French recommendations for the management of non-infectious chronic uveitis.

This French National Diagnostic and Care Protocol (NDPC) includes both pediatric and adult patients with non-infectious chronic uveitis (NICU) or non-infectious recurrent uveitis (NIRU). NICU is defined as uveitis that persists for at least 3 months or with frequent relapses occurring less than 3 months after cessation of treatment. NIRU is repeated episodes of uveitis separated by periods of inactivity of at least 3 months in the absence of treatment. Some of these NICU and NIRU are isolated. Others are associated with diseases that may affect various organs, such as uveitis associated with certain types of juvenile idiopathic arthritis, adult spondyloarthropathies or systemic diseases in children and adults such as Behçet's disease, granulomatoses or multiple sclerosis. The differential diagnoses of pseudo-uveitis, sometimes related to neoplasia, and uveitis of infectious origin are discussed, as well as the different forms of uveitis according to their main anatomical location (anterior, intermediate, posterior or panuveitis). We also describe the symptoms, known physiopathological mechanisms, useful complementary ophthalmological and extra-ophthalmological examinations, therapeutic management, monitoring and useful information on the risks associated with the disease or treatment. Finally, this protocol presents more general information on the care pathway, the professionals involved, patient associations, adaptations in the school or professional environment and other measures that may be implemented to manage the repercussions of these chronic diseases. Because local or systemic corticosteroids are usually necessary, these treatments and the risks associated with their prolonged use are the subject of particular attention and specific recommendations. The same information is provided for systemic immunomodulatory treatments, immunosuppressive drugs, sometimes including anti-TNFα antibodies or other biotherapies. Certain particularly important recommendations for patient management are highlighted in summary tables.

[Sarcoid uveitis: Ophthalmologist's and internist's viewpoints]. / Uvéites sarcoïdosiques : regards croisés de l'ophtalmologiste et de l'interniste.

Sarcoidosis is one of the leading causes of inflammatory eye disease. All ocular structures can be affected, but uveitis is the main manifestation responsible for vision loss in ocular sarcoidosis. Typical sarcoid anterior uveitis presents with mutton-fat keratic precipitates, iris nodules, and posterior synechiae. Posterior involvement includes vitritis, vasculitis, and choroidal lesions. Cystoid macular edema is the most important and sight-threatening consequence of sarcoid uveitis. Patients with clinically isolated uveitis at diagnosis rarely develop other organ involvement. Even though, ocular sarcoidosis can have a severe impact on visual prognosis, early diagnosis and a wider range of available therapies (including intravitreal implants) have lessened the functional impact of the disease, particularly in the last decade. Corticosteroids are the cornerstone of treatment for sarcoidosis, but up to 30% of patients achieve remission with requiring high-dose systemic steroids. In these cases, the use of steroid-sparing immunosuppressive therapy (such as methotrexate) is unavoidable. Among these immunosuppressive treatments, anti TNF-α drugs have been a revolution in the management of non-infectious uveitis.

Murine typhus complicated by sHLH mimicking adult-onset Still's disease.

INTRODUCTION: Adult-onset Still's disease (AOSD) is a rare multisystemic disorder and a diagnostic challenge for physicians because of the wide range of differential diagnoses. Common features of AOSD and secondary hemophagocytic lymphohistiocytosis (sHLH) could favour diagnostic uncertainty, in particular in case of infection-related sHLH. OBSERVATION: A 61-year-old man was admitted to our internal medicine department for suspected AOSD. He reported a 2-week history of sudden onset fever, headaches, myalgia, sore throat, diarrhoea, and an erythematous macular rash of the trunk as well as petechial purpuric lesions on both legs on return from Reunion Island. Laboratory tests found cytopenia, hepatic cytolysis, hypertriglyceridaemia, and hyperferritinaemia. Hemophagocytosis was diagnosed on bone marrow aspiration in favour of the diagnosis of secondary hemophagocytic lymphohistiocytosis (sHLH). Subcutaneous anakinra (100mg) was initiated to treat sHLH with favourable course. Oral doxycycline was added 3days later because of atypical features for AOSD diagnosis such as diarrhoea, hypergammaglobulinaemia, and doubtful serologies for Rickettsia and Coxiella. Three weeks later, Rickettsia typhi serology was checked again and revealed an increase in IgG titer>4 times that confirmed the diagnosis of murine typhus. A diagnosis of murine typhus complicated by sHLH was retained, successfully treated by anakinra and doxycycline. CONCLUSION: Our observation shows that AOSD diagnosis has to be stringent due to the many differential diagnoses, particularly infection complicated by sHLH, which may be rare. It is important to consider murine typhus in patients returning from endemic areas, such as La Reunion or other tropical areas, when they present fever of unknown origin with non-specific clinical features. Moreover, this case illustrates the effectiveness of IL-1 blockers as a treatment for symptomatic sHLH without severity criteria, regardless of the aetiology.

