Anti-TNF vs tocilizumab in refractory uveitic cystoid macular edema due to Behcet's disease. Multicenter study of 49 patients.

OBJECTIVE: To compare the efficacy of TNF inhibitors (adalimumab (ADA) and infliximab (IFX)) vs tocilizumab (TCZ) in patients with refractory cystoid macular edema (CME) due to Behçet's disease (BD). METHODS: Multicenter study of patients with BD-associated CME refractory to conventional and/or biological immunosuppressive drugs. From a cohort of 177 patients treated with anti-TNF and 14 patients treated with TCZ, we selected those with CME at baseline. We analyzed the evolution of macular thickness (main outcome), best-corrected visual acuity (BCVA) and intraocular inflammation (Tyndall and vitritis) from baseline up to 4 years in the 3 groups mentioned. RESULTS: 49 patients and 72 eyes with CME were included. ADA was used in 25 patients (40 eyes), IFX in 15 (21 eyes) and TCZ in 9 (11 eyes). No statistically significant baseline differences were observed between the 3 groups except for a lower basal BCVA in TCZ group and a higher basal degree of intraocular inflammation in ADA group. Most patients from all groups had received several conventional immunosuppressive drugs. In addition, most patients in the group of TCZ had also received anti-TNF agents. Biological therapy was used in monotherapy (n=8) or combined with conventional immunosuppressive drugs (n=41). Macular thickness progressively decreased in the 3 groups, with no signs of CME after 1 year of treatment. Similarly, BCVA improvement and inflammatory intraocular remission was achieved in all groups. CONCLUSION: Refractory CME associated with BD uveitis can be effectively treated either with ADA, IFX or TCZ. Furthermore, TCZ is effective in patients resistant to anti-TNF therapy.

Atypical herpes zoster ophthalmicus with madarosis of upper eyelid, recurrent iridocyclitis and atrophic multifocal chorioretinopathy.

INTRODUCTION: Ocular involvement due to varicella-zoster virus (VZV) infection includes conjunctivitis, scleritis, keratitis, uveitis, and necrotizing retinitis. Non-necrotizing chorioretinopathy as a late manifestation has been described. CASE REPORT: A 50-year-old immunocompetent man developed herpes zoster ophthalmicus (HZO) in the right V1 dermatome with acute anterior uveitis (AAU) treated with oral valaciclovir and topical steroid and a chalazion in the upper eyelid with associated madarosis. Four months later, he presented recurrence of the AAU and multiple areas of chorioretinal atrophy on fundoscopy. Biopsy of the upper eyelid lesion revealed granulomatous inflammation of the eyelid margin and polymerase chain reaction study (PCR) tested positive for VZV-specific DNA. The iridocyclitis was resolved with oral valaciclovir at maximum doses with minimal choroidal pigmentary changes. DISCUSSION: VZV ophthalmic infection starts by reactivation from the trigeminal ganglion, and it spreads to the isthmus of the pilosebaceous follicles and the epidermis, which can cause involvement of follicle and sebaceous glands. Chorioretinopathy is a rare form of late-onset non-necrotizing herpetic uveitis characterized by atrophic-appearing hypopigmented lesions, the pathogenesis of which is unknown. A direct viral infection or secondary to occlusive choroidal vasculitis is postulated at the level of the choriocapillaris and more recently it has been referred to as "choroidal vitiligo" due to possible involvement of choroidal melanocytes, as occurs in cases of cutaneous vitiligo due to VZV infection.

Fungal Necrotizing Scleritis After Intravitreal Injection Therapy.

