Ana M. Suelves

Glaucoma and Uveitis

Despite its relative rarity, uveitis is the third leading cause of preventable blindness worldwide. Glaucoma associated with uveitis is one of the most serious complications of intraocular inflammation. We review in detail the epidemiology and pathogenesis of uveitic glaucoma and the safety and efficacy of the current medical and surgical treatment modalities.

Infliximab for the Treatment of Refractory Noninfectious Uveitis: A Study of 88 Patients with Long-term Follow-up

OBJECTIVE To establish the safety and efficacy of infliximab for the treatment of refractory noninfectious uveitis. DESIGN Retrospective, interventional, noncomparative cohort study. PARTICIPANTS Eighty-eight patients from a single-center private practice. METHODS Patients with chronic, recalcitrant uveitis treated with infliximab (Remicade; Janssen Biotech, Inc., Titusville, NJ) were identified through an electronic medical record database. All charts were reviewed for sex, diagnosis, location of inflammation, presence of vasculitis, prior immunomodulatory treatments, duration of infliximab treatment, dose received, secondary side effects, and other medications continued while receiving treatment with infliximab. MAIN OUTCOME MEASURES The primary outcome measures were the rate of remission, time to remission, relapse rate, failure rate, and patient tolerance. Additional analysis aimed to identity risk factors that would predict a higher success rate of infliximab to treat various types of noninfectious uveitis. RESULTS Of the 72 patients (81.8%) who achieved clinical remission while being treated with infliximab, 42 (58.3%) required additional immunomodulatory medications. At 7, 18.1, and 44.7 weeks, 25%, 50%, and 75% of patients, respectively, achieved clinical remission off all corticosteroids. Thirty-two patients (36.4%) experienced at least 1 side effect while on infliximab therapy, and 17 patients (19.3%) discontinued treatment secondary to 1 or more intolerable side effects. The most common adverse effects were skin rash (9.1%) and fatigue (8%). Factors associated with a higher chance to achieve clinical remission were nonidiopathic uveitis (P < 0.001), intermediate or panuveitis (P < 0.001), absence of vasculitis (P < 0.001), and a starting dose ≥5 mg/kg (P < 0.011). CONCLUSIONS Infliximab induces a high rate of complete clinical remission in recalcitrant uveitis and is well tolerated by most patients.

Neutrophil Collagenase, Gelatinase, and Myeloperoxidase in Tears of Patients with Stevens-Johnson Syndrome and Ocular Cicatricial Pemphigoid

OBJECTIVE To investigate the levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in tears of patients with Stevens-Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP). DESIGN Prospective, noninterventional cohort study. PARTICIPANTS Four SJS patients (7 eyes), 19 OCP patients (37 eyes), and 20 healthy controls who underwent phacoemulsification (40 eyes). METHODS Tear washes were collected from all patients and were analyzed for levels of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MPO, and TIMP-1 using multianalyte bead-based enzyme-linked immunosorbent assays. Total MMP activity was determined using a fluorometric assay. Correlation studies were performed between the various analytes within study groups. MAIN OUTCOME MEASURES Levels of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MPO, and TIMP-1 (in nanograms per microgram of protein) and total MMP activity (in relative fluorescent units per minute per microgram of protein) in tears; MMP-8-to-TIMP-1 ratio; MMP-9-to-TIMP-1 ratio; and the correlations between MMP-8 and MMP-9 and both MMP and MPO. RESULTS MMP-8, MMP-9, and MPO levels were elevated significantly in SJS and OCP tears (SJS>OCP) when compared with controls. The MMP activity was highest in SJS patients, whereas OCP patients and controls showed lower and similar activities. The TIMP-1 levels were decreased in SJS and OCP patients when compared with those in controls, with levels in OCP patients reaching significance. The MMP-8-to-TIMP-1 and MMP-9-to-TIMP-1 ratios were markedly elevated in SJS and OCP tears (SJS>OCP) when compared with those of controls. Across all study groups, MMP-9 levels correlated strongly with MMP-8 and MPO levels, and MMP-8 correlated with MPO, but it did not reach significance in SJS patients. There was no relationship between MMP-7 and MPO. CONCLUSIONS Because MMP-8 and MPO are produced by inflammatory cells, particularly neutrophils, the correlation data indicate that they may be the common source of elevated enzymes, including MMP-9, in SJS and OCP tears. Elevated MMP-to-TIMP ratios and MMP activity suggest an imbalance in tear MMP regulation that may explain the predisposition of these patients to demonstrate corneal melting and chronic complications associated with persistent inflammation. Myeloperoxidase in tears may be a sensitive and specific marker for the quantification of ocular inflammation.

