on behalf of the BIOBADASER GroupObjective. The long-term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long-term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active-surveillance system following the commercialization of the drugs.Methods. We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti-TNF treatment.Results. Seventy-one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January). Conclusion. Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.

Objective. To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists.Methods. Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years.Results. Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (pre-OR) and 2 began treatment after the recommendations were issued (post-OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre-OR, the active TB rate in BIOBADASER patients was 20.9-fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6-and 6.2-fold higher than the background and EMECAR populations, respectively. Post-OR, 324 patients with a tuberculin skin test result >5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03-0.88; P ‫؍‬ 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02-8.2). There were no INH treatmentrelated hospitalizations or deaths.Conclusion. Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists.

In RA, treatment with etanercept has a lower percentage of discontinuation than infliximab and adalimumab. Concomitant use of DMARDs, disease duration before treatment with a biologic and female sex predict time to discontinuation.

Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy.

Objective. To analyze lipid changes in patients with rheumatoid arthritis (RA) and patients with spondyloarthritis (SpA) treated with biologic agents or tofacitinib in randomized clinical trials (RCTs).Methods. A systematic literature search was performed, using the Medline, Embase, Cochrane Library, and Web of Knowledge databases. Meta-analyses were performed using random-effects models to assess changes in the percentage of patients with abnormal lipid values or in the mean percentage of increase in the cholesterol and triglycerides levels.Results. Conclusion. In patients with RA treated with tocilizumab or tofacitinib but not with TNF antagonists, moderate changes in lipids are observed. Whether these changes pertain to the control of inflammation or to the mechanism of action of the biologic agents or tofacitinib remains undetermined.Rheumatoid arthritis (RA) and the spondyloarthritides (SpA) ankylosing spondylitis and psoriatic arthritis have an important impact on a patient's wellbeing, related partly to joint damage, disability, and poor quality of life but also to increased cardiovascular morbidity and mortality (1-3). The most important cause of death in RA and SpA is cardiovascular disease (4-6).

TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program.

Prefoldin (PFD) is a jellyfish-shaped molecular chaperone that has been proposed to play a general role in de novo protein folding in archaea and is known to assist the biogenesis of actins, tubulins, and potentially other proteins in eukaryotes. Using point mutants, chimeras, and intradomain swap variants, we show that the six coiledcoil tentacles of archaeal PFD act in concert to bind and stabilize nonnative proteins near the opening of the cavity they form. Importantly, the interaction between chaperone and substrate depends on the mostly buried interhelical hydrophobic residues of the coiled coils. We also show by electron microscopy that the tentacles can undergo an en bloc movement to accommodate an unfolded substrate. Our data reveal how archael PFD uses its unique architecture and intrinsic coiled-coil properties to interact with nonnative polypeptides.C oiled coils consist of two or more parallel or antiparallel amphipathic ␣-helices that twist around one another to form supercoils (1). The primary sequences of the helices display a heptad repeat (abcdefg), where apolar residues are found preferentially in the first (a) and fourth (d) positions. Although the knobs-into-holes packing of the hydrophobic residues is the predominant stabilizing force for a coiled coil, inter-and intrahelical ionic interactions can act to further stabilize or destabilize its supersecondary structure (1). Coiled coils are found in several molecular chaperones, a diverse family of proteins whose collective cellular role is to ensure the quality control (e.g., folding, assembly, and transport) of nonnative proteins (2, 3). Archaeal prefoldin (PFD) is a chaperone that contains six canonical antiparallel coiled coils whose N-and C-terminal helices project outward from a double ␤-barrel oligomerization domain; the overall shape of the hexameric protein complex, assembled from two PFD␣ and four PFD␤ subunits (␣ 2 ␤ 4 ), resembles a jellyfish with six tentacles (4). In solution, its tentacles are likely to be fully solvated and independently mobile (4). A lower-resolution electron microscope image of recombinant human PFD, which consists of six different proteins (two ␣ class and four ␤ class subunits), reveals that it possesses the same overall structure (5).Like other chaperones, archaeal PFD can selectively interact with and stabilize nonnative (unfolded) polypeptides that expose hydrophobic surfaces in vitro, helping to prevent their aggregation (4, 6, 7). Preliminary studies have shown that deletion of the distal coiled-coil regions in either the ␣ or ␤ subunit abrogates chaperone activity in vitro, implying that PFD grasps its substrates in a multivalent manner (4). Similarly, the eukaryotic PFD-actin complex recently visualized by EM shows that nonnative actin, one of its substrates, makes multiple contacts with the distal regions of the tentacles (5).In the crowded cellular environment, eukaryotic PFD is likely to transiently stabilize ribosome-bound nascent polypeptides (8) before shuttling them to a chaperonin (an ATP-depe...

The results of this study support the hypothesis that the mtDNA haplogroups have a role in the complex osteoarthritic process.