In this document, markers of disease severity include the presence of worsening visual function, bilateral disease, vitreous opacity, macular or optic nerve disease, retinal vascular inflammation, MS, exudative detachment or vision-threatening structural complications, recurrent or chronic disease, and, in some cases, associated systemic disease.9

Elevated reactive aldehyde species (RASP) bolsters a series of proinflammatory reactions involved in different ocular inflammatory processes, including AU.10 This group of drugs includes reproxalap, a novel RASP inhibitor for treating a range of eye conditions such as non-infectious AU, allergic conjunctivitis, and dry eye; nevertheless, there is no experience using it in Spain and there is no supporting evidence of quality. It has therefore not been considered for inclusion in these recommendations.

What is the efficacy and safety of drug treatments available for patients with non-infectious, non-neoplastic anterior uveitis not associated with demyelinating disease?

AU is defined as an intraocular inflammatory process in which the inflammatory reaction is predominantly located in the anterior chamber (AC) of the eye.4 It is the most common anatomical subtype of uveitis in clinical practice. It has been estimated to account for 60% of all cases of uveitis in tertiary referral centres and up to 90% of all cases seen in primary centres.11 Different studies have reported prevalence figures for AU ranging from 54.5 to 81.7 per 100,000 people.12,13 By age group, UA is calculated to comprise 81% of all cases of uveitis in adults and 75% of all paediatric patients.13

Recommendation 1. Topical corticosteroids are recommended as the first treatment option in anterior uveitis, with prednisolone as first line treatment (strong recommendation in favour).

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  In patients with AU with concomitant ocular surface damage, the use of preservative-free and phosphate-free topical corticosteroids is recommended (GCP recommendation).

* In our setting, prednisolone or topical dexamethasone is used interchangeably as first-line treatment in cases of UA (GCP recommendation).

** Even though other corticosteroids, such as difluprednate and loteprednol, have proven to be efficacious and could represent an alternative to prednisolone in certain cases, they are not available for use in our context.

Recommendation 2. Despite the fact that with the evidence currently available it is not possible to make a recommendation for or against generalised treatment with non-steroidal anti-inflammatory drugs for anterior uveitis, the recommendations drafting group suggests that these drugs be used topically to spare corticosteroids and/ or to prevent flare-ups in specific cases of chronic anterior uveitis, such as Fuchs heterochromic uveitis, and as an adjunctive measure in the treatment of uveitic macular oedema. (GCP recommendation).

Nonsteroidal anti-inflammatory drugs (NSAIDs) have the potential of reducing the concomitant use of topical corticosteroids by decreasing the AEs associated with them. Nevertheless, the quality of the evidence identified in the systematic review (SR) is deemed to be low, consisting of old trials16,24,25 and no RCTs that assessed recently introduced NSAIDs could be located; consequently, the RDG zx does not conclude that, on the basis of this evidence, neither a strong nor a weak recommendation can be made to indicate the use of topical NSAIDs to treat the manifestations of UA, and that further well-designed, prospective, controlled studies are necessary. That said, clinical experience of use, as well as some very low quality non-RCTs outside the reviewed body of evidence,26–28 would point to the potential usefulness of the new topical NSAIDs as adjunctive therapy in the treatment of UA manifestations, such as associated MS, and therefore, a GCP recommendation is issued. Based on their own criteria, the RDG zx consider that situations of inequitable access to this group of treatments are unlikely to exist, and that NSAIDs are likely to be accepted by patients, regardless of the potential for more stinging compared to corticosteroids, given that it is a mild, short-lived AE. They do not see any major hurdles to the implementation of topical NSAIDs. In the case of bromfenac and nepafenac, which are not funded by the national health system (NHS), this prescription may not be accepted by some individuals on the basis of price, particularly if given over an intermediate period of time.

A detailed description of the evidence pondered and the process that has led from evidence to recommendations can be found in the Supplementary material (Appendix A Annex II).

Recommendation 3. In patients with recurrent anterior uveitis, especially if associated with spondyloarthritis, sulfasalazine is suggested (weak recommendation in favour).

Recommendation 4. The recommendations drafting group suggests that methotrexate be used as an alternative to sulphasalazine in cases of chronic or recurrent anterior uveitis (idiopathic, associated with spondyloarthritis or other systemic diseases) (GCP recommendation).

On the basis of their clinical experience and low quality evidence identified in the SR that indicates a possible beneficial effect on visual acuity and the risk of relapse, the ERG zx has issued a weak recommendation in favour of the use of sulfasalazine in patients with recurrent UA, with special emphasis on people with spondyloarthritis.29 In addition, based on their own criteria, it considers that sulfasalazine is a low-cost drug and that it will probably be well accepted by patients, inasmuch as it is an oral treatment with few, tolerable AEs in their clinical experience. As a result, they consider that there would be more equitable access to this immunomodulator and that there are no issues associated with its use. If an alternative were to be necessary, the RDG zx suggests the use of methotrexate, based on their experience, and has therefore established a GCP recommendation for this purpose.

