Flares in Biopsy-Proven Giant Cell Arteritis in Northern Italy: Characteristics and Predictors in a Long-Term Follow-Up Study

This study evaluated the frequency, timing, and characteristics of flares in a large cohort of Italian patients with biopsy-proven giant cell arteritis (GCA) and to identify factors at diagnosis able to predict the occurrence of flares. We evaluated 157 patients with biopsy-proven transmural GCA diagnosed and followed at the Rheumatology Unit of Reggio Emilia Hospital (Italy) for whom sufficient information was available from the time of diagnosis until at least 4 years of follow-up. Fifty-seven patients (36.5%) experienced ≥1 flares. Fifty-one (46.4%) of the 110 total flares (88 relapses and 22 recurrences) were experienced during the first 2 years after diagnosis. The majority of relapses occurred with doses of prednisone ≤ 10 mg/day (82.9%), whereas only 3.4% of relapses occurred for doses ≥ 25 mg/day. Polymyalgia rheumatica (46.5%) and cranial symptoms (41.9%) were the most frequent manifestations at the time of the first relapse. Cumulative prednisone dose during the first year and total cumulative prednisone dose were significantly higher in flaring patients compared with those without flares (7.8 ± 2.4 vs 6.7 ± 2.4 g, P = 0.02; 15.5 ± 8.9 vs 10.0 ± 9.2 g, P = 0.0001, respectively). The total duration of prednisone treatment was longer in flaring patients (58 ± 44 vs 30 ± 30 months, P = 0.0001).Patients with disease flares had at diagnosis more frequently systemic manifestations (P = 0.02) and fever ≥ 38°C (P = 0.02), significantly lower hemoglobin levels (P = 0.05), more frequent presence at temporal artery biopsy (TAB) specimens of giant cells (P = 0.04) and intraluminal acute thrombosis (P = 0.007), and more moderate/severe arterial inflammation (P = 0.009) compared with those without flares. In the multivariate model fever ≥ 38 °C (hazard ratio 2.14; 95% confidence interval, 1.06-4.32, P = 0.03) and the severity of inflammatory infiltrate (moderate/severe versus mild) (hazard ratio 5.41; 95% confidence interval, 1.64-17.87, P = 0.006) were significantly associated with an increased risk of flares. In conclusion, a flaring course is common in GCA and it is associated with prolonged GC requirements. Fever at diagnosis and severity of inflammation at TAB appear to predict the development of disease flares

ANCA-associated vasculitis in childhood: Recent advances

Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener’s), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort

Complex interplay between neutral and adaptive evolution shaped differential genomic background and disease susceptibility along the Italian peninsula

The Italian peninsula has long represented a natural hub for human migrations across the Mediterranean area, being involved in several prehistoric and historical population movements. Coupled with a patchy environmental landscape entailing different ecological/cultural selective pressures, this might have produced peculiar patterns of population structure and local adaptations responsible for heterogeneous genomic background of present-day Italians. To disentangle this complex scenario, genome-wide data from 780 Italian individuals were generated and set into the context of European/Mediterranean genomic diversity by comparison with genotypes from 50 populations. To maximize possibility of pinpointing functional genomic regions that have played adaptive roles during Italian natural history, our survey included also ∼250,000 exomic markers and ∼20,000 coding/regulatory variants with well-established clinical relevance. This enabled fine-grained dissection of Italian population structure through the identification of clusters of genetically homogeneous provinces and of genomic regions underlying their local adaptations. Description of such patterns disclosed crucial implications for understanding differential susceptibility to some inflammatory/autoimmune disorders, coronary artery disease and type 2 diabetes of diverse Italian subpopulations, suggesting the evolutionary causes that made some of them particularly exposed to the metabolic and immune challenges imposed by dietary and lifestyle shifts that involved western societies in the last centuries

Intravenous methylprednisolone pulses in hospitalised patients with severe COVID-19 pneumonia, A double-blind, randomised, placebo-controlled trial

