Early Anti-TNF for Crohn's Disease: What the 5-Year PROFILE Follow-Up Reveals
PROFILE five-year follow-up links early infliximab combination therapy to fewer Crohn’s surgeries and hospitalizations. Review the findings and limitations.
At diagnosis, how long can treatment escalation safely wait?
When a patient is newly diagnosed with active Crohn's disease, one of the most consequential decisions concerns treatment timing. Should clinicians initiate effective biologic therapy immediately, or begin with conventional treatment and escalate according to subsequent disease activity?
Historically, step-up treatment has offered an opportunity to avoid exposing some patients to advanced therapies before their individual disease course becomes apparent. The opposing concern is that ongoing inflammation during this period may contribute to irreversible bowel damage, even if treatment is intensified later.
The original PROFILE randomized trial strongly favoured early combination therapy during its first 48 weeks. Yet an important question remained unanswered: would those early benefits translate into fewer clinically significant complications several years after diagnosis?
The five-year follow-up, published in The Lancet Gastroenterology & Hepatology in September 2026, addresses this question.
Patients originally allocated to infliximab-based top-down treatment had substantially fewer Crohn's disease-related abdominal surgeries, hospitalizations and complications than those initially managed using a conventional step-up strategy.
The results provide compelling evidence that initial treatment strategy may have lasting consequences. However, because treatment after the first year was no longer randomized, the findings require careful interpretation before being described as definitive proof of disease modification.
PROFILE was designed to test treatment strategy, not simply drug efficacy
PROFILE was a multicentre, open-label, randomized controlled trial conducted across 40 hospitals in the United Kingdom.
The original study included 386 patients aged 16–80 years with newly diagnosed active Crohn's disease, randomly allocated to two treatment strategies.
Top-down strategy: Patients received infliximab together with an immunomodulator from diagnosis. The permitted immunomodulators included azathioprine, low-dose mercaptopurine with allopurinol, or methotrexate.
Step-up strategy: Patients initially received corticosteroids, with escalation to immunomodulator therapy and subsequently infliximab according to persistent disease activity or flares.
Each group contained 193 patients.
The randomized treatment protocol continued for 48 weeks. After this period, participants returned to standard clinical care at their respective hospitals, and further treatment decisions were made by local clinicians.
The extended follow-up was designed to investigate whether the initial treatment assignment was associated with later outcomes.
Investigators retrospectively examined clinical records through January 2026, extracting information about surgery, hospital admission and progression to complicated Crohn's disease.
Post-week-48 records were available for 358 of the original 386 participants, representing 93% of the trial population.
The median follow-up from randomization was approximately five years, or 1,809 days.
Importantly, the analysis preserved the original randomized groups. Patients were analysed according to their initial assignment rather than their eventual treatment.
This approach retains the value of randomized baseline allocation. Nevertheless, the extended observational period introduces uncertainty because subsequent treatment exposures, monitoring and clinical decisions were not governed by the original trial protocol.
The first-year findings raised the question of durable benefit
The original PROFILE results, published in 2024, demonstrated a substantial difference in the primary clinical outcome during the initial treatment year.
Sustained steroid-free and surgery-free remission occurred in 79% of patients assigned to top-down therapy compared with 15% receiving step-up care.
This finding established a major short-term advantage for early infliximab-based combination treatment in the studied population.
However, achieving remission during the first year and preventing long-term structural disease complications are not equivalent outcomes.
Crohn's disease can progress from predominantly inflammatory activity to complications characterized by stricturing or penetrating behaviour. Such progression may eventually require hospitalization, surgery or repeated intervention.
The crucial unanswered question was whether early disease control merely delayed these adverse outcomes or was associated with a sustained reduction in their occurrence.
The long-term PROFILE analysis provides important information by focusing on more consequential clinical endpoints than short-term remission alone.
Abdominal surgery: The strongest long-term outcome signal
Crohn's disease-related abdominal surgery was the primary outcome of the extended follow-up.
The difference between the original treatment groups was substantial.
Over approximately five years of follow-up, Crohn's disease-related abdominal surgery was required in 6 of 193 patients (3%) initially assigned to top-down therapy, compared with 26 of 193 patients (13%) initially assigned to step-up therapy.
The total number of abdominal operations also differed between groups. Patients in the top-down group underwent six surgeries, whereas those in the step-up group underwent 28 surgeries.
These findings represent an absolute difference of approximately 10 percentage points in the proportion of patients requiring surgery, favouring early top-down therapy.
The results suggest that the initial treatment strategy may have important implications for long-term surgical outcomes in Crohn's disease.
Over approximately five years, 26 patients initially assigned to step-up care underwent 28 Crohn's disease-related abdominal operations.
In contrast, six patients originally allocated to top-down therapy underwent six operations.
The adjusted hazard ratio for time to first surgery, comparing step-up with top-down treatment, was 5.23 (95% CI 1.99–13.76; p=0.0008).
This indicates that the estimated instantaneous rate of first surgery was substantially higher in the step-up group during follow-up.
It should not be interpreted as a fivefold difference in absolute surgical probability.
