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Treatment of giant-cell arteritis with tocilizumab, an interleukin-6 receptor alpha inhibitor, while prednisone was tapered over a 26-week period resulted in higher rates of sustained remission than prednisone tapering plus placebo and reduced the total prednisone dose.

Objectives:To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis.Methods:An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.Results:Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures.Conclusions:On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.

Primary CNS vasculitis is an uncommon disorder of unknown cause that is restricted to brain and spinal cord. The median age of onset is 50 years. The neurological manifestations are diverse, but generally consist of headache, altered cognition, focal weakness, or stroke. Serological markers of inflammation are usually normal. Cerebrospinal fluid is abnormal in about 80-90% of patients. Diagnosis is unlikely in the presence of a normal MRI of the brain. Biopsy of CNS tissue showing vasculitis is the only definitive test; however, angiography has often been used for diagnosis even though it has only moderate sensitivity and specificity. The size of the affected vessels varies and determines outcome and response to treatment. Early recognition is important because treatment with corticosteroids with or without cytotoxic drugs can often prevent serious outcomes. The differential diagnosis includes reversible cerebral vasoconstriction syndromes and secondary cerebral vasculitis.Disclosure of InterestNone declared

Objectives:To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis.Methods:An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.Results:In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures.Conclusions:On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

BackgroundSome cases of unilateral primary central nervous system vasculitis (PCNSV) with relapsing disease involving the same brain hemisphere have been described [1].ObjectivesThe aim of this study was to define the frequency and characteristics of patients with unilateral relapsing involvement in a large cohort of patients with PCNSV.MethodsWe retrospectively studied a cohort of 216 patients with PCNSV seen at the Mayo Clinic, Rochester, MN from 1983 to 2022. Data collected for all cases included comprehensive information about clinical findings, laboratory tests, imaging, CNS biopsy or autopsy, therapies, flares, follow-up functional status and cause of death. Cerebral biopsy specimens were reviewed by one neuropathologist (CG). Angiograms and MRIs were reviewed by a neuroradiologist. For the present study, we specifically identified those patients with at least two flares and imaging at diagnosis and at follow-up showing vasculitis confined to one cerebral hemisphere.ResultsTwenty-five patients (19.8%) had at least two flares. 3 of them (1.4%) had unilateral relapsing vasculitis. All 3 patients had angiography-negative and biopsy-positive PCNSV. One patient had amyloid beta-related angiitis (ABRA), while the other 2 patients had granulomatous-necrotizing and lymphocitic vasculitides, respectively. Hemisphere involvement occurred on the left in two, and on the right in one. In all three patients the main presenting clinical manifestation at diagnosis and at the time of flares was seizures. All had multiple flares (from 4 to 10) and were treated with different traditional immunodepressive drugs and rituximab (RTX) for the steroid-resistance. They received long-term treatment (more than 2 years) with fixed high-dose prednisone (PDN) (in one 40 mg/daily, in the other two 20 mg/daily) because the vasculitic process flared when the PDN dose was reduced. One patient had at MRI prominent leptomeningeal enhancement, while the other two had cerebral lesions with gadolinium enhancement. In all three patients the vasculitic process was confined to the same cerebral hemisphere at diagnosis and during the flares, and at the last available brain MRI performed 35 months, 167 months, and 65 months after the diagnosis, respectively. All 3 patients at last follow-up had slight disability with mild cognitive impairment; one case also had mild left hemiparesis. Spinal fluid examination at diagnosis was normal in 2 patients.ConclusionUnilateral relapsing involvement represents a rare subset of PCNSV with peculiar characteristics and can be observed in all neuropathological patterns.References[1]AbdelRazek MA, Hillis JM, Guo Y, et al. Unilateral Relapsing Primary Angiitis of the CNS: An Entity Suggesting Differences in the Immune Response Between the Cerebral Hemispheres. Neurol Neuroimmunol Neuroinflamm. 2021 Jan 5;8(2):e936.