Relevance of Brain MRI in Patients with Uveitis: Retrospective Cohort on 402 Patients.

AIM: To assess the diagnostic value of brain magnetic resonance imaging (bMRI) for the etiological diagnosis of uveitis and to establish predictive factors associated with its advantageous use. METHODS: Retrospective study on all patients with de novo uveitis who were referred to our tertiary hospital and who underwent a bMRI between 2003 and 2018. RESULTS: bMRI was contributive in 19 out of 402 cases (5%), among patients with a contributive bMRI, 68% had neurological signs. Univariate analysis established that neurological signs (p < .001), granulomatous uveitis (p = .003), retinal vasculitis (p = .002), and intermediate uveitis (p < .001) were all significantly associated with a contributive bMRI. Multivariate analysis confirms the significant association of neurological signs (p < .001) and intermediate uveitis (p = .01). CONCLUSION: bMRI appears to be a relevant exam in specific cases; intermediate/posterior uveitis or panuveitis accompanied by neurological signs, retinal vasculitis, or in patients older than 40, to rule out an oculocerebral lymphoma. ABBREVIATIONS: ACE: Angiotensin-Converting Enzyme; bMRI: Magnetic Resonance Imaging; CBC: Complete Blood cell Count; BMRI: Brain Magnetic Resonance Imaging; CT: Computerized Tomography; MS: Multiple Sclerosis; NS: Neurological Signs; OCL: Oculocerebral Lymphoma; RIS: Radiologically Isolated Syndrome.

[Spontaneous adrenal hematomas. Retrospective analysis of 20 cases from a tertiary center]. / Hématomes surrénaliens non traumatiques : série rétrospective de 20 cas.

INTRODUCTION: Spontaneous adrenal hemorrhages (AH) are a rare condition with no consensus about their management. METHODS: Patients were identified using the Medicalization of the Information System Program database, imaging software and a call for observations to internists, intensivists and obsetricians working at our institution. Adult patients whose medical records were complete and whose diagnosis was confirmed by medical imaging were included. RESULTS: From 2000 to 2007, 20 patients were identified, including 15 were women. The clinical onset of AH was non-specific. In five cases, AH occurred during pregnancy; four of them were unilateral and right sided. The etiology of the other fifteen (bilateral adrenal hemorrhage in 11) were as follows: antiphospholipid syndrome (n=8), heparin-induced thrombocytopenia (n=4), essential thrombocythemia (n=3), spontaneous AH due to oral anticoagulants (n=1), complication of a surgical act (n=3), and sepsis (n=3). In seven cases, two causes were concomitant. The diagnosis of AH was often confirmed by abdominal CT. An anticoagulant treatment was initiated in 16 cases. Ten of the eleven patients presenting with bilateral adrenal hematomas were treated using a long-term substitute opotherapy. One patient died because of a catastrophic antiphospholipid syndrome. CONCLUSION: The clinical onset of HS is heterogeneous and non-specific. The confirmatory diagnosis is often based on abdominal CT. The search for an underlying acquired thrombophilia is essential and we found in this study etiological data comparable to the main series in the literature. Adrenal insufficiency is most of the time definitive in cases of bilateral involvement.

