BioMed Research International
Volume 2018 (2018), Article ID 9460187, 11 pages
https://doi.org/10.1155/2018/9460187

Review Article

The Management of Acute Anterior Uveitis Complicating Spondyloarthritis: Present and Future

Martina Biggioggero,¹ Chiara Crotti,² Andrea Becciolini,¹ Elisabetta Miserocchi,³ and Ennio Giulio Favalli¹

¹Department of Rheumatology, Gaetano Pini Institute, Milan, Italy
²Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, Milan, Italy
³Department of Ophthalmology, Scientific Institute San Raffaele, Milan, Italy

Correspondence should be addressed to Martina Biggioggero; martina.biggioggero@gmail.com

Received 16 June 2018; Revised 5 September 2018; Accepted 26 September 2018; Published 14 October 2018

Academic Editor: Hiroshi Tanaka

Copyright © 2018 Martina Biggioggero et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Spondyloarthropathies (SpA) encompass a group of chronic inflammatory diseases sharing common genetic and clinical features, including the association with HLA-B27 antigen, the involvement of both the axial and the peripheral skeleton, the presence of dactylitis, enthesitis, and typical extra-articular manifestations such as psoriasis, inflammatory bowel disease, and acute anterior uveitis (AAU). The latter is commonly reported as a noninfectious acute inflammation of the anterior uveal tract and its adjacent structures. AAU may affect more than 20% of SpA patients representing the most common extra-articular manifestation of the disease. Considering the potential consequences of untreated AAU, early diagnosis and aggressive treatment are crucial to avoid complications of remittent or chronic eye inflammation, such as visual loss and blindness. The management of SpA has dramatically improved over the last decades due to the development of new treat-to-target strategies and to the introduction of biologic disease modifying antirheumatic drugs (bDMARDs), particularly tumor necrosis factor alpha inhibitors (TNFis), currently used for the treatment of nonresponder patients to conventional synthetic agents. Along with the improvement of musculoskeletal features of SpA, bDMARDs provided an additional effect also in the management of AAU in those patients who are failures to topical and systemic conventional therapies. Nowadays, five TNFis, one interleukin-17, and one interleukin 12/23 blocker are licensed for the treatment of SpA, with different proven efficacy in preventing and treating ocular involvement. The aim of this review is to summarize the current options and to analyze the future perspectives for the management of SpA-associated AAU.

1. Introduction

Spondyloarthropathies (SpA) embrace different chronic inflammatory diseases sharing common genetic (association with HLA-B27 antigen) and clinical features. The principal symptoms are inflammatory chronic back pain, peripheral arthritis (typically asymmetric monoarthritis or oligoarthritis predominantly affecting the joints of the lower extremities), dactylitis, and enthesitis [1]. The disease course is usually complicated by extra-articular manifestations (EAMs), such as psoriasis, inflammatory bowel disease (IBD), and acute anterior uveitis (AAU) [2]. The latter is commonly reported as a noninfectious acute inflammation of the anterior uveal tract and its adjacent structures, which may affect more than 20% of SpA patients representing the most common EAM of the disease [3]. Considering the potential consequences of untreated AAU, early diagnosis and aggressive treatment are crucial to avoid the complications of remittent or chronic eye inflammation such as visual loss and blindness.

In this contest of very heterogeneous disease phenotype, the importance of personalised multidisciplinary management of the disease is mandatory. In the last decades, the development of new classification criteria allowing an earlier diagnosis and the availability of biologic and targeted synthetic therapies has vastly improved the management of SpA patients. Among biologic disease modifying antirheumatic drugs (bDMARDs), tumor necrosis factor alpha inhibitors (TNFis) are currently widely used for the treatment of SpA. To date, five TNFis (infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol) have been licensed for SpA by the European Medicines Agency and the US Food and Drug Administration. Recently, new potential treatment targets in SpA emerged enhancing the available treatment options with novel mechanisms of action. In particular, blockers of interleukin-17 (IL-17; secukinumab and ixekizumab), interleukin 12/23 (IL-12/23; ustekinumab), and phosphodiesterase-4 (PDE4; apremilast) were included in the therapeutic armamentarium for SpA.

Although the efficacy and safety profiles of the different available therapies have been clearly demonstrated for the management of musculoskeletal features of SpA, different performances in preventing and treating ocular involvement were proven.

The aim of this review is to summarize the current options and to analyze the future perspectives for the management of SpA-associated AAU.

2. Classification of Uveitis and Epidemiology of AAU

Uveitis is one of the most common causes of blindness and represent a broad spectrum of disorders characterized by inflammation of the uveal tract (iris, ciliary body, and choroid) and its adjacent structures (vitreous humour, retina, optic nerve, and vessels). According to the Standardization of Uveitis Nomenclature (SUN) criteria, uveitis can be classified according to the anatomic site of inflammation into anterior (characterized by the presence of intraocular inflammation in the anterior chamber), intermediate (inflammation of the pars plana), posterior (inflammation of the posterior segment), or panuveitis (involving anterior and posterior segment) [14]. Uveitis can also be clinically classified by etiology as infectious (bacterial, viral, fungal, or parasitic), noninfectious (with known or unknown systemic association), and masquerade (heterogeneous group of eye diseases that mimic chronic intraocular inflammation). Noninfectious uveitis may be associated with many systemic autoimmune conditions or may occur without extraocular involvement (Table 1) [14]. Accurate data on prevalence of uveitis are lacking, because of differences in clinical and methodological case finding methods, but the reported annual incidence of uveitis is between 17 and 52 per 100.000 persons and the prevalence is 38-714 per 100.000 persons, despite the variability among different geographic areas worldwide [15]. Uveitis can occur at any age, but this disease more commonly affects the working population between 20 and 59 years. No prevalence variations are observed according to gender, but some forms present a sex predominance (i.e., juvenile idiopathic arthritis-related uveitis, more common in female, and HLA-B27 associated uveitis, more common in male) [16, 17]. As shown by epidemiological data, incidence differs among ethnicities: posterior uveitis and panuveitis are, respectively, the second and third most frequent locations in the Western countries (21% and 7%, respectively) [18]; this distribution may suggest a potential role played by genetic factors.

Table 1: Autoimmune disorders associated with noninfectious uveitis.

Systemic immune-mediated causes of uveitis
Uveitis syndromes confined primarily to the eye

(i) Ankylosing spondylitis
(i) Acute posterior multifocal placoid pigmentary epitheliopathy

(ii) Behçet's disease
(ii) Acute retinal necrosis

(iii) Blau syndrome
(iii) Autosomal dominant neovascular inflammatory vitreoretinopathy

(iv) Crohn's disease
(iv) Birdshot choroidopathy

(v) Drug or hypersensitivity reaction
(v) Fuchs heterochromic cyclitis

(vi) Interstitial nephritis
(vi) Glaucomatocyclitic crisis

(vii) Juvenile idiopathic arthritis
(vii) Immune recovery uveitis

(viii) Kawasaki's disease
(viii) Iridocorneal endothelial syndrome

(ix) Multiple sclerosis
(ix) Leber's stellate neuroretinitis

(x) Neonatal onset multisystem inflammatory disease
(x) Multifocal evanescent white dot syndrome

