Reconstructing the pyramid as a therapeutic approach to rheumatoid arthritis

Several recent clinical studies have clearly established that rheumatoid arthritis (RA) is a disease identifiable since its early phases, a disease that can be adequately and efficaciously treated provided the therapeutic program can be started early on. To reach the aim of controlling effectively the disease and of leading the patients to live a normal life, several points must be fulfilled. The first is an early diagnosis obtained through a careful clinical examination along with an appropriate laboratory immunological work-up, followed by an adequate monotherapy within the first 4 months from symptoms onset. The second is the therapeutic re-assessment that needs to be done every three months, to start a possible combination therapy (COMBO), in order to rescue monotherapy failures. The third is the initiation of biological response modifiers (BRMs) within 6 months from monotherapy onset, within 3 months from COMBO in the most resistant cases. Having at hand several molecules with BRMs characteristics, we believe that the future appears much more favourable in most cases even in those with the severe disease

GISEA: an Italian biological agents registry in rheumatology

The GISEA registry is an independent database that was established by the Italian Group for the Study of Early Arthritis (GISEA) in 2008, funded by the Italian Association of Rheumatic Patients (ANMAR - ONLUS). In line with the network's epidemiological strategy, the initial protocol was designed to collect long-term follow-up data concerning patients with rheumatic diseases treated with biological agents in order to investigate the realworld characteristics in terms of disease activity, comorbidities and survival on treatment. We here describe the design and methodology used to collect patient data. Information concerning demographics, disease activity, treatment changes (including the reasons for changing and the duration of each therapy), concomitant therapies and adverse events is available to all the members of the study groups by means of a web-based interface that allows queries and the presentation of numerical data, as well as graphics to illustrate trends. Fourteen Italian rheumatology centres have contributed patients to the database which, at the time writing, includes 5145 patients (72% women) with a mean age of 53 years (range 16-88). The initial diagnoses were rheumatoid arthritis (3494 patients, 67.9%), psoriatic arthritis (833, 16.2%), ankylosing spondylitis (493, 9.6%), undifferentiated spondylo-arthritides (307, 5.9%), enteropathic arthritis (14, 0.3%) and spondylitis following reactive arthritis (4, 0.1%). These patients have been followed for up to 10 years, and 1927 (35.8%) have been treated for at least three years. The biological treatments received include etanercept, infliximab, anakinra, adalimumab, abatacept, rituximab and tocilizumab. A total of 2926 adverse events have been observed, with 1171 patients (22%) reporting at least one. Analysis of the accumulated data will provide insights into the critical early phase of the studied arthritides, and enable us to identify the clinical and laboratory profiles that may predict responsiveness to a specific therapy

Microvascular heart involvement in systemic autoimmune diseases: The purinergic pathway and therapeutic insights from the biology of the diseases

Heart involvement \u2013 often asymptomatic \u2013 is largely underestimated in patients with systemic autoimmune diseases (SADs). Cardiovascular events are more frequent in patients with SADs compared to the general population, owing to the consequences of inflammation and autoimmunity and to the high prevalence of traditional risk factors. Coronary microvascular disease (CMD) is a form of cardiac involvement that is increasingly recognised yet still largely neglected. CMD, the incapacity of the coronary microvascular tree to dilate when myocardial oxygen demand increases or when there is a microvascular spasm (or subclinical myocarditis), is increasingly reported because of the widespread use of new cardiac imaging tools, even in a subclinical phase. The assessment of myocardial coronary flow reserve (CFR) emerged as the most effective clinical tool to detect microvascular damage. The potential causes of microvascular damage, molecular and cellular inflammation along with a pathological CD39-CD73 axis, need always to be considered because data show that they play a role in the occurrence of acute coronary syndromes, heart failure and arrhythmias, even in the early asymptomatic stage. Data suggest that controlling disease activity by means of methotrexate, biologic drugs, antimalarial medications, statins and aspirin, according to indication, might reduce the cardiovascular risk related to macrovascular and microvascular damage in most patients with SADs, provided that they are used early and timely to control diseases. The need of new biomarkers and a careful assessment of myocardial CFR emerged as the most effective clinical tool to detect microvascular damage

Thymosin β4 and β10 in Sjögren's syndrome: Saliva proteomics and minor salivary glands expression

