Enrico Beccastrini

Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Substitute adenine (SA)-2, a synthetic heterocycle chemically related to adenine with substitutions in positions 9-, 2-, and 8- (i.e., 9-benzyl-2-butoxy-8-hydroxyadenine), induces in vitro immunodeviation of Th2 cells to a Th0/Th1 phenotype. In this article, we evaluate the in vivo ability of SA-2 to affect Th2-mediated lung inflammation and its safety. TLR triggering and NF-κB activation by SA-2 were analyzed on TLR-transfected HEK293 cells and on purified bone marrow dendritic cells. The in vivo effect of SA-2 on experimental airway inflammation was evaluated in both prepriming and prechallenge protocols by analyzing lung inflammation, including tissue eosinophilia and goblet cell hyperplasia, bronchoalveolar lavage fluid cell types, and the functional profile of Ag-specific T cells from draining lymph nodes and spleens. SA-2 induced mRNA expression and production of proinflammatory (IL-6, IL-12, and IL-27) and regulatory (IL-10) cytokines and chemokines (CXCL10) in dendritic cells but down-regulated TGF-β. Prepriming administration of SA-2 inhibited OVA-specific Abs and Th2-driven lung inflammation, including tissue eosinophilia and goblet cells, with a prevalent Foxp3-independent regulatory mechanism. Prechallenge treatment with SA-2 reduced the lung inflammation through the induction of a prevalent Th1-related mechanism. In this model the activity of SA-2 was route-independent, but adjuvant- and Ag dose-dependent. SA-2-treated mice did not develop any increase of serum antinuclear autoantibodies. In conclusion, critical substitutions in the adenine backbone creates a novel synthetic TLR7 ligand that shows the ability to ameliorate Th2-mediated airway inflammation by a complex mechanism, involving Th1 redirection and cytokine-mediated regulation, which prevents autoreactivity.

Infliximab and Cogan's syndrome.

Sir, Cogan’s syndrome (CS) is a rare inflammatory disease, with a typical form (TCS) consisting of non-syphilitic interstitial keratitis, hearing loss, and vestibular impairment and an atypical one (ACS) with different ocular lesions, variable vestibular-auditory impairment and systemic inflammation. Hearing loss is usually progressive and bilateral and leads to deafness in 37–67% of the patients. High dose steroids and immunosuppressive therapy treat the first phases, but the disease tends to recur. We describe the effectiveness of infliximab in the treatment of three cases of Cogan’s syndrome and emphasise the importance of an early treatment to prevent irreversible damages. A 30-year-old woman with acute atypical Cogan’s syndrome was treated with methylprednisolone and cyclophosphamide, but a bilateral sensorineural hearing loss and a vestibular hypofunction persisted. Therefore, infliximab was administrated at 3 mg ⁄ kg at weeks 0, 2, 6, and 8, then every 8 weeks in association with methotrexate, giving rapid improvement (Fig. 1a). The treatment was suspended during a pregnancy, completed without complications. A new Cogan’s syndrome flare was treated with infliximab with good disease control in a 5 years follow-up. A 29-year-old man developed an interstitial keratitis and symptoms resembling Meniere disease, with a bilateral, sensorineural hearing loss. After treatment with betamethasone, the patient showed a clinical worsening. Due to a diagnosis of typical Cogan’s syndrome the patient was treated with traditional immunosuppressive therapy, without stable improvement. Therefore, infliximab was administered following international protocol, giving a complete resolution of ocular symptoms and a hearing improvement (Fig. 1b). A 35-year-old man developed atypical Cogan’s syndrome characterised by left hearing loss and anterior scleritis. Despite a pulse therapy of cyclophosphamide and Fig. 2. Endoscopic view of the nasal pack in situ. C O R R E S P O N D E N C E : L E T T E R S Correspondence 441

