Rheumatologist’s Perspective on Non-Infectious Uveitis: Patterns from Tertiary Referral Rheumatologic Clinics in Italy

Non-infectious uveitis (NIU) can be an early or even the first extra-articular manifestation of systemic rheumatic diseases, or the first one; thus, rheumatologists are often involved in the diagnostic and therapeutic assessment of NIU. We evaluated 130 patients with a diagnosis of NIU who were admitted to two Italian rheumatologic clinics (Tor Vergata University Hospital in Rome, and Federico II University in Naples) from January 2018 to December 2021. Anterior uveitis (AU) occurred in 75.4% of patients, followed by posterior uveitis (PU, 21.5%); acute (54.6%) and recurrent (35.4%) NIU were more documented than chronic NIU (10%), and a bilateral involvement was observed in 38.7% of cases. Half of NIU cases were associated with spondyloarthritis (SpA); the remaining were affected by Behçet disease (BD)-related uveitis (13.9%) and idiopathic NIU (9.2%). HLA-B27+ patients (34.8%) had a higher prevalence of anterior and unilateral NIU (p = 0.005) with acute course (p = 0.04) than HLA-B27– patients. On the contrary, HLA-B51+ patients (19.6%) had mostly PU and bilateral NIU (p < 0.0001) and recurrent course (p = 0.04) than HLA-B51– patients. At the first rheumatologic referral, 117 patients (90%) received systemic treatments. Findings from this study demonstrate that rheumatologic referral has a pivotal role in the diagnostic work-up of NIU and may dramatically influence NIU-treatment strategies.


Results
We included 130 patients for a total of 179 affected eyes, with females representing 60% of the study population (n = 79). Data from the study cohort are summarized in Table 1. A previous or current history of smoking occurred in 33% (43/130) of patients, with a prevalent male distribution (p < 0.0001). Concomitant ophthalmologic diseases were revealed in 27.7% of eyes studied, mainly including episcleritis (25%) and keratoconjunc-tivitis sicca (16.7%). No differences resulted between males and females in age at the first rheumatologic referral (males, 43 ± 13.4 y.o. vs. females, 45.3 ± 12.9 y.o.) or age at NIU onset (males, 38.6 ± 13.8 y.o. vs. females 41.4 ± 13.5 y.o.). The referral to rheumatologists ( Table 2) was prescribed by family doctors in half of the cohort (n = 59, 45.4%); in the remaining cases, patients were mainly referred by gastroenterologists (n = 31, 23.9%) and ophthalmologists (n = 28, 21.8%). Joint pain was the main reason for referral (n = 88, 67.7%), whereas NIU itself represented 27.7% of cases, without differences in sex (Table 2). Among the latter group of NIU patients, 72.2% of patients (n = 26) were referred to a rheumatologic evaluation by an ophthalmologist, and in 64% of them a diagnosis of SpA occurred. Table 1. Demographic data from patients in the study populations.

Patterns of NIU in the Study Cohort
The most prevalent anatomic involvement was AU, which occurred in 75.4% of patients, followed by PU (21.5%); there were three cases of PanU and a single case of IU ( Figure 1A). Half of the cohort (n = 71, 54.6%) experienced acute NIU, whereas the remaining had mainly recurrent NIU (n = 46, 35.4%), and chronic NIU was documented in 10% (n = 13) of cases ( Figure 1B). The mean age at NIU onset was younger in patients with recurrent and chronic NIU than acute NIU (38 ± 12.3 y.o. vs. 42.6 ± 14.4 y.o., p = 0.02), with no differences in sex distribution. Unilateral NIU was registered in 81 patients (62.3%), with no difference in sex ( Figure 1C). The age at NIU onset was older in patients with unilateral NIU than in patients with bilateral NIU (42.5 ± 14 y.o. vs. 36.36 ± 14 y.o., p = 0.01). Moreover, patients with unilateral-NIU had AU (p < 0.0005) and acute course (p < 0.00001) at a higher rate compared to patients with bilateral NIU (Figure 2).

