Reproducibility and accuracy of vessel wall MRI in diagnosing giant cell arteritis: a study with readers of varying expertise.

OBJECTIVE: To evaluate the reproducibility of vessel wall magnetic resonance imaging (VW-MRI) in diagnosing giant cell arteritis (GCA) among groups of radiologists with varying levels of expertise. METHODS: This institutional review board-approved retrospective single-center study recruited patients with suspected GCA between December 2014 and September 2021. Patients underwent 3 -T VW-MRI before temporal artery biopsy. Ten radiologists with varying levels of expertise, blinded to all data, evaluated several intracranial and extracranial arteries to assess GCA diagnosis. Interobserver reproducibility and diagnostic performance were evaluated. RESULTS: Fifty patients (27 women and 23 men) with a mean age of 75.9 ± 9 years were included. Thirty-one of 50 (62%) had a final diagnosis of GCA.VW-MRI had an almost perfect reproducibility among expert readers (kappa = 0.93; 95% CI 0.77-1) and substantial reproducibility among all readers, junior and non-expert senior readers (kappa = 0.7; 95% CI 0.66-0.73; kappa = 0.67 95% CI 0.59-0.74; kappa = 0.65; 95% CI 0.43-0.88 respectively) when diagnosing GCA. Substantial interobserver agreement was observed for the frontal branch of superficial temporal artery. Moderate interobserver agreement was observed for the superficial temporal artery and its parietal branch, as well as ophthalmic arteries in all groups of readers. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy varied depending on the group of readers. CONCLUSION: VW-MRI is a reproducible and accurate imaging modality for detecting GCA, even among less-experienced readers. This study advocates for the use of VW-MRI when diagnosing GCA even in less-experienced centers. CLINICAL RELEVANCE STATEMENT: VW-MRI is a reproducible and accurate imaging modality for detecting GCA, even among less-experienced readers, and it could be used as a first-line diagnostic tool for GCA in centers with limited expertise in GCA diagnosis. KEY POINTS: • Vessel wall magnetic resonance imaging (VW-MRI) is a reproducible and accurate imaging modality for detecting giant cell arteritis (GCA) in both extracranial and intracranial arteries. • The reproducibility of vessel wall magnetic resonance imaging for giant cell arteritis diagnosis was high among expert readers and moderate among less-experienced readers. • The use of vessel wall magnetic resonance imaging for giant cell arteritis diagnosis can be recommended even in centers with less-experienced readers.

Characteristics and Prognosis of Binocular Diplopia in Patients With Giant Cell Arteritis.

BACKGROUND: Giant cell arteritis (GCA) is a large vessel vasculitis associated with a risk of permanent ophthalmologic complications. Data about diplopia prognosis in GCA are scarce. This study was designed to better characterize diplopia in newly diagnosed GCA patients. METHODS: All consecutive patients diagnosed with GCA from January 2015 to April 2021 in a French tertiary ophthalmologic center were retrospectively reviewed. GCA diagnosis relied on a positive temporal artery biopsy or high-definition MRI. RESULTS: Among 111 patients diagnosed with GCA, 30 patients (27%) had diplopia. Characteristics of patients with diplopia were similar to other GCA patients. Diplopia resolved spontaneously in 6 patients (20%). Diplopia was attributed to cranial nerve palsy in 21/24 patients (88%), especially third (46%) and sixth cranial nerve (42%). Ocular ischemic lesions occurred in 11 of the 30 patients with diplopia (37%); 2 patients developed vision loss after initiation of corticosteroids. In the remaining 13 patients, diplopia resolved after treatment onset in 12 patients (92%) with a median delay of 10 days. Patients treated intravenously tended to have a quicker improvement than those treated orally, but with a similar resolution rate of diplopia at 1 month. Two patients had relapse of diplopia at 4 and 6 weeks after an initial treatment course of 24 and 18 months, respectively. CONCLUSIONS: Diplopia is a rare feature at GCA diagnosis, but should raise clinician suspicion for GCA when associated with cephalic symptoms and prompt the initiation of corticosteroids to prevent ocular ischemic complications.

Use of Retinal Angiography and MRI in the Diagnosis of Giant Cell Arteritis With Early Ophthalmic Manifestations.

