1H, 13C, and 15N backbone chemical shift assignments of the apo and the ADP-ribose bound forms of the macrodomain of SARS-CoV-2 non-structural protein 3b.

The SARS-CoV-2 genome encodes for approximately 30 proteins. Within the international project COVID19-NMR, we distribute the spectroscopic analysis of the viral proteins and RNA. Here, we report NMR chemical shift assignments for the protein Nsp3b, a domain of Nsp3. The 217-kDa large Nsp3 protein contains multiple structurally independent, yet functionally related domains including the viral papain-like protease and Nsp3b, a macrodomain (MD). In general, the MDs of SARS-CoV and MERS-CoV were suggested to play a key role in viral replication by modulating the immune response of the host. The MDs are structurally conserved. They most likely remove ADP-ribose, a common posttranslational modification, from protein side chains. This de-ADP ribosylating function has potentially evolved to protect the virus from the anti-viral ADP-ribosylation catalyzed by poly-ADP-ribose polymerases (PARPs), which in turn are triggered by pathogen-associated sensing of the host immune system. This renders the SARS-CoV-2 Nsp3b a highly relevant drug target in the viral replication process. We here report the near-complete NMR backbone resonance assignment (1H, 13C, 15N) of the putative Nsp3b MD in its apo form and in complex with ADP-ribose. Furthermore, we derive the secondary structure of Nsp3b in solution. In addition, 15N-relaxation data suggest an ordered, rigid core of the MD structure. These data will provide a basis for NMR investigations targeted at obtaining small-molecule inhibitors interfering with the catalytic activity of Nsp3b.

Therapeutic strategies utilization and resource consumption in patients treated for psoriatic arthritis: findings from a real-world analysis in an Italian setting.

PURPOSE: The purpose of this study was to analyze the therapeutic strategies and estimate the health care resource consumption in patients with psoriatic arthritis (PsA). PATIENTS AND METHODS: An observational retrospective cohort analysis of administrative databases of six Italian Local Health Units was performed. Patients ≥18 years with a hospitalization discharge diagnosis of PsA (International Classification of Diseases, Ninth Revision code: 696.0) or exemption code (045.696.0) for PsA from January 1, 2010 to December 31, 2015 (inclusion period), with at least one prescription of any therapy used for PsA were included. The index date (ID) was the first date matching with at least one of the inclusion criteria during the inclusion period. All patients were followed up after the ID until the end of data availability. Baseline C-reactive protein (CRP) levels (±6 months in relation to the ID) were also analyzed. RESULTS: A total of 2,408 (prevalence 0.83 per 1,000) patients with PsA (male 52%; median age 54 years) were included in the study; patients were already treated for PsA in 42.4% of cases. At 1 year of follow-up, 73% of the patients received one systemic drug, while 22% of patients received two systemic drugs; in addition, our results show an increase in the number of add-on or switches in a longer follow-up period. The utilization of biologic agents was higher among patients with previous PsA treatment, showing a progression of the pathology. Overall, a medium/high level of CRP at baseline was observed among more than half of the overall sample, with slight changes across subgroups in analysis. The average health care costs were €1,966.4 and €13,914 per year for patients treated with conventional systemic therapy and biological agents, respectively. CONCLUSION: A better knowledge of prescription therapeutic scheme and economic burden of PsA could stimulate the rational development of health programs aimed at potentiating services for its management.

Red flags for appropriate referral to the gastroenterologist and the rheumatologist of patients with inflammatory bowel disease and spondyloarthritis.