[Observational study of QuantiFERON® management for ocular tuberculosis diagnosis: Analysis of 244 consecutive tests]. / Étude observationnelle de l'usage du QuantiFERON® pour le diagnostic de tuberculose oculaire, basée sur 244 tests consécutifs.

INTRODUCTION: Ocular tuberculosis (TB) diagnosisremains difficult and quantiferon (QFT) contribution needs still yet to be specified, despite its generalization in France. The purpose of this observational study is to assess in which ocular inflammation (OI) presentation QFT is prescribed and to evaluate the added value of new QuantiFERON®-TB Gold Plus (QFT-Plus) test for diagnosis ocular TB diagnosis. PATIENTS AND METHODS: Monocentric, observational study, carried out in an ophthalmology department over a period of 5 months. Inclusion criteria were defined as an existence of an OI for which a QFT-Plus test was part of the etiological investigations. Of the 316 consecutive files, 72 were excluded (indeterminate test, prescription before anti-TNFα or immunosuppressant initiation, missing data, wrong indication) and 244 were selected and divided into two groups: group one (anterior uveitis/episcleritis, n=129) and group two (intermediate/posterior uveitis/optic neuritis/ocular myositis, n=115). All positive QFT patients underwent an etiological investigation including thoracic imaging. RESULTS: Forty-five patients, aged 52±12 years, had positive QFT (18.5%), including 18 patients for group 1 and 27 for group 2. Living in TB-endemic area, TB exposure and chest imaging abnormalities were identified in 70%, 27% and 22% of cases, respectively. OI was chronic in 36% of cases (group one, 4/18; group two, 12/27). None of the 18 patients, in group 1, received anti-tuberculosis treatment (ATT) or experienced a relapse during one-year follow-up. Four QFT+ patients, from group 2 (15%) had another associated disease explaining their uveitis. Among the 23 other patients without identified etiology, 13 had at least one relevant ophthalmological signs predictive of TB uveitis (posterior synechiae, retinal vasculitis and/or choroidal granuloma) (59%). Eleven patients received a 6-month ATT trial. Radiological abnormalities and granulomas at angiography were significantly more frequent among treated patients (p=0.03 and 0.001, respectively). A full OI recovery was observed for 8 patients (73%), considered ex-post as ocular TB. Nine patients in group 2 received rifampicin/isoniazid dual therapy for 3 months, but no conclusion could be drawn as to the benefit of such prescription on OI. QFT rate comparison, according to CD4 stimulation by ESAT-6/CFP-10 peptides or by CD4/CD8 co-stimulation, was comparable and found only 4 cases of discrepancy (1.6%). None of these 4 cases had ocular TB diagnosis. CONCLUSION: Positive QFT frequency among patients consulting for posterior OI remains high. In this study, radiological abnormalities and granulomas at angiography seemed to be more closely related to clinician decision for starting ATT trial in QFT+ patients, which was effective in 73% of cases. QFT-Plus does not seem more relevant than QFT-TB in exploring an OI. Prospective studies are necessary to codify QFT management in the etiological assessment of OI and clearly define ATT trial indications as well as their modalities.

Sarcoidosis diagnosed in the elderly: a case-control study.

