Managing Psoriatic Arthritis With Inflammatory Bowel Disease and/or Uveitis

Psoriatic arthritis (PsA) is a chronic inflammatory disease that presents with psoriasis (PsO), peripheral and axial arthropathy. The heterogeneity of disease presentation leads to the term “psoriatic disease (PsD)” which is thought to better encompass the range of clinical manifestations. PsA is associated with several comorbidities such as cardiovascular diseases, metabolic syndrome and other extra-articular manifestations including uveitis, and inflammatory bowel disease (IBD). While novel therapeutics are being developed following advances in our understanding of the pathogenesis of the disease, the diverse combinations of PsA with its various comorbidities still pose a clinical challenge in managing patients with PsA. This article reviews our current understanding of the pathogenesis of PsA and how various pathways in the pathogenesis lead to the two comorbid extra-articular manifestations – uveitis and IBD. We also review current evidence of treatment strategies in managing patients with PsA with comorbidities of uveitis and/or IBD.


INTRODUCTION
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis (PsO) (1). It belongs to the family of spondyloarthritis (SpA) and the musculoskeletal manifestations include peripheral arthritis, dactylitis, enthesitis, and axial arthropathy. The impact of PsA extends beyond skin and joints to disability, fatigue, anxiety, depression, and poor quality of life (2,3). PsA is associated with comorbidities such as obesity, metabolic syndrome, insulin resistance, and cardiovascular disease (4). The extra-articular manifestations of PsA include inflammatory bowel disease (IBD) and uveitis (5). In recent years, there are advancements in therapeutic options to treat musculoskeletal manifestations of PsA (6), but research to understand the pathogenesis of extra-articular manifestations and their treatment options is still in infancy. The purpose of this review is to summarize the current understanding of pathogenesis of PsA and the extra-articular manifestations and their treatment options.

EXTRA-ARTICULAR MANIFESTATIONS IBD
Crohn's disease (CD) and ulcerative colitis (UC) are the two main forms of IBD. CD is characterized by chronic, patchy granulomatous inflammation with skip lesions, affecting any part of the gastrointestinal tract, especially the terminal ileum and colon. The inflammation is transmural which can lead to fibrosis, stricture, and fistula. In contrast, UC is characterized by continuous mucosal inflammation extending from the rectum proximally toward the colon. Differentiating these two conditions is important as each has diverse prognoses and differential responses to treatment (7). The clinical presentations of IBD include recurrent abdominal pain, bloody diarrhea, and mucus in the stool. Patients with CD can present with intestinal obstruction, recurrent fistulas, and other perianal findings. Systemic symptoms include fatigue, weight loss, fever, and symptoms of anemia. The standardized mortality ratio for CD ranges from 1.2 to 1.9 times the general population (8). The prognosis of IBD has improved in recent decades due to therapeutic advances.
Amongst patients with IBD, extraintestinal manifestations are common, including musculoskeletal (axial and peripheral arthropathy and arthritis), ocular (uveitis, scleritis and episcleritis), and skin. Inflammatory arthropathies are reported up to 40% of patients with IBD (9). While asymptomatic sacroiliitis may be seen in up to three-quarters of IBD patients, the reported prevalence of seronegative SpA ranges from 18-45%, and ankylosing spondylitis (AS) 3-9.9% (10,11). Peripheral arthritis is reported in 7-16% of IBD patients. Peripheral arthritis is mainly asymmetrical and oligoarticular, usually acute and occurs during IBD exacerbations, and self-limiting. However, it may also persist for months or years. Its onset usually coincides with or after IBD but may precede IBD. Enthesitis and dactylitis were reported in 2-4% of patients (12).

