Alberto Floris

Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: Systematic literature review and analysis of a monocentric cohort

The use of biologic drugs has been linked with the paradoxical development of systemic and organ specific autoimmune processes. The aim of this study was to describe the features of biologics-induced autoimmune renal disorders (AIRD) through a systematic review and a cohort study of 707 adult patients affected with Rheumatoid Arthritis (RA), Ankylosing Spondylitis (SA) and Psoriatic Arthritis (PsA). The literature search identified 2687 articles of which 21 were considered relevant for the present study, accounting for 26 case reports. The cohort analysis retrieved 3 cases. According to clinical manifestations and kidney histology the identified AIRD cases were classified as: a) glomerulonephritis associated with systemic vasculitis (GNSV), b) glomerulonephritis in lupus-like syndrome (GNLS), c) isolated autoimmune renal disorders (IARD). Twenty-two out of 29 cases with AIRD were reported in patients affected by RA, 5 in AS and 2 in PsA. The biologic drug most frequently associated with development of AIRD was Etanercept (15 cases, 51.7%), followed by Adalimumab (9 cases, 31.0%) and Infliximab (3 cases, 10.3%) while Tocilizumab and Abatacept were reported in 1 case (3.4%) for each. Thirteen out of 29 (44.8%) cases were classified as affected by IARD, 12 (41.3%) as GNSV and 4 (13.9%) as GNLS. Worse prognosis was associated with GNSV and lack of biologic withdrawal. Although rare, AIRD may be life-threatening and may lead to renal failure and death. If AIRD occurs, biologic drugs must be stopped and patient should be treated according to clinical manifestations and kidney biopsy findings.

Predictors of flares in Systemic Lupus Erythematosus: Preventive therapeutic intervention based on serial anti-dsDNA antibodies assessment. Analysis of a monocentric cohort and literature review

Patients with Systemic Lupus Erythematosus (SLE) may experience flare of disease activity. The aim of this study was to assess incidence, clinical features and predictors of flares, focusing on the relationship with serially assessed anti-double stranded DNA antibodies (anti-dsDNA) serum levels by Farr assay and pre-emptive therapeutic approaches of flares, through the analysis of a monocentric cohort of SLE patients and a literature review. Clinical and laboratory data of 120 out of 334 SLE patients, fulfilling inclusion criteria for enrolment and followed up between 1997 and 2012, were retrospectively collected. For the purposes of the study, a flare was defined as any new SLE manifestation or worsening of a pre-existing manifestation resulting in change of therapy. A review of the literature was performed searching for articles published between 1980 and 2015. Over a median (IQR) follow-up of 5.9 (3.0-8.9) years, 87 flares were recorded in 59 (49%) patients. The estimated incidence rate was 0.11 flare per patient-year, at the low-end of values reported in literature (0.19-1.76 patient-year). In our cohort, fluctuating anti-dsDNA serum levels were associated with flare development whereas precautionary change of therapy in presence of increased anti-dsDNA levels >50% was effective in preventing flares (p<0.05). Results from literature review highlighted that increasing anti-dsDNA and precautionary change of therapy were predictive and pre-emptive of flares, respectively, in some studies but not in others. Differences in laboratory methods and patient selection, in terms of ethnicity, disease duration, and background therapy are likely to be crucial in determining discordant results.

Population-based analysis of hospitalizations in a West-European region revealed major changes in hospital utilization for patients with systemic lupus erythematosus over the period 2001–2012

Objective The objective of this paper is to evaluate hospital admissions in systemic lupus erythematosus (SLE) patients through a retrospective population-based study analyzing hospitalization data during 2001–2012 in Sardinia, an Italian region with universal health system coverage. Methods Data on the hospital discharge records with the ICD-9-CM code for SLE (710.0) were obtained from the Department of Health and Hygiene and analyzed, mostly focusing on primary and non-primary diagnosis and Diagnosis-Related Group (DRG) code. In order to establish the significance of the annual trend for number and type of primary and non-primary discharge diagnosis, the two-tailed Cochran-Armitage test for trend was applied. In order to estimate SLE prevalence, data from administrative database and medical records were assembled. Results This study included 6222 hospitalizations in 1675 patients (87% women). Hospitalizations with SLE as primary diagnosis were 3782 (58.0%) and significantly decreased during the study period. The annual number of renal, hematologic and neuropsychiatric disorders as non-primary diagnosis associated with SLE remained constant; however, their percentage increased (p < 0.0001) because of a declining number of admissions for SLE without associated diagnosis and without complications. Hospitalizations with SLE as non-primary diagnosis showed a significant upward trend in number and percentage of cerebrovascular accident (p = 0.0004), acute coronary syndrome (p = 0.0004) and chronic renal failure (p = 0.0003) as underlying primary diagnosis, while complications of pregnancy, labor and childbirth (p = 0.3375), malignancies (p = 0.6608) and adverse drug reactions (p = 0.2456) did not show statistically significant changes. Infections showed an increasing trend between 2001 and 2012 but did not reach statistical significance (p = 0.0304). After correction for hospitalization (93.8%) and survival (91.1%) rates calculated over the study period, the 2012 SLE prevalence in Sardinia was estimated to be 99.3 per 100,000 inhabitants. Conclusions While overall hospitalizations for SLE patients declined, those for cerebrovascular accident, acute coronary syndrome and chronic renal failure as underlying primary diagnosis increased during the study period.