The observed proportions correspond to an absolute difference of approximately ten percentage points.
For clinicians, the importance lies in the nature of the endpoint. Abdominal surgery is a consequential outcome reflecting significant disease burden and treatment requirements.
The difference is also unlikely to be explained simply by unequal access to advanced medication throughout the entire follow-up, because substantial numbers of patients in both groups subsequently received biologic or immunomodulator therapy.
Nevertheless, the analysis cannot determine precisely how much of the difference arose from the initial treatment period versus later treatment patterns or other factors.
The signal extended beyond surgery to hospitalization and disease progression
The long-term findings were not restricted to abdominal surgery.
Two additional outcomes supported the association between early top-down therapy and a more favourable subsequent disease course.
Crohn's disease-related hospitalization
Hospital admission unrelated to surgery occurred in:
22 of 193 patients (11%) initially assigned to top-down treatment.
41 of 193 patients (21%) initially assigned to step-up treatment.
Time to first Crohn's disease-related hospitalization was shorter in the step-up group, with an adjusted hazard ratio of 2.01 (95% CI 1.18–3.41).
Hospitalization is a relevant measure of disease burden, although the number of admissions does not fully capture symptom severity, functional impairment or cumulative healthcare costs.
Progression to complicated disease
Progression from inflammatory Crohn's disease to stricturing or penetrating complications occurred in:
13 of 193 patients (7%) in the top-down group.
32 of 192 patients (17%) in the step-up group.
The adjusted hazard ratio for time to disease progression was 2.46 (95% CI 1.25–4.86).
This outcome is particularly relevant to the concept of disease modification.
Preventing or delaying stricturing and penetrating complications may represent a more meaningful long-term treatment objective than symptom suppression alone.
The parallel findings across surgery, hospitalization and disease progression make the overall result clinically persuasive.
Yet the outcomes are interrelated, and the analysis does not establish the biological mechanism responsible for their differences.
Later escalation did not eliminate the original treatment gap
Perhaps the most thought-provoking observation was that the initial difference between treatment groups persisted despite subsequent changes in therapy.
By the end of follow-up, 172 of 193 patients (89%) originally assigned to step-up treatment had received a biologic or immunomodulator.
The corresponding figure in the top-down group was 191 of 193 (99%).
Furthermore, 91 patients in the step-up group, representing 47%, started anti-TNF therapy within the first year after randomization.
Despite this relatively early escalation in a substantial proportion of the comparator group, subsequent surgery remained more frequent among patients originally assigned to step-up management.
This observation raises the possibility that the earliest period after diagnosis represents an important therapeutic opportunity.
One interpretation is that establishing effective inflammatory control before complications develop may produce benefits that cannot be fully recovered through later escalation.
However, the study did not directly prove that delayed treatment caused irreversible damage.
Patients requiring escalation may have had different patterns of persistent inflammation, disease activity or treatment response. Subsequent clinical management was not randomized, and the comparison among patients who escalated treatment was not itself a randomized treatment-timing experiment.
The findings therefore support the importance of treatment timing without defining a precise biological window beyond which effective intervention becomes less beneficial.
Does PROFILE demonstrate disease modification?
Disease modification is an important but demanding concept in inflammatory bowel disease.
Symptom control and remission demonstrate treatment efficacy. Disease modification implies that treatment changes the subsequent course of illness, potentially preventing structural complications and other adverse outcomes.
The long-term PROFILE results are consistent with this possibility.
Patients who received top-down therapy from diagnosis experienced fewer operations, fewer hospitalizations and less progression to complicated disease several years later.
These are outcomes that matter directly to patients and clinicians.
The investigators interpreted their results as suggestive of a disease-modifying effect and argued that early effective therapy should receive greater consideration as a standard treatment strategy in newly diagnosed moderate-to-severe Crohn's disease.
However, a distinction must be maintained between the authors' interpretation and established clinical guidance.
The initial treatment assignment was randomized, but the five-year care pathway was not.
Consequently, the study supports an association between early top-down treatment and improved long-term outcomes, with a strong contribution from the original randomized design. It does not isolate a specific causal mechanism or establish that all later differences resulted solely from treatment during the initial 48 weeks.
Nor does it demonstrate that every biologic therapy or advanced treatment strategy would produce equivalent long-term outcomes.
The intervention specifically involved infliximab combined with an immunomodulator.
Long-term safety remains less certain than the efficacy signal
Earlier initiation of combination immunosuppression inevitably raises questions about cumulative treatment safety.
In the extended analysis, serious infections occurred in 12 of 193 patients (6%) initially assigned to step-up treatment and 14 of 193 patients (7%) initially allocated to top-down therapy.
Malignancies were reported in five patients (3%) in the step-up group and three patients (2%) in the top-down group.
No statistically discernible safety difference was identified between the strategies for these outcomes.
However, these numbers should not be interpreted as evidence that the treatments have equivalent long-term safety.
The extended follow-up was not powered to detect uncommon adverse events or small differences in serious infection and malignancy risk.
