Pharmacological management of spondyloarthritis associated with inflammatory bowel disease: a systematic review of efficacy, safety, and emerging therapies

Abstract

Background

Spondyloarthritis (SpA) is a prevalent extraintestinal symptom of inflammatory bowel disease (IBD), impacting up to 20% of patients and considerably contributing to the disease burden. The coexistence of inflammatory bowel disease and spondyloarthritis poses therapeutic problems due to the necessity for simultaneous management of intestinal and musculoskeletal inflammation.

Objective

To conduct a comprehensive review and synthesis of the current evidence regarding pharmacological treatments for IBD-associated SpA. This review will assess the efficacy of these treatments on both gut and joint symptoms, as well as their safety profiles and therapeutic positioning.

Methods

A thorough search of PubMed, Scopus, and the Cochrane Library was performed till May 2025. Studies were included if they focused on adult patients with concurrent IBD and SpA, and assessed pharmacological treatments. Data extraction adhered to PRISMA criteria. The risk of bias was evaluated via the Newcastle–Ottawa Scale, SANRA, and qualitative assessment for expert consensus.

Results

Thirteen studies were included, comprising observational cohorts, narrative reviews, and expert consensus guidelines. Tumour necrosis factor inhibitors (TNFi), including infliximab and adalimumab, consistently demonstrated dual efficacy in improving gastrointestinal and musculoskeletal outcomes, notably reducing disease activity indices such as BASDAI, ASDAS, and CDAI. Conventional synthetic DMARDs, such as methotrexate and sulfasalazine, provided modest benefit in peripheral arthritis but lacked efficacy for axial SpA and intestinal inflammation. Emerging therapies—particularly ustekinumab (IL-12/23 inhibitor) and vedolizumab (gut-selective anti-integrin)—were considered valuable options in TNFi-refractory patients. However, their impact on axial symptoms remains uncertain, and guidelines advise caution in such phenotypes. Janus kinase inhibitors (e.g., tofacitinib, upadacitinib) have shown promise in both ulcerative colitis and axial SpA, but require further validation in IBD-SpA overlap populations. IL-23 blockers and TYK2 inhibitors are under investigation, particularly for gut-dominant disease, though evidence in SpA is limited. IL-17 inhibitors, while effective in SpA, are generally contraindicated in IBD due to risk of intestinal flares. Combination strategies, including dual-biologic therapies or biologic–DMARD regimens, are increasingly explored for complex or refractory cases, with observational data suggesting clinical benefit and acceptable safety under close monitoring.

Conclusion

TNFi remains to be the cornerstone treatment for IBD-associated SpA. Biologic alternatives like ustekinumab and vedolizumab provide targeted options for specific individuals; nevertheless, additional data is required regarding axial involvement. An individualised, multidisciplinary therapy approach is crucial. Future research should focus on head-to-head trials, long-term safety assessments, and prediction biomarkers to enhance personalised treatment in this dual disease scenario.

Prospero registration ID

1,084,370.

Introduction

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, recurrent inflammatory disorder of the gastrointestinal tract, with a prevalence surpassing 0.3% in North America and Europe [1]. In addition to intestinal symptoms, IBD is frequently associated with extraintestinal manifestations (EIMs), affecting up to 50% of patients [2]. Among these, musculoskeletal involvement—particularly spondyloarthritis (SpA)—is one of the most common and disabling conditions, observed in up to 40% of IBD cases when subclinical manifestations are included [3, 4].

IBD-associated spondyloarthritis (IBD-SpA) refers to the coexistence of clinically confirmed IBD and SpA, encompassing both axial and/or peripheral musculoskeletal manifestations, ranging from from isolated sacroiliitis to advanced sacroiliac and spinal ankylosis [5]. Importantly, musculoskeletal symptoms alone do not necessarily equate to a diagnosis of SpA. A formal rheumatological evaluation is essential, incorporating assessment for common differential diagnoses, targeted clinical examination, and relevant imaging modalities (e.g., MRI for sacroiliitis, ultrasound for enthesitis), with confirmation of classification according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. The diagnosis of IBD is generally based on standard endoscopic, histologic, and/or radiologic findings, as per international guidelines.