Uveitis
Uveitis is the inflammation of the uveal tract of the eye which comprises of the iris, ciliary body, and choroid. Adjacent structures including retina, optic nerve, vitreous, and sclera may also be affected. Clinically, uveitis is categorized anatomically -anterior, intermediate, posterior, or panuveitis (31). There is an increased association of ocular manifestations amongst patients with PsD (32,33). Other presentations like vitritis, retinal vasculitis, and cystoid macular edema involving the posterior chamber are sight-threatening (34,35). The prevalence of uveitis increases with disease duration, lifelong prevalence is over 40%. Among patients with SpA, acute anterior uveitis (AAU) is most common (26) and its prevalence varied with the type of SpA: 33% in AS; 37% in IBD-associated arthritis; 26% in reactive arthritis; 25% in PsA; and 13% in undifferentiated SpA (36,37). In both Asian and Western populations, uveitis is common in patients with severe PsO and those with PsA (38,39). Uveitis in SpA usually presents with a 'unilateral alternating' pattern, sudden in onset, confined to the anterior chamber, and completely resolves between episodes (40). In contrast, uveitis in PsA is insidious in onset, bilateral with a chronic relapsing course. PsA patients with both uveitis and axial arthropathy tend to be male and HLA-B * 27 positive (41,42). HLA-DR * 13 positivity is also associated with uveitis in patients with PsA (43). Uveitis may also precede the development of PsA in patients with PsO (44).
In a genetically predisposed individual, environmental factors including mechanical stress may trigger enthesitis -a hallmark clinical presentation of SpA including PsA (57,58). Mechanical stress and trauma release damage-associated molecular patterns (DAMPs), triggering the production of prostaglandin E2 (PGE2) (59) by resident mesenchymal cells, which recruit innate immune cells to perpetuate inflammation. PGE2 also induces T cell secretion of IL-17, a key driver in PsA pathogenesis (58,60). Innate immune cells such as dendritic cells (DCs), monocytes/macrophages, neutrophils, and innate lymphoid cells (ILCs) corroborate with adaptive immune cells to perpetuate inflammation in PsA (61). Additionally, plasmacytoid dendritic cells (pDCs) infiltrate the synovium to act as antigen presenting cells (APCs), triggering downstream expression of TNF-α, IFNγ, and IL-2 from CD68+ macrophage-like-synoviocytes that mediate synovial inflammation and bone erosions (62,63). TNFα synergizes with DCs to activate and polarize Th17 cells (64). In addition to Th17 cells, type 3 innate lymphoid cells (ILCs) (65,66), mucosal-associated variant T (MAIT) cells (67,68), and FIGURE 1 | The interplay of genetic, immune, and other factors results in inflammation of the various domains -skin, joints, gut, and eye -in PsD. Common genetic associations (highlighted in red) can be found amongst the three manifestations. Gut dysbiosis is thought to contribute to the pathogenesis for the three manifestations by leakage of bacterial antigen into systemic circulation thereby resulting in inflammation and/or trafficking of immune subsets to and from the GI mucosa and other sites. In PsA enthesitis and uveitis, mechanical stress triggers the release of PGE2, resulting in the recruitment and activation of innate immune cells (DC, neutrophils, macrophages, ILC like type 3 ILC, MAIT cells, γδ T cells) which perpetuate inflammation. Furthermore, these innate cells secrete cytokines, notably IL-23, which polarize and maintain Th17 cells which are central to the IL-23/IL-17 axis which is believed to be important in the pathogenesis of PsD. HLA, human leukocyte antigen; IL-23R, interleukin-23 receptor; IL-23A, interleukin-23A; IL-12B, interleukin-12B; TRAF3IP2, tumor necrosis factor receptor-associated factor 3-interacting protein 2; TYK2, tyrosine kinase 2; NOD2, nucleotide-binding oligomerization domain-containing protein 2; STAT3, signal transducer and activator of transcription 3; CARD9, caspase recruitment domain family Member 9; TNF, tumor necrosis factor; MICA, major histocompatibility complex class I chain-related gene A; KIR, killer immunoglobulin receptor; DC, dendritic cell; ILC, innate lymphoid cell; MAIT, mucosal-associated invariant T cell; Th17, T helper 17 cell; IL-17, interleukin-17; IL-2, interleukin-2; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon gamma. Created with BioRender.com.
γδ T cells (69) are recruited to the synovium and produce IL-17A upon stimulation (70). In short, the IL-23/IL-17 axis is the central driver of inflammation in PsA (71-75).

Pathogenesis of IBD
Genetic predisposition increases the risk of developing IBD amongst patients with PsA and SpA. HLA-B27 is the major HLA associated with IBD risk. 25-78% of patients with AS and IBD are HLA-B27 positive (9,76,77). HLA-DRB1 * 01:03 is also common between AS and IBD (76,(78)(79)(80). Non-HLA polymorphisms such as nucleotide-binding oligomerization domain-containing protein 2 (NOD2) polymorphisms increase the risk of CD about 4-40 times and is associated with sacroiliitis amongst patients with IBD. NOD2, an intracellular receptor expressed by immune and intestinal cells, is involved in the activation of NFκB and inducing pro-inflammatory genes in innate immune cells (81)(82)(83)(84)(85). IL-23R polymorphisms modify susceptibility to IBD, where a loss-of-function mutation may have protective effect against IBD (86). Polymorphisms in genes related to the IL-23/IL-17 axis such as IL-12B, signal transducer and activator of transcription 3 (STAT3), and caspase recruitment domain family member 9 (CARD9) are associated with CD (87). Once again, this highlights the IL-23/IL-17 axis as a major pathogenetic pathway for IBD manifestations in patients with PsA.
The microbiome plays an important role in gastrointestinal health, and dysbiosis of the microbiota is observed in patients with IBD. Microbiota in IBD patients is less diverse compared to healthy controls. Gastrointestinal bacteria may invade the sterile inner colonic adherent mucus layer, disrupt epithelial architecture, and allow leakage of bacterial antigen into the systemic circulation to induce and perpetuate inflammation (88)(89)(90). A "gut-joint axis" has been proposed where immune cells traffic between the two domains (91,92). Fecal microbiota transplantation (FMT) has shown promising results in the treatment of UC in a Cochrane Database systematic review (93). Positive clinical outcomes are associated with higher dosage and delivery of FMT via lower gastrointestinal tract (94), and may be dependent on stool donor (95). However, a recent RCT on FMT in 31 patients with active PsA randomized to FMT vs. sham treatment was not efficacious for arthritis (96). Further study is required.
In patients with IBD, the number of IL-17-secreting MAIT cells (97), was increased in the gastrointestinal tract as compared to the peripheral blood, echoing PsA studies showing depleted MAIT cells in blood, and increased MAIT cells in inflamed synovia and psoriatic skin (67,68). γδ T cells are found in colonic mucosa and represent around 40% of intraepithelial lymphocytes (98). In contrast to PsA, the presence of γδ T cells appears to be protective and anti-inflammatory in patients with IBD. Different subtypes of γδ T cells may behave differently in different cytokine environments, explaining the diverse observations of γδ T cells in PsA and IBD (99,100). As with PsA, Th17 cells are major players in IBD (101). The chemokine receptor CCR6 is the main surface marker of the Th17 lineage. CCL20, a ligand for CCR6, is elevated in IBD gut epithelium and likely contributes to recruitment of CCR6+ type 3 ILC, Th17, and dendritic cells (102,103). Due to high levels of IL-17 and IL-23 in IBD gut epithelia, the IL-23/IL-17 pathway was thought to be a therapeutic target (104)(105)(106). However IL-23 inhibition showed efficacy in patients with IBD but IL-17 inhibition lead to disease exacerbation (107). A possible explanation for this paradox is that IL-17 plays a role in maintaining intestinal barrier and microbial defense (108-110).

