Abstract
Objective
Remission in patients with inflammatory bowel disease appears to plateau at 30–50% within the first year of biological monotherapy. Patients with Crohn’s disease (CD) and ulcerative colitis (UC) on monotherapy with biologics or small molecules may face this therapeutic ceiling, not reaching remission in relation to bowel inflammation and/or extraintestinal manifestations (EIM). Dual therapy, combining two advanced therapies, has been proposed for this challenging population. We aimed to investigate real-life safety, steroid free- and clinical response in dual therapy.
Materials and Methods
Medical records from September 2018 to September 2023 were reviewed for CD and UC patients undergoing dual therapy with biologics and/or small molecules due to refractory bowel inflammation or EIM in outpatient gastroenterology clinics at Aarhus University Hospital and Regional Hospital Randers. Patients treated for at least three months were included and followed until treatment discontinuation or the end of the study. Patient characteristics, clinical outcomes, adverse events, and clinical response data were collected at baseline and follow-up.
Results and Conclusions
Seventy-four patients (47 with CD and 27 with UC) received a total of 79 dual therapies. The median dual therapy duration was 488 days for CD and 412 days for UC. The most common combinations were adalimumab/ustekinumab in CD (46%) and adalimumab/vedolizumab in UC (35%). Clinical response at follow-up was achieved in 50% of CD patients and 45% of UC patients and steroid-free follow-up in 80% of CD patients and 52% of UC patients. Severe adverse events (SAEs) occurred in eight out of 79 dual therapies. Treatment failure and adverse events within the first three months of dual therapy were not included. This study demonstrates substantial rate of clinical response and an acceptable safety profile in complex IBD patients receiving dual therapy. Still, the risk of SAEs must be balanced against the therapeutic benefit.
Keywords: Crohn’s disease, ulcerative colitis, biological therapy, dual therapy, safety
Introduction
Biologic therapy and small molecule drugs have transformed the therapeutic paradigm for inflammatory bowel diseases (IBD), particularly Crohn’s disease (CD) and ulcerative colitis (UC). These therapies, designed to target specific inflammatory pathways in the immune system, offer significant advantages over traditional immunosuppressive treatments, including improved efficacy and favorable safety profiles.1,2 However, a subset of patients experiences an inadequate response to biologic agents or small molecule drugs as monotherapy. The inadequate response includes primary and secondary treatment failure and partial treatment response resulting in prolonged periods with disease activity, which increases the risk of complications and sick leave.3,4 In addition, IBD can be complicated by the presence of extraintestinal manifestations (EIM). In 6–47% of patients, IBD-related manifestations outside the gut involve the joints, eyes, hepatobiliary tract and skin. EIMs do not necessarily respond to the same treatment as intestinal inflammation which may complicate the treatment strategy.5
Treatment of complex IBD, comprising refractory IBD (IBD patients with chronic disease activity), complicated fistulizing disease and refractory EIM, may include the combined use of two biologic agents and/or small molecule drugs targeting different immunological pathways. Drugs should be considered by merit and mechanism and not sequenced as conventional to advanced.6 This strategy holds potential to modulate immunological pathways by synergistic or complementary modes of action, potentially overcoming the therapeutic ceiling in these patients.7 New randomized controlled trials are also focusing of biological combinations to improve anti-inflammatory efficacy (DUET-UC and DUET-CD).
Emerging biosimilars have lessened the concern regarding treatment costs, and there is a growing awareness that the benefit of (early) aggressive treatment exceeds the risk of disease complications imposed by inadequately treated inflammation.8,9 As a result, “Treat to the Target” has been introduced as new paradigm in the treatment of inflammatory bowel disease.10,11
Despite a growing body of evidence supporting dual therapy, there is still a need for more knowledge concerning the optimal combination of drugs, dosage, treatment duration, and the risk of side effects.
Recycling strategies defined as prior exposure to one of the two drugs used in dual therapy may be effective despite previously experienced loss of response to the particular drug.12,13 Until now only two randomized trials tested dual therapy,14,15 and existing evidence arises from retrospective studies, meta-analysis and case reports. These studies have shown promising results in terms of both efficacy and safety. A recent retrospective Canadian study on 105 IBD patients showed 12 months cumulative clinical and endoscopic response in 60% and 32% of the IBD patients, respectively.16
Several studies suggest synergistic effects of combining two advanced therapies, although the underlying mechanisms and the extent of these potential synergistic effects are not yet fully understood.17,18 The aim of this retrospective study was to assess maintenance of clinical response and safety of dual therapy in complex, refractory adult CD and UC, including therapeutic recycling.
