I am happy to say that this is the last nightcall that I will have this year!
Today, I’ve compiled some of my favorite posts from the past year. I started this blog a little more than 10 years ago. I am grateful for the encouragement/suggestions from many people to help make this blog better. Also, I want to wish everyone a Happy New Year.
Recent articles indicate the possibility of preclinical disease detection of inflammatory bowel disease; perhaps this is analagous to the “precrime’ detection in The Minority Report which allowed the police to arrest people before they committed their crime.
In this study from Sweden, the authors used biobanked plasma samples from 72 individuals with ulcerative colitis (UC) and matched healthy controls (n=140). Then the findings were validated in an inception cohort (n=101 with UC and 50 healthy controls. In addition, a cohort of heathy twin siblings of patients with UC (n=41) were matched with healthy controls (n=37).
Key findings:
Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls
MMP10, CXCL9, CXCL11, and MCP1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings. This up-regulation is triggered by exposure to genetic and early environmental factors.
The discussion elaborates on the role of these proteins.
“MMP10 is classified as a stromelysin. Upregulated levels of stromelysin have been detected in inflamed segments of the colon from patients with ulcerative colitis….The observed preclinical upregulation of MMP10 [thought to promote wound healing] in plasma might indicate that endogenous pathways for wound healing are up-regulated several years before clinically overt ulcerative colitis to counteract disease progression and maintain mucosal homeostasis”
“Eotaxin (CCL11) is a potent chemoattractant of monocytes…eosinophilic-driven inflammation represents an early element in the pathogenesis of ulcerative colitis”
“CXCL9 and CXCL11 has been observed previously in inflamed colonic tissue specimens and blood from patients with ulcerative colitis… Both chemokines are regulated by IFN-gamma and attract CXCR3-positive CD4þ T cells and natural killer cells to the inflammatory site”
My take: This study shows up-regulation of 6 plasma proteins indicating activation of both pro-inflammatory and tissue-repairing pathways several years before clinically overt UC. It offers hope of intervention to prevent the development of UC.
In this study, the authors measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS).
Key finding:
“High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.
In this open-label trial of adults with mild-to-moderate biologic naive Crohn’s disease, key findings:
At week 6, 13 (68%) of 19 patients in the CDED plus partial enteral nutrition group and 12 (57%) of 21 patients in the CDED group had achieved clinical remission (p=0·4618)
Among the 25 patients in remission at week 6, 20 (80%) were in sustained remission at week 24 (12 patients in the CDED plus partial enteral nutrition group and eight in the CDED alone group)
14 (35%) of 40 patients were in endoscopic remission at week 24 (eight patients in the CDED plus partial enteral nutrition group and six in the CDED alone group)
My take: Dietary therapy may be effective option for motivated adult patients with Crohn’s disease.
This retrospective study used data from 331 patients (n=107 with IBD). Fecal calprotectin (FC) was done between 30 days and 1 day before colonoscopy.
Key findings:
Correlation with endoscopy: median FC was lowest for all IBD patients with no active disease (181 μg/g) and highest in severe disease (921 μg/g), with significant difference between no disease and moderate and severe disease (P = 0.019, 0.003), and between mild and severe disease (P = 0.012)
Correlation with histology: median FC was lowest with no active disease (328 μg/g) and highest in severe disease (895 μg/g), with significant difference between no disease and moderate and severe disease (P = 0.021, 0.018)
The control population had median FC of 35.5 compared to 181 μg/g for the IBD population in endoscopic remission (P = 0.018).
My take: Calprotectin levels are particularly helpful as a screen for IBD (probably using threshold of at least 120) and its use to monitor clinical response. This study shows it has some utility in predicting disease severity.
Figure 1: Fecal calprotectin association with endoscopic disease severity of IBD (A), Crohn’s disease (B) and ulcerative colitis (C). IBD = inflammatory bowel disease.
In this retrospective review (1998-2018), the authors identified 39 patients with esophageal Crohn disease (ECD) who met inclusion criteria.
Key findings:
35 (92%) had a clinical response to treatment and 21 (55%) went into clinical remission
ECD seems to be associated with more disabling intestinal CD phenotypes. Of the 39 patients, 10 (26%) had stricturing phenotype and 21 (54%) had penetrating phenotype; 19 (49%) had perianal disease
“Initial treatment after diagnosis with anti-TNFalpha agents compared to other biologics was associated with greater improvement in clinical (97% vs 71%; P=0.02) and endoscopic response (95% vs. 40%; P<0.01) and in clinical remission (64.5% vs. 14.2%; P=0.01).”
Initial treatment with an anti-TNFalpha agent was initial treatment in 18 patients with ECD; 14 had an inflammatory, 3 had a stricturing, and 1 had a fistulizing phenotype.
While this study showed better response to anti-TNFalpha agents compared to other biologics (eg. anti-IL-12/IL-23 agents), this may be due to a selection bias as other biologics are often used as a second-line treatment and are selected more often in refractory disease.
My take: Esophageal Crohn’s disease is a rare diagnosis and appears associated with more severe disease.
Chesapeake and Ohio Canal National Historic Park (near Washington D.C.)
In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52.
Key findings:
Vedolizumab induced greater histologic remission than adalimumab:
week 14: Geboes: 16.7% vs 7.3%, RHI: 25.6% vs 16.1%
week 52: Geboes: 29.2% vs 8.3%, RHI: 37.6% vs 19.9%
Histologic outcomes were generally better in anti–TNF-naïve vs -failure patients
My take: This study shows that histologic outcomes with vedolizumab, similar to clinical outcomes, were better than with adalimumab. Some of this difference could be due to the trail design which did not allow optimization of adalimumab dosing.
In this study of 27,321 patients enrolled in the ImproveCareNow (ICN) learning health system, key findings:
Corticosteroid use decreased from 28% (2007) to 12% (2018)
Black patients received corticosteroids more commonly than white patients. This disparity improved as corticosteroid use decreased in both groups
Anti-tumor necrosis factor-alpha medication use <120 days after diagnosis was associated with a reduction in corticosteroid use
As corticosteroid use decreased, steroid-sparing therapy use increased and height and weight z scores improved, particularly among children with Crohn disease
27 centers (31%) had a significant reduction in steroid use, 5 (6%) had a significant increase, and 45 (52%) had variability in steroid use. 9 centers (11%) had <2 years of data.
My take: These findings are expected but nice to see. Patients in the ICN are using less steroids and growing better. Given the variation in care among centers, there is more work needed.
The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response
It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10–15 mg/mL was achieved
Consensus was also achieved regarding the utility of proactive TDM for anti–tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance.
More data are needed with regard to proactive TDM for biologics other than anti-TNF agents
There are no differences in interpreting TDM between originator biologics and biosimilars
When considering switching within drug class in case of secondary loss of response to a first anti-TNF drug because of the development of antidrug antibodies, an immunomodulator should be added to a subsequent anti-TNF therapy
Low-titer antidrug antibodies can be overcome by treatment optimization (dose escalation, dose interval shortening, and/or addition of an immunomodulator)
My take: This article should help support the practice of proactive TDM and discourage stopping anti-TNF agents until an adequate therapeutic level is achieved.
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A recent study (MT Dolinger et al. Inflamm Bowel Dis 2021; 27: 1210-1214) and the associated editorial (D Geem, S Kugathasan. Inflamm Bowel Dis 2021; 27: 1361-1362) describe the use of multiple therapies (biologics and small molecule therapy) to target refractory pediatric inflammatory bowel disease. Since the term “combination therapy” is already in broad use for those receiving a biologic agent and an immunomodulator, I plan to refer to these new combinations as ‘dual immunotherapy’ for IBD.
Dolinger et al (Dual Biologic and Small Molecule Therapy for the Treatment of Refractory Pediatric Inflammatory Bowel Disease) described 16 children with dual immunotherapy. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn’s disease ) achieved steroid-free remission at 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis.
Except for “anti-TNF medications (infliximab and adalimumab), no other biologic therapies are FDA-approved for children with IBD”
“Clinical disease remission is achieved in only 40-60% of patients on anti-TNF medications”
With ustekinumab, “limited pediatric data reveal that in patients who have failed at least 1 biologic therapy, 38.6-58% achieve clinical remission by week 52…[And] vedolizumab …demonstrated steroid-free remission in 20% by week 22 in a single-center prospective observational cohort study.”
The response to dual immunotherapy is most likely due to the synergistic effects of two medications rather than the start of a new medication. The authors note a prior study which showed a positive experience of adding ustekinumab in 5 children who developed severe paradoxical psoriasis with infliximab and in another subset of pediatric patients, there was improvement with combination vedolizumab/infliximab (Paediatr Drugs 2020; 22: 409-416)
My take (borrowed from editorial): “Given the phenotypic heterogeneity of pediatric IBD and the multiple inflammatory immune pathways implicated in its pathogenesis, the approach of biologic monotherapy–may not be suitable for all patients…patients may require specific combinations…to quell multiple arms of their dysregulated immune response.” More trials are needed to determine the safety of these regimens (especially with regard to malignancy and infections).
In an observational prospective longitudinal study of with newly diagnosed Crohn’s disease in 156 adults followed for nearly 1.5 years, Yanai et al found that 52 patients (33.3%) had an indolent course of CD, 29 (18.5%) required hospitalizations, and 75 (48%) were recommended to start steroid, immunomodulator, or biologic therapies. An “indolent course” indicated a lack of needing steroids, immunomodulators, anti-TNF agents, hospitalization or surgery. Key findings:
There were 4 factors associated with complicated course in treatment-naïve patients: body mass index <25 kg/m2 (hazard ratio [HR], 2.45; 95% CI, 1.07–5.43; P = .033), serum level of vitamin B12 <350 pg/mL (HR, 2.78; 95% CI, 1.21–6.41; P = .016), white blood cells ≥7 × 103/μL (HR, 2.419; 95% CI, 1.026–5.703; P = .044), and serum level of ALT ≥25 IU/L (HR, 2.680; 95% CI, 1.186–6.058; P = .018).
This model discriminated between patients with vs without a complicated course of disease with 90% and 89% accuracy at 6 and 12 months after diagnosis, respectively. A validation cohort demonstrated a discriminatory ability of 79% at 3 months after diagnosis, and a nomogram was constructed (see below)
Points on the nomogram are based on: BMI <25 kg/m2 = 87 or ≥25 kg/m2 = 0, WBC <7 × 103/μL = 0 or ≥7 × 103/μL = 83, vitamin B12 <350 pg/mL = 100 or ≥350 pg/mL = 0, and ALT <25 IU/L = 0 or ≥25 IU/L = 76. The sum score for all variables corresponds with the probability of having an indolent course of disease at different time points after diagnosis.
My take: In this study, low BMI, low Vit B12, high wbc, and high ALT were associated with a more complicated course. These particularly risk factors do not seem intuitive to me. These findings need to be looked at in the pediatric age group, which likely has a lower rate of an indolent course.
In this retrospective study of 270 consecutive adult patients with acute severe ulcerative colitis (ASUC) (2002-2017), the cumulative risk of colectomy was 12.3% (95% CI, 8.6–16.8). Key findings:
Based on multivariate analysis, previous treatment with TNF antagonists or thiopurines (hazard ratio [HR], 3.86), Clostridioides difficile infection (HR, 3.73), serum level of C-reactive proteinabove 3.0 mg/dL (HR, 3.06), and serum level of albumin below 3.0 g/dL (HR, 2.67) were associated with increased risk of colectomy
The cumulative risks of colectomy within 1 y in patients with scores of 0, 1, 2, 3, or 4 were 0.0%, 9.4% (95% CI, 4.3%–16.7%), 10.6% (95% CI, 5.6%–17.4%), 51.2% (95% CI, 26.6%–71.3%), and 100%. Negative predictive values ranged from 87% (95% CI, 82%–91%) to 92% (95% CI, 88%–95.0%). Findings from the validation cohort were consistent with findings from the derivation cohort.
My take: These findings confirm other studies in patients with ulcerative colitis which have shown that each of these criteria were predictors of severe disease.
