Long-term persistence and effects of fetal microchimerisms on disease onset and status in a cohort of women with rheumatoid arthritis and systemic lupus erythematosus

BACKGROUND: The discovery of a fetal cells transfer to the mother is a phenomenon with multiple implications for autoimmunity and tolerance. The prevalence and meaning of the feto-maternal microchimerism (MC) in rheumatic diseases has not been thoroughly investigated. The aim of this study was to analyze the prevalence of fetal MC in patients with inflammatory rheumatic diseases and to investigate the association of MC with disease onset and current status. METHODS: A total of 142 women who gave birth to at least one male offspring were recruited: 72 women with rheumatoid arthritis (RA), 16 women with systemic lupus erythematosus (SLE), and 54 healthy women. For the detection of fetal microchimerism a nested PCR method was used to amplify a Y chromosome specific sequence (TSPY1). For characterization of disease activity we analyzed autoantibody profiles and X-rays in RA, and in addition complement levels in SLE respectively. RESULTS: A significant higher prevalence of fetal MC was found in RA (18%) and SLE (31%) compared to controls (3.7%) (p = 0.02 and p = 0.006, resp.). The mean age at disease onset was comparable in MC + and MC- RA patients. Disease onset occurred 18.7 (MC +) and 19.8 (MC-) years post partum of the first son, respectively. The presence of anti-CCP and RF did not differ significantly, anti-CCP were found in 75% of MC + and 87% of MC- patients, RF in 75% of both MC + and MC- patients. A slightly higher mean Steinbrocker score in MC + patients was associated with longer disease duration in MC + compared to MC- RA. In SLE patients the mean age at disease onset was 42.6 years in MC + and 49.1 years in MC- patients. Disease onset occurred 24.0 and 26.4 years post partum of the first son for MC + and MC- patients, respectively. The presence of ANA and anti-dsDNA antibodies, C3, C4 and CH50 did not differ significantly. CONCLUSION: Our results indicate a higher frequency of long-term male MC in RA and SLE patients compared with controls without impact on disease onset and status in RA and SLE

Complex genetic predisposition in adult and juvenile rheumatoid arthritis

BACKGROUND: Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are complex multifactorial diseases caused by environmental influences and an unknown number of predisposing genes. The present study was undertaken in order to investigate association of polymorphisms in candidate genes with RA and JRA in German subjects. RESULTS: Up to 200 unrelated German RA and JRA patients each and 300–400 healthy controls have been genotyped for HLA-DRB1, TNFa, TNFA -238a/g, TNFA -308a/g, TNFA -857c/t, TNFR1 -609g/t, TNFR1 P12P, TNFR2 del 15bp, IKBL -332a/g, IKBL -132t/a, IKBL C224R, CTLA4 -318c/t, CTLA4 T17A, PTPRC P57P, MIF -173g/c, the MIF and IFNG microsatellites as well as for D17S795, D17S807, D17S1821 by polyacrylamide gel electrophoresis, single-strand conformation polymorphism analysis, restriction fragment length polymorphism analysis or allele specific hybridization. None of the investigated genetic markers is associated with both, RA and JRA, but there are some statistically significant differences between patients and controls that have to be discussed sensibly. CONCLUSIONS: The difficulty in investigating the genetics of complex disorders like RA and JRA may arise from genetic heterogeneity in the clinically defined disease cohorts (and generally limited power of such studies). In addition, several to many genes appear to be involved in the genetic predisposition, each of which exerting only small effects. The number of investigated patients has to be increased to establish the possibility of subdivison of the patients according their clinical symptoms, severity of disease, HLA status and other genetic characteristics

Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low – results from RABBIT, the German biologics register

We investigated the frequency of remission according to the disease activity score (DAS28) definition, modified American Rheumatology Association (ARA) criteria, and the frequency of an achievement of a functional status above defined thresholds ('functional remission', 'physical independence') in rheumatoid arthritis (RA) patients treated with either biologics or conventional DMARDs. We used the data of a prospective cohort study, the German biologics register RABBIT (German acronym for Rheumatoid Arthritis – Observation of Biologic Therapy) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics (BIOL; n = 818) or a conventional DMARD (n = 265). Logistic regression analysis was applied to adjust for differences in baseline risks. Taking risk indicators such as previous DMARD failures or baseline clinical status into account, we found that biologics doubled the chance of remission compared to conventional DMARD therapies (DAS28 remission, adjusted odds ratio (OR) 1.95 (95% confidenece interval (CI) 1.2–3.2)); ARA remission, OR 2.05 (95% CI 1.2–3.5)). High remission rates (DAS28 remission, 30.6%; ARA remission, 16.9%) were observed in BIOL patients with a moderate disease activity (DAS28, 3.2 to 5.1) at the start of treatment. These rates decreased to 8.5% in patients with DAS28 > 6. Sustained remission at 6 and 12 months was achieved in <10% of the patients. Severely disabled patients (≤50% of full function) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence (≥67% of full function) than controls (OR 3.88 (95% CI 1.7–8.8)). 'Functional remission' (≥83% of full function) was more often achieved in BIOL than in controls (OR 2.18 (95% CI 1.04–4.6)). In conclusion, our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence. However, temporary or even sustained remission remain ambitious aims, which are achieved in a minority of patients only