BACKGROUND: Giant cell arteritis (GCA) is a vasculitis often revealed by visual signs. Diagnosis is challenging and urgent. Retinal angiography (RA) and MRI allow effective diagnosis. We compared those and proposed an imaging-based approach to diagnose GCA in ophthalmological practice. METHODS: We conducted a retrospective study based on the data collected from patients suspected to have GCA on ophthalmological findings. Fluorescein (FA) and indocyanine green (ICG) RAs and MRI were performed and compared with final diagnosis. RESULTS: Among the 41 patients included, 25 were diagnosed with GCA. Sensitivities and specificities of FA and ICG were not different. MRI showed a higher sensitivity and specificity. The approach consisting in performing RA followed by MRI provided a better accuracy. CONCLUSION: Our study shows that RA can be supplemented by MRI in a specialized center to provide the most accurate diagnosis in GCA revealed by visual signs.

PARACENTRAL ACUTE MIDDLE MACULOPATHY IN GIANT CELL ARTERITIS.

PURPOSE: To report the occurrence of paracentral acute middle maculopathy (PAMM) in giant cell arteritis (GCA), describe its features and outcomes, and identify risk factors associated with PAMM in patients with GCA. METHODS: Review of medical records of patients with GCA who were examined in the Rothschild Foundation Hospital. Patients were divided into three groups: GCA with PAMM (Group 1), GCA with ophthalmic involvement but without PAMM (Group 2), and GCA without ophthalmic involvement (Group 3). We analyzed the data for age, sex, medical history, laboratory testing, visual acuity, and posterior segment vascular involvement. RESULTS: Among the 96 patients who met the inclusion criteria, 52 had ophthalmic involvement, and 16 patients were included in Group 1 (GCA with PAMM). In this subgroup, the mean age was 81.6 years and was found to be older than other groups. The visual prognosis was similar between Groups 1 and 2. Of the 20 eyes with PAMM, 35% were also associated with homolateral anterior ischemic optic neuropathy. No statistical difference was found in initial symptoms, signs, and laboratory testing. CONCLUSION: Paracentral acute middle maculopathy is frequently observed lesions in ocular GCA. Patients can present with isolated findings of PAMM as the only indication of GCA. Optical coherence tomography of the macula should be routinely performed in patients with suspected GCA, specifically if they complain of visual changes, to look for signs of ischemia in the middle layers of the retina. Isolated PAMM should raise suspicion for GCA in patients at risk.

Validation of a multimodal algorithm for diagnosing giant cell arteritis with imaging.

PURPOSE: The purpose of this study was to identify which combination of imaging modalities should be used to obtain the best diagnostic performance for the non-invasive diagnosis of giant cell arteritis (GCA). MATERIALS AND METHODS: This IRB-approved prospective single-center study enrolled participants presenting with a suspected diagnosis of GCA from December 2014 to October 2017. Participants underwent high-resolution 3T magnetic resonance imaging (MRI), temporal and extra-cranial arteries ultrasound and retinal angiography (RA), prior to temporal artery biopsy (TAB). Diagnostic accuracy of each imaging modality alone, then a combination of several imaging modalities, was evaluated. Several algorithms were constructed to test optimal combinations using McNemar test. RESULTS: Forty-five participants (24 women, 21 men) with mean age of 75.4 ± 16 (SD) years (range: 59-94 years) were enrolled; of these 43/45 (96%) had ophthalmological symptoms. Diagnosis of GCA was confirmed in 25/45 (56%) patients. Sensitivity and specificity of MRI, ultrasound and RA alone were 100% (25/25; 95% CI: 86-100) and 86% (19/22; 95% CI: 65-97), 88% (22/25; 95% CI: 69-97) and 84% (16/19; 95% CI: 60-97), 94% (15/16; 95% CI: 70-100) and 74% (14/19; 95% CI: 49-91), respectively. Sensitivity, specificity, positive predictive and negative predictive values ranged from 95 to 100% (95% CI: 77-100), 67 to 100% (95% CI: 38-100), 81 to 100% (95% CI: 61-100) and 91 to 100% (95% CI: 59-100) when combining several imaging tests, respectively. The diagnostic algorithm with the overall best diagnostic performance was the one starting with MRI, followed either by ultrasound or RA, yielding 100% sensitivity (22/22; 95% CI: 85-100%) 100% (15/15; 95% CI: 78-100) and 100% accuracy (37/37; 95% CI: 91-100). CONCLUSION: The use of MRI as the first imaging examination followed by either ultrasound or RA reaches high degrees of performance for the diagnosis of GCA and is recommended in daily practice.

Early diffusion-weighted MRI at 3 Tesla detects ischemic changes of the optic nerve in anterior ischemic optic neuropathy.

