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Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles that each subset plays in autoimmunity are not well studied. In this study, we show that circulating monocytes from patients with autoimmune uveitis exhibit a skewed phenotype toward intermediate CD14++CD16+ cells, and that this is associated with glucocorticoid therapy. We further demonstrate that CD14++CD16+ monocytes from patients and healthy control donors share a similar cell-surface marker and gene expression profile. Comparison of the effects of intermediate CD14++CD16+ monocytes with classical CD14++CD16− and nonclassical CD14+CD16++ monocytes revealed that the intermediate CD14++CD16+ subset had an attenuated capacity to promote both naive CD4+ T cell proliferation and polarization into a Th1 phenotype, and memory CD4+ T cell proliferation and IL-17 expression. Furthermore, CD14++CD16+ cells inhibit CD4+ T cell proliferation induced by other monocyte subsets and enhance CD4+ T regulatory cell IL-10 expression. These data demonstrate the impact of glucocorticoids on monocyte phenotype in the context of autoimmune disease and the differential effects of monocyte subsets on effector T cell responses.

The aim of this study is to characterise the choroidal features of patients diagnosed with sarcoid- and tuberculosis (TB)-associated granulomatous uveitis using spectral domain optical coherence tomography (OCT).Twenty-seven patients (27 eyes) diagnosed with sarcoid- (13 eyes) and TB (14 eyes)-related uveitis were included in this retrospective, cross-sectional study. Over a six-month period, patients diagnosed with sarcoid and TB granulomatous uveitis were scanned using enhanced depth imaging OCT. Clinical and demographical characteristics were recorded, including the method of diagnosis, disease activity, site of inflammation (anterior or posterior), treatments, and visual acuity (VA). Manual segmentation of the choroidal layers was performed using custom image analysis software.The main outcome measure was OCT-derived thickness measurements of the choroid and choroidal sublayers (Haller's large vessel and Sattler's medium vessel layers) at the macula region. The ratio of Haller's large vessel to Sattler's medium vessel layer was significantly different at the total macula circle in eyes diagnosed with TB uveitis (1.47 (=140.71/95.72 μm)) compared with sarcoid uveitis (1.07 (=137.70/128.69 μm)) (P=0.001). A thinner choroid was observed in eyes with a VA ≥0.3 LogMAR (Snellen 6/12; 198.1 μm (interquartile range (IQR)=147.0-253.4 μm) compared with those with VA0.3 LogMAR (292.4 μm (IQR=240.1-347.6 μm)) at the total macula circle (P=0.004). At the foveal central subfield, the median choroidal thickness was 336.8 μm (IQR=272.3-375.4 μm) in active compared with 239.3 μm (IQR=195.3-330.9 μm) in quiescent disease (P=0.04).A disproportionately enlarged Sattler's layer may indicate a diagnosis of sarcoid-related uveitis, and choroidal thickening may be a feature of active granulomatous uveitis.

Annexin-A1 (Anx-A1) is an endogenous anti-inflammatory molecule and while described as a repressor of innate immune responses, the role of Anx-A1 in adaptive immunity, and in particular in T helper (Th) cell responses, remains controversial. We have used a T-cell mediated mouse model of retinal autoimmune disease to unravel the role of Anx-A1 in the development of autoreactive Th cell responses and pathology. RBP1-20-immunized C57BL/6 Anx-A1(-/-) mice exhibit significantly enhanced retinal inflammation and pathology as a result of an uncontrolled proliferation and activation of Th17 cells. This is associated with a limited capacity to induce SOCS3, resulting in un-restricted phosphorylation of STAT3. RBP1-20-specific CD4(+) cells from immunized Anx-A1(-/-) animals generated high levels of Th17 cells-associated cytokines. Following disease induction, daily systemic administration of human recombinant Anx-A1 (hrAnx-A1), during the afferent phase of disease, restrained autoreactive CD4(+) cell proliferation, reduced expression of pro-inflammatory cytokines IL-17, IFN-γ and IL-6 and attenuated autoimmune retinal inflammatory disease. Furthermore, in man, Anx-A1 serum levels when measured in active uveitis patient sera were low and associated with the detection of IgM and IgG anti-Anx-A1 antibodies when compared to healthy individuals. This data supports Anx-A1 as an early and critical regulator of Th17 cell driven autoimmune diseases such as uveitis.

Cardiac emergencies in pregnancy and the postpartum period are rare but often life-threatening. An emergency physician’s differential diagnosis for chest pain in the peripartum patient often includes serious etiologies such as pulmonary embolism or myocardial infarction (MI). A lesser-known but important consideration on the differential for MI is that of a spontaneous coronary artery dissection (SCAD). SCAD is defined as an intramural hematoma within the coronary artery that compresses the true lumen. Expansion by increased pressures may lead to subsequent myocardial ischemia and infarction. This condition is the most common cause of pregnancy-associated MI and is reported as the cause of MI in 24% to 35% of all women younger than 50 years. This condition is predominately seen in young healthy females with no traditional risk factors for coronary artery or cardiac disease, and typically in the postpartum period. SCAD in the peripartum period is defined as pregnancy-associated spontaneous coronary artery dissection (PASCAD). Abnormal ECG changes, elevated troponins, and regional wall motional abnormalities on echocardiography are all diagnostic findings of SCAD, which can be ultimately confirmed with coronary angiography. Failure to immediately address this condition can lead to acute heart failure, cardiogenic shock, and death. Thrombolytic treatment may be harmful and is not recommended, and percutaneous coronary intervention can result in the iatrogenic propagation of further coronary dissection. As a result, the management for suspected SCAD involves emphasis on urgent transfer and urgent coronary artery angiography to determine appropriate treatment modalities.

