Ibrutinib-Related Uveitis: A Case Series from Two Tertiary Centres in the United Kingdom.

PURPOSE: Ibrutinib is an irreversible Bruton's tyrosine kinase inhibitor that disrupts B-cell receptor signalling. It is licensed for treatment of low-grade B-cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma and lymphoplasmacytic lymphoma. A few case reports in the literature suggest that uveitis may be a side effect of ibrutinib treatment. A strong association between ibrutinib and uveitis is yet to be established in significant numbers. METHODS: The study is a retrospective case series, reporting cases of uveitis associated with ibrutinib from two tertiary centres in the United Kingdom: Liverpool University Hospitals NHS Foundation Trust and University Hospitals of Leicester NHS Trust. RESULTS: The study reports eight cases presenting over a four year period, with mean age of 66.8 years. Onset of uveitis was between 9 and 48 (median 14) months from commencing ibrutinib, categorising it as a Type D or delayed drug reaction. Cases included unilateral and bilateral; anterior, intermediate, posterior and panuveitis. There was an association with cystoid macular oedema or disc swelling. Severity varied from mild, to severe and vision threatening. Presenting visual acuity ranged from 6/9 to 6/60. In all eight cases, uveitis resolved after ibrutinib cessation. In two cases, reintroducing ibrutinib caused uveitis recurrence. CONCLUSION: Our case series provides evidence suggestive of a connection between ibrutinib and development of uveitis. Ibrutinib related uveitis appears to be more common than previously recognised. Ibrutinib cessation, if appropriate, appears to be the definitive management. Patients with ibrutinib-related uveitis benefit from multidisciplinary management involving communication between ophthalmologist and haemato-oncologist.

Lessons of the month 2: Retinal vasculitis: a first presentation of Takayasu's arteritis.

Takayasu's arteritis is a chronic, systemic, large-vessel vasculitis affecting the aorta and its primary branches. However, coronary, renal and pulmonary arteries and small vessel involvement has been documented. We describe a rare case of Takayasu's arteritis with extensive supra-aortic arch disease, manifesting with bilateral occlusive retinal vasculitis as a first presentation. This is elicited by fundus findings of vascular sheathing and fundus fluoresceine angiography evidence of retinal vessel occlusion and peripheral capillary non-perfusion.

Fatal insomnia: the elusive prion disease.

A previously well 54- year-old woman presented with a short history of diplopia, cognitive decline, hallucinations and hypersomnolence. The patient had progressive deterioration in short-term memory, ocular convergence spasm, tremor, myoclonus, gait apraxia, central fever, dream enactment and seizures. Results of investigations were normal including MRI brain, electroencephalogram, cerebrospinal fluid (CSF, including CSF prion protein markers) and brain biopsy. The patient died from pneumonia and pulmonary embolus. Brain postmortem analysis revealed neuropathological changes in keeping with Fatal familial insomnia (FFI); the diagnosis was confirmed on genetic testing. FFI is caused by an autosomal dominant and highly penetrant pathogenic Prion Protein gene PRNP Although usually familial, fatal insomnia (FI) also occurs in a rare sporadic form. FI is a rare human prion disease with prominent sleep disturbance, autonomic, motor, cognitive and behavioural involvement. Patient management is with best supportive care and early suspected diagnosis allows for timely palliation.

Evaluation of the systemic micro- and macrovasculature in stable angina: A case-control study.

AIMS: The diagnosis of stable angina involves the use of probability estimates based on clinical presentation, age, gender and cardiovascular risk factors. In view of the link between the cardiac and systemic vasculature we tested whether non-invasive measures of systemic micro- and macrovascular structure and function differentiate between individuals with flow-limiting coronary artery disease (CAD) and those with normal coronary arteries (NCA). METHODS AND RESULTS: We recruited 84 patients undergoing elective coronary angiography for investigation of symptoms of stable angina. Patients were selected for either having significant CAD or NCA (n = 43/41; age, 56±7 vs 57±7 years, P = 0.309). Only microvascular endothelial function, measured using the Endo-PAT2000 device to determine reactive hyperaemia index (CAD vs. NCA; 1.9 [1.5; 2.3] vs. 2.1 [1.8; 2.4], P = 0.03) and sonographic carotid plaque score (CAD vs. NCA; 3.0 [1.5; 4.5] vs. 1.2 [0; 2.55], P<0.001) were significantly different between patients with CAD and NCA. No significant differences were detected in reflection magnitude (CAD vs. NCA; 1.7 [1.5; 1.8] % vs 1.7 [1.5; 1.9] %, P = 0.342), pulse wave velocity (CAD vs. NCA; 7.8±1.4 m/sec vs. 8.3±1.5 m/sec, P = 0.186), carotid intima-media thickness (CAD vs. NCA; 0.73±0.10 mm vs. 0.75±0.10 mm, P = 0.518) or carotid distensibility (CAD vs. NCA; 3.8±1.2 10-3/kPa vs. 3.4±0.9 10-3/kPa, P = 0.092). Also, the c-statistic of the pre-test probability based on history and traditional risk factors (c = 0.665; 95% CI, 0.540-0.789) was improved by the addition of the inverse RHI (c = 0.720; 95% CI, 0.605-0.836), carotid plaque score (c = 0.770, 95% CI, 0.659-0.881), and of both markers in combination (c = 0.801; 95% CI, 0.701-0.900). CONCLUSION: There are distinct differences in the systemic vasculature between patients with CAD and NCA that may have the potential to guide diagnostic and therapeutic decisions. Carotid artery plaque burden and microvascular function appear to be most promising in this context.

Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes.

The aim of the present study was to determine whether the endothelial dysfunction associated with CAD (coronary artery disease) and T2D (Type 2 diabetes mellitus) is concomitant with elevated mtROS (mitochondrial reactive oxygen species) production in the endothelium and establish if this, in turn, regulates the activity of endothelial AMPK (AMP-activated protein kinase). We investigated endothelial function, mtROS production and AMPK activation in saphenous veins from patients with advanced CAD. Endothelium-dependent vasodilation was impaired in patients with CAD and T2D relative to those with CAD alone. Levels of mitochondrial H(2)O(2) and activity of AMPK were significantly elevated in primary HSVECs (human saphenous vein endothelial cells) from patients with CAD and T2D compared with those from patients with CAD alone. Incubation with the mitochondria-targeted antioxidant, MitoQ(10) significantly reduced AMPK activity in HSVECs from patients with CAD and T2D but not in cells from patients with CAD alone. Elevated mtROS production in the endothelium of patients with CAD and T2D increases AMPK activation, supporting a role for the kinase in defence against oxidative stress. Further investigation is required to determine whether pharmacological activators of AMPK will prove beneficial in the attenuation of endothelial dysfunction in patients with CAD and T2D.