OBJECTIVES: To assess the impact of timing from visual symptoms' onset to diffusion-weighted (DW) 3 T MRI completion to detect ischemic changes of the optic disc and optic nerve in AION patients. METHODS: This IRB-approved retrospective single-center study included 3 T MRI data from 126 patients with AION and 111 controls with optic neuritis treated between January 2015 and May 2020. Two radiologists blinded to all data individually analyzed imaging. A senior neuroradiologist resolved any discrepancies by consensus. The primary judgment criterion was the restricted diffusion of the optic disc and/or the optic nerve assessed subjectively on the ADC maps. ADC values were also measured. Spearman rank correlations were used to examine the relationships between timing from visual symptoms' onset to MRI completion and both the restricted diffusion and the ADC values. RESULTS: One hundred twenty-six patients (47/126 [37.3%] women and 79/126 [62.7%] men, mean age 69.1 ± 13.7 years) with AION were included. Restricted diffusion of the optic disc in AION eyes was more frequent in the early MRI group than in the late MRI group: 35/49 (71.4%) eyes versus 3/83 (3.6%) eyes, p < 0.001. ADC values of the pathological optic discs and optic nerves were lower in the early MRI group than in the late MRI group: 0.61 [0.52-0.94] × 10-3 mm2/s versus 1.28 [1.01-1.44] × 10-3 mm2/s, p < 0.001, and 0.74 [0.61-0.88] × 10-3 mm2/s versus 0.89 [0.72-1.10] × 10-3 mm2/s, p < 0.001, respectively. CONCLUSIONS: DWI MRI showed good diagnostic performance to detect AION when performed early after the onset of visual symptoms. KEY POINTS: • Restricted diffusion of the optic disc in eyes affected by AION was significantly more likely to be observed in patients who had undergone MRI within 5 days after onset of visual symptoms. • ADC values of the pathological optic discs and optic nerves were significantly lower in patients who had undergone MRI within 5 days after onset of visual symptoms of AION: 0.61 × 10-3 mm2/s versus 1.28 × 10-3 mm2/s, p < 0.001, and 0.74 × 10-3 mm2/s versus 0.89 × 10-3 mm2/s, p < 0.001, respectively. • The optimal threshold for timing from visual symptoms' onset to MRI completion to detect restricted diffusion of the optic disc and/or optic nerve was 5 days, with an AUC of 0.88 (CI95%: 0.82-0.94).

Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity.

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.

High-resolution MRI demonstrates signal abnormalities of the 3rd cranial nerve in giant cell arteritis patients with 3rd cranial nerve impairment.

OBJECTIVE: To determine the sensitivity and specificity of high-resolution (HR) MRI for detecting signal abnormalities of cranial nerves (CN) in giant cell arteritis (GCA) patients presenting with diplopia. METHODS: This IRB-approved retrospective single-center study included GCA patients who underwent 3-T HR MRI from December 2014 to January 2020. Two radiologists, blinded to all data, individually assessed for the presence of enhancement of the 3rd, 4th, and/or 6th CN on post-contrast HR imaging and high signal intensity on HR T2-WI, for signal abnormalities of extraocular muscles and the brainstem, and for inflammatory changes of the ophthalmic and extracranial arteries. A Fisher's exact test was used to compare patients with or without diplopia. RESULTS: In total, 64 patients (42/64 (66%) women and 22/64 (34%) men, mean age 76.3 ± 8 years) were included. Of the 64 patients, 14 (21.9%) presented with diplopia. Third CN enhancement was detected in 7/8 (87.5%) patients with 3rd CN impairment, as compared to no patients with 4th or 6th CN impairment or to patients without diplopia (p < 0.001). Third CN abnormal high signal intensity on HR T2-WI was detected in 4/5 patients (80%) with 3rd CN impairment versus none of other patients (p < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value for detecting 3rd CN signal abnormalities were of 0.88, 1, 1, and 0.99 and 0.8, 1, 1, and 0.98 for post-contrast HR imaging and HR T2-WI, respectively. CONCLUSIONS: HR MRI had excellent diagnostic sensitivity and specificity when detecting signal abnormalities of the 3rd CN in GCA patients presenting with 3rd CN impairment. KEY POINTS: • Third cranial nerve enhancement was detected in all patients with 3rd cranial nerve impairment except for one with transient diplopia. • The "check mark sign" might be useful to identify 3rd cranial nerve signal abnormalities in the orbital apex. • No signal abnormalities of the 4th or 6th cranial nerves could be detected on high-resolution MRI.

