Publications by authors named "Marcello Govoni"

132 Publications

From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis.

Front Pharmacol 2021 15;12:672515. Epub 2021 Jun 15.

Rheumatology Unit, Department of Medical Sciences, Università degli Studi di Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Cona, Italy.

Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically "predictive": the expected response is based on stratification according to clinical, imaging, and laboratory data, with a "heuristic" approach based on "trial and error". Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially "broad-spectrum" mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of "refractory to a treatment" patients, other pathways might be hyperactivated, with opposing, synergistic, or redundant biological significance. On the contrary, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment. In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis regarding studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.
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http://dx.doi.org/10.3389/fphar.2021.672515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241099PMC
June 2021

Serum Antibodies Against the Oncogenic Merkel Cell Polyomavirus Detected by an Innovative Immunological Assay With Mimotopes in Healthy Subjects.

Front Immunol 2021 8;12:676627. Epub 2021 Jun 8.

Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Merkel cell polyomavirus (MCPyV), a small DNA tumor virus, has been detected in Merkel cell carcinoma (MCC) and in normal tissues. Since MCPyV infection occurs in both MCC-affected patients and healthy subjects (HS), innovative immunoassays for detecting antibodies (abs) against MCPyV are required. Herein, sera from HS were analyzed with a novel indirect ELISA using two synthetic peptides mimicking MCPyV capsid protein epitopes of VP1 and VP2. Synthetic peptides were designed to recognize IgGs against MCPyV VP mimotopes using a computer-assisted approach. The assay was set up evaluating its performance in detecting IgGs anti-MCPyV on MCPyV-positive (n=65) and -negative (n=67) control sera. Then, the ELISA was extended to sera (n=548) from HS aged 18-65 yrs old. Age-specific MCPyV-seroprevalence was investigated. Performance evaluation indicated that the assay showed 80% sensitivity, 91% specificity and 83.9% accuracy, with positive and negative predictive values of 94.3% and 71%, respectively. The ratio expected/obtained data agreement was 86%, with a Cohen's kappa of 0.72. Receiver-operating characteristic (ROC) curves analysis indicated that the areas under the curves (AUCs) for the two peptides were 0.82 and 0.74, respectively. Intra-/inter-run variations were below 9%. The overall prevalence of serum IgGs anti-MCPyV in HS was 62.9% (345/548). Age-specific MCPyV-seroprevalence was 63.1% (82/130), 56.7% (68/120), 64.5% (91/141), and 66.2% (104/157) in HS aged 18-30, 31-40, 41-50 and 51-65 yrs old, respectively (p>0.05). Performance evaluation suggests that our indirect ELISA is reliable in detecting IgGs anti-MCPyV. Our immunological data indicate that MCPyV infection occurs asymptomatically, at a relatively high prevalence, in humans.
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http://dx.doi.org/10.3389/fimmu.2021.676627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217635PMC
June 2021

Relevant domains and outcome measurement instruments in Neuropsychiatric Systemic Lupus Erythematosus: a systematic literature review.

Rheumatology (Oxford) 2021 Mar 31. Epub 2021 Mar 31.

Department of Medical Sciences, Rheumatology Unit, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Cona (Ferrara), Italy.

Objectives: Although neuropsychiatric involvement in Systemic Lupus Erythematosus (NPSLE) is one of the most complex and troubling manifestations of the disease, validated outcome instruments to be used as sensitive endpoints in controlled clinical trials are lacking. We set out a systematic literature review (SLR) to identify outcome measurement instruments and domains used to assess NPSLE.

Methods: The Preferred Reporting Items for systematic reviews and Meta-analysis (PRISMA) guidelines were used. Articles available in English (1967-2020), listed in PubMed, EMBASE, PsycINFO, Cochrane Library and EULAR outcome measures library were screened. All domains and outcome measurement instruments were characterized according to the OMERACT Filter 2.1, considering core areas (manifestations/abnormalities, life impact, death/lifespan, societal/resource use) and contextual factors.

Results: Of 3,392 abstracts evaluated, 83 studies were included in the SLR (15,974 patients, females 89.9%). Eligible studies included domains and instruments pertinent to all core areas defined by OMERACT, except for "societal/resource use". The most common core areas were "manifestations/abnormalities", covering 10 domains pertinent to laboratory and instrumental markers, indexes and neuropsychiatric dimension (cognitive, neurologic and psychiatric field), and "life impact", covering 7 domains related to physical function (from both the perspective of the patient and the physician), pain and quality of life.

Conclusion: Our study revealed great heterogeneity in the instruments derived from populations with NPSLE and none of these had high-quality evidence. This supports the need to develop and further validate a core domain set and outcome measurement instruments to promote clinical research in this field, enhancing comparability across studies.
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http://dx.doi.org/10.1093/rheumatology/keab324DOI Listing
March 2021

Long-term methotrexate use in rheumatoid arthritis patients: real-world data from the MARTE study.

Minerva Med 2021 Apr 8;112(2):246-254. Epub 2021 Feb 8.

S.C. Rheumatology, Department of Locomotor System, ASL3 Genovese, Genoa, Italy.

Background: The MARTE study investigated the demographic, clinical, and therapeutic characteristics of rheumatoid arthritis (RA) patients ongoing methotrexate (MTX) treatment for longer than 8 years.

Methods: This cross-sectional, observational study considered 587 RA patients from 67 Rheumatology Units across Italy. Data collected included demographic, clinical, and therapeutic characteristics, focusing on MTX prescription patterns (route of administration, dosing regimens, treatment duration, and discontinuation).

Results: As initial therapy, 90.6% of patients received one conventional synthetic Disease Modifying Anti Rheumatic Drug (csDMARD), with treatment started within the first 3 months from diagnosis in half of the patients. MTX was the first csDMARD in 46.2% of patients. The prevalent route of administration at diagnosis was the intramuscular (60.5%), while at study entry (baseline) 57.6% were receiving subcutaneous MTX. Patients who required a higher MTX dose at study entry were those who received a significantly lower starting MTX dose (P<0.001). Significantly higher MTX doses were currently required in men (P<0.001), current smokers (P=0.013), and overweight patients (P=0.028), whereas patients on oral therapy received significantly lower doses of MTX (P<0.001).