Safety information was also extracted retrospectively rather than collected through a consistently standardized long-term surveillance protocol.
A single death occurred in the top-down group from acute myeloid leukemia. According to the investigators, specialist review considered it most likely age-related and unrelated to Crohn's disease or treatment.
The event cannot establish a treatment relationship.
Overall, the reported safety findings are reassuring in that no large difference was detected, but they do not resolve the broader long-term risk–benefit balance of prolonged combination therapy.
What the design allows clinicians to conclude—and what it does not
Several features strengthen confidence in the PROFILE follow-up.
The initial randomized trial was multicentre, included a substantial number of newly diagnosed patients and compared well-defined treatment strategies.
The extended analysis achieved high medical-record availability and examined objective outcomes rather than relying exclusively on symptoms.
Surgery, hospitalization and progression to complicated disease are clinically relevant endpoints.
However, important constraints remain.
First, retrospective outcome collection can introduce ascertainment differences or incomplete documentation.
Second, treatments after week 48 reflected local practice rather than standardized randomized management. Differences in drug exposure, disease monitoring and escalation decisions could influence later outcomes.
Third, although follow-up data were available for 93% of participants, the remaining patients contribute uncertainty. Participants without extended records were censored at week 48.
Fourth, the overall number of surgical events was relatively small. Consequently, the confidence interval surrounding the surgery hazard ratio was wide.
Fifth, the step-up comparator may not fully represent contemporary treatment strategies used in all specialist IBD services.
Finally, patients with mild Crohn's disease were excluded from the trial population described in the long-term report.
This is a particularly important boundary.
The results should not be extrapolated automatically to mild disease, patients with different treatment contraindications or clinical circumstances in which the risks of combination treatment may outweigh anticipated benefits.
What should change in conversations about newly diagnosed Crohn's disease?
The strongest practical contribution of PROFILE is to the discussion surrounding early treatment decisions.
In patients with newly diagnosed active Crohn's disease resembling the trial population, delayed escalation should not automatically be viewed as a strategy without potential long-term consequences.
The findings support discussing both immediate remission and longer-term complications when evaluating treatment options.
For gastroenterologists, this means that the initial treatment conversation can appropriately include the possibility of reducing future surgery, hospitalization and disease progression, while acknowledging uncertainty about the size of the benefit in an individual patient.
For IBD fellows, PROFILE illustrates why trials assessing symptom remission and trials evaluating long-term disease course answer related but distinct questions.
For researchers, it highlights the value of retaining randomized cohorts for extended assessment of objective outcomes.
Nevertheless, this study alone should not be used to prescribe infliximab combination therapy universally, replace current guidelines or create a new treatment algorithm.
Treatment selection still requires assessment of inflammatory activity, disease behaviour, comorbidity, medication risks, patient preferences and locally applicable clinical guidance.
The findings strengthen the rationale for early effective treatment. They do not eliminate the need for individualized decisions.
The next questions: Timing, treatment choice and durability
PROFILE leaves several important questions open.
Would similar long-term benefits occur with other advanced therapies initiated at diagnosis?
Can comparable results be achieved without prolonged combination immunosuppression?
Is there a definable interval after diagnosis during which starting advanced treatment has the greatest effect on future complications?
Which patients are most likely to benefit from immediate therapy, and which might safely avoid it?
Prospective studies comparing contemporary treatment strategies, incorporating standardized monitoring and evaluating longer-term safety, would help address these issues.
Future research should also distinguish the effect of treatment timing from the effect of the specific treatment selected.
Ultimately, confirming disease modification requires more than demonstrating sustained differences between groups. It requires understanding how treatment changes the trajectory of complications over time.
Clinical Takeaway: The first treatment decision may have consequences for years
The five-year PROFILE follow-up provides important evidence that early infliximab-based combination therapy in newly diagnosed active Crohn's disease is associated with fewer abdominal surgeries, hospitalizations and stricturing or penetrating complications than conventional step-up treatment.
The findings build upon a strong original randomized comparison and support the clinical importance of early effective inflammatory control.
However, because treatment after the first year was not randomized, definitive causal claims about long-term disease modification remain premature.
GastroAGI perspective: The principal practice signal is not that every patient requires the same biologic regimen. It is that the timing of effective treatment deserves substantial consideration from diagnosis, particularly in patients with active disease comparable to the PROFILE population.
The challenge now is to identify which patients benefit most, determine whether other advanced treatment strategies provide similar protection, and establish the long-term safety and durability of earlier intervention.
Primary Reference
Noor NM, Sharip MT, Zheng H, et al. Long-term outcomes of top-down therapy versus a conventional step-up strategy in adults newly diagnosed with Crohn's disease: 5-year follow-up of the PROFILE trial. The Lancet Gastroenterology & Hepatology. 2026;11(11):960–970. Published online September 2026.
DOI: https://doi.org/10.1016/S2468-1253(26)00192-5
Supporting clinical news source
Evans A. PROFILE follow-up links anti-TNF at diagnosis to fewer Crohn's surgeries. GI & Hepatology News. 9 October 2026.
References
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