A detailed description of the evidence examined and the process leading from evidence to recommendations can be found in the Supplementary material (Appendix A Annex II).

Recommendation 5. In patients with refractory or recurrent anterior uveitis, the use of adalimumab is recommended for those in whom conventional therapies have failed (weak recommendation in favour).

Recommendation 6. Other monoclonal antibodies inhibiting TNFα, such as certolizumab, golimumab, or infliximab, may also be used in cases of refractory or recurrent anterior uveitis (GCP recommendation).

Recommendation 7. The recommendations drafting group zx does not recommend etanercept or anti-IL17A drugs as treatment for anterior uveitis (GCP recommendation).

On this group of drugs, the SR identified only one RCT on adalimumab, which reports a risk-benefit balance that has been considered probably favourable to the intervention and whose quality of evidence on the effects is low.30 With this evidence in mind and based on their clinical experience, the RDG has issued a weak recommendation in favour of the use of adalimumab for UA. Based on low quality non-RCT studies identified by the RDG outside the reviewed body of evidence,31–34 and its own judgement and experience, two GCP recommendations have been issued, one in favour of the use of other TNFα inhibitor monoclonal antibodies, such as certolizumab, golimumab or infliximab, in refractory or recurrent UA, and one against the use of etanercept and anti-IL17A drugs for UA in general. The RDG considers that biosimilars are available for adalimumab at an affordable annual cost per patient. Access to the drug is unlikely to be a problem, even though it has no indication for idiopathic UA not associated with systemic disease, so off-label use must be requested. Administration may require access to a uveitis unit, which could affect equity for patients who do not have access to a uveitis unit or qualified specialists in their health centre. The RDG does not consider that there are overall barriers to the implementation of adalimumab therapy for the treatment of UA.

A detailed description of the evidence considered and the process that has led from evidence to recommendations can be found in the Supplementary material (Appendix A Annex II).

What are the efficacy and safety of pharmacological treatments in those individuals with non-anterior, non-infectious, non-neoplastic uveitis not accompanied by demyelinating disease?

Non-anterior, non-infectious, non-neoplastic, non-associated with demyelinating disease (NANIND) uveitis are likely to be of autoimmune origin and pose a significant threat to sight.35 They include IU, PU, and panuveitis. Prognosis is more serious in those that involve the posterior pole and can cause significant visual complications and even blindness, with the obvious loss of patients’ quality of life, in addition to the significant costs that this entails.36–38 They may be limited to the eye or occur as manifestations of underlying systemic diseases.39 Steroid treatment tends to be the initial approach in these patients40,41; however, other immunosuppressive treatments are often required to control the disease.42

Recommendation 8. In non-anterior, non-infectious, non-neoplastic uveitis not associated with demyelinating disease (NANIND), systemic corticosteroids are recommended to control acute inflammation, notably when there is a risk of vision loss and in cases of bilateral involvement (strong recommendation in favour).

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  The use of high-dose intravenous corticosteroids should be explored for severe, bilateral NANIND uveitis (GCP recommendation).

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  If systemic corticosteroids are initiated, titration to the lowest effective dose possible to control inflammation and, once achieved, a gradual tapering of the dose with close monitoring of both uveitis activity and possible adverse drug events is suggested (GCP recommendation).

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  Systemic corticosteroids can be evaluated as a preliminary therapy, or when commencing synthetic or biological immunomodulators if necessary, thanks to their rapid effect (GCP recommendation).

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  Periocular injections should be contemplated, particularly in acute, unilateral episodes of NANIND uveitis, using the injection method the specialist feels most comfortable with, depending on their experience (GCP recommendation).

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  In severe NANIND uveitis or uveitis refractory to periocular injections, the use of sustained-release corticosteroid implants is recommended, whether dexamethasone or fluocinolone acetonide, most notably in those cases in which the disease is limited to the eye and is unilateral (strong recommendation in favour).

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  In elderly patients or individuals who have other concomitant pathologies that make the use of conventional synthetic or biological immunomodulatory drugs inadvisable or contraindicated, sustained-release corticosteroid implants (dexamethasone and fluocinolone acetonide) should be weighed up (GCP recommendation).

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  Use of intravitreal corticosteroid injections other than implants is not advised, as safer and more effective alternatives are available (GCP recommendation).