The pathogenesis of this clinical overlap is multifactorial, involving shared genetic predispositions such as HLA-B27 and IL23R variants, activation of the IL-23/IL-17 axis, intestinal dysbiosis, and bidirectional gut–joint immune crosstalk mediated by innate and adaptive immune cells. Managing patients with concurrent IBD and SpA remains a significant therapeutic challenge, largely due to the lack of standardised treatment protocols tailored to dual-disease management. Tumour necrosis factor inhibitors (TNFi) are the mainstay of therapy because of their proven dual efficacy; however, several drugs (e.g., etanercept, IL-17 inhibitors) are either ineffective or contraindicated in active IBD despite established musculoskeletal benefits [8, 9]. Conversely, vedolizumab and ustekinumab offer gut-specific control but have limited musculoskeletal efficacy. The introduction of Janus kinase inhibitors (JAKi) has broadened treatment possibilities, although their precise role in the management of IBD-SpA is still under investigation [10–12].

Recent studies have also highlighted gaps in diagnosis and referral, with many patients experiencing delayed recognition of SpA features in the context of IBD, leading to postponed initiation of appropriate therapy [13]. Furthermore, the absence of robust clinical trials specifically addressing IBD-SpA populations hampers evidence-based decision-making, as current recommendations are largely extrapolated from single-disease studies.

This systematic review aims to critically evaluate and synthesise the current evidence on pharmacological treatments for IBD-associated SpA, with particular focus on their comparative efficacy, safety profiles, and the evolving role of emerging therapeutic agents in dual-targeted care.

Methods

Protocol and registration

This systematic review was carried out in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards [1, 14]. The review protocol was not registered in advance.

Criteria for eligibility

Studies were deemed eligible for inclusion if they satisfied the following criteria:

• Population: Adults (≥ 18 years) diagnosed with inflammatory bowel disease, specifically Crohn’s disease (CD) or ulcerative colitis (UC), and concomitant spondyloarthritis, encompassing both axial and peripheral phenotypes. Where specified in the original studies, the diagnosis of IBD was based on standard endoscopic, histologic, and/or radiologic criteria, while SpA diagnosis required rheumatological evaluation with documentation of classification according to ASAS criteria. Imaging modalities (MRI, radiography, ultrasound) and clinical examination were used to confirm inflammatory musculoskeletal involvement and to exclude common differential diagnoses such as mechanical back pain, osteoarthritis, or fibromyalgia.

• Intervention: Pharmacological treatments, including conventional disease-modifying antirheumatic drugs (cDMARDs), biologic therapies (e.g., tumour necrosis factor inhibitors (TNFi), interleukin-12/23 inhibitors, interleukin-17 inhibitors, integrin blockers), and targeted synthetic agents (e.g., Janus kinase (JAK) inhibitors).

• Outcomes: Documented clinical efficacy for musculoskeletal and/or intestinal manifestations was assessed using validated outcome measures, where reported in the included studies. For SpA, these included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP), and patient-reported outcomes such as visual analogue scales (VAS) for pain. For IBD, common measures included the Crohn’s Disease Activity Index (CDAI), Harvey–Bradshaw Index (HBI), Mayo Clinic Score for ulcerative colitis, and endoscopic remission rates. Adverse events and safety outcomes were extracted as reported.

• Study design: Original research publications (observational studies, clinical trials, consensus statements). Narrative reviews were included if they systematically examined therapy strategies for dual illness.

• Language: English.

• Publication period: No date restriction were applied.

• Exclusion criteria:

  • Studies focussing solely on IBD or SpA without assessing their coexistence: Case reports, editorials, commentaries, or conference abstracts.
  • Studies restricted to paediatric populations.

Information sources and search strategy

A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Library, including all research published until May 2025. The search terms comprised a blend of Medical Subject Headings (MeSH) and free-text keywords: “inflammatory bowel disease,” “Crohn disease,” “ulcerative colitis,” “spondyloarthritis,” “axial spondyloarthritis,” “peripheral arthritis,” “biologics,” “DMARDs,” “TNF inhibitors,” “JAK inhibitors,” “IL-17,” “IL-23,” “vedolizumab,” and “ustekinumab.”

Study selection

After the removal of duplicates, two reviewers conducted an independent screening of titles and abstracts. A comprehensive review of the whole text was performed for papers that potentially met the predefined inclusion criteria. Discrepancies were addressed by consensus or third-party arbitration.

Data extraction

Two reviewers used a standardised data extraction form to independently gather the following:

• Study characteristics: author, year, design, and sample size.

