Ralph D. Levinson

Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease

OBJECTIVE To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. METHODS Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. RESULTS Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. CONCLUSION TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis.

The Tubulointerstitial Nephritis and Uveitis Syndrome

The worlds medical literature on tubulointerstitial nephritis and uveitis (TINU) syndrome was reviewed, and data on 133 patients with TINU syndrome were identified. The median age of onset was 15 years (range 9-74 years) with a 3:1 female-to-male predominance. Common laboratory abnormalities included elevated Westergren erythrocyte sedimentation rates and elevated urinary beta-2-microglobulin levels. Ocular symptoms preceded systemic symptoms in 21% of cases, and followed systemic symptoms by up to 14 months in 65% of cases. Uveitis involved only the anterior segment in 80% of cases. Uveitis was bilateral at presentation in 77% of cases. Patients were treated with systemic corticosteroids in 80% of cases and with immunosuppressive drugs in 9% of cases. Uveitis recurred or followed a chronic course in 56% of patients and persisted for several years in some cases. Ocular complications (including posterior synechiae, cataracts, and elevated intraocular pressure) were reported in 21% of cases. The visual prognosis appears to be good. Persistent renal dysfunction was reported in 11% of cases, including five patients who required renal dialysis. TINU syndrome is a distinct clinical entity that may be under-recognized and may account for some cases of unexplained chronic or recurrent uveitis. It is important for ophthalmologists, nephrologists, and primary care providers to be familiar with this disorder to ensure early diagnosis and appropriate treatment.

Mesenchymal Stem Cell Population Derived from Human Pluripotent Stem Cells Displays Potent Immunomodulatory and Therapeutic Properties

Mesenchymal stem cells (MSCs) are being tested in a wide range of human diseases; however, loss of potency and inconsistent quality severely limit their use. To overcome these issues, we have utilized a developmental precursor called the hemangioblast as an intermediate cell type in the derivation of a highly potent and replenishable population of MSCs from human embryonic stem cells (hESCs). This method circumvents the need for labor-intensive hand-picking, scraping, and sorting that other hESC-MSC derivation methods require. Moreover, unlike previous reports on hESC-MSCs, we have systematically evaluated their immunomodulatory properties and in vivo potency. As expected, they dynamically secrete a range of bioactive factors, display enzymatic activity, and suppress T-cell proliferation that is induced by either allogeneic cells or mitogenic stimuli. However, they also display unique immunophenotypic properties, as well as a smaller size and >30,000-fold proliferative capacity than bone marrow-derived MSCs. In addition, this is the first report which demonstrates that hESC-MSCs can inhibit CD83 up-regulation and IL-12p70 secretion from dendritic cells and enhance regulatory T-cell populations induced by interleukin 2 (IL-2). This is also the first report which shows that hESC-MSCs have therapeutic efficacy in two different autoimmune disorder models, including a marked increase in survival of lupus-prone mice and a reduction of symptoms in an autoimmune model of uveitis. Our data suggest that this novel and therapeutically active population of MSCs could overcome many of the obstacles that plague the use of MSCs in regenerative medicine and serve as a scalable alternative to current MSC sources.

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals.

Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR–HLA gene combinations in disease. Here, we characterized KIR–HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29. KIR–HLA pairs implicated for weak inhibition (KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4T80) in combination with activating KIR genes associated with autoimmunity (KIR2DS2, 2DS3 and 2DS4) augment the risk of developing BCR in HLA-A*29-positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA-Bw4I80 and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4I80 and KIR2DS1+HLA-C2) was observed in HLA-A*29-negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.

HLA-DRB1*0102 is associated with TINU syndrome and bilateral, sudden-onset anterior uveitis but not with interstitial nephritis alone

Background Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis. Previously, the authors had demonstrated a strong association of human leukocyte antigen (HLA) DRB1*0102 with TINU. Here, the authors performed HLA analysis on subjects with isolated bilateral sudden-onset uveitis (as in the TINU subtype) or with isolated tubulointerstitial nephritis (TIN). Methods Patients with sudden onset, anterior, bilateral uveitis not fulfilling a diagnosis of TINU were identified. Pathology reports were reviewed to identify subjects with biopsy-proven TIN. Molecular typing of the HLA-DRB1 gene was performed by the Luminex technology-based sequence-specific oligonucleotide (SSO) hybridisation method (One Lambda, Canoga Park, California). HLA-DRB1 allele frequencies were compared with normal published controls (http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi dbMHC Europe cohort) and the published TINU cohort (n=18). Results The authors included 28 subjects with uveitis and 14 with TIN. There was a significantly higher frequency of DRB1*0102 in the isolated uveitis cohort versus in normal controls (10.7% vs 0.6%, respectively, p<0.0001; RR 14.3 (6.9–29.8)). None of the nephritis patients showed this HLA subtype. Another association with HLA-DRB1*08 was seen in the isolated uveitis cohort with an allele frequency of 10.7% versus 2.7% in normal controls (p=0.0019; RR 4.0 (1.8–9.0)). In contrast, the HLA-DRB1*08 was not different from controls in the TINU cohort (allele frequency 2.8%, p=not significant). Conclusion The incidence of HLA-DRB1*0102 is increased in sudden-onset bilateral anterior uveitis, as seen in patients with TINU. The same allele does not appear to occur in increased frequency in patients with isolated TIN. HLA DRB1*0102 might predispose to this subset of uveitis.

Tubulointerstitial nephritis and uveitis syndrome.