Thyroid eye disease (TED) is a potentially sight-threatening and cosmetically disfiguring condition arising in 25–50% of patients with Graves’ hyperthyroidism. CIRTED is the first study to evaluate the long-term role of radiotherapy and prolonged immunosuppression with azathioprine in treating TED, one aim of which was to validate the use of the English version of GO-QOL in an UK population with TED. In a three stage design over a 48 week period, the GO-QOL was tested and compared to a general measure of quality of life (WHOQOL-Bref). In stage 1 utilising a standard 14 day test-retest design both GO-QOL subscales achieved Cronbach’s alphas demonstrating excellent validity and internal reliability (Visual Function 0.929 and 0.931; Appearance 0.888 and 0.906). In stage 2, Repeated Measures ANOVA demonstrated longitudinal validity, with both subscales of the GO-QOL showing significant change over time (Visual Function, η2 = 0.114, p < .001; Appearance, η2 = 0.069, p < .002). In stage 3 the GO-QOL showed discriminant validity at the week 48 time point, with the visual function subscale being able to detect changes in groups identified by clinicians (using BCCOM ratings of improvement or deterioration), while both subscales could detect group differences when based on participants’ subjective ratings of TED noticeability and severity. The results of this project provide support for the English translation of the GO-QOL as an outcome measure for patients with moderately severe active Graves’ orbitopathy/TED

Summary The aim of this study was to quantify the proportion of regulatory T cells (Treg) and cytokine expression by peripheral blood mononuclear cells (PBMCs) in patients with active non-infectious uveitis, and to evaluate the effect of in-vitro treatment with infliximab, dexamethasone and cyclosporin A on Treg levels and cytokine production in PBMCs from uveitis patients and healthy subjects. We included a group of 21 patients with active non-infectious uveitis and 18 age-matched healthy subjects. The proportion of forkhead box protein 3 (FoxP3)+ Treg cells and intracellular tumour necrosis factor (TNF)-α expression in CD4+ T cells was determined by flow cytometry. PBMCs were also either rested or activated with anti-CD3/anti-CD28 and cultured in the presence or absence of dexamethasone, cyclosporin A and infliximab. Supernatants of cultured PBMCs were collected and TNF-α, interleukin (IL)-10, IL-17 and interferon (IFN)-γ levels were measured by enzyme-linked immunosorbent assay (ELISA). No significant differences were observed in nTreg levels between uveitis patients and healthy subjects. However, PBMCs from uveitis patients produced significantly higher amounts of TNF-α and lower amounts of IL-10. Dexamethasone treatment in vitro significantly reduced FoxP3+Treg levels in PBMCs from both healthy subjects and uveitis patients, and all tested drugs significantly reduced TNF-α production in PBMCs. Dexamethasone and cyclosporin A significantly reduced IL-17 and IFN-γ production in PBMCs and dexamethasone up-regulated IL-10 production in activated PBMCs from healthy subjects. Our results suggest that PBMCs from patients with uveitis express more TNF-α and less IL-10 than healthy subjects, and this is independent of FoxP3+ Treg levels. Treatment with infliximab, dexamethasone and cyclosporin A in vitro modulates cytokine production, but does not increase the proportion of FoxP3+ Treg cells.

Background Bronchiectasis is a chronic lung condition commonly affecting adults in middle to later years. Quality of life can be poor with a chronic, productive cough, dyspnoea and significant fatigue. Treatments aim to reduce symptoms, exacerbation frequency and severity, preserve lung function and improve health related quality of life. Regular, often twice daily nebulised antibiotics are commonly used in managing bronchiectasis. This patient population typically has severe bronchiectasis requiring multiple other medications. Little is known on patients’ views and preferences for such therapies. We aimed to assess this and define patient preferences and experiences. Methods We conducted three focus groups and three single interviews to define patients’ experience of nebulised antibiotics. 19 patients and/or carers attended focus groups providing in-depth information of lived experience using inhaled antibiotics. Thematic data analysis (TA) was used to derive a patient experience survey and a further 120 adult bronchiectasis patients completed surveys. Results Thematic analysis of the focus group data identified that many patients found nebulised therapy an imposition on their daily routine and this impaired adherence. Reducing treatment burden/time administering therapy was important. Others reported that nebulisation time was a period of rest, often incorporated into daily routines. The survey data showed although 70% of those currently taking nebulised antibiotics found them easy/very easy to administer, 10% found these hard/very hard to administer. 20% found taking the nebuliser in front of others “uncomfortable”. When nebulising, 47% excluded themselves in a separate room on a daily basis. 53% stopped nebulised therapy during vacations. If an inhaler that was as effective as nebulised therapy at preventing exacerbations was available 76% strongly agreed/agreed that they preferred an antibiotic delivered by an inhaler over a nebuliser if it was as effective at preventing exacerbations. 16% stated a preference for nebulised. Notably, only 10% wished to remain on nebulised therapy. Conclusions Bronchiectasis patients do not fully adhere with current treatments based upon treatment burden, life experience and lay knowledge. Inhaled antibiotics via dry power devices are quicker and easier to use and preferred by patients providing they were at least as effective as current nebulised treatments.

Purpose To perform qualitative and quantitative analyses of retinal and choroidal morphology in patients with punctate inner choroidopathy (PIC) using enhanced depth imaging optical coherence tomography (EDI-OCT). Design Cross-sectional, consecutive series. Participants A total of 2242 patients attending 2 tertiary referral uveitis clinics at Moorfields Eye Hospital were screened; 46 patients with PIC diagnosis were identified, and 35 eyes (35 patients) had clinically inactive PIC had EDI-OCT images that met the inclusion criteria. Methods Punctate inner choroidopathy lesions were qualitatively assessed for retinal features, such as (1) focal elevation of the retinal pigment epithelium (RPE), (2) focal atrophy of the outer retina/RPE, and (3) presence of sub-RPE hyperreflective deposits and choroidal features: (a) presence of focal hyperreflective dots in the inner choroid and (b) focal thinning of the choroid adjacent to PIC lesions. Quantitative analyses of the retina, choroid, and choroidal sublayers were performed, and associations with clinical and demographic data were examined. Main Outcome Measures Prevalence of each lesion pattern and thickness of retinal and choroidal layers. Results A total of 90 discrete PIC lesions were captured; 46.6% of PIC lesions consisted of focal atrophy of the outer retina and RPE; 34.4% consisted of sub-RPE hyperreflective deposits; and 18.8% consisted of localized RPE elevation with underlying hyporeflective space. Focal hyperreflective dots were seen in the inner choroid of 68.5% of patients, with 17.1% of eyes presenting focal choroidal thinning underlying PIC lesions. By excluding high myopes, patients with "atypical" PIC had reduced retinal thickness compared with patients with "typical" PIC (246.65±30.2 vs. 270.05±24.6 μm; P = 0.04), and greater disease duration was associated with decreases in retinal thickness ( r = −0.53; P = 0.01). A significant correlation was observed between best-corrected visual acuity and foveal retinal thickness ( r = −0.40; P = 0.03). Conclusions In a large series of patients with clinically inactive PIC, one fifth of the lesions analyzed revealed RPE elevation with underlying hyporeflective space, described before as a sign of activity and suggesting subclinical inflammation. Retinal thickness seems to be associated with disease type and duration of disease in non–highly myopic eyes. Improved visualization of the inner choroid using EDI-OCT may allow noninvasive assessment of inflammatory status.

