Introduction

OZA is approved in multiple countries for treatment of moderately to severely active UC in adults. In the phase 3 TN study, OZA was efficacious for up to 52 wk in pts with moderately to severely active UC. CRP is a widely used serum indicator of inflammation and prognosis in inflammatory bowel disease.

Aims & Methods

The effect of OZA on CRP levels and the association of CRP levels with OZA efficacy were assessed in all TN pts. During the 10-wk induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or placebo (PBO) or received open-label OZA 0.92 mg in Cohort 2. Pts with clinical response to OZA at Week (W) 10 were rerandomized to OZA or PBO for maintenance through W52. Serum CRP levels were assessed at baseline (BL) through W52. Disease activity scores (rectal bleeding subscore [RBS], stool frequency subscore, Physician’s Global Assessment subscore, endoscopy subscore, and partial and total Mayo scores) were assessed at BL and W10. Efficacy endpoints (clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10. Associations of CRP levels with disease activity and efficacy endpoints were assessed using Spearman’s correlation and logistic regression, respectively.

Results

645 pts were randomized to OZA (n=429) or PBO (n=216) and 367 pts received open-label OZA for 10 wk; 230 and 227 OZA-treated pts who responded were rerandomized to OZA and PBO, respectively, for maintenance through W52 (69 PBO-treated pts who responded continued on PBO). Pts on OZA showed reductions from BL in CRP levels at W10, which was significant vs PBO (P<0.001, both cohorts) (Table). Reductions in CRP levels were significantly greater in pts with vs without clinical response at W10 in all treatment groups (P<0.001, all groups) (Table). Significantly greater reductions in CRP levels occurred with OZA vs PBO at W10 regardless of prior biologic or anti–tumor necrosis factor exposure (P<0.05, all groups). Reductions in CRP levels were maintained through W52; pts who continued OZA had similar reductions at W52 as pts who switched to PBO (Table). Decreases in CRP levels in W52 responders were maintained through W52 of treatment, while W52 nonresponder CRP levels started to rise following induction toward BL values (Table). BL CRP levels were significantly positively correlated with most BL disease activity scores (Spearman’s rho 0.2–0.3, P<0.05, all scores) except RBS. BL CRP levels and change in CRP levels at W5 were prognostic for W10 response. Higher BL CRP levels were associated with lower endoscopic improvement, mucosal healing, and histologic remission at W10 and greater reductions in CRP levels at W5 were associated with better clinical response at W10, independent of treatment. Change in CRP levels at W10 was significantly positively correlated with change in most disease activity scores at W10 with OZA and PBO (Spearman’s rho 0.1–0.3, P<0.05, all scores in both groups) except endoscopy with PBO.

Conclusion

In moderately to severely active UC pts, OZA led to reductions in CRP levels. Higher BL CRP levels were associated with worse disease outcomes and greater reductions in CRP levels were associated with better disease outcomes regardless of treatment, supporting CRP levels as a prognostic biomarker for UC.

Disclosure

This study was funded by Bristol Myers Squibb, Princeton, NJ, USA
SH, RM, CW, YH, and AP: employees and/or shareholders of Bristol Myers Squibb.
DTR: received grant support from Takeda; consulted for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chronicles, ClostraBio, Connect BioPharma, EcoR1, Eli Lilly, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen, Kaleido Biosciences, Pfizer, Prometheus Biosciences, Reistone, Seres Therapeutics, Syneos, Takeda, Target RWE, and Trellus Health.

Introduction

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases are different but show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DC) are phagocytic professional antigen presenting cells that link the innate and adaptive immune systems. Indeed, they are the only cell type able to stimulate naïve T cells generating an antigen-specific immune response. In humans, DC can be divided into plasmacytoid (pDC) and c conventional type 1 and 2 (cDC1, cDC2). Although cDC migration towards the GI mucosa is enhanced in IBD, the mechanisms underlying these migrations and whether biological drugs can modulate them are currently unknown.