PURPOSE: To report a case of infectious necrotizing scleritis secondary to Aspergillus terreus after intravitreal injection therapy. METHODS: This is a case report with literature review. RESULTS: A 98-year-old woman receiving intravitreal aflibercept injections for neovascular age-related macular degeneration in the left eye presented with severe pain, redness, and purulent discharge at the injection site. She was initially treated with topical fortified antibiotics, and clinical improvement was achieved, although microbial cultures showed negative results. Two months later, she presented with severe ocular pain and was diagnosed with anterior necrotizing scleritis. Scleral scrapings were collected for cultures, and intensive topical antibiotic therapy was reintroduced. Evaluation for autoimmune etiology and microbiological testing showed negative results. Because of the progression of the scleral necrotic area, empirical therapy with topical voriconazole was initiated, and surgical debridement was performed. Finally, the culture was positive for A. terreus. The modified therapy consisted of topical voriconazole and oral voriconazole for 3 months with an excellent clinical outcome. CONCLUSIONS: To our knowledge, this is the first case of fungal necrotizing scleritis secondary to intravitreal injection. Diagnosis was delayed due to its chronic clinical course and the slow fungal growth in culture media, but the combined medical and surgical approach resulted in a satisfactory outcome.

Choroidal lymphoma diagnosed by polymerase chain reaction-based clonality assessment.

PURPOSE: To report a case of primary choroidal lymphoma that was confirmed by polymerase chain reaction-based clonality testing. CASE REPORT: A 50-year-old woman presented with unilateral progressive vision loss. Fundus examination and B-ultrasonography demonstrated diffuse choroidal thickening without vitritis. Pars plana vitrectomy and subretinal biopsy were performed, and histopathologic analysis revealed choroidal B-cell lymphoid hyperplasia without evidence of neoplasia. Extraocular extension was ruled out, and transitory improvement was observed with oral steroids. After 1-year follow-up, she was referred to our hospital and clonality testing was performed using the samples taken months before. First, we used a forensic DNA extraction kit, and then, a multiplex polymerase chain reaction was carried out using the IgH Rearrangements Molecular Analysis Kit. Clonal rearrangement was identified for the immunoglobulin heavy chain framework regions 1 and 2, and B-cell choroidal lymphoma was confirmed. The patient began treatment with intravitreal rituximab, but no response was observed. Finally, complete regression was achieved using external beam radiotherapy. CONCLUSION: Polymerase chain reaction-based clonality testing can be a valuable tool to confirm a choroidal lymphoproliferative process.

Adalimumab in Elderly Patients with Non-Infectious Uveitis. Safety and Efficacy.

Purpose: To assess the efficacy and safety of adalimumab in elderly patients with noninfectious uveitis (NIU).Methods: An observational, retrospective, multicenter study was done. Changes in best-corrected visual acuity (BCVA), inflammatory activity parameters, central retinal thickness (CRT), and the occurrence of adverse events (AE) developed during follow-up were recorded.Results: A total of 82 eyes from 41 patients 60 years of age and older with noninfectious uveitis treated with adalimumab were included. A significant improvement in BCVA (71.5 to 75.4 letters, p = .001) and in CRT (311.1 µm to 265 µm, p = .001) was observed. Moreover, a significant decrease from baseline in the rate of patients with anterior chamber cell (ACC) >0+ (34.6% to 5.7%, p = <0.001) or vitreous haze>0+ (21.3% to 4.3%, p = .002) was determined. AEs were observed in 11 patients (26.8%).Conclusion: Adalimumab can be safe and efficacious for the treatment of NIU in patients 60 years of age and older.

Biologic therapy in severe and refractory peripheral ulcerative keratitis (PUK). Multicenter study of 34 patients.

PURPOSE: We assessed the efficacy and safety of biologic therapy in severe and refractory Peripheral Ulcerative Keratitis (PUK). DESIGN: Open-label multicenter study of biologic-treated patients with severe PUK refractory to conventional immunosuppressive drugs. SUBJECTS: We studied 34 patients (44 affected eyes) (24 women/10 men; mean age, 55.26±17.4 years). PUK was associated with a well-defined condition in 29 of them (rheumatoid arthritis [n = 20], psoriatic arthritis [n = 2], inflammatory bowel disease [n = 2], Behçet disease [n = 1], granulomatosis with polyangiitis [n = 1], microscopic polyangiitis [n = 1], systemic lupus erythematosus [n = 1] and axial spondyloarthritis [n = 1]). Besides topical and oral systemic glucocorticoids, patients had received: methylprednisolone pulses [n = 9], and conventional immunosuppressive drugs, mainly methotrexate [n = 18], and leflunomide [n = 7]. Eleven patients had required ocular surgery prior to biologic therapy. METHODS: Following biologic therapy, baseline main outcomes were compared with those found at 1st week, 1st and 6th months and 1st year. MAIN OUTCOME MEASURES: Efficacy and safety of biologic therapy. Efficacy was analyzed by the assessment of corneal inflammation (corneal thinning, central keratolysis and ocular perforation); other causes of ocular surface inflammation (scleritis, episcleritis); intraocular inflammation (uveitis); visual acuity and glucocorticoid sparing effect. RESULTS: The first biologic agents used were anti-TNFα drugs (n = 25); adalimumab (n = 16), infliximab (n = 8), etanercept (n = 1), and non-TNFα agents (n = 9); rituximab (n = 7), tocilizumab (n = 1) belimumab (n = 1) and abatacept (n = 1). During the follow-up, switching to a second biologic agent was required in 12 of the 25 (48%) patients treated with anti-TNFα drugs. However, no switching was required in those undergoing biologic therapy different from anti-TNFα agents. The main outcome variables showed a rapid and maintained improvement after a mean follow-up of 23.7 ± 20 months. Major adverse effects were tachyphylaxis, relapsing respiratory infections, supraventricular tachycardia, pulmonary tuberculosis and death, one each. CONCLUSIONS: Biologic therapy is effective and relatively safe in patients with severe and refractory PUK. Non-anti-TNFα agents appear to be effective in these patients.

Anti-IL6-Receptor Tocilizumab in Refractory and Noninfectious Uveitic Cystoid Macular Edema: Multicenter Study of 25 Patients.

PURPOSE: Cystoid macular edema (CME) is a leading cause of blindness. This study assessed the efficacy and safety of tocilizumab (TCZ) in refractory CME. DESIGN: Retrospective case series. METHODS: Patients with CME secondary to noninfectious uveitis who had inadequate response to corticosteroids and at least 1 conventional immunosuppressive drug, and in most cases to other biological agents, were studied. CME was defined as central retinal thickness greater than 300 µm. The primary outcome measure was macular thickness. Intraocular inflammation, best-corrected visual acuity (BCVA), and corticosteroid-sparing effect were also analyzed. RESULTS: A total of 25 patients (mean ± standard deviation age 33.6 ± 18.9 years; 17 women) with CME were assessed. Underlying diseases associated with uveitis-related CME are juvenile idiopathic arthritis (n = 9), Behçet disease (n = 7), birdshot retinochoroidopathy (n = 4), idiopathic (n = 4), and sarcoidosis (n = 1). The ocular patterns were panuveitis (n = 9), anterior uveitis (n = 7), posterior uveitis (n = 5), and intermediate uveitis (n = 4). Most patients had CME in both eyes (n = 24). TCZ was used in monotherapy (n = 11) or combined with conventional immunosuppressive drugs. Regardless of the underlying disease, compared to baseline, a statistically significant improvement in macular thickness (415.7 ± 177.2 vs 259.1 ± 499.5 µm; P = .00009) and BCVA (0.39 ± 0.31 vs 0.54 ± 0.33; P = .0002) was obtained, allowing us to reduce the daily dose of prednisone (15.9 ± 13.6 mg/day vs 3.1 ± 2.3 mg/day; P = .002) after 12 months of therapy. Remission was achieved in 14 patients. Only minor side effects were observed after a mean follow-up of 12.7 ± 8.34 months. CONCLUSION: Macular thickness is reduced following administration of TCZ in refractory uveitis-related CME.