Background: In the present study, we investigated whether thymosin β (Tβ) in saliva and in minor salivary glands is differentially expressed in patients with primary Sjögren's syndrome (pSS) and patients with autoimmune diseases (systemic sclerosis [SSc], systemic lupus erythematosus [SLE], and rheumatoid arthritis [RA], with and without sicca syndrome [ss]). Methods: Saliva specimens of nine patients with pSS, seven with ss/SSc, seven with ss/SLE, seven with ss/RA, seven with SSc, seven with SLE, and seven with RA, as well as ten healthy subjects, were analyzed using a high-performance liquid chromatograph coupled with a mass spectrometer equipped with an electrospray ionization source to investigate the presence and levels of Tβ4, Tβ4 sulfoxide, and Tβ10. Immunostaining for Tβ4 and Tβ10 was performed on minor salivary glands of patients with pSS and ss. Results: Tβ4 levels were statistically higher in patients with pSS with respect to the other subgroups. Tβ10 was detectable in 66.7 % of patients with pSS and in 42.8 % of those with ss/SSc, while Tβ4 sulfoxide was detectable in 44.4 % of patients with pSS and in 42.9 % of those with ss/SSc. Tβ10 and Tβ4 sulfoxide were not detectable in patients without associated ss and in healthy control subjects. Regarding thymosin immunostaining, all patients had immunoreactivity for Tβ10, and a comparable distribution pattern in the four different subgroups of patients was observed. Tβ4 immunoreactivity was present in patients with ss/SSc and those with ss/SLE, while it was completely absent in patients with pSS and those with ss/RA. Conclusions: Our data show that higher salivary Tβ expression characterizes patients with pSS, while Tβ4 sulfoxide and Tβ10 salivary expression was selectively present in patients with sicca symptoms. Moreover, at the immunohistochemical level in patients with pSS, minor salivary glands showed a peculiar pattern characterized by immunostaining for Tβ10 in acinar cells in the absence of any reactivity for Tβ4. These findings, taken together, suggest a different role for Tβ4 and Tβ10 in patients with pSS who have ss and other autoimmune disease

Safety of anti-tumor necrosis factor-α therapy in patients with rheumatoid arthritis and chronic hepatitis C virus infection

The prevalence of concurrent rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection is probably underestimated because of the increasing spread of this virus worldwide, especially in developing countries. In these patients, anti-tumor necrosis factor-alpha (anti-TNF-alpha) therapy may aggravate hepatitis and increase viremia. We evaluated the safety of these treatments, which remain controversial. Thirty-one HCV-positive patients (23 women, 8 men, mean age 59+/-13 yrs, mean disease duration 13+/-11.5 SD yrs) with active RA [Disease Activity Score 28 (DAS28)>3.2] unresponsive to conventional therapies were treated with TNF-alpha blockers (infliximab 11, etanercept 17, adalimumab 3) at standard dosages. Safety and efficacy were evaluated at the third month of treatment and at the patient's last observation. A significant clinical-serological improvement was recorded at the 3-month reevaluation. Mean values of patients assessment of general health on visual analog scale (range 0.100) decreased from 69+/-29 (SD) to 35+/-27 (por=2 log10) in 4 cases. Previous observations had suggested the safety of TNF-alpha blockers for treatment of RA in patients with concurrent HCV infection. Given the clinical-therapeutic implications, our results support the safety of TNF-alpha blockers in patients with HCV, provided there is close monitoring of clinical and virological data (mainly ALT and HCV viremia)

Mycophenolic acid in rheumatology: mechanisms of action and severe adverse events.

MPA is clinically administered as morfolinoethyl ester (mycophenolate mofetil, MMF) or, more recently, as a salt (enteric-coated mycophenolate sodium). It is a fermentation product of Penicillium brevicompactum and other analogue fungi, identified by Gosio in 1893 as a weak antibacterial agent; in 1969 Franklin and Cook discovered its capacity to inhibit the inosine mono phosphate dehydrogenase (IMPDH), an enzyme involved in purine nucleotide synthesis (1)..

The Italian registry of aggressive rheumatoid arthritis -- the GIARA project.

