Introduction

The use of biologics has improved the outcome for patients with inflammatory bowel disease (IBD) treatment. However, most biologics, particular TNF inhibitors, can reactivate latent tuberculosis infections (LTBI). (1) It is therefore common practice to screen patients for tuberculosis (TB) before initiating biologic treatment. The value of chest X-ray (CXR) as a screening instrument for latent tuberculosis is contested. This, some guidelines recommend always using CXR in addition to an immunological assay test like a QuantiFERON-TB (QFT) test, while others recommend CXR be used under certain conditions, only, such as in immunocompromised patients or if the immunological assay produces a positive result. (2)

Aims & Methods

The primary objective of the present study was to investigate if a chest X-ray identifies patients with latent tuberculosis who are not identified with a QuantiFERON-TB test when screening for latent tuberculosis infection before starting biologic treatment in inflammatory bowel disease patients.
A secondary objective was to identify possible patient characteristics which could increase the necessity for a chest X-ray when screening.

This study was a single center, retrospective cohort study of all IBD patients at the Department of Medical Gastroenterology at Odense University Hospital in Denmark who initiated biologic treatment between Oct. 2017 to Oct. 2022.
The primary outcome of interest in this study was the test results for the QFT test and the CXR. Secondary outcomes of interest were patient characteristics thought to influence either the strength of the QFT test or the likelihood of a patient having LTBI.
The test results were compiled and presented together in a 3x2 table. The total number of patients who received a negative QFT test result, but a TB suspect CXR would represent the number of patients who would be of increased risk of LTBI reactivation when starting biologic treatment without a CXR.

Results

The population studied was low risk for TB and had few risk factors for having false negative QFT results except for concurrent glucocorticoid treatment and inflammatory activity. None of the 8 TB cases present in the population were identified based solely on a suspect chest X-ray (see table). Since no patients had a negative QFT combined with suspect CXR, patient characteristics associated with such an outcome could not be identified.

Conclusion

This results indicate that the benefits of supplementing a QFT test with a CXR are limited and is unlikely to outweigh the cost of patient test-burden, radiation exposure, and economic resources when screening for LTBI in a low endemic population.
While it remains likely that imaging still plays an important role in certain subgroups of patients with higher TB incidence, no characteristics could be identified in this study due to the low-endemic nature of the study population.

References

1. Byun JM, Lee CK, Rhee SY, Kim HJ, Im JP, Park DI, et al. Risks for opportunistic tuberculosis infection in a cohort of 873 patients with inflammatory bowel disease receiving a tumor necrosis factor-α inhibitor. Scand J Gastroenterol. 2015;50(3):312-20.
2. Hasan T, Au E, Chen S, Tong A, Wong G. Screening and prevention for latent tuberculosis in immunosuppressed patients at risk for tuberculosis: a systematic review of clinical practice guidelines. BMJ Open. 2018;8(9):e022445.

Disclosure

Sebastian Bonde Christiansen: No CoI
Mark A. Ainsworth: consultancy for Abbvie and Janssen

Introduction

When starting immunosuppressive therapy in patients with inflammatory bowel disease (IBD), screening test for latent tuberculosis infection (LTBI) and subsequent preventive treatment for positive patients are recommended to reduce the risk of tuberculosis reactivation especially in moderate-burden countries like Japan. However, the prevalence of LTBI and TB in patients with IBD and its influence in the selection of immunosuppressive therapy remain uncertain.

Aims & Methods

Our multicenter study group (IBD-Quality team; IBD Q-shu all institutional study team) conducted a retrospective study to clarify the prevalence of LTBI and the difference in therapeutic management according to the LTBI status in Japanese patients with IBD. Electronic clinical records of each institution during the period between July 2010 and June 2020 were reviewed to assess patients’ clinical profile and subsequent medication after screening test of LTBI. LTBI was defined as positive when interferon γ release assays (IGRAs) or tuberculin test was positive with normal chest X-ray.