Purpose To obtain measurements of vitreous signal intensity from optical coherence tomography (OCT) image sets in patients with uveitis, with the aim of developing an objective, quantitative marker of inflammatory activity in patients with this disease. Design Retrospective, observational case-control series. Participants Thirty patients (30 eyes) with vitreous haze secondary to intermediate, posterior, or panuveitis; 12 patients (12 eyes) with uveitis but without evidence of vitreous haze; and 18 patients (18 eyes) without intraocular inflammation or vitreoretinal disease. Methods Clinical and demographic characteristics were recorded, including visual acuity (VA), diagnosis, and anatomic type of uveitis. In each eye, the anterior chamber (AC) was graded for cellular activity and flare according to standardized protocols. The presence and severity of vitreous haze were classified according to the National Eye Institute system. Spectral-domain OCT images were analyzed using custom software. This software provided an "absolute" measurement of vitreous signal intensity, which was then compared with that of the retinal pigment epithelium (RPE), generating an optical density ratio with arbitrary units ("VIT/RPE-Relative Intensity"). Main Outcome Measures Correlation between clinical vitreous haze scores and OCT-derived measurements of vitreous signal intensity. Results The VIT/RPE-Relative Intensity was significantly higher in uveitic eyes with known vitreous haze (0.150) than in uveitic eyes without haze or in healthy controls (0.0767, P = 0.0001). The VIT/RPE-Relative Intensity showed a significant, positive correlation with clinical vitreous haze scores ( r = 0.566, P = 0.0001). Other ocular characteristics significantly associated with VIT/RPE-Relative Intensity included VA ( r = 0.573, P = 0.0001), AC cells ( r = 0.613, P = 0.0001), and AC flare ( r = 0.385, P = 0.003). Measurement of VIT/RPE-Relative Intensity showed a good degree of intergrader reproducibility (95% limits of agreement, −0.019 to 0.016). Conclusions These results provide preliminary evidence that OCT-derived measurements of vitreous signal intensity may be useful as an outcome measure in patients with uveitis. If validated in future studies, such measures may serve as an objective, quantitative disease activity end point, with the potential to improve the "signal:noise" ratio of clinical trials in this area, thus enabling smaller studies for the same power. The incorporation of automated vitreous analysis in commercial OCT systems may, in turn, facilitate monitoring and re-treatment of patients with uveitis in clinical practice.

The term autoimmune retinopathy encompasses a spectrum of rare autoimmune diseases that affect retinal function, often but not exclusively at the level of the photoreceptor. They typically present with painless visual loss, which may be accompanied by normal fundus examination. Some are progressive, often rapidly. They present a diagnostic challenge because there are no standardised clinical or laboratory based diagnostic criteria. Included within the spectrum are cancer-associated retinopathy, melanoma-associated retinopathy and presumed non-paraneoplastic autoimmune retinopathy. Differentiation from other retinopathies can be challenging, with overlap in symptoms, signs, and investigation findings, and an absence of pathognomonic features. However, technological developments in ophthalmic imaging and serological investigation over the past decade are adding novel dimensions to the investigation and classification of patients with these rare diseases. This review addresses the clinical, imaging, and serological features of the autoimmune retinopathies, and discusses the relative strengths and limitations of candidate diagnostic features.

Idiopathic panuveitis is a diagnosis of exclusion that lacks distinguishing features on fluorescein and indocyanine green angiography. Choroidal hypoperfusion or ischaemia has been implicated in panuveitis of different aetiologies. In this study, we use enhanced depth imaging optical coherence tomography (OCT) to examine the choroid and its vasculature in patients with this disease. In this retrospective, cross-sectional study, OCT-derived measurements of retinal and choroidal thickness were obtained after manual segmentation using custom software. Choroidal measurements were further subdivided into Haller’s large vessel layer (HLVL) and Sattler’s medium vessel layer (SMVL), and correlated with clinical parameters. Twenty-one eyes from 21 patients were included. A reduction in hypo-reflective spaces, corresponding to vascular lumens, was observed in HLVL. The mean thickness of both the choroid (233.7 ± 73.3 μm), and HLVL (167.8 ± 53.7 μm), was less than that previously reported for normal eyes. Choroidal thickness expressed as a ratio to retina thickness showed significant correlation to visual acuity (r = 0.58, p = 0.006). This correlation was maintained in the ratio between HLVL and retinal thickness (r = 0.56, p = 0.009), but not in SMVL to retinal thickness (r = 0.352, p = 0.12). This study reports novel OCT-derived parameters in patients with idiopathic panuveitis. We noted loss of hyporeflectivity in HLVL, and thinning of both HLVL and the choroid as a whole. The observed correlation between visual acuity and the ratio of choroidal to retinal thickness is a strong enhanced depth imaging (EDI)-OCT derived candidate for prospective validation in future studies.