Pa erns of NIU in the Study Cohort
The most prevalent anatomic involvement was AU, which occurred in 75.4% of patients, followed by PU (21.5%); there were three cases of PanU and a single case of IU ( Figure 1A). Half of the cohort (n = 71, 54.6%) experienced acute NIU, whereas the remaining had mainly recurrent NIU (n = 46, 35.4%), and chronic NIU was documented in 10% (n = 13) of cases ( Figure 1B). The mean age at NIU onset was younger in patients with recurrent and chronic NIU than acute NIU (38 ± 12.3 y.o. vs. 42.6 ± 14.4 y.o., p = 0.02), with no differences in sex distribution. Unilateral NIU was registered in 81 patients (62.3%), with no difference in sex ( Figure 1C). The age at NIU onset was older in patients with unilateral NIU than in patients with bilateral NIU (42.5 ± 14 y.o. vs. 36.36 ± 14 y.o., p = 0.01). Moreover, patients with unilateral-NIU had AU (p < 0.0005) and acute course (p < 0.00001) at a higher rate compared to patients with bilateral NIU (Figure 2).

Pa erns of NIU in the Study Cohort
The most prevalent anatomic involvement was AU, which occurred in 75.4% of patients, followed by PU (21.5%); there were three cases of PanU and a single case of IU ( Figure 1A). Half of the cohort (n = 71, 54.6%) experienced acute NIU, whereas the remaining had mainly recurrent NIU (n = 46, 35.4%), and chronic NIU was documented in 10% (n = 13) of cases ( Figure 1B). The mean age at NIU onset was younger in patients with recurrent and chronic NIU than acute NIU (38 ± 12.3 y.o. vs. 42.6 ± 14.4 y.o., p = 0.02), with no differences in sex distribution. Unilateral NIU was registered in 81 patients (62.3%), with no difference in sex ( Figure 1C). The age at NIU onset was older in patients with unilateral NIU than in patients with bilateral NIU (42.5 ± 14 y.o. vs. 36.36 ± 14 y.o., p = 0.01). Moreover, patients with unilateral-NIU had AU (p < 0.0005) and acute course (p < 0.00001) at a higher rate compared to patients with bilateral NIU (Figure 2).   Patients with unilateral and bilateral noninfectious uveitis. In black, unilateral; in grey, bilateral. Categorical variables were presented with percentages and were compared using the Chi-squared test or Fisher's exact test when appropriate. A p-value < 0.05 was considered significant (*** p < 0.001; **** p < 0.0001).

Figure 5.
Patterns of noninfectious uveitis in patients with and without inflammatory-bowel-diseaseassociated spondyloarthritis (IBD-SpA). In black, patients with IBD-SpA; in grey, patients without IBD-SpA. Categorical variables were presented with percentages and were compared using the Chi-squared test or Fisher's exact test when appropriate. A p-value < 0.05 was considered significant (* p < 0.05).

Figure 5.
Pa erns of noninfectious uveitis in patients with and without inflammatory-bowel-d ease-associated spondyloarthritis (IBD-SpA). In black, patients with IBD-SpA; in grey, patients wi out IBD-SpA. Categorical variables were presented with percentages and were compared using t Chi-squared test or Fisher's exact test when appropriate. A p-value < 0.05 was considered significa (* p < 0.05).

Figure 6.
Pa erns of noninfectious uveitis in patients with and without axial spondyloarthritis (a SpA). In black, patients with ax-SpA; in grey, patients without ax-SpA. Categorical variables we presented with percentages and were compared using the Chi-squared test or Fisher's exact t when appropriate. A p-value < 0.05 was considered significant (* p < 0.05).   Figure 7. Pa erns of noninfectious uveitis in patients with and without Behçet disease (BD). In bla patients with BD; in grey, patients without BD. Categorical variables were presented with perce ages and were compared using the Chi-squared test or Fisher's exact test when appropriate. A value < 0.05 was considered significant (**** p < 0.0001).

Treatment Strategies in NIU
Ninety percent of patients (n = 117) received a systemic treatment at the fir tologic referral (Table 4)  Categorical variables were presented with percentages and were compared using the Chisquared test or Fisher's exact test when appropriate. A p-value < 0.05 was considered significant (* p < 0.05; ** p < 0.01; **** p < 0.0001).

Discussion
Findings from this population-based study described the extent and pa erns of N from real-life data by Italian adult patients referred to two tertiary rheumatologic clini

Discussion
Findings from this population-based study described the extent and pa erns of NIU from real-life data by Italian adult patients referred to two tertiary rheumatologic clinics.