Results

This retrospective study included 10 institutions of IBD-Quality team, where 4257 IBD patients (Crohn’s disease: CD 1646, Ulcerative colitis: UC 2611) were treated during the study period. LTBI was diagnosed in 69 patients (1.62%), and their mean ages of the diagnosis of IBD and LTBI were 40.9 ± 2.2 years and 51.8 ± 2.1 years, respectively. Of the 69 patients, 47 patients (68%) were having clinically active IBD, 3 patients (4.4%) had been treated for TB before the diagnosis of IBD, and 5 patients (7.3%) had a family history of TB. After the diagnosis of LTBI, 57 patients (82.6%) were treated for LTBI (LTBI treatment group), whereas the remaining 12 patients were followed up without treatment of LTBI (non-LTBI treatment group). In LTBI treatment group, patients were treated with anti-TNFα antibody in 40 cases (70.2%), JAK inhibitors in 3 cases (5.2%), ustekinumab in 12 cases, and vedolizumab in 5 cases. During the observation period, two patients (1 CD and 1 UC) developed TB 9 and 18 months after completing LTBI treatment, and they were treated with anti-TNFα antibody and JAK inhibitor, respectively. On the other hand, patients in non-LTBI treatment group were treated with ustekinumab in 2 cases, vedolizumab in 1 case, and other drugs in 9 cases, however, neither anti-TNFα antibody nor JAK inhibitors were used. No patient developed TB in the non-LTBI treatment group during the observation period.

Conclusion

The prevalence of LTBI was 1.62% (95% CI; 1.28-2.05) and the rate of developing TB during IBD treatment was 0.05%(95% CI; 0.013-1.17). No cases of TB were observed in the LTBI-negative group during the study period. Although rare, TB can develop in patients with IBD treated with immunosuppressive treatment even after LTBI treatment. Careful follow-up with imaging modalities for TB seems to be mandatory, and further research is required to determine the possible influence of immunosuppressive therapies for the development of TB in patients with IBD.

Introduction

Therapeutic progress in inflammatory bowel disease (IBD) is limited by the lack of understanding of the pathophysiology and the mechanisms involved in response or lack/loss of response to treatments. IBD patients are treated with anti-inflammatory drugs, including biologics such as anti-tumor necrosis factor (TNF) agents, which have been crucial in achieving steroid-free remission and prevention of long-term complications. However, a significant subgroup of patients becomes refractory to these biologicals due to the development of immunogenicity, characterized by the presence of anti-drug antibodies (ADAs). The antibody production and peripheral tolerance are initiated and maintained within lymphoid organs, such as the peripheral lymph nodes, but the exact role of immune cells in these lymphoid structures and whether they are involved in anti-drug antibody (ADA) formation is unknown.

Aims & Methods

We aimed to unravel the pathophysiology behind the development of anti-drug antibodies. Therefore, we performed ultrasound-guided inguinal lymph node needle biopsies from which we isolated leukocytes along with PBMCs from the same patients. Leukocyte populations were analyzed at single cell level via high dimensional phenotyping through mass cytometry (CyTOF).

Results

Using this unique approach, we have so far results from 4 Crohn’s Disease (CD) patients with ADAs (75% females, 50% active disease) and 4 without ADAs (50% females, 75% active disease). Active disease was defined, as an observation of an elevated CRP (c-reactive protein) (>5 mg/L) and/or calprotectin >250 (mg/kg), including symptoms (Harvey-Bradshaw index score > 4 or disease activity index score-CDAI >150).
The proportion of CD4⁺ TEMRA (terminally differentiated effector memory T-cells), CD4⁺ effector and central memory T-cells were increased in the peripheral lymph nodes of patients that developed immunogenicity. Mature NK cells, classical and non-classical monocytes were also increased. Furthermore, the levels of the alpha-4 integrin expression were higher in the lymph node T-lymphocytes, as well as, in the lymph node naïve and memory B-cell subsets in the patient group with ADAs.

Table: Cytometry and Biochemical Characteristics.

Conclusion

Lymph node T-helper cells, monocytes and NK cells potentially play a role in the development ADAs in IBD patients treated with biologics. Although, there was no significant difference in the proportion of naïve and memory B-cells, our findings concerning the alpha-4 integrin expression levels also indicate that both lymph node T and B-lymphocytes, are possibly characterized by a higher migratory potential during immunogenicity conditions.

References

1. Stein RE, Lee DY, Leonard MB, et al. The association between drug levels, anti-drug antibodies, and therapeutic response during infliximab therapy in pediatric Crohn’s disease. J Crohns Colitis 2014; 8: S434.
2. Bodini G, Savarino V, Dulbecco P, et al. The influence of anti-adalimumab antibodies on adalimumab trough levels, TNF-alpha levels and clinical outcome. J Crohns Colitis 2014; 8: S42
3. Stefan S, Sandborn WJ, Choi J, et al. Anti-drug antibodies separate responses of markers of inflammation (c-reactive protein, fecal calprotectin) in Crohn’s disease patients treated with certolizumab pegol. Inflamm Bowel Dis 2014; 20: S68.
4. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs. 2017;31(4):299-316. doi:10.1007/s40259-017-0231-8.
5. Brun MK, Goll GL, Jørgensen KK, et al. Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial. J Intern Med. 2022;292(3):477-491. doi:10.1111/joim.13495.