Aims & Methods

This study aimed to analyze DC migratory capacity towards the GI mucosa, and whether biological drugs with different mechanisms of action can modulate this process in health and IBD.This is a cross-sectional observational postmarketing study where the modulatory effect of different biological treatments on samples from patients with an endoscopic diagnosis of IBD and healthy controls was studied ex vivo. Peripheral blood mononuclear cells (PBMC) were obtained from 15 patients per group and were cultured in presence of golimumab or ustekinumab. Following culture, surface markers expression was determined, assessing the differential effect of biological drugs (if any) over the DC subsets in the different groups. After that, the migratory capacity of circulating DC towards CCL2, CCL25, and MadCam1 from the different study groups was determined. Finally, we evaluated the DC migratory capacities in presence of biological drugs or with culture media alone.

Results

The cDC2 subset showed higher expression levels of β7 and CCR5 compared to cDC1. Golimumab and ustekinumab did not modify the expression of the homing markers in any studied subset in pDC and cDC2.On the contrary, in cDC1 both golimumab and ustekinumab increased CCR6 expression in qCD patients and CCR9 in aUC patients. Regarding to the migratory capacities of the different DC subsets toward intestinal chemoattractants ustekinumab decreased the migratory capacity of cDC2 from CD patients towards a medium supplemented with MadCam1 and increases toward CCL2 in case of cDC1 from CU. In the case of migratory capacities of cDC2 from HC were increased by ustekinumab and golimumab toward CCL2 and CCL25 just in case of golimumab.

Conclusion

cDC2 showed more migratory profile markers than other DC populations. Golimumab and ustekinumab modify the expression of the homing markers just in cDC1 subset. Nevertheless, ustekinumab and golimumab modify the migratory capacities of cDC in IBD patients and HC, but do not exert any effect on pDC. These effects occur in a different manner in CD and UC indicates that the behavior of cDC is different in CD and UC, and that the migration capacity of this subset is not dependent exclusively on homing markers.

Introduction

Cobitolimod (MW 5925.18 Da) is a DNA-based oligonucleotide functioning as an immunomodulatory Toll-like receptor 9 agonist. Cobitolimod is in phase III clinical development as a new therapy for moderate to severe left-sided ulcerative colitis (UC). This phase Ib study aimed to evaluate the pharmacokinetics (PK), safety and tolerability of rectally administered cobitolimod in patients with moderate to severe UC.

Aims & Methods

The phase Ib open-label study was conducted at a single center in Sweden (NCT05404074). The patients had moderate to severe UC defined by a 3-component Mayo score of 5 to 9, with an Investigator read endoscopic subscore ≥2, and with stool frequency and rectal bleeding subscores each ≥1. Patients received one cobitolimod enema (500 mg/50 ml) at week 0, and blood samples for PK analysis were collected pre-dose, 15 min, 30 min, 1h, 2h, 4h, 8h, 12h and 24h after dosing. Patients received a second cobitolimod enema (500 mg/50 ml) at week 3, and at week 6 the degree of clinical remission was evaluated. Clinical remission was defined by the 3-component Mayo score with a rectal bleeding subscore = 0, a stool frequency subscore ≤1 (≥1 point decrease from baseline), and an Investigator read endoscopic subscore ≤1. Patients in clinical remission at week 6 received a third cobitolimod enema (500 mg/50 ml), and blood samples were collected for a second PK analysis as described above. The primary endpoint was PK parameters: maximum plasma concentration (C_max), time to C_max (T_max), area under the curve from 0 to timepoint t (AUC_t) and half-life (T_1/2). Secondary endpoints included safety and tolerability.

Results

Eight patients with active disease were enrolled in the study and included in the safety analysis set. One patient was excluded from the pharmacokinetic analysis set (PKAS) due to an immediate bowel movement following administration. Of the 7 patients included in the PKAS, 4 patients achieved clinical remission at week 6. Rectal administration of 500 mg cobitolimod at week 0 resulted in median C_max of 21.7 ng/ml, median T_max of 1h, median T_last of 4h, and median AUC_0-last of 71.7 h*ng/ml (n=7). For the 4 patients in remission at week 6, corresponding numbers were: median C_max of 15.5 ng/ml, median T_max of 0.5h, median T_last of 4h and median AUC_0-last of 27.6 h*ng/ml. T_1/2 was <2.5h both at week 0 and week 6.
In total, 24 adverse events occurred in the study, out of which the majority was mild and judged as unlikely related to study drug. No serious adverse events were reported.