BACKGROUND: Studies on sarcoidosis in elderly patients are scarce and none have specifically evaluated patients aged ≥75 at onset. AIM: We aimed to analyse the characteristics of patients with sarcoidosis diagnosed after 75 and to compare them with those of younger patients. DESIGN: Multicenter case-control study comparing elderly-onset sarcoidosis (EOS) with young-onset sarcoidosis (YOS) seen at Lyon University Hospitals between 2006 and 2018. METHODS: Using our institutional database, we included 34 patients in the EOS group and compared them with 102 controls from the YOS group in a 1:3 ratio. Demographic characteristics, medical history, clinical presentation, laboratory and imaging findings, sites of biopsies, histological analyses, treatments and outcomes were recorded using a comprehensive questionnaire. RESULTS: There were more Caucasians in the EOS group (94.1% vs. 59.8%; P < 0.001), who had significantly more comorbidities (mean, 3.1 ± 2 vs. 1.1 ± 1.6; P < 0.001). In the EOS group, there was less pulmonary involvement (26.5% vs. 49%; P = 0.022), less lymphadenopathy (2.9% vs. 16.7%; P = 0.041), no erythema nodosum (0% vs. 12.8%; P = 0.029) and no arthralgia (0% vs. 25.5%; P = 0.001). Conversely, uveitis was more common in the EOS group (55.9% vs. 20.6%; P < 0.001). Pathological confirmation was obtained significantly less frequently in the EOS group (67.7% vs. 85.3%; P = 0.023). Corticosteroid-related side effects were significantly more common in the EOS group (100% vs. 75.9%; P = 0.030). CONCLUSION: Epidemiology and clinical presentation of EOS differs from YOS, including more comorbidities and more uveitis. Elderly patients are more prone to corticosteroid side effects.

[Adult-onset Still's disease complications]. / Complications de la maladie de Still de l'adulte.

Adult-onset Still's disease (AOSD), first described in 1971 by Bywaters, is a rare systemic auto-inflammatory disorder of unknown etiology, characterized by a symptomatic triad associating prolonged fever, polyarthritis and rash. The management of this disease has significantly improved since its first description, and, although the overall prognosis of the AOSD is good, with a low attributable mortality, below 3% (but up to 18% depending on the series), some rare complications are still possible, can be life-threatening and change the prognosis of the disease. A literature search was performed to review AOSD's complications: reactive hemophagocytic lymphohystiocytosis, coagulation disorders, fulminant hepatitis, cardiovascular (pericarditis, myocarditis, HTAP) or pulmonary complications, neurologic, renal complications, and AA amyloidosis. For most of AOSD-related complications, corticosteroids remain the first-line treatment, in association with supportive care measures in case of severe complications. In case of inadequate response, multidisciplinary care with concil from a referral center is advised, and IL-1 or IL-6 blockers, but also ciclosporine, are the molecule to use in second intention.

Clinical and etiologic characteristics of de novo uveitis in patients aged 60 years and above: experience of a French tertiary center.

PURPOSE: To describe the characteristics of de novo uveitis in patients ≥ 60 years old. METHODS: Retrospective review of patients with uveitis followed in our tertiary center over a 14-year period. Patients aged 60-70 years and patients aged > 70 years were compared. RESULTS: A total of 283/1044 (27.1%) patients with uveitis were ≥ 60 years of age. Idiopathic uveitis (36.1%) and sarcoidosis (31.5%) were the most frequent etiologies. Sarcoidosis was significantly more frequent (31.5% vs. 13.7%, p < 0.0001) after the age of 60 years. Intraocular lymphoma (5.0% vs. 1.1%) and herpes virus infection (5.0% vs. 0.9%) were also more common in this age group, unlike HLA B27-related uveitis and spondyloarthritis (4.6% vs. 14.9%). Pure ophthalmologic entities: birdshot retinochoroidopathy (2.8%) or Fuchs uveitis (0.4%), were rare in patients ≥ 60 years of age and Posner Scholssman, Pars planitis, White dots syndrome, Behçet's disease, and Multiple Sclerosis were never reported. In patients > 70 years old, idiopathic uveitis (41.1% vs. 31.7%) and presumed sarcoidosis (56.5% vs. 25.6%) were more frequent than in the 60-70-year age group. CONCLUSION: In our center, sarcoidosis is the leading cause of non-idiopathic uveitis in older patients. Idiopathic uveitis and other entities account for less than two-thirds of cases. Ophthalmologic entities are rare after 60 years of age. We also report for the first time the characteristics of uveitis after 70 years of age.

[Acquired hemophilia A revealing lung cancer]. / Une hémophilie A acquise ayant révélé un cancer du poumon.