Recommendation 9. In moderate or severe chronic non-anterior, non-infectious, non-neoplastic, not associated with demyelinating disease (NANIND) uveitis, the use of conventional synthetic immunomodulators is recommended for long-term control of inflammation and/ or as corticosteroid-sparing agents (strong recommendation in favour).

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  The conventional synthetic immunomodulators recommended are mycophenolate (mycophenolate mofetil and sodium), cyclosporine, methotrexate, tacrolimus, azathioprine, and cyclophosphamide, in this last case for individuals refractory to other treatments or if their indication depends on another type of extraocular condition (weak recommendation in favour).

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  There are no data to support the use of one conventional synthetic immunomodulator over another; the choice, therefore, will depend on each subject's characteristics, underlying systemic disease, tolerance to the drug, and on the experience with and availability of the drug (GCP recommendation).

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  The combination of conventional synthetic immunomodulators might be explored in cases in which adequate control is not achieved with monotherapy, as well as in association with biological immunomodulators (GCP recommendation).

Recommendation 10. TNF-α-inhibiting monoclonal antibodies, particularly adalimumab, are recommended for the treatment of severe or treatment-resistant NANIND uveitis (strong recommendation in favour).

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  Infliximab, golimumab, certolizumab, tocilizumab, and rituximab can serve as alternatives to adalimumab, if deemed necessary (GCP recommendation).

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  Etanercept is disadvised for NANIND uveitis management (GCP recommendation).

Recommendation 11. The RDG does not recommend secukinumab to treat NANIND uveitis (weak recommendation against).

Recommendation 12. In light of the lack of evidence regarding the intravitreal delivery route is not recommended in subjects with NANIND uveitis (GCP recommendation).

In individuals with uveitic macular oedema, how efficacious and how safe are drug treatments?

MO is an inflammatory process that causes fluid to accumulate in the area of the retina that is responsible for central vision, the macula.66 It is one of the leading causes of vision loss in uveitis. According to several studies, it accounts for 41% of vision loss and 29% of blindness in uveitis.67,68 UMO can appear in any type of uveitis, although it is more common in PU and IU than in anterior uveitis. Since the appearance and development of optical coherence tomography (OCT), with which macular oedema is quantified, its treatment has changed radically and is currently a priority to prevent vision loss in uveitis.

Recommendation 13. Systemic corticosteroids are advised for uveitic macular oedema and, if administered locally, periocular corticosteroids or dexamethasone or fluocinolone implants (strong recommendation in favour).

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  The use of intravitreal triamcinolone is not advocated, as it is not indicated and there are effective alternatives, such as dexamethasone and fluocinolone implants (weak recommendation against).

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  As for the methods of periocular injection, the method the specialist feels most confident in, depending on his or her own expertise, should be used, as no difference in efficacy and safety has been observed (GCP recommendation).

Recommendation 14. In patients with mild uveitic macular oedema, the use of acetazolamide is recommended as a therapeutic option for initial and short-term treatment (GCP recommendation).

The RDG has issued a good clinical practice recommendation for the use of acetazolamide in mild UMO based on their experience and the low quality of the evidence about its possible protection against VA impairment.79–81 Based on their own estimation, the RDG consider that there are unlikely to be concerns about the equality of the intervention, as the drug is widely available to any specialist and to patients. It also does not consider that there are likely to be acceptability issues with acetazolamide treatment, always bearing in mind that the patient must be evaluated comprehensively. Acetazolamide is available in Spain and used in many centres to treat UMO in clinical practice, so no barriers to its implementation are to be expected. Patients treated with acetazolamide should undergo a general work-up and associated pathologies (renal, ion) and the use of concomitant drugs should be considered. If use is prolonged, kidney function and ion parameters should be monitored by laboratory testing.

An in-depth description of the evidence considered and the process that has taken the evidence to recommendations can be found in the Supplemental material (Appendix A Annex II).

Recommendation 15. There is insufficient evidence to recommend methotrexate, mycophenolate, cyclosporin A, tacrolimus, or azathioprine for the treatment of uveitic macular oedema; however, they are indicated as a therapeutic option in treatment-resistant cases or as corticosteroid-sparing agents (GCP recommendation).