• Demographics: classification of inflammatory bowel disease and spondyloarthritis phenotype.

• Interventions: used pharmaceuticals, class, and dosage.

• Outcomes: clinical efficacy for intestinal and/or joint illness, safety and tolerance, remission criteria.

Risk of bias assessment

Observational studies were evaluated with the Newcastle–Ottawa Scale (NOS) [2, 15]. Narrative reviews were assessed using the SANRA criteria [3, 16], and consensus suggestions were subjectively evaluated for methodological rigour and transparency.

Data synthesis

Given the heterogeneity of the study design, patient populations, and outcome measures, a narrative synthesis was implemented. Results were categorised by pharmaceutical class and therapeutic goal. Findings were contextualised by IBD phenotype (CD versus UC) and SpA subtype (axial versus peripheral) where applicable. A meta-analysis was not conducted.

Results

Study selection

A thorough search approach was carried out across PubMed, Scopus, and the Cochrane Library, resulting in 417 articles (Fig. 1). Following the removal of duplicates (n = 129), 288 records were subjected to title and abstract screening. Out of these, 71 full-text articles were evaluated for eligibility according to established inclusion criteria focused on management strategies for inflammatory bowel disease-associated spondyloarthritis, specifically regarding pharmacological interventions. Ultimately, 13 studies met the inclusion criteria and were included in the systematic review, which includes original research articles, narrative reviews, and expert recommendations.

Fig. 1.

Prisma flow diagram

Study characteristics

The 13 studies included were published from 2011 to 2024 (Table 1). They consisted of:

Table 1.

Characteristics of included studies

Authors	Year	Study design	Sample size	Population	Drugs by class	TNF inhibitor used	Dose and administration	Reported efficacy	Outcome measures used	IBD Safety profile	SpA diagnosis method
Peluso et al.	2013	Narrative Review	NA	IBD patients with SpA	NSAIDs, Sulfasalazine, Methotrexate, Anti-TNFs	Infliximab, Adalimumab	Infliximab 5 mg/kg IV at 0, 2, 6 weeks, then every 8 weeks; Adalimumab 40 mg SC every other week	Good SpA control with inhibitors; limited with NSAIDs	BASDAI, CDAI	NSAIDs risky; Biologics preferred	Confirmed SpA diagnosis (axial and peripheral)
Michetti et al.	2023	Observational Cohort Study	316	Enteropathic SpA patients	NSAIDs, DMARDs, Anti-TNFs	Adalimumab	Adalimumab 40 mg SC every other week	Biologics reduced disease activity	BASDAI, CDAI, ASDAS CRP	Biologics improved IBD outcomes	Confirmed axial and peripheral SpA
Rosenbaum and Dave	2011	Narrative Review	NA	IBD patients with musculoskeletal manifestations	NSAIDs, Sulfasalazine, Methotrexate, Anti-TNFs	Infliximab, Adalimumab	Infliximab 5 mg/kg IV at 0, 2, 6 weeks, then every 8 weeks; Adalimumab 40 mg SC every other week	Inhibitors effective; DMARDs moderate	BASDAI, CDAI	NSAIDs contraindicated; Biologics safe	MSK symptoms, no consistent SpA classification
IG-IBD/SIR	2023	Consensus Recommendation	NA	IBD-SpA guidelines	Anti-TNFs, JAK inhibitors, IL-17 inhibitors (cautious)	Infliximab, Adalimumab, Certolizumab	Standard dosing	TNFi recommended first-line; JAK second-line	Not applicable	TNFi safe; IL-17 risky	Guideline-based definitions of SpA
Kumar et al.	2020	Narrative Review	NA	Crohn’s disease with SpA	Anti-TNFs, IL-23/17 inhibitors	Infliximab, Adalimumab	Standard dosing	TNFi effective; Emerging therapies promising	Not applicable	TNFi safe	Diagnosis based on clinical overlap, not detailed
Luchetti et al.	2017	Observational Cohort Study	52	IBD patients with SpA	Adalimumab (Anti-TNF)	Adalimumab	Adalimumab 40 mg SC every other week	Significant improvements in disease activity scores	BASDAI, CDAI, ASDAS CRP	Adalimumab safe and effective for IBD	Confirmed axial SpA
Olivieri et al.	2014	Expert Consensus	NA	IBD-SpA management scenarios	NSAIDs, Anti-TNFs, Methotrexate	Infliximab, Adalimumab	Standard dosing	TNFi effective; Multidisciplinary approach emphasized	Not applicable	TNFi safe; NSAIDs cautious	Generalised classification
Felice et al.	2018	Narrative Review	NA	IBD patients with SpA and paradoxical arthritis	Steroids, Sulfasalazine, Anti-TNFs, Vedolizumab, Ustekinumab	Infliximab, Adalimumab, Vedolizumab	Standard dosing	Anti-TNFs effective; Emerging biologics discussed	Not applicable	Vedolizumab gut-specific; TNFi safe	Peripheral SpA mainly
Romano et al.	2019	Narrative Review	NA	Crohn’s patients with extraintestinal SpA	TNFi, Ustekinumab, Vedolizumab	Infliximab, Adalimumab, Vedolizumab, Ustekinumab	Standard dosing	TNFi first choice; Ustekinumab alternative	Not applicable	TNFi safe; Vedolizumab limited efficacy for SpA	SpA not clearly defined
Cozzi et al.	2023	Narrative Review	NA	IBD with SpA overlap	Anti-TNFs, IL-23 blockers, JAK inhibitors	Adalimumab, Infliximab	Standard dosing	Biologics promising dual benefit	Not applicable	Favorable safety profile	SpA overlap suggested, not confirmed
Goupille et al.	2024	Therapeutic Update	NA	Axial SpA and IBD	Anti-TNFs, IL-17, JAK inhibitors	Various	Standard dosing	Positioning of new biologics discussed	Not applicable	IL-17 risky; JAK promising	Confirmed axial SpA
Ben Nessib et al.	2020	Expert Consensus	NA	IBD-associated SpA	Anti-TNFs, cDMARDs	Adalimumab, Infliximab	Standard dosing	Consensus on biologic prioritization	Not applicable	TNFi safe	Confirmed axial and peripheral SpA
Stolwijk et al.	2013	Observational Cohort Study	426	IBD patients self-reporting SpA features	Not intervention-focused	None specified	NA	Undiagnosed SpA features prevalent	Not applicable	NA	Unconfirmed SpA; self-reported symptoms

• 6 narrative reviews (Peluso et al., 2013; Rosenbaum and Dave, 2011; Kumar et al., 2020; Felice et al., 2018; Romano et al., 2019; Cozzi et al., 2023),

• 3 observational cohort studies (Michetti et al., 2023; Luchetti et al., 2017; Stolwijk et al., 2013),

• 3 expert consensus recommendations (Olivieri et al., 2014; IG-IBD/SIR, 2023; Ben Nessib et al., 2020),

• 1 comprehensive therapeutic update (Goupille et al., 2024).

Recent narrative reviews and consensus statements have presented new insights into treatment algorithms, safety profiles of newer treatments (such as JAK inhibitors and IL-23 blockers), and combination strategies for difficult patients. The observational study conducted by Stolwijk et al. (2013) encompassed more than 400 IBD patients and underscored the prevalence of undiagnosed SpA characteristics and the postponement of referrals to rheumatology.

The three cohort studies comprised 52 to 426 patients, primarily diagnosed with Crohn’s disease and/or ulcerative colitis, exhibiting diverse symptoms of axial or peripheral spondyloarthritis.

Safety outcomes

Safety data were variably reported across the included studies, with several articles providing only qualitative assessments and limited quantitative data. Table 2 summarises the reported safety outcomes for each drug class and agent, as described in the original studies. The most commonly reported safety concerns included an increased risk associated with NSAID use in IBD patients, the risk of paradoxical inflammation such as IBD flare with IL-17 inhibitors, and the generally favourable gut-specific safety profile of vedolizumab. Anti-TNF agents were frequently reported as safe and effective for both musculoskeletal and intestinal manifestations, although the risk of infection was noted in some reports. It is important to note that the table reflects only outcomes explicitly described in the included studies and does not incorporate additional data from external sources.

Table 2.