PURPOSE: To report the clinical outcomes of adalimumab therapy in cases of birdshot chorioretinitis (BCR) with cystoid macular edema (CME) refractory to conventional immunotherapy.METHODS: This is a retrospective case series of three BCR patients treated with adalimumab for refractory CME. The main outcome measure was central subfield thickness (CST) on optical coherence tomography. Any patients treated with local steroids and/or receiving systemic steroids higher than 40 mg prednisolone daily during adalimumab therapy were excluded.RESULTS: At baseline, all patients were receiving systemic corticosteroids and two second-line immunosuppressive agents. The mean duration of treatment with adalimumab was 31.2 months (range 17.2-52). The mean CST was 327 ± 112.7 μm (mean ± SD) at baseline and 256.2 ± 39.7 μm at 6 months and 235.5 ± 32.5 μm at 12 months. Adalimumab permitted cessation or reduction in the daily dose of oral prednisolone plus withdrawal of a second-line agent in all patients.CONCLUSIONS: In these patients, adalimumab was effective in the treatment of refractory CME.

Infliximab is an antibody that neutralizes TNF-α and is used principally by systemic administration to treat many inflammatory disorders. We prepared the antibody mimetic Fab-PEG-Fab (FpFinfliximab) for direct intravitreal injection to assess whether such formulations have biological activity and potential utility for ocular use. FpFinfliximab was designed to address side effects caused by antibody degradation and the presence of the Fc region. Surface plasmon resonance analysis indicated that infliximab and FpFinfliximab maintained binding affinity for both human and murine recombinant TNF-α. No Fc mediated RPE cellular uptake was observed for FpFinfliximab. Both Infliximab and FpFinfliximab suppressed ocular inflammation by reducing the number of CD45+ infiltrate cells in the EAU mice after a single intravitreal injection at the onset of peak disease. These results offer an opportunity to develop and formulate for ocular use, FpF molecules designed for single and potentially multiple targets using bi-specific FpFs.

Background: Twice daily nebulised antibiotics are used in 10-20% of patients with bronchiectasis. This patient population typically has severe bronchiectasis requiring multiple treatments. Methods: 16 patients and/or carers attended focus groups providing in-depth information of lived experience using nebulised antibiotics. Thematic data analysis (TA) allowed questionnaire development that was applied to a larger group of users. Results: TA of the focus group data identified that many patients found nebulised therapy an imposition on their daily routine and impaired adherence. Reducing treatment burden / time taken was important. Others reported that nebulisation time was a period of rest, incorporated into fixed daily routines. Data from questionnaires showed 70% of patients currently taking nebulised antibiotics found them easy/very easy to administer, 10% found these hard/very hard to administer. 20% found taking the nebuliser in front of others “uncomfortable”. When nebulising, 47% excluded themselves in a separate room. 53% stopped nebulised therapy during vacations. If an inhaler was available, that was as effective as nebulised therapy at preventing exacerbations, 53% strongly agreed/agreed that they preferred an antibiotic delivered by an inhaler over a nebuliser. 16% stated a preference for nebulised. 10% wished to remain on nebulised therapy. Conclusions: Bronchiectasis patients do not fully adhere with their treatments citing treatment burden, lay knowledge and previous experience. Clinicians should recognise challenges to adherence and act in partnership to promote treatment options that facilitate concordance.

© 2016 PUBLISHED BY ELSEVIER INC. Purpose To develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts. Design Modified Delphi process. Methods A survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement. Results There was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies. Conclusions Consensus was achieved using a modified Delphi process to develop diagnostic criteria for nonparaneoplastic AIR. There is enough equipoise to justify randomized, placebo-controlled trials to determine whether patients with nonparaneoplastic AIR should be treated with long-term immunomodulatory therapy. Efforts to develop a standardized 2-tier assay system for the detection of antiretinal antibodies have been initiated as a result of this study.

The ophthalmic manifestations of dengue fever include a visually impairing maculopathy, where patients are left with a central or paracentral relative scotoma. The authors present a case of a 26-year-old female patient returning from Thailand with unilateral reduction in visual acuity and a central scotoma associated with dengue fever. The authors report the use of the optical coherence tomography angiography (OCTA) as a noninvasive imaging platform to demonstrate its value in showing the persistent changes corresponding to the functional central scotoma in dengue-related maculopathy, which often cannot be visualized clinically or by standard OCT and fundus fluorescein angiography. [ Ophthalmic Surg Lasers Imaging Retina . 2016;47:1057–1060.]

Purpose\ud \ud The purpose of the study was to report a case of multiple sclerosis (MS)-associated uveitis refractory to conventional immunosuppressants, with subsequent remission following treatment with alemtuzumab.\ud \ud \ud Methods\ud \ud Case report Patient was treated with intravenous alemtuzumab, a lymphocyte depleting anti-CD52 monoclonal antibody that has recently been approved for use in relapsing MS.\ud \ud \ud Results\ud \ud A 17-year-old female presented with bilateral optic neuritis and subsequently bilateral intermediate uveitis and secondary macular oedema. She was diagnosed with active relapsing MS for which she received treatment with alemtuzumab. The intraocular inflammation previously refractory to conventional immunosuppressants responded to alemtuzumab, inducing remission.\ud \ud \ud Conclusions\ud \ud To our knowledge, this is the first such report of alemtuzumab treatment in MS-associated ocular inflammatory disease and may demonstrate a potential utility for this drug in related conditions.

Pleuritic pain, a sharp discomfort near the chest wall exacerbated by inspiration is associated with a number of pathologies. Pulmonary embolus and infection are two common causes but diagnosis can often be challenging, both for experienced physicians and trainees. The underlying anatomy and pathophysiology of such pain and the most common aetiologies are presented. Clinical symptoms and signs that may arise alongside pleuritic pain are then discussed, followed by an introduction to the diagnostic tools such as the Wells’ score and current guidelines that can help to select the most appropriate investigation(s). Management of pulmonary embolism and other common causes of pleuritic pain are also discussed and highlighted by a clinical vignette.