Collaboration between gastroenterologists and rheumatologists is recommended for the correct management of patients with associated spondyloarthritis (SpA) and inflammatory bowel disease (IBD). We aimed to establish the appropriateness of several red flags for a prompt specialist referral. A systematic review of the literature was performed using the GRADE method to describe the prevalence of co-existing IBD-SpA and the diagnostic accuracy of red flags proposed by a steering committee. Then, a consensus among expert gastroenterologists and rheumatologists (10 in the steering committee and 13 in the expert panel) was obtained using the RAND method to confirm the appropriateness of each red flag as 'major' (one sufficient for patient referral) or 'minor' (at least three needed for patient referral) criteria for specialist referral. The review of the literature confirmed the high prevalence of co-existing IBD-SpA. Positive and negative predictive values of red flags were not calculated, given the lack of available data. A consensus among gastroenterology and rheumatology specialists was used to confirm the appropriateness of each red flag. Major criteria to refer patients with SpA to the gastroenterologist included: rectal bleeding, chronic abdominal pain, perianal fistula or abscess, chronic diarrhoea and nocturnal symptoms. Major criteria to refer patients with IBD to the rheumatologist included: chronic low back pain, dactylitis, enthesitis and pain/swelling of peripheral joints. Several major and minor red flags have been identified for the diagnosis of co-existing IBD-SpA. The use of red flags in routine clinical practice may avoid diagnostic delay and reduce clinic overload.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting tumour necrosis factor-α (TNF-α) and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Preclinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis and other granulomatous conditions (mostly resulting from the reactivation of a latent infection). In addition, it may lead to the occurrence of other serious infections (bacterial, fungal, opportunistic and certain viral infections). These associated risks seem to be lower for etanercept than other agents. Screening for latent tuberculosis infection should be performed before starting anti-TNF-α therapy, followed by anti-tuberculosis therapy if appropriate. Screening for chronic hepatitis B virus (HBV) infection is also recommended, and antiviral prophylaxis may be warranted for hepatitis B surface antigen-positive individuals. No benefit is expected from the use of antibacterial, anti-Pneumocystis or antifungal prophylaxis. Pneumococcal and age-appropriate antiviral vaccinations (i.e. influenza) should be administered. Live-virus vaccines (i.e. varicella-zoster virus or measles-mumps-rubella) may be contraindicated in people receiving anti-TNF-α therapy, although additional data are needed before definitive recommendations can be made. IMPLICATIONS: Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy.

Classification and clinical assessment.

There are at least nine classification criteria for psoriatic arthritis (PsA) that have been proposed and used in clinical studies. With the exception of the ESSG and Bennett rules, all of the other criteria sets have a good performance in identifying PsA patients. As the CASPAR criteria are based on a robust study methodology, they are considered the current reference standard. However, if there seems to be no doubt that they are very good to classify PsA patients (very high specificity), they might be not sensitive enough to diagnose patients with unknown early PsA. The vast clinical heterogeneity of PsA makes its assessment very challenging. Peripheral joint involvement is measured by 78/76 joint counts, spine involvement by the instruments used for ankylosing spondylitis (AS), dactylitis by involved digit count or by the Leeds dactylitis index, enthesitis by the number of affected entheses (several indices available) and psoriasis by the Psoriasis Area and Severity Index (PASI). Peripheral joint damage can be assessed by a modified van der Heijde-Sharp scoring system and axial damage by the methods used for AS or by the Psoriatic Arthritis Spondylitis Radiology Index (PASRI). As in other arthritides, global evaluation of disease activity and severity by patient and physician and assessment of disability and quality of life are widely used. Finally, composite indices that capture several clinical manifestations of PsA have been proposed and a new instrument, the Psoriatic ARthritis Disease Activity Score (PASDAS), is currently being developed.

Treatment patterns of anti-TNF agents in Italy: an observational study.

OBJECTIVE: This study aims to provide a description of real life treatment patterns of biologic anti-TNF in 23 Italian Rheumatology centers. METHODS: This was an observational, multicenter, retrospective study. Patients >18 years of age, diagnosed with rheumatoid arthritis and treated with the first biologic anti-TNF agent between the 1st July 2002 to the 31st March 2004 were included. Total follow-up was 36 months. RESULTS: In total, 248 patients were first treated with infliximab, 259 with etanercept and 196 with adalimumab. First course of therapy with infliximab was associated with lower cumulative drug survival than the other two agents. At 36 months, 74.7% of patients on etanercept, 72.0% of those on adalimumab and 57.7% of subjects receiving infliximab were still on therapy. In total, 149 patients switched to a second anti-TNF agent. At 24 months of the second line treatment, 75%, 22%, and 54% of infliximab, etanercept and adalimumab recipients, respectively, had discontinued their second anti-TNF. CONCLUSIONS: Anti-TNF agents may be associated to a rather high incidence of discontinuation and dose adjustments over a 36-month period, with a possible effect on healthcare expense. In particular, infliximab was associated with a higher incidence of discontinuations compared with etanercept and adalimumab.

Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders?

Recent evidence suggests that idiopathic nonspecific interstitial pneumonia (iNSIP) is a distinct clinical entity amongst other idiopathic interstitial pneumonias, and some data seem to suggest a possible pathogenetic role of autoimmunity. The aim of the present study was to assess if iNSIP might represent an early lung manifestation of an autoimmune disease. After initial review of cases found in the medical records database by searching for the term "NSIP" (n = 63), 37 iNSIP cases were identified, and were re-evaluated using a dynamic integrated multidisciplinary approach. 27 cases with iNSIP were selected for the study. Mean ± sd age at first respiratory symptom was 54.2 ± 8 yrs, 70% were females, and 59% were never-smokers. At follow-up (mean ± sd 59.7 ± 29 months, range 12-138 months), autoimmune diseases occurred in 14 (52%) patients, with seven (26%) cases of autoimmune thyroiditis, six (22%) of undifferentiated connective tissue disease and three (11%) of connective tissue disease. Patients developing autoimmune diseases were older and more frequently never-smoking females. In >50% of patients diagnosed with iNSIP, evidence of autoimmune diseases develops within 2 yrs, suggesting a probable link between the clinical entity of iNSIP and autoimmune disorders.

Serum levels of long pentraxin PTX3 in patients with polymyalgia rheumatica.

OBJECTIVES: To evaluate PTX3 feasibility to provide a prognostic tool in PMR clinical practice. METHODS: Circulating PTX3 levels were measured in 93 PMR patients at disease onset and during corticosteroid therapy and in 46 normal controls (NC) by ELISA. RESULTS: No difference in PTX3 concentrations was observed between NC and PMR either at disease onset and during follow-up or between groups of patients defined according to the presence of recurrence/relapse. CONCLUSIONS: PTX3 serum levels do not increase significantly in active PMR. Further studies on patients with giant-cell arteritis could evaluate whether large vessel involvement may be associated to increased PTX3 levels.

Protein Z G79A and A-13G gene polymorphisms in Italian patients with Behçet's disease.

OBJECTIVE: To investigate potential associations between A-13G and G79A polymorphisms of the protein Z gene and venous thrombosis and other clinical manifestations in Italian patients with Behçet's disease (BD). METHODS: 176 Italian patients who satisfied the International Study Group criteria for BD and 134 healthy age- and sex- matched blood donors were genotyped for A-13G and G79A polymorphisms of the protein Z gene by molecular methods. 113 and 112 of the 176 BD patients were also genotyped for factor V Leiden and prothrombin gene G20210A polymorphisms. Serological HLA class B51 typing was performed by a standard microlymphocytotoxicity technique. The patients were subgrouped according to the presence or absence of clinical manifestations. RESULTS: The distribution of allele and genotype frequencies of A-13G and G79A polymorphisms did not differ significantly between BD patients and healthy controls.The frequencies of carriage rates of protein Z G79A and A-13G polymorphisms in BD patients with and without DVT were similar. Similarly, no associations between thrombotic events and the protein Z gene polymorphisms studied were observed in BD patients carrying factor V Leiden or prothrombin gene G20210A mutations. No significant associations were observed between protein Z polymorphisms and the occurrence of specific clinical findings. CONCLUSION: No association between DVT and A-13G or G79A polymorphisms of the protein Z gene was found in Italian BD patients. Furthermore, these protein Z polymorphisms in BD do not seem to increase the risk of DVT due to factor V Leiden or prothrombin gene G20210A mutations.

