Our results showed that almost 60% of SpA patients had some active EMM and in about half of them it guided the current therapeutic decision-making in a real-life scenario. In addition, we observed a more specific approach focusing on them, including higher prescription rate in conventional DMARDs-naïve patients previously.

Although a large prospective cohort with 12 years of follow-up, the Outcome in Ankylosing Spondylitis International Study (OASIS), has not found any association among EMMs and physical disability, quality of life, or radiographic damage in 216 patients with AS [27], most studies have highlighted the relevance of them on the quality of life in SpA patients, as well as the association with direct and indirect costs and difficulties in clinical management [28, 29]. Nonetheless, no clinical trial has evaluated the EMMs as a central point of therapeutic decision-making. To the best of our knowledge, this is the first large study that addressed the efficacy and safety peculiarities of them in SpA patients over time in clinical practice, regardless of musculoskeletal axial or peripheral predominance, highlighting a relevant and current unmet need.

In general, the EMMs had high prevalence in SpA patients, as demonstrated in a large British cohort involving more than 4000 AS patients and almost 29,000 healthy controls matched for age and sex (11.4% for rAAU, 4.4% for Ps and 3.7% for IBD). The overall incidence per 1000 patient-years, as well as the cumulative incidence in 20 years and the adjusted risk ratio (8.9, 24.5% and 15.5 for rAAU; 3.4, 10.1% and 1.5 for Ps and 2.4, 7.5% and 3.3 for IBD, respectively), demonstrated that the risks were higher in the first years for Ps and IBD but keep increasing over time for rAAU [7, 30, 31]. However, only 60% of European and Canadian rheumatologists routinely have evaluated them, even though they agree that the therapeutic strategy is different when musculoskeletal (MSK) complaints are concomitantly with EMMs in SpA patients [32]. According to our cohort, the Ps activity was the most frequent, but the active rAAU was the EMM with greater dissociation from joint disease activity and that was used as treatment strategy turning point in more than 90% of patients.

Another interesting approach is to screen the EMMs to reduce the diagnostic delay in SpA, especially for differential diagnosis with other inflammatory arthritis [33]. Recently, several strategies have been adopted for identifying them in patients with Ps [13, 22], such as the Psoriasis Arthritis Screening and Evaluation (PASE) [35], Psoriasis Epidemiology Screening Tool (PEST) [36, 37], and Early Psoriatic Arthritis Screening Questionnaire (EARP) [38]; uveitis, including the DUET [39], FOCUS Initiative [40], and Sentinel Collaborative Project [41]; and IBD (ASAS criteria [11] and the DETAIL questionnaire [42]). Although these strategies had not been evaluated in our study, we could realize that a driven sight to them would be important to integrate rheumatologists, dermatologists, ophthalmologists, and gastroenterologists for therapeutic decision-making as well. For instance, Ps patients had a longer delay until the appointment with the rheumatologist, emphasizing an important unmet need and the necessity the greater interaction with dermatologists. On the other hand, the access to and faster scheduling with the rheumatologist was more frequent for patients with IBD, although the time was more than 5 years, on average. Our data confirm the possibility of multidisciplinary assessment regarding EMMs in SpA patients [43, 44].

Comorbidities also represent relevant outcomes regarding clinical management of SpA patients, especially due to concomitant medications, increased risk of toxicity, and decision-making [45], and have been more valued recently [46, 47]. An interesting finding in our cohort was the lower prevalence of fibromyalgia (less than 15%), when considering only the current active EMMs, than that reported in patients with AS and non-radiographic axial SpA (around 20–25%) [8, 34, 48,49,50]. On the other hand, our data corroborate the higher rate of metabolic syndrome in Ps [51] and osteoporosis in patients with IBD, which may be associated with the longer systemic use of GCs, chronic inflammation and intestinal malabsorption of calcium, vitamin D, and other nutrients essential for bone health [52]. These three comorbidities are also important in a real-life study, especially related to need for using corticosteroid sparing drugs to minimize risk of weight increase, bone loss, hypertension, lipid and glucose changes, and non-alcoholic steatohepatitis (NASH), as well as to improve the interpretation of disease activity tools based on patient-reported outcomes (PROs) and to reduce confounders factors for the therapeutic decision-making.

By using EMMs in therapeutic decision-making, we observed significant clinical improvement in the three groups, especially in those with rAAU or IBD, with complete resolution in 85% or 75% of cases, respectively. Psoriasis lesions also improved overall, but there was greater difficulty in achieving complete and sustained remission during the first year, suggesting the greater complexity of psoriatic disease itself in despite of higher frequency of TNF inhibitors and wide care offered by dermatology and rheumatology combined approach. Moreover, it is worthy addressing that we used a stricter criterion for defining skin remission (PASI below 1). Although with several definitions regarding skin remission in patients with psoriatic arthritis and psoriasis, including PASI75, PASI90, PASI100, and BSA for instance, we decided to use the PASI as more trustworthy parameter based on the skin domain from the Minimal Disease Activity (MDA)’s definition [17, 58]. Also, it would be an endpoint easier for using in the clinical practice and might reflect better the “skin well-being” related to the patient-reported outcomes.