Purpose To compare tacrolimus monotherapy with tacrolimus and prednisone therapy for the maintenance of disease remission in subjects with noninfectious posterior segment intraocular inflammation (PSII). Design Randomized, controlled, phase 2b, open-label, dual-center noninferiority trial. Participants Fifty-eight patients with sight-threatening PSII. Methods Patients requiring a second-line systemic immunosuppressive agent to control their PSII were treated with therapeutic doses of oral tacrolimus. Those subjects who subsequently were able to taper their prednisone dose to 10 mg daily without disease reactivation were assigned randomly either to stop prednisone or to continue 7.5 to 10 mg prednisone daily for 9 months. Main Outcome Measures Change in logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) and rate of patient withdrawal resulting from treatment inefficacy or intolerance. Results Thirty-five patients successfully tapered their prednisone to 10 mg daily. Of these, 16 were allocated randomly to receive tacrolimus monotherapy and 19 to continue taking prednisone and tacrolimus dual therapy. The difference in the mean change in VA for monotherapy compared with the dual therapy group was less than 1 logMAR letter (logMAR, −0.008; 95% confidence interval, −0.108 to 0.092; P = 0.870). The proportion of patients who tolerated treatment and maintained disease remission for 9 months after randomization also was similar in both groups (monotherapy, 62.5%; dual therapy, 68.4%; P = 0.694). All monotherapy treatment failures were the result of disease reactivation, whereas 50% of dual-therapy failures were the result of drug intolerance. Conclusions This study provides preliminary evidence that corticosteroids can be withdrawn in tacrolimus-treated patients who are able to achieve control of PSII with 10 mg prednisone daily, and any advantage of dual therapy in the prevention of disease reactivation was offset by its greater treatment intolerance. These findings support the further evaluation of corticosteroid-free treatment in future phase 3 trials (International Standard Randomised Controlled Trial Number Register identification, ISRCTN46576063). Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

The term pulmonary renal vasculitis syndrome describes a clinical syndrome of diffuse alveolar haemorrhage (DAH) complicating acute glomerulonephritis that often heralds severe, life-threatening systemic vasculitis requiring urgent, aggressive therapy. "Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis" and glomerular basement membrane ("Goodpasture's") disease are the commonest causes but other pathologies including systemic lupus erythematosus and the anti-phospholipid syndrome are also implicated. Such patients hence present most commonly to rheumatologists and nephrologists but usually require input from a number of specialties, respiratory and critical care medicine in particular. Such care is typically provided in specialist centres able to offer plasma exchange and experience in the use of immunosuppressants. We review clinical features, advances in therapy and understanding of pathophysiology.

Understanding immune mechanisms of noninfectious intraocular inflammation via animal models, and the relatively more restricted insights that can be achieved through studies in humans, continues to generate successful immunotherapies. This translational conduit elaborates immunopathogenic mechanisms, and illuminates further prospects of tailored therapies and biomarkers of disease activity and prognosis. More recently, our increased understanding has moved on from the success of previous biologic therapies, such as anti-TNF and IFN-α treatments, revealing other possible avenues to target; for example, Th17 cells, immune cell migration and the use of T-regulatory and dendritic cells to induce immunological tolerance. We now recognize that the ocular environment is endowed with many regulatory mechanisms but is hardly privileged in as much as ocular inflammation remains prevalent. Nevertheless, future therapeutic and diagnostic developments will harness our understanding of the local immunoregulatory networ...

Despite a lack of robust evidence, anti-TNF therapies are in wide use for the treatment of noninfectious ocular inflammatory diseases. There is a clear rationale, based on mechanistic and preclinical efficacy data, for their use in posterior segment intraocular inflammation. However, their increasing use for other indications has been largely extrapolated from the benefit observed in autoinflammatory and autoimmune systemic diseases. Given their cost and the potential for significant adverse events, this review highlights the evidence for their continued use, possibilities for switching anti-TNF agents, and ways of reducing the risk of therapy.

A 55-year-old woman with type II diabetes and resistant hypertension presented to her GP in July 2008 complaining of lethargy, breathlessness, and joint pains. In 2007, based upon a positive antinuclear antibody test (ANA) in the context of pancytopenia, arthralgia, and a persistent malar rash, she had been diagnosed with systemic lupus erythematosis (SLE) by her referring hospital. Her regular medications were perindopril 4 mg daily, amlodipine 5 mg daily, atenolol 100 mg daily, and hydralazine 25 mg twice daily which she had started in 2005. She had remained on hydralazine, despite the diagnosis of SLE, treatment of which was limited to intra-articular corticosteroid injections. In July 2008 she was referred to our renal unit with acute kidney injury (AKI). Upon arrival, examination revealed a malar rash, and a soft systolic murmur. The remainder of the examination was unremarkable. Her blood pressure was 163/81 and she was afebrile. Laboratory investigations confirmed AKI with a serum creatinine of 300 lmol/L, (previously 148 lmol/L in May 2008, and 82 lmol/L in March 2008). Full blood count revealed pancytopenia, and her blood film showed rouleaux formation with occasional spherocytes. ANA remained positive, and she had now developed high titres of serum anti neutrophil cytoplasmic antibodies of the anti-myeloperoxidase subtype (p-ANCA), which were previously negative (See Table 1). Despite immediate cessation of hydralazine and appropriate rehydration, over the following days, her clinical condition deteriorated. A widespread, florid vasculitic rash developed, accompanied by arthralgia, intermittent pyrexia, and a rising serum creatinine. Her symptoms and immunological profile were consistent with hydralazine-induced SLE (although renal involvement in this setting is unusual). However, the presence of serum ANCA and the florid vasculitic rash also made ANCA-associated vasculitis (AAV) a likely diagnosis. Since these two conditions were potentially therapeutically distinct, she underwent renal and skin biopsies, and a bone marrow aspirate and trephine. The renal biopsy confirmed the diagnosis of AAV with pauci-immune crescentic glomerulonephritis, occurring alongside hydralazineinduced lupus syndrome, complicated by autoimmune pancytopenia, the underlying cause of which was attributed to prolonged use of hydralazine. She was treated with three intravenous pulses of methylprednisolone (500 mg) and five sessions of plasma exchange—3 L exchanges with 1.5 L 5% human albumin solution and 1.5 L fresh frozen plasma (FFP). She required three sessions of haemodialysis and, following recovery of her white cell N. Sangala R. W. Lee C. Horsfield D. J. A. Goldsmith (&) Renal and Histopathology Departments, Kings Health Sciences, London 0207-188-5708, UK e-mail: David.goldsmith@gstt.nhs.uk