Tubulointerstitial nephritis and uveitis (TINU) syndrome was first described 30 years ago. The syndrome is defined as the concurrence of acute interstitial nephritis (AIN) and uveitis without a known underlying systemic disease that can cause ocular and renal inflammation. As even the largest case series of TINU syndrome are retrospective with small numbers of patients and variable (and often short) follow-up, we still do not have a full understanding of the course of the uveitis. However, TINU syndrome is likely underrecognized, and in fact may be a relatively common cause of bilateral anterior uveitis of sudden onset, especially in younger patients. As such, it is important that ophthalmologists become more aware of the syndrome.

HLA-A29 and Birdshot Chorioretinopathy

Birdshot chorioretinopathy primarily affects patients of European descent. At least 96%, if not all patients, are HLA-A29 carriers. HLA-A*29:01 and HLA-A*29:02, the two main subtypes of HLA-A29, differ only by a single mutation. In the general population HLA-A*29:02 is most frequent in whites, while HLA-A*29:01 is more frequent in Asians. The differential distribution of HLA-A*29:01 and HLA-A*29:02 has been actively debated as an explanation for the selective development of the disease in patients of European descent, but is no longer a valid argument. Another factor, probably not HLA linked, is either protective in Asians and in Africans or, conversely, triggers an autoimmune reactivity that is possibly present in whites and absent in Asians and in Africans. HLA-A*29:02 transgenic mice in which a spontaneous posterior uveitis is observed after 6 months of age provide further evidence that the HLA-A29 molecule plays a role in the pathogenesis of the disease.

Birdshot retinochoroidopathy: immunopathogenesis, evaluation, and treatment

Birdshot retinochoroidopathy (BSR) is a bilateral posterior uveitis. A putative organ-specific autoimmune disease, it is strongly associated with the HLA-A29 allele, and understanding the immunopathogenesis of BSR is of great interest. The clinical features include minimal anterior uveitis, vitritis, retinal vasculitis, cystoid macular edema, and distinctive hypopigmented choroidal lesions. Findings on electrophysiology studies and angiography have implications for understanding the pathophysiology of the disease, and may be useful for following the course of BSR and the response to therapy in individual patients. The decision to initiate therapy can be difficult, but corticosteroids and immunosuppressive agents are often used.

Ischemic maculopathy in patients with acquired immunodeficiency syndrome

PURPOSE To describe the characteristics of ischemic maculopathy in patients with human immunodeficiency virus (HIV) infection, as a means of understanding this uncommon disorder more fully. METHODS This is a multicenter, retrospective review of clinical data available for five HIV-infected patients who were given the diagnosis of ischemic maculopathy. RESULTS All cases had been diagnosed on the basis of fluorescein angiograms obtained after patients complained of vision loss. Four of the five patients had bilateral macular disease. Visual acuity at presentation in the nine affected eyes ranged from 20/20 to count fingers. Vision loss was gradual in both eyes of one patient and was abrupt in onset in seven eyes. Each of the seven eyes with abrupt vision loss had opacification of the superficial retina and/or intraretinal hemorrhages near the fovea. Fluorescein angiography revealed enlargement of the foveal avascular zone and mild staining of the juxtafoveal vessels in affected eyes. Six eyes had active or clinically inactive cytomegalovirus retinitis at presentation, and a seventh eye developed cytomegalovirus retinitis 2 weeks later. All patients were receiving anticytomegalovirus drugs when they developed visual symptoms. Visual acuity remained stable in five eyes, became worse in two eyes, and improved in two eyes; final visual acuity ranged from 20/25 to count fingers. CONCLUSIONS Ischemic maculopathy may cause profound and permanent vision loss in HIV-infected individuals. Fluorescein angiography should be considered in all HIV-infected patients with unexplained loss of vision. The pathogenesis of ischemic maculopathy remains unknown.

Relationship of AcrySof acrylic and PhacoFlex silicone intraocular lenses to visual acuity and posterior capsule opacification

Purpose: To compare the changes in visual acuity and the development of posterior capsule opacification (PCO) with AcrySof® acrylic intraocular lenses (IOLs) (Alcon Laboratories) and second‐generation PhacoFlex® silicone IOLs (Allergan). Setting: Eye Associates of New Mexico and Southwest Colorado, Albuquerque, New Mexico, USA. Methods: Medical charts of patients having cataract extraction with implantation of an AcrySof MA30BA or MA60BM (MA30/60) or PhacoFlex SI‐30NB or SI‐40NB (SI‐30/40) IOL between January 1995 and June 1997 were abstracted. Analyzed were the changes in visual acuity and development of PCO 1 month postoperatively and at the last available ophthalmologist visit or the visit before neodymium:YAG (Nd:YAG) capsulotomy. Results: Patients with MA30/60 acrylic IOLs were significantly older, had a worse preoperative best corrected visual acuity (BCVA), and had more concomitant ocular diseases than those with SI‐30/40 silicone IOLs. The change in BCVA from preoperatively to 1 month postoperatively was equivalent in the 2 lens groups. The BCVA declined from 1 month postoperatively to the last recorded or pre‐Nd:YAG visit. This decline was greater in eyes with SI‐30/40 silicone IOLs than in those with MA30/60 acrylic IOLs. Although the decrease in BCVA between IOL types was not significantly different, eyes with a SI‐30/40 silicone IOL were significantly more likely to develop PCO and have Nd:YAG capsulotomy. Eyes developing PCO had a statistically significant decline in BCVA from 1 month postoperatively to the last/pre‐Nd:YAG visit. Conclusions: The MA30/60 acrylic lenses were associated with lower PCO and Nd:YAG capsulotomy rates than second‐generation SI‐30/40 silicone IOLs. Patients with MA30/60 IOLs also tended to have less of a decrease in visual acuity than patients with SI‐30/40 silicone lenses, probably as a result of the difference in PCO rates between groups.