Toll-like receptor 4 (TLR4) gene polymorphisms in Italian patients with Behçet's disease.

OBJECTIVE: To investigate potential associations between toll-like receptor 4 (TLR4) gene polymorphisms and susceptibility to, clinical features, and severity of Behçet's disease (BD). METHODS: A total of 189 Italian patients who satisfied the International Study Group criteria for BD and 210 healthy age- and sex-matched blood donors were genotyped for two coding single nucleotide polymorphisms of TLR4 (Asp299Gly and Thr399Ile) by molecular methods. The patients were subgrouped according to the presence or absence of clinical manifestations. Severity score was calculated. RESULTS: The distribution of allele and genotype frequencies did not differ significantly between the BD patients and the healthy controls. No significant associations were found when BD patients with and those without clinical manifestations were compared. No association between TLR4 polymorphisms and severity score was observed. CONCLUSION: Our data suggest that the TLR4 gene polymorphisms are not associated with susceptibility to, clinical expression of, and severity of BD in Italian patients.

The psoriatic arthritis cost evaluation study: a cost-of-illness study on tumour necrosis factor inhibitors in psoriatic arthritis patients with inadequate response to conventional therapy.

OBJECTIVE: To evaluate costs, benefits and cost-effectiveness of anti-TNF agents in PsA patients with inadequate response to conventional treatment. METHODS: A total of 107 patients, from nine Italian rheumatology centres, with different forms of PsA were given anti-TNF treatment, mainly etanercept (87%). Information on resource use, health-related quality of life, disease activity, function and laboratory values were collected at baseline and through out the 12 months of therapy. Cost (expressed in euro 2007) and utility (measured by EuroQol) before and after anti-TNF therapy initiation were compared in order to estimate the incremental cost per quality-adjusted life year (QALY) gained, and cost-effectiveness acceptability curve was calculated. RESULTS: At the end of 12 months, there was a significant increase in direct cost due to an increase of drug cost caused by TNF inhibitors that was only partially offset by the decrease in indirect cost. In the last 6 months of therapy, the direct cost increased by euro5052, the cost for the National Health System (NHS) by euro5044 and the social cost by euro4638. However, a gain of 0.12 QALY resulted in a cost per QALY gained of euro40 876 for the NHS and of euro37 591 for the society. The acceptability curve showed that there would be a 97% likelihood that anti-TNF therapy would be considered cost-effective at willingness-to-pay threshold of euro60 000 per QALY gained. CONCLUSION: Cost-effectiveness ratios are within the commonly accepted willingness-to-pay threshold. These results need to be confirmed in larger samples of patients.

Frequency and duration of clinical remission in patients with peripheral psoriatic arthritis requiring second-line drugs.

OBJECTIVE: To evaluate the frequency and duration of clinical remission in patients with PsA. METHODS: All consecutive new outpatients with peripheral PsA requiring second-line drugs and RA observed between January 2000 and December 2005 were included in a prospective, case-control study. Primary end point was to assess the frequency of remission in peripheral PsA compared with RA. Secondary end points were to compare the duration of clinical remission during treatment and after therapy interruption, ACR 20, 50, 70 response rates and to detect any remission predictor at diagnosis. Treatment regimen was standardized in both groups. From January 2003 to December 2005, therapy was suspended in PsA patients and controls if achieving remission. RESULTS: One or more episodes of remission occurred in 57/236 (24.1%) PsA patients and in 20/268 (7.5%) controls (P < 0.001). The mean duration of remission was of 13 +/- 9.4 months in PsA patients and 4 +/- 3.7 in controls (P > 0.001). Remission episodes were more frequent in PsA patients treated with anti-TNF compared with those receiving traditional DMARDs (P > 0.001), with no differences regarding the duration. After therapy interruption, the remission duration was 12 +/- 2.4 months in PsA and 3 +/- 1.5 in RA (P < 0.001). No remission predictor at diagnosis resulted by multivariate analysis. CONCLUSION: Remission is possible in up to 24% of patients with peripheral PsA. It is significantly more frequent, but not longer, in patients receiving anti-TNF drugs compared with those treated with traditional DMARDs. Patients remain in remission for a long period after therapy interruption, thus suggesting an intermittent therapeutic strategy.