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:Unruptured intracranial aneurysms (UIAs) are rarely reported in primary central nervous system vasculitis (PCNSV).Objectives:In this study we described the clinical findings, response to therapy, and outcomes of UIA in a large cohort of PCNSV patients. We also compared PCNSV patients with and without a co-occurring UIA.Methods:Retrospective single-center study utilizing a cohort of 216 consecutive patients with PCNSV who were evaluated at the Mayo Clinic over a 40-year period. The diagnosis of PCNSV was based on brain or spinal cord biopsy, cerebral angiography or both. UIAs were identified on cerebral angiography. The clinical, laboratory, radiologic and pathologic findings, management, and outcomes of patients with UIA were described and compared with those without UIA.Results:12/216 (5.5%) patients with PCNSV had at least one UIA. Biopsy was positive in one patient and showed necrotizing vasculitis. Eleven patients had evidence of UIA on angiogram at diagnosis. One patient developed an aneurysm during the follow-up in association with a worsening of vasculitic radiological findings. The most common presenting symptom for PCNSV in the setting of UIA was headache (67%), followed by persistent neurologic deficit or stroke (50%). Most patients with UIA presented with multiple cerebral infarcts on MRI (67%), one patient had subarachnoid hemorrhage, and one left parieto-occipital intracerebral hematoma, both unrelated to the aneurysm. Black blood imaging was performed in 4 patients and 2 showed segmental circumferential mural enhancement involving multiple vessels. Two patients had 2 UIAs, while the other 10 had 1. The most frequent UIA location was internal carotid artery (50%), followed by anterior cerebral artery (21%). Ten of the UIAs were < 5 mm in diameter, and 3 were 5-7 mm in diameter; the size was not available for one. All UIAs were unchanged in size and configuration during follow-up and no new aneurysms were detected. Compared to the 204 patients with PCNSV without a UIA, no significant clinical differences were observed, except for a reduced disability at last follow-up (p = 0.038). An increased survival trend for UIA patients was also observed: at the end of follow-up no patients with aneurysms died, compared to 46 (22.5%) of the 204 patients without UIA (p = 0.09).Conclusion:Intracranial aneurysms uncommonly occur in PCNSV. Patients with UIA in the setting of PCNSV had a good prognosis in this small series of patients with co-occurring UIA and PCNSV.REFERENCES:[1] Salvarani C, Brown RD Jr, Hunder GG. Adult primary central nervous system vasculitis. Lancet 2012; 380:767–777.[2] Brown RD Jr, Broderick JP. Unruptured intracranial aneurysms: epidemiology, natural history, management options, and familial screening. Lancet Neurol 2014; 13:393-404.Table 1.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:In a previous study we have demonstrated that powerDoppler US (PDUS) is able to detect the iloprost (ILO) acute effect on subcutaneous vascularization of periungual (PU) and finger pulp (FP) subcutaneous areas in SSc patients with long-lasting disease. Few studies have explorated the chronic effect of ILO infusion in this group of patient.Objectives:We aim to evaluate the variation of the acute vascular effects of ILO infusion at baseline (T0) and at the second ILO infusion 4 weeks apart (T1).Methods:Twenty-eight consecutive SSc patients who met the ACR/EULAR criteria for SSc referring to our tertiary center for ILO infusion were enrolled in the study. FP and PU vascularization of the 1st, 2nd and 3rd finger of the dominant hand were evaluated before (ILO-B) and after (ILO-A) ILO infusion (dosage 0.5-2.0 ng/kg/min for 4-6 hours) at baseline (T0) and at ILO infusion 4 weeks later (T1) using an Esaote MylabClassC, (Genoa, Italy) machine equipped with a 22-8 Mhz multifrequency linear probe. All the exams were performed after at least 30 minutes of acclimatation in a room with an ambient temperature ranging from 20 to 24 ° C by the same operator (PM). All the images with the highest presence of PD signal were stored for subsequent examination by a rheumatologist (ST) blind to images sequency. The presence of PD signal in every image was scored according to a semiquantitative 0-5 scale. The value of each finger (FP & PU) were summed up to obtain a total patient PD score (TotPDS). No improvement in TotPDS score was defined when the difference between ILO-A and ILO-B TotPDS (Δ TotPDS) was < 0; while improvement was considered when Δ TotPDS was > 1. Values of TotS and its variations (ILO-B minus ILO-A) at T0 and T1 were compared by T-test for paired samples. Clinical demographic and US data entered in a multivariate logistic regression analysis to evaluate the presence of factors predictive of TotS variation at T0 and T1.Results:Clinical and laboratory features of the 28 enrolled pts are reported in Table 1. TotPDS variations after the 1st and 2nd ILO infusion are reported in table 1. There were no statistical differences between ILO-B and ILO-A TotPDS at T0 and T1 examination. T0 Δ TotPDS was statistically lower than T1 Δ TotPDS. T1 Δ TotPDS was grater than T0 Δ TotPDS in 17 pts (60.7%), unchanged or lower in 11 pts (39.3%). At multivariate logistic regression analysis no baseline clinical, demographic or US characteristics of the patients were predictive of the TotPDS positive variation between T0 and T1 ILO infusion.Table 1.Clinical, laboratory and PDUS characteristics of 28 SSC patients, before and after ILO treatment.number (%)Mean ± SDP valueDisease Duration (y)14.4±11.3Age (y)57.5±12.6Female26 (92.9%)Iloprost therapy duration (y)7.2±6.5Disease featuresDigital UlcersCalcinosisEsophageal involvementArthritisILDHAP20 (71%)9 (32%)15 (54%)6 (21%)8 (29%)7 (25%)Cutaneous subset of diseaseDiffuseLimitedOther14 (50%)13 (46%)1 (4%)Ultrasound TotPDST0 ILO-B TotPDS9.33±6.160.631T1 ILO-B TotPDS8.89±5.90T0 ILO-A TotPDS15.59±5.370.244T1 ILO-A TotPDS17.30±7.52T0 Δ TotPDS4.46±7.21< 0.001T1 Δ TotPDS10.32±6.28Conclusion:PDUS examination of the PU and FP area can demonstrate an ILO chronic effect in SSc patients with long-lasting disease.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