(xi) Psoriatic arthritis
(xi) Pars planitis

(xii) Reactive arthritis
(xii) Punctate inner choroidopathy

(xiii) Relapsing polychondritis
(xiii) Serpiginous choroidopathy

(xiv) Sarcoidosis
(xiv) Subretinal fibrosis and uveitis syndrome

(xv) Sjögren's syndrome
(xv) Sympathetic ophthalmia

(xvi) Sweet syndrome
(xvi) Trauma

(xvii) Systemic lupus erythematosus

(xviii) Ulcerative colitis

(xix) Vasculitis

(xx) Vitiligo

(xxi) Vogt-Koyanagi-Harada syndrome

Anterior uveitis is the most common type of uveitis encountered in Western countries, while posterior and panuveitis are more frequently seen in developing countries due to the higher incidence of infectious uveitis involving the posterior segment of the eye. As mentioned before, the link between SpA and uveitis has been well described, since uveitis is the most common EAM in SpA and its main clinical presentation is with acute onset. However, about 50% of patients tend to have recurrent disease. [19]. It has been shown that AAU is the most common SpA-related type of uveitis accounting for almost 85% of cases in the USA [20]. A study conducted on more than 500 Spanish patients referred to an ophthalmologic centre for AAU reported that SpA was the most frequent systemic disease associated with AAU, diagnosed in about one quarter of cases [21]. In the DUET study, the prevalence of presumed idiopathic AAU, which was found to be associated with a SpA, was about 40% of patients [22]. The authors proposed an algorithm for early referral from ophthalmologists, in order to promptly diagnose an underlying SpA in presumed idiopathic AAU. Furthermore, HLA-B27 uveitis is commonly a nongranulomatous AAU [23]; so far, the lifetime cumulative incidence of AAU is higher in HLA-B27 positive subjects compared to general population, 1% versus 0.2%, respectively [24]. In the DUET study, HLA-B27 demonstrated to be the strong predictor of underlying SpA; in fact on multiple regression the detection of HLA-B27 was associated with an Odd’s Ratio of 38.6. They suggest combining HLA-B27 positivity with low back pain to significantly improve the probability of an early diagnosis (sensitivity 95%, specificity 98%, and Likelihood Ratio 56 in the DUET algorithm) [22]. According to a systematic meta-analysis, the prevalence of AAU in SpA is 32.7% [19]. Prevalence enhances with disease duration, reaching 43% for over 30 years of disease [19], and varies between different forms: it is lower in undifferentiated SpA (13%) while it is higher in ankylosing spondylitis (AS) (33.2%) [19]. As shown by Zeboulon and colleagues [19], prevalence changes also according to the sex of patient: female prevalence is higher than male (Odds Ratio [OR] 1.3; confidence interval [CI] 95% 1,1-1,4). However, data on sex differences in prevalence of AAU have not been fully elucidated in the literature [25–27].

3. Pathogenesis of AAU in SpA

Definitive data about pathogenesis of AAU in SpA are still lacking, albeit some reports derived from experimental animal models have contributed to point out some evidences. Unlike other classical systemic inflammatory disorders, SpA are not characterized by defined serological markers to assist the diagnosis (e.g., autoantibodies), with the exception of HLA-B27 (a class I major histocompatibility complex–encoded allele). HLA-B27 is commonly linked to the whole group of diseases and in particular to AS [28] and has been included in the clinical arm of the classification criteria of axial SpA provided by the Assessment of Spondyloarthritis International Society (ASAS) [29]. Moreover, HLA-B27 has been associated with the development of SpA-related AAU [30–32], which is significantly more common in HLA-B27 positive patients compared to the negative ones (27.7% versus 9.7%, respectively; p<0.05) [33]. From a pathogenic point of view, HLA-B27 is involved in the development of SpA together with a rich mixture of over 20 genes [34] and with environmental factors such as entheseal mechanical stress and gut microbiome [35, 36]. Despite the more recent advances, our understanding of the molecular mechanisms of HLA-B27 in the pathogenesis of SpA and in particular SpA-related AAU is far from being complete. Models of HLA-B27 transgenic rats and mice develop spontaneous inflammatory diseases in gastrointestinal tract, vertebral joints, skin, and nails, but uveitis is infrequent, suggesting the need of additional factors in the induction of AAU [37, 38]. Another significant association between AAU and SpA was observed for other three nonmajor histocompatibility complex loci: IL23R, the intergenic region 2p15, and ERAP1 [39]. Besides the genetic component, the development of AAU involves other factors. The intravitreal injection of Gram-negative endotoxin can induce a bilateral, dose-dependent, self-limited AAU [40]. Moreover, recurrent uveitis similar to human AAU has been demonstrated in transgenic rats infected with Salmonella or Yersinia [41], suggesting the potential role for concomitant infections in determining the onset of full-blown AAU in individuals carrying a HLA-B27 genetic susceptibility to the disease. Finally, TNF alpha levels were observed to be high in both aqueous humor and serum of patients affected by noninfectious uveitis, with a direct correlation with the disease activity [42].

4. Clinical Presentation of AAU

The most common ocular symptoms of AAU are acute eye pain, redness, and intense photophobia. Nonspecific visual changes such as floaters and different degrees of visual acuity loss may be present [43]. AAU associated with SpA is frequently characterized by sudden onset and is often unilateral or unilateral alternating, anterior and recurrent.

Anterior uveitis associated with SpA is typically a nongranulomatous type of uveitis characterized by the presence of fine keratic precipitates visible at the slit lamp examination of the anterior segment. Intraocular pressure is usually low due to severe inflammation of the ciliary body. In severe forms of acute anterior uveitis, hypopyon and fibrin can be visualized as a white and dense clot in the anterior chamber.

Posterior synechia, cataract, and secondary glaucoma are the most common ocular complications of uveitis. In about 15 to 20 % of patients the uveitis may have a more severe and chronic course and may involve the posterior segment with macular edema, retinal vasculitis, and papillitis leading to visual loss [44].

Some authors speculate on the prognosis of HLA-B27 related AAU, reporting a higher frequency of recurrence and a worse outcome compared with HLA-B27 negative patients [45, 46].

The use of bDMARDs could significantly affect the prognosis of AAU associated with SpA [47]. In fact, the clinical course and the number of relapses of AAU have been hugely improved by TNFis [48]. Furthermore, the overall prognosis of AAU is quite good in TNFis treated SpA and only a minority of patients reported permanent visual loss [49].

5. Treatment of AAU in SPA

The management of uveitis reserves actually several clinical challenges. The therapeutic approach for uveitis requires careful consideration regarding etiology, involved anatomic site, chronicity, prior medication failure, and potential ophthalmic and systemic risks of proposed therapy: a definite diagnosis is crucial to establish an appropriate therapy. Treatment of noninfectious uveitis may be local, systemic, or a combination of the two. The therapeutic strategy evaluates the underlying diagnosis, severity of the disease, laterality, and presence of comorbidities. The treatment of SpA associated AAU should include the management of acute attack and the prevention of recurrences.