Pathogenesis of Uveitis
The HLA-B * 27 is associated with increased risk of AAU (111), and is a common risk locus for PsA (and other SpA) and uveitis (112). HLA haplotypes such as HLA-A * 02 (113), HLA-DRB1 * 08-03 (114), HLA-B * 58 (115) were also associated with development of uveitis. Other non-HLA susceptibility loci are major histocompatibility complex class I chain-related gene A (MICA) (116,117), IL-10 (118), TNF (119), killer immunoglobulin receptor (KIR) (120), and polymorphisms in IL-23R, which all participate in immune response (121). Nonetheless, positive risk polymorphisms do not necessarily translate to uveitis. Other environmental and undiscovered factors are likely required to initiate uveitis in patients with SpA.
The eye is an immunologically privileged organ with a local inhibitory microenvironment, entailing immune ignorance and tolerance to prevent inflammation. The blood-retina barrier and absence of efferent lymphatics reduces exposure of the eye to the circulating immune system (122). In uveitis, infiltration of immune cells into the eye and disrupts the immunologically quiescent environment. However, the trigger of this infiltration is undetermined (123). Some evidence implicates the perturbation of the gut microbiome to SpA-associated uveitis. Animal studies demonstrated trafficking of leucocytes from intestine to eye, supporting the concept of a gut-eye axis (124). Further evidence from retina-specific TCR transgenic mice reared under germfree conditions showed that the severity of uveitis was reduced in the absence of gut microbiota. This reduction of severity was associated with a reduction in Th17 cells in the lamina propria of the intestine. Reconstitution of gut microbiota increased retinaspecific T cell signaling (125). McGonagle et. al (2015) proposed that anterior uveal structures are analogous to entheses due to their mechanical and structural roles in lens suspension. The repeated contractions and relaxations of these structures expose them to mechanical stress just like musculoskeletal entheses, thus providing the initial stimuli for inflammation (126). Like entheseal mesenchymal cells in enthesitis, cells in ciliary body express IL-23R, suggesting receptiveness to IL-23 signaling (127). In patients with uveitis, serum IL-17A levels were elevated during active disease (128). Association between Th17 and the development of uveitis has been observed in animal and clinical studies highlighting the importance of the IL-23/IL-17 axis in driving inflammation in PsA and uveitis (129)(130)(131)(132). However, clinical trials have yet to demonstrate the efficacy of IL-17 inhibition in uveitis (133).

MANAGEMENT OF EXTRA-ARTICULAR MANIFESTATIONS IN PSA
Therapeutic advances in the last decade for PsA and PsO have improved quality of life of many. The European League Against Rheumatism (EULAR) developed algorithm treatment recommendations for the musculoskeletal manifestations of PsA (134). However, patients who have co-existing nonmusculoskeletal manifestations such as IBD and uveitis pose a clinical challenge. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendation guideline highlighted a domain-driven approach focused on peripheral, axial, dactylitis, enthesitis, skin and nails (135,136). The evidence for optimal treatment options for extra-articular manifestations in PsA is lacking and relies on evidence built in the fields of IBD and uveitis as independent conditions. Regardless of domains, the treatment goals are moving toward achieving low or minimal disease activity. Although some treatment options are common across the different domains, the doses may be different.   We summarize the usual doses used for various domains in Table 1.

Therapeutic Goals
The treatment targets for patients with IBD are clinical remission, mucosal healing, and restoring quality of life (137,138). The importance of mucosal healing defined as restitution of the intestinal lining and regression or disappearance of endoscopic lesions has been emphasized. Achievement of this target is associated with reduced risk of relapse, reduced hospitalization rates, steroid-free remission, and resection-free status (139)(140)(141).
With medical advancements, the need for bowel resection is substantially reduced (142).

