To the best of our knowledge, this is the largest population-based drug utilization study on biological drugs in older patients with IMIDs that was conducted in Europe and in Italy, specifically. At the same time, outdated evidence exists outside the European setting [13]. As for the Italian setting, only one study conducted at 47 Italian IBD centers (2013–2018), which included about 200 patients with inflammatory bowel diseases, was found [14].

From 2010 to 2022, we observed approximately a sixfold increase in the use of biologic drugs among older individuals with IMIDs, particularly those affected by RA and PsO. This trend aligns with evidence suggesting an increase in the prevalence of IMIDs in individuals aged over 60 years [15], which, as expected, has led to a corresponding rise in biological drug use. In addition, the extension of indications for biological drugs over this period has likely contributed to this increase.

Biological drugs more frequently prescribed in older patients were adalimumab and etanercept, with a notable increase in the prevalence of adalimumab use following the approval of its biosimilar. This increase is in line with regional guidelines recommending the use of the biologic with the lowest cost when safety and efficacy are comparable [16,17,18]. Accordingly, an Italian retrospective observation study on 89 patients aged ≥ 65 years demonstrated that adalimumab and etanercept were appropriate for the long-term management of older patients affected by psoriasis and psoriatic arthritis, showing a good benefit and risk profile [19]. However, the proportion of patients using TNF-alpha inhibitors as first-line treatment slightly declined over the study period, likely reflecting the more recent approval and increasing adoption of anti-interleukin and anti-integrin therapies as first-line options in older patients.

Notably, a slight decrease in biological drug use was observed between 2019 and 2020, probably as an effect of the COVID-19 pandemic. Another Italian study documented reduced biological drug use in patients with IMID in 2020 because of the COVID-19 pandemic [20]. These findings can be related to (1) concerns about the use of immune-modulating therapies in patients with IMID owing to the increased risk of severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) infection during the pandemic, as well as (2) logistical difficulties in accessing the hospitals for the management of chronic autoimmune diseases [20].

Our large-scale cohort study also reported information on more than 1900 patients over the age of 80 years who have been excluded from pivotal clinical trials of biological drugs in IMID. In scientific literature, no information on the efficacy and safety of biological drugs in this population is still available, and cohort studies of very old patients receiving biologics should be carried out urgently [3]. Moreover, polypharmacy is a common condition in the older population. Differences in the frequency of polypharmacy were found according to first-line biological therapy (i.e., patients taking abatacept or TNF-alpha inhibitors reported higher polypharmacy at baseline with respect to those patients starting with vedolizumab); polypharmacy is more common in RA, for which these drugs are approved, unlike vedolizumab [21, 22].

Notably, in contrast with the clinical guidelines’ recommendation for each IMID, we observed 193 (less than 1%) patients receiving at least one JAKi dispensing before starting biological treatment. According to a recently published study reporting an increased risk of major adverse cardiovascular events (MACE) and malignancies in patients aged 50 years and older receiving JAKi [23], regulatory agencies, such as the European Medicines Agency (EMA) and Food and Drug Administration (FDA), issued warnings [24, 25] recommending the restricted use of JAKi in older patients or those with pre-existing risk factors for cardiovascular disease or cancer.

Our findings highlighted that, overall, 50% of patients discontinue treatment with biological drugs after 1 year. However, differences were observed according to the indication of use and biological drug. Patients with IBD starting with ustekinumab (n = 180) or vedolizumab (n = 1197) showed the highest persistence to treatment. According to EMA recommendations, both these drugs should be used when conventional therapy or TNF-alpha inhibitors are ineffective, no longer effective, or cannot be tolerated by the patient [26, 27]. Consequently, their use as first-line treatments should be limited, especially considering that, with the introduction of biosimilars, off-patent TNF-alpha inhibitors are generally more economical than more recently approved biological drugs. However, existing studies have not established a preferred sequencing order of biological therapies for patients with IBDs [28, 29]. Nonetheless, evidence from literature highlights the favorable profile of ustekinumab and vedolizumab in the older population. For instance, a retrospective study of older patients with Crohn’s disease conducted in Canada between January 2000 and January 2020, suggests that ustekinumab is an effective and safe biological option for older patients [30], while another study conducted across four UK centers found comparable safety and efficacy compared with TNF-alpha inhibitors [31]. Similarly, a multicenter, multinational retrospective study conducted on 111 patients with vedolizumab and 60 patients with ustekinumab above the age of 60 years demonstrated comparable effectiveness and a favorable safety profile in older patients with IBDs [32]. Another recent study supports considering vedolizumab and ustekinumab as potential first-line treatment options for moderate-to-severe IBD in older patients [33], despite other aspects that were not considered in this study (i.e., health care expenses), which should be taken into account. These results were also confirmed by studies conducted in the adult population, reporting favorable safety [34] and efficacy [35] profiles for both drugs, even if real-world evidence found in literature is mainly related to second- or further-line treatment [36,37,38]. Finally, the recently published guidelines regarding the management of moderate-to-severe UC suggest that vedolizumab may be preferred among agents of similar efficacy in patients particularly vulnerable to infectious complications, such as older frail adults [39].