The rapid expansion in the therapeutic modalities available for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitides (AAV), with clear limitations in existing strategies, prompted us to undertake a review of novel therapies reported in MEDLINE and EMBASE. Tumour necrosis factor (TNF)-alpha antagonism with infliximab is described favourably in retrospective series and open-label trials. However, evidence from the WGET (Wegener's Granulomatosis Etanercept Trial) does not support the clinical use of etanercept, and a significantly higher malignancy rate following TNFalpha inhibition questions the role of this approach. Uncontrolled evidence alone supports remission induction with rituximab-mediated B-lymphocyte depletion and may be less effective in predominantly granulomatous AAV. Remission following T-lymphocyte depletion can be achieved with alemtuzumab and antithymocyte globulin, but it is not yet clear what the clinical role will be for these agents in AAV. In addition, these agents are associated with prolonged lymphopenia and pulmonary complications, respectively. Stem cell transplantation to support immune reconstitution following the use of such agents has been trialled in AAV, but studies included very few patients. Purine and pyrimidine antimetabolites mycophenolate mofetil and leflunomide are likely to play an important role in the treatment of AAV, but results supporting remission maintenance and induction in the former are limited to uncontrolled trials, such that their use remains experimental at this time. Similarly, 15-deoxyspergualin may provide an alternative to cyclophosphamide but awaits randomized controlled trial evidence. The MEPEX (MEthylprednisolone versus Plasma EXchange) trial supports plasma exchange in renal disease but this may be limited by pulmonary complications. Randomized controlled evidence also exists for intravenous immunoglobulin, although improvement may not be sustained. Antimicrobial therapy may be of use in Wegener's granulomatosis patients with predominantly upper respiratory tract involvement. Safety concerns, notably of infection and malignancy, were common and need to be explored in subsequent trials. In addition, concomitant immunosuppressants and non-standardized definitions were major limitations, and future studies of these and newer agents must follow agreed standards of study design and reporting to facilitate clearer interpretation of the circumstances (e.g. disease stage, severity or organ involvement) under which these agents perform optimally. Consequently, use is still limited to centres experienced in such agents and mostly in the context of clinical trials.

To provide contemporary data on the aetiology of paediatric rhegmatogenous retinal detachment (RRD) in the UK population. Retrospective case series. Eighty-eight eyes in 82 patients (aged 0–16 years) were treated for RRD at Bristol Eye Hospital between 1 January 1990 and 31 December 2004. Seventy-three per cent of patients were male and the main predisposing factors were trauma (53%), associated conditions (27%), and high myopia (17%). Nineteen per cent of RRDs were idiopathic, and the majority of these were due to infero-temporal dialyses. The macula was detached on presentation in 66% of eyes. The principal causes of paediatric RRDs have not changed over the past 40 years. Those due to congenital cataracts, retinopathy of prematurity, uveitis, and glaucoma are now less prevalent, presumably reflecting advances in their management. Differences with other contemporary series may arise from geographical variation in the prevalence of myopia and other associated conditions, as well as institutional referral patterns. Full examination of the retinal periphery is advised for children with eye injuries (to exclude dialyses).

Optical coherence tomography angiography (OCTA) provides noninvasive in vivo vascular imaging of the retina and choriocapillaris. To highlight OCTA utility, the authors align structural changes and their resolution with functional outcome. The authors present a case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and sequential changes during transition to inactive disease. In the acute phase, altered flow and nonperfusion were seen in defined islands of choriocapillaris. Over time, progressive reperfusion was observed and accompanied clinical resolution and functional visual restoration. The imaging features acquired described the level of nonperfusion the authors had assumed when extrapolating findings from multiple independent imaging modalities. [ Ophthalmic Surg Lasers Imaging Retina. 2016;47:677–681.]

Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

In this study we investigated the role of blood CD1c + myeloid dendritic cells 1 (mDC1), a key mDC subtype, in patients with autoimmune uveitis. We observed a significant increase of blood CD1c + mDC1 in uveitis patients. The increased CD1c + mDC1 exhibited high HLADR expression and less antigen uptake. CD1c + mDC1 were divided into two subpopulations. CD1c hi mDC1 subpopulation showed less antigen uptake and higher HLADR expression compared to CD1c lo mDC1 subpopulation. Importantly, the CD1c hi mDC1 subpopulation was increased in uveitis patients. In vitro , mature monocyte-derived dendritic cells (MoDCs), characterized by lower levels of antigen uptake, induced more CD4 + CD62L - T helper cell proliferation. The mature phenotype and function of CD1c + mDC1 were regulated by TNFα via a p38 MAPK-dependent pathway. These data show that alterations in the systemic immune response are involved in the pathogenesis of autoimmune uveitis and invite the therapeutic possibility of attenuating uveitis by manipulating blood CD1c + mDC1.

Anterior segment optical coherence tomography (AS-OCT) provides higher resolution images than ultrasound biomicroscopy (UBM), but has limitations in visualizing structures behind the pigmented epithelium of the iris. However, all other structures lying above the pigmented epithelium, such as

The signal intensity from inflamed extra-ocular muscles on short tau inversion recovery (STIR)-sequence magnetic resonance imaging (MRI) is known to correlate with clinical scores of thyroid eye disease (TED) severity. Twenty-one patients who had undergone repeated MRI scanning for TED were studied retrospectively. Signal intensity of extra-ocular muscles (from STIR-sequence MRI) and cross-sectional area (from STIR and T1 MRI) were correlated with Mourits' clinical activity score (CAS). The area of highest signal intensity within the most inflamed extra-ocular muscle, and the average cross-sectional signal intensity of the most inflamed extra-ocular muscle reliably correlated with CAS, and this was maintained as disease activity changed over time. In contrast, isolated measures of muscle cross-sectional area did not correlate with CAS. The extra-ocular muscle cross-sectional area calculated from STIR-sequence MR images was greater than that measured on T1 images. This suggests that muscle area from STIR-sequence MRI may also detect peri-muscular inflammation. We conclude that the peak signal intensity from the most inflamed extra-ocular muscle remains the most reliable correlate of clinical disease activity obtained from these images. STIR-sequence MRI scans provide a number of useful measures of disease activity in TED.