Conclusions: The MARTE study confirms once again the potential of the proper use of MTX in the treatment of RA. Data from our study suggest that a higher dose of MTX should be used since the first stages in overweight patients, men, and smokers.
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http://dx.doi.org/10.23736/S0026-4806.21.06902-0DOI Listing
April 2021

Longitudinal changes in cerebral white matter microstructure in newly diagnosed systemic lupus erythematosus patients.

Rheumatology (Oxford) 2021 Jun;60(6):2678-2687

Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

Objectives: To evaluate longitudinal variations in diffusion tensor imaging (DTI) metrics of different white matter (WM) tracts of newly diagnosed SLE patients, and to assess whether DTI changes relate to changes in clinical characteristics over time.

Methods: A total of 17 newly diagnosed SLE patients (19-55 years) were assessed within 24 months from diagnosis with brain MRI (1.5 T Philips Achieva) at baseline, and after at least 12 months. Fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity values were calculated in several normal-appearing WM tracts. Longitudinal variations in DTI metrics were analysed by repeated measures analysis of variance. DTI changes were separately assessed for 21 WM tracts. Associations between longitudinal alterations of DTI metrics and clinical variables (SLEDAI-2K, complement levels, glucocorticoid dosage) were evaluated using adjusted Spearman correlation analysis.

Results: Mean MD and RD values from the normal-appearing WM significantly increased over time (P = 0.019 and P = 0.021, respectively). A significant increase in RD (P = 0.005) and MD (P = 0.012) was found in the left posterior limb of the internal capsule; RD significantly increased in the left retro-lenticular part of the internal capsule (P = 0.013), and fractional anisotropy significantly decreased in the left corticospinal tract (P = 0.029). No significant correlation was found between the longitudinal change in DTI metrics and the change in clinical measures.

Conclusion: Increase in diffusivity, reflecting a compromised WM tissue microstructure, starts in initial phases of the SLE disease course, even in the absence of overt neuropsychiatric (NP) symptoms. These results indicate the importance of monitoring NP involvement in SLE, even shortly after diagnosis.
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http://dx.doi.org/10.1093/rheumatology/keaa677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213425PMC
June 2021

Methotrexate in Italian patients wiTh Rheumatoid Arthritis (MITRA study): an observational study about the use of methotrexate in early RA patients and the adherence to the EULAR 2013 recommendations. A project of the Italian Society for Rheumatology.

Clin Exp Rheumatol 2020 Dec 18. Epub 2020 Dec 18.

Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, Milan, Italy; Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Italy.

Objectives: To assess the delay between the disease onset and the beginning of methotrexate (MTX) treatment in RA patients and to evaluate the Italian rheumatologists' adherence to the EULAR 2013 recommendations.

Methods: MITRA is an Italian multicentre observational study carried out on DMARD-naïve RA patients recruited in an 18-month period starting from 2015. The data related to the patients' characteristics at baseline will be presented.

Results: 332 patients from 13 Italian centres were recruited: the median delay between the onset of symptoms and the beginning of MTX was 197 days (102-431); in 20% of patients a treatment with DMARDs was started within the first 90 days from the onset of symptoms. The clinical target selected was DAS28 remission in 64.2% of cases and low disease activity in 35.8%. Among patients in DAS28 high disease activity, 92.6% received a control visit which was rescheduled within the first 3 months, similarly to those in DAS28 moderate disease activity (91.6%). A DMARD monotherapy was prescribed in 319 patients, while a combined therapy of DMARDs was preferred in 13 cases; 282 patients were treated with MTX. Glucocorticoids were prescribed in 229 patients: the median dosage was of 5 mg (IQR 5-7.5) of prednisone equivalent/day.

Conclusions: Diagnostic delay in RA patients continues to be longer than expected. The choice of low disease activity as a target is still very frequent and tight control does not seem to be based on disease activity. This paper offers a realistic and detailed picture of the clinical practice among Italian rheumatologists.
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December 2020

The management of neuropsychiatric lupus in the 21st century: still so many unmet needs?

Rheumatology (Oxford) 2020 12;59(Suppl5):v52-v62

Division of Rheumatology, Department of Medicine and Department of Pathology, Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, Nova Scotia, Canada.

Neuropsychiatric (NP) events occur in the majority of patients with SLE and predominantly affect the CNS in addition to the peripheral and autonomic systems. Approximately 30% of all NP events are attributable to SLE (NPSLE) and present most frequently around the time of SLE onset. NPSLE is associated with increased morbidity and mortality and the proposed pathogenesis includes both ischaemic and neuroinflammatory mechanisms. Following diagnosis and causal attribution, the treatment of NPSLE is tailored to the type of NP event, the predominant putative pathogenic pathway and the activity and severity of the clinical event. There is a dearth of controlled clinical trials to guide management, but therapeutic options include symptomatic, antithrombotic and immunosuppressive agents that are supported by observational cohort studies. Our objective was to review what is currently known about NPSLE and to identify deficiencies in diagnostic biomarkers, novel therapies and clinical trials for this manifestation of SLE.
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http://dx.doi.org/10.1093/rheumatology/keaa404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719041PMC
December 2020

Discordance between patient and physician global assessment of disease activity in Behçet's syndrome: a multicenter study cohort.

Arthritis Res Ther 2020 11 25;22(1):278. Epub 2020 Nov 25.

Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, SS 554, 09042, Monserrato, Cagliari, Italy.

Background: To compare the patients' and physician's global assessment of disease activity in Behçet's syndrome (BS) and investigate the frequency, magnitude, and determinants of potential discordance.