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

Anti-interleukin 6 receptor tocilizumab in refractory uveitis associated with Behçet's disease: multicentre retrospective study.

Objective: To assess the efficacy of tocilizumab (TCZ) in refractory uveitis of Behçet's disease (BD). Methods: Multicentre study of patients with BD-associated uveitis. Patients were refractory to conventional and biologic immunosuppressive drugs. The main outcome measures were intraocular inflammation, macular thickness, visual acuity and corticosteroid-sparing effects. Results: We studied 11 patients (7 men) (20 affected eyes); median age 35 years. Uveitis was bilateral in nine patients. The patterns of ocular involvement were panuveitis (n = 8, with retinal vasculitis in 4), anterior uveitis (n = 2) and posterior uveitis (n = 1). Cystoid macular oedema was present in seven patients. The clinical course was recurrent (n = 7) or chronic (n = 4). Before TCZ, patients had received systemic corticosteroids, conventional immunosuppressants and the following biologic agents: adalimumab (n = 8), infliximab (n = 4), canakimumab (n = 1), golimumab (n = 3), etanercept (n = 1). TCZ was used as monotherapy or combined with conventional immunosuppressants at 8 mg/kg/i.v./4 weeks (n = 10) or 162 mg/s.c./week (n = 1). At TCZ onset the following extraocular manifestations were present: oral and/or genital ulcers (n = 7), arthritis (n = 4), folliculitis/pseudofolliculitis (n = 4), erythema nodosum (n = 2), livedo reticularis (n = 1) and neurological involvement (n = 2). TCZ yielded rapid and maintained improvement in all ocular parameters of the patients, with complete remission in eight of them. However, this was not the case for the extraocular manifestations, since TCZ was only effective in three of them. After a mean (s.d.) follow-up of 9.5 (8.05) months, TCZ was withdrawn in two cases, due to a severe infusion reaction and arthritis impairment, respectively. Conclusion: TCZ could be a therapeutic option in patients with BD and refractory uveitis.

Surgical Management of a Patient with Anterior Megalophthalmos, Lens Subluxation, and a High Risk of Retinal Detachment.

The early development of lens opacities and lens subluxation are the most common causes of vision loss in patients with anterior megalophthalmos (AM). Cataract surgery in such patients is challenging, however, because of anatomical abnormalities. Intraocular lens dislocation is the most common postoperative complication. Patients with AM also seem to be affected by a type of vitreoretinopathy that predisposes them to retinal detachment. We here present the case of a 36-year-old man with bilateral AM misdiagnosed as simple megalocornea. He had a history of amaurosis in the right eye due to retinal detachment. He presented with vision loss in the left eye due to lens subluxation. Following the removal of the subluxated lens, it was deemed necessary to perform a vitrectomy in order to prevent retinal detachment. Seven months after surgery, an Artisan® Aphakia iris-claw lens was implanted in the anterior chamber. Fifteen months of follow-up data are provided.

The effect of biologic therapy different from infliximab or adalimumab in patients with refractory uveitis due to Behçet's disease: results of a multicentre open-label study.