Reported safety outcomes for each drug class and agent in the included studies as described by the original authors

Study	Year	Class	Agent	Reported safety outcome	Adverse effects
Peluso et al.	2013	NSAIDs, Sulfasalazine, Methotrexate, Anti-TNFs	Infliximab, Adalimumab	NSAIDs risky; Biologics preferred	Risk reported
Michetti et al.	2023	NSAIDs, DMARDs, Anti-TNFs	Adalimumab	Biologics improved IBD outcomes	Improved outcomes
Rosenbaum and Dave	2011	NSAIDs, Sulfasalazine, Methotrexate, Anti-TNFs	Infliximab, Adalimumab	NSAIDs contraindicated; Biologics safe	Contraindicated in certain cases, Generally safe
IG-IBD/SIR	2023	Anti-TNFs, JAK inhibitors, IL-17 inhibitors (cautious)	Infliximab, Adalimumab, Certolizumab	TNFi safe; IL-17 risky	Risk reported, Generally safe
Kumar et al.	2020	Anti-TNFs, IL-23/17 inhibitors	Infliximab, Adalimumab	TNFi safe	Generally safe
Luchetti et al.	2017	Adalimumab (Anti-TNF)	Adalimumab	Adalimumab safe and effective for IBD	Generally safe
Olivieri et al.	2014	NSAIDs, Anti-TNFs, Methotrexate	Infliximab, Adalimumab	TNFi safe; NSAIDs cautious	Generally safe
Felice et al.	2018	Steroids, Sulfasalazine, Anti-TNFs, Vedolizumab, Ustekinumab	Infliximab, Adalimumab, Vedolizumab	Vedolizumab gut-specific; TNFi safe	Generally safe
Romano et al.	2019	TNFi, Ustekinumab, Vedolizumab	Infliximab, Adalimumab, Vedolizumab, Ustekinumab	TNFi safe; Vedolizumab limited efficacy for SpA	Generally safe
Cozzi et al.	2023	Anti-TNFs, IL-23 blockers, JAK inhibitors	Adalimumab, Infliximab	Favorable safety profile	Generally safe
Goupille et al.	2024	Anti-TNFs, IL-17, JAK inhibitors	Various	IL-17 risky; JAK promising	Risk reported
Ben Nessib et al.	2020	Anti-TNFs, cDMARDs	Adalimumab, Infliximab	TNFi safe	Generally safe
Stolwijk et al.	2013	Not intervention-focused	None specified	NA	Not reported

Discussion

Overview and main findings

The management of inflammatory bowel disease associated with spondyloarthritis (IBD-SpA) presents a distinctive therapeutic challenge due to the need to control inflammation in two interconnected but phenotypically heterogeneous disease domains. The coexistence of these conditions often results in a more complex disease course, greater symptom burden, and increased risk of disability. Optimal management requires pharmacological strategies capable of achieving control of both intestinal and musculoskeletal manifestations, while maintaining a favourable safety profile.

This systematic review examined thirteen eligible studies, including observational cohorts, narrative reviews, and expert consensus guidelines, to summarise the evidence on pharmaceutical interventions for IBD-SpA [1–9]. Across studies, tumour necrosis factor inhibitors (TNFi) emerged as the most consistently effective agents for simultaneous management of gastrointestinal and joint inflammation. Agents such as adalimumab and infliximab have demonstrated significant improvement in validated outcome measures, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP), and Crohn’s Disease Activity Index (CDAI), alongside reductions in corticosteroid dependency and promotion of mucosal healing [2, 9]. These benefits align with their mechanism of action, which targets a central cytokine involved in both intestinal and articular inflammatory cascades.

Conventional disease-modifying antirheumatic drugs (cDMARDs), including methotrexate and sulfasalazine, continue to play a role in selected patients, particularly those with peripheral arthritis [1, 3, 5]. However, their limited efficacy in axial SpA with minimal or no impact on intestinal symptoms, and they have shown to be unefficacious on axial. This is consistent with the understanding that axial inflammation is driven predominantly by cytokine pathways inadequately targeted by these agents.

Role of glucocorticoids

Glucocorticoids retain utility for the short-term control of acute flares affecting either the gut or the joints. In IBD, systemic corticosteroids such as prednisone are effective for induction of remission, but their long-term use is precluded by substantial adverse effects, including osteoporosis, metabolic syndrome, and increased infection risk [10, 11]. In peripheral SpA, short courses of oral or intra-articular corticosteroids may be used for rapid symptom control, especially in patients unresponsive to NSAIDs or cDMARDs [12, 13]. However, their role in axial SpA is minimal, reflecting limited efficacy in modifying central joint inflammation. International guidelines emphasise their role as a bridging therapy, with rapid transition to DMARDs or biologics when sustained disease control is needed [12, 14, 15].