Road to remission: a comprehensive review of therapy in uveitis

Introduction: Although uveitis remains the third leading cause of preventable blindness in the US, the care and management of patients with uveitis and ocular inflammatory disease sit poised to make evolutionary if not revolutionary changes in the years ahead. This review serves to highlight important advances in the pharmacologic options available for the treatment of uveitis and ocular inflammation. Areas covered: Advances in steroid therapy (both topical and extended delivery), updates in the clinical safety of systemic immune modulation, and the emerging therapies for uveitis and ocular inflammatory disease are some of the areas covered in this review. Expert opinion: Corticosteroids have been the mainstay in the care of patients with ocular inflammatory disorders for many years. Indeed, some physicians still use only steroids for treating inflamed eyes. However, the mission is remission of all corticosteroids in order to prevent the complications associated with long-term corticosteroid use. The goal is to achieve quiescence through aggressive use of corticosteroids to extinguish the fire and then move along to achieve steroid-free remission through immunosuppressant agents.

Serous macular detachment associated with dome-shaped macula and tilted disc.

Introduction: An entirely new type of staphyloma has been recently described as dome-shaped macula (DSM). It is characterized by an abnormal convex macular contour within the concavity of a posterior staphyloma. We found DSM associated with serous macular detachment (SMD) and tilted disc in two consecutive cases. Case Reports: Case 1: A 37-year-old female presented to our department because of sudden onset blurred vision in her right eye (OD). The best-corrected visual acuity (BCVA) was 0.5 in both eyes. Funduscopy evidenced bilateral tilted disc associated with posterior staphyloma. Optical coherence tomography (OCT) demonstrated a DSM with SMD in her OD. After 15 months of follow-up, BCVA of her OD remained stable with chronic SMD. Case 2: A 32-year-old female presented to our department because of blurred vision in her OD. The BCVA was 0.4 in the OD and 1.0 in the left eye (OS). Bilateral tilted disc and posterior staphyloma were evidenced in the funduscopy. OCT demonstrated a bilateral DSM with SMD in her OD. After 45 months of follow-up, two further episodes of transient SMD were observed in her OD and seven in her OS. The final BCVA was 0.63 in the OD and 0.8 in the OS. Discussion: SMD associated with tilted disc constitutes a potential cause of subretinal fluid accumulation in myopic patients. OCT is essential for the detection of both SMD and DSM.