Table 1. PK parameters per patient

Conclusion

The study demonstrates that rectally administered cobitolimod results in a low systemic exposure of short duration both in patients with active disease and in clinical remission. Cobitolimod was safe and well tolerated at a dose of 500 mg.

Disclosure

Thomas Knittel is a consultant for and a shareholder in InDex Pharmaceuticals, Sweden. Pernilla Sandwall is a former employee and a shareholder in InDex Pharmaceuticals, Sweden. Christine Dieterich Johansson is employed by InDex Pharmaceuticals, Sweden. Arezou Zargari is employed by and a shareholder in InDex Pharmaceuticals, Sweden. Johan Bring is a consultant for InDex Pharmaceuticals, Sweden. Per Hellström receives consultancy fees from: Clinical trial consultants, Sweden; ROSE pharma, USA; Pharmanovia, Denmark; Swedish Agricultural University, Uppsala; Pharmacosmos, Denmark; Stockholm Diabetes Association, Sweden; Celltrion, Finland; Mag-tarmförbundet, Sweden; Karolinska Institutet, Sweden; Bristol-Myers Squibb, Sweden; ClinSmart, Sweden; InDex Pharmaceuticals, Sweden; Takeda pharmaceutical company; Mediahuset, Sweden; Bonnier Healthcare Sweden; Folkuniversitetet, Stockholm, Sweden; Biogaia, Stockholm, Sweden; Norgine, Denmark; Nanologica AB, Södertälje, Sweden.

Introduction

Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC). Previous analyses of data from the phase 2b/3 SELECTION trial (NCT02914522) demonstrated that FIL 200 mg (FIL200) improved health-related quality of life (HRQoL) and led to comprehensive disease control (comprising clinical, biomarker, HRQoL and endoscopic improvements) in patients with UC.¹

Aims & Methods

We evaluated individual Inflammatory Bowel Disease Questionnaire (IBDQ) item data from SELECTION to assess which items drive the benefits of FIL treatment. In SELECTION, adults with moderately to severely active UC were randomized 2:2:1 to receive FIL200, FIL 100 mg or PBO once daily for 11 weeks in Induction Studies A and B (biologic-naive and -experienced patients, respectively). Patients who responded to FIL were rerandomized 2:1 to continue their induction FIL dose in the 47-week Maintenance Study. In this post hoc analysis, standardized effect sizes (SES) were calculated to evaluate the relative magnitude of the difference in mean scores of individual IBDQ items at week 10 (W10) between FIL200 versus PBO-treated patients, and at week 58 (W58) between patients who continued FIL200 treatment (FIL200→FIL200) versus those who were rerandomized to PBO (FIL200→PBO). SES were also calculated for the mean change in score of individual IBDQ items from baseline to W10, and from maintenance baseline to W58. SES were categorized by Cohen’s thresholds (‘trivial’ [<0.2]; ‘small’ [≥0.2–<0.5]; ‘moderate’ [≥0.5–<0.8]; and ‘large’ [≥0.8]). A last observation carried forward imputation approach was used for missing data.

Results

At W10, patients treated with FIL200 overall (n=506) had improvements in all individual IBDQ items versus those treated with PBO (n=277) and had moderate to large increases from baseline (SES ≥0.5) in all individual IBDQ items. The IBDQ items with the five largest SES for FIL200 versus PBO at W10 (analysed by induction study), and for FIL200→FIL200 (n=199) versus FIL200→PBO (n=98) at W58 are summarized in the Table. FIL200 treatment consistently resulted in the largest benefits in items related to pain (‘abdominal pain’ and ‘abdominal cramps’), ability to engage socially (‘satisfied with life’, ‘depressed or discouraged’, ‘social engagement’ and ‘problems with activities’) and bowel urgency (‘loose bowel movements’ and ‘finding a washroom’) versus PBO at W10, and versus FIL200→PBO at W58

Table. Top five individual IBDQ item scores ranked by SES for FIL200 versus PBO groups at W10 and FIL200→FIL200 versus FIL200→PBO groups at W58.