Interestingly, the improvement of musculoskeletal complaints was not as significant as the improvement of EMMs that motivated the therapeutic decision. Some hypotheses to explain this can be highlighted, such as a lower frequency of joint disease activity (remission or low disease activity in approximately 25 to 40% of patients with Ps and rAAU, respectively) and dissociation between articular and extra-articular involvement in patients with long-term disease.

Although the profile of biological agents, including first prescription and survival rate, may vary according to the EMM, the monoclonal TNF inhibitors were more prescribed for patients with rAAU and IBD, according to current recommendations [15,16,17,18,19]. In our cohort, these data are supported because more than half of the patients in IBD and rAAU groups required only one change in treatment, suggesting effectiveness of this strategy over time. Moreover, most of them had switched to another monoclonal TNF antagonist. However, SpA patients with Ps required more treatment changes demonstrating the difficulty of managing them.

Another interesting finding in our cohort was the lack of combined medication before the EMM comes up to provide a decision-making (30% in Ps and IBD, 50% in rAAU), as well as the low baseline prescription rates of DMARDs (20% in rAAU and IBD patients, and 50% for Ps patients) and biological agents (15% in Ps, 30% in AAUr, 40% in IBD), which suggests that extra-muskuloskeletal involvement was recent and relevant for clinical management, regardless of joint complaints [53].

MTX was the anchor drug more used in SpA patients with current active and concomitant rAAU and Ps, but it was not the main therapeutic strategy chosen by Rheumatologist because it was already being used by more than 50% of patients with Ps. The most important strategy involving synthetic or conventional DMARDs, as the first therapeutic approach, was a combination of DMARDs, such as leflunomide or cyclosporin, although this strategy has not been sustained over 12 months, suggesting lower efficacy or higher toxicity. In cases of current active IBD in SpA patients, sulfasalazine was used as an anchor medication, as it saw a threefold increase in its prescription in the first 3 months.

The EMMs were decisive for the DMARDs prescription, with a frequency of approximately 30% in Ps, 40% in IBD, and 60% in rAAU. In addition, they were responsible by higher prescription of biological agents (fourfold increase for TNF inhibitors in the first 6 months and an 15% increment considering other mechanisms of action in patients with Ps activity after 12 months).

In SpA patients with active rAAU and IBD, there was a 2- to threefold increase of using monoclonal TNFi, especially adalimumab and infliximab, and the need to maintain them over the 12 months, with a low likely of switching. In addition, they were important for reducing the systemic use of GCs, especially in patients with active Ps, but they were not significant in those with rAAU (15%) or IBD (25%). Around 10–20% of patients with Ps and rAAU persisted using topical formulations of GCs, highlighting a severity of these cases and difficulty to control the extra-articular disease activity even using other systemic drugs concomitantly.

Considering all 3 EMMs related to the SpA concept, rAAU was characterized by greater axial involvement (higher frequency of positivity for HLA-B27, earlier disease onset, younger age, a higher rate of syndesmophytes as evaluated by the modified Stoke Ankylosing Spondylitis Spine Score [mSASSS], more stablished impairment on radiographic sacroiliac joints [8], and a higher likelihood of a family history. On the other hand, the peripheral involvement can also occur in 30% of axial cases and it is an important aspect for therapeutic decision-making, especially in patients with Ps and IBD [54]. As it occurred in a large portion of our sample (50–70%), we cannot rule out the possibility of it having also been considered in the decision-making along with the respective extra-articular manifestation, especially in those with psoriasis [55], and it may have determined the worst efficacy and lower survival rate of TNFi [56].

Our study has some limitations, such as the measurement of adherence to treatment and the lack of use of specific instruments for each EMM that are often used in randomized clinical trials (SUN criteria for rAAU, PASI 75 and 90 for Ps, and CDAI for IBD). On the other hand, it has many strengths, including real-life data and incorporation of simpler outcomes, such as complete resolution or not of the EMM, allowing the therapeutic strategy could have had a greater impact on the quality of life of patients and a lower rate of loss to follow-up over 12 months. However, more randomized, and controlled studies are needed to determine the role of EMMs regarding the therapeutic decision-making in SpA patients, as well as an economic resource-use analysis [57].

We found a high prevalence of EMM (50%) that were used to guide treatment decision-making in patients with SpA, regardless of musculoskeletal condition. Therapeutic decision-making based on EMMs could promote a change in behavior and achievement of better overall disease activity control, especially in patients with rAAU and IBD15−8. In addition, the first management strategy was effective in most patients and no serious adverse events were observed after the decision had been made.

In conclusion, our results emphasize the relevance of considering the EMMs in the clinical and epidemiological context of SpA, especially regarding decision-making in clinical practice, as well as to evaluate the therapeutic response and to be added to the treat-to-target approach. In addition, they emphasize the need to consider instruments that can assess the global disease activity and the relevance for a multidisciplinary in SpA patients [15,16,17,18,19]. More recently, minimal disease activity has incorporated the PASI or BSA data for a more complete evaluation of patients with PsA [58]. Similarly, these strategies should be also used for the rAAU and IBD.