The quality of the included articles was in general poor or moderate. We found 2 RCTs,[11,105] the rest were observational studies. Their mean study duration varied from 5 months to 20 years, and the number of AU patients from 9 to 274, in whom clinical characteristics were also very heterogeneous (see Table 1). In most cases, criteria to define the anatomic classification of uveitis and efficacy definitions were not clear. Besides, some of the studies only included AU patients with a systemic disease associated, basically SpA,[11,100,102,108,110] others mixed populations[101,104,106] and in some articles this data was not described (probably idiopathic AU patients).[99,103,105,107,109]
The number of AU flares before and after treatment was the most evaluated outcome along with AU activity and corticosteroids use. However, we found a great variability between studies in the type of outcomes and definitions.
In patients with idiopathic AU or associated systemic disease, most of them MTX and biologics naïve, MTX significantly decreased the number of AU flares and activity, and increased the time interval between flares (Tables 2 and 3). MTX doses in these patients ranged from 7.5 to 25 mg/wk and this effect was described in the short and long term. In the subgroup of patients taking systemic corticosteroids at baseline, the dose of these drugs was progressively tapered until discontinuation in many of them.[99,103] One study also depicted the same results regardless of HLA-B27 status (positive or negative). Reported AEs were the same as those previously described for MTX.
A 3-months RCT published in 1969 compared AZA (100 mg/d) with placebo in 16 patients with AU. The authors did not find differences in visual acuity, number of anterior chamber cells, AU flares, or intraocular pressure after 3 months of treatment. Another prospective study analyzed the effect of AZA in AU patients of whom 24% were refractory to other immunomodulators. AZA significantly improved ocular inflammation and decreased systemic corticosteroids doses. At 6 months and 1 year, 24% and 35% of patients, respectively, showed no ocular activity. AEs were the same as those usually registered for this drug.
We included 3 articles reporting the outcomes of adalimumab (ADA) in AU. All were observational studies in which the majority of participants were SpA-associated AU patients (up to 40% refractory to other anti-TNFα agents). In this population, ADA improved different outcomes, including the number of AU flares, ocular inflammation, and dose of corticosteroids. This effect remained in the long term.[101,108,109] One of these studies also showed that the rate of AU flares was reduced by 51% in all study patients, by 58% in 274 patients with a history of AU, by 68% in 106 patients with a recent history of AU, and by 50% in 28 patients with symptomatic AU at baseline. AU flares during ADA treatment in this work were predominantly mild. Expected AE were registered in all studies.
Two more reports analyzing GLM in patients with AU, refractory to immunomodulators including biologic therapies in many patients were included.[100,110] Both studies analyzed a total of 27 patients with SpA-associated AU. The first one depicted a significant improvement in visual acuity, number of UA flares, and need of systemic steroids during a mean follow-up of almost 1 year. On the other hand, 1 patient developed a malignant hypertension and stopped GLM. In the second one, most patients had rapid and progressive improvement in visual acuity and inflammatory parameters as well as in the steroid need. The number of AU flares also decreased but this difference was nonsignificant. In this study, 87% of patients also reached clinical remission after a median follow-up of 23 months.
We have performed an SLR to analyze the efficacy and safety of immunomodulators when used for treatment of adult patients with noninfectious and nonmalignant AU. To our knowledge, this is the first one specifically designed to analyze patients with AU.
Currently, there is a lack of robust evidence in clinical practice regarding the use of immunomodulators in these patients. Even with this limitation, there is some evidence supporting the use of MTX, SSZ, AZA, CsA, ADA, and GLM.
More specifically, as first line immunomodulators, but also in patients resistant to other immunosuppressive agents, MTX, SSZ, and CsA have shown effectiveness to prevent AU flares, improve visual acuity, and to decrease systemic steroids dose in the short and the long term (up to 3 years). These results have been described in patients with idiopathic AU and patients with an associated systemic disease. In the case of AZA, this drug could also be effective in improving ocular inflammation and in reducing systemic corticosteroids need, in patients who are naïve or refractory to other immunomodulators. This effect has been depicted in the short and long term as well. On the other hand, the evidence also supports the use of ADA and GLM, in different clinical aspects of AU (including refractory patients to other immunomodulators), as they have improved outcomes of interest including AU flares, degree of ocular inflammation, and the need for corticosteroids treatment. In addition, we have evidence of immunomodulators’ benefit in the short and the long term. Besides, the AEs reported did not differ from those reported when used these drugs for treatment of other immune-mediated conditions.
As commented before, regarding the study populations, the included studies analyzed patients with idiopathic AU and patients with an associated systemic disease in whom immunomodulators achieved a good response in many of them. In the case of patients with an associated systemic disease, most of them were SpA patients, especially AS, but the studies also included patients with other types of SpA like psoriatic arthritis. Moreover, 1 study found that MTX improved outcomes in both, HLA-B27 positive and negative patients. In this article, although the rate of flares decreased, all the observed flares occurred in the HLA-B27 positive patients.
The selection criteria of the immunomodulators were not described in detail. Classical immunomodulators were used as first-line agents in patients with inadequate response to topical treatments and/or systemic corticosteroids, but also in refractory patients to other immunomodulators, as depicted for anti-TNFα therapies. Doses and routes of administration were those recommended in the summary of products characteristics, and almost 100% of treatments with immunomodulatory drugs were used in monotherapy. Unfortunately there were no comparative studies between immunomodulators.
The main limitation of this SLR is the quality of the included studies that was quite poor in general, limiting the generalization of conclusions. This lack of robust evidence probably, at least in part, might have been solved in daily practice using the evidence and experience from other chronic immune-mediated diseases. Another of the main limitations of the SLR is the lack of proper standardization of the uveitis anatomic classification and definition of outcomes. Therefore, we excluded many articles that actually analyzed patients with AU but did not perform subanalysis of patients with AU. The same way comparisons between studies results were very complicated and a meta-analysis was not possible.
Interestingly, we did not include any article with other biologics like infliximab or tocilizumab. We found some reports during the selection process but eventually excluded them because they did not meet the inclusion criteria, mainly due to lack of subanalysis or due to the sample size of the studies. However, in the literature there are some case series suggesting that these drugs could be effective as those reported with ADA or GLM.[112–114] In the case of etanercept, observational reports have indicated lower effectiveness and some paradoxical occurrence of uveitis following treatment with this agent.
In summary, even with all the limitations exposed previously, immunomodulators could be effective in patients with noninfectious and nonmalignant AU in order to prevent flares and improve other ocular outcomes. However, more research is needed in order to properly define the role of each immunomodulator in this population.
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