Acquired hemophilia A (AHA) is a rare disease, defined by the production of anti-factor VIII antibodies causing disordered hemostasis. It is idiopathic in 50% of cases, but sometimes associated with solid tumors. We report a case where AHA led to the diagnosis of lung cancer. CASE REPORT: An 82-year-old man with spontaneous hematomas on his trunk and extremities, and isolated prolongation of activated partial thromboplastin time was admitted to the emergency room. A severely reduced factor VIII level and a high factor VIII inhibitor title confirmed the diagnosis of AHA. Thoracic computed tomography scan found a suspect lung nodule and biopsy was consistent with a primary lung adenocarcinoma. The patient received recombinant factor VIII, immunosuppressive therapies, and finally lung stereotactic radiotherapy. Thirty months after diagnosis, the patient is in complete remission both from AHA and from his lung cancer. CONCLUSIONS: Acquired hemophilia A is a rare but potentially severe disease, which may be idiopathic or linked to a solid tumor. The severity of AHA depends on both the volume of hemorrhage and the presence of associated diseases.

[Therapeutic strategy for the treatment of non-infectious uveitis proposed by an expert panel]. / Avis d'experts pour le traitement des uvéites non infectieuses.

Conventional immunosuppressive drugs, anti-TNF alpha and other biotherapies used in clinical practice are capable of controlling non-infectious anterior uveitis, posterior uveitis and panuveitis. The present work has been led by a multidisciplinary panel of experts, internists, rheumatologists and ophthalmologists and is based on a review of the literature. In case of corticodependency or sight-threatening disease, conventional immunosuppressive drugs (methotrexate, azathioprine and mycophenolate mofetil) and/or anti-TNF alpha (adalimumab, infliximab) are used to achieve and maintain remission. Interferon is an efficient immunomodulatory treatment, as a second-line therapy, for some therapeutic indications (refractory macular edema, Behçet's vascularitis). Other biologics, especially tocilizumab, are showing promising results. Local treatments (corticosteroids, sirolimus etc.) are adjuvant therapies in case of unilateral inflammatory relapse. Therapeutic response must be evaluated precisely by clinical examination and repeated complementary investigations (laser flare photometry, multimodal imaging, perimetry, electroretinography measures).

[Scleritis and systemic diseases: What should know the internist?] / Sclérites et maladies systémiques : que doit savoir l'interniste ?

Scleritis is an inflammatory disease of the sclera; outer tunic of the eye on which the oculomotor muscles are inserted. It can be associated with a systemic disease up to one time out of 3. These associated diseases are mainly rheumatoid arthritis, vasculitis, including granulomatosis with polyangiitis in the first line and spondyloarthropathies. Before mentioning such an etiology, it is necessary to eliminate an infectious cause, mainly herpetic, which is regularly underestimated. The classification of scleritis is clinical. We distinguish between anterior scleritis and posterior scleritis. Anterior scleritis is diffuse or nodular, usually of good prognosis. Anterior necrotizing scleritis with inflammation is often associated with an autoimmune disease, necrotizing scleritis without inflammation usually reflects advanced rheumatoid arthritis. The treatment of these conditions requires close collaboration between internists and ophthalmologists to decide on the use of corticosteroid therapy with or without immunosuppressors or biotherapies.

[Management of orbital inflammation in internal medicine. Proposal for a diagnostic work-up]. / Orbitopathies inflammatoires. Que doit savoir l'interniste ?