Regulatory T Cells in Blood of Patients with Birdshot Retinochoroidopathy

Birdshot retinochoroidopathy (BSCR) is an autoimmune disorder whose pathogenesis has not been clearly elucidated. Experimental studies have shown that a specific human major histocompatibility complex allele (human leukocyte antigen [HLA]-A29) confers susceptibility to disease. The most favored pathogenic hypothesis proposes that self-peptides, associated with HLA-A29, may drive the positive selection of developing thymocytes, which are specific for particular autoantigens, located in the retina or choroid. Recently, there has been increasing attention toward regulatory T cells (Tregs) in the development of systemic autoimmune disorders, such as diabetes mellitus, rheumatoid arthritis, and systemic lupus erythematosus. Evidence suggests that Tregs exert effects on autoreactive T cells, which have escaped the tolerance-inducing mechanisms, as well as on antigen-presenting cells. We conducted a prospective, case-control study to assess the percentage of Tregs in the peripheral blood of patients with active BSCR. We chose to measure CD4 CD25 Foxp3 Treg cells because recent efforts have shown that natural Tregs specifically express the transcription factor Foxp3. Additionally, firm evidence has been provided for CD4 CD25 Foxp3 Tregs as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. The New England Institutional Review Board approved this study and a signed informed consent was obtained from all participants. Blood samples from 12 patients (age range, 30–70 years) with clinical suspicion of BSCR, HLA-A29 positive and history of untreated disease were included in the study. Blood from 5 healthy individuals with no evidence of ocular or autoimmune systemic disease were used as controls. The blood samples were collected from April 2010 to December 2011, labeled, and transported immediately to the Massachusetts General Hospital for analysis of peripheral blood leukocytes by flow cytometry. The biomarkers utilized to appropriately identify and purify activated Tregs included CD3, CD4, CD25, CD45, CD127, and Foxp3. A sequential gating method was used to analyze CD127 and FOXP3 data. First, a gate was placed around the population of events that are CD45 and low inside scatter and were labeled as lymphocytes. Cells that fell within the lymphocyte gate and were CD3 CD4 were labeled CD4 T cells. CD25 expression on the CD4 T-cell population was gated as follows: CD25high , CD25low , and CD25. FOXP3 expression on all 3 populations was analyzed and the percentage of FOXP3 positive versus negative was determined. Potential differences between groups were evaluated using a t-test analysis. Seven patients were later excluded from the analysis because of laboratory error whereby antibodies to identify Tregs were inadvertently not added to the specimen. Flow cytometric analysis revealed no difference in the percentage of Tregs (CD4 CD25 ) between active BSCR patients (n 5) and controls (n 5; 5.5 1 vs 5 1.17; P 0.05). However, the percentage of FOXP3 -positive cells among Tregs (CD4 CD25 ) was significantly lower in BSCR patients (86 3.5) compared with normal controls (100; P 0.05; Figs 1 and 2, available at http:// aaojournal.org). Our study further demonstrated that of the subpopulation of Tregs in peripheral blood of patients with BSCR, the percentage of CD4 CD25 Foxp3 Tregs was significantly lower in BSCR patients compared with controls, whereas there was no difference between CD4 CD25 Tregs in both groups. The role of Tregs cells has been previously studied in other ocular disorders. Nanke et al demonstrated that the levels of CD4 CD25 bright Tregs were significantly decreased in Behçet’s patients before an ocular attack. Unlike our study, they did not use Foxp3 as a marker to detect human Tregs. Additionally, Chen et al studied Tregs in Vogt-Kayanagi-Harada syndrome and found significantly decreased frequencies of CD4 CD25 Tregs and percentages of FOXP3 cells in these Treg cells in patients with active VogtKayanagi-Harada syndrome. Our pilot study showed for the first time that CD4 CD25 Foxp3 Tregs might be involved in the regulation of ocular self-tolerance in patients with BSCR. It also supports previous observations that dysfunctional Treg cells may predispose to an ocular attack. Further comprehension of the crucial role that induced Tregs play in preventing unwanted ocular immune responses is warranted to develop specific therapeutic strategies.

Profile of Local Interleukin Expression in a Cohort of Ocular Cicatricial Pemphigoid Patients

PURPOSE We investigated the expression of IL-1, IL-6, IL-12, IL-13, and IL-17 in the conjunctiva of patients with ocular cicatricial pemphigoid (OCP), also labeled as ocular mucous membrane pemphigoid (MMP). METHODS A retrospective case-control study was done on 5 biopsy-proven OCP subjects and 6 healthy volunteers. Conjunctival specimens were obtained, and the local expression of IL-1, IL-6, IL-12, IL-13, and IL-17 was studied by immunohistochemistry. Clinical and therapeutic features were collected during follow-up. RESULTS No remarkable IL-1, IL-6, IL-12, IL-13, or IL-17 expression was observed in normal conjunctival specimens. All OCP samples had remarkable amounts of IL-12 and IL-17 expression especially in the epithelium and stroma; there also was stromal overexpression of IL-6. The mean follow-up after the biopsy was 13 months (range 9-15 months). CONCLUSIONS Our results demonstrated, for the first time to our knowledge, a local overexpression of IL-6, IL-12, and IL-17 in conjunctiva of OCP compared to controls.