Methods: A total of 226 adult BS patients with a median (IQR) age of 46.9 (35.6-55.2) years were enrolled across Italy, Greece, Portugal, and Spain. Demographic, clinical, and therapeutic variables, as well as the patient reported outcomes, were collected at the recruitment visit. The physical (PCS) and mental (MCS) component summary scores of the Short Form Questionnaire 36 (SF-36) and the Behçet's syndrome Overall Damage Index (BODI) were calculated. Disease activity was assessed by the patients' (PtGA) and physician's global assessment (PGA) in a 10-cm visual analog scale, as well as the Behçet Disease Current Activity Form (BDCAF). Discordance (∆) was calculated by subtracting the PGA from the PtGA and defined as positive (PtGA>PGA) and negative (PtGA
Results: Median PtGA and PGA scores were 2.0 (0.3-5.0) and 1.0 (0.0-3.0) cm, respectively. The discordance prevalence varied (from 29.6 to 55.3%) according to the cutoff applied, and the majority (> 80%) of disagreements were due to patients rating higher their disease activity. Higher values of BDCAF were associated to increased rate of positive discordance. When BDCAF = 0, the median (IQR) values of PtGA and PGA were 0.2 (0-2) and 0 (0-1), respectively. PCS (adjusted odds ratio (adjOR) 0.96 per unit, 95% CI 0.93-0.98, p = 0.006) and MCS (adjOR 0.96 per unit, 95% CI 0.93-0.99, p = 0.003) were independently associated with positive discordance using both cutoffs. Active ocular involvement emerged as a potential determinant of negative discordance (adjOR 5.88, 95% CI 1.48-23.30, p = 0.012).

Conclusions: PtGA and PGA should be considered as complementary measures in BS, as patients and physicians may be influenced by different factors when assessing active disease manifestations. Particularly, PtGA may be a useful tool in the assessment of BS disease activity, as it carries a low risk to misclassify an inactive disease, and may allow to capture aspects of the patient's health that negatively affect his well-being and the treatment.
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http://dx.doi.org/10.1186/s13075-020-02362-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687797PMC
November 2020

The IMMENSE Study: The Interplay Between iMMune and ENdothelial Cells in Mediating Cardiovascular Risk in Systemic Lupus Erythematosus.

Front Immunol 2020 29;11:572876. Epub 2020 Oct 29.

Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.

Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3CD31CXCR4 T cells (T), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a T subset with immunosenescent features, such as the loss of CD28. Therefore, the aim of this study was to elucidate the interplay between T subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients and 10 healthy controls (HCs) were recruited. Flow cytometric analysis of endothelial progenitor cells (EPCs) and T subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)- were measured. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects' serum stimulation were also evaluated. Results showed that the percentage of T and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28 cells among T subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to T cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of T and inversely related to the CD28 T subsets. We indirectly evaluated the role of the T subset on the endothelium upon stimulation with serum from subjects with a low percentage of T CD3 cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of T compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the CD28 subset exerts detrimental role over the T phenotype, where T could exert an anti-inflammatory effect on endothelial cells and might orchestrate IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.
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http://dx.doi.org/10.3389/fimmu.2020.572876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658008PMC
June 2021

Criterion validity of ultrasound in the identification of calcium pyrophosphate crystal deposits at the knee: an OMERACT ultrasound study.

Ann Rheum Dis 2021 02 28;80(2):261-267. Epub 2020 Sep 28.

Rheumatology Department, University of Medicine and Pharmacy of Craiova, Craiova, Romania.

Objective: To evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard.

Methods: Consecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0-3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other's findings.

Results: 11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%-sensitivity of 91% (range 71%-87% in single sites) and specificity of 59% (range 68%-92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation.

Conclusion: Ultrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.
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http://dx.doi.org/10.1136/annrheumdis-2020-217998DOI Listing
February 2021

Definition of fibromyalgia severity: findings from a cross-sectional survey of 2339 Italian patients.

Rheumatology (Oxford) 2021 02;60(2):728-736

Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objective: To establish optimal cut-off values for the scores of the revised Fibromyalgia Impact Questionnaire (FIQR), the modified Fibromialgia Assessment Scale (FAS 2019mod), and the Polysymptomatic Distress Scale (PDS) in order to distinguish five levels of FM disease severity.

Methods: Consecutive FM patients were evaluated with the three clinimetric indices, and each patient was required to answer the anchor question: 'In general, would you say your health is 1 = very good, 2 = good, 3 = fair, 4 = poor, or 5 = very poor?'-which represented the external criterion. Cut-off points were established through the interquartile reconciliation approach.

Results: The study sample consisted of 2181 women (93.2%) and 158 men (6.8%), with a mean age of 51.9 (11.5) years, and mean disease duration was 7.3 (6.9) years. The overall median FIQR, FAS 2019 mod and PDS scores (25th-75th percentiles) were respectively 61.16 (41.16-77.00), 27.00 (19.00-32.00) and 19.0 (13.00-24.00). Reconciliation of the mean 75th and 25th percentiles of adjacent categories defined the severity states for FIQR: 0-23 for remission, 24-40 for mild disease, 41-63 for moderate disease, 64-82 for severe disease and >83 for very severe disease; FAS 2019 mod: 0-12 for remission, 13-20 for mild disease, 21-28 for moderate disease, 29-33 for severe disease and >33 for very severe disease; PDS: 0-5 for remission, 6-15 for mild disease, 16-20 for moderate disease, 21-25 for severe disease and >25 for very severe disease.

Conclusions: Disease severity cut-offs can represent an important improvement in interpreting FM.
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http://dx.doi.org/10.1093/rheumatology/keaa355DOI Listing
February 2021

Development and preliminary validation of the Behçet's syndrome Overall Damage Index (BODI).

RMD Open 2020 07;6(2)

Rheumatology Unit, AOU University Clinic of Cagliari, Cagliari, Italy.

Objective: To develop and validate the evidence-based and consensus-based Behçet's Syndrome Overall Damage Index (BODI).

Methods: Starting from 120 literature-retrieved preliminary items, the BODI underwent multiple Delphi rounds with an international multidisciplinary panel consisting of rheumatologists, internists, ophthalmologists, neurologists, and patient delegates until consensus was reached on the final content. The BODI was validated in a cross-sectional multicentre cohort of 228 patients with Behçet's syndrome (BS) through the study of (a) correlation between BODI and Vasculitis Damage Index (VDI) and (b) correlation between BODI and disease activity measures (ie, Behçet's Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA)), c) content and face validity and (d) feasibility.