Conclusion

FIL200 treatment provides improvements in HRQoL versus PBO, with large SES seen for most IBDQ items, and the greatest improvements in items related to pain, social engagement and bowel urgency over 58 weeks. This analysis reveals the specific IBDQ items that drive the benefits to HRQoL of FIL and adds further evidence to that showing that FIL contributes to restoration of health through comprehensive disease control for patients with UC.¹

References

1. Schreiber S et al. J Crohns Colitis 2023; https://doi.org/10.1093/ecco-jcc/jjad018

Disclosure

BF reports grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Janssen Biotech/Centocor, Johnson & Johnson/Janssen, Pfizer, Receptos and Takeda; and personal fees from Ablynx, ActoGeniX, AdMIRx, Inc., Akebia Therapeutics, Inc., Allergan, Atlantic Pharmaceuticals, Avaxia Biologics, Inc., Avir Pharma, Baxter Healthcare Corporation, Biogen Idec, BiomX Israel, Boehringer Ingelheim, Boston Pharmaceuticals, Calypso Biotech, Celgene, Elan/Biogen, Eli Lilly, enGene, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, gIcare Pharma, Gilead, Given Imaging, Gossamer Bio, GSK, Inception IBD, Inc., Ironwood Pharmaceuticals, Japan Tobacco Company, Kyowa Hakko Kirin Co. Ltd, Lexicon Pharmaceuticals, Lycera, Mesoblast, Millennium Pharmaceuticals, MSD, Nestlé, Nextbiotix, Novartis, Novo Nordisk, Par’Immune, Progenity, Prometheus Therapeutics and Diagnostics, Protagonist, Qu Biologics, Salix Pharmaceuticals, Shire, Sienna Biopharmaceuticals, Sigmoid Pharma, Synergy Pharma, Teva Pharmaceuticals, TiGenix, Tillotts Pharma, UCB, Vertex Pharmaceuticals, VHsquared, Vivelix Pharmaceuticals, Wyeth, Zealand Pharma and Zyngenia.
SV reports grants from AbbVie, Galapagos, J&J, Pfizer and Takeda; consulting and/or speaker fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma and Zealand Pharma.
LP-B reports speaking fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Genentech, Gilead, Janssen Pharmaceuticals, Medac Pharma, MSD, Pfizer, Sandoz, Takeda, Tillotts Pharma, Viatris and Vifor Pharma;grants from Celltrion, Fresenius Kabi and Takeda; and consulting fees from AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celltrion, CONNECT Biopharma, Cytoki Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, H.A.C. Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen Pharmaceuticals, medac Pharma, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharmaceutical, OSE

Introduction

Crohn's disease is characterised by accumulation of immune cells in the intestinal mucosa. This includes effector T cells, thought to play key roles in disease through cytotoxic activity and pro-inflammatory cytokine production. The CCR9-CCL25 axis is the dominant chemokine system that mediates recruitment of mononuclear cells into small bowel mucosa. We sought to develop a novel humanized anti–CCR9 mAb with enhanced effector function (AZD7798) that potently depletes circulating and tissue resident CCR9 expressing cells.

Aims & Methods

Mice were immunized with CCR9 overexpressing cells and CCR9 hybridomas binders were selected. A lead clone was then humanised and optimised via CDR mutagenesis. Cell binding assays was used to identify specific binders to human and cynomolgus CCR9, and antibody-dependent cell-mediated cytotoxicity (ADCC) was confirmed in Molt4 as well as primary human PBMCs. CCR9 expressing cells in human peripheral blood as well a human gut tissue were characterised by flow cytometry. Finally, CCR9 cell depletion flow cytometric assays were established to investigate circulating CCR9 cell depletion in non-human primates (Macaca fascicularis) at a dose of 10 mg/kg, and ileal depletion was assessed by immunohistochemistry.

