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1.  Lots of autoantibodies equal lupus? 
Autoantibodies may be found years before an autoimmune disease becomes clinically apparent. For systemic lupus erythematosus (SLE), those to RNA-binding proteins, to phospholipids, and to double-stranded DNA, in particular, have been found in sera of SLE patients years before the diagnosis was made. New data now show in an unbiased way that, in patients with early SLE, no single antibody class or specificity is associated with progression to SLE. Rather, an increasing number of autoantibody specificities, such as to thyroid antigens, was observed in patients progressing. This points to more generalized B cell autoreactivity during progression to SLE, underlying lupus disease manifestations.
doi:10.1186/ar4126
PMCID: PMC3672808  PMID: 23347779
2.  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
3.  International cohort study of 73 anti-Ku-positive patients: association of p70/p80 anti-Ku antibodies with joint/bone features and differentiation of disease populations by using principal-components analysis 
Introduction
An international cohort study of 73 anti-Ku-positive patients with different connective tissue diseases was conducted to differentiate the anti-Ku-positive populations of patients based on their autoantibody profile and clinical signs/symptoms and to establish possible correlations between antibodies against Ku p70 and Ku p80 with autoimmune diseases.
Methods
Sera of anti-Ku-positive patients were collected from six European centers and were all secondarily tested (in the reference center); 73 were confirmed as positive. Anti-Ku antibodies were detected with counter-immunoelectrophoresis (CIE), line immunoassay (LIA), and immunoblot analyses. All clinical and laboratory data were follow-up cumulative data, except for anti-Ku antibodies. Statistical analyses were performed by using R (V 2.12.1). The Fisher Exact test was used to evaluate the association between anti-Ku antibodies and diagnosis, gender, clinical signs, and other observed antibodies. The P values were adjusted for multiple testing. Separation of disease populations based on the presence of antibodies and clinical signs was investigated by principal-components analysis, which was performed by using thr// R's prcomp function with standard parameters.
Results
A 16% higher prevalence of anti-Ku p70 was found over anti-Ku p80 antibodies. In 41 (57%) patients, a combination of both was detected. Five (7%) patients, who were CIE and/or LIA anti-Ku positive, were negative for both subsets, as detected with the immunoblot; 31% of the patients had undifferentiated connective tissue disease (UCTD); 29% had systemic sclerosis (SSc); 18% had systemic lupus erythematosus (SLE); 11% had rheumatoid arthritis; 7% had polymyositis; and 3% had Sjögren syndrome.
Conclusions
A significant positive association was found between female patients with anti-Ku p70 and joint/bone features, and a significant negative association was found between female patients with anti-Ku p80 only and joint/bone features (P = 0.05, respectively). By using the first and the third components of the principal-component analysis (PCA) with 29 parameters evaluated, we observed that the anti-Ku-positive population of UCTD patients had overlapping parameters, especially with SLE, as opposed to SSc, which could be helpful in delineating UCTD patients.
doi:10.1186/ar3550
PMCID: PMC3392788  PMID: 22226402
4.  Tophaceous Gout and Renal Insufficiency: A New Solution for an Old Therapeutic Dilemma 
Case Reports in Medicine  2011;2011:397646.
The prevalence of gout is increasing with increased life expectancy. Approximately half of the patients with gout have some degree of renal impairment. If both conditions persistently coexist, and in severe tophaceous gout, in particular, treatment has been difficult. We here report on the case of an 87-year-old woman, who had been suffering from recurrent gouty arthritis over 4 years. Monthly polyarthritis attacks were accompanied by subcutaneous tophi. Serum uric acid levels were constantly above 600 μmol/L (10 mg/dL). Allopurinol was no option because of intolerance, while benzbromarone was ineffective because of renal impairment. Therefore, the novel xanthin oxidase inhibitor febuxostat was started, achieving rapid control of serum urate levels (<360 μmol/L). After initial worsening of inflammation in the first weeks, gouty attacks stopped and all tophi resolved within the following 10 months. Renal function remained stable.
doi:10.1155/2011/397646
PMCID: PMC3099210  PMID: 21629805
5.  Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) 
Introduction
Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods
Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results
A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions
Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
doi:10.1186/ar3337
PMCID: PMC3218885  PMID: 21569519
6.  The EUSTAR model for teaching and implementing the modified Rodnan skin score in systemic sclerosis 
Annals of the Rheumatic Diseases  2007;66(7):966-969.
Objective
To evaluate the ability to teach scleroderma experts and young rheumatologists to perform the modified Rodnan skin score test.
Methods
Three international “teaching courses for teachers” were conducted with 6–9 experts who performed 3–9 skin score tests each. In addition, an international course for 90 young rheumatologists, in which 18 patients with systemic sclerosis (SSc) participated, was also organised. Finally, a local repeated training course for 5–9 rheumatologists was performed, in which 6–7 patients with SSc participated.
Results
When 6–9 scleroderma specialists investigated the patients, the intraclass correlation coefficient (ICC) showed “good” to “excellent” values (0.865 and 0.710, respectively). When 90 young rheumatologists were involved in one teaching course, the coefficient of variation (CV) was relatively satisfactory (35%) owing to the high number of investigators, and with a considerable within‐patient SD value of 5.4.