Medical Therapies for CD
Corticosteroids can be used to induce clinical remission. It is given either topically as ileal-release budesonide for active mild-to-moderate CD or systemically for moderateto-severe CD (132). However, systemic corticosteroid should not be used for maintenance (143,144). Early initiation of corticosteroid-sparing immunomodulators such as azathioprine (AZA), mercaptopurine or methotrexate (MTX) for maintenance should be considered, although the level of evidence supporting efficacy of these drugs is relatively low (144,145). Monoclonal antibody targeting TNFα (TNF inhibitors, TNFi) has become the standard of care for patients with moderateto-severe, active CD. Infliximab (IFX), adalimumab (ADA), and certolizumab (CZP) have demonstrated efficacy in inducing remission and maintenance in RCTs, and well supported by meta-analyses (146,147). We summarized the major RCTs supporting the efficacies of TNFi in IBD Table 2. In a Cochrane Database Systematic review, CD patients who responded to induction by TNFi were more likely to maintain remission at 52 weeks with TNFi compared to placebo (147). Continued treatment with TNFi reduces surgery and hospitalization for CD (168,169). Combination therapy of IFX with AZA was more efficacious than either agent alone in achieving response, inducing clinical and histological remission (156), suggesting synergistic effect. TNFi appears to be more effective when given at earlier stage of disease, with higher rates of response and remission, than given at later stage of disease (170,171). Early escalation to TNFi treatment should be considered for patients with extensive disease and poor prognostic factors (144,145).
Vedolizumab (VZD) is a monoclonal antibody targeting α4β7 integrin, which reduces lymphocytes trafficking to the gastrointestinal tract by blocking lymphocyte surface α4β7 binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The efficacies of VZD in induction and maintenance in CD have been demonstrated in the GEMINI-2 (172) and GEMINI-3 trials (173) ( Ustekinumab (UST) is an antibody targeting the IL-12/23 p40 subunit. The efficacy of UST in inducing remission in CD has been shown in UNITI-1 and UNITI-2 trials in patients with inadequate response to TNFi, and without prior TNFi failure, respectively. Responders from both studies were randomized to the IM-UNITI maintenance study and demonstrated significantly higher clinical remission rates [high dose: 53%, P = 0.005; low dose: 49%, P = 0.04)] compared to placebo (36%) at week 44 (162). There is no head-to-head study comparing efficacies between TNFi, VZD and UST. The choice of biological treatment is a shared decision between clinician and patient, and according to the individual risk-benefit preferences.
Risankizumab (RZB), an IL-23/p19 inhibitor met the primary remission induction endpoints in CD in two phase III RCTs, ADVANCE (NCT03105128) and MOTIVATE (NCT03104413) (174). Patients in remission from ADVANCE and MOTIVATE were recruited to the Phase III open-label maintenance study, FORTIFY, showing RZB 360 mg every 8 weeks achieved the coprimary endpoints of clinical remission and endoscopic response at 52 weeks (175).
Blocking IL-17, however, has not been effective in CD. In a phase II trial evaluating safety and efficacy of brodalumab (BRO), a monoclonal antibody targeting IL-17 receptor, the primary induction endpoint was not met. The trial was terminated early due to a disproportionate number of cases of worsening CD (160). In a phase II RCT, two doses of 10 mg/kg secukinumab (SEC) given intravenously on days 0 and 22, failed to meet the primary endpoint and had more adverse events compared to placebo (176). However, the use IL-17i is not associated with increased incidence of IBD. Data from the SEC development program pooling 7,355 patients with a cumulative exposure of 16,227 person-years of patients exposed to SEC for PsO, PsA or SpA, no increase in exposure adjusted incidence rates of IBD was observed (15). Similarly, events of IBD remained low in the ixekizumab development program that pooled data from 15 RCTs in PsO and PsA (177).
Phase II RCT results for the Janus kinase inhibitor (JAKi), upadacitinib (UPA), in CD are promising. Endoscopic but not clinical remission increased with dose during the induction period (167). However, in a phase II trial for JAKi, tofacitinib (TOF), no statistically significant differences in clinical responses between TOF and placebo were observed at week 4 (164) ( Table 2).

Medical Treatment for UC
Oral 5-ASA (5-aminosalicylic acid) is the standard therapy for induction in mild-to-moderately active UC. For those failing 5-ASA or with moderate-to-severe UC, a short 6-to 8-week course of oral corticosteroid is indicated. 5-ASA and thiopurines can be used as maintenance therapy. Like the treatment strategy for CD, early escalation to biologic therapies should be considered for those who failed induction therapy with corticosteroid, or failed maintenance with immunomodulators, and those with poor prognostic factors. TNFi [IFX, ADA, golimumab (GOL)], α4β7 integrin inhibitor (VZD) and IL12/23i (UST) are approved treatments for induction and maintenance of UC ( Table 3). A combination of TNFi with an immunomodulator is more effective. In the UC-SUCCESS trial, patients treated with IFX and AZA were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy (181).   In a head-to-head study (VARSITY) comparing TNFi and VZD in patients with moderate-to-severe UC, 769 patients with moderate-to-severe active UC were randomized to receive VDZ or ADA (185). Only 26% of patients in either group were on concomitant immunomodulators. At week 52, a higher percentage of patients achieved clinical remission (31.3 vs. 22.5%; P = 0.006), and endoscopic improvement (39.7 vs. 27.7%; P < 0.001) in VDZ compared to ADA group. Whilst corticosteroidfree clinical remission occurred at a higher rate in the group receiving ADA compared to VDZ (21.8 vs. 12.6%; difference, −9.3 percentage points; 95% CI, −18.9 to 0.4). Despite a slight superiority of VDZ over ADA, more data are pending for consistency and class effect. The choice of biologics is, again, a shared decision between between clinician and patient.
Due to the ineffectiveness of IL-17i for CD, there have not been trials for their use in UC. As for IL-23i, there is an ongoing phase II/III trial of RZB for UC (NCT03398148).
In contrast to CD, the JAKi, TOF, was approved for use in moderate-to-severe UC based on three pivotal phase III OCTAVE studies, showing a significantly greater percentage of clinical remission at week 8 for induction, and remission at week 52 for maintenance in TOF compared to placebo group (186). UPA met the clinical remission, endoscopic improvement and histological improvement endpoints in a phase III induction trial for moderate-to-severe UC (187).