A major achievement in nosology has been the development of novel classification criteria for Behçet disease (BD), called “International criteria for Behçet’s disease” (ICBD) (1). Data on 2556 patients with BD diagnosed by experts and 1163 controls mimicking BD were collected from 27 countries, and the best discriminatory variables used to create a scoring scheme with a defined diagnostic cut-off. These criteria were tested in a validation set, yielding a sensitivity of 95% with a specificity of 91%, proving more sensitive in the same set than the International Study Group for Behçet disease (ISGB) criteria, although at the price of a somewhat reduced specificity. In 2012, ANCA-associated vasculitis has been in the forefront of research. A genome-wide association study performed in a large UK cohort and replicated in a different cohort of patients with granulomatosis with polyangiitis and microscopic polyangiitis provided evidence for distinct genetic associations of these two disorders (2). Interestingly, the strongest genetic associations were found with the antigenic specificities of ANCA rather than with the clinical phenotypes. A meta-analysis published last year aimed to investigate whether rising or persistently elevated ANCA titers might predict future relapses in patients with ANCA-associated vasculitis (3). The results derived from 18 studies demonstrated that ANCA titers were only modestly predictive of relapses. A prospective, randomized controlled trial (MAINRITSAN) on 114 patients with ANCA-associated vasculitis has compared azathioprine (2 mg/kg/day) with rituximab (500 mg every 6 months) for remission maintenance (4). The primary end point of the study was the rate of major relapses at 28 months. 27% of patients in the azathioprine arm relapsed compared to 4% of those who received rituximab. Adverse events were overall comparable in the two groups. These findings suggest that rituximab might have a pivotal role not only in induction, but also in maintenance of remission in patients with ANCA-associated vasculitis. With regard to giant cell arteritis (GCA), a study by our group re-assessed the histological alterations found in the temporal arteries from a large cohort of patients (5). In most cases, the histological pattern was that of a classical transmural infiltrate, but in some patients the inflammation appeared to be restricted to the vasa vasorum, to the periadventitial small vessels, or both. Visual loss was equally frequent in all groups of patients. These findings suggest that non-classical inflammatory patterns should be recognized as part of the spectrum of the histological abnormalities associated with GCA. Last year also witnessed a significant progress in the treatment of large-vessel vasculitis, including GCA and Takayasu’s arteritis (TAK). Interleukin-6 has emerged as a pivotal cytokine driving inflammation in large-vessel vasculitis. On the basis of this rationale, 19 patients with GCA and 9 of those with TAK were treated with the interleukin-6 receptor inhibitor tocilizumab (6,7). Most patients had refractory disease, but a few had new onset of vasculitis. A favorable response was reported in virtually all patients treated, although some patients relapses after tocilizumab was withdrawn. Controlled studies are warranted to confirm these encouraging results and to define the precise role of tocilizumab in newly diagnosed and refractory GCA and Takayasu’s arteritis. Davatchi F et al, JEADV 2013 (in press) Lyons PA et al, New Engl J Med 2012; 367-214 Tomasson G, Rheumatol 2012; 51:100 Guillevin L, Arthritis Rheum 2012; 10 (Suppl):S706 Restuccia G, Arthritis Rheum 2012; 64:549 Unizony S et al, Curr Opin Rheumatol 2013; 25:3 Salvarani C et al, Rheumatol 2012; 51:151 Disclosure of Interest None Declared