Results: The final BODI consists of 4 overarching principles and 46 unweighted-items grouped into 9 organ domains. It showed good to excellent reliability, with a mean Cohen's k of 0.84 (95% CI 0.78 to 0.90) and a mean intra-class correlation coefficient of 0.88 (95% CI 0.80 to 0.95). Overall, 128 (56.1%) patients had a BODI score ≥1, with a median score of 1.0 (range 0-14). The BODI significantly correlated with the VDI (r=0.693, p<0.001), demonstrating to effectively measure damage (construct validity), but had greater sensitivity in identifying major organ damage and did not correlate with disease activity measures (ie, BDCAF: p=0.807, PGA: p=0.820, PtGA: p=0.794) discriminating damage from the major confounding factor. The instrument was deemed credible (face validity), complete (content validity) and feasible by an independent group of clinicians.

Conclusions: Pending further validation, the BODI may be used to assess organ damage in patients with BS in the context of observational and controlled trials.
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http://dx.doi.org/10.1136/rmdopen-2020-001192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425117PMC
July 2020

Impact of the new 2019 EULAR/ACR classification criteria for Systemic Lupus Erythematosus in a multicenter cohort study of 133 women with undifferentiated connective tissue disease.

Arthritis Care Res (Hoboken) 2020 Jul 23. Epub 2020 Jul 23.

Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy.

Objective: We aimed to investigate the impact of applying the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE) in a previously described cohort of women with undifferentiated connective tissue disease (UCTD).

Methods: This study included 133 women with UCTD. At the time of inclusion into the study, none of the patients meet any classification criteria for other defined systemic connective tissue disease.

Results: When applying the 2019 EULAR/ACR classification criteria to the cohort, 22 patients (17%) fulfilled the classification criteria of SLE. Patients classified as SLE had significantly higher frequency of mucocutaneous manifestations (23%vs.5%;p=0.007), arthritis (59%vs.17%; p<0.001), isolated urine abnormalities (18%vs.1%;p<0.001) and highly specific antibodies (50%vs.15%;p<0.001). At follow-up, these patients were statistically significantly more likely to fit also the ACR 1997 and SLICC criteria (18.2%vs. 1.8%;p<0.001). Patients who were diagnosed as SLE per the ACR 1997 and SLICC criteria during the follow-up scored significantly more points in the new 2019 EULAR/ACR classification criteria when compared to the other UCTD patients (mean score 8.3±3.7 vs. 4.5±4;p<0.05).

Conclusion: When applying the 2019 EULAR/ACR criteria for SLE in a cohort of patient with UCTD, we observed that in up to 17% of cases the original classification could be challenged. New implementation will help to early identify patients at higher risk of developing more severe CTD manifestations.
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http://dx.doi.org/10.1002/acr.24391DOI Listing
July 2020

Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort.

Ann Rheum Dis 2020 07 22;79(7):943-950. Epub 2020 Apr 22.

Department of Medicine, Division of Rheumatology, University of Padua, Padova, Italy

Objectives: Remission in systemic lupus erythematosus (SLE) is defined through a combination of 'clinical SLE Disease Activity Index (cSLEDAI)=0', 'physician's global assessment (PGA) <0.5' and 'prednisone (PDN) ≤5 mg/day'. We investigated the performance of these items, alone or in combination, in defining remission and in predicting SLICC/ACR Damage Index.

Methods: We tested seven potential definitions of remission in SLE patients followed-up for ≥5 years: PDN ≤5 mg/day; PGA <0.5; cSLEDAI=0; PGA <0.5 plus PDN ≤5 mg/day; cSLEDAI=0 plus PGA <0.5; cSLEDAI=0 plus PDN ≤5 mg/day; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5. The effect of these definitions on damage was evaluated by Poisson regression analysis; the best performance was identified as the lowest Akaike and Bayesian information criterion (AIC and BIC). Positive and negative predictive values in identifying no damage increase were calculated.

Results: We included 646 patients (mean±SD disease duration 9.2±6.9 years). At multivariate analysis, ≥2 consecutive year remission according to all definitions protected against damage (OR, 95% CI: PGA <0.5 0.631, 0.444 to 0.896; cSLEDAI=0 0.531, 0.371 to 0.759; PGA <0.5 plus PDN ≤5 mg/day 0.554, 0.381 to 0.805; cSLEDAI=0 plus PGA <0.5 0.574, 0.400 to 0.826; cSLEDAI=0 plus PDN ≤5 mg/day 0.543, 0.376 to 0.785; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA <0.5 0.532, 0.363 to 0.781, p<0.01 for all), except PDN ≤5 mg/day, which required four consecutive years (OR 0.534, 95% CI 0.325 to 0.877, p=0.013). Positive and negative predictive values were similar; however, cSLEDAI=0 showed the best performance (AIC 1082.90, BIC 1109.72, p<0.0001). Adding PGA <0.5 and/or PDN ≤5 mg/day to cSLEDAI=0 decreased remission duration (-1.8 and -1.5 year/patient, respectively) without increasing cSLEDAI=0 performance in predicting damage accrual.

Conclusions: cSLEDAI=0 is the most attainable definition of remission, while displaying the best performance in predicting damage progression in the short-to-mid-term follow-up.
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http://dx.doi.org/10.1136/annrheumdis-2020-217070DOI Listing
July 2020

The two faces of the same medal… or maybe not? Comparing osteoarthritis and calcium pyrophosphate deposition disease: a laboratory and ultrasonographic study.

Clin Exp Rheumatol 2021 Jan-Feb;39(1):66-72. Epub 2020 Apr 9.

Section of Rheumatology, Department of Medical Sciences, University of Ferrara, Italy.

Objectives: Osteoarthritis (OA) and calcium pyrophosphate deposition disease (CPPD) are frequently associated but the real relation between these diseases is not still understood. The aim of this paper is to investigate the characteristics in terms of inflammation, anatomical changes and synovial fluid (SF) features in knees of patients with OA and CPPD.