Discussion
Findings from this population-based study described the extent and patterns of NIU from real-life data by Italian adult patients referred to two tertiary rheumatologic clinics. Our data demonstrate that rheumatologic referral has a pivotal role in the diagnostic workup of NIU and may dramatically impact treatment strategies in NIU. Particularly among patients referred to rheumatologists, NIU itself amounted to almost a third of the reasons for referral, with joint pain being the most frequent. NIU patients showed mainly AU, unilateral involvement, and acute course. Moreover, in half of them, a diagnosis of SpA, also including PsA, occurred. HLA-B27 and HLA-B51 positivity appeared to be related to different predominant NIU patterns. Furthermore, at the first rheumatologic referral, the majority of NIU patients received DMARD treatment. The present representative NIU cohort showed that both the age at onset and the sex distribution were comparable with data documented by the authors in recent Italian and Portuguese studies on NIU patients referred to rheumatology units [34,35]. Furthermore, we registered a slightly higher prevalence of females with NIU referred to rheumatologic units. Since immune-mediated diseases represent the main cause of NIU, it is fair to expect that NIU may predominantly affect females. A previous or current history of smoking occurred in a third of the cohort, with a prevalent male distribution: As is known, smoking may worsen the course of NIU, but having a previous or current smoking habit was not associated with any NIU pattern in our cohort [36]. Accordingly, the age at both NIU onset and first rheumatologic referral was similar between males and females. The rheumatologic referral was mainly addressed by family doctors, whereas a similar distribution occurred in the proportion of NIU patients referred by gastroenterologists and ophthalmologists. Although joint pain represented the main cause for referral, in up to a third of cases NIU itself represented the reason for the rheumatologic evaluation. Specifically, the latter patients were referred mainly by ophthalmologists, and in more than half of them, concomitant SpA or BD was diagnosed. These findings are consistent with evidence describing NIU as an early or even the first manifestation of such rheumatologic diseases and support the crucial role of ophthalmologists in promptly referring NIU patients to rheumatologists [37].
In our cohort, and in accordance with evidence from the literature, AU was the most prevalent anatomic involvement registered [9]. In addition, AU has been confirmed to be more frequent than PU in patients suffering from PsA or IBD-SpA [38][39][40][41]. Although IU is not very frequent, accounting for only about 10-15% of all NIU, it is interesting to note that only one patient affected by bilateral idiopathic IU, namely, parsplanitis, was discovered in our cohort. This patient was referred by an ophthalmologist for a systemic work-up, and since there were no associated ocular complications such as macular oedema, a systemic therapy was not started. However, in most cases, IU takes on idiopathic forms or is secondary to multiple sclerosis or sarcoidosis, and patients may be referred to neurologists or pulmonologists rather than rheumatologists [42]. Interestingly, patients experiencing recurrent and chronic NIU were younger at onset than patients with acute NIU, as were patients with bilateral NIU compared to patients with unilateral NIU. Patients with unilateral NIU also showed acute course and anterior involvement more frequently than patients with bilateral NIU, as well as a significantly higher proportion of concomitant PsA. Our analysis confirmed correlation between anterior involvement, unilaterality, and acute course, especially in PsA patients, as also highlighted in recent Korean and Spanish multicenter studies [43,44]. Several studies have attempted to characterize uveitis among patients with PsA. In a study on 16 adult PsA patients, Paiva and colleagues found that an insidious onset of uveitis, chronic course, bilateral involvement, and posterior eye disease were more common in association with PsA and IBD compared to the typical HLA-B27associated NIU noted in patients with ankylosing spondylitis (AS) [45]. Recent evidence in a cohort of PsA patients demonstrated a prevalence of NIU at 4.9% with acute course in all cases, as well as anterior (80%) and unilateral (80%) involvement [46]. In the latter study, 45% of the patients diagnosed with PsA and NIU had HLA-B27 positivity: NIU showed features belonging to HLA-B27 + -associated NIU, such as acute course, anterior involvement, and unilateral involvement. In our cohort of PsA patients, HLA-B27 was found in 40.9%, and similar to the aforementioned study, all of these patients had acute NIU, with almost all experiencing unilateral and anterior involvement, thus confirming the hypothesis of a potential HLA-B27 signature in characterizing NIU clinical presentation in these patients. No differences in sex have been revealed in the distribution of patterns of NIU in the type of course, in the whole cohort, or by stratifying according to associated rheumatologic diseases. Regarding the impact of sex on NIU, current data suggest that acute AU associated with SpA affects males more frequently than females, and typically occurs in young adults [16]. Moreover, male sex, hypopyon, increased ESR, or an associated SpA are potential risk factors for frequent relapses of HLA-B27-associated NIU [47]. In addition, the authors reported that males were more likely than females to develop psoriasis or PsA among patients with NIU [48]. Regarding concomitant rheumatologic diagnoses, almost half of NIU patients had a diagnosis of IBD-SpA, ax-SpA, PsA, or BD, with a similar prevalence. RA and CTDs represented the minority of cases, since in these pathologies NIU occurs less frequently than other ocular involvements such as dry eye (keratoconjunctivitis sicca) or episcleritis [49]. Interestingly, in almost 10% of patients, a defined rheumatologic diagnosis could not be performed; thus, NIU was defined as idiopathic. In these patients, AU and bilateral involvement were registered more frequently. PsA patients as well as BD patients showed a more defined NIU pattern by reporting AU, acute involvement, and unilateral involvement in the first group (PsA) and PU, recurrent/chronic, and bilateral involvement in the second (BD). In addition, in patients with concomitant SpA (both