Adult primary central nervous system vasculitis (aPCNSV) is an uncommon disorder of unknown cause that is limited to the brain and spinal cord. The median age of onset is 50 years. The neurological manifestations are diverse, but commonly include headache, altered cognition, focal weakness, or stroke. Serological markers of inflammation are usually normal. Cerebrospinal fluid is abnormal in approximately 80-90% of the cases. The diagnosis is unlikely in the presence of a normal magnetic resonance imaging (MRI) of the brain. Biopsy of central nervous system tissue showing vasculitis is the only definitive test, however angiography has often been used for diagnosis even though it has only moderate sensitivity and specificity. To prevent misdiagnosis, particularly with the reversible cerebral vasoconstriction syndromes, new criteria based on the levels of certainty of the diagnosis of aPCNSV have been proposed. Advances in the neuroimaging techniques visualizing the wall of intracranial blood vessels have improved the capacity to distinguish inflammatory from non-inflammatory vascular lesions. These techniques could play in the future an important role in the diagnosis of aPCNSV. Studies of larger number of cases have revealed a more varied histopathological inflammatory picture and disclosed an association with amyloid angiopathy. It has also been recognized that aPCNSV is a heterogeneous disorder encompassing clinical subsets that differ in terms of prognosis and therapy. Finally, differently from earliest reports that suggested a poor prognosis with a fatal outcome in the majority of the cases, a large recent study from Mayo Clinic has described a more favorable course with good response to therapy and a favorable outcome in 81% of cases. Glucocorticoids alone or in combination with cyclophosphamide constitute the first line of treatment of PCNSV. TNFalpha blockers and mycophenolate mofetil can successfully treat patients with resistant disease.Early recognition is important because treatment with corticosteroids with or without cytotoxic drugs may prevent serious outcomes. A better understanding of the molecular mechanisms associated with the pathogenesis of aPCNSV should provide opportunities to improve therapy. Disclosure of Interest None Declared

Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.