Enrico Tombetti

Treatment of Refractory Takayasu Arteritis with Tocilizumab: 7 Italian Patients from a Single Referral Center

Objective. The aim of our study was to evaluate the safety and the efficacy of tocilizumab (TCZ) for refractory Takayasu arteritis (TA). Methods. We retrospectively assessed the outcome of blocking interleukin (IL)-6 with TCZ in 7 consecutive patients with refractory TA using a combination of clinical and imaging assessment. Results. During a median followup visit at 14 months, 4 patients taking TCZ [including 2 nonresponders to tumor necrosis factor (TNF) inhibitors] achieved clinical response, suggesting a nonredundant role for IL-6 in TA. Inflammatory markers normalized in all patients treated with TCZ. However, vascular progression occurred in 4 patients, suggesting the involvement of other inflammatory pathways and confirming the limitations of erythrocyte sedimentation rate and C-reactive protein for disease activity assessment while taking TCZ. Three patients experienced adverse events and 2 suspended TCZ. Conclusion. TCZ may be effective in a subset of patients with refractory TA, even in cases of unresponsiveness to TNF inhibitors. Inflammatory markers are not valid markers of TA activity on TCZ. Further studies are needed to confirm these preliminary observations.

Systemic pentraxin-3 levels reflect vascular enhancement and progression in Takayasu arteritis

IntroductionProgression of arterial involvement is often observed in patients with Takayasu arteritis (TA) thought to be in remission. This reflects the failure of currently used biomarkers and activity criteria to detect smouldering inflammation occurring within arterial wall. Pentraxin-3 (PTX3) is a soluble pattern recognition receptor produced at sites of inflammation and could reveal systemic as well as localized inflammatory processes. We verified whether the blood concentrations of PTX3 and of C-reactive protein (CRP) in patients with Takayasu arteritis (TA) might reflect vascular wall involvement, as assessed by signal enhancement after contrast media administration, and the progression of arterial involvement.MethodsA cross-sectional single-centre study was carried out on 42 patients with TA that comprised assessment of PTX3, of CRP and erythrocyte sedimentation velocity (ESR). In total, 20 healthy controls and 20 patients with Systemic Lupus Erythematous (SLE) served as controls. Vascular imaging was carried out by magnetic resonance angiography, doppler ultrasonography and computed tomography angiography.ResultsPatients with TA and SLE had higher plasmatic PTX3 and CRP concentrations than healthy controls (P = 0.009 and 0.017, respectively). PTX3 levels did not correlate with those of CRP. Patients with active systemic TA had significantly higher concentrations of CRP but similar levels of PTX3 than patients with quiescent disease. In contrast, patients with vascular inflammation detectable at imaging had higher PTX3 concentrations (P = 0.016) than those in which vessel inflammation was not evident, while CRP levels were similar. The concentration of PTX3 but not that of CRP was significantly higher in TA patients with worsening arterial lesions that were not receiving antagonists of tumor necrosis factor-? or interleukin-6.ConclusionsArterial inflammation and progression of vascular involvement influence plasma PTX3 levels in TA, while levels of CRP accurately reflect the burden of systemic inflammation. These results support the contention that PTX3 reflects different aspects of inflammation than CRP and might represent a biomarker of actual arteritis in TA.

Anti-cytokine treatment for Takayasu arteritis: State of the art.

Takayasu arteritis (TA) is a rare and idiopathic large-vessel arteritis typically affecting young women which has important morbidity and mortality. There are no animal models of TA and pathogenesis is still mysterious. Clinical assessment lacks accurate activity indexes and is based on the integration of clinical, laboratory and radiological data. TA rarity has hampered randomized clinical trials and the achievement of high-quality evidence to guide clinical activity. Prevention of vascular progression, with progressive vessel wall remodelling and hyperplasia, is the main therapeutic goal. Medical therapy remains the mainstay of management and comprises traditional immunosuppressive agents and anti-inflammatory drugs, such as steroids and blockers of pivotal cytokines, TNF-α and IL-6. These strategies however only partially limit vascular progression, indicating that local molecular events are involved. Here we discuss recent data suggesting that selected cellular components of TA lesions should be evaluated as novel therapeutic targets.

Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis

Fibrosis of the skin and of internal organs, autoimmunity, and vascular inflammation are hallmarks of Systemic Sclerosis (SSc). The injury and activation of endothelial cells, with hyperplasia of the intima and eventual obliteration of the vascular lumen, are early features of SSc. Reduced capillary blood flow coupled with deficient angiogenesis leads to chronic hypoxia and tissue ischemia, enforcing a positive feed-forward loop sustaining vascular remodelling, further exacerbated by extracellular matrix accumulation due to fibrosis. Despite numerous developments and a growing number of controlled clinical trials no treatment has been shown so far to alter SSc natural history, outlining the need of further investigation in the molecular pathways involved in the pathogenesis of the disease. We review some processes potentially involved in SSc vasculopathy, with attention to the possible effect of sustained vascular inflammation on the plasticity of vascular cells. Specifically we focus on mesenchymal transition, a key phenomenon in the cardiac and vascular development as well as in the remodelling of injured vessels. Recent work supports the role of transforming growth factor-beta, Wnt, and Notch signaling in these processes. Importantly, endothelial-mesenchymal transition may be reversible, possibly offering novel cues for treatment.