Doppler ultrasound and giant cell arteritis

Objective To evaluate the utility of ultrasound in aiding the diagnosis of giant cell arteritis (GCA), in monitoring the response to corticotherapy, and in detecting early relapses. Methods A pilot study, prospective, included 10 patients with suspected GCA. All patients underwent ultrasound examination of both temporal arteries before temporal artery biopsy (TAB), 3 weeks after starting treatment, and 3 months after diagnosis. For this study, the histological findings alone were used to define if patients were suffering from GCA. The findings on ultrasound were compared with the results of biopsy. The best place to perform TAB was observed by ultrasound. Results All patients with positive biopsy were detected with ultrasound. No false positives were observed on ultrasound. The results presented give a sensibility, specificity, and positive predictive value of 100% for the use of ultrasound in the diagnosis of GCA. Two relapses were detected early by ultrasound during the follow-up. Conclusions This pilot study suggests that eco-doppler may be a useful tool in diagnosis and clinic follow-up in patients with suspected GCA.

Anterior chamber intraocular lens implantation in patients with a history of chronic uveitis: five-year follow-up.

Purpose To compare the incidence of long‐term complications after cataract surgery with primary anterior chamber intraocular lens (AC IOL) implantation in uveitic patients and patients without a history of intraocular inflammation (control group). Setting Single‐center private practice. Design Retrospective clinical study. Methods The study comprised patients who between November 2005 and August 2010 had cataract extraction followed by AC IOL implantation because conventional placement was not possible. Outcome measures were the incidence of intraoperative and postoperative complications, preoperative corrected distance visual acuity (CDVA), and CDVA after 1 year. Results Of the 39 patients identified through electronic medical records, 17 (17 eyes) had a history of chronic uveitis and 22 (23 eyes) had no intraocular inflammatory disease. There were no significant differences in the incidence of intraoperative and postoperative complications between the 2 groups during follow‐up (range 12 to 68 months) (P=.702). Although uveitic eyes had a greater risk for epiretinal membrane formation, the incidence of uveitis flareups attributed to the IOL and deposits on IOL surfaces was comparable to that in the control group (P<.001). The CDVA improved significantly in both groups 1 year after surgery (P<.01 and P<.001, respectively). Conclusion In uveitic eyes with inadequate capsule support, AC IOL implantation restored visual function without a significant increase in long‐term postoperative complications compared with eyes that had no history of uveitis. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Long-term safety and visual outcomes of anterior chamber intraocular lens implantation in patients with a history of chronic uveitis

PURPOSE: To compare the visual outcomes and prevalence of long‐term complications in patients with quiescent uveitis after phacoemulsification with traditional in‐the‐bag intraocular lens (IOL) implantation versus primary or secondary anterior chamber (AC) IOL implantation due to inadequate capsule support. SETTING: Single‐center private practice. DESIGN: Retrospective observational cohort study. METHODS: Patients with quiescent uveitis who had cataract surgery with subsequent AC IOL implantation were identified through an electronic medical record database. They were age matched with patients with uveitis who had conventional placement of a posterior chamber (PC) IOL. The rate of postoperative complications and corrected distance visual acuity (CDVA) were reviewed preoperatively and 1, 3, and 6 months and 1, 2, 3, and 4 years postoperatively. RESULTS: The incidence of postoperative complications was not statistically different for any criterion except posterior capsule opacification development in the PC IOL cohort (relative risk, 0.071). The mean follow‐up was 36.11 months ± 17.3 (SD) in the AC IOL group and 53.72 ± 20.4 months in the PC IOL group. The mean preoperative CDVA was 1.49 ± 1.07 logMAR in the AC IOL group and 0.5 ± 0.26 logMAR in the PC IOL group. Both groups had a significant improvement in CDVA visual acuity 3 years postoperatively (P=.001 and P=.010 respectively). CONCLUSIONS: In uveitic eyes with inadequate capsule support, AC IOL implantation was safe and effective in providing satisfactory improved CDVA without a significant increase in long‐term complications compared with eyes that had PC IOL placement. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.