Emerging and targeted therapies

Beyond anti-TNFs, several newer biologic and targeted synthetic agents are under investigation or in early clinical use for IBD-SpA. Ustekinumab, targeting the p40 subunit of IL-12/23, and vedolizumab, a gut-selective α4β7 integrin inhibitor, are viable options for anti-TNF–refractory patients, particularly where gastrointestinal control is prioritised. Nevertheless, the rheumatologic recommendations do not consider indicated the use of ustekinumab and vedolizumab in case of axial SpA or axial Psoriatic Arthritis, and responses are better for peripheral joint involvement [15].

Janus kinase inhibitors (JAKi) such as tofacitinib, upadacitinib, and filgotinib have attracted growing attention for their potential to control both domains of IBD-SpA. Upadacitinib, in particular, has demonstrated robust improvements in BASDAI and ASDAS scores in axial SpA, along with induction and maintenance of remission in ulcerative colitis [16–19]. Despite these promising results, data specific to IBD-SpA overlap populations are lacking and many safety concerns—including herpes zoster reactivation, thromboembolic events, and lipid profile changes are rising [20–22]. This is due to to the lack of specific RCTs tailored to the SpA-IBD patients’ population. However, this is a common pitfall for all the bDMARDs used in SpA-IBD, and in such cases, it is important to consider the data on the safety and efficacy of JAKi and selective anti-IL23s in both spondyloarthritis and IBD. However, recent data suggests that although studies and/or RCTs tailored to this specific patient group are still lacking, JAKi have demonstrated high efficacy on both gut and joint inflammation in RCTs and observational studies in IBD and SpAs patients, respectively. This efficacy has been achieved with a good safety profile, particularly in patients under 60 years old and without cardiovascular comorbidities [23].

IL-23 blockers, such as risankizumab, guselkumab, and mirikizumab, act upstream in the IL-23/IL-17 pathway. Risankizumab has secured approval for Crohn’s disease with high rates of clinical and endoscopic remission [24, 25], while its efficacy in psoriatic arthritis and peripheral spondyloarthritis is established. However, responses in axial disease have been inconsistent, reflecting mechanistic data indicating that established axial inflammation may be less IL-23 dependent [26].

TYK2 inhibitors, including deucravacitinib, represent another novel class with early positive results in psoriasis and psoriatic arthritis. Trials in IBD are ongoing, and although theoretical rationale supports their dual potential in IBD-SpA, clinical validation is awaited [27].

IL-17 inhibitors remain effective in axial SpA, but their use in IBD is restricted due to reports of exacerbating intestinal inflammation [8, 28]. This illustrates the complexity of selecting agents that optimise control in both domains without worsening either condition.

Position of Anti-TNFs and guideline alignment

The findings of this review reinforce existing guidelines and real-world data positioning anti-TNFs as first-line biologics for IBD-SpA. Hence, the IG-IBD and Italian Society of Rheumatology recommend anti-TNFs as the preferred option due to their dual efficacy [29–31]. Observational data by Luchetti et al. [32] and Michetti et al. [33] confirmed significant clinical improvements and high remission rates, while Stolwijk et al. [34] highlighted the diagnostic overlap and necessity for multidisciplinary coordination. Cozzi et al. and Goupille et al. [35, 36] discussed the positioning of newer biologics, noting that while vedolizumab and ustekinumab offer targeted benefits, their axial efficacy remains questionable. Ben Nessib et al. [29] advocated for coordinated gastroenterology–rheumatology management. However, it should be noted that there is more data available on therapy with TNFi in this particular group of patients because they have been using it since the late 1990s/early 2000s. In this regard, recent recommandations advocate for the use of TNFi inhibitors in IBD-SpA [14, 15]. Felice et al. [37] observed suboptimal articular responses to vedolizumab despite intestinal remission. A meta-analysis by De Marco et al. [38] further confirmed anti-TNFs’ superiority over conventional therapy for extraintestinal manifestations. Hence, European Crohn’s and Colitis Organisation (ECCO) and the european Alliance of Associations for Rheumatology (EULAR) guidelines consistently recommend early anti-TNF initiation for IBD-SpA [14, 15].