New Approaches in Tumor Necrosis Factor Antagonism for the Treatment of Psoriatic Arthritis: Certolizumab Pegol

The pathogenesis of psoriatic arthritis (PsA) is still under discussion but great advances have been made in the last 2 decades that confirm the central role of tumor necrosis factor-α (TNF-α) in its inflammatory milieu. New therapeutic approaches have been proposed, and new molecules with anti-TNF-α activity have been chemically altered to improve their pharmacological properties. Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF that has been shown clinically to be effective in the treatment of rheumatoid arthritis (RA), skin psoriasis, and PsA. This article summarizes available data on its clinical efficacy and safety profile in the treatment of patients with PsA.

Musculoskeletal manifestations as determinants of quality of life impairment in patients with systemic lupus erythematosus

Objective The objective of this study was to identify determinants of health-related quality of life (HRQoL) impairment in patients with systemic lupus erythematosus (SLE). Methods Overall, 101 SLE patients were recruited; 37 healthy subjects and 35 rheumatoid arthritis (RA) patients served as controls. HRQoL was evaluated using three patient reported outcomes (PROs): the Short Form-36 version 2 (SF-36v2) health survey, the fatigue scale version 4 (FACITv4) and the Heath Assessment Questionnaire (HAQ). A large set of demographic and clinical variables, including SLE arthritis subtypes, was evaluated searching for factors independently associated with worse QoL. Multivariate models were applied to identify factors independently associated with outcomes. Bonferroni’s corrected p values < 0.05 were considered significant. Results SLE patients showed worse results than healthy controls (p < 0.01) in all SF-36v2 domains and, with reference to the mental QoL, also than RA patients (p < 0.01). Jaccoud’s deformities, active arthritis, and fibromyalgia were the only factors independently associated with worse results in both physical and mental components summary of the SF-36v2 (p < 0.01) and FACITv4 fatigue scale (p < 0.01). Fragility fractures, deformities, and active arthritis negatively affected disability perception measured by the HAQ (p < 0.01). No statistically significant differences in perceived HRQoL were highlighted between patients with deforming and erosive arthritis. However, they had significantly worse results than patients with non-deforming non-erosive arthritis across all investigated PROs (p < 0.01). Conclusion In order to limit musculoskeletal manifestations as a source of impaired QoL in SLE patients, therapeutic strategies targeted to successfully manage active arthritis and fibromyalgia and to prevent deforming damage are needed.

The proposed role of ultrasound in the management of giant cell arteritis in routine clinical practice.

Objective To develop and explore a protocol for using colour duplex sonography (CDS) in the routine care of GCA. Methods We tested CDS of temporal arteries and axillary arteries (AXs) on consecutive patients with suspected or established GCA, between July 2014 and September 2016. Results We assessed 293 patients [age 72 (10), female/male 196/97], of whom 118 had clinically confirmed GCA. Seventy-three percent of patients had already received high-dose glucocorticoids (GCs) for 17 (33) days. Among new referrals with <7 days of GC treatment (n = 55), the sensitivity of CDS was 63.3% (95% CI: 44%, 80%), specificity 100% (95% CI: 83%, 100%), positive predictive value 100% and negative predictive value 64.5% (95% CI: 53%, 74%). Sensitivity rose to 81.8% in patients with jaw claudication and high inflammatory markers. During the observation period, the rate of temporal artery biopsies decreased from 72 (42%) to 36 (25%) (P = 0.002). CDS was positive in 21% of 89 follow-up scans in asymptomatic individuals, compared with 37% in patients experiencing clinical flares. Over time, the number of halos reduced; only new or flaring patients showed a halo in four or more sites. The diameter of axillary halos reduced from referral [1.6 (0.4) mm] to follow-up [1.4 (0.2) mm, P = 0.01] or flares [1.4 (0.2) mm, P = 0.02]. Conclusion CDS provides high positive predictive value for diagnosing GCA and allows for a significant reduction in temporal artery biopsies. We explored the role of CDS in detecting flares and demonstrated a relationship to the extent of the distribution of halos, but not to their size.

