remission.
  • Patients with trough levels of 10 to 15 ng/mL had the highest response (86%) and remission (57%).
  • Adverse events were common (75% of patients); 8 (33%) required dose reduction and 6 (25%) led to treatment discontinuation.  Frequent adverse events included acute kidney injury (29%), paresthesia (29%), headache (17%), and tremor (17%).
  • 54% of patients in this series required surgery within a median of 10 months after starting tacrolimus.
  • Of the patients who achieved remission (n=5), 2 were transitioned to immunomodulator therapy to minimize long-term toxicity. 1 patient did well after stopping all therapy during a 6 month followup.  1 patient stopped treatment due to paresthesias and 1 patient continued therapy for 2.5 years.

The study does not describe the use of antibiotics for the prevention of Pneumocystis jiroveci pneumonia.

Take-home message: Tacrolimus doesn’t look too promising for refractory disease.

Related blog post:

Additional references:

  • -IBD 2008; 14: 7-12. Tacrolimus of minimal efficacy for UC and Crohn’s. Some achieve response (22/32 in UC and 7/15 in Crohn’s) only 3/32 UC with remission and 1/15 Crohn’s with remission
  • -Gut 2006; 55: 1255-1262. Use of prograf in refractory UC. Troughs 10-15, then 5-10 after remission; partial response in 68% at week 2 & 58% at week 10 (n=19)
  • -Gastroenterol 2003; 125: 380. Tacrolimus helped but did not cure fistulizing disease
  • -J Pediatr 2000; 137: 794-799. n=14.
  • -Am J Gastro 1997; 92: 876. Use in fistualizing Crohn’s.
  • -Am J Gastro 1998; 93: 18. Use in IBD.
  • -IBD 1999; 5: 239. Combined c azathioprine for perianal fistulae. response: initial 2.4weeks, 12.2weeks complete. 7/11 c complete response.
  • -IBD 2009; 15: 193. topical tacrolimus for proctitis. 10/12 w proctitis responded to 2 mg or 4 mg enema in 100 mL of sterile water.
  • -IBD 2007; 13: 245. Use for perianal disease.
  • -Gut 2000; 47: 436-440. Topical tacrolimus may be effective in the treatment of oral and perineal Crohn’s disease.