5.1. Topical Therapy

The first-line symptomatic treatment of acute attack of AAU consists in a cycloplegic agent combined with corticosteroids, which may be administered systemically, topically, or by subconjunctival injection. Periocular prednisolone acetate and intraocular dexamethasone are the most commonly used local treatment in patients with HLA-B27 associated uveitis with posterior pole complications. In a minority of cases, subconjunctival corticosteroid injections may be needed, only when a marked anterior segment inflammation results in significant loss of vision [50]. In the SITE (Systemic Immunosuppressive Therapy for Eye Diseases) cohort periocular corticosteroids were found to be effective in reducing intraocular inflammation and improving visual acuity in AAU [51]. An exciting area of research sustained by recent advances in bioengineering is the development of intravitreal implants releasing corticosteroids or other compounds. These delivery devices may be classified into surgical nonbiodegradable and bioerodible implants, with different durations and safety profiles [38]. These novel approaches for the delivering of therapeutic substances derive from the need of developing local therapies characterized by faster effect on targeted tissues, avoiding undesirable systemic side effects. The available ocular implants have been mainly developed for releasing corticosteroids such as dexamethasone or fluocinolone acetonide [52]. Topical cycloplegics are often used in tandem with topical corticosteroids to break and to prevent the formation of posterior synechiae.

5.2. Conventional Synthetic DMARDs Disease-Modifying Antirheumatic Drugs (csDMARDs)

The key for the treatment of noninfectious uveitis relapsing or refractory to topic therapy is the control of systemic inflammation generated by the underlying autoimmune disease [53]. Systemic corticosteroids are often administered when topical treatment is inadequately effective, especially for bilateral uveitis. However, the prolonged use of moderate to high doses is significantly limited by serious side effects related to corticosteroid cumulative dose over time [54], leading to the potential introduction of an immunosuppressive agent as a corticosteroid-sparing therapy. The addition of methotrexate produced the resolution of noninfectious uveitis, despite corticosteroid withdrawal, in about 60% of patients within one year [55]. Furthermore, it decreases the frequency of AAU flares during the progressive tapering of systemic corticosteroids treatment [56]. Data on sulfasalazine for the treatment of AAU are very limited, with a single paper reporting a significant reduction in the number of AAU flares and improvement in visual acuity in SpA [56]. Similarly, leflunomide had only few anecdotal data regarding the treatment of uveitis [57]. Azathioprine is moderately effective in the treatment of noninfective uveitis, mainly the intermediate form of the disease [58]. The use of systemic cyclosporine for intermediate and posterior uveitis is well described by several papers showing a comparable efficacy with corticosteroids [59]. In particular, cyclosporine offered both a complete remission in more than 30% and a significant corticosteroid-sparing effect in at least 20% of treated patients [60]. However, the lack of data on the treatment of anterior uveitis and the overall unfavorable long-term safety profile, in terms of nephrotoxic effects and hypertension, are main limitations for the extensive use of cyclosporine for the management of SpA-related AAU. Other systemic immunomodulatory medications for uveitis are now very infrequently used because of their potential toxicity, particularly for alkylating agents, in consideration of the availability of more targeted therapies such as biologics.

In conclusion, systemic immunosuppressive drugs have a potential in the management of AAU, even if their use showed no proven efficacy in the treatment of axial and enthesopathic involvement of SpA, limiting the opportunity to treat SpA-related AAU and the underlying disease with the same drug.

5.3. Biologic and Targeted Synthetic DMARDs

To date SpA has fewer therapeutic options than rheumatoid arthritis and could exhibit heterogeneous therapeutic responses considering different site involvements. Given the complexity of SpA, a tailored management of the disease that includes targeted DMARDs (biologic and small molecules) is mandatory.

5.3.1. Role of Targeted DMARDs in SpA

Biologic DMARDs are defined as manufactured therapies by recombinant DNA (deoxyribonucleic acid) technology and include bioengineered soluble receptors, monoclonal antibodies, Fab fragments, and cytokines that affect the expression of pro- and anti-inflammatory components of the immune system. To date the major class of bDMARDs employed in SpA care is the successful use of TNF blockade in persistently high disease activity despite conventional treatments [61]. TNFis can be divided into three categories: a fusion protein that forms unstable complexes with the TNF (etanercept), monoclonal antibodies recognizing and binding to TNF (infliximab, adalimumab, and golimumab), and a Fab’ fragment of a monoclonal antibody coupled with polyethylene glycol (certolizumab pegol). TNFis demonstrated to be highly effective in targeting the different disease musculoskeletal manifestations and could ameliorate the disability and quality of life, acting on general symptoms such as fatigue. Long-term follow-up studies suggest a retention rate maintained for several years of treatment with an optimal safety profile [62]. Nevertheless, a significant proportion of patients showed an inadequate or poor response and others experienced drug-related adverse events. Consequently, alternative mechanisms of action (MoA) may be welcomed for these patients. The IL-23/IL-17 axis is strongly implicated in the pathogenesis of SpA and there is increased interest in the potential role of therapeutic strategies targeting this way. Secukinumab, a high-affinity, fully human monoclonal antibody that selectively inhibits IL-17A, showed a rapid-onset efficacy in treating SpA with a wide range of clinical benefits [63–69]. Ixekizumab, a monoclonal antibody that selectively targets interleukin-17A actually licensed for PsO, improved the signs and symptoms of patients with active PsA with a safety profile [70, 71]. Ustekinumab, an anti-IL-12/IL-23 monoclonal antibody, is safe and effective for patients with active PsA and AS [72–74]. Recently, the therapeutic armamentarium for PsA has been enriched with apremilast, a phosphodiesterase-4 inhibitor that demonstrated clinically meaningful sustained improvements with a good tolerance and safety profile [75–77].

5.3.2. Role of Targeted DMARDs in AAU

To date, bDMARDs have been used off-label to treat AAU because none of these therapies has been approved yet for adults, despite that their clinical efficacy has been reported in an amount of clinical cases and case series [78].

TNF alpha is essential in the intraocular immune response and in the autoregulation of the physiologic apoptosis of ocular cells. Preclinical studies give several evidences that TNF blocking can be a possible therapeutic strategy in uveitis. In fact, TNFis switch the immune response towards a Th2 prevalent mechanism, decreasing also disease activity [79]. Experimental autoimmune uveitis models highlighted that TNF alpha is increased not only in the typical autoimmune uveitis inflammatory infiltrates, but also in some retinal cells [80]. Moreover, the production of TNF alpha is regulated by ocular resident cells, macrophages, and activated T cells [81], possibly influencing the disease course. TNF alfa has a pivotal role in the pathogenesis of uveal inflammation; firstly, it recruits leukocytes to the eye in the early phase of the disease, through chemokines production and promotion of leukocytes adhesion to vascular endothelium. Secondly, TNF alpha promotes maturation of dendritic cells, improving the ability to act as presenting cells to T cells. Thirdly, TNF alpha can directly activate macrophages and promote T cells-effector function. Lastly, as mentioned, TNF alpha leads to apoptosis, of both infiltrating cells and resident ocular cells [82]. In clinical studies TNF alpha directly causes tissue damage through reactive oxygen species, breaking down the blood-ocular barrier and promoting angiogenesis [83]. TNF alpha could be related to endothelial tissue by the upregulation of vascular endothelial growth factor, whose effect is linked to cystoid macular edema and choroidal neovascularization [84]. These evidences give support to the use of TNFis in clinical practice. In fact, TNFis are the most frequently reported biologic drugs for the treatment of uveitis (Table 2). As was mentioned above, TNF alpha levels are high in both aqueous humor and the serum of patients affected by noninfectious uveitis; moreover there is a direct correlation between TNF alpha levels and the disease activity [42].

Table 2: Characteristics of main trials on Spondyloarthritis-related anterior acute uveitis treated with biological DMARDs.