Materials and Methods
In this retrospective study, medical records from patients followed at the gastroenterology out-patient clinics at Aarhus University Hospital and Regional Hospital Randers were reviewed from September 2018 to September 2023. The inclusion criteria were patients diagnosed with CD, indeterminate IBD or UC, age 18 years and above, dual therapy for at least three months including infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, upadacitinib, or ozanimod. Indeterminate IBD will be presented under the UC group. This study focuses on safety and maintenance of clinical response during dual therapy. Therefore, a minimum duration of dual therapy was chosen to exclude incidental overlap of treatments and to ensure an adequate induction period for the most recently initiated therapy. An example of overlap could be changing monotherapy with one biological treatment to another biological monotherapy treatment without a prior wash out period. By defining a minimum duration of three month, we are inherently not able to determine the number of non-responders in patients where dual therapy was initiated but terminated before three months.
Patients who had experienced two or more different combinations of dual therapies were re-included if the new treatment combination had been used for more than three months. Indications for dual therapy were: Refractory IBD, EIM or perianal disease. Patients were followed until treatment discontinuation or to the end of the study period.
Patient characteristics and medical history were recorded at baseline. Biochemical parameters (calprotectin, haemoglobin, CRP, leucocytes, albumin), patient reported outcomes (PRO) (number of stools, nighttime stools, bloody stools, and abdominal pain) and activity scores (Harvey-Bradshaw Index19 (HBI) score and Simple Clinical Colitis Activity Index20 (SCCAI) score) were recorded at baseline and at follow-up. Being a real-life retrospective study, biochemical parameters, activity scores and PRO were not used standardized in all IBD patients, resulting in several missing values. Therefore, we could not evaluate clinical remission according to international standards; instead, clinical response was chosen as the primary outcome. The major part of endoscopies were performed due to suspicion of disease activity, and not as a routine clinical evaluation of treatment response and efficacy.
Patients were mainly included due to disease activity on monotherapy with biochemical signs of activity and clinical symptoms (Table 1). Secondly, dual therapy was introduced to treat activity in EIMs or development of EIMs on monotherapy with biological treatment.
Table 1.
Efficacy of Combined Treatment Estimated by Patients Reported Outcomes, Biochemical Parameters and Activity Scores
| Crohn’s Disease (n = 50) | Ulcerative Colitis (n = 29) | |||||||
|---|---|---|---|---|---|---|---|---|
| Patient Reported Outcomes | ||||||||
| Baseline | Follow Up | Paired Number | P* | Baseline | Follow Up | Paired Number | P* | |
| Stools, median (P. 0.25–0.75)* | 4 (2–7) | 2 (2–6) | 42 | 0.03 | 6 (2–7) | 3 (1–3) | 24 | 0.02 |
| Blood in stool, n (%) | 10 (21%) | 4 (9%) | 46 | 0.02 | 20 (71%) | 8 (28%) | 28 | 0.1 |
| Abdominal pain, n (%) | 26 (57%) | 20 (43%) | 43 | 0.8 | 12 (48%) | 9 (32%) | 25 | 0.02 |
| Nightly stool, n (%) | 15 (31%) | 11 (24%) | 47 | 0.56 | 7 (30%) | 3 (12%) | 26 | 0.04 |
| Biochemical parameters | ||||||||
| CRP (mg/L) median (P. 0.25–0.75) | 4 (4–13.3) | 4 (4–9.5) | 46 | 0.42 | 4 (4–26.9) | 4 (4–5.4) | 26 | 0.02 |
| Calprotectin (mg/kg), median (P. 0.25–0.75) | 1019 (661–2378) | 646 (68–717) | 29 | 0.001 | 1803 (387–1235) | 257 (30–399) | 16 | 0.02 |
| Haemoglobin (mmol/l) mean, (95% CI) | 8.4 (8–8.6) | 8.0 (8–8.6) | 46 | 0.71 | 8.21 (7.89–8.53) | 8.55 (8.19–8.9) | 26 | 0.03 |
| Leucocytes (109/L), median (P. 0.25–0.75) | 8 (6.5–9) | 8.4 (6–8.3) | 46 | 0.42 | 7 (6.9–12.5) | 8 (6.9–10) | 26 | 0.15 |
| Albumin (g/L), mean (95% CI) | 37.2 (35.9–38.5) | 37.6 (36.3–39) | 46 | 0.56 | 37.4 (36.1–38.7) | 39 (37.6–40.6) | 26 | 0.03 |
| Disease activity scores | ||||||||
| HBI score, median (P. 0.25–0.75) | 6 (4–9) | 4 (3–8) | 23 | 0.05 | ||||
| SCCAI score, median (P. 0.25–0.75) | 6 (5–8) | 2 (0.5–3.5) | 19 | 0.02 | ||||
Notes: *Benjamini–Hochberg adjusted P value.