Successful Treatment of Ocular Sarcoidosis with Rituximab

Sarcoidosis is a multisystem inflammatory disease of undetermined origin. Thoracic involvement is the most common, with lymphoadenopathy and a various degree of lung lesions, such as granulomatous nodules and diffuse interstitial thickening, potentially leading to lung fibrosis. Skin, joints, heart, brain, and eye, however, can also be involved with a wide spectrum of clinical manifestations. Ocular sarcoidosis occurs approximately in one-third of patients, also in apparent absence of disease manifestations in other locations and can potentially involve any element of the eye. Among ocular lesions, however, some are more suggestive of sarcoidosis, such as bilateral granulomatous uveitis. Despite the recent advances in the development of new therapeutic agents, sarcoidosis remains a great therapeutic challenge, because of the current lack of data on the efficacy of the immunosuppressive and biological treatments. A 50-year-old woman was referred to our Center for relapsing uveitis. She had been facing recurrent severe uveitis involving both the eyes for 3 years, with poor and transitory responses to topical treatments and oral steroid therapy. Uveitis recurred regularly shortly after steroid withdrawal. A complete ophthalmic evaluation revealed a bilateral granulomatous panuveitis characterized by anterior chamber Tyndall, keratic precipitates, synechiae, vitreous opacity 3þ in RE and 1þ in LE, and cystoid macular edema OU. Best-corrected visual acuity (BCVA) was 0.70 logMAR RE and 0.20 logMAR LE (Figure 1). A systemic disease was suspected because of the concomitant presence of multiple, raised, erythematous lesions on the anterior surface of the lower legs, identifiable as erythema nodosum, and neurological symptoms, consisting of left arm paresthesias. A brain nuclear magnetic resonance (NMR) was performed, revealing the presence of multiple, nonenhancing lesions of the white matter, compatible with neurosarcoidosis. Full blood count, metabolic panel, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and the other laboratory tests gave results within normal limits. Antinuclear antibodies (ANA), anti-dsDNA, anti-extractable nuclear antigens (ENA), anti-neutrophil cytoplasm antibodies (ANCA), anti-phospholipid antibodies (aPL), and lupus anticoagulant (LAC) tests were also negative. Angiotensin converting enzyme (ACE), however, was significantly increased (106 U/L). A high-resolution CT of the lung with contrast revealed multiple nodular bilateral lung lesions with mild hilar and mediastinal lymphoadenopathies. To confirm the diagnostic hypothesis we also performed a scintigraphy that revealed abnormal gallium uptake by both parotid glands and lungs. The patient did not consent to a bronchoscopy, but the lung involvement was clinically mild, so the predictive value of such a procedure was low. We started topical therapy (dexamethasone 2% and tropicamide 1%) and oral prednisone

Cytomegalovirus retinitis following intravitreal dexamethasone implant in a patient with central retinal vein occlusion.

ciations between subfoveal choroidal thickness (SFCT) and age, refractive error (RE) and axial length (AL) have been demonstrated, although findings are inconsistent and variability in SFCT cannot be fully explained by these factors alone. The high vascular structure of the choroid suggests that some variation in SFCT may be the result of changes in the choroidal blood flow. This study investigated the effects of ocular perfusion pressure (OPP), blood pressure [systolic (SBP) and diastolic (DBP)] and intra-ocular pressure (IOP) on SFCT in normal individuals and also the effect of age, gender, RE and AL. Participants were healthy volunteers, recruited from staff and students from the Ophthalmology Department at St James’s University Hospital, Leeds. Inclusion criteria were as follows: age from 18 to 60 years, no history of ocular disease including ocular surgery and laser, myopia less than 6D and written, informed consent. Ethical approval was obtained from the Leeds Institute of Health Sciences and Leeds Institute of Genetics, Health and Therapeutics and Leeds Institute of Molecule Medicine Joint Ethics Committee (HSLTLM/11/043). OPP formula: OPP = 2/3[DBP + 1/3(SBP DBP)] IOP. All data were collected from participants on the same day, as close in time to OCT imaging as possible. Mean age of the 46 participants was 35.83 (range: 22–60) years, and 21 were male. Mean SFCT was 313.1 lm (SD = 77.0 lm) in the right eyes. Data for right eyes were used for analysis. There was a significant negative correlation between SFCT and the following variables on univariate analysis: AL (p = 0.001, r = 0.47, r = 0.22), SBP (p = 0.041, r = 0.30, r = 0.09), OPP (p = 0.045, r = 0.29, r = 0.08) and a non-significant trend suggesting association between SFCT and DBP (p = 0.053, r = 0.28, r = 0.08), RE (p = 0.055, r = 0.28, r = 0.08) (Fig. 1). Using multiple regression analysis, only AL was found to be a significant independent variable (p = 0.024, r = 0.265). No association seen with other variables. This study identified a modest, negative correlation between SFCT and SBP. SBP has been shown to influence CT, although limited consensus exists. Previous reports state acute rises in blood pressure do not cause significant changes in CT, and therefore, blood pressure-associated variation in CT may occur over a relatively greater time scale (Alwassia et al. 2013). A modest, negative association between SFCT and OPP was found. This finding has been reported previously (Kim et al. 2012). Kim et al. (2012) proposed that relatively thicker choroids may require a lower OPP to maintain ocular blood flow, and in relatively thinner choroids, a higher OPP may be required to compensate for potential reductions in choroidal blood flow. Poor ocular blood flow, secondary to reduced OPP, has been shown to increase the risk of ocular ischaemia, with the fovea at particular risk (Levin et al. 2011; Schmidl et al. 2011). Given the association between SFCT and a range of physiological variables, care needs to be taken in attributing variation in CT as the basis for ocular disease. Rishi et al. (2013) report a study of polypoidal choroidal vasculopathy (PCV) compared to agematched controls and eyes with other forms of neovascular AMD. Eyes with PCV had higher mean OPP than controls and eyes with AMD. This suggests differences in SFCT between diseased and healthy eyes may more likely be the result of physiological variation in ocular and systemic factors. The studied variables here and others need further study to explain fully the variation in SFCT seen in normal individuals and in others with systemic vascular disease.

The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 and Th1 cell development

Rai, a Shc adapter family member, acts as a negative regulator of antigen receptor signaling in T and B cells. Rai−/− mice develop lupus‐like autoimmunity associated to the spontaneous activation of self‐reactive lymphocytes. Here, we have addressed the potential role of Rai in the development of the proinflammatory Th1 and Th17 subsets, which are centrally implicated in the pathogenesis of a number of autoimmune diseases, including lupus. We show that Rai−/− mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments on naive and effector/memory CD4+ T cells demonstrate that Rai−/− favors the development and expansion of Th17 but not Th1 cells, indicating that Rai modulates TCR signaling to antagonize the pathways driving naive CD4+ T cell differentiation to the Th17 lineage, while indirectly limiting Th1 cell development in vivo. Th1 and Th17 cell infiltrates were found in the kidneys of Rai−/− mice, providing evidence that Rai−/− contributes to the development of lupus nephritis, not only by enhancing lymphocyte activation but also by promoting the development and expansion of proinflammatory effector T cells. Interestingly, T cells from SLE patients were found to have a defect in Rai expression, suggesting a role for Rai in disease pathogenesis.

Lobular panniculitis with small vessel vasculitis associated with ulcerative colitis

We report a rare case of lobular panniculitis with small vessel vasculitis, presenting with fever, cutaneous lesions, and systemic manifestations involving the visceral fat and associated with ulcerative colitis. The patient was treated with cyclophosphamide and prednisolone, which successfully cured the systemic disease, with resolution of the inflammatory infiltrates.

Systemic lupus erythematosus: immunopathogenesis and novel therapeutic targets.

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases with multiorgan involvement. SLE presents many genetic and epigenetic associations and the pathogenesis is characterized by a complex network of alterations affecting both adaptative and innate immunity. The disclosure of novel mechanisms of SLE pathogenesis suggested new therapeutic targets, based on interference with the cytokine pathways or on depletion of the immune cells.

Rispondono I Medici

Il Medico di Medicina Generale (MMG) riveste un ruolo fondamentale nel Sistema Sanitario Nazionale, rappresentando il primo referente per il paziente che si presenta con un problema clinico.