Reference
Study design
Diagnosis
Number of patients
Drug
Outcomes

Dobner BC 2013 [4]
Observational, retrospective, multicentric
SpA
60
ADA
Improvement criteria of visual activity and steroid sparing

van Denderen JC 2014 [5]
Observational, prospective
AS
71
ADA
Number of flares before and after drug treatment

Rudwaleit M 2009 [6]
Prospective open-label study
AS
274
ADA
Number of AAU flares

Hernandez MV 2016 [7]
Observational, multicentric, retrospective
SpA
14
CZP
Visual acuity

Yazgan S 2016 [8]
Observational, retrospective
AS
12
GOL
Steroid sparing, visual acuity and number of flares

Calvo-Río V 2016 [9]
Observational, prospective
SpA
15
GOL
Visual acuity

Faez S 2013 [10]
Retrospective case series
SpA
3
GOL
Visual acuity

Kim M 2016 [11]
Retrospective cohort study
AS
143
ADA, IFX, ETN
Number of flares and reduction in systemic medication

Wendling D 2014 [12]
Retrospective, cohort study
AS
2115
IFX, ADA, ETN
Risk of developing AAU

Lie E 2017 [13]
Observational, retrospective
AS
1365
IFX, ADA, ETN
AAU incidence before and after treatment

ADA: adalimumab; IFX: infliximab; ETN: etanercept; GOL: golimumab; CZP: certolizumab Pegol; AAU: acute anterior uveitis; SpA: Spondyloarthritis; AS: Ankylosing spondylitis.

In this study authors considered uveitis in general; however AAU were in 83.3% of patients.

In this study authors considered uveitis in general; however AAU were the majority of cases: 88% of patients in IFX group, 97% in ADA, and 63.2% in ETN.

Retrospective studies on TNFis have been focused on underlying systemic disease with associated uveitis and some prospective studies have been successfully completed [78]. Several studies suggest that monoclonal antibodies are more effective than soluble receptors for the treatment of uveitis. The most important real-life experience reported with infliximab and adalimumab showed a clinical remission in over 60% of treated patients [15]. Further studies are needed to clarify a controversial area that is the potential paradoxical role of TNFis as a cause of uveitis [85, 86].

In animal models infliximab has shown a good safety profile and efficacy in the treatment of uveitis and dry eye and in scarring healing on the eye’s surface [87–89]. It is successfully used also in Behçet associated uveitis and in JIA associated forms [90]. Infliximab has shown to be effective also in uveitis associated with other systemic immune mediated conditions rather than SpA, such as, sarcoidosis or inflammatory bowel diseases [91]. In a prospective study conducted on 23 patients with various underlying etiologies of resistant uveitis, 78 % of patients on infliximab therapy reported a clinical success at week 10, as judged by a composite clinical end point combining visual acuity, control of intraocular inflammation, ability to taper concomitant therapy, and improvement of fluorescein angiography and/or optical coherence tomography [92]. In a retrospective study on recalcitrant uveitis treated with infliximab, 81.8% of the patients achieved clinical remission and only 58.3% required additional immunomodulatory medications [93]. The mechanism of action of infliximab is related to the neutralization of soluble and membrane-bound form of TNF, as explained by its rapid and effective action, inhibiting a broad range of TNF action, as mentioned above [83]. Controversial results were obtained with intravitreal injection of infliximab when systemic administration is not indicated. Initially, this new route of administration showed promising results with a significant visual acuity improvement and macular thickness reduction in patients with chronic noninfectious uveitis [94, 95], unfortunately not confirmed in subsequent studies, reporting electroretinographic abnormalities, severe panuveitis, and modest efficacy for the long-term control of uveitis [96–98]. Adalimumab has a number of publications supporting its efficacy and good safety profile for the treatment of uveitis; it has demonstrated good responses in SpA-associated uveitis and HLA-B27-associated uveitis [91]. Recently, three prospective multicenter open-label phase III trials (VISUAL I, II, and III) have been conducted to assess the effectiveness and safety of adalimumab versus placebo [99–101]. In the VISUAL I study, 217 active noninfectious intermediate uveitis, posterior uveitis, or panuveitis, despite prior prednisone treatment for 2 or more weeks, were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. The median time to adalimumab failure was 24 weeks, with an early and sustained separation of the treatment-failure curves, indicating that patients receiving adalimumab were significantly less likely to have treatment failure than those who received placebo. The VISUAL II trial assessed that adalimumab versus placebo significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in 229 patients with inactive, noninfectious uveitis controlled by systemic corticosteroids. Treatment failure occurred more frequently in the placebo group compared with the adalimumab one (55% versus 39%), as the time to treatment failure was significantly improved in the adalimumab group compared with the placebo one (p=0,004). The rate of adverse events was similar between groups. The impact of adalimumab on immunosuppressant use in 371 patients with active or inactive noninfectious intermediate, posterior, or panuveitis was analysed in the VISUAL III study, in which the long-term treatment with adalimumab reflected a reduction in csDMARDs dose and dependence in both groups.

Recently, these evidences had led to Food and Drug Administration and European Medicines Agency approval of adalimumab for the management of noninfectious intermediate uveitis, posterior uveitis, and panuveitis in adults. Adalimumab is licensed for the treatment of pediatric chronic noninfectious AAU in patients from 2 years of age, who have had an inadequate response to conventional therapies or in whom conventional therapy is inappropriate.

Etanercept is a therapeutic option in SpA but its efficacy on uveitis is much debated [11, 48, 91, 102, 103]. Braun and colleagues reported a greater reduction in uveitis flares with infliximab compared with etanercept in AS [48]. Similar results were observed in a retrospective analysis on 2115 AS patients with a higher risk of new-onset uveitis in patients treated with etanercept compared with monoclonal antibodies (infliximab and adalimumab) [12]. Galor et al. [104] compared etanercept to infliximab for the treatment of a variety of inflammatory eye diseases including HLA-B27-associated uveitis, showing a greater efficacy of infliximab compared with etanercept in decreasing the number of uveitis recurrences (0 versus 59%, respectively). On the other hand, in a meta-analysis Migliore et al. compared TNFis versus placebo in the treatment of uveitis in AS patients reporting a positive efficacy of all TNFis, including etanercept [103]. Accordingly, Kim et al. described a similar rapid improvement of uveitis with a reduction of the number of flare-ups in patients treated with infliximab, adalimumab, or etanercept [11].

Golimumab and certolizumab pegol efficacy in the treatment of uveitis has been reported only in few case reports and small case series of heterogeneous subgroups of patients, including patient nonresponders to prior TNFi [7, 105–110]. Further data are needed to make any statement.

The ability of other mechanisms of action to manage uveitis in SpA is still under delineation. The involvement of IL-23-IL17 pathway and the consequent pivotal role of autoreactive T cells in the pathogenesis of noninfectious uveitis provide a rationale for treatment of AAU with IL-17 inhibitors [33]. However, secukinumab did not meet the primary efficacy end points as a therapy in uveitis not specifically SpA-related in three RCTs versus placebo but reported a beneficial effect in reducing concomitant csDMARDs use [111]. A prospective nonrandomized pilot study to investigate ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis, or panuveitis (STAR study) is now ongoing (ClinicalTrials.gov Identifier: NCT02911116). Apremilast was not studied in AAU SpA-related. Ocular involvement is actually under assessment in a phase 3 randomized double-blind study designed to evaluate the efficacy and safety of apremilast in active Behcet’s disease (ClinicalTrials.gov Identifier: NCT02307513) [112].