axial SpA and IBD-SpA) the most frequent NIU was AU. These results in our cohort are consistent with those reported in the literature [50,51]. Given the close association between NIU and HLA [52], a relevant proportion of NIU patients from the cohort underwent an HLA-typing study for the detection of B27/B51 haplotypes, mainly at the follow-up and without a difference in sex. The HLA-typing study was requested especially in patients with signs and symptoms of SpA (such as inflammatory low-back pain and dactylitis) and BD (such as oral and genital ulcers and folliculitis), in the context of providing further elements in support of the diagnostic suspicion. The prevalence of HLA-B27 positivity was almost 35%, whereas that of HLA-B51 positivity amounted to 20%. Furthermore, our study confirmed that HLA-B27 + patients tended to develop an associated AU, which can be often acute or recurrent and unilateral. In fact, approximately 60 to 80% of these NIU patients are HLA-B27 + , whereas SpA is detected in 58% to 78% of cases among HLA-B27 + NIU patients [53]. In our study cohort, a diagnosis of BD occurred more frequently in HLA-B51 + than in HLA-B51patients: Accordingly, HLA-B51 + patients had mostly PU, recurrent/chronic course, and bilateral involvement than HLA-B51patients. Interestingly, the age of NIU onset was younger in HLA-B51 + than in HLA-B51patients, and, since HLA-B51 positivity is correlated to a greater probability of developing a clinical phenotype of BD with more severe ocular and neurological involvement [54], it is reasonable to also have expected a more precocious onset of NIU than in HLA-B51patients. HLA genotyping was performed in all subjects using real-time polymerase chain reaction (PCR). Next-generation sequencing (NGS)-based HLA typing could be performed in future investigations since HLA typing by NGS seems to provide superior accuracy compared to traditional methods, in accordance with evidence from recent studies [55].
Uveitis can also occur in RA, CTDs, and vasculitis, but less frequently than other ocular involvements, such as scleritis, episcleritis, and keratoconjunctivitis sicca [49]. Nevertheless, in 25 NIU patients of our cohort (19.2%) it was possible to formulate a concomitant diagnosis of one of these diseases (11 RA, 10 CTDs, 4 small-vessels vasculitis). AU was the most frequent anatomic involvement and the most frequent course was acute in all these diseases, as reported in the literature [49], whereas unilaterality was more frequently documented only in RA and CTDs. From the whole NIU cohort, we identified a subset of patients, representing a quarter of the cohort, who were already on treatment at NIU onset, and they were mainly on cDMARDs. However, the proportion of patients receiving additional therapies at the rheumatological follow-up was similar in patients who were already on treatment at NIU onset and in those who were treatment-naive at NIU onset. At the first rheumatologic referral, almost half of patients started cDMARDs as a first-line CC-sparing therapy, in monotherapy or combination, whereas bDMARDs were used in a quarter of patients. The choice of treatment was made considering not only NIU itself but also any eventual associated rheumatologic disease, with the selection of a therapy that could control all clinical manifestations of the disease. Of note, in patients with active NIU or a history of relapsing NIU, a therapy aimed at controlling ocular inflammation was preferred, in accordance with evidence-based guidelines [56,57].
The present study documents how a multidisciplinary approach can improve the rate of appropriate diagnosis, giving patients prompt access to specific treatment. The NIU diagnostic work-up is closely related to prompt collaboration among different clinicians, mainly including ophthalmologists and rheumatologists. This is because the diagnosis of NIU can be challenging, and a multi-disciplinary approach is needed to improve the early detection and the targeted management of patients. Systemic diseases such as IBD, SpA, etc., can affect patients with NIU who concurrently present an increased risk of developing severe visual disturbance such as blindness or low vision. Representative associated diseases vary depending on the type of NIU, as BD is mainly associated with panuveitis, posterior NIU, and anterior NIU; sarcoidosis with posterior and intermediate NIU; and JIA, SpA, and IBD with anterior NIU. Panuveitis can be also related to other associated autoimmune disorders and Vogt-Koyanagi-Harada syndrome. Nevertheless, diagnosis of NIU can be a challenge because the cause is often not clinically evident, and the differential diagnosis depends on the recognition that uveitis is not a unique disease but can be considered a group of disorders based on its potential associations with primary ocular conditions as well as systemic inflammatory diseases [12]. Starting from these considerations, all patients with NIU should be considered to be affected by more than one disorder, including ocular diseases and the potential associated systemic disease. The combined approach with a tight follow-up, specifically a closer collaboration between ophthalmologists and rheumatologists, who play a major role in diagnosing and providing appropriate treatments for patients with systemic immune disease, may benefit long-term outcomes. Although corticosteroids remain the first drug of choice in the case of active uveitis, given the risk of developing both ocular and systemic side effects, it is advisable to use them only for short periods. Hence, especially for recurrent and chronic uveitis, there is a need to treat and control associated systemic disorders using steroidsparing immunosuppressive drugs. In fact, a recent retrospective study showed that the combined ophthalmologic and rheumatologic approach led to more usage and variety of immunosuppressive drugs compared to independent management [58]. Certainly, there is a lack of prospective studies evaluating how the early multidisciplinary approach could better control ocular inflammation and reduce the development of complications and reduced visual acuity. How the combined approach affects the treatment strategies and outcomes in patients with NIU certainly requires further prospective investigations aiming at assessing both the clinical outcome and the response to therapy in order to provide more evidence on potential targets to treat in NIU by stratifying patients according to age, sex, and associated diseases.

