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1.  Challenges in understanding Sjögren's syndrome - improved insights into the pathogenesis generate hope for innovative therapies? 
The reviews in this series on Sjögren syndrome provide an up-to-date summary and perspectives on the pathogenesis of this interesting entity with glandular and frequently systemic manifestations, the value of preclinical models, and our current understanding of therapeutic approaches. The last of these includes what has been learned from trials blocking tumor necrosis factor and, more recently, anti-CD20 therapy. Potential therapeutic targets, such as blockade of the B cell-activating factor, the role of interferon-alpha, and targeting CD22, are discussed.
doi:10.1186/ar3425
PMCID: PMC3239360  PMID: 21888689
3.  (Auto)immunity to cartilage matrix proteins - a time bomb? 
Geng and colleagues consolidate and detail the role of cartilage oligomeric matrix protein (COMP) as a (potential) autoantigen in experimental and human arthritis, a finding also supported by the detection of COMP fragments and anti-COMP antibodies in rheumatoid arthritis serum and/or synovial fluid and by synovial B-cell responses against COMP. The reactivity to COMP is yet another example of how, in addition to collagen II and the large aggregating proteoglycan, cartilage-specific proteins can induce arthritis and contribute to autoimmunity. Progression of cartilage damage and degradation in disease is believed to promote the autoimmune reaction to cartilage components. However, Geng and colleagues show that anti-COMP mAbs bind in vivo to undamaged cartilage, as previously also observed for anti-collagen II antibodies. Whether this autoimmunity also involves modifications of cartilage matrix proteins, such as citrullination, remains to be further investigated. Latent, subpathogenic (auto)immune reactions directed against cartilage matrix proteins may thus eventually contribute to the outbreak of human arthritis.
doi:10.1186/ar4123
PMCID: PMC3745647  PMID: 23336107
4.  Towards the elucidation of the true impact of adipocytokines on cardiovascular risk in rheumatoid arthritis 
Adipo(cyto)kines are mostly produced by adipose tissue and orchestrate the adverse impact of excess adiposity on cardiovascular risk. Adipokines also contribute importantly to the pathophysiology of rheumatoid arthritis. Congruent with data reported in previous investigations, Kang and colleagues report in this issue of Arthritis Research & Therapy that adipokine concentrations are further associated with metabolic risk and inflammation and that the leptin–adiponectin ratio associates with the carotid artery resistive index in rheumatoid arthritis. Guided by evidence reported thus far on cardiovascular risk, we discuss six reasons why careful elucidation of adipokine–cardiovascular risk relations is needed in rheumatoid arthritis.
doi:10.1186/ar4412
PMCID: PMC4061720  PMID: 24611178
5.  PEG-ing down (and preventing?) the cause of pegloticase failure 
Pegloticase is a powerful but underutilized weapon in the rheumatologist’s armamentarium. The drug’s immunogenicity leads to neutralizing antibody formation and rapid loss of efficacy in roughly one-half of all patients, which remains an impediment to broader use. New data, however, suggest that drug survival might improve with concomitant immunosuppressive agent (s), which merits further study. Efficacy appears to be unchanged when pegloticase is infused at 3-week (rather than 2-week) intervals. Stretching the time between infusions may also improve patient adherence and allow for earlier identification of transient responders.
doi:10.1186/ar4572
PMCID: PMC4060209  PMID: 25142440
6.  Understanding IFNλ in rheumatoid arthritis 
Unraveling the mechanisms underlying the inflammatory response in rheumatoid arthritis is crucial in order to better understand the disease and to develop novel therapeutic approaches. Although the effect of type I interferons on fibroblasts and in the context of rheumatoid arthritis has been described for some time, little is known on the effects of the type III interferons, also known as IFNλ. In a previous issue, Xu and colleagues demonstrate that one of the members of the IFNλ family, IFNλ1, enhances Toll-like receptor expression and consequently promotes the production of proinflammatory cytokines known to be involved in initiating and maintaining the inflammatory responses in rheumatoid arthritis.
doi:10.1186/ar4445
PMCID: PMC3978858  PMID: 24443794
7.  Mesenchymal stem cell therapy in osteoarthritis: advanced tissue repair or intervention with smouldering synovial activation? 
Although it is generally accepted that osteoarthritis is a degenerative condition of the cartilage, other tissues such as synovium in which immunological and inflammatory reactions occur contribute to the development of joint pathology. This sheds new light on the potential mechanism of action of mesenchymal stem cell therapy in osteoarthritis. Rather than tissue repair due to local transformation of injected mesenchymal stem cells to chondrocytes and filling defects in cartilage, such treatment might suppress synovial activation and indirectly ameliorate cartilage damage. Desando and co-workers report in Arthritis Research & Therapy that intra-articular delivery of adipose-derived stem cells attenuates progression of synovial activation and joint destruction in osteoarthritis in an experimental rabbit model. Clinical studies are warranted to see whether this approach might be a novel way to combat development of joint destruction in inflammatory subtypes of osteoarthritis.
doi:10.1186/ar4190
PMCID: PMC3672811  PMID: 23521980
8.  Kidney disease in lupus is not always 'lupus nephritis' 
In lupus erythematosus, elevated serum creatinine levels and urinary abnormalities implicate a kidney disorder, which may not always be lupus nephritis as defined by the current classification of the International Society of Nephrology/Renal Pathology Society. The signs of renal dysfunction may be caused by lupusunrelated renal injury such as drug toxicity or infection or by lupus-associated mechanisms that are not part of the classification, such as minimal change nephrotic syndrome or thrombotic microangiopathy. The latter seems to complicate lupus nephritis more frequently than previously thought. An unbiased assessment of kidney disease in lupus requires a kidney (re-)biopsy to define the appropriate management.
doi:10.1186/ar4166
PMCID: PMC3672669  PMID: 23448342
9.  To target or not to target APRIL in systemic lupus erythematosus: that is the question! 
Among the cytokines that regulate B-cell homeostasis are the TNF-like ligands B-lymphocyte stimulator (BLyS; also B-cell activation factor) and a proliferation-inducing ligand (APRIL). BLyS and APRIL share two receptors; that is, B-cell maturation antigen and transmembrane activator and CAML interactor. Therapeutic approaches using biologics are limited for treatment of lupus patients. One previously approved drug is belimumab, which antagonizes the B-cell stimulator BLyS. Atacicept, another biologic inhibiting BLyS and APRIL, was terminated for serious adverse events - raising the question of whether APRIL should be neutralized in autoimmune diseases.
doi:10.1186/ar4160
PMCID: PMC3672817  PMID: 23438039
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  T cells as key players for bone destruction in gouty arthritis? 
The deposition of monosodium urate (MSU) crystals in synovial fluid and tissue leads to gouty arthritis frequently associated with synovial inflammation and bone erosions. The cellular mechanism that links MSU crystals to an increased number of osteoclasts has not yet been fully understood. In a recent issue of Arthritis Research & Therapy Lee and colleagues proposed that bone destruction in chronic gouty arthritis is at least in part dependent on expression by T cells of receptor activator of NF-κB ligand (RANKL). The authors showed that pro-resorptive cytokines such as IL-1β, IL-6, and TNFα are expressed within tophi and stromal infiltrates. In vitro stimulation with MSU crystals revealed monocytes as a source for these cytokines, whereas T cells produce RANKL, the major trigger of osteoclastogenesis.
doi:10.1186/ar3508
PMCID: PMC3334629  PMID: 22136246
17.  The new era of autoimmune disease research 
Recent genome-wide association studies have advanced our understanding of genetic factors that underlie systemic lupus erythematosus (SLE), a multifactorial autoimmune disease characterized by various clinical manifestations. SLE also has an environmental component, which can trigger or exacerbate the disease. Despite extensive efforts aimed at elucidating the cellular and biological abnormalities that arise in the immune system of patients with SLE, its pathology remains unclear. Lee and colleagues recently carried out gene expression profiling of patients with SLE followed by bioinformatics analysis and discovered the existence of abnormal regulatory networks and potential key molecules. The authors found that ATP synthesis and DNA repair pathways may be involved in the pathogenesis, providing a potential explanation for photosensitivity experienced by patients with SLE.
doi:10.1186/ar3335
PMCID: PMC3218883  PMID: 21639950
18.  Nordic walking in fibromyalgia: a means of promoting fitness that is easy for busy clinicians to recommend 
A total of 67 women with fibromyalgia were recruited to an exercise study and were randomized to moderate-to-high-intensity Nordic walking (age 48 ± 7.8 years) or to a control group engaging in supervised low-intensity walking (age 50 ± 7.6 years). A total of 58 patients completed. Significantly greater improvement in the 6-minute walk test was found in the Nordic walking group (P = 0.009), compared with the low-intensity walking group. A significantly larger decrease in exercise heart rate (P = 0.020) and significantly improved scores on the Fibromyalgia Impact Questionnaire Physical function (P = 0.027) were found in the Nordic walking group as compared with the low-intensity walking group. No between-group difference was found for the Fibromyalgia Impact Questionnaire total or pain scores. The authors conclude that moderate-to-high intensity aerobic exercise by means of Nordic walking twice a week for 15 weeks was found to be a feasible mode of exercise, resulting in improved functional capacity and a decreased level of activity limitations.
doi:10.1186/ar3225
PMCID: PMC3157638  PMID: 21345243
19.  Vasculogenesis in rheumatoid arthritis 
Decreased number and impaired functions of endothelial progenitor cells (EPCs) leading to impaired vasculogenesis have been associated with rheumatoid arthritis (RA). Defective vasculogenesis has also been implicated in premature atherosclerosis in RA. Recently, early-outgrowth monocytic and late-outgrowth hemangioblastic EPC subsets have been characterized. Hemangioblastic EPCs may exert increased numbers in active RA and may play a role in vascular repair underlying RA.
doi:10.1186/ar2943
PMCID: PMC2888181  PMID: 20346090
20.  Is interleukin-1 a good target for therapeutic intervention in intervertebral disc degeneration: lessons from the osteoarthritic experience 
IL-1 plays a key role in disc degeneration and could be a valid target for inhibiting this process. IL-1 receptor antagonist (IL-1ra) might be a good candidate to inhibit IL-1 activity. However, many questions need to be addressed before contemplating therapy in humans. IL-1 blockade is also a great challenge in osteoarthritis and results from animal models suggest that IL-1ra may have beneficial effects. The clinical benefit of a local injection of IL-1ra in knee osteoarthritis may be limited by the antagonist's short half-life. Further studies with longer-lasting antagonists are needed to explore this new therapeutic approach.
doi:10.1186/ar2324
PMCID: PMC2246235  PMID: 18086327
21.  Goldilocks, vitamin D and sarcoidosis 
While low levels of vitamin D can increase the risk for osteoporosis, excessive amounts of vitamin D may also be problematic. Hypercalcemia and hypercalcuria due to increased vitamin D activity occur in a significant proportion of sarcoidosis patients. Saidenberg-Kermanac’h and colleagues compared vitamin D levels with bone fragility fractures in their sarcoidosis clinic. They found that a 25-(OH) vitamin D level between 10 and 20 ng/ml was associated with the lowest risk of bone fractures and paradoxically higher levels increased the risk of bone fractures. Using less vitamin D supplementation may simultaneously lower the risk for bone fracture and hypercalcemia in sarcoidosis.
doi:10.1186/ar4568
PMCID: PMC4060200  PMID: 25166268
22.  Using Discrete Choice Experiment to elicit patient preferences for osteoporosis drug treatments: where to from here? 
Osteoporosis is a disease that increases skeletal fracture risk and places a significant health and economic burden on patients, families, and health systems. Many treatment options exist, but patient use is suboptimal, thus undermining the potential cost-effectiveness of treatments. In the previous issue of Arthritis Research & Therapy, Hiligsmann and colleagues expanded the findings of previous studies to report, from a sample of 257 patients with osteoporosis, the preference to trade off clinical outcomes for the amenity provided by convenient dosing regimens. This editorial critiques the strengths and limitations of the methods, discusses the potential utility of patient treatment preferences, and suggests avenues for further research.
doi:10.1186/ar4501
PMCID: PMC4060568  PMID: 25167089
23.  Cathelicidin antimicrobial peptide as a serologic marker and potential pathogenic factor in antineutrophil cytoplasmic antibody-associated vasculitis 
Antineutrophil cytoplasmic antibodies are associated with pauci-immune small-vessel vasculitis and crescentic glomerulonephritis. Cathelicidin LL37 is the human member of a family of antimicrobial peptides that are released from activated neutrophils and monocytes at sites of acute inflammation. Zhang and colleagues evaluated serum levels of cathelicidin LL37 and interferon-alpha in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and glomerulonephritis. Increased levels of cathelicidin LL37 and interferon-alpha were associated with AAV patients, particularly those with glomerular crescent formation. Cathelicidin LL37 may also be involved in the pathogenesis of AAV and thus could be a target for novel therapy. Cathelicidin LL37 is a promising new biomarker for active AAV, including aggressive crescentic glomerulonephritis, and may prove to be both a prognostic marker and a guide for treatment.
doi:10.1186/ar4495
PMCID: PMC3978818  PMID: 25164257
24.  What autoantibody tests should become widely available to help scleroderma diagnosis and management? 
Anti-Th/To autoantibodies have been recognized as serological markers of systemic sclerosis (SSc) for more than 20 years. However, validated immunoassay kits to test this specificity have not been commercially available. SSc autoantibodies are basically mutually exclusive and are associated with a certain subset of the disease and/or with organ involvement. Anti-Th/To are generally considered to be markers of the limited cutaneous type of SSc with the involvement of certain internal organs. The excellent correlation between anti-Rpp25 as detected by their novel chemiluminescent method and anti-Th/To as detected by immunoprecipitation suggest that the new assays may become widely available tests for clinicians in future and could help to clarify the clinical significance of anti-Th/To in SSc as well as other conditions over different races or countries.
doi:10.1186/ar4241
PMCID: PMC3978467  PMID: 23856077
25.  Synovial fluid CD1c+ myeloid dendritic cells – the inflammatory picture emerges 
Dendritic cells (DCs) comprise a heterogeneous group of antigen-presenting cells with many specialized functions, including essential constitutive roles in priming immune and autoimmune responses and in the maintenance of peripheral self-tolerance. At the interface of the innate and adaptive immune systems, they contribute considerably to the production of inflammatory and anti-inflammatory mediators with diverse functions. Emerging evidence suggests that the wide involvement of DCs in immunity and tolerance reflects the function of specialized DC subsets.
doi:10.1186/ar4420
PMCID: PMC3978489  PMID: 24365031

Results 1-25 (213)