Abbreviations: (P. 0.25–0.75), percentile 25%–75%; number, number of paired data; CI, confidence interval; CRP, C-reactive protein; HBI, Harvey-Bradshaw score; SCCAI, Simple Clinical Colitis Activity Index.
Clinical response was evaluated unblinded by the two authors (AMH and MB) based on 1. Reduced symptom load measured by PRO and improved biochemical parameters (physician’s global assessment); 2. Steroid-free follow-up as a surrogate marker for response; 3. Absence of an increase in the current medication regimen due to disease activity, as determined by the treating physician, serving as a proxy indicator of adequate disease control on the existing dual therapy. If all three parameters were met, the patient was characterised as clinical responder. Data assessment was not conducted independently by both authors. Thus, an inter-rater agreement was not calculated.
Treatment efficacy regarding EIM was evaluated by clinical response defined as improved clinical parameters and physician’s global assessment.
Adverse events (AE) were evaluated at follow-up. Adverse events were defined as any reported side effect related or unrelated to the dual therapy. Severe Adverse Events (SAE) were defined as events related or unrelated to dual therapy resulting in death, life threatening events, hospitalization for more than 12 hours, elongation of a hospitalization. IBD related surgery and disease activity resulting in hospitalization were not defined as adverse events but as disease activity and treatment failure.
Approvals
The local ethic committee of the Central Denmark Region concluded that this study should be conducted as a quality assurance study. Under Danish law, quality assurance studies that aim to evaluate or improve existing clinical practices without introducing new treatments or interventions are not classified as biomedical research and therefore do not require ethical committee approval or informed consent from patients. The study was approved by the hospital boards at the Regional Hospital Randers and Aarhus University Hospital.
The data accessed complied with relevant data protection and privacy.
Statistics
Paired results were tested for normal distribution with Q-Q plots. Normal distributed paired results were tested with student’s T test and presented with mean and 95% confidence intervals. Non-parametric paired results were tested with Wilcoxon signed rank test and presented with medians and 25% and 75% percentiles. Non-parametric unpaired results were analysed with Wilcoxon rank sum test. In case of missing data, the patient was excluded from the specific data analysis but included in analyses where data was sufficient. Missing data were not handled with imputation but instead with a complete case approach.
Being a retrospective study, the sample size was determined by the number of eligible patients available during the study period. Therefore, an a priori power calculation was not applicable. Statistical analyses were performed with Stata 18.5 (StataCorp LLC, Texas, USA). Significance was defined as a two-sided p-value below 0.05. To account for multiple comparisons (Table 1), p-values were adjusted using the Benjamini–Hochberg procedure controlling the false discovery rate at 5%.
Results
Patient Characteristics
A total of 74 patients (47 with CD and 27 with UC) received a total of 79 dual therapies (50 CD treatments and 29 UC treatments) during the study period. The patient characteristics are presented in Table 2. In CD, the median duration of dual treatment was 488 days, and the most frequent combinations were adalimumab/ustekinumab (46%) and adalimumab/vedolizumab (42%). The most common indication for dual therapy was ongoing disease activity despite treatment with monotherapy (66%). Therapeutic recycling strategy was applied in 27 (54%) of the CD patients. In UC, the median duration of dual therapy was 412 days, with 35% on dual therapy with adalimumab/vedolizumab and 28% on vedolizumab/tofacitinib treatment. In UC, recycling strategy was used in 7 (24%) patients.
Table 2.
