Douglas A. Jabs

Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia.

Paraneoplastic pemphigus is a newly recognized disease that occurs in some patients with lymphoproliferative neoplasms and occasionally, solid tumors. Patients present with an acute illness of the mucosa and skin that shares clinical and histologic features with erythema multiforme, toxic epidermal necrolysis, and pemphigus vulgaris. These patients have antibodies against a complex of epithelial proteins that are present in desmosomes and hemidesmosomes. The course is usually fatal, except in some patients who undergo total resection of their neoplasm.

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

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.

Ocular Involvement in Chronic Sarcoidosis

Although spontaneous remissions often occur in sarcoidosis, chronic persistent disabling disease is also observed. Of a series of 183 patients with chronic sarcoidosis, 47 (26%) had ophthalmic involvement. In this series, chronic sarcoid was defined as disease for a minimum of five years. Patients were followed primarily for their systemic disease for a mean of 13 years. Uveitis developed in 35 patients (19%) and was an early manifestation in 32 (91%). The course of the ocular disease did not necessarily parallel that of the systemic disease. Despite the chronic nature of the underlying disease, the anterior uveitis did not pursue a chronic course in 15 of 33 patients (45%) and was generally characterized by a single episode at the onset of disease. Chronic uveitis and secondary glaucoma were poor prognostic signs, as eight of 11 patients with uveitis and glaucoma suffered severe visual loss.

Ocular Manifestations of Acquired Immune Deficiency Syndrome

The ocular complications of acquired immune deficiency syndrome (AIDS) include: (1) a noninfectious microangiopathy, most often seen in the retina, consisting of cotton-wool spots with or without intraretinal hemorrhages and other microvascular abnormalities; (2) opportunistic ocular infections, primarily cytomegalovirus (CMV) retinitis; (3) conjunctival, eyelid, or orbital involvement by those neoplasms seen in patients with AIDS (i.e., Kaposis sarcoma and lymphoma); and (4) neuro-ophthalmic lesions. In a series of 200 AIDS patients evaluated clinically, AIDS retinopathy was present in 66.5%. Sixty-four percent had cotton-wool spots, and 12% had intraretinal hemorrhages. Cytomegalovirus retinitis was diagnosed in 28% of AIDS patients. Neuro-ophthalmic lesions were found in 8% of all AIDS patients and were present in 33% of those patients with cryptococcal meningitis. Acquired immune deficiency syndrome retinopathy was present in 40% of 35 patients with the AIDS-related complex (ARC) and in 1.3% of 232 patients with asymptomatic human immunodeficiency virus (HIV) infection, evaluated photographically. These results suggest that the prevalence of AIDS retinopathy increases with increasing severity of HIV infection, and that CMV retinitis presents a significant vision-threatening problem in AIDS patients.

Episcleritis and scleritis: clinical features and treatment results.

PURPOSE To evaluate the clinical experience with episcleritis and scleritis at a tertiary care eye center. METHODS Retrospective chart review. RESULTS One hundred thirty-four patients with scleral inflammation were seen over a 12-year period. Thirty-seven patients had episcleritis, and 97 patients had scleritis. Ocular complications occurred in only 13.5% of patients with episcleritis but in 58.8% of patients with scleritis (P <.0001). No patient with episcleritis had a decrease in visual acuity, whereas 15.9% of patients with scleritis did. Only 16.7% of patients with episcleritis required more than topical corticosteroids for treatment, and these patients required oral nonsteroidal anti-inflammatory drugs. Conversely, 30.4% of patients with scleritis required nonsteroidal anti-inflammatory drugs, 31.9% oral prednisone, and 26.1% systemic immunosuppressive drugs (P <.0001). Necrotizing scleritis and posterior scleritis more often were associated with ocular complications, occurring in 91.7% and 85.7%, respectively, than were diffuse anterior scleritis and nodular anterior scleritis (P =.020). Patients with necrotizing scleritis and posterior scleritis were more likely to be treated with oral corticosteroids or immunosuppressive drugs (90% and 100%, respectively) than were patients with diffuse anterior scleritis and nodular anterior scleritis (56.4% and 21.4%, respectively, P =.002). CONCLUSIONS Scleritis is a severe ocular inflammation, often associated with ocular complications, and nearly always treated with systemic medications. Nearly 60% of these patients will need oral corticosteroids or immunosuppressive drugs to control the disease.

Gut Epithelial Barrier Dysfunction and Innate Immune Activation Predict Mortality in Treated HIV Infection

BACKGROUND While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear. METHODS We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4(+) T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency. RESULTS Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4(+) T-cell count (all P ≤ .001). A higher percentage of CD38(+)HLA-DR(+) cells in the CD8(+) T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4(+) T-cell count. Frequencies of senescent (defined as CD28(-)CD57(+) cells), exhausted (defined as PD1(+) cells), naive, and CMV-specific T cells did not predict mortality. CONCLUSIONS Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.

Expert Panel Recommendations for the Use of Anti–Tumor Necrosis Factor Biologic Agents in Patients with Ocular Inflammatory Disorders

TOPIC To provide recommendations for the use of anti-tumor necrosis factor α (TNF-α) biologic agents in patients with ocular inflammatory disorders. CLINICAL RELEVANCE Ocular inflammatory diseases remain a leading cause of vision loss worldwide. Anti-TNF-α agents are used widely in treatment of rheumatologic diseases. A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions. METHODS A systematic review of published studies was performed. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria. RESULTS Numerous studies including controlled clinical trials have demonstrated that anti-TNF-α biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the expert panel makes the following recommendations. CONCLUSIONS Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçets disease. Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.

Cytomegalovirus Retinitis and Viral Resistance: Ganciclovir Resistance

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with AIDS and a substantial cause of visual loss. With long-term therapy, resistant CMV may develop. In a prospective study of 108 patients with CMV retinitis, 80.6% of patients were found to have either a positive blood culture or positive urine culture for CMV at the diagnosis of retinitis. At diagnosis of retinitis, 0.9% and 2.7% of patients had a ganciclovir-resistant blood culture isolate and urine culture isolate, respectively. Of 76 patients initially treated with ganciclovir, 11.4% had a resistant blood or urine culture isolate by 6 months of treatment and 27.5% by 9 months. The development of ganciclovir resistance during follow-up correlated with the occurrence of CMV retinitis in the contralateral eye (odds ratio = 9.06, P = .003).

Treatment of Cytomegalovirus Retinitis with Ganciclovir

Eighteen immunocompromised patients with cytomegalovirus (CMV) retinitis were treated with ganciclovir, an investigational antiviral drug. CMV retinitis in association with acquired immune deficiency syndrome (AIDS) developed in 17 patients; CMV retinitis developed in one patient after cardiac transplantation. Fourteen patients responded to ganciclovir treatment with improvement in CMV retinitis. In 11 patients, the response was classified as complete; in three patients, the response was partial. Continued improvement in the retinitis was often seen while the patient was on maintenance treatment. Maintenance ganciclovir therapy was required; relapse occurred in five of seven patients in whom ganciclovir treatment was interrupted. The major limiting toxic side effect of ganciclovir was neutropenia, which necessitated temporary discontinuation of ganciclovir in five patients but was reversible in all cases. Ganciclovir appears to be an effective therapy for CMV retinitis, but chronic maintenance therapy is required.