Cogan's syndrome.

Work originating in the 1940s led to the characterization of a rare, chronic inflammatory disorder with a unique predilection for the cornea and vestibuloauditory apparatus, now called Cogan's syndrome (CS) after the ophthalmologist who first described it. CS occurs primarily in young adults and typically presents with interstitial keratitis (IK) and Ménière's-like episodes developing within several months of each other. The inflammatory process may target other ocular sites, and the disease itself may be accompanied by aortitis or a Takayasu's-like or medium-sized vessel vasculitis. Morbidity in CS results from deafness and complications from cardiovascular disease. Most evidence suggests that the ocular and vestibuloauditory manifestations are not a consequence of vasculitis but rather mediated by other immunologic mechanisms, possibly organ-specific autoimmunity. The cornerstone of treatment in CS is corticosteroids, topically for IK and systemically for inner ear dysfunction. Early corticosteroid therapy appears to be critical for reversing hearing loss. Cochlear implants can partially restore auditory function and have been a salvation for patients who suffer from deafness as a result of permanent cochlear damage.

Methotrexate treatment for sarcoid-associated panuveitis.

OBJECTIVE: To determine the safety and efficacy of low-dose methotrexate (MTX) for sarcoid-associated panuveitis. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Twenty eyes from 11 patients were analyzed. Eight patients had sarcoidosis. Three patients were clinically suspected of sarcoidosis despite negative laboratory testing. All charts of patients with sarcoidosis and idiopathic uveitis seen by the Duke Uveitis Service from 1989 to 1997 were retrospectively reviewed. Those with sarcoid-associated or sarcoid-suspected panuveitis treated with MTX with a minimum of 6 months of follow-up were studied. INTERVENTION: Low-dose MTX was administered to patients weekly and patients were followed with serial ophthalmologic and medical examinations. MAIN OUTCOME MEASURES: Visual acuity, oral and topical corticosteroid requirements, anterior chamber inflammation, and ability to undergo successful cataract extraction were used to measure the efficacy of MTX therapy. RESULTS: After MTX treatment was initiated, 90% of eyes had preserved or improved visual acuity. Mean initial Snellen visual acuity was 20/62 and mean final acuity was 20/40 (P = 0.044). Of those patients initially requiring oral corticosteroids, the dosage was decreased in 100%, and they were completely discontinued in 86%. The mean initial oral corticosteroid dose was 26.6 mg and the mean final dose was 1.5 mg (P = 0.012). Topical corticosteroids were decreased in 63% of eyes. The mean initial use was once every 1.6 hours, and the mean final use was once every 3.9 hours (P = 0.001). Ninety-five percent of eyes had stabilized or decreased inflammation. The mean initial inflammation score was 1.2, and the mean final score was 0.5 (P = 0.007). Five of six eyes previously unable to have cataract extraction because of uncontrolled inflammation became quiet on MTX and underwent surgery. One hundred percent of these eyes had improved vision after surgery. Side effects were mild and transient or reversible. CONCLUSION: Low-dose MTX is an effective and safe adjunct to treat chronic sarcoid-associated panuveitis.

Uveitis in the southeastern United States.

PURPOSE: Previous epidemiologic studies of uveitis have focused on predominantly Caucasian populations, and none have been based in the Southeast. We analyzed the epidemiology of uveitis among a referral population with a high percentage of African Americans in the United States. METHODS: We evaluated demographic data from 385 consecutive patients referred to the Duke Uveitis Clinic. RESULTS: Of the 385 patients, 120 (31%) were African American and 258 (67%) Caucasian; 237 (62%) were female and 148 (38%) male. The most common diagnoses among the 385 patients were idiopathic panuveitis (64 patients [17%]), idiopathic anterior uveitis (47 patients [12%]), pars planitis (46 patients [12%]), sarcoidosis (44 patients [11%]), and toxoplasmosis (39 patients [10%]). These diagnoses were also the most common among the 120 African American patients: 33 patients (28%) had idiopathic panuveitis, 30 (25%) had sarcoidosis, 10 (8%) had idiopathic anterior uveitis, 8 (7%) had toxoplasmosis, and 6 (5%) had pars planitis. Among the 258 Caucasian patients, the most common diagnoses were pars planitis (39 patients [15%]), idiopathic anterior uveitis (37 patients [14%]), toxoplasmosis (30 patients [12%]), idiopathic panuveitis (28 patients [11%]), and multifocal choroiditis and panuveitis (MCP) (17 patients [7%]). Categorizing diagnoses of all 385 patients by anatomic location, panuveitis was most frequent (148 patients [38%]), followed by anterior uveitis (97 patients [25%]), posterior uveitis (93 patients [24%]), and intermediate uveitis (47 patients [12%]). CONCLUSIONS: The higher frequency of sarcoidosis and idiopathic panuveitis than previously reported is related to our larger African American population base. The racial composition of the Southeast does not, however, account for differences such as our higher percentage of MCP; it is possible that other genetic or environmental factors play a role in this region.