The “multifaceted” onset of vasculitis neuropathy

The article from Lozeron et al. [1], published in this issue of Internal and Emergency Medicine, underscores the importance of recognizing or suspecting a systemic vasculitis in patients who complain of atypical or refractory sciatica-like symptoms. Vasculitides is a group of systemic diseases characterized by a protean clinical presentation, usually with a pattern of multi-organ involvement, which if not promptly diagnosed, may be responsible for severe morbidity and mortality [2]. The following article reminds us that besides usual peripheral neurological presentations classically associated with systemic vasculitides, i.e., multifocal motor neuropathy or less frequently symmetric peripheral neuropathies, unusual neurological symptoms can in rare instances mark the disease onset [3]. Even if lumbosacral radiculoplexus neuropathy is mainly associated with microischemic events and diabetes mellitus, which was correctly ruled out in 8 of the study patients, it is also described in non-diabetic patients who probably suffered an underlying autoimmune microvasculitis process [4]. The possibility of an autoimmune lombosacral plexus radiculitis should be particularly looked for when sciatica-like symptoms, in non-diabetic patients, are not fully explained by radiological spine findings; or when the controlateral limb is subsequently involved, in a pattern ultimately resembling a multifocal neuropathy. Furthermore, these patients often undergo unnecessary and repeated spine surgery procedures. Besides the importance of a thorough history taking and physical examination, the authors underscore the role of correctly performing a nerve conduction study. This examination shows axonal damage and asymmetric multifocal involvement, giving an early basis for suspecting a vasculitis, and for performing subsequent investigations. The other fundamental step is a peripheral nerve biopsy, a very useful procedure especially when a vasculitis is suspected in patients with an atypical neurologic pattern of presentation. In this following study, biopsy specimens show fibrinoid necrosis in all patients, histologically supporting the classification criteria for diagnosing polyarteritis nodosa, confirming the well-known concept that this entity is probably the vasculitis most often associated with peripheral multifocal neuronal involvement [5, 6]. In summary, this article should remind us of what suspecting a rare disease in clinical practice means for doctors, and the importance of looking ‘‘beyond’’ common symptoms when these are atypical or refractory to standard treatment [7]. Regarding this last matter in particular, it is really worthwhile to underscore the fundamental role of tertiary referring centers for rare diseases, such as the center for rare peripheral neuropathies that conducted the study, since they probably represent the place where difficult-to-treat or refractory patients can have the best or the only chance to achieve a definitive and correct diagnosis.

FRI0348 Biological treatment of behçet’s disease according to different clinical “phenotypes”: a retrospective study on 90 patients

Background Behçet disease is considered a systemic vasculitidis-like process that can express with different clinical phenotypes. Anti TNFs agents are a well established therapy for patients with refractory Behçet disease, particularly when severe visual involvement or life threatening complications are present. Objectives To evaluate different clinical phenotypes, other than severe ocular-neuro Behçet, which required an anti-TNF immunosoppressive therapy to obtain Behçet disease control (arthritis-mucocutaneous Behcet, entero-Behcet, vascular-Behçet). Methods We retrospectively evaluated clinical data of 93 patients (51 females, 42 males) who had been referred to our Center for overt or suspected Behçet disease over the last 10 years. Patients were hence divided into 2 groups: 75 patients fulfilling the International Study Group (ISG) criteria for Behçet syndrome (group 1) and 18 patients who, although not meeting international criteria, were considered to have a clinical presentation suggestive of “incomplete” Behçet disease (group 2). Results 25/93 of patients (26%) were treated with an anti TNF agent in both the groups. In group 1 22/75 (29%) patients had been treated with at least one biological agent during the disease course. Fig. 1 describes the predominant Behçet phenotype that determined the choice of starting an anti-TNF therapy in group 1. Only 3/18 (16%) patients in group 2 were treated with biological therapy: 1 with etanercept (spondyloarthritis overlap) and 2 with adalimumab (recurrent superficial thrombophlebitis). Both Infliximab and adalimumab were well tolerated and lead to optimal disease control, since switching from one biological agent to another for therapeutic failure was necessary in less than 5% of patients. Image/graph Conclusions Infliximab and adalimumab were the most commonly used first line biological agents to treat severe or refractory Behçet patients. Infliximab was the first choice agent particularly when severe ocular or nervous system involvement were present. Over the last 5 years we have more commonly prescribed adalimumab to treat other protean features of Behçet syndrome, owing to good efficacy and its easier subcutaneous administration. Eye involvement was the main indication to start a biological anti-TNF therapy in patients with severe Behçet disease who have been followed at our center. Disclosure of Interest: None Declared