Several factors were found to have a potential impact on discontinuation of the first-line of biological drug at 1 year of follow-up: patients with polypharmacy and female and older patients were commonly reported to have an increased risk of discontinuation. Female sex was also previously reported as a predictive factor for discontinuation of biological therapies for psoriasis, confirming our study’s results [40]. As van der Schoot et al. reported, the higher discontinuation rates among females may be partially explained by a greater incidence of adverse events, such as infections [40]. In addition, other studies have shown that female patients experience a higher symptomatic disease burden than males, along with a greater impact on mental health and quality of life [41, 42]. As expected, older age was also usually found as a predictive factor for discontinuation; older patients, who usually have worse baseline disease activity [43], may be more susceptible to adverse events, which may have resulted in high rates of nonpersistence. In older patients with IBDs receiving biological drugs, advanced age is associated with higher infection risk, and these patients have a threefold increased risk of developing infections compared with younger patients [5, 44]. However, it is crucial to additionally evaluate the efficacy of biologic drugs in older patients, as there is a lack of evidence supporting their benefit–risk profile in this population [45]. Without considering expected efficacy, weighing the risks and benefits of these therapies becomes difficult, especially in older populations where comorbidities and frailty may complicate treatment outcomes and choices. For instance, certain biological drugs are contraindicated in the presence of specific comorbidities, which are often more prevalent in older patients. For example, the use of infliximab is not recommended in patients with moderate-to-severe heart failure [46]. Therefore, therapeutic decisions must carefully consider the individual patient’s overall health status and the potential for achieving meaningful clinical benefit.

Given that approximately 50% of older patients discontinue biological therapies within the first year, it is essential to focus on practical strategies to improve treatment outcomes for this population: (1) it is crucial to generate robust evidence that helps clinicians select the most suitable biological drug, considering the patient’s individual characteristics to ensure optimal safety and efficacy; (2) clinicians must closely monitor older patients to identify and manage potential adverse effects and drug interactions that could lead to treatment discontinuation, and (3) a multidisciplinary approach involving specialists (rheumatologists, dermatologists, gastroenterologists, and geriatricians) is essential to address the complexity of managing multiple conditions in older patients with IMIDs.

Finally, we believe real-world evidence can play a pivotal role in evaluating biological drugs’ effectiveness and safety profiles, as already mentioned in other observational studies [47,48,49]. In particular, our findings emphasize the importance of conducting large-scale studies using multiple distributed databases, as they provide a sufficiently large sample size to assess the safety and effectiveness of individual therapies in older patients. To generate stronger evidence, new study designs, such as clinical trial emulation, could be used to improve the quality of the available evidence. In addition, linking administrative data with other data sources could offer valuable information not captured in administrative datasets alone. Leveraging these approaches will be crucial in guiding clinical decision-making and informing future clinical guidelines for older populations.

This study has several strengths. First, we included a large cohort of patients (about 25,000 incident biological drug users with IMIDs) with an overall follow-up of 10 years. Secondly, the long-term study period allowed the description of the pattern of biological drug use over time and persistence to index biological drugs at 5 years of follow-up after the index date. Moreover, we considered all the biological drugs approved for IMIDs, thus not restricting the analysis to drugs approved for only one of these diseases, as done in previous studies. Finally, we explored the predictive factors of discontinuation of biological drugs, which have not been investigated so far in the older population.

Nevertheless, some limitations warrant caution. First, we found that about 16.3% of patients had a missing indication. Notably, within the anti-interleukin class, most of the missing indications (about 70%) were related to patients treated with tocilizumab. Tocilizumab is approved for RA and other indications such as giant cell arteritis and COVID-19. In particular, giant cell arthritis is a disease with an average age of onset of 70 years [50]. The developed META-algorithm used to distinguish by indications for the use of biological drugs in administrative data [8] did not track indications such as giant cell arthritis or COVID-19, thus explaining the higher proportion of tocilizumab patients without an indication. Despite its limitations, a previously published validation study reported high validity estimates in detecting RA, AS, CU, CD, and PsO/PsA in the VALORE distributed database network. Second, information such as disease severity was not available in administrative data, thus limiting the interpretation of our findings. Third, while DDDs were used to calculate treatment coverage, variations in dosage based on patient weight could not be fully excluded. However, for most indications, there is no clear indication of dosage changes for older patients compared with the general adult population in the biological drug product summary characteristics. As previously mentioned, in future observational studies, one approach to overcoming these limitations would be to link administrative data with additional sources, such as registries.