Results

8,448 hybridoma were screened and 10 unique hits were identified. The AZD7798 parent antibody was humanised and optimised leading to 40 fold potency improvement. AZD7798 demonstrated specific binding to human and cynomolgus, but not murine, CCR9. In the absence of NK cells, AZD7798 prevented binding of CCL25 to CCR9, and in the presence of NK cells induced potent ADCC in an in vitro human PBMC assay. We showed that CCR9 is highly expressed in human intestinal tissue, with highest levels in the ileum (small intestine). Memory T cells, B cells and T regs accounted for the majority of intestinal CCR9 expression, with minimal expression on other immune populations. CCR9-expressing CD4+ and CD8+ T cells showed increased pro-inflammatory cytokine production compared to CCR9-negative T cells, demonstrating their pathogenic potential. Finally, in cynomolgus monkey, AZD7798 depleted circulating and ileal CCR9 expressing T cells, achieving complete depletion in blood within 2 days.

Conclusion

AZD7798 delivers potent blood and tissue depletion of CCR9 expressing mononuclear cells in-vivo, in non-human primates. Safety of AZD7798 is currently being assessed in Ph1, clin trial registry number NCT05452304. This might provide a novel treatment approach for small bowel inflammatory diseases, including Crohn’s disease.

Disclosure

All authors are employees/shareholders of AstraZeneca

Introduction

Ulcerative colitis (UC) is a refractory inflammatory bowel disease of the colon with repeated relapses and remissions that requires lifelong treatment. Previous studies indicated that proinflammatory cytokines involved the onsets and developments of UC. New treatments for targeting these cytokines, such as TNF-α, IL-12 and IL-23 have been developed in a recent decade, underlying that immune abnormalities are the core for the etiology of UC.
Platelets play a role not only in hemostatic coagulation but in inflammatory mediator by interacting with various cells in the innate and adaptive immunity. Chronic inflammatory response confers platelets activation leading to elevated platelet count and hypercoagulability. Moreover, platelets aggregates with leukocyte in active inflammatory milieu. In fact, thrombocytosis, thromboembolism and upregulation of platelet-monocyte complex (PMC) in UC patients have been reported, implying that platelets could be novel biomarker, therapeutic target and clues for elucidating the pathology of UC. However, the clinical significance of platelet activation and PMC formation in UC is not fully elucidated and few studies were conducted to assess how platelet activation contributes to disease aggravations of UC. Therefore, we comprehensively analyzed platelet activation and platelet-monocyte complex by focusing on a correlation with clinical severity of UC.

Aims & Methods

Patients with UC (n=70) including MES0-2 group (n=34) and MES3 group (n=27), diagnosed according to a combination of symptoms, endoscopic findings, histologic findings, and the absence of alternative diagnoses, and age and sex-matched healthy controls (HCs) (n =19) were enrolled for this study. We analyzed the surface markers such as CD62P, CD40L, CD63, PAC-1 and Annexin V on CD61+ platelets by flowcytometry (FCM) in patients with UC in comparison with those in healthy adults. We also analyzed the proportion of CD61+CD14+ platelet-monocyte complexes and quantified the activation of PMCs by FCM. Moreover, we also investigated the correlation among surface markers, proportion of platelet-monocyte aggregates and Mayo endoscopic score (MES) in UC patients.

Results

The expression of CD62P but not other surface markers on platelets was significantly upregulated in UC when compared to HCs (p<0.01), and was significantly upregulated in in MES3 group when compared to the MES0-2 group (P<0.001). The proportion of PMC was also higher in MES3 groups when compared to MES0-2 group (P<0.05), and was markedly reduced by treatment (P<0.05). In addition, CD16+ monocytes, phenotypically mature and pro-inflammatory cell population, were increased in patients with UC when compared to HCs (P<0.01). The expression of CD16 on monocytes aggregated with platelets was significantly higher when compered to that without platelet (P<0.001).

Conclusion

Our study suggests that platelet activation accelerates mucosal inflammation via adhesion with monocytes in UC and contributes to the aggravation of disease.

References

Semple JW, et al. Platelets and the immune continuum.
Nat Rev Immunol. 2011 Apr;11(4):264-74.
Collins CE, et al. Platelets circulate in an activated state in inflammatory bowel disease.
Gastroenterology. 1994 Apr;106(4):840-5.

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.