6. Future Perspectives

Although targeted therapies have provided a larger armamentarium to treat uveitis, challenges remain. Among small molecules, tofacitinib is an oral inhibitor of Janus kinase (JAK) 1 and 3 that is under investigation for the treatment of AS [113] and PsA in patients previously not responder to csDMARDs [114] or to TNFis [115]. To date, no clinical trials evaluating the efficacy of JAK inhibitors in uveitis have been conducted. The immunomodulatory effect of topical ophthalmic tofacitinib has been evaluated in dry eye disease, with a reduction of conjunctival cell surface HLA-DR expression and tear levels of proinflammatory cytokines and inflammation markers after 8 weeks of treatment [116].

7. Conclusions

The management of SpA and related AAU is extremely complex due to the pleomorphic characteristics of these diseases. Multidisciplinary approach is mandatory to achieve the target of an early diagnosis and aggressive treatment, in order to prevent disease progression and damage. The treatment armamentarium of SpA has been considerably improved over the last decades due to the development of new targeted drugs that provided an additional effect also in the management of AAU. The first line of treatment in AAU remains a combination of topical corticosteroids and mydriatic agents, reserving systemic corticosteroids for patients with refractory and severe involvement. The introduction of corticosteroid-sparing csDMARDs is a therapeutic option. Among csDMARDs, methotrexate and cyclosporine reported the most solid data in AAU treatment with an acceptable safety profile. TNFis are the most frequently used bDMARDs in the treatment of both SpA and AAU. In particular, monoclonal antibodies TNFis resulted more effective than etanercept in AAU potentially due to the paradoxical effect and a lower efficacy of the fusion protein. New mechanisms of action targeting the IL-23-IL17 pathway are still under delineation and further data are needed to make any statement.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

M. Dougados and D. Baeten, “Spondyloarthritis,” The Lancet, vol. 377, no. 9783, pp. 2127–2137, 2011.

I. E. Van Der Horst Bruinsma and M. T. Nurmohamed, “Management and evaluation of extra-articular manifestations in spondyloarthritis,” Therapeutic Advances in Musculoskeletal Disease, vol. 4, no. 6, pp. 413–422, 2012.

A. B. Bacchiega, G. G. Balbi, M. L. Ochtrop, F. A. de Andrade, R. A. Levy, and X. Baraliakos, “Ocular involvement in patients with spondyloarthritis,” Rheumatology, vol. 56, no. 12, pp. 2060–2067, 2017.

B. C. Dobner, R. Max, M. D. Becker et al., “A three-centre experience with adalimumab for the treatment of non-infectious uveitis,” British Journal of Ophthalmology, vol. 97, no. 2, pp. 134–138, 2013.

J. C. Van Denderen, I. M. Visman, M. T. Nurmohamed, M. S. A. Suttorp-Schulten, and I. E. Van Der Horst-Bruinsma, “Adalimumab significantly reduces the recurrence rate of anterior uveitis in patients with ankylosing spondylitis,” The Journal of Rheumatology, vol. 41, no. 9, pp. 1843–1848, 2014.

M. Rudwaleit, I. Olivieri, K. A. Boki et al., “Adalimumab is effective and well tolerated in treating patients with ankylosing spondylitis who have advanced spinal fusion,” Rheumatology, vol. 48, no. 5, pp. 551–557, 2009.

M. V. Hernández, M. Mesquida, V. Llorens, and et al., “Effectiveness of Certolizumab Pegol in Patients with Uveitis Refractory to Other Tumor Necrosis Factor Inhibitors. Report of 22 Cases,” Arthritis & Rheumatism, vol. 68, 10, 2016.

S. Yazgan, U. Celik, M. Işık et al., “Efficacy of golimumab on recurrent uveitis in HLA-B27-positive ankylosing spondylitis,” International Ophthalmology, vol. 37, no. 1, pp. 139–145, 2017.

V. Calvo-Río, R. Blanco, M. Santos-Gómez et al., “Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients,” Seminars in Arthritis and Rheumatism, vol. 46, no. 1, pp. 95–101, 2016.

S. Faez, A.-M. Lobo, L. Sobrin, and G. N. Papaliodis, “Treatment of seronegative spondyloarthropathy-associated uveitis with golimumab: Retrospective case series,” Clinical & Experimental Ophthalmology, vol. 42, no. 4, pp. 392–395, 2014.

M. Kim, J. Won, S. Y. Choi, J. H. Ju, and Y. Park, “Anti-TNFα Treatment for HLA-B27-Positive Ankylosing Spondylitis–Related Uveitis,” American Journal of Ophthalmology, vol. 170, pp. 32–40, 2016.

D. Wendling, A. Joshi, P. Reilly, Y. J. Jalundhwala, M. Mittal, and Y. Bao, “Comparing the risk of developing uveitis in patients initiating anti-tumor necrosis factor therapy for ankylosing spondylitis: An analysis of a large US claims database,” Current Medical Research and Opinion, vol. 30, no. 12, pp. 2515–2521, 2014.

E. Lie, U. Lindström, T. Zverkova-Sandström et al., “Tumour necrosis factor inhibitor treatment and occurrence of anterior uveitis in ankylosing spondylitis: Results from the Swedish biologics register,” Annals of the Rheumatic Diseases, vol. 76, no. 9, pp. 1515–1521, 2017.

D. A. Jabs, R. B. Nussenblatt, and J. T. Rosenbaum, “Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop,” American Journal of Ophthalmology, vol. 140, no. 3, pp. 509–516, 2005.

S. Pasadhika and J. T. Rosenbaum, “Update on the use of systemic biologic agents in the treatment of noninfectious uveitis,” Biologicals, vol. 8, pp. 67–81, 2014.

S. Amur, A. Parekh, and P. Mummaneni, “Sex differences and genomics in autoimmune diseases,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. J254–J265, 2012.

Q. Lu, “The critical importance of epigenetics in autoimmunity,” Journal of Autoimmunity, vol. 41, pp. 1–5, 2013.

R. S. Grajewski, A. Caramoy, K. F. Frank et al., “Spectrum of Uveitis in A German Tertiary Center: Review of 474 consecutive patients,” Ocular Immunology and Inflammation, vol. 23, no. 4, pp. 346–352, 2015.

N. Zeboulon, M. Dougados, and L. Gossec, “Prevalence and characteristics of uveitis in the spondyloarthropathies: A systematic literature review,” Annals of the Rheumatic Diseases, vol. 67, no. 7, pp. 955–959, 2008.

D. C. Gritz and I. G. Wong, “Incidence and prevalence of uveitis in Northern California: the Northern California Epidemiology of Uveitis Study,” Ophthalmology, vol. 111, no. 3, pp. 491–500, 2004.

E. Pato, A. Banares, J. A. Jover et al., “Undiagnosed spondyloarthropathy in patients presenting with anterior uveitis,” The Journal of Rheumatology, vol. 27, no. 9, pp. 2198–2202, 2000.

M. Haroon, M. O'Rourke, P. Ramasamy, C. C. Murphy, and O. FitzGerald, “A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: The DUET (Dublin Uveitis Evaluation Tool),” Annals of the Rheumatic Diseases, vol. 74, no. 11, pp. 1990–1995, 2015.

J. T. Rosenbaum, “Characterization of uveitis associated with spondyloarthritis,” The Journal of Rheumatology, vol. 16, no. 6, pp. 792–796, 1989.