Patient Characteristics
| Crohn’s Disease | Ulcerative Colitis | |
|---|---|---|
| Number | 47 | 27 |
| Dual therapy, n | 50 | 29 |
| Female, n (%) | 22 (47%) | 17 (63%) |
| Age, median | 35 | 37 |
| Disease duration, years, median | 10.5 | 5.5 |
| Time from diagnosis to combined therapy, years, median | 13.5 | 7 |
| Crohn’s disease Montreal classification, n (%) | ||
| L1 | 7 (14%) | |
| L2 | 13 (26%) | |
| L3 | 30 (60%) | |
| L4 | 18 (36%) | |
| B1 | 9 (18%) | |
| B2 | 22 (44%) | |
| B3 | 16 (32%) | |
| P | 20 (40%) | |
| Ulcerative colitis, Montreal classification, n (%) | ||
| E1 | 4 (14%) | |
| E2 | 4 (14%) | |
| E3 | 18 (62%) | |
| Pouchitis, n (%) | 1 (3%) | |
| Indeterminate IBD, n (%) | 1 (3%) | |
| Previous surgery, n (%) | 27 (54%) | 3 (10%) |
| Previous immune modulating treatment, n (%) | ||
| Azathioprine | 37 (74%) | 24 (83%) |
| 5-aminosalicylic acid | 6 (12%) | 22 (76%) |
| Methotrexate | 6 (12%) | 1 (3%) |
| Prednisolone and/or budesonide | 32 (64%) | 22 (76%) |
| Previous biologics and small molecules (BioSM) | ||
| Infliximab | 43 (86%) | 26 (90%) |
| Adalimumab | 26 (52%) | 14 (48%) |
| Golimumab | 2 (4%) | 5 (17%) |
| Vedolizumab | 18 (36%) | 11 (40%) |
| Ustekinumab | 15 (30%) | 9 (31%) |
| Tofacitinib | 0 | 6 (21%) |
| Maximum 2 types of previous BioSM | 32 (64%) | 17 (59%) |
| More than 2 types of previous BioSM | 18 (36%) | 12 (41%) |
| Immune modulators during dual therapy, n (%) | ||
| Azathioprine | 9 (18%) | 3 (10%) |
| 5-aminosalicylic acid | 0 | 7 (24%) |
| Methotrexate | 0 | 0 |
| Ciclosporine | 0 | 0 |
| Sulfasalazine | 1 (2%) | 0 |
| Prednisolone and/or budesonide | 7 (14%) | 9 (31%) |
| Indication for dual therapy, n (%) | ||
| Failure to monotherapy | 32 (64%) | 19 (66%) |
| Spondylitis/arthritis (EIM) | 4 (10%) | 4 (14%) |
| Hidroadenitis (EIM) | 1 (2%) | 0 |
| Perianal disease | 10 (20%) | 0 |
| Recycling bioSM | 27 (54%) | 7 (24%) |
| Combination of dual therapy | ||
| Infliximab/ustekinumab | 1 (2%) | 0 |
| Adalimumab/vedolizumab | 21 (42%) | 10 (35%) |
| Adalimumab/ustekinumab | 23 (46%) | 3 (10%) |
| Adaliumab/tofacitinib | 1 (2%) | 1 (3%) |
| Adalimumab/upadacitinib | 1 (2%) | 0 |
| Vedolizumab/ustekinumab | 2 (4%) | 3 (10%) |
| Vedolizumab/tofacitinib | 1 (2%) | 8 (28%) |
| Ustekinumab/tofacitinib | 0 | 3 (10%) |
| Tofacitinib/ozanimod | 0 | 1 (3%) |
| Duration of dual therapy, days median | 488 | 412 |
Abbreviations: BioSM, biological therapy and/or small molecules; n, number; %, percentage.
Clinical Response of Dual Therapy
To evaluate the clinical response of dual therapy, we analysed changes in PRO, disease activity scores and biochemical parameters from baseline to follow-up (Table 1). CD patients reported significantly reduced stool frequency and presence of bloody stools. In UC, dual therapy reduced stool frequency, presence of abdominal pain, and stools during the night.
Biochemical parameters and disease activity scores were also affected by dual therapy. In CD, faecal calprotectin levels and HBI scores were significantly reduced. However, the number of paired observations was reduced to 29 (58%) calprotectin levels and 23 (46%) paired HBI scores. UC patients responded to treatment with reduced SSCAI scores, CRP and faecal calprotectin as well as increased haemoglobin and albumin levels. Nineteen (66%) UC patients had paired SCCAI scores and 16 (55%) had paired calprotectin levels.