Methods: Consecutive patients older than 55 years with knee pain and swelling were enrolled. All patients underwent a complete clinical examination, a US examination of the affected joint, arthrocentesis of the knee and analysis of synovial fluid, including dosing of inorganic ions and number of crystals. The gold standard for the diagnosis was the microscopic analysis of the SF.

Results: Sixty-seven patients were enrolled, 25 affected by OA and 42 by CPPD. At US, a significantly higher amount of effusion and synovitis was identified in patients with CPPD but there were no significant differences regarding structural changes. At the SF analysis, the white blood cell (WBC) count was higher in patients with CPPD who also presented a higher number of polymorphonuclear cells and a lower number of monocytes. Regarding the inorganic ion concentration, the statistical analysis did not reveal any differences. The number of crystals in the SF, correlated with a larger effusion, higher grade of synovitis and a higher WBC count.

Conclusions: A higher degree of inflammation was found in patients with CPPD. The findings suggest that longitudinal studies would be useful to better understand the evolution of the diseases and highlight the need for different treatment strategies.
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February 2021

Early Disease and Low Baseline Damage as Predictors of Response to Belimumab in Patients With Systemic Lupus Erythematosus in a Real-Life Setting.

Arthritis Rheumatol 2020 08 12;72(8):1314-1324. Epub 2020 Jun 12.

Università degli Studi di Genova, Genoa, Italy.

Objective: To investigate predictors of response, remission, low disease activity, damage, and drug discontinuation in patients with systemic lupus erythematosus (SLE) who were treated with belimumab.

Methods: In this retrospective study of a multicenter cohort of SLE patients who received intravenous belimumab, the proportion of patients who achieved remission, low disease activity, and treatment response according to the SLE Responder Index 4 (SRI-4) was determined, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) was used to score disease damage yearly over the follow-up. Predictors of outcomes were analyzed by multivariate logistic regression with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: The study included 466 patients with active SLE from 24 Italian centers, with a median follow-up period of 18 months (range 1-60 months). An SRI-4 response was achieved by 49.2%, 61.3%, 69.7%, 69.6%, and 66.7% of patients at 6, 12, 24, 36, and 48 months, respectively. Baseline predictors of response at 6 months included a score of ≥10 on the SLE Disease Activity Index 2000 (SLEDAI-2K) (OR 3.14 [95% CI 2.033-4.860]) and a disease duration of ≤2 years (OR 1.94 [95% CI 1.078-3.473). Baseline predictors of response at 12 months included a score of ≥10 on the SLEDAI-2K (OR 3.48 [95% CI 2.004-6.025]) and an SDI score of 0 (OR 1.74 [95% CI 1.036-2.923]). Baseline predictors of response at 24 months included a score of ≥10 on the SLEDAI-2K (OR 4.25 [95% CI 2.018-8.940]) and a disease duration of ≤2 years (OR 3.79 [95% CI 1.039-13.52]). Baseline predictors of response at 36 months included a score of ≥10 on the SLEDAI-2K (OR 14.59 [95% CI 3.54-59.79) and baseline status of current smoker (OR 0.19 [95% CI 0.039-0.69]). Patients who were in remission for ≥25% of the follow-up period (44.3%) or who had low disease activity for ≥50% of the follow-up period (66.1%) accrued significantly less damage (P = 0.046 and P = 0.007). A baseline SDI score of 0 was an independent predictor of achieving low disease activity in ≥50% of the follow-up period and remission in ≥25% of the follow-up period. Our findings suggest that the lower the baseline damage, the greater the probability of achieving remission over the course of ≥25% of the follow-up. Further, there was a negative association between the number of flares reported prior to belimumab initiation and the frequency of belimumab discontinuation due to inefficacy (P = 0.009).

Conclusion: In patients with active SLE and low damage at baseline, treatment with belimumab early in the disease may lead to favorable outcomes in a real-life setting.
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http://dx.doi.org/10.1002/art.41253DOI Listing
August 2020

Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

Ann Rheum Dis 2020 04 24;79(4):453-459. Epub 2020 Feb 24.

CaRE Arthritis LTD, University of Alberta, Edmonton, Alberta, Canada.

Objectives: To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target.

Methods: RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models.

Results: In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52).

Conclusion: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.
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http://dx.doi.org/10.1136/annrheumdis-2019-216819DOI Listing
April 2020

Ultrasonographic and clinical assessment of peripheral enthesitis and arthritis in an Italian cohort of inflammatory bowel disease patients.

Semin Arthritis Rheum 2020 06 11;50(3):436-443. Epub 2020 Jan 11.

Reumatologia, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy; Reumatologia e, Azienda Ospedaliero-Unversitaria di Modena e Università di Modena e Reggio Emilia, Modena, Italy. Electronic address:

Aims: To evaluate the prevalence of clinical and ultrasonographic musculoskeletal involvement in Italian patients with inflammatory bowel disease (IBD).

Methods: In this cross-sectional multicenter study, 148 consecutive patients with IBD were evaluated by a gastroenterologist and a rheumatologist. All patients underwent a B-mode and power Doppler ultrasonographic examination of 6 pairs of entheses and of knee and ankle joints.

Results: A positive history for at least one musculoskeletal manifestation was reported by 40.5% of patients, more frequently in ulcerative colitis (UC) (p = 0.033). Inflammatory back pain was reported by 13.5% of patients, and a past history of peripheral arthritis by 14.9%, entheseal inflammation by 14.2% and dactylitis by 2.7%. At clinical examination, arthritis was observed in 19.6% of patients and enthesitis in 33%. Oligoarthritis and enthesitis at clinical examination were more frequently observed in UC than in Crohn disease (CD). 37.8% of total IBD patients fulfilled ASAS classification criteria for axial and/or peripheral spondyloarthritis, 8.1% ASAS classification criteria for axial spondyloarthritis, and 29.7% ASAS classification criteria for peripheral spondyloarthritis. With ultrasonographic examination, signs of entheseal involvement were observed in 87.8% of patients, while at power Doppler, ≥1 abnormality was observed in 27.1%. ASAS+ patients compared to those ASAS- had a significantly higher frequency at ultrasonography of acute entheseal abnormalities, power Doppler entheseal positivity and joint involvement. These abnormalities at ultrasonography were also observed in 34%, 13% and 12% of ASAS- patients.