Implication of the deacetylase sirtuin-1 on synovial angiogenesis and persistence of experimental arthritis.

OBJECTIVES: To decipher the phenotype of endothelial cells (ECs) derived from circulating progenitors issued from patients with rheumatoid arthritis (RA). METHODS: RA and control ECs were compared according to their proliferative capacities, apoptotic profile, response to tumour necrosis factor (TNF)-α stimulation and angiogenic properties. Microarray experiments were performed to identify gene candidates relevant to pathological angiogenesis. Identified candidates were detected by RT-PCR and western blot analysis in ECs and by immunohistochemistry in the synovium. Their functional relevance was then evaluated in vitro after gene invalidation by small interfering RNA and adenoviral gene overexpression, and in vivo in the mouse model of methyl-bovine serum albumin-(mBSA)-induced arthritis. RESULTS: RA ECs displayed higher proliferation rate, greater sensitisation to TNF-α and enhanced in vitro and in vivo angiogenic capacities. Microarray analyses identified the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) as a relevant gene candidate. Decreased SIRT1 expression was detected in RA ECs and synovial vessels. Deficient endothelial SIRT1 expression promoted a proliferative, proapoptotic and activated state of ECs through the acetylation of p53 and p65, and lead the development of proangiogenic capacities through the upregulation of the matricellular protein cysteine-rich angiogenic protein-61. Conditional deletion of SIRT1 in ECs delayed the resolution of experimental methyl-bovine serum albumin-(mBSA)-induced arthritis. Conversely, SIRT1 activation reversed the pathological phenotype of RA ECs and alleviates signs of experimental mBSA-induced arthritis. CONCLUSIONS: These results support a role of SIRT1 in RA and may have therapeutic implications, since targeting angiogenesis, and especially SIRT1, might be used as a complementary therapeutic approach in RA.

Involvement of Tumor Necrosis Factor Receptor Type II in FoxP3 Stability and as a Marker of Treg Cells Specifically Expanded by Anti-Tumor Necrosis Factor Treatments in Rheumatoid Arthritis.

OBJECTIVE: To study the involvement of Treg cells expressing tumor necrosis factor receptor type II (TNFRII) in exerting control of inflammation in experimental models and in the response to anti-TNF treatments in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA). METHODS: The role of TNFRII in Treg cells was explored using a multilevel translational approach. Treg cell stability was evaluated by analyzing the methylation status of the Foxp3 locus using bisulfite sequencing. Two models of inflammation (imiquimod-induced skin inflammation and delayed-type hypersensitivity arthritis [DTHA]) were induced in TNFRII-/- mice, with or without transfer of purified CD4+CD25+ cells from wild-type (WT) mice. In patients with RA and those with SpA, the evolution of the TNFRII+ Treg cell population before and after targeted treatment was monitored. RESULTS: Foxp3 gene methylation in Treg cells was greater in TNFRII-/- mice than in WT mice (50% versus 36.7%). In cultured Treg cells, TNF enhanced the expression, maintenance, and proliferation of Foxp3 through TNFRII signaling. Imiquimod-induced skin inflammation and DTHA were aggravated in TNFRII-/- mice (P < 0.05 for mice with skin inflammation and P < 0.0001 for mice with ankle swelling during DTHA compared to WT mice). Adoptive transfer of WT mouse Treg cells into TNFRII-/- mice prevented aggravation of arthritis. In patients with RA receiving anti-TNF treatments, but not those receiving tocilizumab, the frequency of TNFRII+ Treg cells was increased at 3 months of treatment compared to baseline (mean ± SEM 65.2 ± 3.1% versus 49.1 ± 5.5%; P < 0.01). In contrast, in anti-TNF-treated patients with SpA, the frequency of TNFRII+ Treg cells was not modified. CONCLUSION: TNFRII expression identifies a subset of Treg cells that are characterized by stable expression of Foxp3 via gene hypomethylation, and adoptive transfer of TNFRII-expressing Treg cells ameliorates inflammation in experimental models. Expansion and activation of TNFRII+ Treg cells may be one of the mechanisms by which anti-TNF agents control inflammation in RA, but not in SpA.

Increased diagnostic accuracy of giant cell arteritis using three-dimensional fat-saturated contrast-enhanced vessel-wall magnetic resonance imaging at 3 T.