In general, 25 (50%) CD patients achieved clinical response at follow-up and 38 (76%) did not receive steroids (prednisolone or budesonide) during follow-up (Table 3). Endoscopy was performed in 27 (54%) CD patients during follow up, and 5 (19%) of these patients achieved endoscopic response. In UC, 13 (45%) patients achieved clinical response at follow-up. Steroid-free follow-up was obtained in 15 (52%) patients. Endoscopy was performed in 20 (69%) UC patients and 5 (25%) patients achieved endoscopic response.
Table 3.
Treatment Efficacy
| Crohn’s Disease | Ulcerative Colitis | |
|---|---|---|
| Clinical response | 25 out of 50 (50%) | 13 out of 29 (45%) |
| Steroid free follow-up period | 38 out of 50 (76%) | 15 out of 29 (52%) |
| EIM response | 2 out of 5 (40%) | 2 out of 4 (50%) |
| Clinical response after recycling | 11out of 27 (41%) | 2 out of 7 (29%) |
Notes: Clinical response defined as: reduced symptom load and improved clinical parameters and steroid-free follow-up together with no treatment escalation.
Abbreviation: EIM, extra intestinal manifestations.
Only five (10%) CD and four (14%) UC patients were in dual therapy due to EIM. Two out of five CD and two out of four UC patients achieved clinical response at follow-up.
Clinical Response During Recycling Biological Therapies
Reintroduction of previously discontinued therapies performed an acceptable clinical response particularly in CD. The reason for recycling biological therapies was either prior failure to monotherapy or changed combination of dual therapy where patient had failed to a former combination. Eleven out of 27 (41%) CD patients, who resumed previously discontinued therapies achieved clinical response at follow-up. In UC, a recycling strategy was only employed in seven patients, two (29%) of whom achieved clinical response at follow-up,
Overall, in both CD and UC, the effectiveness of treatment was unaffected by the number of prior treatments administered before initiating dual therapy.
Safety on Concomitant Treatment with Thiopurines or Steroids
Additional treatment with immune modulators and/or steroids may potentially increase the risks of infections during dual therapy. In CD, nine patients (18%) received concomitant thiopurines, three in antibody prophylactic dosage (50 mg/day) and six in therapeutic dosages (2.0–2.5 mg/kg/day). None of these patients developed infections during follow-up and five out of nine patients reached clinical response. In UC, three patients were treated concomitant with thiopurines, one in antibody prophylactic dosage (50 mg/day) and two in therapeutic dosages (2.0–2.5 mg/kg/day). One patient had pneumonia requiring hospitalization, one had relapsing tonsillitis and was treated with antibiotics, and one had Clostridioides difficile infection and underwent colectomy.
Seven CD patients were treated with local or systemic corticosteroids at any time during follow-up concomitant with dual therapy. One of these patients had cystitis. In UC, nine patients received local or systemic corticosteroids during follow-up. One patient had COVID‑19, and one patient had relapsing tonsillitis (receiving both corticosteroids and thiopurines during dual therapy).
Safety
During follow-up, AE were recorded in 22 out of 50 CD treatments and in 14 out of 29 UC dual therapies (Table 4). Severe adverse events were recorded in four CD and in four UC patients. Five events were due to infections.
Table 4.
Adverse Events Specification
| Crohn’s Disease | Ulcerative Colitis | |
|---|---|---|
| Events | ||
| Adverse Events, n | 22 (44%) | 14 (48%) |
| Severe Adverse Events (SAEs), n | 4 (8%) | 4 (15%) |
| SAE specifications | ||
| Severe infections | 3 | 2 |
| Clostridioides difficile | 0 | 1 |
| Anastomosis bleeding | 1 | 0 |
| Pilonidal cyst operation | 0 | 1 |
Notes: Dual therapy related and unrelated adverse events and severe adverse events during follow up.
Only one patient was hospitalized due to severe disease activity. As earlier defined, this was not registered as a severe adverse event but as treatment failure.
Need for IBD related surgery was expected in this refractory IBD population and was considered as treatment failure rather than complications to dual treatment and is therefore not included in the SAEs. Surgery during follow-up was observed in 17 CD patients and one UC patient. Ten CD patients underwent fistula debridement, four had intestinal resections performed and two had stricture dilatation performed. One UC patient required colectomy in the study period due to refractory Clostridioides difficile infection. No cancer and no deaths were observed during follow-up. Specification of surgeries is shown in Table 5.
Table 5.