Conclusions: Musculoskeletal manifestations occur frequently in patients with IBD. Ultrasonographic entheseal and joint involvement were also observed in asymptomatic patients.
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http://dx.doi.org/10.1016/j.semarthrit.2020.01.001DOI Listing
June 2020

A multicentre study of 244 pregnancies in undifferentiated connective tissue disease: maternal/fetal outcomes and disease evolution.

Rheumatology (Oxford) 2020 09;59(9):2412-2418

Center of Research of Immunopathology and Rare Diseases - Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy.

Objectives: To investigate fetal/perinatal and maternal outcomes from a large multicentre cohort of women diagnosed with UCTD.

Methods: This multicentre retrospective cohort study describes the outcomes of 224 pregnancies in 133 consecutive women with a diagnosis of UCTD, positive for ANA and aged <45 years old at study inclusion.

Results: Of the 224 pregnancies analysed, 177 (79%) resulted in live births, 45 (20.1%) in miscarriages (defined as pregnancy loss before 12 weeks' gestation), 2 (0.9%) in stillbirths (pregnancy loss after 20 weeks' gestation) and 6 (2.7%) cases showed intrauterine growth restriction. Miscarriages and stillbirths were strongly associated with the presence of aPL and ENA antibodies (P < 0.05). Maternal pregnancy complications were as follows: 5 (2.2%) cases developed pre-eclampsia, 11 (4.9%) cases gestational hypertension and 12 (5.4%) cases gestational diabetes. Joint involvement represented the most frequent clinical manifestation of the cohort (57.9%), followed by RP (40.6%), photosensitivity (32.3%) and haematological manifestations (27.1%). The rate of disease evolution of our cohort from a diagnosis of UCTD to a diagnosis of definite CTD was 12% within a mean time of 5.3 ± 2.8 years. With a total follow-up after first pregnancy of 1417 patient-years, we observed the evolution to a defined CTD in one out of every 88 patient- years.

Conclusion: In our multicentre cohort, women with UCTD had a live birth rate of 79%. Women with UCTD should be referred to specialist follow-up when planning a pregnancy. ENA profiling and aPL testing should be mandatory in this setting, and further therapeutic approaches and management should be planned accordingly.
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http://dx.doi.org/10.1093/rheumatology/kez620DOI Listing
September 2020

Alveolar haemorrhage in ANCA-associated vasculitis: Long-term outcome and mortality predictors.

J Autoimmun 2020 03 9;108:102397. Epub 2020 Jan 9.

Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy.

Introduction: Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV).

Objectives: The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset.

Materials And Methods: A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed.

Results: One-hundred and six patients were included (median age at onset of 55 years [IQR 42-67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13-77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4-9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51-13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality.

Conclusions: Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.
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http://dx.doi.org/10.1016/j.jaut.2019.102397DOI Listing
March 2020

Correction to: Management of adult-onset Still's disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts.

Arthritis Res Ther 2020 Jan 9;22(1). Epub 2020 Jan 9.

Division of Rheumatology, ASST Gaetano Pini-CTO, Milan, Italy.

Following publication of the original article [1], it was brought to our attention that the AOSD Consensus Group was incorrectly tagged and therefore not searchable. The publishers apologize for this error.
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http://dx.doi.org/10.1186/s13075-019-2094-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953133PMC
January 2020

Improved Pregnancy Outcome in Patients With Rheumatoid Arthritis Who Followed an Ideal Clinical Pathway.

Arthritis Care Res (Hoboken) 2021 02;73(2):166-172

University of Ferrara, Cona (Ferrara), and Italian Society for Rheumatology, Milan, Italy.

Objective: To assess the effect of optimal management of pregnancy on a composite outcome of miscarriage and complicated birth among women with rheumatoid arthritis (RA).

Methods: Data were extracted from health care databases of the Lombardy Region, Italy (2004-2013) as a part of the Record-Linkage on Rheumatic Diseases Study. Analyses included women with RA identified through a copayment exemption code (International Classification of Diseases, Ninth Revision, Clinical Modification code 714.0) and controls from the general population, ages 18-50 years. Seven health care quality indicators (HCQI) were constructed and summarized in 3 pathway indicators: diagnostic, therapeutic, and prenatal follow-up. Complicated birth or miscarriage were used to identify the adverse pregnancy outcome (APO). The relationship between HCQI and APO was analyzed using logistic models, and the results were presented as odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results: Data from the study cohort included the first pregnancy observed in 443 patients with RA compared with 6,097 women belonging to the general population. In the RA population, patients who followed the 3 pathway indicators had a reduced risk of overall APO, with an OR of 0.60 (95% CI 0.39-0.94), and reduced risk of miscarriage/perinatal death, with an OR of 0.40 (95% CI 0.24-0.69), compared to those who did not follow the pathway indicators. Compared with the general population, patients with RA who met all HCQI during pregnancy displayed a risk of APO with an OR of 0.92 (95% CI 0.61-1.38) and miscarriage/perinatal death with an OR of 0.77 (95% CI 0.47-1.29).

Conclusion: The adherence to an ideal clinical pathway of pregnancy management in women with RA restored the risk of APO to that expected for the general population.
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http://dx.doi.org/10.1002/acr.24116DOI Listing
February 2021

Risk factors of damage in early diagnosed systemic lupus erythematosus: results of the Italian multicentre Early Lupus Project inception cohort.

Rheumatology (Oxford) 2020 09;59(9):2272-2281

Rheumatology Unit, University of Cagliari and AOU University Clinic, Cagliari.

Objective: To investigate risk factors for damage development in a prospective inception cohort of early diagnosed SLE patients.

Methods: The Early Lupus Project recruited an inception cohort of patients within 12 months of SLE classification (1997 ACR criteria). At enrolment and every 6 months thereafter, the SLICC/ACR Damage Index was recorded. The contribution of baseline and time-varying covariates to the development of damage, defined as any SLICC/ACR Damage Index increase from 0 to ≥1, was assessed using univariate analysis. Forward-backward Cox regression models were fitted with covariates with P < 0.05 to identify factors independently associated with the risk of damage development.

