Sana S. Siddique

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.

Systemic therapy with conventional and novel immunomodulatory agents for ocular inflammatory disease.

Ocular inflammatory disease is the third leading cause of blindness in the United States. In addition to the conventional immunomodulatory agents, which include antimetabolites, alkylating agents, and antibiotics such as cyclosporine, many of which have been used in the treatment of this disease for decades, several new treatment modalities have emerged within the past 10 years. We review in detail the characteristics, safety, and efficacy of the conventional immunomodulators, the more novel agents such as the biologics, and investigational drugs that appear promising in the treatment of ocular inflammatory disease.

Infliximab Treatment of Patients with Birdshot Retinochoroidopathy

PURPOSE To report the outcomes of infliximab treatment of birdshot retinochoroidopathy (BSRC) refractory to conventional immunomodulatory therapy. DESIGN Retrospective case series. PARTICIPANTS Twenty-two refractory birdshot retinochoroidopathy patients (44 eyes) who received infliximab between July 2005 and June 2012 were identified by retrospective chart review. METHODS All patients received 4 to 5 mg/kg infliximab at 4- to 8-week intervals. Data regarding patient demographics, use of immunosuppressive drugs, biologic agents, and reason for conventional therapy discontinuation were gathered. Disease activity markers, including signs of ocular inflammation, fluorescein angiography evidence of retinal vasculitis or papillitis, indocyanine green angiography evidence of active choroiditis, electroretinography parameters indicative of stable or worsening of retinal functions, and optical coherence tomography findings indicative of static or worsening macular edema were recorded. MAIN OUTCOME MEASURES Abolition of all evidence of active inflammation, visual acuity (VA), presence of cystoid macular edema at 6 months and 1 year, and adverse responses to infliximab. RESULTS Mean duration of disease before starting infliximab was 58.6 months. Before infliximab therapy, all patients received and failed conventional immunosuppressive therapy. Ten patients had received another biologic agent. After initiating infliximab, control of inflammation was achieved in 81.8% at 6 months and in 88.9% at the 1-year follow-up. Three patients had active inflammation during therapy. The rate of cystoid macular edema decreased from 22.7% at baseline to 13.9% at 6 months and 6.7% at 1 year after receiving the drug. Initial VA of 20/40 or better was found in 34 eyes (84.1%). At 6 months and 1 year, 91.7% and 94.4% of eyes, respectively, had VA of 20/40 or better. Six patients had adverse events; infliximab therapy was discontinued in these patients because of neuropathy, drug-induced lupus, allergic reaction, or fungal infection. CONCLUSIONS The data suggest that infliximab is effective for controlling inflammation in otherwise treatment-refractory cases of BSRC.

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.

Poor Documentation of Inflammatory Bowel Disease Quality Measures in Academic, Community, and Private Practice

BACKGROUND & AIMS Quality measures are used to standardize health care and monitor quality of care. In 2011, the American Gastroenterological Association established quality measures for inflammatory bowel disease (IBD), but there has been limited documentation of compliance from different practice settings. METHODS We reviewed charts from 367 consecutive patients with IBD seen at academic practices, 217 patients seen at community practices, and 199 patients seen at private practices for compliance with 8 outpatient measures. Records were assessed for IBD history, medications, comorbidities, and hospitalizations. We also determined the number of patient visits to gastroenterologists in the past year, whether patients had a primary care physician at the same institution, and whether they were seen by a specialist in IBD or in conjunction with a trainee, and reviewed physician demographics. A univariate and multivariate statistical analysis was performed to determine which factors were associated with compliance of all core measures. RESULTS Screening for tobacco abuse was the most frequently assessed core measure (89.6% of patients; n = 701 of 783), followed by location of IBD (80.3%; n = 629 of 783), and assessment for corticosteroid-sparing therapy (70.8%; n = 275 of 388). The least-frequently evaluated measures were pneumococcal immunization (16.7% of patients; n = 131 of 783), bone loss (25%; n = 126 of 505), and influenza immunization (28.7%; n = 225 of 783). Only 5.8% of patients (46 of 783) had all applicable core measures documented (24 in academic practice, none in clinical practice, and 22 in private practice). In the multivariate model, year of graduation from fellowship (odds ratio [OR], 2.184; 95% confidence interval [CI], 1.522-3.134; P < .001), year of graduation from medical school (OR, 0.500; 95% CI, 0.352-0.709; P < .001), and total number of comorbidities (OR, 1.089; 95% CI, 1.016-1.168; P = .016) were associated with compliance with all core measures. CONCLUSIONS We found poor documentation of IBD quality measures in academic, clinical, and private gastroenterology practices. Interventions are necessary to improve reporting of quality measures.

Cataract surgery in patients with history of uveitis

Cataract surgery in patients with uveitis is not as simple as any senile cataract surgery. Recent evidence suggests that useful visual outcome can be achieved in most of the cases if they are handled meticulously. Key factors leading to improved visual outcome are absolute control of preoperative inflammation with diligent use of immunomodulatory drugs, meticulous surgery along with early detection and care of postoperative complications. Modern technologies in the intraocular lens designs and materials have contributed to the success. In this article, we review the literature on this subject with emphasis on the importance of the use of immunomodulatory drugs to control preoperative and postoperative intraocular inflammation and avoid complications.

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.

Immunohistochemical differences between normal and chronically inflamed conjunctiva: diagnostic features.

Purpose:There is widespread misinterpretation of normal conjunctival fibrinogen. In differentiating between normal conjunctiva and cicatrizing conjunctivitis, including ocular cicatricial pemphigoid, atopic keratoconjunctivitis, and lichen planus, it is important to properly evaluate and characterize the histologic appearance of the structures seen and not base a diagnosis on just the presence or absence of certain features. One feature of conjunctival histology prone to misinterpretation and misdiagnosis is the presence of subepithelial fibrinogen, particularly when the diagnosis of lichen planus is being considered. Although the presence of subepithelial fibrinogen in oral mucous membranes and in skin can be indicative of lichen planus, such is not the case for conjunctiva. An erroneous diagnosis of lichen planus based on the presence of conjunctival subepithelial fibrinogen can initiate prolonged treatment with topical steroids leading to avoidable, blinding, complication, and further, delay therapy for the real cause of the conjunctivitis. We conducted a cross sectional, controlled, blinded and prospective Institutional Review Board–approved study on the occurrence and pattern of fibrinogen at the epithelial basement membrane zone (BMZ) of normal and inflamed conjunctiva. Methods:Bulbar conjunctiva was obtained from 10 cases of undiagnosed chronic conjunctivitis of at least 6 months duration and 8 patients with normal conjunctiva. Immunofluorescent staining with antifibrinogen antibodies, periodic acid-schiff stain (PAS), and Giemsa staining were performed. Results:BMZ fibrinogen was found in all cases. This layer was linear, smooth, and continuous in normal conjunctiva and 7 cases of chronic conjunctivitis. It was fragmented and lumpy in 1 case of ocular cicatricial pemphigoid (OCP) and showed spikes and spurs in 2 cases of lichen planus. Conclusions:BMZ fibrinogen is a normal component of the conjunctiva and its morphological features rather than its mere presence should be assessed as a diagnostic tool.

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.