Killer‐Cell Immunoglobulin‐Like Receptors (KIR) and HLA‐Class I Heavy Chains in Ankylosing Spondylitis

Postmarketing Phase IV

Demyelinating syndrome in SLE encompasses different subtypes: Do we need new classification criteria? Pooled results from systematic literature review and monocentric cohort analysis

OBJECTIVE To describe features of demyelinating syndrome (DS) in systemic lupus erythematosus (SLE). METHODS A systematic review using a combination of Mesh terms in PubMed and a retrospective analysis of 343 adult patients with SLE were carried out to identify patients with DS. Retrieved cases were classified as affected with DS according to 1999 ACR nomenclature and attributed to SLE by applying the 2015 algorithm. DS defined according to the clinical but not temporal 1999 ACR criteria was classified as clinically isolated syndrome (CIS). RESULTS Estimated prevalence of DS (including CIS) in the SLE cohort was 1.3% and incidence rate was 1.5 cases per 1000 patient-years. Overall, 100 cases from literature review and 4 from SLE cohort were identified and are presented as a whole: 49 (47.1%) were classified as neuromyelitis optica spectrum disorders (NMOSD), 29 (27.9%) as CIS, 14 (13.5%) as NMO, 7 (6.7%) as DS prominently involving the brainstem and 5 (4.8%) as DS prominently involving the brain. DS was the SLE onset manifestation in 41 (39.4%) patients. Longitudinally extensive transverse myelitis was the most frequent manifestations being present in 73 (70.2%) patients (37 NMOSD, 21 CIS, 14 NMO, 1 DSB). Methylprednisolone (79.8%) and cyclophosphamide (55.8%) pulses, but also plasma-exchange (16.3%) and rituximab (7.6%) in relapsing-refractory cases, were mostly prescribed. Complete recovery rate ranged between 62% in CIS to 7% in NMO. CONCLUSION DS in SLE is rare (1%) and encompasses different subtypes including CIS. Timely diagnosis and early treatment are recommended to minimize complications.

THU0296 The role of ultrasound in the management of giant cell arteritis (GCA) in routine clinical practice

Background Colour Doppler sonography (CDS) is an emerging diagnostic tool for giant cell arteritis (GCA), however, its use in routine practice is still not widespread. Objectives To develop a protocol using CDS and explore its value in the routine care of patients with GCA. Methods We developed a structured scanning protocol for CDS of temporal and axillary arteries (total of 8 anatomical sites scanned per patient) based on previously published methods. We tested the protocol on consecutive patients referred to a single rheumatology centre, with suspected or established GCA, between July 2014 and September 2016. We defined a positive scan by the presence of halo in at least one branch of a temporal artery (TA) or one axillary artery (AX). We report data from the first 293 consecutively scanned cases. Results We assessed 293 patients (mean age 72±10, female/male 196/97), of whom 118 had clinically confirmed GCA. Amongst new referrals with confirmed diagnosis of GCA, 44% had a positive scan; two patients with a positive scan did not have GCA. 82% of new referrals patients showed exclusive TA involvement, 25% concomitant AX, and 4% exclusive AX involvement. High-dose glucocorticoid therapy had already been started in 78% of these patients for an average of 17±33 days. Amongst this group, the sensitivity of CDS was 46% (95% IC 37%>55%), specificity 98% (95% CI 93%>99.8%), positive predictive value 96% (88%>99.6%), and negative predictive value 60% (95% IC 52%>68%). During the period of observation, the rate of temporal artery biopsies (TAB) decreased significantly from 42% to 25% (p=0.002). During follow up, CDS was positive in 21% of 89 routine scans in asymptomatic individuals, compared to 58% in patients with confirmed clinical flares (45% of whom had negative inflammatory markers). Over time, the number of halos per patient reduced; only new or flaring patients showed a halo in >4 sites. Halo size at the TA did not change significantly (average thickness 0.6±0.1 mm), however, the size of AX artery halos significantly reduced from first referral (1.6±0.4 mm) to follow up (1.4±0.2, p=0.01) or during subsequent flares (1.4±0.2, p=0.02). Conclusions We have developed and tested a standardised methodology for CDS evaluation of GCA. CDS provides a high positive predictive value for a diagnosis of GCA in unselected patients from routine clinical practice, although prior high dose glucocorticoid therapy is likely to reduce its sensitivity. CDS allows for a significant reduction of TAB. We explored the role of CDS to detect disease flares and demonstrated a significant reduction in the extent of abnormalities, and of the size of halo of the AX arteries during follow up or flares. These findings could have a significant impact on the management of patients with suspected and confirmed GCA. Disclosure of Interest None declared

Current perspective on the role of the interleukin-23/interleukin-17 axis in inflammation and disease (chronic arthritis and psoriasis).

TH17 is a lymphocyte subset, which is characterized by its polarization to secrete interleukin (IL)-17. IL-23 is the pivotal mediator responsible for TH17 differentiation and the IL-23/IL-17 axis has been strongly implicated in the pathogenesis of several immune mediated diseases, in particular chronic arthritis and skin psoriasis. This review will summarize the basic immunology and the new monoclonal antibodies, which antagonize this pathway allowing a new therapeutic approach.