OBJECTIVES: To compare the diagnostic accuracy of 3D versus 2D contrast-enhanced vessel-wall (CE-VW) MRI of extracranial and intracranial arteries in the diagnosis of GCA. METHODS: This prospective two-center study was approved by a national research ethics board and enrolled participants from December 2014 to October 2017. A protocol including both a 2D and a 3D CE-VW MRI at 3 T was performed in all patients. Two neuroradiologists, blinded to clinical data, individually analyzed separately and in random order 2D and 3D sequences in the axial plane only or with reformatting. The primary judgment criterion was the presence of GCA-related inflammatory changes of extracranial arteries. Secondary judgment criteria included inflammatory changes of intracranial arteries and the presence of artifacts. A McNemar's test was used to compare 2D to 3D CE-VW MRIs. RESULTS: Seventy-nine participants were included in the study (42 men and 37 women, mean age 75 (± 9.5 years)). Fifty-one had a final diagnosis of GCA. Reformatted 3D CE-VW was significantly more sensitive than axial-only 3D CE-VW or 2D CE-VW when showing inflammatory change of extracranial arteries: 41/51(80%) versus 37/51 (73%) (p = 0.046) and 35/50 (70%) (p = 0.03). Reformatted 3D CE-VW was significantly more specific than 2D CE-VW: 27/27 (100%) versus 22/26 (85%) (p = 0.04). 3D CE-VW showed higher sensitivity than 2D CE-VW when detecting inflammatory changes of intracranial arteries: 10/51(20%) versus 4/50(8%), p = 0.01. Interobserver agreement was excellent for both 2D and 3D CE-VW MRI: κ = 0.84 and 0.82 respectively. CONCLUSIONS: 3D CE-VW MRI supported more accurate diagnoses of GCA than 2D CE-VW. KEY POINTS: • 3D contrast-enhanced vessel-wall magnetic resonance imaging is a high accuracy, non-invasive diagnostic tool used to diagnose giant cell arteritis. • 3D contrast-enhanced vessel-wall imaging is feasible for clinicians to complete within a relatively short time, allowing immediate assessment of extra and intracranial arteries. • 3D contrast-enhanced vessel-wall magnetic resonance imaging might be considered a diagnostic tool when intracranial manifestation of GCA is suspected.

Three Tesla 3D High-Resolution Vessel Wall MRI of the Orbit may Differentiate Arteritic From Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: Anterior ischemic optic neuropathy (AION) is the most common cause of acute optic neuropathy in older patients. Distinguishing between arteritic AION (A-AION) and nonarteritic (NA-AION) is paramount for improved patient management. PURPOSE: The aim of this study was to evaluate 3-dimensional high-resolution vessel wall (HR-VW) magnetic resonance imaging (MRI) at 3 T to discriminate A-AION from NA-AION. MATERIALS AND METHODS: This prospective single-center study was approved by a national research ethics board and included 27 patients (17 A-AION and 10 NA-AION) with 36 AIONs from December 2014 to August 2017 who underwent 3 T HR-VW MRI. Two radiologists blinded to clinical data individually analyzed the imaging separately and in random order. Discrepancies were resolved by consensus with a third neuroradiologist. The primary diagnostic criterion was the presence of inflammatory changes of the ophthalmic artery. Secondary diagnostic criteria included the presence of an enhancement of the optic nerve or its sheath, the optic disc, or inflammatory changes of posterior ciliary or extracranial arteries. A Fisher exact test was used to compare A-AION from NA-AION patients. RESULTS: Inflammatory changes of the ophthalmic artery were present in all patients with A-AION but in none of NA-AION (P < 0.0001). Its sensitivity, specificity, positive predictive value, and negative predictive value were 100%. Inflammatory changes of posterior ciliary arteries were significantly more likely in A-AOIN (82% vs 0%, P < 0.0001). Interreader and intrareader agreements were almost perfect (κ = 0.82-1). CONCLUSIONS: High-resolution vessel wall MRI seems highly accurate when distinguishing A-AION from NA-AION and might be useful to improve patient management.

Corneal and scleral involvement in inflammatory rheumatic disease: Rheumatologists and ophthalmologists exchanging views.