Objective. In 1999, the Italian Society of Rheumatology started a project to determine the prevalence and clinical characteristics of aggressive rheumatoid arthritis (ARA). Methods. For I year, all patients with RA for 2 to 2 to 1.5, female sex, and RF positivity. Conditions other than RA were recorded in about 50% of the patients, and only 30%-40% were taking disease modifying antirheumatic drugs. Conclusion. In an Italian RA population, the GIARA (Gruppo Italiano Artrite Reumatoide Aggressiva) criteria for ARA were met by 15% of the patients with disease duration of 2 years, but erosions were seen in 35%. Upon referral, most of the RA patients were inadequately treated and had other conditions

The role of lithospheric flexure in the landscape evolution of the Wilkes Subglacial Basin and Transantarctic Mountains, East Antarctica

Reconstructions of the bedrock topography of Antarctica since the Eocene–Oligocene Boundary (ca. 34 Ma) provide important constraints for modelling Antarctic ice sheet evolution. This is particularly important in regions where the bedrock lies below sea level, since in these sectors the overlying ice sheet is thought to be most susceptible to past and future change. Here we use 3D flexural modelling to reconstruct the evolution of the topography of the Wilkes Subglacial Basin (WSB) and Transantarctic Mountains (TAM) in East Antarctica. We estimate the spatial distribution of glacial erosion beneath the East Antarctic Ice Sheet, and restore this material to the topography, which is also adjusted for associated flexural isostatic responses. We independently constrain our post‐34 Ma erosion estimates using offshore sediment stratigraphy interpretations. Our reconstructions provide a better‐defined topographic boundary condition for modelling early East Antarctic Ice Sheet history. We show that the majority of glacial erosion and landscape evolution occurred prior to 14 Ma, which we interpret to reflect more dynamic and erosive early ice sheet behaviour. In addition, we use closely‐spaced 2D flexural models to test previously proposed hypotheses for a flexural origin of the TAM and WSB. The pre‐34 Ma topography shows lateral variations along the length of the TAM and WSB that cannot be explained by uniform flexure along the front of the TAM. We show that some of these variations may be explained by additional flexural uplift along the south‐western flank of the WSB and the Rennick Graben in northern Victoria Land

Electrical structure across a major ice-covered fault belt in northern Victoria Land (East Antarctica)

A Geomagnetic Depth Sounding profile was performed across the glaciated Rennick Graben and the adjacent fault-bounded terranes of northern Victoria Land in East Antarctica. Induction arrows analysis and a 2D inversion model provide a unique deep electrical resistivity window beneath these fault zones. The electrical resistivity break across the Lanterman Fault is apparently restricted to the upper crust, suggesting that this strike-slip fault may not represent a deep lithospheric suture. Further east, a westward-dipping conductor is traced to a depth of 40 km beneath the Robertson Bay Terrane. It may image a remnant of the paleo-Pacific oceanic plate, which subducted beneath the Bowers Terrane. Within the Wilson Terrane, the Rennick Graben is an upper-crust resistive block. The Rennick Graben lacks a deep crustal or upper mantle conductor, in contrast to several continental rifts. However, similar resistive lower crust underlies some other major strike-slip fault belts

Distribution of subglacial sediments across the Wilkes Subglacial Basin, East Antarctica

Topography, sediment distribution, and heat flux are all key boundary conditions governing the dynamics of the East Antarctic Ice Sheet (EAIS). EAIS stability is most at risk in Wilkes Land across vast expanses of marine-based catchments including the 1400 km × 600 km expanse of the Wilkes Subglacial Basin (WSB) region. Data from a recent regional aerogeophysical survey (Investigating the Cryospheric Evolution of the Central Antarctic Plate (ICECAP)/IceBridge) are combined with two historical surveys (Wilkes basin/Transantarctic Mountains System Exploration-Ice-house Earth: Stability or DYNamism? (WISE-ISODYN) and Wilkes Land Transect (WLK)) to improve our understanding of the vast subglacial sedimentary basins impacting WSB ice flow and geomorphology across geologic time. Analyzing a combination of gravity, magnetic and ice-penetrating radar data, we present the first detailed subglacial sedimentary basin model for the WSB that defines distinct northern and southern subbasin isopachs with average sedimentary basin thicknesses of 1144 m ± 179 m and 1623 m ± 254 m, respectively. Notably, more substantial southern subbasin sedimentary deposition in the WSB interior supports a regional Wilkes Land hypothesis that basin-scale ice flow and associated glacial erosion is dictated by tectonic basement structure and the inherited geomorphology of preglacial fluvial networks. Orbital, temperate/polythermal glacial cycles emanating from adjacent alpine highlands during the early Miocene to late Oligocene likely preserved critical paleoclimatic data in subglacial sedimentary strata. Substantially thinner northern WSB subglacial sedimentary deposits are generally restricted to fault-controlled, channelized basins leading to prominent outlet glacier catchments suggesting a more dynamic EAIS during the Pliocene