Medical Treatment for Uveitis
Prompt control of inflammation using topical corticosteroid is the first-line treatment for anterior uveitis in SpA. Typically, prednisolone acetate 1% eye drops are used as for severe AAU while milder corticosteroids such as dexamethasone 0.1% may be used for maintenance. A mydriatic drug is often prescribed together to reduce the development of posterior synechia and reduce pain from ciliary body spasm. Periocular corticosteroid injections or intravitreal implants can be used for more chronic cases. Adverse effects of corticosteroid in the eyes include cataract and ocular hypertension in up to 30% of patients. Oral corticosteroids may be used for acute management of severe and sight-threatening posterior uveitis such as vasculitis and cystoid macular edema, however, immunotherapy should be considered early in these cases to reduce recurrences (188). Traditional immunomodulators such as sulfasalazine (SSZ) and MTX may be tried although few data have supported their efficacy. Monoclonal antibody-TNFi including IFX, ADA, GOL and CZP are considered as effective treatment options for both acute flares and reducing recurrences of AAU (189). We summarize the major RCTs of therapeutic options for uveitis in Table 4. In a post-hoc analysis pooling data from four RCTs with TNFi in AS, the frequency of AAU flares was substantially lower among IFX or etanercept (ETN) treated than placebo treated patients. Lower frequency of AAU flares was seen in the open-labeled extension phase compared to the placebo phase of the trial (TNFi: 6.8 flares per 100 patient-years compared to PBO: 15.6 per 100 patient-years, p = 0.01) (198). ADA is the only TNFi licensed for treatment of non-infectious uveitis in adult following favorable results in 2 phase III RCTs. In the VISUAL I study, patients with active non-infectious intermediate, posterior uveitis or panuveitis were randomized to receive ADA or placebo after a prednisolone burst (60 mg) with tapering course. Patients treated with ADA were less likely than those treated with placebo to have treatment failure (hazard ratio, HR, 0.50; 95% CI, 0.36 to 0.70; P < 0.001). The VISUAL II study recruited 226 patients with inactive, noninfectious intermediate, posterior, or panuveitis controlled by 10-35 mg/day of prednisone were randomized to ADA vs. placebo. All patients underwent a mandatory prednisolone tapering to 0 mg by week 19. The time to treatment failure was significantly longer in ADA compared to placebo arm (median >18 months vs. 8.3 months; HR 0.57, 95% CI 0.39-0.84; p = 0.004) (191). ADA is also licensed for juvenile idiopathic arthritis-related uveitis. In an open-label study in 93 AS patients with history of uveitis, GOL reduced uveitis flares compared to patients' historical control 12month prior to initiation of GOL (192). There is an ongoing phase III 96-week open-label study for CZP in 115 patients with axial SpA and recurrent uveitis. In the 48-week interim analysis of 85 patients, uveitis flares were substantially reduced during the CZP treated period compared to the historical rates (64.0 and 31.5% respectively) (193). The use of ETN in the management of uveitis has diminished in favor of other TNFi because of its weaker ability in preventing flares.
Despite implicated in the pathogenesis of uveitis, inhibiting IL-17A was not effective for uveitis. In three RCTs, SEC failed to meet the primary efficacy endpoints (194). In another RCT comparing three doses of SEC, statistical higher response rates and remission on day 57 for the high dose regimen (30 mg/kg intravenously Q2W for 4 doses) was seen compared to the other two lower dose regimens, suggesting a higher dose intravenous regimen may be required to deliver SEC in therapeutic concentrations (195). Results are awaiting for two trials using UST in active sight-threatening uveitis (STAR) (196) and Behçet uveitis (STELABEC) (197), which may provide insight for its potential use in PsA related uveitis.
Minimal data exist for use of JAKi in uveitis. One phase 2 RCT evaluating filgotinib (FIL) in patients with active non-infectious uveitis (NCT03207815) is ongoing.