Corneal and scleral disorders related to inflammatory rheumatic diseases vary both in frequency and in severity. Sicca syndrome and its complications are the most common ocular manifestations and, together with episcleritis, can usually be managed by topical treatments. In contrast, the various forms of scleritis and peripheral ulcerative keratitis generally require systemic glucocorticoid therapy and the initiation or intensification of immunosuppressive treatment. Corneal and scleral manifestations are inaugural in a few patients with chronic inflammatory rheumatic disease. No direct information is available on the frequency of severe corneal and scleral involvement, which can only be estimated by extrapolating data from case-series or cohorts, many of which are historical. Similarly, given the absence of randomized controlled trials, treatment decisions must rely on clinical experience acquired in referral centers and on reports of small case-series studies. The rheumatologist and ophthalmologist must work closely together to ensure the prompt and optimal management of these potentially serious conditions.

Developments with experimental and investigational drugs for axial spondyloarthritis.

INTRODUCTION: Axial spondyloarthritis (AxS pA) is a chronic inflammatory disease for which, until recently, there were no valid therapeutic alternatives to TNF-α blocking agents. This unmet clinical need led to explore several therapeutic targets, from proinflammatory cytokines to intracellular signaling systems. The recent approval of Secukinumab, an anti-IL-17A monoclonal antibody, marked a new step in the evolution of AxSpA treatment. Areas covered: the authors review and discuss all the biological or synthetic agents that are currently developed or that have been tested in AxSpA. News from relevant press releases by manufacturers on past, current and future developments are also reported. Several agents that target IL-17 are currently between phase 2 and 3 of clinical development. Ustekinumab, a monoclonal antibody that blocks IL-23 and IL-12 is also in phase 3 after encouraging results from a pilot study. Expert opinion: The advent of agents that target the IL-23/IL-17 axis promises to reshape the therapeutic landscape for AxSpA in the next few years. Open questions in the research agenda for these agents involve their positioning in the therapeutic strategy, their efficacy on the spectrum of skeletal and extraskeletal manifestations of AxSpA, their effect on new bone formation and their long-term tolerance.

Progressive multifocal leukoencephalopathy and rheumatoid arthritis treatments.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system due to reactivation of the JC virus (JCV). PML is extremely uncommon despite the high prevalence of the virus in the general population. No specific treatment is available, and the prognosis is bleak. The diagnosis is based on brain imaging findings, detection of the JCV genome in cerebrospinal fluid samples and, in some cases, histological studies of the brain lesions. The pathophysiological mechanisms that drive the development of PML are incompletely understood. However, a consistent feature is the presence of a predisposing factor, most notably immunosuppression. The risk of developing PML varies with the underlying disease (e.g., HIV infection or autoimmune disease) and with the drugs used to treat them. Biologics have been ranked according to the risk of PML during their use. Natalizumab, a monoclonal antibody given to treat multiple sclerosis, is among the drugs associated with a high risk of PML. Patients given natalizumab are now closely monitored based on anti-JCV antibody titers and index values. In rheumatology, the expanding use of biologics has led to an increase in cases of PML, with rituximab being associated with the highest risk. Given the absence of specific recommendations, exhaustive registries and postmarketing observational studies are urgently needed to gauge the risk of PML according to the underlying disease and drug treatments, with the goal of defining optimal monitoring protocols.

Management of severe and refractory Mooren's ulcers with rituximab.

PURPOSE: Management of severe and refractory Mooren's ulcers is challenging as it encompasses tectonic surgical treatment and aggressive immunosuppressive therapies. Efficacy of rituximab in the management of severe Mooren's ulcers has never been reported. METHODS: Five patients (six eyes) from the Cornea and External Disorders department at the Rothschild Ophthalmologic Foundation (Paris, France) were treated for severe Mooren's ulcer unresponsive to conventional treatments between 2008 and 2016. Conventional treatment included topical steroid and ciclosporin 2%, high doses of systemic corticosteroids and/or cyclophosphamide and conjunctival resection with amniotic membrane graft. These patients received two infusions of 1000 mg of rituximab at 2 weeks interval. Epithelial healing, inflammation, additional surgery, systemic corticosteroids and rituximab-related side effects were reported. RESULTS: The mean follow-up was 46.8 months. Following rituximab treatment, we observed a complete healing of Mooren's ulcer within 2 weeks in all patients. Peripheral lamellar keratoplasty was associated when peripheral corneal perforation occurred (5/6 affected corneas). Systemic corticosteroids had been discontinued in all patients. Two recurrences occurred 13 and 53 months after the first rituximab infusion and where successfully treated with a new infusion. No rituximab-related adverse events were reported. CONCLUSIONS: Rituximab was effective in the management of severe Mooren's ulcers and could be an alternative to cyclophosphamide. Additional studies should assess the role of this biotherapy in the management of immunological corneal ulcer.