A. Linssen, A. Rothova, H. A. Valkenburg et al., “The lifetime cumulative incidence of acute anterior uveitis in a normal population and its relation to ankylosing spondylitis and histocompatibility antigen HLA-B27,” Investigative Ophthalmology & Visual Science, vol. 32, pp. 2568–2578, 1991.

F. J. Jimenez-Balderas and G. Mintz, “Ankylosing spondylitis: Clinical course in women and men,” The Journal of Rheumatology, vol. 20, no. 12, pp. 2069–2072, 1993.

R. Will, L. Edmunds, J. Elswood, and A. Calin, “Is there sexual inequality in ankylosing spondylitis? A study of 498 women and 1202 men,” The Journal of Rheumatology, vol. 17, no. 12, pp. 1649–1652, 1990.

B. Kidd, M. Mullee, A. Frank, and M. Cawley, “Disease expression of ankylosing spondylitis in males and females,” The Journal of Rheumatology, vol. 15, no. 9, pp. 1407–1409, 1988.

R. A. Colbert, M. L. Delay, E. I. Klenk, and G. Layh-Schmitt, “From HLA-B27 to spondyloarthritis: A journey through the ER,” Immunological Reviews, vol. 233, no. 1, pp. 181–202, 2010.

M. Rudwaleit, D. Van Der Heijde, R. Landewé et al., “The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection,” Annals of the Rheumatic Diseases, vol. 68, no. 6, pp. 777–783, 2009.

D. Wakefield, J. H. Chang, S. Amjadi, Z. MacOnochie, A. A. El-Asrar, and P. McCluskey, “What is new HLA-B27 acute anterior uveitis?” Ocular Immunology and Inflammation, vol. 19, no. 2, pp. 139–144, 2011.

M. A. Khan, I. Kushner, and W. E. Braun, “Comparison of clinical features in HLA‐B27 positive and negative patients with ankylosing spondylitis,” Arthritis & Rheumatism, vol. 20, no. 4, pp. 909–912, 1977.

M. A. Khan, I. Kushner, and W. E. Braun, “Association of HLA-A2 with uveitis in HLA-B27 positive patients with ankylosing spondylitis,” The Journal of Rheumatology, vol. 8, no. 2, pp. 295–298, 1981.

M. A. Khan, M. Haroon, and J. T. Rosenbaum, “Acute anterior uveitis and spondyloarthritis: more than meets the eye,” Current Rheumatology Reports, vol. 17, article 59, 2015.

C. International Genetics of Ankylosing Spondylitis, A. Cortes, and J. Hadler, “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci,” Nature Genetics, vol. 45, no. 7, pp. 730–738, 2013.

R. J. Lories and I. B. McInnes, “Primed for inflammation: Enthesis-resident T cells,” Nature Medicine, vol. 18, no. 7, pp. 1018-1019, 2012.

T. Gill, M. Asquith, J. T. Rosenbaum, and R. A. Colbert, “The intestinal microbiome in spondyloarthritis,” Current Opinion in Rheumatology, vol. 27, no. 4, pp. 319–325, 2015.

R. E. Hammer, S. D. Maika, J. A. Richardson, J.-P. Tang, and J. D. Taurog, “Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β2m: an animal model of HLA-B27-associated human disorders,” Cell, vol. 63, no. 5, pp. 1099–1112, 1990.

S. D. Khare, H. S. Luthra, and C. S. David, “Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking ß2-microglobulin: A model of human spondyloarthropathies,” The Journal of Experimental Medicine, vol. 182, no. 4, pp. 1153–1158, 1995.

J. Fernandez-Melon, S. Munoz-Fernandez, V. Hidalgo et al., “Uveitis as the initial clinical manifestation in patients with spondyloarthropathies,” The Journal of Rheumatology, vol. 31, no. 3, pp. 524–527, 2004.

J. T. Rosenbaum, H. O. McDevitt, R. B. Guss, and P. R. Egbert, “Endotoxin-induced uveitis in rats as a model for human disease,” Nature, vol. 286, no. 5773, pp. 611–613, 1980.

S. Baggia, J. L. Lyons, E. Angell et al., “A Novel Model of Bacterially-Induced Acute Anterior Uveitis in Rats and the Lack of Effect from HLA-B27 Expression,” Journal of Investigative Medicine, vol. 45, no. 5, pp. 295–301, 1997.

J. Heo, Y. J. Sepah, J. Yohannan et al., “The role of biologic agents in the management of non-infectious uveitis,” Expert Opinion on Biological Therapy, vol. 12, no. 8, pp. 995–1008, 2012.

M. Prete, R. Dammacco, M. C. Fatone, and V. Racanelli, “Autoimmune uveitis: clinical, pathogenetic, and therapeutic features,” Clinical and Experimental Medicine, vol. 16, no. 2, pp. 125–136, 2016.

R. V. Agrawal, S. Murthy, V. Sangwan, and J. Biswas, “Current approach in diagnosis and management of anterior uveitis,” Indian Journal of Ophthalmology, vol. 58, no. 1, pp. 11–19, 2010.

W. J. Power, A. Rodriguez, M. Pedroza-Seres, and C. S. Foster, “Outcomes in anterior uveitis associated with the HLA-B27 haplotype,” Ophthalmology, vol. 105, no. 9, pp. 1646–1651, 1998.

A. Rothova, W. G. Van Veenendaal, and A. Linssen, “Clinical features of acute anterior uveitis,” American Journal of Ophthalmology, vol. 103, no. 2, pp. 137–145, 1987.

J. H. Lee, M. Choi, T. H. T. Rim, S. C. Lee, and C. S. Lee, “Clinical Characteristics and Prognostic Factors in Ankylosing Spondylitis Associated Uveitis,” Ocular Immunology and Inflammation, pp. 1–6, 2017.

J. Braun, X. Baraliakos, J. Listing, and J. Sieper, “Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept,” Arthritis & Rheumatology, vol. 52, no. 8, pp. 2447–2451, 2005.

F. Cantini, C. Nannini, E. Cassarà, O. Kaloudi, and L. Niccoli, “Uveitis in spondyloarthritis: An overview,” The Journal of Rheumatology, vol. 93, pp. 27–29, 2015.

P. Sève, L. Kodjikian, L. Adélaïde, and Y. Jamilloux, “Uveitis in adults: What do rheumatologists need to know?” Joint Bone Spine, vol. 82, no. 5, pp. 308–314, 2015.

R. O. Kaçmaz, J. H. Kempen, C. Newcomb et al., “Cyclosporine for Ocular Inflammatory Diseases,” Ophthalmology, vol. 117, no. 3, pp. 576–584, 2010.

D. J. Lee, “Intraocular implants for the treatment of autoimmune uveitis,” Journal of Functional Biomaterials, vol. 6, no. 3, pp. 650–666, 2015.

V. L. Perez, A. M. Saeed, Y. Tan, M. Urbieta, and F. Cruz-Guilloty, “The eye: A window to the soul of the immune system,” Journal of Autoimmunity, vol. 45, pp. 7–14, 2013.

D. A. Jabs, J. T. Rosenbaum, C. S. Foster, and etal., “Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel,” American Journal of Ophthalmology, vol. 130, 492, no. 4, p. 513, 2000.

S. Gangaputra, C. W. Newcomb, T. L. Liesegang et al., “Methotrexate for Ocular Inflammatory Diseases,” Ophthalmology, vol. 116, no. 11, pp. 2188–e1, 2009.