Results: Overall, 230 patients with a mean (s.d.) age of 36.5 (14.4) years were eligible for this study; the mean number of visits per patient was 5.3 (2.7). There were 51 (22.2%) patients with SLICC/ACR Damage Index ≥1 after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months. Dyslipidaemia [P = 0.001; hazard ratio (HR) 2.9; 95% CI 1.5, 5.6], older age (P = 0.001; HR 3.0; 95% CI 1.6, 5.5), number of organs/systems involved (P = 0.002; HR 1.4; 95% CI 1.1, 1.8) and cardiorespiratory involvement (P = 0.041; HR 1.9; 95% CI 1.0, 3.7) were independently associated with an increased risk of developing damage. Risk profiles for damage development differed for glucocorticoid-related and -unrelated damage. HCQ use (P = 0.005; HR 0.4; 95% CI 0.2, 0.8) reduced the risk of glucocorticoid-unrelated damage.

Conclusion: We identified risk factors of damage development, but little effect of glucocorticoids, in this early SLE cohort. Addressing modifiable risk factors from the time of SLE diagnosis might improve patient outcomes.
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http://dx.doi.org/10.1093/rheumatology/kez584DOI Listing
September 2020

Management of adult-onset Still's disease with interleukin-1 inhibitors: evidence- and consensus-based statements by a panel of Italian experts.

Arthritis Res Ther 2019 12 11;21(1):275. Epub 2019 Dec 11.

Division of Rheumatology, ASST Gaetano Pini-CTO, Milan, Italy.

Background: Adult-onset Still's disease (AOSD) is a rare inflammatory condition characterized by fever, rash, and arthritis. Because of its rarity, clinical trials are inherently small and often uncontrolled. Our objective was to develop recommendations for the use of interleukin (IL)-1 inhibitors in the management of patients with AOSD, based on the best evidence and expert opinion.

Methods: A panel of 10 experts (9 rheumatologists and 1 pediatrician) was established. The first step was dedicated to a comprehensive literature review and development of statements. Two separate literature searches were performed on the MEDLINE (Pubmed), EMBASE, and BIOSIS databases through April 2018 to identify (1) differences and similarities between AOSD and pediatric Still's disease (systemic juvenile idiopathic arthritis [SJIA]) and (2) the efficacy and safety of IL-1 inhibitors in AOSD treatment. In the second step, the statements were submitted in a Delphi process to a panel of 67 rheumatologists. Consensus threshold was set at 66%: positive, > 66% of voters selected scores 3 to 5; negative, > 66% of voters selected scores 1 or 2. In the third step, the voting results were analyzed, and the statements were finalized.

Results: Eleven statements were developed. Forty-six of 67 rheumatologists (72%) participated in the Delphi process. A positive consensus was reached after the first round of voting and was full (> 95%) on the majority of statements. A large consensus was achieved in considering AOSD and SJIA as the same disease. The use of anti-IL-1 therapies in refractory patients was considered quite safe and effective both as the first and as a subsequent line of biologic treatment, especially in systemic patients. Because of the lack of head-to-head comparisons, a different profile of efficacy among IL-1 inhibitors could not be established. There was a large consensus that failure of the first IL-1 inhibitor does not preclude response to another one. The lack of studies comparing early versus late treatment did not allow to draw conclusions; however, data from SJIA suggest a better response in early treatment.

Conclusions: The Delphi method was used to develop recommendations that we hope will help clinicians in the management of patients with AOSD refractory to conventional therapies.
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http://dx.doi.org/10.1186/s13075-019-2021-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907145PMC
December 2019

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course.

J Clin Med 2019 Nov 18;8(11). Epub 2019 Nov 18.

Department of Rheumatology, S. Maria Hospital-IRCCS, 42123 Reggio Emilia, Italy.

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.
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http://dx.doi.org/10.3390/jcm8112013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912490PMC
November 2019

The Role of the Multidisciplinary Evaluation of Interstitial Lung Diseases: Systematic Literature Review of the Current Evidence and Future Perspectives.

Front Med (Lausanne) 2019 31;6:246. Epub 2019 Oct 31.

Section of Rheumatology, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria Sant'Anna di Ferrara, Cona, Italy.

The opportunity of a multidisciplinary evaluation for the diagnosis of interstitial pneumonias highlighted a major change in the diagnostic approach to diffuse lung disease. The new American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guidelines for the diagnosis of idiopathic pulmonary fibrosis have reinforced this assumption and have underlined that the exclusion of connective tissue disease related lung involvement is mandatory, with obvious clinical and therapeutic impact. The multidisciplinary team discussion consists in a moment of interaction among the radiologist, pathologist and pulmonologist, also including the rheumatologist when considered necessary, to improve diagnostic agreement and optimize the definition of those cases in which pulmonary involvement may represent the first or prominent manifestation of an autoimmune systemic disease. Moreover, the proposal of classification criteria for interstitial lung disease with autoimmune features (IPAF) represents an effort to define lung involvement in clinically undefined autoimmune conditions. The complexity of autoimmune diseases, and in particular the lack of classification criteria defined for pathologies such as anti-synthetase syndrome, makes the involvement of the rheumatologist essential for the correct interpretation of the autoimmune element and for the application of classification criteria, that could replace clinical pictures initially interpreted as IPAF in defined autoimmune disease, minimizing the risk of misdiagnosis. The aim of this review was to evaluate the available evidence about the efficiency and efficacy of different multidisciplinary team approaches, in order to standardize the professional figures and the core set procedures that should be necessary for a correct approach in diagnosing patients with interstitial lung disease.
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http://dx.doi.org/10.3389/fmed.2019.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842981PMC
October 2019

Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicentre retrospective study.

Intern Med J 2020 09;50(9):1085-1090

Rheumatology Unit, University of Modena and Reggio Emilia, Univeritary Hospital Policlinico of Modena, Modena, Italy.

Background: Interstitial lung disease (ILD) is the most severe extra-articular manifestation of rheumatoid arthritis (RA). Although it is responsible of 10-20% of all RA mortality, no controlled studies are available for the treatment of RA-ILD and its therapeutic approach is still debated.