Cervical interspinous bursitis in active polymyalgia rheumatica.

OBJECTIVE: To evaluate the inflammatory involvement of cervical interspinous bursae in patients with polymyalgia rheumatica (PMR) using MRI. METHODS: In all, 12 consecutive, untreated new patients with PMR were investigated. Five patients with fibromyalgia, two patients with cervical osteoarthritis and six patients with spondyloarthritis with neck pain served as controls. MRI of the cervical spine was performed in all 12 PMR case patients and in 13 control patients. Two of the four patients with PMR with pelvic girdle pain also had MRI of the lumbar spine. RESULTS: MRI evidence of interspinous cervical bursitis was found in all patients with PMR, and in three patients with fibromyalgia, in two with psoriatic spondylitis and one with cervical osteoarthritis. A moderate to marked (grade >or=2 on a semiquantitative 0-3 scale) cervical bursitis occurred significantly more frequently in patients with PMR than in control patients (83.3% compared with 30.7%, p = 0.015). In all patients and controls with cervical bursitis the involvement was found at the C5-C7 cervical interspaces. MRI of the lumbar spine showed lumbar interspinous bursitis at the L3-L5 lumbar interspaces in the two patients with PMR and pelvic girdle pain examined. CONCLUSIONS: Cervical interspinous bursitis is a likely basis for discomfort in the neck of patients with PMR. The prominent inflammatory involvement of cervical bursae supports the hypothesis that PMR is a disorder of prominent involvement of extra-articular synovial structures.

Italian evidence-based recommendations for the management of ankylosing spondylitis: the 3E Initiative in Rheumatology.

OBJECTIVE: The 3E (Evidence, Expertise, Exchange) Initiative is a multinational effort of rheumatologists aimed at developing evidence-based recommendations addressing specific questions relevant to clinical practice. The objective of the Italian part of the 3E Initiative was to develop new recommendations designed to help Italian rheumatologists in everyday clinical practice management of patients suffering from ankylosing spondylitis (AS). METHODS: An international scientific committee selected a set of questions concerning the diagnosis, monitoring, and treatment of AS using a Delphi procedure. Evidence-based answers to each question were sought by a systematic literature search in MedLine for papers published up to August 2006. A panel of 55 Italian rheumatologists with expertise in the field of AS used the evidence thus gathered to develop recommendations, filling gaps in evidence with their expert opinion. RESULTS: After discussion and votes, the panel developed 12 statements/recommendations: 3 concerning diagnosis (low back pain approach, early diagnosis, and GPs referral recommendations); 3 concerning monitoring (disease activity, severity, and prognosis), and 6 concerning treatment (bisphosphonates role; treatment of enthesitis; inter-agent safety/efficacy, long-term safety/efficacy, efficacy on different disease manifestations, and the role on inflammatory bowel disease flare precipitation of NSAIDs/COX-II inhibitors). CONCLUSION: Italian recommendations for the management of AS in everyday practice were developed. Their dissemination and implementation in daily clinical practice should help to improve practice uniformity and eventually optimize the management of AS patients.

Lack of association of the -463 G/A myeloperoxidase promoter polymorphism with Behcet's disease in Italian patients.