Purpose Myeloid dendritic cells (mDCs) play an important role in autoimmune diseases. However, the role of blood CD1c(+) myeloid dendritic cells 1 (mDC1s), the subset of human blood mDCs, is not well understood in noninfectious uveitis. Methods Fresh peripheral blood samples from human noninfectious uveitis patients (n = 32) and healthy controls (HCs) (n = 64) were stained with FITC-Lineage 1 (Lin1), PERCP-HLADR, and PE-CD1c antibodies. The levels of mDC1 were quantified by using flow cytometric analysis. Longitudinal data from patients (n = 16) were analyzed to correlate the levels of mDC1 with disease activity. Results Blood CD1c(+) mDC1 and its subpopulation, CD1c(hi) mDC1, were increased in uveitis patients compared with HCs. Longitudinal data demonstrated that both the CD1c(+) mDC1 and CD1c(hi) mDC1 subpopulation reflected a dynamic change in clinical uveitis activity: CD1c expression was increased in active uveitis but decreased when uveitis became inactive. Conclusions Given these observations, an alteration in blood CD1c(+) mDC1 and the CD1c(hi) mDC1 subpopulation could be a potential biomarker to monitor clinical uveitis activity within patients.

AIM: Two studies were carried out to establish, validate and assess descriptors for use in the differential diagnosis for mammographic calcifications. METHODS: In Study 1, eleven radiologists were asked to 'think out loud' as they interpreted 20 sets of calcifications. Participants used 159 terms to describe calcifications. We used this data to design a scheme with 50 descriptors. In Study 2, ten radiologists used the scheme to describe 40 sets of calcifications. We assessed the capacity of the terms to discriminate between benign and malignant calcifications, testing them against radiologists' assessments of malignancy and follow-up data. RESULTS: All descriptors were used by at least 5 radiologists. Five additional descriptors were required. With some exceptions, properties that discriminated between benign and malignant outcomes were highly correlated with radiologists' assessment of risk. Many descriptors have a fairly low sensitivity but high specificity. CONCLUSIONS: Our data suggest that radiologists consider a wide range of features than is included in existing reporting schemes. Our scheme allows a richer characterization of calcifications, potentially improving the reporting and understanding of these abnormalities.

Borrelia burgdorferi is a known infective cause of neuroretinitis. We present a case of B burgdorferi neuroretinitis complicated by macular hole in a 22-year-old man. The neuroretinitis was managed with early high-dose intravenous corticosteroid and oral antibiotic. The macular hole was managed with macular hole surgery after intraocular inflammation had resolved.

Intravenous immunoglobulin (IVIg) therapy has multiple mechanisms of immunomodulatory action. We wished therefore to assess its efficacy in a spectrum of patients with refractory uveitis. Retrospective review of clinical charts was conducted to document response to IVIg treatment in consecutive patients with treatment-refractory uveitis. Main outcome measures were control of intraocular inflammation, visual acuity, progression of the disease, and complications. Four (two male) patients, with a mean age at the beginning of the treatment of 47 years (range: 39–64), were included in the study. Indication for treatment was patients with active non-infectious uveitis refractory to steroids and immunomodulatory therapy. All patients received a course of 0.5 g/kg per day of IVIg for three consecutive days, repeating this course at a mean of 11 week (range: 2–39 weeks) intervals when indicated clinically. The median duration of the IVIg therapy was 7 months (range: 3–14 months). In three patients treatment resulted in stabilisation and prevention of progression of the disease, and additionally in two patients it facilitated a decrease in prednisolone dose. Treatment failed to induce long-term remission in one patient with recurrence of macular oedema. IVIg was well tolerated with neither immediate nor longer-term adverse events observed. In three out of four cases IVIg was an effective adjunctive therapy and well tolerated for the management of treatment-refractory uveitis.

Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects.

Bilateral chronic anterior uveitis is an extra-articular feature of juvenile idiopathic arthritis. Although figures vary, uveitis occurs in approximately 11%-13% of patients with this disease and is most commonly associated with the female gender, oligoarthritis, and presence of antinuclear antibodies. The disease has an insidious onset and is often asymptomatic. Managing patients with juvenile idiopathic arthritis-associated uveitis remains challenging as the disease may prove to be refractory to traditional treatment regimens. Stepwise immunomodulatory therapy is indicated, with new biologic drugs being used last in cases of refractory uveitis. Small scale studies and practice have provided the evidence to undertake randomized control trials to evaluate the efficacy, safety, and cost-effectiveness of anti-tumor necrosis factor-α therapies, such as infliximab and adalimumab. These have demonstrated promising results, with further data awaited from ongoing trials for adalimumab (as SYCAMORE and ADJUVITE trials). Lower grade evidence is supporting the use of newer biologics such as rituximab, daclizumab, tocilizumab, and abatacept in those cases refractory to anti-tumor necrosis factor-α therapy.

Objectives Vascular compliance is emerging as a useful cardiovascular risk factor. The aim of this study was to investigate the association between arterial stiffness and stroke severity at presentation and 3 weeks. Methods Forty two patients with acute ischemic stroke (55% male, mean age 71 years) were recruited over 15-months. Stroke subtypes were classified into lacunar circulation infarct (LACI), partial anterior circulation infarct (PACI), and posterior circulation infarct (POCI). Arterial stiffness was measured by QKD (defined as the time interval between the appearance of the Q wave [Q] on the ECG and the arrival of the diastolic Korotkoff [K] sound over the brachial artery in diastole [D]; QKD It is measured in milliseconds) using 24-hour ambulatory blood pressure (BP) and electrocardiogram monitoring. The measured QKD values were then corrected for a heart rate of 60 bpm and a systolic BP of 100 mm Hg (QKD100-60). Stroke severity was assessed on admission and at 3 weeks using the National Institutes of Health Stroke Scale (NIHSS). Results Regression analysis for all patients showed a weak non-significant correlation between arterial stiffness and stroke severity. However, on performing subgroup analysis using Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, we found that in large-artery atherosclerosis, arterial stiffness predicted stroke severity significantly at baseline (r = .45, b = .093, P = .04), but not significant for cardio embolism or small-artery occlusion subtypes. QKD100-60 and stroke severity were not significantly associated in week 3. There was no difference in NIHSS scores at weeks 0 and 3, or in QKD100-60 between LACI, PACI, and POCI, or dipper versus non-dippers and reverse dippers. Conclusion Further research is needed to explore the association between QKD and stroke severity.