Disclosure

The authors state no conflict of interest.

Introduction

QuantiFERON-TB is replacing the tuberculin skin test for latent TB screening in IBD patients before starting biologic therapy(1). Indeterminate results may cause delays in treatment initiation and necessitate further evaluation(2).

Aims & Methods

This is a retrospective chart review study conducted at King Fahad Medical City, Riyadh , Saudi Arabia, to investigate factors associated with indeterminate QuantiFERON-TB results in patients with inflammatory bowel disease (IBD).

Results

A total of 300 participants were included, with 53.2% diagnosed with Crohn’s disease (CD) and 46.8% with ulcerative colitis (UC). Indeterminate QuantiFERON-TB results were observed in 4.7% of cases. None of these patients showed positive seroconversion or developed active tuberculosis during the follow-up period up to the study's completion.

Conclusion

Indeterminate QuantiFERON-TB results were significantly associated with factors like geographical region, elevated WBC, hypoalbuminemia, elevated CRP, and steroid use, highlighting the need to consider these variables in latent TB screening for IBD patients. Importantly, none of the patients developed active TB or showed positive seroconversion.

References

1. Cabriada, J. M., et al. (2018). Comparison of QuantiFERON-TB Gold and Tuberculin Skin Test for Screening Latent Tuberculosis in Inflammatory Bowel Disease Patients. Journal of Crohn's and Colitis, 12(7), 862-868.
2. Hradsky, M., et al. (2014). Impact of Indeterminate Results on the Timing of Anti-TNF Therapy in Inflammatory Bowel Disease Patients. Clinical Gastroenterology and Hepatology, 12(6), 1040-1046.

Introduction

As well as having a major impact on bone metabolism, vitamin D (vitD) is recognised as an immunomodulatory hormone with a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). Low vitD levels in patients with IBD are associated with active inflammation, disease severity, poor quality of life and adverse clinical outcomes. Furthermore, lower vitD levels in patients with IBD were shown to be associated with higher pro-inflammatory cytokine profiles. Therefore, it is plausible that vitD may have use as a therapeutic agent in IBD. Our previous work suggests that pre-treatment with vitD may improve effectiveness of biologic drugs such as TNF-α inhibitors and the anti-integrin agent vedolizumab (VDZ). However, data in this context is limited.

Aims & Methods

The aim of this study was to explore potential effects of serum vitD levels on biologic treatment response in IBD patients. A retrospective cohort study was conducted to monitor ambulant treatment of IBD patients with biologics in relationship to their vitD levels. Medical records and routine blood and stool samples of 162 adult IBD patients were assessed at therapy start and 8-weekly thereafter. Samples were analysed for standard blood count, total 25OHD, albumin and inflammation parameters (hsCRP, ESR and faecal calprotectin (FC)) by standard methods. Biologic treatments (infliximab (IFX), its biosimilars (IFX-s), VDZ and ustekinumab (UST)) were administered over 1 year. Drug and anti-drug antibody (ADA) levels were measured with systems provided by Immundiagnostik AG, Bensheim, Germany. VitD values were dichotomized into deficient (≤ 30ng/mL) and sufficient (>30ng/mL). A positive treatment response was defined according to evidence of inflammation as shown by change in hsCRP-levels from baseline to the last two samples monitored. IBM SPSS Statistics 24 was used for statistical analysis.

Results

162 patients with IBD (91 with Crohn’s disease (CD)/ 71 with ulcerative colitis (UC); 81 f/81 m; age 40.2±11.5y) were enrolled. At baseline, 40.7 % used vitD supplementation, 10.5 % were biologic naïve and 50.6 % were vitD deficient. No conclusive relations were found between baseline vitD or supplementation status with drug or ADA levels. However, higher vitD levels over time were associated with positive treatment response for patients on IFX and UST (p<0.05). Treatment specific analysis revealed no significant associations between drug TCs and overall vitD status or treatment response. In descriptive analysis, pre-treatment vitD status was not associated with demographic or clinical characteristics but positively associated with mean corpuscular volume (MCV) and FC and inversely related to transferrin. Ultimately, 72.8 % of patients responded to biologic treatment. Response was related to disease location in CD (p = 0.011) and positively associated with naivety to biologics (p = 0.040). Treatment responders had significantly higher Hb, iron, TSAT and significantly lower ESR, hsCRP and FC.