OBJECTIVES: To assess the efficacy of other biologic therapies, different from infliximab (IFX) and adalimumab (ADA), in patients with Behçet's disease uveitis (BU). METHODS: Multicenter study of 124 patients with BU refractory to at least one standard immunosuppressive agent that required IFX or ADA therapy. Patients who had to be switched to another biologic agent due to inefficacy or intolerance to IFX or ADA or patient's decision were assessed. The main outcome measures were the degree of anterior and posterior chamber inflammation and macular thickness. RESULTS: Seven (5.6%) of 124 cases (4 women/3 men; mean age, 43 (range 28- 67) years; 12 affected eyes) were studied. Five of them had been initially treated with ADA and 2 with IFX. The other biologic agents used were golimumab (n=4), tocilizumab (n=2) and rituximab (n=1). The ocular pattern was panuveitis (n=4) or posterior uveitis (n=3). Uveitis was bilateral in 5 patients (71.4%). At baseline, anterior chamber and vitreous inflammation were present in 6 (50%) and 7 (58.3%) of the eyes. All the patients (12 eyes) had macular thickening (OCT>250µm) and 4 of them (7 eyes), cystoid macular edema (OCT>300 µm). Besides reduction anterior chamber and vitreous inflammation, we observed a reduction of OCT values, from 330.4±58.5 µm at the onset of the biological agent to 273±50 µm at month 12 (p=0.06). Six patients achieved a complete remission of uveitis. CONCLUSIONS: The vast majority of patients with BU refractory to standard immunosuppressive drugs are successfully controlled with ADA and/or IFX. Other biologic agents appear to be also useful.

Anti-TNF-α therapy in patients with refractory uveitis due to Behçet's disease: a 1-year follow-up study of 124 patients.

OBJECTIVE: The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behçet's disease (BD). METHODS: We performed a multicentre study of 124 patients with BD uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load. RESULTS: Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening [optical coherence tomography (OCT) >250 µm] and 35 (49 eyes) had cystoid macular oedema (OCT>300 µm) that improved from 420 µm (s.d. 119.5) at baseline to 271 µm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases. CONCLUSION: Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.

Preoperative factors influencing success in pterygium surgery.

BACKGROUND: To identify preoperative, perioperative and postoperative risk factors that influence the success of pterygium surgery. METHODS: This is a prospective study of thirty-six patients with primary or recurrent pterygia. A detailed anamnesis and an ophthalmological examination were performed looking for the following factors: age, race, latitude and altitude of the main place of residence, hours of exposure to the sun, use of protective measures against UV-radiation, classification of pterygium, width of the pterygium at limbus, surgical technique (conjunctival autograft plus suturing versus tissue glue), graft alterations (misapposition, granuloma, haemorrhage, oedema, retraction or necrosis), and postoperative symptoms (foreign-body sensation, pain). The examinations were performed 2 and 7 days and 2, 6 and 12 months after surgery. In addition, recurrence was defined as any growth of conjunctiva into the cornea. RESULTS: A logistic regression and a survival analysis have been used to perform data analysis. A total number of 36 patients completed a one year follow-up. A total of 13 patients were born and lived in Spain, and 26 came from other countries, mostly Latin America. A total number of 8 males (no women) presented a recurrence, mainly between 2 and 6 months. The hours of sun exposure through their life was independently related to surgical success. Pterygia of less than 5 mm of base width showed a weak positive correlation with recurrence. None of the other factors considered were significantly related to recurrence. CONCLUSIONS: Male gender and high sun exposure are strongly and independently related to surgical success after the removal of pterygia.

Studying hypertension in ocular fundus images using Hausdorff dispersion ordering.

Retinal arterial and vein diameters are altered in individuals at risk of cardiovascular events mainly due to high blood pressure. The measurement of retinal vessel diameters has been proved to reflect individuals' vascular health. Dispersion of such measures which are obtained by means of ocular fundus images is a major factor not usually considered in clinical research. In this paper, a method to evaluate if different levels of clinically relevant covariables induce greater dispersion in retinal arterial and vein diameters is proposed. A multivariate dispersion ordering, the Hausdorff dispersion order, is used to compare the level of dispersion in such diameters for different groups of patients. Our statistical conclusions show that dispersion is higher in individuals with long-standing hypertension and in those who need two or more drugs to control hypertension. Hereby, dispersion is increased in the most severely ill persons. However, a greater level of smoking seems to be associated with a lesser dispersion. Dispersion of the vessel diameters must be taken into account in the image analysis of retinal vessel diameters because the comparison between homogeneous groups will produce highly accurate results in medical research.