Surgery Specification
| Crohn’s Disease | Ulcerative Colitis | |
|---|---|---|
| Need for surgery | 17 (34%) | 1 (3%) |
| Colectomy | 1 (2%) | 1 (3%) |
| Fistula debridement | 10 (20%) | 0 |
| Resection of small intestine | 4 (8%) | 0 |
| Dilatation of fibrotic stenosis | 2 (4%) | 0 |
Discussion
We report the safety and the ability to sustain a clinical response of advanced combination therapy in a Danish cohort of refractory and complex adult IBD patients, of whom 46% had received monotherapy with more than two biologics or small molecule drugs before introducing dual therapy. In 70% of the patients, inadequate response to monotherapy prompted a clinical decision to initiate dual therapy. In the remaining cohort, the indication for dual therapy was EIMs or perianal CD. Surgery should always be considered in refractory disease but is not always desirable or even possible especially in CD. This may be reflected in our material including an overweight of CD patients.
The major concern in using dual therapy is the risk of SAEs which must always be balanced against therapeutic benefits. In the present study, patients on average received dual therapy for more than one year. Despite the long treatment duration, our study revealed no new safety concerns. During the study period, we recorded eight SAEs in 79 dual therapies (10.1%). Five infections lead to hospitalization, none of these were considered opportunistic.
Treatment with corticosteroids, AZA/6MP, and infliximab is associated with increased risk of opportunistic infection. When used in combination, these drugs synergistically increase the likelihood of opportunistic infections.21 In the present study, 36% of the patients received concomitant treatment with thiopurines or corticosteroids. Five of these patients experienced a non-opportunistic infection of which two led to hospitalization and were registered as SAEs mentioned above. All UC patients receiving thiopurines contracted an infection although this finding should be interpreted with caution, as it is based on only a small number of UC patients receiving thiopurines. The study does not allow to confirm any relation between thiopurine dose (whether therapeutic or for antibody prophylaxis) and the risk of infection.
The overall risk of serious infections related to biologic monotherapy is 4–6%.22 Data from the VEGA study combining guselkumab and golimumab in a Phase 2 RCT showed no safety concerns.17 In recent meta-analyses addressing safety and efficacy during dual therapy, SAEs were seen in approximately 7–13%, including infections leading to hospitalization.23–25 This frequency of SAEs corresponds to the findings of the present study, supporting the perception of a manageable risk of infections in patients on dual therapy. It is, however, important to note that patients receiving dual therapy for less than three months were not included in this study; consequently, early adverse events were not captured. Accordingly reported SAE rate should be interpreted with caution, as the three-month inclusion criterion may introduce survivorship bias; thus, the findings reflect the safety profile among patients who remained on treatment for at least three months.
Nevertheless, we find that the low incidence of overall and severe adverse events observed during prolonged dual therapy in this study remains an important finding. Larger studies are needed to evaluate the risk of serious infections in specific subgroups concerning age, comorbidity, IBD severity, and BMI.
Despite the severity of IBD described in this cohort, we observed a pooled clinical response in 48% of CD and UC patients as well as significant improvement in biochemical parameters. Similar findings have been observed in both small cohorts and in recent meta-analyses.13,23,24,26,27 The response rates in the present study were substantial even in patients who had been exposed to more than two biologics/small molecule drugs as monotherapy before starting dual therapy (40%). Overall, we found no significant difference in the response rate between patients exposed to more or less than two drugs previously, or whether they were diagnosed with CD or UC. The primary endpoint (clinical response) was not reached in the important VEGA study investigating the efficacy and safety of short-term combination therapy with biologics in patients with moderate to severe ulcerative colitis. We, however, noted that twice as many patients in the combination therapy group achieved the endpoint of clinical remission when compared with either monotherapy group.17 We must await more randomized trials before making firm conclusions on the efficacy of dual therapy.
At follow-up, 73% of the patients in present study were corticosteroid-free (systemic and/or local). Other studies observed a reduction in corticosteroid use during dual therapy.23,28 This is an important parameter when evaluating the overall efficacy of dual therapy.
Being far from naïve to biologics/small molecule drugs, 46% of the patients in the present study had previously been exposed to one of the two drugs later used for combination. Of those, 62% reached clinical response. Recycling strategies were also found to be successful in other studies.13,23 This is important since patients on dual therapy often have a high number of previously failed biologic/small molecule drugs, which limits further therapeutic choices.