Impact of disease activity and treatment of comorbidities on the risk of myocardial infarction in rheumatoid arthritis

Background The aim was to estimate the impact of individual risk factors and treatment with various disease-modifying antirheumatic drugs (DMARDs) on the incidence of myocardial infarction (MI) in patients with rheumatoid arthritis (RA). Methods We analysed data from 11,285 patients with RA, enrolled in the prospective cohort study RABBIT, at the start of biologic (b) or conventional synthetic (cs) DMARDs. A nested case–control study was conducted, defining patients with MI during follow-up as cases. Cases were matched 1:1 to control patients based on age, sex, year of enrolment and five cardiovascular (CV) comorbidities. Generalized linear models were applied (Poisson regression with a random component, conditional logistic regression). Results In total, 112 patients developed an MI during follow-up. At baseline, during the first 6 months of follow-up and prior to the MI, inflammation markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) but not 28-joint-count disease activity score (DAS28) were significantly higher in MI cases compared to matched controls and the remaining cohort. Baseline treatment with DMARDs was similar across all groups. During follow-up bDMARD treatment was significantly more often discontinued or switched in MI cases. CV comorbidities were significantly less often treated in MI cases vs. matched controls (36 % vs. 17 %, p < 0.01). In the adjusted regression model, we found a strong association between higher CRP and MI (OR for log-transformed CRP at follow-up: 1.47, 95 % CI 1.00; 2.16). Furthermore, treatment with prednisone ≥10 mg/day (OR 1.93, 95 % CI 0.57; 5.85), TNF inhibitors (OR 0.91, 95 % CI 0.40; 2.10) or other bDMARDs (OR 0.85, 95 % CI 0.27; 2.72) was not associated with higher MI risk. Conclusions CRP was associated with risk of MI. Our results underline the importance of tight disease control taking not only global disease activity, but also CRP as an individual marker into account. It seems irrelevant with which class of (biologic or conventional) DMARD effective control of disease activity is achieved. However, in some patients the available treatment options were insufficient or insufficiently used - regarding DMARDs to treat RA as well as regarding the treatment of CV comorbidities

Canakinumab for Treatment of Adult-Onset Still's Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): phase II, randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial

Background: Inhibition of interleukin (IL)-1 represents a promising treatment option in adult-onset Still's disease (AOSD). Objective: To investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multicentre, double-blind, randomised, placebo-controlled trial. Methods Patients with AOSD and active joint involvement (tender and swollen joint counts of >= 4 each) were treated with canakinumab (4 mg/kg, maximum 300 mg subcutaneous every 4 weeks) or placebo. The primary endpoint was the proportion of patients with a clinically relevant reduction in disease activity at week 12 as determined by the change in disease activity score (Delta DAS28>1.2). Results At enrolment, patients had high active disease with a mean DAS28(ESR) of 5.4 in the canakinumab and 5.3 in the placebo group, respectively. In the intention-to-treat analysis, 12 patients (67%) in the canakinumab group and 7 patients (41%) in the placebo group fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher American College of Rheumatology (ACR) 30% (61% vs 20%, p=0.033), ACR 50% (50% vs 6.7%, p=0.009) and ACR 70% (28% vs 0%, p=0.049) response rates were observed in the canakinumab group compared with the placebo group. Two patients in the canakinumab group experienced a serious adverse event. Conclusion Although the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD

Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases

The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti–interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways

Biologic interventions for fatigue in rheumatoid arthritis

BACKGROUND: Fatigue is a common and potentially distressing symptom for patients with rheumatoid arthritis (RA), with no accepted evidence-based management guidelines. Evidence suggests that biologic interventions improve symptoms and signs in RA as well as reducing joint damage.OBJECTIVES: To evaluate the effect of biologic interventions on fatigue in rheumatoid arthritis.SEARCH METHODS: We searched the following electronic databases up to 1 April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Controlled Trials Register, the National Research Register Archive, The UKCRN Portfolio Database, AMED, CINAHL, PsycINFO, Social Science Citation Index, Web of Science, and Dissertation Abstracts International. In addition, we checked the reference lists of articles identified for inclusion for additional studies and contacted key authors.SELECTION CRITERIA: We included randomised controlled trials if they evaluated a biologic intervention in people with rheumatoid arthritis and had self reported fatigue as an outcome measure.DATA COLLECTION AND ANALYSIS: Two reviewers selected relevant trials, assessed methodological quality and extracted data. Where appropriate, we pooled data in meta-analyses using a random-effects model.MAIN RESULTS: We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti-tumour necrosis factor (anti-TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non-anti-TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti-interferon gamma monoclonal antibody). All but two of the studies were double-blind randomised placebo-controlled trials. In some trials, patients could receive concomitant disease-modifying anti-rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F), Short Form-36 Vitality Domain (SF-36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta-analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of -0.43 (95% confidence interval (CI) -0.38 to -0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT-F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti-TNF agents, this stood at -0.42 (95% CI -0.35 to -0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT-F score; and for non-anti-TNF agents, it was -0.46 (95% CI -0.39 to -0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT-F score. In most studies, the double-blind period was 24 weeks or less. No study assessed long-term changes in fatigue.AUTHORS' CONCLUSIONS: Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti-TNF and non-anti-TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism