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1.  Lupus nephritis - alarmins may sound the alarm? 
A growing body of literature has documented the elevated levels of the alarmin HMGB1 in lupus skin and serum. Two recent reports highlight the increased expression of HMGB1 in lupus nephritis, within the diseased kidneys or in the urine. Taken together with previous reports, these findings suggest that the interaction of HMGB1 with a variety of receptors, including receptor for advanced glycation end products (RAGE) and Toll-like receptors, might play a role in the pathogenesis of lupus nephritis. These studies introduce urinary HMGB1 as a novel biomarker candidate in lupus nephritis. Whether alarmins would be effective in sounding the alarm at the incipience of renal damage remains to be ascertained.
doi:10.1186/ar4109
PMCID: PMC3674625  PMID: 23270666
3.  Metabolic factors in osteoarthritis: obese people do not walk on their hands 
Obesity is an important risk factor for the development and progression of osteoarthritis (OA). Recently, the paradigm that obesity predisposes people to OA because of extra-mechanical loading only has shifted to the paradigm that metabolic factors (adipokines) are also involved in the pathophysiology of OA. In a cross-sectional study in the previous issue of Arthritis Research & Therapy, Massengale and colleagues investigated the association between one of the adipokines - leptin - and hand OA. Hand joints are an ideal target to investigate the role of adipokines since they are not weight-bearing. Interestingly, no association with OA was found, bringing into question a metabolic, rather than a mechanical, explanation for the association between obesity and OA.
doi:10.1186/ar3894
PMCID: PMC3580548  PMID: 22809017
4.  Vaccination under TNF blockade - less effective, but worthwhile 
Only after biological response modifiers have become available have we begun to understand some of the complex functions of TNF in the human immune system. TNF is clearly essential for fighting intracellular pathogens, but probably not essential for fighting tumors. TNF influence on the humoral immune response, in contrast, has been more complicated to decipher, since TNF blockade is associated with both autoantibody formation and (somewhat) reduced responses to vaccination. Novel data now show that TNF is good for the humoral immune response. Vaccinations still work, however, and should be strongly recommended.
doi:10.1186/ar3808
PMCID: PMC3446474  PMID: 22577892
5.  Implication of new atherosclerotic carotid plaques in the cardiovascular outcome of patients with rheumatoid arthritis 
Early detection of atherosclerosis is of major importance to reduce the increased incidence of cardiovascular (CV) complications observed in patients with rheumatoid arthritis (RA). Prospective studies have shown that an abnormally increased carotid intima-media thickness and the presence of plaques assessed by carotid ultrasound are good markers to predict the development of CV events in these patients. Age, classic CV risk factors, and corticosteroid use are also predictors of new plaque formation in patients with RA. Active treatment of the disease may decrease the inflammatory burden, leading to a reduction in the progression of subclinical atherosclerosis in these patients.
doi:10.1186/ar3733
PMCID: PMC3446405  PMID: 22414597
6.  Plasma proteins take their toll on the joint in osteoarthritis 
In their recent study, Sohn and colleagues identify multiple plasma proteins in the synovial fluid of patients with osteoarthritis (OA) and demonstrate the capacity of several of the proteins to activate macrophages via the innate immune receptor Toll-like receptor-4 (TLR-4). The authors speculate that the plasma proteins transit into the synovial compartment at sites of tissue damage where the endothelial barrier may be compromised, thus bringing them into contact with the articular surface and cells within the synovium. These results demonstrate a novel mechanism by which synovial inflammation can be initiated in patients with OA and how this process may contribute to the pathogenesis of OA joint pathology.
doi:10.1186/ar3741
PMCID: PMC3446406  PMID: 22385929
7.  Inhibiting citrullination in rheumatoid arthritis: taking fuel from the fire 
Citrullination is a post-translational modification catalysed by peptidylarginine deiminase and is a common feature of inflammation. The presence of anti-citrullinated protein/peptide antibodies (ACPA), however, is unique to rheumatoid arthritis. Several lines of evidence suggest that ACPA are important in the pathogenesis of rheumatoid arthritis. A popular hypothesis for this pathogenesis is a two-hit model. The first hit gives rise to ACPA, and the second hit, an unrelated episode of synovial inflammation accompanied by citrullination, is perpetuated by the pre-existing antibodies. This model suggests that reducing citrullination might ameliorate disease. Recent findings indicate that citrullination closely correlates with inflammation, and that glucocorticoids decrease peptidylarginine deiminase expression independent of their other anti-inflammatory effects.