Combination therapy

In addition to monotherapy, combination strategies are gaining interest for managing refractory or complex IBD-SpA. Dual-biologic regimens or biologic plus cDMARD approaches may optimise control across both domains [39–41]. In a multicenter retrospective cohort of 68 patients with Crohn’s disease or ulcerative colitis and SpA, initiating, switching, or adding a biologic at the diagnosis of the second disease significantly increased 90-day clinical improvement rates (68% vs. 32%; OR 3.69; p = 0.004) [42]. Multiple case series and small cohorts describe successful use of vedolizumab combined with other biologics (e.g., anti-TNFs, ustekinumab) in refractory patients, achieving remission in both domains without substantial short-term safety risks [43]. A large Spanish series of 36 refractory SpA/PsA patients (69% with IBD) treated with 39 different DTT regimens reported 69% treatment retention at 14.9 months, major clinical improvement in 69%, and only four serious adverse events [44]. Altieri et al. (2025) concluded that DTT may be a safe and effective option in selected refractory cases, particularly for extraintestinal manifestations, provided that it is administered under strict multidisciplinary supervision.

Strengths and limitations

Strengths of this review include the integration of recent therapeutic advances, incorporation of both clinical trial and real-world evidence, and focus on both efficacy and safety in IBD-SpA. Limitations include the predominance of non-randomised designs, heterogeneity in outcome measures, small sample sizes, and lack of studies targeting true overlap populations. Evidence for newer classes such as JAKi, IL-23 blockers, and TYK2 inhibitors in IBD-SpA remains sparse, identifying an important research gap.

Clinical implications and future directions

Anti-TNFs should remain the cornerstone for IBD-SpA treatment. Ustekinumab is appropriate for peripheral-predominant cases, while vedolizumab should be reserved for patients with severe intestinal disease and minimal axial involvement. IL-17 inhibitors should be avoided in active IBD. JAKi, IL-23 blockers, and TYK2 inhibitors offer promising avenues but require more robust data before routine adoption. A multidisciplinary approach, incorporating gastroenterologists and rheumatologists, is crucial for enhancing therapy techniques and improving patient outcomes [28–30, 45]. Future research should prioritise comparative RCTs of anti-TNFs versus newer agents, assess long-term safety of targeted therapies, develop predictive biomarkers, and explore microbiome- and multi-omics–driven precision medicine strategies.

Conclusion

This comprehensive review, incorporating the most recent observational data and expert assessments, affirms that tumour necrosis factor inhibitors are still considered the fundamental treatment due to their dual efficacy on intestinal and musculoskeletal symptoms supported by data collected since the late 90s. Conventional DMARDs, regardless of their restricted effectiveness in axial spondyloarthritis or intestinal inflammation, remain relevant in the treatment of peripheral arthritis. Recent medicines, such as JAKi and selective anti-IL23 inhibitors as risankizumab and guselkumab, have demonstrated efficacy, particularly in instances intolerant or refractory to anti-TNF therapy, although their advantages in axial symptoms are still constrained. Janus kinase inhibitors (JAKi) and selective anti-IL23s are emerging as intriguing therapeutic alternatives; nevertheless, their long-term safety has been demonstrated only in rheumatic diseases, as rheumatoid arthritis, axialSpa and PsA.

Inhibitors of tyrosine kinase 2 are under investigation for their ability to concurrently manage intestinal and joint inflammation. Simultaneously, combination strategies—specifically dual biologic regimens or biologic-DMARD combinations—have shown initial success in resistant phenotypes, especially in addressing intricate extraintestinal symptoms, with rigorous multidisciplinary oversight. Considering the risks of IL-17 inhibitors in active inflammatory bowel disease, treatment should be customized according to individual disease characteristics and concomitant conditions.

Future research should emphasize prospective controlled trials, the identification of predictive biomarkers, and the integration of microbiome and immunogenetic data to facilitate personalized therapy. A patient-centered, phenotype-driven methodology—based on robust collaboration between gastroenterologists and rheumatologists—is crucial for enhancing long-term outcomes and quality of life in this intricate overlap syndrome.

Author contributions

All authors contributed to the conception, literature search, data extraction, and drafting of the manuscript. All authors read and approved the final manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

As this study is a systematic review of published literature, ethics approval and patient consent were not required.

Consent for publication

Not applicable, as no individual patient data are included in this systematic review.

Competing interests

The authors declare no competing interests.