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.

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.

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.

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.

Disease-modifying antirheumatic drug therapy for psoriatic arthritis.

As erosive and deforming arthritis is present in 40% of patients with psoriatic arthritis (PsA), early and aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) may be as effective in controlling the progression of the disease as it is for rheumatoid arthritis (RA). Methotrexate (MTX), sulfasalazine (SSZ), and cyclosporine (CsA) are the most widely used DMARDs in the treatment of PsA and are safe and effective in patients with active peripheral arthritis, although they do not appear to be effective on axial manifestations. No controlled study has evaluated the efficacy of these drugs on the progression of radiological damage. It has recently been demonstrated that leflunomide and anti-tumor necrosis factor (TNF) agents are effective in PsA and psoriasis. The symptomatic improvement has been important and sustained and side effects minimal. In particular, inhibitors of TNF appear to have excellent potential to treat PsA. These agents are able to slow joint damage in rheumatoid arthritis and they are effective on spinal symptoms in ankylosing spondylitis. Hopefully, these findings will prove true in PsA as well.

A comparison of cyclosporine, sulfasalazine, and symptomatic therapy in the treatment of psoriatic arthritis.

OBJECTIVE: To compare the efficacy and tolerability of cyclosporine (CSA) with that of symptomatic therapy (ST) alone and sulfasalazine (SSZ) in the treatment of psoriatic arthritis (PsA). METHODS: Twelve rheumatology centers recruited 99 patients with active PsA in a 24 week, prospective, randomized, open, controlled study. The patients were treated with CSA (3 mg/kg/day) or SSZ (2,000 mg/day) plus ST, or ST alone (nonsteroidal antiinflammatory drugs, analgesics, and/or prednisone < or = 5 mg/day). The primary endpoint was the 6 month change in pain. Analyses were on the basis of the intention-to-treat principle. RESULTS: In comparison with both SSZ and ST, there was a statistically significant difference in favor of CSA in terms of the mean changes in the pain score (p < 0.05), which was considered the primary response variable. A significant decrease in favor of CSA versus ST alone was also observed for swollen joint count (p = 0.05), tender joint count (p = 0.01), joint/pain tenderness score (p = 0.002), patient and physician global assessment by at least one point (p = 0.04 and 0.01, respectively), total Arthritis Impact Measurement Scale score (p = 0.002), and spondylitis functional index (p = 0.002). There was a statistically significant difference in the ACR 50% and ACR 70% response rates between the CSA and ST groups (p = 0.02, 0.05). Comparing the SSZ and ST alone groups, only the spondylitis functional index decreased significantly in the SSZ treated patients (p = 0.03). The Psoriasis Area and Severity Index was significantly lower in the CSA than in the ST and SSZ groups (p = 0.0001 and 0.01, respectively). Decrease in erythrocyte sedimentation rate was significant only in the SSZ versus the ST group (p = 0.02), whereas reduction in C-reactive protein was significant in the CSA treated patients compared with the ST group (p = 0.006). The most common adverse event in the CSA group was mild, reversible kidney dysfunction. CONCLUSION: The results of this open trial confirm that CSA is well tolerated by patients with PsA and suggest that it is more efficacious than ST or SSZ.

Characterization of the binding interface between the copper chaperone Atx1 and the first cytosolic domain of Ccc2 ATPase.

The interaction of the copper chaperone Atx1 and the first cytosolic domain of Ccc2 ATPase, Ccc2a, was investigated by NMR in solution. In particular, a solution of Cu(I)-15NAtx1 was titrated with apo-Ccc2a, and, vice versa, a solution of Cu(I)-15NCcc2a was titrated with apo-Atx1. By following the 15N and 1H chemical shifts, a new species is detected in both experiments. This species is the same in both titrations and is in fast exchange with the parent species on the NMR time scale. Nuclear relaxation data are consistent with the formation of an adduct. Judging from the nuclear Overhauser effect spectroscopy patterns, the structure of Cu(I)-15NCcc2a in the presence of apo-Atx1 is not significantly altered, whereas Cu(I)-15NAtx1 in the presence of apo-Ccc2a experiences some changes with respect to both the apoproteins and the Cu(I)-loaded proteins. The structure of the Cu(I)-15NAtx1 moiety in the adduct was obtained from 1137 nuclear Overhauser effects to a final root mean square deviation to the mean structure of 0.76 +/- 0.13 A for the backbone and 1.11 +/- 0.11 A for the heavy atoms. 15N and 1H chemical shifts suggest the regions of interaction that, together with independent information, allow a structural model of the adduct to be proposed. The apo form of Atx1 displays significant mobility in loops 1 and 5, the N-terminal part of helix alpha1, and the C-terminal part of helix alpha2 on the ms-micros time scale. These regions correspond to the metal binding site. Such mobility is largely reduced in the free Cu(I)-Atx1 and in the adduct with apo-Ccc2a. The analogous mobility of Ccc2a in both Cu(I) and apo forms is reduced with respect to Atx1. Such an adduct is relevant as a structural and kinetic model for copper transfer from Atx1 to Ccc2a in physiological conditions.

Distal extremity swelling with pitting edema in psoriatic arthritis: a case-control study.

OBJECTIVE: To evaluate the frequency and the clinical characteristics of distal extremity swelling with pitting edema in patients with psoriatic arthritis (PsA). METHODS: This was a case-control study of consecutive outpatients with PsA (old and new diagnosis) observed over a 3-month period in three secondary referral centers in Italy. As controls we used the two consecutive rheumatic outpatients, excluding those with spondylarthropathies, observed after a PsA patient. The demographic and clinical features were assessed by clinical examination and review of the medical records. RESULTS: A total of 183 patients with PsA and 366 controls were evaluated. Distal extremity swelling with pitting edema was recorded in 39/183 (21%) PsA patients and in 18/366 (4.9%) controls (p < 0.0001). In 8/39 (20%) patients this feature presented as a first, isolated manifestation of PsA, and in 8 others it was associated with other features of PsA at diagnosis. The upper and lower extremities were affected, predominantly asymmetrically, in 40% and 60% of the cases respectively. In patients with pitting edema compared to those without this feature, the frequency of Achilles enthesitis and plantar fasciitis, calculated together, was higher (p < 0.05) and the duration of arthritis was significantly lower (p = 0.02). In 7 patients the clinical evidence of a predominant involvement of tenosynovial structures was confirmed by MRI. CONCLUSION: Upper or lower distal extremity swelling with pitting edema due to tenosynovitis, usually unilateral, is a common feature in PsA patients and may represent the first, isolated manifestation of the disease.

RS3PE syndrome: an overview.

More than ten years ago McCarty et al. described the RS3PE syndrome based on their study of 23 patients. Numerous additional cases have since been reported. In addition to the isolated or "pure" type which probably forms part of the clinical spectrum of polymyalgia rheumatica, inflammatory swelling with pitting edema of the dorsum of the hands and/or feet can be observed in different inflammatory rheumatic diseases as well as in haematological and solid malignancies.

Paraneoplastic remitting seronegative symmetrical synovitis with pitting edema.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a syndrome that may be associated with many conditions, including malignancy. Three further cases of paraneoplastic RS3PE are described and the literature is reviewed. Paraneoplastic RS3PE is more frequently associated with solid tumors, in particular adenocarcinoma. The two clinical characteristics suggestive of paraneoplastic RS3PE are systemic sign/symptoms and the poor response to corticosteroid therapy.