doi:10.1186/ar3740
PMCID: PMC3392831  PMID: 22380578
10.  Imaging joints for calcium pyrophosphate crystal deposition: a knock to the knees 
With advanced age, articular calcium pyrophosphate crystal deposition (CPPD) is common. Defining who has CPPD is of growing importance, given increases in longevity in many countries and the frequent association of chondrocalcinosis with osteoarthritis. Chondrocalcinosis detected by plain radiography serves as a major screening tool, but how many and which sites to screen have not been adequately defined in the past. The work of Abhishek and colleagues in the previous issue of Arthritis Research and Therapy sheds new light on the incomplete information from knee radiographs, and helps position us to learn more about the epidemiology, pathophysiology, diagnosis, and clinical impact of CPPD.
doi:10.1186/ar4097
PMCID: PMC3674586  PMID: 23270654
11.  Can measuring urinary biomarkers improve the management of lupus nephritis? 
Although renal biopsy is the most accurate way of assessing renal inflammation in patients with lupus nephritis (LN), the technique is invasive and cannot be performed frequently. Currently used blood and urine biomarkers have limited utility in monitoring the activity of nephritis. In a previous issue of Arthritis Research and Therapy, Singh and colleagues showed that measuring urinary levels of vascular cell adhesion molecule 1 could be useful in both diagnosing and monitoring LN. These levels are higher in patients with lupus than controls, are higher in lupus patients who have active renal disease compared with those who do not, and correlate significantly with the histological activity index in renal biopsies of patients with LN.
doi:10.1186/ar4098
PMCID: PMC3674604  PMID: 23256781
12.  Ways forward to identify new ACPA targets in RA 
Anti-citrullinated protein antibodies (ACPAs) of the IgG subtype have become a critical hallmark of HLA-associated rheumatoid arthritis (RA) and point to important contributions from the adaptive immune system. To dissect the contributing autoimmune reactions, investigators must not only identify the protein targets of ACPA but also define the precise peptides recognized by the immune system. Several possible approaches could be used to achieve this goal, and sensitive mass spectrometry of relevant tissue is a promising way forward in advancing our detailed understanding of autoimmune immune reactions involved in RA pathogenesis.
doi:10.1186/ar4031
PMCID: PMC3580505  PMID: 23025589
15.  Inflammation, endothelial function and atherosclerosis in rheumatoid arthritis 
Different techniques have proven to be useful in determining the presence of subclinical cardiovascular disease in patients with rheumatoid arthritis (RA). Doppler imaging with iontophoresis of acetylcholine and flow-mediated, endothelium-dependent vasodilation give information on endothelial dysfunction, an early step in the atherogenesis process. However, there is no good correlation between these two surrogate markers of cardiovascular disease in RA. A single determination of routine laboratory markers of inflammation does not seem to relate to endothelial function in RA. Further research is needed to determine whether microvascular endothelial function is a better predictor of cardiovascular outcome than macrovascular endothelial function in patients with RA.
doi:10.1186/ar3891
PMCID: PMC3580546  PMID: 22808986
16.  Statins: a revised appraisal for potential additional future treatment indications 
Beside statins' well established positive influence on atherosclerotic vascular disease caused by hypercholesterolemia through selective competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, additional effects on the immune system have been described for them. These observations have raised great hopes for additional future treatment indications, including rheumatoid arthritis and multiple sclerosis. Ten years of searching for such novel treatment indications have not led to breakthroughs and future efforts must be seen with skepticism.
doi:10.1186/ar3880
PMCID: PMC3446530  PMID: 22747898
18.  Approaching the immunophysiology of steroid resistance 
Wang and colleagues have investigated a mechanistic basis for resistance to steroid therapy in systemic lupus erythematosus patients. Their examination reveals significant differences in macrophage migration inhibitory factor (MIF)-dependent expression of IκB, which is a critical cellular regulator of the broadly proinflammatory transcription factor NF-κB. Their studies also suggest that MIF may be a clinically useful biomarker in systemic lupus erythematosus and support the therapeutic targeting of MIF as a means to reduce clinical steroid resistance.
doi:10.1186/ar3820
PMCID: PMC3446475  PMID: 22640701
19.  Nothing lasts forever - a critical look at sustained remission 
Remission is key to prevent progression of rheumatoid arthritis, but it is still rarely seen in clinical practice, not to speak of sustained remission, which is the best possible disease outcome of rheumatoid arthritis. New strategies and recommendations focus on achievement of remission, but it is unclear how long remission can actually be maintained in clinical practice. A study by Prince and colleagues gives insights into this question, and raises some other questions for the future.
doi:10.1186/ar3795
PMCID: PMC3446473  PMID: 22577881
20.  Knotting the NETs: Analyzing histone modifications in neutrophil extracellular traps 
Neutrophil extracellular chromatin traps (NETs) are a recently described mechanism of innate immune responses to bacteria and fungi. Evidence indicates that NETs are induced by inflammation, that they contribute to diverse disease pathologies, and that they associate with bactericidal substances. Genomic DNA is released in NETs, leading to a cell death that has been labeled NETosis. Although NETosis clearly differs from apoptosis, the classical form of cell death, recent experiments indicate a connection between NETosis and autophagy. The regulated deployment of NETs may require covalent modification of histones, the basic DNA-binding proteins that organize chromatin in the cell's nucleus and within NETs. Histone modification by peptidylarginine deiminase 4 (PAD4) is necessary for NET release. The functions of additional histone modifications, however, remain to be tested.
doi:10.1186/ar3773
PMCID: PMC3446426  PMID: 22524286
21.  What is the future of CCR5 antagonists in rheumatoid arthritis? 
Fleishaker and colleagues reported on a double-blind placebo controlled clinical trial of a C-C chemokine-receptor type 5 (CCR5) antagonist, maraviroc, in rheumatoid arthritis (RA) patients with inadequate response to methotrexate, showing that it was ineffective. Two additional CCR5 antagonists, SCH351125 and AZD5672, also failed to demonstrate clinical efficacy. In addition, CCR5-blocking antibodies could not inhibit synovial fluid-induced monocyte chemotaxis. Thus, CCR5 appears not to be a desirable target in RA treatment. Given the multiple functions of CCR5, redundancies in the chemokine system, and patient selection in the trial, we overview the recent understanding for chemokine receptor blockade in the treatment of RA
doi:10.1186/ar3775
PMCID: PMC3446428  PMID: 22494450
22.  Meryl Streep and the problems of clinical trials 
A clinical trial of lupus patients with nephritis was established to determine any possible role for Atacicept, a biologic drug that blocks two B-cell-activating factors (BLyS and APRIL). The trial was stopped after just six patients had been enrolled because three patients developed serious infections. Initial concerns that the biologic was the main cause of the increased susceptibility to these infections have had to be revised on close inspection of the data. The evidence clearly points to a previously unrecognised capacity for mycophenolate to cause notable drops in immunoglobulin levels as the prime suspect.
doi:10.1186/ar3751
PMCID: PMC3446407  PMID: 22494430
23.  HMGB1: a smoking gun in lupus nephritis? 
High-mobility group box 1 protein (HMGB1) is a prototypic alarmin that is released from activated and dying cells. Because of its proinflammatory activities, HMGB1 could mediate key events in the pathogenesis of systemic lupus erythematosus, a possibility supported by elevations of HMGB1 in patient blood and increased expression in renal biopsies. The biology of HMGB1 is complicated, however, and its activity is dependent on redox state as well as binding to other molecules such as cytokines. Defining more precisely the role of HMGB1 in lupus will require treatment studies to block the activity of this alarmin in animal models and ultimately patients.
doi:10.1186/ar3754
PMCID: PMC3446408  PMID: 22423653
24.  Clinical examination or whole-body magnetic resonance imaging: the Holy Grail of spondyloarthritis imaging 
Whole-body magnetic resonance imaging allows acquisition of diagnostic images in the shortest scan time, leading to better patient compliance and artifact-free images. Methods of clinical examination of the anterior chest wall joints vary between physician groups and consideration of the rules of rib motion is suggested. The type of joint and its synovial lining may also aid imaging/clinical correlation. This well-written study by experts in the field with a standardized design and methodology allows good scientific analysis and suggests the advantages of whole-body magnetic resonance imaging in anterior chest wall imaging. Selection of clinical examination criteria and specific joints may have had an influence on the study results and the lack of association reported.
doi:10.1186/ar3737
PMCID: PMC3392828  PMID: 22380535
25.  Role of environmental factors in autoantibody production - importance of a detailed analysis in a small cohort 
In the previous issue of Arthritis Research & Therapy, Muro and colleagues reported a detailed epidemiologic analysis in central Japan on one of the new myositis-specific autoantibodies to MDA-5 (melanoma differentiation-associated gene 5), which is associated with clinically amyopathic dermatomyositis accompanying interstitial lung disease. The increasing prevalence of anti-MDA-5, higher prevalence in small rural towns, and geographical clustering in two areas along the Kiso River suggest a role of environmental factors associated with rural communities or the river/water system or both. A detailed analysis of a small cohort may offer clues, which is ignored in multi-center studies, to the pathogenesis of systemic rheumatic diseases and autoantibody production.
doi:10.1186/ar3739
PMCID: PMC3392830  PMID: 22380573

Results 1-25 (551)