A. Gómez-Gómez, E. Loza, M. P. Rosario et al., “Efficacy and safety of immunomodulatory drugs in patients with anterior uveitis,” Medicine, vol. 96, no. 42, p. e8045, 2017.

M. Roy, “Early clinical experience with leflunomide in uveitis,” Canadian Journal of Ophthalmology, vol. 42, no. 4, p. 634, 2007.

J. E. Thorne, D. A. Jabs, F. A. Qazi, D. N. Quan, J. H. Kempen, and J. P. Dunn, “Mycophenolate mofetil therapy for inflammatory eye disease,” Ophthalmology, vol. 112, no. 8, pp. 1472–1477, 2005.

R. B. Nussenblatt, A. G. Palestine, C. C. Chan, G. Stevens Jr., S. D. Mellow, and S. B. Green, “Randomized, double-masked study of cyclosporine compared to prednisolone in the treatment of endogenous uveitis,” American Journal of Ophthalmology, vol. 112, no. 2, pp. 138–146, 1991.

G. Multicenter Uveitis Steroid Treatment Trial Research, J. H. Kempen, M. M. Altaweel et al., “The multicenter uveitis steroid treatment trial: rationale, design, and baseline characteristics,” American Journal of Ophthalmology, vol. 149, no. 4, pp. 550–561, 2010.

D. van der Heijde, S. Ramiro, R. Landewe et al., “2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis,” Annals of the Rheumatic Diseases, vol. 76, no. 6, pp. 978–991, 2017.

E. G. Favalli, C. Selmi, A. Becciolini et al., “Eight-Year Retention Rate of First-Line Tumor Necrosis Factor Inhibitors in Spondyloarthritis: A Multicenter Retrospective Analysis,” Arthritis Care & Research, vol. 69, no. 6, pp. 867–874, 2017.

I. B. McInnes, P. J. Mease, C. T. Ritchlin et al., “Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study,” Rheumatology, vol. 56, no. 11, pp. 1993–2003, 2017.

D. van der Heijde, R. B. Landewé, P. J. Mease et al., “Brief Report: Secukinumab Provides Significant and Sustained Inhibition of Joint Structural Damage in a Phase III Study of Active Psoriatic Arthritis,” Arthritis & Rheumatology, vol. 68, no. 8, pp. 1914–1921, 2016.

P. J. Mease, I. B. McInnes, B. Kirkham et al., “Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis,” The New England Journal of Medicine, vol. 373, no. 14, pp. 1329–1339, 2015.

I. B. McInnes, J. Sieper, J. Braun et al., “Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial,” Annals of the Rheumatic Diseases, vol. 73, no. 2, pp. 349–356, 2013.

I. B. McInnes, P. J. Mease, B. Kirkham et al., “Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial,” The Lancet, vol. 386, no. 9999, pp. 1137–1146, 2015.

X. Baraliakos, A. J. Kivitz, A. A. Deodhar et al., “Long-term effects of interleukin-17A inhibition with secukinumab in active ankylosing spondylitis: 3-year efficacy and safety results from an extension of the Phase 3 MEASURE 1 trial,” Clinical and Experimental Rheumatology, vol. 36, no. 1, pp. 50–55, 2018.

H. Marzo-Ortega, J. Sieper, A. Kivitz et al., “Secukinumab and Sustained Improvement in Signs and Symptoms of Patients With Active Ankylosing Spondylitis Through Two Years: Results From a Phase III Study,” Arthritis Care & Research, vol. 69, no. 7, pp. 1020–1029, 2017.

P. Nash, B. Kirkham, M. Okada et al., “Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial,” Lancet, vol. 389, no. 10086, pp. 2317–2327, 2017.

P. J. Mease, D. Van Der Heijde, C. T. Ritchlin et al., “Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: Results from the 24-week randomised, double-blind, placebocontrolled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1,” Annals of the Rheumatic Diseases, vol. 76, no. 1, pp. 79–87, 2017.

I. B. McInnes, A. Kavanaugh, and A. B. Gottlieb, “Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial,” The Lancet, vol. 382, no. 9894, pp. 780–789, 2013.

C. Ritchlin, P. Rahman, A. Kavanaugh et al., “Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial,” Annals of the Rheumatic Diseases, vol. 73, no. 6, pp. 990–999, 2014.

D. Poddubnyy, K.-G. A. Hermann, J. Callhoff, J. Listing, and J. Sieper, “Ustekinumab for the treatment of patients with active ankylosing spondylitis: Results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS),” Annals of the Rheumatic Diseases, vol. 73, no. 5, pp. 817–823, 2014.

P. H. Schafer, P. Chen, L. Fang, A. Wang, and R. Chopra, “The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: Substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1),” Journal of Immunology Research, vol. 2015, 2015.

M. Cutolo, G. E. Myerson, R. M. Fleischmann et al., “A phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: Results of the PALACE 2 trial,” The Journal of Rheumatology, vol. 43, no. 9, pp. 1724–1734, 2016.

C. J. Edwards, F. J. Blanco, J. Crowley et al., “Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: A phase III, randomised, controlled trial (PALACE 3),” Annals of the Rheumatic Diseases, vol. 75, no. 6, pp. 1065–1073, 2016.

K. Lee, A. Bajwa, C. A. Freitas-Neto, J. L. Metzinger, B. A. Wentworth, and C. S. Foster, “A comprehensive review and update on the non-biologic treatment of adult noninfectious uveitis: Part I,” Expert Opinion on Pharmacotherapy, vol. 15, no. 15, pp. 2141–2154, 2014.

A. D. Dick, L. Duncan, G. Hale, H. Waldmann, and J. Isaacs, “Neutralizing TNF-alpha activity modulates T-cell phenotype and function in experimental autoimmune uveoretinitis,” Journal of Autoimmunity, vol. 11, no. 3, pp. 255–264, 1998.

Y. de Kozak, M.-C. Naud, J. Bellot, J.-P. Faure, and D. Hicks, “Differential tumor necrosis factor expression by resident retinal cells from experimental uveitis-susceptible and -resistant rat strains,” Journal of Neuroimmunology, vol. 55, no. 1, pp. 1–9, 1994.

A. D. Dick, J. V. Forrester, J. Liversidge, and A. P. Cope, “The role of tumour necrosis factor (TNF-α) in experimental autoimmune uveoretinitis (EAU),” Progress in Retinal and Eye Research, vol. 23, no. 6, pp. 617–637, 2004.

S. Nakamura, T. Yamakawa, M. Sugita et al., “The role of tumor necrosis factor-alpha in the induction of experimental autoimmune uveoretinitis in mice,” Investigative Ophthalmology & Visual Science, vol. 35, no. 11, pp. 3884–3889, 1994.

T. K. Khera, A. D. Dick, and L. B. Nicholson, “Mechanisms of TNFalpha regulation in uveitis: focus on RNA-binding proteins,” Progress in Retinal and Eye Research, vol. 29, no. 6, pp. 610–621, 2010.

E. Giraudo, L. Primo, E. Audero et al., “Tumor necrosis factor-α regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells,” The Journal of Biological Chemistry, vol. 273, no. 34, pp. 22128–22135, 1998.

M. Santos Lacomba, C. Marcos Martín, J. M. Gallardo Galera et al., “Aqueous humor and serum tumor necrosis factor-α in clinical uveitis,” Ophthalmic Research, vol. 33, no. 5, pp. 251–255, 2001.