MANAGEMENT OF PSA WITH CONSIDERATION OF EXTRA-ARTICULAR MANIFESTATIONS
Given the heterogeneity in manifestations, enhanced collaboration between disciplines are required to deliver optimal care for PsD (199). While collaborations between rheumatologists and dermatologists are increasing (200), collaborations with gastroenterologists and ophthalmologists have traditionally been weaker. Apart from setting up combined clinics, collaborations between disciplines can take other forms as determined by needs and circumstances of different institutions. Minimally, identifying key stakeholders specializing in the care of PsA patients and keeping them in close communication over the management plan is essential. These collaborations serve both clinical and educational needs. Close collaboration between the various disciplines will help in early diagnosis of the various manifestations, providing expert advice on choice of therapeutics to create a patient-centric, individualized care plan for the heterogeneous manifestations. Often, the therapeutics will need to cover multiple domains, but the predominant domain should drive the therapeutic option of choice in the shared decision-making process. For severe IBD in the setting of PsA with peripheral manifestations, traditional immunomodulators can be considered for maintenance. TNFi (monoclonal antibodies) is a better option for patients with axial arthropathy. UST is effective for IBD but is less effective on peripheral arthritis as compared to TNFi or IL-17i, and ineffective for axial arthropathy. While IL-17i is an effective treatment for both peripheral and axial arthropathy, and probably does not increase the risk of IBD, it is not recommended for patients with underlying active IBD, due to its possibility of exacerbating pre-existing disease. IL-23i may be promising for IBD but its use requires caution in patients with predominant axial arthropathy. JAKi is effective for UC, peripheral and axial arthropathy, but may exacerbate CD. VDZ is effective for both CD and UC but has no indication for all other manifestations in PsA. With these considerations, TNFi (monoclonal antibodies) with or without concomitant immunosuppressants would be the best option for PsA patients with IBD. IBD is a chronic relapsing condition, and often requires higher doses of TNFi for induction than arthritis alone. Collaboration between rheumatologist and gastroenterologist is invaluable to ensure the optimal choice of treatment regimen.
Uveitis can be serious and sight threatening. Patients with symptoms of possible uveitis should have access to ophthalmology care promptly and given appropriate treatment for uveitis. Uveitis can arise even when arthritis is under control; it may manifest either suddenly or insidiously. It is important that patients are educated to be aware of the symptoms of uveitis and seek appropriate care when the needs arise. Care models like enquiry hotline, early referral or walk-in ophthalmology clinics are examples that may facilitate early diagnosis. For subsequent management, collaboration between rheumatologist and ophthalmologist is essential to ensure regular assessment of response to therapy and to modify management accordingly.
If uveitis fails to respond to topical corticosteroids, or fails to be weaned, or is severe at the onset, an escalation to either conventional immunomodulators or biological agents should be considered. The use of systemic corticosteroid is best avoided, given the risk of severe PsO flare upon its withdrawal. For patients with peripheral musculoskeletal manifestations (peripheral arthritis, enthesitis and dactylitis), MTX, SSZ or leflunomide (LEF) can be tried for maintenance, but an early escalation to TNFi (monoclonal antibodies) should be considered if these options fail. Traditional immunomodulators are not effective for axial arthropathy, thus for patients with active axial arthropathy TNFi (monoclonal antibodies) would be a good choice. Some patients may require higher or more frequent doses of TNFi especially for severe uveitis, highlighting again the importance of collaboration between rheumatologist and ophthalmologist for drug titration. IL-17i is an effective treatment for axial arthropathy, but SEC may not be effective for AAU at standard dose, and more data is still needed to inform the use of other IL-17i.
All in all, detailed considerations of all domains and extraarticular manifestations are necessary to formulate the best therapeutic option. Multi-disciplinary collaborative care models are advocated for optimal care for patients with PsA, and especially so for those who present with co-morbidities.

AUTHOR CONTRIBUTIONS
AlC and YL conceptualized the project. AlC, TC, and YL collected relevant data for review and drafted the manuscript. AnC, WC, GA, and YL critically appraised the content of manuscript. All authors approved the final version of manuscript.