Management options for Takayasu arteritis

Introduction: Takayasu arteritis (TA) is a rare, large vessel vasculitis, which is characterized by substantial morbidity and premature mortality. Several approaches have been used in the recent years for the management of the disease, with some promising results. The best therapeutic strategies still need to be identified. Areas covered: This article discusses the main clinical features of TA and the recent insights into diagnosis and treatments. A search has been undertaken on PubMed and Scopus databases and the most relevant references have been considered. Expert opinion: The identification of the most effective regimens able to control TA unrelenting vascular inflammation without undue toxicity remains a challenge. To define the validated biomarkers and the activity criteria reflecting the specific features of vascular inflammation, and possibly predicting its outcome, represents a critical challenge for physicians in the next years.

Chromogranin-A production and fragmentation in patients with Takayasu arteritis

BackgroundChromogranin-A (CgA) is a secretory protein processed into peptides that regulate angiogenesis and vascular cells activation, migration and proliferation. These processes may influence arterial inflammation and remodelling in Takayasu arteritis (TA).MethodsPlasma levels of full-length CgA (CgA439), CgA fragments lacking the C-terminal region (CgA-FRs) and the N-terminal fragment, CgA1–76 (vasostatin-1, VS-1) were analysed in 42 patients with TA and 20 healthy age-matched controls. Vascular remodelling was longitudinally assessed by imaging. CgA peptides were related to markers of systemic and local inflammation, disease activity and vascular remodelling.ResultsLevels of CgA-FRs and VS-1 were increased in TA. Treatment with proton-pump inhibitors (PPIs) and arterial hypertension partially accounted for CgA levels and high inter-patient variability. CgA439, CgA-FRs and VS-1 levels did not reflect disease activity or extent. Markers of systemic or local inflammation correlated with higher CgA-FRs and VS-1 in normotensive patients and with higher CgA439 in hypertensive patients. Treatment with non-biologic anti-rheumatic agents was associated with increased CgA-FRs and a distinctive regulation of CgA processing. Reduced blood levels of anti-angiogenic CgA peptides were associated with vascular remodelling in the groups of patients on PPIs and with arterial hypertension.ConclusionsThe plasma levels of CgA fragments are markedly increased in TA as a consequence of disease- and therapy-related variables. Anti-angiogenic forms of CgA may limit vascular remodelling. Given the effect of the various CgA peptides, it is advisable to limit the therapeutic prescriptions that might influence CgA-derived peptide levels to clearly agreed medical indications until further data become available.

Drug induced exfoliative dermatitis: state of the art

Drug induced exfoliative dermatitis (ED) are a group of rare and severe drug hypersensitivity reactions (DHR) involving skin and usually occurring from days to several weeks after drug exposure. Erythema multiforme (EM), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the main clinical presentations of drug induced ED. Overall, T cells are the central player of these immune-mediated drug reactions. Here we provide a systematic review on frequency, risk factors, pathogenesis, clinical features and management of patients with drug induced ED.

Large vessel vasculitis: the search for response biomarkers.

The most common large vessel vasculitides (LVV) in adults are giant cell arteritis (GCA) and Takayasu arteritis (TA) [1]. The former is seen in those >50 years, while the latter typically affects those under 40 years. GCA and TA share histologic features, including focal granulomatous pan-arteritis characterized by lymphomonocytic infiltration and occasional multinucleate giant cells. The resulting intimal hyperplasia predisposes to luminal obstruction, arterial wall remodeling with disruption of elastic laminae, excessive deposition of extracellular matrix, and fibrosis. Understanding of LVV pathogenesis remains limited and all aspects of clinical management are suboptimal. The few available clinical trials are limited to GCA, and TA remains an orphan disease. Diagnosis is typically delayed and understanding of pathogenesis is poor. Treatment options are limited, with undue reliance upon corticosteroids resulting in significant side effects [2–4]. Disease complications can be severe and life-threatening. The lack of disease-specific biomarkers is a critical contributor to this rather dismal picture. However, recent renewed efforts raise the hope of significant advances in disease management. The focus of this editorial is to briefly present our view of biomarker research in GCA and TA, presenting recent advances and the main unmet needs and pitfalls.

Application of imaging techniques for Takayasu arteritis

Arterial injury with subsequent remodelling and predisposition to arterial stenosis and/or dilation are the hallmarks of Takayasu arteritis. The degree of arterial damage closely aligns with prognosis and therefore its prevention is the predominant aim of therapy. Non-invasive imaging has greatly improved our ability to identify the extent and severity of disease and to monitor its progress. However, many questions remain concerning the optimal use of individual modalities at different stages of disease. Imaging methods for the quantification of arterial damage are lacking. Likewise, no single technique can accurately determine disease activity within the arterial wall or distinguish inflammatory and non-inflammatory disease progression. The aim of this review is to outline current imaging strategies in Takayasu arteritis, their individual roles in diagnosis and disease monitoring and potential future advances.

Takayasu arteritis: advanced understanding is leading to new horizons

Although outcomes in Takayasu arteritis (TAK) are improving, diagnosis is typically delayed and significant arterial injury accrues. While wider use of non-invasive imaging is impacting this, the onus remains with clinicians to consider a diagnosis of TAK earlier. Meanwhile, morbidity and mortality in TAK remains increased. Herein we review the current situation, outline recent advances and summarize remaining challenges. Understanding of disease pathogenesis remains poor. However, recent genetic data and identification of pathogenic cytokines may facilitate the search for biomarkers capable of distinguishing active and inactive disease, inflammatory and non-inflammatory arterial remodelling. Imaging is critical for TAK, and each modality has important strengths and limitations. Dependence upon CS therapy remains too high. However, the impact of combination immunosuppressive therapy is now recognized, biologic therapies are increasingly available and new agents offer promise. Multicentre clinical trials are now required, and these will depend upon development of defined clinical and imaging end-points.