Repeated teaching of 5–9 young rheumatologists in local courses clearly improved the consistency. The ICC increased from 0.496 to a “good” level of 0.722. The within‐patient SD values for intraobserver variability ranged between 2.5 and 2.9. The intraobserver CV was about 20%.
Conclusions
This study strongly supports the need for standardisation among different centres when using skin scoring for clinical trials. The intraobserver variability and within‐patient SD values can be significantly reduced by repeated teaching. For inexperienced rheumatologists, at least one repeated teaching course is needed.
doi:10.1136/ard.2006.066530
PMCID: PMC1955103  PMID: 17234649
8.  The role of tumor necrosis factor-alpha in systemic lupus erythematosus 
Murine models of systemic lupus erythematosus (SLE) have shown apparently contradictory evidence in that either (a) tumor necrosis factor (TNF) expression was low and TNF administration helpful or (b) TNF was high and TNF blockade of therapeutic benefit, depending on the mouse model investigated. In fact, TNF apparently has both effects, checking autoimmunity, at least to some degree, and fostering inflammation. TNF blockade regularly, but transiently, induces or increases autoantibodies to chromatin and to phospholipids. At the same time, open-label data suggest that TNF blockade suppresses inflammatory manifestations of SLE, and long-term benefit was seen in patients with lupus nephritis. A controlled clinical trial is under way.
doi:10.1186/ar2341
PMCID: PMC2374473  PMID: 18226185
9.  Listeria-Associated Arthritis in a Patient Undergoing Etanercept Therapy: Case Report and Review of the Literature 
Journal of Clinical Microbiology  2005;43(5):2537-2541.
Listeriosis can be a cause of infectious arthritis. Here, we present a case of articular listeriosis in a patient with rheumatoid arthritis receiving treatment with etanercept, a tumor necrosis factor antagonist. We review the literature of articular listeriosis and discuss the role of tumor necrosis factor blockade in precipitating listeriosis.
doi:10.1128/JCM.43.5.2537-2541.2005
PMCID: PMC1153789  PMID: 15872306
10.  SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus 
Arthritis Research & Therapy  2003;5(4):172-177.
Tumor necrosis factor (TNF) is a proinflammatory cytokine and a B-cell growth factor. It has numerous possible effects on T lymphocytes and dendritic cells, and it influences apoptosis. These differential effects may in part explain why patients under TNF-blocker therapy can develop autoantibodies to nuclear antigens, and may shed some light on the finding that low TNF fosters autoimmune disease in some mouse strains. On the contrary, TNF is increased in the blood and in the inflamed kidneys of systemic lupus erythematosus patients. Several studies in lupus-prone mice other than the F1 generation of New Zealand Black mice crossed with New Zealand White mice suggest that TNF is highly proinflammatory in the efferent limb and is potentially detrimental in lupus organ disease. Therefore, TNF blockade probably constitutes an efficacious therapeutic option.
doi:10.1186/ar770
PMCID: PMC165063  PMID: 12823847
autoantibodies; cytokines; immune regulation; inflammation; SLE
11.  Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria 
Annals of the Rheumatic Diseases  2011;70(11):1986-1990.
Background
Remission is the established goal in rheumatoid arthritis (RA) treatment. Although originally defined by a disease activity score in 28 joints (DAS28) <2.6, more stringent criteria may imply the absence of disease activity. The 2011 ACR/EULAR remission criteria provide the newest and most stringent definition of remission.
Objectives
To evaluate post hoc the remission by ACR/EULAR criteria and compare the criteria with the conventional DAS28 in TAMARA, an open-label phase IIIb tocilizumab (TCZ) trial including patients with active RA receiving inadequate disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor α (TNFα) inhibitor treatment.
Results
286 patients were enrolled, 99.7% of patients were receiving a conventional DMARD and 41.6% had TNFα inhibitor pretreatment. Baseline mean DAS28 of 6.0 ± 1.0 fell to 2.6 ± 1.5 at week 24. DAS28 <2.6 was achieved by 47.6% at week 24. Remission rates with the new ACR/EULAR Boolean-based criteria for clinical studies were 15.0% after 12 weeks and 20.3% after 24 weeks. Of note, 13.5% of patients with previous TNFα blocker inadequate response still achieved remission according to the new ACR/EULAR criteria after 24 weeks. Clinical Disease Activity Index and Simplified Disease Activity Index remission rates were 24.1% and 25.2%, respectively.
Conclusions
Under the definition of the new stringent 2011 ACR/EULAR remission criteria, patients with active RA despite DMARD treatment and even after inadequate response to TNFα inhibitors, receiving TCZ showed significant rates of remission. Similar remission rates were achieved, when clinical practice criteria, not inclusive of acute phase reactants, were used.
doi:10.1136/ard.2011.152678
PMCID: PMC3184242  PMID: 21875873
12.  Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis 
Annals of the Rheumatic Diseases  2012;71(11):1771-1782.
Objectives
To develop recommendations for the management of adult and paediatric lupus nephritis (LN).
Methods
The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.
Results
Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IVA or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.
Conclusions
Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.
doi:10.1136/annrheumdis-2012-201940
PMCID: PMC3465859  PMID: 22851469

Results 1-12 (12)