The evidence identified for methotrexate, mycophenolate, and cyclosporin A is scarce and of low or very low quality;52,82,83 nevertheless, based on their own criteria and experience, the RDG resolved to issue a GCP recommendation in favour of their use. Likewise, no evidence was found regarding the use of tacrolimus and azathioprine in cases of UMO; however, and on the basis of the RDG's judgement and expertise, these treatments are included in the recommendation in favour. Two RCTs of the drug sirolimus reported together in the same article58 were identified; nonetheless, inasmuch as it is not available in our setting, it was not judged relevant to issue a recommendation on its use. The RDG consider that some of the drugs reviewed, such as methotrexate, mycophenolate, cyclosporin A, tacrolimus, and azathioprine, which are used in routine clinical practice in cases in which oedema is accompanied by other inflammatory signs, is acceptable and feasible, despite the fact that some of them are not approved in the technical data sheet. Similarly, they also point out that the use of intravitreal sirolimus and cyclosporin G is not feasible at present, given that these medications are not commercially available. If systemic drugs such as methotrexate, mycophenolate, or cyclosporine are used, the RDG deem that an overall examination of the patient should be performed, taking into account concomitant conditions and pharmaceuticals, along with regular monitoring that includes blood tests (complete blood count, complete biochemistry) and urine tests to monitor side effects.

An in-depth description of the evidence considered and the process that has taken the evidence to recommendations can be found in the Supplemental material (Appendix A Annex II).

Recommendation 16. Non-steroidal anti-inflammatory drugs are suggested as one option for coadjuvant therapy in patients with mild uveitic macular oedema (GCP recommendation).

*While the evidence on the efficacy of topical indomethacin points toward some limited efficacy in resolving uveitic macular oedema, it is not available for use in our setting.

The SR of the literature identified very limited evidence on these drugs in subjects with UMO. Only one RCT evaluated topical indomethacin versus placebo,84 which is not available in Spain, but has issued a GCP recommendation regarding the use of NSAIDs in mild UMO based on its clinical experience in improving mild oedema. In addition, a study of intravitreal diclofenac was located, the quality of evidence for which was judged to be very low, and the RDG did not consider issuing a recommendation given that it is not used in routine clinical practice. The RDG, based on their own judgement, consider interventions with NSAIDs to be very accessible. There are unlikely to be acceptability issues with a topical treatment, but some clinicians and patients may be against an intravitreal injection, due to the higher risks involved and the need for a certain degree of experience to administer it. The NSAIDs reviewed in the localised literature are not available/ indicated in Spain. The NSAIDs used in routine clinical practice (nepafenac, bromfenac), although relatively low in cost, may present problems, since patients have to pay for them in full, increasing inequity in patients with lower economic capacity.

An in-depth description of the evidence considered and the process that has taken the evidence to recommendations can be found in the Supplemental material (Appendix A Annex II).

Recommendation 17. Intravitreal anti-VEGF drugs are advised for uveitic macular oedema when there is a contraindication to corticosteroids (GCP recommendation).

Recommendation 18. In patients with uveitic macular oedema, the use of TNFα-inhibiting monoclonal antibodies, and more specifically adalimumab, is suggested on the basis of good results in clinical practice (GCP recommendation).

Recommendation 19. The recommendations drafting group considers that the poor quality of the evidence available does not justify a recommendation for rituximab, sarilumab, or cytotoxic drugs in individuals with uveitic macular oedema (GCP recommendation).

If the uveitic macular oedema is refractary:

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  Tocilizumab is suggested, or interferon alfa may also be considered depending on the person’s experience with the drug, given the increased occurrence of adverse events and the difficulty in accessing the drug (GCP recommendation).

The evidence identified concerning this class of drugs exhibits low certainty. Based on two studies that have assessed intravitreal injection of bevacizumab versus the same route of administration of triamcinolone,72,73 a GCP recommendation has been issued in favour of the use of anti-VEGF agents to treat UMO, in particular when there is a contraindication to corticosteroids, or those forms of UMO in the context of uveitis whose activity is controlled. Taking into account the poor quality of the evidence and the risk-benefit balance of the comparisons between interventions identified in the SR, the RDG concludes that it is not possible to recommend either in favour or against the use of sarilumab,85 tocilizumab,86 rituximab, and combined cytotoxic therapy;87 but based on their own judgement, they suggest the use of tocilizumab for refractory UMO. The same is true for subcutaneous interferon alfa, which requires experience in its use and, in some cases, is also difficult to access. Moreover, based on the RDG's judgement and expertise, they have issued a GCP recommendation in favour of the use of adalimumab. Biologics may not be accessible to all specialists, depending on the hospital, and may reduce equality, inasmuch as they are not approved for UMO as per the technical specifications, in addition to being expensive. However, there would be no inequality for the patient if the treatment cost is covered by the hospital pharmacy. The RDG consider that there are likely to be no acceptability concerns regarding the treatments. As for the feasibility of implementation, the RDG believe that there may be some difficulty, given that these treatments are not approved on the technical specifications for UMO and, as such, authorisation from hospital management is required for their use. In the particular case of interferon alpha, access is highly restricted to certain hospitals and certain specialists, and could therefore present serious difficulties in its use.

An in-depth description of the evidence considered and the process that has taken the evidence to recommendations can be found in the Supplemental material (Appendix A Annex II).