Inflammatory orbitopathies relate to an inflammatory state originating within the orbit and its adnexes, except the inner ocular globe. Orbital inflammation (OI) may be either localized manifestation of a proven or like autoimmune disease, or local response from immune system against infectious, structural or tumoral antigens. We review the clinical manifestations of OI, which provide helpful clues to the diagnosis and describe the inflammatory, infectious and neoplastic conditions classically associated with OI. Autoimmune diseases are probably the most common causes of OI associated with a bilateral dacryoadenitis (e.g., sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease). We focused on a major part of the IgG4-RD spectrum, the IgG4-related orbital disease which has been recently described and the idiopathic orbital inflammation syndrome that one should consider in patients 40 years of age or older with non specific inflammation OI on biopsy but without underlying local or systemic disease. An algorithm for the diagnostic approach of OI was proposed. If systemic explorations fail to diagnose an underlying disease, histopathologic control is required for distinguishing non-specific OI from other differential diagnosis, especially lymphoma. In the cases of pure myositic locations and posteriorly located tumours where biopsy could damage to the optic nerve, analysis of orbital lesions in T2W IRM sequence may be helpful to distinguish idiopathic OI (IOI) from lymphoma. When the diagnostic work-up fails, a corticosteroid trial could be used, but its beneficial effect has to be cautiously interpretated before definitively diagnosing IOI. Finally, treatments used in main infllammatory orbitopathies were also reviewed.

[Thymoma and autoimmune diseases]. / Thymomes et maladies auto-immunes.

The association between thymoma and autoimmunity is well known. Besides myasthenia gravis, which is found in 15 to 20% of patients with thymoma, other autoimmune diseases have been reported: erythroblastopenia, systemic lupus erythematosus, inflammatory myopathies, thyroid disorders, Isaac's syndrome or Good's syndrome. More anecdotally, Morvan's syndrome, limbic encephalitis, other autoimmune cytopenias, autoimmune hepatitis, and bullous skin diseases (pemphigus, lichen) have been reported. Autoimmune diseases occur most often before thymectomy, but they can be discovered at the time of surgery or later. Two situations require the systematic investigation of a thymoma: the occurrence of myasthenia gravis or autoimmune erythroblastopenia. Nevertheless, the late onset of systemic lupus erythematosus or the association of several autoimmune manifestations should lead to look for a thymoma. Neither the characteristics of the patients nor the pathological data can predict the occurrence of an autoimmune disease after thymectomy. Thus, thymectomy usefulness in the course of the autoimmune disease, except myasthenia gravis, has not been demonstrated. This seems to indicate the preponderant role of self-reactive T lymphocytes distributed in the peripheral immune system prior to surgery. Given the high infectious morbidity in patients with thymoma, immunoglobulin replacement therapy should be considered in patients with hypogammaglobulinemia who receive immunosuppressive therapy, even in the absence of prior infection.

[Uveitis: Diagnostic work-up. Recommendations from an expert committee]. / Prise en charge diagnostique des uvéites : recommandations d'un groupe d'experts.

INTRODUCTION: Diagnostic work-up of uveitis involves many uncertainties. Search for an etiology should take into account the epidemiology of uveitis and focus on the most severe diseases or those, which can be treated. This work was undertaken to establish recommendations for the diagnosis work-up of uveitis. METHODS: Recommendations were developed by a multidisciplinary panel of 15 experts, including internists, ophthalmologists and a rheumatologist and are based on a review of the literature with regard to effectiveness of investigations and the results of the ULISSE study, which is the first prospective study assessing the efficiency of a standardized strategy for the etiological diagnosis of uveitis. Children, immunocompromised patients, severe retinal vasculitis and specific ophthalmological entities are excluded from these recommendations. RESULTS: Investigations should be first guided by the history and physical examination. Serological screening for syphilis is the only test appropriate in all forms of uveitis. If no diagnosis is made after this stage, we propose investigations guided by the anatomic characteristics of uveitis. It includes HLA B27 testing (in unilateral acute anterior non-granulomatous uveitis), serum angiotensin converting enzyme, interferon-gamma release assay and chest CT (chronic uveitis), cerebral MRI and anterior chamber tap with IL10 analysis (intermediate or posterior uveitis in patients over 40 years). Investigations ordered in the absence of orientation are almost always unhelpful. CONCLUSIONS: We propose a strategy for the etiologic diagnosis of uveitis. The recommendations should be updated regularly. The efficiency of more invasive investigations has yet to be evaluated.