Rationale: Pulse glucocorticoid therapy is used in hyperinflammation related to coronavirus 2019 (COVID-19). We evaluated the efficacy and safety of pulse intravenous methylprednisolone in addition to standard treatment in COVID-19 pneumonia. Methods: In this multicenter, randomised, double-blind, placebo-controlled trial, 304 hospitalised patients with Covid-19 pneumonia were randomised to receive 1 g of methylprednisolone intravenously for 3 consecutive days or placebo in addition to standard dexamethasone. The primary outcome was the duration of the patient hospitalisation, calculated as the time interval between randomisation and hospital discharge without the need of supplementary oxygen. The key secondary outcomes were survival free from invasive ventilation with orotracheal intubation and overall survival. Results: Overall, 112 of 151 (75.4%) patients in the pulse methylprednisolone arm and 111 of 150 (75.2%) in the placebo arm were discharged from hospital without oxygen within 30 days from randomisation. Median time to discharge was similar in both groups [15 days (95% confidence interval (CI), 13.0 to 17.0) and 16 days (95%CI, 13.8 to 18.2); hazard ratio (HR), 0.92; 95% CI 0.71-1.20; p=0.528]. No significant differences between pulse methylprednisolone and placebo arms were observed in terms of admission to Intensive Care Unit with orotracheal intubation or death (20.0% versus 16.1%; HR, 1.26; 95%CI, 0.74-2.16; p=0.176), or overall mortality (10.0% versus 12.2%; HR, 0.83; 95%CI, 0.42-1.64; p=0.584). Serious adverse events occurred with similar frequency in the two groups. Conclusions: Methylprenisolone pulse therapy added to dexamethasone was not of benefit in patients with COVID-19 pneumonia. Message of the study: Pulse glucocorticoid therapy is used for severe and/or life threatening immuno-inflammatory diseases. The addition of pulse glucocorticoid therapy to the standard low dose of dexamethasone scheme was not of benefit in patients with COVID-19 pneumonia

Performance of the new 2012 EULAR/ACR classification criteria for polymyalgia rheumatica: comparison with the previous criteria in a single-centre study

To compare the performance of published classification/diagnostic criteria for polymyalgia rheumatica (PMR), including the new 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, in a single-centre study

New indications for biological therapies

Biological agents have originally been developed to treat refractory arthritis, but evidence has been accruing, supporting their use in vasculitis as well. In the large-vessel vasculitides giant cell arteritis and Takayasu arteritis, TNF-α inhibitors have shown some efficacy in patients with relapsing disease. In contrast, in patients with recent onset of giant cell arteritis, TNF-α inhibitors failed to provide a significant benefit over and above that conferred by glucocorticoids alone. More recent, preliminary data suggest a role for the interleukin-6 receptor antagonist tocilizumab in both resistant and treatment-naïve giant cell arteritis and Takayasu arteritis. Biological agents have also been proposed to treat difficult anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Uncontrolled observations suggest that the TNF-α inhibitor infliximab might be beneficial in resistant cases. On the contrary, a randomized controlled trial did not show superiority of the recombinant human soluble TNF-α p75 receptor fusion protein etanercept over placebo in maintaining remission in granulomatosis with polyangiitis. Two randomized controlled trials have demonstrated that the anti-CD20 monoclonal antibody rituximab was as effective as the standard-of-care agent cyclophosphamide in inducing remission. In addition, rituximab appeared to be superior to cyclophosphamide in inducing remission in the subset of patients with relapsing disease. These findings prove that biological therapy has a role in vasculitis. Research is investigating novel therapies as well as focusing on how to best use the available drugs

Multidisciplinary focus on cyclosporin A

Cyclosporin A (CsA) has been proved to be effective in the treatment of severe cutaneous psoriasis and psoriatic arthritis (PsA). In psoriasis, CsA therapy can be used as: (1) intermittent short-course therapy; (2) continuous long-term therapy; (3) crisis intervention; and (4) a combination of sequential and rotational therapy. Several open prospective studies have shown the short-term efficacy of CsA in PsA. While there were no randomized controlled trials (RCT) comparing CsA to placebo, 3 published controlled trials compared CsA to other disease modifying antirheumatic drugs (DMARD). These studies support the efficacy of CsA in patients with PsA and peripheral arthritis. However, no conclusions can be drawn on the efficacy of CsA for dactylitis and axial disease. Long-term studies have shown the persistent efficacy and safety of CsA in PsA. The beneficial effects of CsA in angiogenesis-related diseases such as PsA and cutaneous psoriasis may also be mediated by its ability to block the angiogenic effects induced by vascular endothelial growth factor

Tocilizumab for polymyalgia rheumatica: report of two cases and review of the literature

Glucocorticoids (GC) are the mainstay of treatment of polymyalgia rheumatica (PMR). However GC-related adverse events occur frequently, particularly in patients with relapsing disease. Several studies have demonstrated that IL-6 is a key player in the pathogenesis of PMR

Tocilizumab: a novel therapy for patients with large-vessel vasculitis

Treatment of large-vessel vasculitis (LVV) remains challenging. Patients usually respond to glucocorticoid (GC) therapy, but often relapse on tapering of the GC dose or after GC withdrawal. In addition, GCs are fraught with numerous adverse events. The aim of this study was to assess the efficacy and safety of the anti-IL-6 receptor (IL-6R) antibody tocilizumab (TCZ) in patients with LVV