OBJECTIVE: To investigate potential associations between the -463 G/A myeloperoxidase (MPO) promoter polymorphism and susceptibility to, and clinical expression of, Behçet's disease (BD). METHODS: One hundred and seventy-five Italian patients who satisfied the International Study Group criteria for BD and 235 healthy age- and sex-matched blood donors were genotyped for the -463 G/A promoter polymorphism of the MPO gene by molecular methods. The patients were subgrouped according to the presence or absence of clinical manifestations. RESULTS: The distribution of allele and genotype frequencies of the MPO -463A/G polymorphism did not differ significantly between the BD patients and the healthy controls. Carriers of the -463 A allele (A/A or A/G) [odds ratio (OR) 0.7, 95% confidence interval (CI) 0.5-1.1] and homozygosity for A allele (OR 0.3, 95% CI 0.1-1.3) were less frequent among BD patients than among the controls, but the difference was not statistically significant. No significant associations were found when BD patients with and those without clinical manifestations were compared. CONCLUSION: Our data suggest that the -463 G/A promoter polymorphism of the MPO gene is not associated with susceptibility to, and clinical expression of, BD in Italian patients.

Long-term efficacy of infliximab in refractory posterior uveitis of Behcet's disease: a 24-month follow-up study.

OBJECTIVES: To evaluate the long-term efficacy and safety of infliximab in patients with Behçet's disease (BD) and refractory bilateral posterior uveitis, and to assess the proportion of relapse-free subjects through months 12 and 24. METHODS: Open-label, multicentre, 24-month, prospective, follow up study on 12 consecutive patients with BD and refractory posterior uveitis who had failed at least one immunosuppressive drug. At baseline patients received prednisolone 1 mg/Kg/day with rapid tapering and nine infliximab infusions (5 mg/kg) over a 12-month period. Non-responders after the third infusion withdrew from the study. Patients were evaluated for ocular inflammation degree, visual acuity (VA), number of ocular attacks and incidence of adverse events (AEs). RESULTS: At 12-month visit, 9/12 (75%) patients achieved a complete remission with no relapse during the treatment period. All had a dramatic improvement of ocular inflammation after the first infusion, six were in complete remission after three infusions, and three after four. All these patients suspended corticosteroids at week 22. At 24-month visit, seven out of nine (78%) were still in remission. Mean VA improved from 0.2 +/- 0.6 to 0.5 +/- 0.2 (P < 0.001), and ocular attacks dropped from 40 in the year before therapy to 5 after infliximab cessation (P < 0.001). One patient had a partial remission with two relapses during treatment, and 2/12 (17%) patients showed no improvement. Infliximab was well tolerated with no serious AEs. CONCLUSIONS: Infliximab is rapidly effective and safe in a high proportion BD patients with refractory posterior uveitis, and may be helpful to prevent recurrences.

Recommendations of the Italian Society for Rheumatology for the use of biologic (TNF-alpha blocking) agents in the treatment of psoriatic arthritis.

AIM: To propose recommendations for the use of biologic (TNF-alpha blocking) agents in the treatment of psoriatic arthritis (PsA). METHODS: We developed these recommendations by reviewing the evidence published in medical journals and in abstracts of the American College of Rheumatology (ACR) and of the European League against Rheumatism. A draft of the recommendations was circulated to a group of Italian Rheumatologists with a special interest in PsA and in therapy with biologic agents, and their suggestions were incorporated in the final version. RESULTS: A consensus was achieved regarding the initiation and the monitoring of anti-TNF-alpha agents in PsA. More specifically, we propose that anti-TNF-alphaagents be considered in active PsA resistant to non-steroidal anti-inflammatory drugs, to at least two local steroid injections and at least 2 conventional disease-modifying anti-rheumatic agents (in cases of oligo/monoarthritis and/or enthesitis), and to at least two conventional disease-modifying anti-rheumatic agents (in patients with peripheral joints synovitis). Disease activity monitoring should be based on a variety of outcome measures including the ACR response criteria modified for use in PsA, the Bath ankylosing spondylitis disease activity index (BASDAI), and the Maastricht ankylosing spondylitis enthesis score (MASES). A favorable Expert opinion, based on evaluation of clinical symptoms and signs, of laboratory investigations (particularly acute phase reactants), and of imaging studies (whenever appropriate) should also be obtained. CONCLUSION: These recommendations may be used for guidance in deciding which patients with PsA should receive biologic therapy. Regular updates of these recommendations will be implemented on the basis of the results of new clinical studies and of data from post-marketing surveillance.