L. L. Lim, F. W. Fraunfelder, and J. T. Rosenbaum, “Do tumor necrosis factor inhibitors cause uveitis? A registry-based study,” Arthritis & Rheumatology, vol. 56, no. 10, pp. 3248–3252, 2007.

D. Wendling and C. Prati, “Paradoxical effects of anti-TNF-alpha agents in inflammatory diseases,” Expert Review of Clinical Immunology, vol. 10, no. 1, pp. 159–169, 2014.

M. Diaz-Llopis, S. García-Delpech, D. Salom et al., “High-dose infliximab prophylaxis in endotoxin-induced uveitis,” Journal of Ocular Pharmacology and Therapeutics, vol. 23, no. 4, pp. 343–350, 2007.

Z. Li, W. Choi, H.-J. Oh, and K. C. Yoon, “Effectiveness of topical infliximab in a mouse model of experimental dry eye,” Cornea, vol. 31, no. 11, pp. S25–S31, 2012.

G. Ferrari, F. Bignami, C. Giacomini, S. Franchini, and P. Rama, “Safety and efficacy of topical infliximab in a mouse model of ocular surface scarring,” Investigative Ophthalmology & Visual Science, vol. 54, no. 3, pp. 1680–1688, 2013.

G. Levy-Clarke, D. A. Jabs, R. W. Read, J. T. Rosenbaum, A. Vitale, and R. N. Van Gelder, “Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders,” Ophthalmology, vol. 121, no. 3, pp. 785.e3–796.e3, 2014.

M. Cordero-Coma, T. Yilmaz, and S. Onal, “Systematic review of anti-tumor necrosis factor-alpha therapy for treatment of immune-mediated uveitis,” Ocular Immunology and Inflammation, vol. 21, no. 1, pp. 19–27, 2013.

E. B. Suhler, J. R. Smith, T. R. Giles et al., “Infliximab therapy for refractory uveitis: 2-year results of a prospective trial,” JAMA Ophtalmology, vol. 127, no. 6, pp. 819–822, 2009.

E. B. Suhler, J. R. Smith, M. S. Wertheim et al., “A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes,” JAMA Ophtalmology, vol. 123, no. 7, pp. 903–912, 2005.

M. Farvardin, M. Afarid, M. Mehryar, and H. Hosseini, “Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis,” Retina, vol. 30, no. 9, pp. 1530–1535, 2010.

M. Giganti, P. M. Beer, N. Lemanski, C. Hartman, J. Schartman, and N. Falk, “Adverse events after intravitreal infliximab (Remicade),” Retina, vol. 30, no. 1, pp. 71–80, 2010.

L. Arias, J. M. Caminal, M. B. Badia, M. J. Rubio, J. Catala, and O. Pujol, “Intravitreal infliximab in patients with macular degeneration who are nonresponders to antivascular endothelial growth factor therapy,” Retina, vol. 30, no. 10, pp. 1601–1608, 2010.

L. Wu, E. Hernandez-Bogantes, J. A. Roca, J. F. Arevalo, K. Barraza, and A. F. Lasave, “Intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: A pilot study from the Pan-American collaborative retina study group,” Retina, vol. 31, no. 2, pp. 298–303, 2011.

G. J. Jaffe, A. D. Dick, A. P. Brézin et al., “Adalimumab in patients with active noninfectious uveitis,” The New England Journal of Medicine, vol. 375, no. 10, pp. 932–943, 2016.

Q. D. Nguyen, P. T. Merrill, G. J. Jaffe et al., “Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial,” The Lancet, vol. 388, no. 10050, pp. 1183–1192, 2016.

E. B. Suhler, A. Adán, A. P. Brézin et al., “Safety and Efficacy of Adalimumab in Patients with Noninfectious Uveitis in an Ongoing Open-Label Study: VISUAL III,” Ophthalmology, vol. 125, no. 7, pp. 1075–1087, 2018.

B. Raffeiner, F. Ometto, L. Bernardi, C. Botsios, and L. Punzi, “Inefficacy or paradoxical effect? Uveitis in ankylosing spondylitis treated with etanercept,” Case Reports in Medicine, vol. 2014, Article ID 471319, 4 pages, 2014.

A. Migliore, E. Bizzi, M. Bernardi, A. Picchianti Diamanti, B. Laganà, and L. Petrella, “Indirect comparison between subcutaneous biologic agents in ankylosing spondylitis,” Clinical Drug Investigation, vol. 35, no. 1, pp. 23–29, 2015.

A. Galor, V. L. Perez, J. P. Hammel, and C. Y. Lowder, “Differential Effectiveness of Etanercept and Infliximab in the Treatment of Ocular Inflammation,” Ophthalmology, vol. 113, no. 12, pp. 2317–2323, 2006.

J. Sieper, R. Landewé, M. Rudwaleit et al., “Effect of Certolizumab Pegol Over Ninety-Six Weeks in Patients With Axial Spondyloarthritis: Results from a Phase III Randomized Trial,” Arthritis & Rheumatology, vol. 67, no. 3, pp. 668–677, 2015.

V. Llorenç, M. Mesquida, M. Sainz de la Maza et al., “Certolizumab Pegol, a New Anti-TNF-α in the Armamentarium against Ocular Inflammation,” Ocular Immunology and Inflammation, pp. 1–6, 2016.

M. Rudwaleit, J. T. Rosenbaum, R. Landewé et al., “Observed Incidence of Uveitis Following Certolizumab Pegol Treatment in Patients With Axial Spondyloarthritis,” Arthritis Care & Research, vol. 68, no. 6, pp. 838–844, 2016.

M. Cordero-Coma, V. Calvo-Rio, A. Adan et al., “Golimumab as rescue therapy for refractory immune-mediated uveitis: a three-center experience,” Mediators of Inflammation, vol. 2014, Article ID 717598, 5 pages, 2014.

E. Miserocchi, G. Modorati, I. Pontikaki, P. L. Meroni, and V. Gerloni, “Golimumab treatment for complicated uveitis,” Clinical and Experimental Rheumatology, vol. 31, no. 2, pp. 320-321, 2013.

E. Miserocchi, G. Modorati, I. Pontikaki, P. L. Meroni, and V. Gerloni, “Long-term treatment with golimumab for severe uveitis,” Ocular Immunology and Inflammation, vol. 22, no. 2, pp. 90–95, 2014.

A. D. Dick, I. Tugal-Tutkun, S. Foster et al., “Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials,” Ophthalmology, vol. 120, no. 4, pp. 777–787, 2013.

P. Lin, E. B. Suhler, and J. T. Rosenbaum, “The future of uveitis treatment,” Ophthalmology, vol. 121, no. 1, pp. 365–376, 2014.

W. P. Maksymowych, D. V. Heijde, X. Baraliakos et al., “Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients,” Rheumatology, 2018.

P. Mease, S. Hall, O. FitzGerald et al., “Tofacitinib or adalimumab versus placebo for psoriatic arthritis,” The New England Journal of Medicine, vol. 377, no. 16, pp. 1537–1550, 2017.

D. Gladman, W. Rigby, V. F. Azevedo et al., “Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors,” The New England Journal of Medicine, vol. 377, no. 16, pp. 1525–1536, 2017.

J.-F. Huang, R. Yafawi, M. Zhang et al., “Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease,” Ophthalmology, vol. 119, no. 7, pp. e43–e50, 2012.