Hypotony and Anterior Uveitis following Dual Therapy with Nivolumab and Ipilimumab for Metastatic Melanoma: A Case Report.

Purpose: To describe a rare case of hypotony and anterior uveitis following dual therapy with nivolumab and ipilimumab for metastatic melanoma. Methods: Case report. Results: Here, we present the case of a 64-year-old man taking nivolumab and ipilimumab dual therapy for BRAF+ (v-raf murine sarcoma viral oncogene homolog B1) metastatic melanoma. After treatment for 3 months, he presented to the ophthalmology clinic with bilateral intraocular pressures of 1 mmHg, bilateral keratic precipitates, cataracts, posterior synechiae, and anterior chamber inflammation. He improved with topical medications and the cessation of immunotherapy. Conclusions: Immunotherapies are a novel class of chemotherapy that has increased in prevalence for the treatment of numerous malignancies. There are many rare complications from these medications that are sparsely reported. Knowledge of ocular hypotony as a potential consequence of nivolumab and ipilimumab is important, particularly as it may arise months after treatment initiation and necessitate immunotherapy cessation.

Best practices in scleroderma: an analysis of practice variability in SSc centres within the Canadian Scleroderma Research Group (CSRG).

OBJECTIVES: There is currently no consensus on best practice in systemic sclerosis (SSc). To determine if variability in treatment and investigations exists, practices among Canadian Sclerodermia Research Group (CSRG) centres were compared. METHODS: Prospective clinical and demographic data from adult SSc patients are collected annually from 15 CSRG treatment centres. Laboratory parameters, self-reported socio-demographic questionnaires, current and past medications and disease outcome measures are recorded. For centres with >50 patients enrolled, treatment practices were analysed to determine practice variability. RESULTS: Data from 640 of 938 patients within the CSRG database met inclusion criteria, where 87.3% were female, the mean ± SEM age was 55.3±0.5, 48.9% had limited SSc and 47.8% had diffuse SSc (and 3.3% uncharacterised). Some investigation and treatment practices were inconsistent among 6 centres including proportion receiving: PDE5 (phosphodiesterase type 5) inhibitors for Raynaud's phenomenon (p=0.036); cyclophosphamide (p=0.037) and azathioprine (p=0.037) for treatment of ILD; and current use of D-penicillamine, although uncommon, varied among sites. Annual echocardiograms and PFTs were frequently done and did not vary among sites but the rate of pulmonary arterial hypertension (PAH) was directly related to site size and this was not the case for other organ involvement. CONCLUSIONS: Despite routine tests within a database, site variation in SSc with respect to investigations and management among CSRG centres exists suggesting a need for a standardised approach to the investigation and treatment of SSc. One can speculate that larger centres are more export in detecting PAH.

The effect of connexin43 on the level of vascular endothelial growth factor in human retinal pigment epithelial cells.

BACKGROUND: Connexins (Cx) are the basic units of gap junctions and contribute to cellular integrity by promoting intercellular communication. Disruption of the retinal pigment epithelial monolayer may be an early event in the pathogenesis of age-related macular degeneration, a condition in which vascular endothelial growth factor (VEGF) is known to be of importance. This study was designed to assess the effect of connexin43 (Cx43) expression and gap junctional intercellular communication (GJIC) on the expression and secretion of VEGF from the retinal pigment epithelium under normal cell culture and oxidative stress conditions. METHODS: Stable cell lines of ARPE-19 were produced in which wild-type Cx43 was either over-expressed, down-regulated by targeted shRNA, or functionally inhibited by co-expression of a disease-linked dominant-negative mutant (G21R). Pharmacologic blockade of GJIC was accomplished with flufenamic acid. Oxidant challenge was performed with tert-butyl hydroperoxide (tBH). VEGF gene expression and secretion were assessed by real-time PCR and ELISA respectively. RESULTS: Over-expression of Cx43 in ARPE-19 cells reduced both gene expression and secretion of VEGF. Down-regulation of Cx43 increased gene expression and secretion of VEGF. Increased secretion of VEGF was also observed in ARPE-19 cells expressing a dominant-negative mutant of Cx43, and when GJIC was blocked. Over-expression of Cx43 reduced tBH-induced secretion of VEGF from ARPE-19 cells. CONCLUSIONS: These studies show that Cx43 protects against oxidative stress-induced VEGF secretion in ARPE-19 cells, and thus has important implications in understanding the pathogenesis of age-related macular degeneration.

Validating the use of a stereoscopic robotized teleophthalmic drone slit lamp.

OBJECTIVE: To validate the use of a mechanized remotely operated stereoscopic drone slit lamp (DSL) in assessing anterior segment pathology in ophthalmology patients compared with conventional slit lamp (CSL). METHODS: Patients were recruited from eye clinics at Hotel Dieu Hospital in Kingston, Ontario, Canada. Each patient was assessed by 2 examiners. Examiners consisted of ophthalmology residents and staff attendings. Each examiner assessed the anterior chamber (AC) depth, presence or absence of cells, and/or presence of flare of the patient first using the DSL, followed by CSL. Qualitative data were collected on the ability to assess corneal integrity, infiltrates, foreign bodies, epithelial defects, and conjunctival injection using the DSL. RESULTS: 48 eyes of 42 participants were examined using the DSL and CSL. No significant within-examiner differences in AC depth or cell were detected. There was substantial agreement between the DSL and CSL when assessing AC cell and flare (κ = 72.6 and κ = 60.4, respectively) and moderate agreement when assessing AC depth (κ = 42.5). The DSL compared with CSL had a sensitivity and specificity of 98.3% (95% confidence interval [CI] 94-100) and 100% (95% CI 98.7-100), respectively, for detecting AC cell. The DSL had sensitivity and specificity of 100% (95% CI 97.5-100) and 88.2% (95% CI 80.2-96.1), respectively, for detecting AC flare. CONCLUSIONS: There was substantial agreement between the DSL and CSL when assessing AC depth, cell, and flare. Sensitivity and specificity for assessing these findings ranged from 88.2% to 100%. This DSL provides excellent capability for examination of anterior segment pathology in live patients, performing similarly to a CSL.

Agreement with guidelines from a large database for management of systemic sclerosis: results from the Canadian Scleroderma Research Group.

OBJECTIVE: We determined congruence with published guidelines from the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trials and Research group, for systemic sclerosis (SSc) investigations and treatment practices within the Canadian Scleroderma Research Group (CSRG). METHODS: Investigations and medication use for SSc complications were obtained from records of patients with SSc in the CSRG to determine adherence to guidelines for patients enrolled before and after the guidelines were published. RESULTS: The CSRG database of 1253 patients had 992 patients with SSc enrolled before publication of the guidelines and 261 after. For pulmonary arterial hypertension (PAH) treatment, there were no differences in use before and after the guidelines, yet annual echocardiograms for PAH screening were done in 95% of patients enrolled before the guidelines and in only 86% of those enrolled after (p <0.0001), and fewer followup echocardiograms were done 1 year later in the latter group (88% vs 59%). No differences were found for the frequency of PAH-specific treatment; 60% had ever used calcium channel blockers for Raynaud's phenomenon, with no differences in the groups before and after the guidelines. But the use of phosphodiesterase type 5 inhibitors (which does not have guidelines) was increased in the after-guidelines group. Proton pump inhibitors were used in > 80% with gastroesophageal reflux disease before and after the guidelines. One-quarter with gastrointestinal symptoms were taking prokinetic drugs. For those with past SSc renal crisis, use of angiotensin-converting enzyme inhibitors was not different before and after the guidelines. For early diffuse SSc < 2 years, ever-use of methotrexate was similar (one-quarter of each group); and for symptomatic interstitial lung disease, 19% had ever used cyclophosphamide before the guidelines and 9% after (p = nonsignificant). CSRG practices were generally comparable to recently published guidelines; however, use of iloprost and bosentan was low for digital ulcers because these drugs are not approved for use in Canada. CONCLUSION: There did not seem to be an increase in adherence to recommendations once the guidelines were published. For many guidelines, 25% to 40% of patients who would qualify received the recommended treatment.

Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group.

OBJECTIVE: This study was performed to determine the prevalence of elevated C-reactive protein (CRP) levels and the significance of CRP in clinical parameters in systemic sclerosis (SSc; scleroderma) patients. METHODS: Canadian Scleroderma Research Group data were used. Statistical comparisons were made for CRP levels ≤8 mg/liter versus >8 mg/liter, early (≤3 years from first non-Raynaud's phenomenon symptom) versus late SSc, and diffuse cutaneous SSc (dcSSc) versus limited cutaneous SSc (lcSSc). A survival analysis was analyzed between patients with normal versus elevated CRP levels. RESULTS: A total of 1,043 patients (mean ± SD age 55.4 ± 12.1 years, mean ± SD disease duration of 11.0 ± 9.5 years) were analyzed; elevation of CRP level and erythrocyte sedimentation rate (ESR; >20 mm/hour) occurred in 25.7% and 38.2%, respectively. Mean ± SD baseline CRP level in dcSSc (11.98 ± 25.41 mg/liter) was higher than in lcSSc (8.15 ± 16.09 mg/liter; P = 0.016). SSc patients with an early disease duration had a higher mean ± SD CRP level (12.89 ± 28.13 mg/liter) than those with a late disease duration (8.60 ± 17.06 mg/liter; P = 0.041). Although not consistent in all subsets, CRP was significantly associated (P < 0.01) with ESR, modified Rodnan skin score (MRSS), worse pulmonary function parameters, disease activity, damage, and Health Assessment Questionnaire. CRP level seemed to normalize in many SSc patients over time. Total lung capacity <80% predicted, MRSS, and serum creatinine were predictors of elevated CRP levels in SSc (odds ratio [OR] 2.76 [95% confidence interval (95% CI) 1.73-4.40], P = 0.0001; OR 1.03 [95% CI 1.01-1.05], P = 0.005; and OR 1.005 [95% CI 1.001-1.010], P = 0.02, respectively). Survival for patients with elevated CRP levels was less than for patients with normal CRP levels (P = 0.001). CONCLUSION: CRP level is elevated in one-quarter of SSc patients, especially early disease. It is correlated with disease activity, severity, poor pulmonary function, and shorter survival.

Associations with digital ulcers in a large cohort of systemic sclerosis: results from the Canadian Scleroderma Research Group registry.

OBJECTIVE: Digital ulcers are a common complication of systemic sclerosis (SSc; scleroderma). Approximately half of SSc patients have had a digital ulcer, but information is lacking on whether digital ulcers are associated with patient demographics and clinical outcomes. We wanted to determine the associations between digital ulcers and other SSc vascular complications and organ involvement. METHODS: Data from the Canadian Scleroderma Research Group are collected annually on SSc patients, including presence, location, and number of digital ulcers; complications from digital ulcers; internal organ involvement; skin score; and laboratory results. Correlation coefficients, chi-square test, and logistic regression modeling were done to determine the associations of digital ulcers with other factors, including internal organ complications. RESULTS: A total of 938 patients were included; 86% were women, the mean age was 55 years, the mean disease duration was 13.6 years, and 50% had limited cutaneous SSc. Eight percent had a digital ulcer currently and 44% had a digital ulcer ever; 53.1% had digital pitting scars. Digital ulcers were associated with increased modified Rodnan skin score (P = 0.0001), hand and finger skin score (P = 0.0001), Health Assessment Questionnaire score (P = 0.0001) and disease duration (P = 0.001), younger age of SSc onset (P = 0.0001), interstitial lung disease (ILD; P = 0.0001), and topoisomerase I (Scl-70) antibodies (P = 0.0001) in limited and diffuse cutaneous SSc subsets. Digital ulcers were not associated with sex (P = 0.95), smoking (P = 0.9), pulmonary arterial hypertension (PAH; P = 0.35), and scleroderma renal crisis (SRC; P = 0.569). Digital ulcers were further associated with reduced diffusing capacity for carbon monoxide (DLCO; P = 0.0001) and esophageal involvement (P = 0.0001) in diffuse cutaneous SSc only. CONCLUSION: Digital ulcers are associated with worse disease, including skin and lung involvement, but are not associated with PAH and SRC. However, the low DLCO that is associated with SRC could represent ILD or microvasculopathy.