Arthritis syndromes associated with human T cell lymphotropic virus type I infection.

Arthritis syndromes occur associated with HTLV-I infection both in the presence and in the absence of clinical ATL, and polyarthritis may be the presenting manifestation of HTLV-I-associated ATL. In both clinical settings, HTLV-I-infected T cells home to affected joints, and tax-transgenic mouse studies have suggested a pathogenic role for the HTLV-I tax gene in inducing synovial cell proliferation in HAA. Understanding the pathogenesis of rheumatoid arthritis-like arthritis syndromes that occur in the setting of HTLV-I infection should also provide insights into understanding of cellular and molecular mechanisms of synovial cell proliferation in HTLV-I-negative rheumatoid arthritis.

Transcranial doppler sonography to monitor cerebral vasculitis.

We describe a patient with cerebral vasculitis treated with prednisone and cyclophosphamide and followed by serial transcranial Doppler sonography and arteriography. Proximal cerebral angiographic abnormalities correlated with transcranial Doppler abnormalities. The abnormalities gradually normalized with treatment and correlated with the findings of followup arteriography, which also showed improvement in the vascular morphology. Transcranial Doppler sonography is useful in following proximal cerebral vascular abnormalities in some cases of cerebral vasculitis.

Changing concepts in pathophysiology of the vasculitides.

Vasculitis is a clinicopathologic process that involves inflammation and necrosis of blood vessels, resulting in a wide range of clinical diseases. The pathogenesis of vasculitis has been attributed to immunologic mechanisms, including immune complexes, cellular immunity, and humoral immunity, with numerous inciting events such as infection, drugs, malignancy, or toxins. Inflammatory cytokine production and adhesion molecule activation or upregulation are important determinants of the pathogenic inflammatory responses noted in vasculitis. Endothelial cells may be targeted by anti-endothelial cell antibodies and are central targets of numerous proinflammatory cytokines in vasculitis pathogenesis. Finally, antineutrophil cytoplasmic antibodies (ANCA) and T-cell responses to the protein targets of ANCA may play a role in vessel damage in ANCA-associated vasculitis.

Analysis of corneal and conjunctival microenvironments using monoclonal antibodies.

PURPOSE: The authors phenotypically compared epithelial and nonepithelial components of human corneal and conjunctival microenvironments using a panel of monoclonal antibody reagents that included markers of epithelial cell maturation, markers of mesodermal-derived fibrous tissue and vessels, markers of specific keratins, and markers of major histocompatibility complex Class I and II antigens. METHODS: Corneoscleral rims obtained after trephination of the donor button for use in penetrating keratoplasty procedures were studied. RESULTS: A comparison of cornea and conjunctiva with anti-epithelial and antikeratin antibodies demonstrated that corneal and conjunctival keratinocytes undergo similar antigenically defined pathways of maturation. However, the reactivity of antibody 12/1-2 (antibody against low molecular weight keratins) with conjunctival but not corneal basal cells suggested differences in keratin expression between the two epithelial types. Using antibodies against major histocompatibility complex Class I and II antigens, it was demonstrated the two tissues were similar with Class I determinants found on all epithelial, stromal, and endothelial cells, and Class II determinants found on Langerhans' cells, vessels, and a subset of stromal cells. CONCLUSIONS: The availability of tissue-specific markers of epithelial and nonepithelial components of the cornea and conjunctiva should be of use in the study of the roles the ocular microenvironment might play in the pathogenesis of ocular inflammatory diseases.

Cyclosporin A therapy for Wegener's granulomatosis.

Five patients with active Wegener's granulomatosis were treated with the immunosuppressive agent Cyclosporin A, along with low dose prednisone. All five patients had previously taken cyclophosphamide, but further treatment with this agent was not desired, either due to patient choice, drug toxicity or malignancy. In initial doses of up to 5mg/kg/day, CyA showed efficacy but when lowered to 1-2mg/kg/day, mild disease flares occurred. CyA may provide an alternative to traditional therapy in selected patients with WG.

Oral health and oral health behaviour in a population of diabetic outpatient clinic attenders.

The control of oral health in individuals suffering from diabetes mellitus may affect a diabetic individual's insulin requirements. This study examined the oral health status and behaviours of a group of diabetic patients and compared the results to those obtained in a recent UK national survey of oral health. The results showed that, despite reporting higher levels of oral self-care, the diabetic population suffered from higher rates of caries than "normal" individuals. These differences could not be accounted for by the treatment received from dentists. It is concluded that diabetic patients are more caries prone than the general population and that the cause of this difference should be sought, as the traditional aetiological agent for caries cannot account for the increased caries rate. If the aetiology of the findings of this study were determined, progress could be made in the search for indicators of increased caries risk.

Measurement of an adhesion molecule as an indicator of inflammatory disease activity. Up-regulation of the receptor for hyaluronate (CD44) in rheumatoid arthritis.

The hyaluronate receptor (CD44) molecule is a multifunctional cell surface protein involved in T cell activation, monocyte cytokine release, fibroblast locomotion, and lymphocyte binding to high endothelial venules. To study the roles CD44 molecules play in inflammatory synovitis, we measured expression of CD44 in inflamed and noninflamed synovial fluid and tissue, using indirect immunofluorescence assays on tissue sections and quantitative Western blot analysis. The ability of purified CD44 protein to modulate T cell responses was tested in T cell activation assays in which CD44-containing liposomes were added in vitro. CD44 was widely expressed on many synovial cell types, and synovial tissue from rheumatoid arthritis (RA) patients contained 3.5 times more CD44 than tissue from osteoarthritis patients and 10.7 times more than tissue from patients with joint trauma. The level of soluble CD44 in RA synovial fluid was elevated only in fluids with low cell counts (less than or equal to 7,000/mm3), and not in RA synovial fluid with higher cell counts. Soluble purified CD44 protein in liposomes partially suppressed T cell activation in vitro. These data demonstrate that CD44 is up-regulated on many synovial cell types in patients with RA, and that the level of CD44 present in synovial tissue is related to the degree of synovial inflammation. Determination of ways to inhibit the proinflammatory functions of immune cell membrane CD44 molecules may provide new therapeutic modalities for RA.

Anti-ligand antibodies as potential autoantigens: in vitro and in vivo characteristics of anti-bungarotoxin antibodies in the idiotype network.

Some antibodies to ligands of a receptor will have combining sites that structurally resemble the receptor's binding site for that ligand. The network hypothesis predicts that anti-idiotypic antibodies to these anti-ligand antibodies will also bind to the receptor. We pursued these hypotheses in the well-defined ligand-receptor system, alpha-bungarotoxin(BTX)-acetylcholine receptor (AChR). Monoclonal antibodies (mAbs) to BTX were generated; native BTX was used as the immunogen to optimize the probability of obtaining mAbs to the AChR binding site. These mAbs were then characterized for their ability to "mimic" AChR in the following in vitro assays: neutralization of BTX binding to native AChR on the surface of the cell line TE671, formation of a ternary complex with 125BTX-AChR, and ability of cholinergic ligands to interfere with binding to BTX. Three aBTX mAbs which had in vitro attributes of the AChR on the basis of these assays, were injected into C3H mice and serial sera tested for antibodies to Torpedo and murine AChR. Anti-AChR antibodies directed primarily to the gamma and delta subunits of the Torpedo AChR were detected, as well as low amounts of anti-mouse AChR antibody. The generation of anti-AChR antibodies by immunization with aBTX antibodies supports the network hypothesis and provides a theoretical basis for initiation of autoimmunity to cell receptors.

Effect of smoking in a controlled study of ranitidine treatment in gastroesophageal reflux disease.

Smoking has been shown to be a factor in acid peptic disease. A recent U.S. multicenter trial investigating use of ranitidine in the treatment of gastroesophageal reflux disease provided an opportunity to compare smokers and nonsmokers with regard to demographic features, manifestations of disease, and symptomatic response to treatment. A comparison of characteristics of smokers and nonsmokers revealed similar pretrial clinical findings. No significant differences between groups were found with regard to previous complications or recent symptoms of gastroesophageal reflux disease. There were also no significant differences in the way smokers and nonsmokers responded to treatment. Subjects on ranitidine, regardless of their smoking status, showed significantly greater improvement in heartburn symptoms and consumed less antacid than subjects who received placebo. Results of these analyses indicate that smoking as an independent variable was not related to symptomatic response or esophageal healing and that ranitidine was similarly effective in decreasing heartburn symptoms in smokers and nonsmokers.

Rheumatologic manifestations of cancer.

A variety of musculoskeletal syndromes have been described in association with malignancy. The majority of such descriptions have dealt with the connective tissue disorder as a paraneoplastic syndrome, frequently the presenting feature of an otherwise occult malignancy. This may range from the well known syndrome of HOA, heralding lung cancer, to a lesser known association of pyogenic arthritis due to an unusual enteric pathogen, signaling colon cancer. Conversely, the connective tissue disorder may precede the malignancy, and by virtue of its pathophysiology or its therapy, foster the subsequent development of cancer. Awareness of these associations may lead to earlier cancer detection, and hence, potentially more effective therapy.