Aims: To analyse the evolution of ILD in a population of RA patients treated with tocilizumab (TCZ).

Methods: In this national multicentre study, we retrospectively collected patients with RA-ILD treated with at least one dose of TCZ. For each patient, disease activity and serological data were evaluated. Moreover, we analysed the evolution of high-resolution computed tomography (HRCT) and pulmonary function tests, including forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO).

Results: Twenty-eight RA-ILD patients were identified (females/males 18/10, mean age 61.6 years), with a mean follow up for TCZ therapy of 30 months. At the end of follow up, FVC remained stable in 14 (56%) patients, improved in 5 (20%) and worsened in 6 (24%). DLCO remained stable in 14 (56%) patients, improved in 5 (20%) and worsened in 6 (24%), even though in 3 patients DLCO and FVC showed an opposite trend. HRCT remained stable in the majority (25) of cases, worsened in two patients with a usual interstitial pneumonia pattern and improved in only one case with a non-specific interstitial pneumonia pattern.

Conclusions: The management of RA-ILD patients remains a critical unmet need. TCZ demonstrated a good safety profile in patients with RA-ILD and a potential effect on the stabilisation of lung involvement.
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http://dx.doi.org/10.1111/imj.14670DOI Listing
September 2020

Biological and synthetic target DMARDs in psoriatic arthritis.

Pharmacol Res 2019 11 1;149:104473. Epub 2019 Oct 1.

Department of Medical Sciences, Section of Rheumatology, University of Ferrara and Azienda Ospedaliero-Universitaria Sant'Anna, Cona, Ferrara, Italy.

Psoriatic arthritis (PsA) is a chronic multi-faceted immune-mediated systemic disorder, characterized by articular, cutaneous, enthesis, nail and spine involvement. Articular manifestations of PsA are particularly common and highly disabling for patients, while the heterogeneous clinical subsets of the disease are challenging for clinicians. In recent years, research has made many advances in understanding the pathogenesis of the disease from genetic, epigenetic and molecular points of view. New drugs are now available for the treatment of this condition, and, in particular, TNF-alfa inhibitors, historically the first biologicals approved in PsA, are now juxtaposed by new biological disease modifying anti-rheumatic drugs (bDMARDs) with different modes of action. Targeting IL-12/IL-23 p40 common subunit with ustekinumab, IL-17A with secukinumab and ixekizumab, T cells co-stimulation with abatacept, is now possible, safe and effective. Moreover, targeted synthetic molecules with oral administration are available, with the possibility to interfere with phosphodiesterase-4 and JAK/STAT pathways. Indeed, new drugs are under development, with the possibility to target selectively IL-17 receptor, IL-23, and other key molecular targets in the pathogenesis of this condition. In this narrative review, we provide an up-to-date overview of the current application of biological and targeted synthetic DMARDs in the field of PsA, with particular regard to the clinical significance of this possibility to target a higher number of distinct immune-pathways.
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http://dx.doi.org/10.1016/j.phrs.2019.104473DOI Listing
November 2019

Adherence to Treat-to-target Management in Rheumatoid Arthritis and Associated Factors: Data from the International RA BIODAM Cohort.

J Rheumatol 2020 06 15;47(6):809-819. Epub 2019 Sep 15.

From the Department of Rheumatology, Leiden University Medical Center, Leiden; Zuyderland Medical Center, Heerlen; Academic Medical Center/University of Amsterdam, Amsterdam University Medical Center, Amsterdam; Amsterdam Rheumatology and Immunology Center, locations Reade and Amsterdam, University Medical Center, Amsterdam, the Netherlands; Newman Clinical Research, Department of Rheumatology, St. Vincent's University Hospital, Dublin, Ireland; Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet - Glostrup, University of Copenhagen, Copenhagen, Denmark; University of Alberta, Edmonton, Alberta; The Arthritis Program Research Group, Newmarket, Ontario; Divisions of Rheumatology and Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario; Rheumatology Department, Centre Intégré Universitaire en Santé et Services Sociaux (CIUSSS) de l'Estrie-Centre Hospitalier Universitaire de Sherbrooke (CHUS), Université de Sherbrooke, Sherbrooke, Quebec; Departments of Medicine and Community Health Services, Cumming School of Medicine, University of Calgary, Calgary, Alberta; CaRE Arthritis Ltd., Edmonton, Alberta, Canada; Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Divisions of Rheumatology and Internal Medicine, Catholic University of the Sacred Heart, Rome; Department of Rheumatology, Università di Verona, Verona; St. Anna Hospital, Ferrara (loc. Cona); Department of Rheumatology, Istituto Ortopedico Gaetano Pini, Milan, Italy; Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany; Departement de rhumatologie, Université de Montpellier, Centre Hospitalier Universitaire (CHU) Montpellier, Montpellier; Service de rhumatologie, Centre National de Référence des Maladies Autoimmunes Rares de l'Adulte CERAINO, and UMR1227, Lymphocytes B et Autoimmunité (LBAI), Université de Brest, INSERM, LabEx Immunothérapies Grand Ouest (IGO), Brest; Paris Descartes University, Rheumatology Department, Cochin Hospital, AP-HP, INSERM (U1153): Clinical Epidemiology and Biostatistics, PRES Sorbonne Paris-Cité, Paris; Centre de Rhumatologie, Hôpital Pierre Paul Riquet - Purpan, CHU de Toulouse, Toulouse; Service de Rhumatologie, CHU Bordeaux Pellegrin, Bordeaux, France; Divisions of Rheumatology and Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, Maryland, USA; Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Objective: Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T.

Methods: Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score ≤ 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model).

Results: A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02-1.19), smoking (OR 1.32, 95% CI 1.08-1.63) and high number of tender joints (OR 1.03, 95% CI 1.02-1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50-0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model.

Conclusion: Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features. [Rheumatoid Arthritis (RA) BIODAM cohort; ClinicalTrials.gov: NCT01476956].
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http://dx.doi.org/10.3899/jrheum.190303DOI Listing
June 2020
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