Patients
The entry-selection criterion of this cross-sectional descriptive study consisted of having a diagnosis of NIU delivered by an expert ophthalmologist. Additional inclusion criteria were (1) age of NIU onset ≥ 16 years old, and (2) admission to the rheumatologic clinics at Tor Vergata University Hospital in Rome and Federico II University Hospital in Naples (Italy) between January 2018 and December 2021. NIU clinical presentation was classified in accordance with the Standardization of Uveitis Nomenclature (SUN) Working Group criteria [59]. The demographic and clinical data collected were sex, smoking habits, age at onset and admission, course and anatomic patterns, HLA-B27 and -B51 presence/absence, reason for rheumatologic referral, associated rheumatologic diseases, and treatments. A diagnosis of concomitant SpA, SpA-IBD, PsA, BD, JIA, and rheumatoid arthritis (RA) was defined in accordance with the respective international classification criteria [60][61][62][63][64][65]. In all cases, HLA typing was performed on patients' DNA that was extracted from venous EDTA-anticoagulated blood and analyzed by using real-time polymerase chain reaction (PCR) according to the manufacturer's instructions (XeliGen RT System, Eurospital SPA, Italy, in most cases, and analogous RealTime PCR-based systems in the remaining cases).

Statistical Analysis
Mean and standard deviation (SD) expressed normally distributed variables. Continuous variables were compared using the parametric unpaired t test or the nonparametric Mann-Whitney U test when appropriate. Categorical variables were presented with absolute frequencies and percentages and were compared using the Chi-squared test or Fisher's exact test when appropriate. A p-value < 0.05 was considered significant. All statistical analyses were performed using GraphPad Prism version 9 (GraphPad Software, San Diego, CA, USA).

Conclusions
To the best of our knowledge, this is the first study that evaluated which type of physician refers patients with NIU to rheumatologic units, and it is important to note that in most cases family doctors play this pivotal role. Hence, there is a need to establish short routes that allow patients to be directed to reference centers directly from the territory, especially those who do not have active uveitis, so they can quickly access dedicated facilities such as ophthalmological emergency rooms. Our findings document that the interplay between ophthalmologists and rheumatologists is crucial in the setting of NIU and, above all, there should be an early rheumatological referral to diagnose any underlying rheumatological disease early and offer the patient a potential timely immunosuppressive treatment. Hence, there is a need to strengthen the role of international registries that help clinicians in caring for patients with NIU by collecting data on the course of disease and the response to therapies [66]. Prospective observational registries evaluating clinical characteristics, management, and outcomes can facilitate clinicians in their complex decision-making processes in NIU diagnostic and therapeutic work-up, and, thus, can improve the clinical care in the setting of a multicenter collaboration.

Institutional Review Board Statement:
The study was carried out according to the Declaration of Helsinki and conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines. The study protocol was approved by the ethical committee of the University of Rome Tor Vergata and University of Naples Federico II.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The data from this study are available upon a reasonable request addressed to the corresponding author.