The most widely used combination of drugs in our study may have been inspired by prior studies reporting high remission rate as well as an acceptable rate of SAEs for certain combinations. In UC, 35% of the patients were treated with adalimumab/vedolizumab. In a recent meta-analysis the pooled response rate among patients on vedolizumab/anti-TNF-α was 77.9%.24 Consequently, the concomitant use of anti-TNF-α agents with vedolizumab may provide a complementary mechanism to enhance therapeutic outcomes. For CD, adalimumab/ustekinumab was the most used combination. Response rates among patients on ustekinumab/anti-TNF-α were 90.8% in the meta-analysis.24
Anti-TNF-α antibodies and anti-IL-23 antibodies target separate intracellular signaling pathways (ie NF‑κB and JAK/STAT respectively), potentially leading to synergistic effects. Moreover, the inhibition of IL-23 may be effective in patients who do not respond to anti-TNF-α through the ability to suppress the mechanism leading to TNF-α drug resistance.29,30 In a study by Jacobsen et al, the JAK/STAT-pathway was up-regulated in intestinal biopsies from patients refractory to TNF-α therapy.18 This observation favors the concept of combining anti-TNF-α therapy with JAK/STAT inhibitors.–
Clinical response was overall defined by physician’s global assessment based on PRO, clinical measurements, absence of corticosteroids at the follow up visit, and/or no treatment escalation made at the time of follow up. This composite definition was necessitated by the retrospective nature of the study. Although endoscopic healing (and histological remission) is an important long-term treatment target, it was not possible to obtain for all patients. However, both symptomatic relief and biomarkers are widely accepted immediate and intermediate medium-term treatment goals according to the STRIDE II criteria.31 We could not evaluate patients strictly according to the STRIDE II criteria for clinical response and clinical remission or according to Mayo score/HBI due to missing data at the individual patient level. Nevertheless, we consider the reported response rates in the present study to be reliable, as they are supported by significant improvements across multiple biomarkers and PRO during dual therapy. In addition, the observed response rates are in line with those reported in comparable studies.16
The strength of the present study includes a large cohort of patients receiving dual therapy with a substantial follow-up period.
The primary limitation of the study is the retrospective design. Follow-up durations varied among patients, ranging from three months to over a year, potentially influencing response rates and the incidence of SAEs. Further, the potential for survivorship bias should be considered when interpreting the safety findings, as patients remaining on treatment for at least three months may represent a selected population with greater treatment tolerance. Additionally, mild infections may have been unreported in outpatient settings, leading to a possible underestimation of AEs. Patient heterogeneity in terms of dual therapy indications, prior treatments, and concomitant use of thiopurines or corticosteroids further impacted comparability, restricting the evaluation of dual therapy efficacy. Moreover, response assessment was based on multiple parameters, not all of which were available for every patient which limit the strength of the statistical analyses. Endoscopic response was not systematically assessed and therefore not suitable as an evaluation of response. Overall results from this retrospective study with its limitations should be considered as approximate.
Conclusion
This retrospective study with a non-standardized composite outcome demonstrates a substantial rate of clinical response and an acceptable safety profile in complex IBD patients receiving long-term dual therapy. Though the risk of SAEs must always be balanced against the therapeutic benefits, dual therapy may represent a promising treatment approach for complex IBD. Dual therapy should be reserved for selected patients where no other treatment options are available. Future research is required with standardized outcomes like endoscopic evaluation to establish both long-term efficacy and safety profile of dual therapy and to evaluate different dosages, treatment duration, and specific combinations of drugs.
Acknowledgment
We thank Jacob Redder from Department of Data and Data Utilization, Central Denmark Region for his expertise in data extraction.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Jens Kelsen: Advisory board: J&J, Takeda, AbbVie, Celltrion. Speaker: J&J, Takeda, Eli Lilly, BMS
Jørgen Agnholt: Advisory board: AbbVie, Pfizer, Bristol-Meyers Squibb. Speaker: Bristol-Meyers Squibb, Takeda, Norgine, Janssen, Pfizer, Astra Zeneca
The authors report no other conflicts of interest in this work.
The abstract of this paper was presented at the ECCO Conference 2025 as a poster presentation with interim findings. The poster abstract “Efficacy and Safety of Dual Therapy for Refractory Inflammatory Bowel Disease in a Danish Cohort” was published in Journal of Crohn’s and Colitis.32
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