Purpose To determine whether patients with juvenile systemic granulomatous disease (JSGD) (Blau syndrome) and uveitis have a characteristic ocular phenotype. Methods Clinical and imaging data were collected retrospectively from patients attending the Regional Combined Paediatric Rheumatology and Ocular Inflammatory Service, Bristol Eye Hospital. General demographic information, laterality of the uveitis, age at onset, anatomical classification and course of the uveitis, clinical phenotype and specific NOD2 mutation were recorded for each patient. Results Seventeen eyes from nine patients (five males; four females) were included in the study. Mean age at the disease onset was 15 months, range 1–84 months. Eight patients had bilateral uveitis. Anterior uveitis was present in five eyes, intermediate uveitis in two eyes, and there were 10 eyes with panuveitis, manifesting as multifocal choroiditis. Appearance of optic disc included indistinct disc margins in six eyes, optic nerve head pallor in six eyes, optic disc vessel sheathing in four eyes, and there was peripapillary hypo/hyperpigmentation in 13 eyes accompanied with characteristic peripapillary nodular excrescences. Among NOD2 mutations, the p.R334W was the most commonly detected (n: four cases), and three patients carried novel variants, the p.E338D and p.D390V variants in one patient, and the p.H520Y and p.Q809K variants in two different patients. Conclusions Chronic bilateral panuveitis and a nodular peripapillary appearance in childhood onset uveitis are characteristic features of JSGD, which support the need for an appropriate genetic NOD2 analysis.

This work aims to assist in the differential diagnosis of mammographic abnormalities. A prototype CAD system is being developed which will incorporate a knowledge base describing the characteristic features of benign and malignant calcifications. The knowledge base will provide advice to assist radiologists in assessing the significance of prompts placed by the CAD system. In this paper, we describe a study to elicit the radiological knowledge to be represented in the system. Using a set of descriptors derived in an earlier study, we obtained assessments and detailed descriptions of 40 sets of calcifications from 10 expert radiologists. This allowed us to identify a set of arguments relating descriptions of calcifications to assessments of the risk of malignancy. The study provides valuable data on the significance and salience of certain characteristics of mammographic calcifications. This data provides the basis of a mapping between image processing measurements and symbolic knowledge.

Objective.To assess the safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious childhood uveitis.Methods.Subjects were retrospectively selected from a database. Patients were included if they were diagnosed with chronic, noninfectious uveitis at 16 years of age or under and treated with triple immunosuppressive therapy for at least 6 months (following failure of a combination of 2 immunosuppressants). Patient demographics, diagnoses, duration of uveitis, drug dosages, active joint inflammation, and ophthalmologic data were recorded. Efficacy outcomes for triple therapy were recorded at 6 months.Results.Thirteen patients with bilateral uveitis were included. Using Standardized Uveitis Nomenclature (SUN) criteria, at 6 months only 11 eyes (42%) had a 2-step improvement in anterior chamber cell inflammation (n = 26). In addition, 2 patients required additional oral corticosteroid treatment. There were 4 significant infectious adverse events during a total of 21.9 patient-years (PY) on triple therapy (0.18 events per PY).Conclusion.In this group of children with refractory uveitis, addition of a third immunosuppressive agent did not confer substantial benefit in redressing ocular inflammation and was associated with significant infections in a minority of patients.

The rules of engagement for health researchers are starting to change. Traditional concepts of academic individualism and elite institutions are being challenged by a range of infl uences that are pulling researchers in a collegiate direction. Our obligation is to ensure that the fruits of our innovations are widely disseminated for the benefi t of all. We are increasingly incentivised—by the National Institute for Health Research (NIHR) and other bodies—to interact with each other. Far-reaching networks have been established, both to promote national engagement in clinical trials and to achieve high impact through the practical application of advances generated through health research across the National Health Service (NHS). These strategies are becoming embedded in usual clinical practice and the culture shift towards collective empowerment is now also trickling from applied research in common diseases through to early phase human research in tertiary care disciplines.

Advanced lung cancer has poor survival with few therapies. EGFR tyrosine kinase inhibitors (TKIs) have high response rates in patients with activating EGFR mutations, but acquired resistance is inevitable. Acquisition of the EGFR T790M mutation causes over 50% of resistance; MET amplification is also common. Preclinical data suggest synergy between MET and EGFR inhibitors. We hypothesized that EGFR-MET dimerization determines response to MET inhibition, depending on EGFR mutation status, independently of MET copy number. We tested this hypothesis by generating isogenic cell lines from NCI-H1975 cells, which co-express L858R and T790M EGFR mutations, namely H1975L858R/T790M (EGFR TKI resistant); H1975L858R (sensitized) and H1975WT (wild-type). We assessed cell proliferation in vitro and tumor growth/stroma formation in derived xenograft models in response to a MET TKI (SGX523) and correlated with EGFR-MET dimerization assessed by Förster Resonance Energy Transfer (FRET). SGX523 significantly reduced H1975L858R/T790M cell proliferation, xenograft tumor growth and decreased ERK phosphorylation. The same was not seen in H1975L858R or H1975WT cells. SGX523 only reduced stroma formation in H1975L858R. SGX523 reduced EGFR-MET dimerization in H1975L858R/T790M but induced dimer formation in H1975L858R with no effect in H1975WT. Our data suggests that MET inhibition by SGX523 and EGFR-MET heterodimerisation are determined by EGFR genotype. As tumor behaviour is modulated by this interaction, this could determine treatment efficacy.