Conclusion

Our results support a protective role of vitD in IBD patients treated with the biologic agents IFX and UST, shown here for the first time for UST. Interestingly, not the initial vitD status, but permanently sufficient vitD levels were decisive for improved treatment response. Therefore, regular vitD monitoring and long-term vitD substitution in patients with low vitD levels is indicated.

Disclosure

Olivia Schütte, Lea Tessmer and Julia Stötzel have nothing to disclose. Aysegül Aksan is an employee of Immundiagnostik AG.
Oliver Schröder: Lecturing fees: Abbvie, Falk, Janssen, Takeda, Norgine and Pfizer. Congress expenses: Falk, Pfizer.
Jürgen Stein: Consulting: Abbvie, Bristol Myers Squibb, Dr Schär, Falk, Ferring, Fresenius Kabi, Immundiagnostik, Janssen, Medice, MSD, Pfizer, Pharmacosmos, Shire, Takeda, Thermofisher, Vifor. Board member: Abbvie, Bristol Myers Squibb, Dr Schär, Ferring, Fresenius Kabi, Immundiagnostik, Janssen, MSD, NPS, Pharmacosmos, Takeda, Vifor and Shield. Lecturing fees: Vifor Pharma

Introduction

Biologic drugs are key in the current treatment of patients with inflammatory bowel disease (IBD). Identifying patients at high risk of primary non-response or loss of response is key to individualize treatment

Aims & Methods

Aim: To identify risk factors associated with primary nonresponse, loss of response and adverse effects to the first biologic drug used in patients with IBD.
Methoids: Single-centre retrospective cohort study including all consecutive patients with IBD naïve to biologic treatment who have started biologic treatment from 2000 to January 2022. A minimum follow-up of 6 months from the start of the biologic was required. Only the first biologic used in each patient was evaluated. HLA-DQA1 genotyping was done in all patients. Primary response rate was assessed at 24 weeks. Regression analyses were used to assess risk factors. The possible risk factors evaluated were sex, HLADQA1 genotype, smoking at diagnosis, body mass index, age at diagnosis, disease type, location, extent and phenotype disease according to Montreal classification, type biologic drug, disease severity at biologic initiation (Mayo index and Harvey Bradshaw index), combotherapy (≥ 6 months), and history of IBD resective surgery.

Results

A total of 421 patients were included, 290 with Crohn's disease and 131 with Ulcerative Colitis. 51.1% were male. The mean age at biologic initiation was 39 years. The most commonly used biologic was infliximab (IFX) (50.1%), followed by adalimumab (ADA) (46.8%). 46.1% carried HLADQA1*05 allele/s and 24.2% carried HLADQA1*03 allele/s. Almost half of the patients (47.7%) were treated with combotherapy ( biologic + inmmunomodulator). The primary response rate was high: 84.8% (IFX 82.5%, ADA 87.8%). The loss of response rate was 33.3% (IFX 29.9%, ADA 35.5%), with a mean time of 5 years. Adverse effects occurred in 22.1% of patients (IFX 28.9%, ADA 16.2%). In multivariate analysis, carrying HLADQA1*05 allele was the only factor of all evaluated that was associated with an increased risk of loss of response [Odds Ratio: 1.83 (1.16-2.87), p=0.009], while carrying an HLADQA1*03 allele was protective for loss of response [Odds ratio: 0.37 (0.15- 0.89), p=0.026]. Female sex [Odds ratio: 1.61 (1.04-2.49), p=0.032)], the use of infliximab [Odds ratio: 2.00 (1.28-3.14), p=0.003] and the use of higher than standard doses in the IFX induction regimen [Odds Ratio: 3.28 (1.10-9.81), p=0.034] were identified as risk factors for the development of adverse effects.

Conclusion

1) Our results support that carrying HLADQA1*05 increases the risk of secondary loss of response to anti-TNF drugs and suggest that carrying HLADQA1*03 decreases this risk.
2) Female sex is an independent risk factor for the development of adverse effects to anti-TNF drugs.
3) Infliximab is the biologic drug with the highest rate of adverse effects and the use of higher than standard doses during induction is associated with an increased risk of adverse effects.