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1.  Physiological evidence for diversification of IFNα- and IFNβ-mediated response programs in different autoimmune diseases 
Background
Activation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). While IFNα contributes to SLE pathology, IFNβ therapy is often beneficial in MS, implying different immunoregulatory roles for these IFNs. This study was aimed to investigate potential diversification of IFNα-and IFNβ-mediated response programs in autoimmune diseases.
Methods
Peripheral blood gene expression of 23 prototypical type I IFN response genes (IRGs) was determined in 54 healthy controls (HCs), 69 SLE (47 test, 22 validation), 149 IFNβ-treated MS (71 test, 78 validation), 160 untreated MS, 78 IIM and 76 RA patients. Patients with a type I IFN signature were selected for analysis.
Results
We identified IFNα- and IFNβ-specific response programs (GC-A and GC-B, respectively) in SLE and IFNβ-treated MS patients. Concordantly, the GC-A/GC-B log-ratio was positive for all SLE patients and negative for virtually all IFNβ-treated MS patients, which was confirmed in additional cohorts. Applying this information to other autoimmune diseases, IIM patients displayed positive GC-A/GC-B log-ratios, indicating predominant IFNα activity. The GC-A/GC-B log-ratio in RA was lower and approached zero in part of the patients, implying relative importance of both clusters. Remarkably, GC-A/GC-B log-ratios appeared most heterogeneous in untreated MS; half of the patients displayed GC-A dominance, whereas others showed GC-B dominance or log-ratios near zero.
Conclusions
Our findings show diversification of the type I IFN response in autoimmune diseases, suggesting different pathogenic roles of the type I IFNs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0946-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0946-9
PMCID: PMC4756531  PMID: 26882897
Type I interferons; Gene expression profiling; Autoimmune diseases; Rheumatic diseases; Multiple sclerosis
3.  Sex differences in risk and heritability estimates on primary knee osteoarthritis leading to total knee arthroplasty: a nationwide population based follow up study in Danish twins 
Background
Symptomatic knee osteoarthritis is a highly age and sex associated complex disease. Little is known about the causes behind this age and sex associated increase, or if genetic and environmental factors impacts differently by gender. Our study examined the risk and heritability of primary knee osteoarthritis leading to total knee arthroplasty and whether these differences were attributable to sex and age differences in heritability.
Methods
All twins of known zygosity from The Danish Twin Register alive in 1997 were examined in a nationwide population based follow-up study collecting information on all twins recorded in The Danish Knee Arthroplasty from 1997 to follow-up in 2010. Our main outcomes were the cumulative incidence, probandwise concordance rates, heritability, within pair correlations in monozygotic and dizygotic twin pairs and the genetic and environmental influence estimated in models taking into account that individuals may not have had a total knee arthroplasty at follow up.
Results
92,748 twins were eligible for analyses and 576 twins had a record of primary knee osteoarthritis in The Danish Knee Arthroplasty Register at follow-up comprising 358 female and 218 male twin cases. The risk increased particular after the age of 50 years displaying significant sex differences in the elderly. In the sex stratified analyses a discrete genetic component was found in females, but in males no genetic component could be detected. In both genders common and unique environmental factors were highly significant. In the sex-adjusted analysis an additive genetic component of 18 % (0; 62), a shared environmental component of 61 % (25; 97) and an individual environmental component of 21 % (6; 36) accounted for the variation in liability to primary total knee arthroplasty.
Conclusion
The risk of primary total knee arthroplasty increases significantly after the age of 50 years, in particular in females, displaying significant sex differences in the elderly. After sex-adjustment 82 % of the variation in liability to primary total knee arthroplasty was attributable to common and unique environmental factors; the remaining 18 % of this variation was attributable to additive genetic factors indicating a pivotal impact of environmental factors on this disease.
doi:10.1186/s13075-016-0939-8
PMCID: PMC4750301  PMID: 26864139
Knee osteoarthritis; Cumulative incidence; Twin study; Heritability; Total knee arthroplasty
4.  PD-L1-expressing neutrophils as a novel indicator to assess disease activity and severity of systemic lupus erythematosus 
Background
It is well-known that increased frequency of neutrophils was found in patients with systemic lupus erythematosus (SLE). However, the immunomodulatory roles and mechanisms of neutrophils in SLE are poorly understood.
Methods
Patients with SLE were recruited from the First Affiliated Hospital of Nanchang University. The medical history, clinical manifestations, physical examination, laboratory measurements, therapeutic regimen and treatment response were recorded. The expression of costimulatory molecules including programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), T-cell immunoglobulin and mucin domain–containing protein 3 (Tim-3), CD40, T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT), CD80 and CD86 on neutrophils were determined by flow cytometry. The frequencies of PD-L1-expressing neutrophils in patients with SLE were further analyzed for their correlation with markers of autoimmune response, inflammation, disease activity and severity of SLE.
Results
The frequency of PD-L1-expressing neutrophils was significantly elevated in SLE patients compared to the healthy controls (P < 0.0001). The frequency of PD-L1-expressing neutrophils in patients with SLE was increased significantly in subjects with high ANA titre, high anti-nRNP/Sm, high levels of inflammatory markers and high SLE Disease Activity Index (SLEDAI) score. Furthermore, the percentages of PD-L1-expressing neutrophils were significantly decreased in SLE patients that received a 15-day regular treatment with corticosteroids and immunosuppressive drugs (P = 0.0075).
Conclusion
The frequency of PD-L1-expressing neutrophils is elevates in patients with SLE, correlates with the disease activity and severity of SLE, and may serves as a negative feedback mechanism preventing potential tissue damage caused by excessive autoimmune responses in patients with SLE.
doi:10.1186/s13075-016-0942-0
PMCID: PMC4751645  PMID: 26867643
Systemic lupus erythematosus; PD-L1; Neutrophils
5.  The assessment of serum-mediated phagocytosis of necrotic material by polymorphonuclear leukocytes to diagnose and predict the clinical features of systemic lupus erythematosus: an observational longitudinal study 
Background
Serum-mediated phagocytosis of antibody- and complement-opsonized necrotic cell material (NCM) by polymorphonuclear leukocytes can be quantified by using a flow cytometry–based assay. The phagocytosis of necrotic cell material (PNC) assay parallels the well-known lupus erythematosus cell test. In this study, we aimed to investigate the diagnostic accuracy of the assay and the relationship with clinical manifestations and disease activity in systemic lupus erythematosus (SLE).
Methods
The diagnostic accuracy for SLE diagnosis of the PNC assay was studied by cross-sectional assessment of blood samples from 148 healthy control subjects and a multicenter rheumatic group (MRG) of 529 patients with different rheumatic symptoms. A cohort of 69 patients with an established SLE diagnosis (SLE cohort) underwent longitudinal clinical and laboratory follow-up for analysis of the temporal relationships between PNC positivity and specific clinical manifestations.
Results
In 35 of 529 MRG patients, 13 of whom had SLE, the PNC assay result was positive. Combined positivity of the PNC assay and anti–double-stranded DNA antibodies increased specificity and positive predictive value for SLE diagnosis to 0.99 and 0.67, respectively. In the longitudinal study, 42 of 69 SLE cohort patients had positive results in the PNC assay at least once. PNC assay positivity was associated with current hematological manifestations and could predict mucocutaneous manifestations. When combined with hypocomplementemia, PNC positivity preceded increased Systemic Lupus Erythematosus Disease Activity Index 2000 score, glomerulonephritis, and alopecia.
Conclusions
Serum-mediated PNC by polymorphonuclear leukocytes is commonly but not exclusively seen in patients with SLE. The PNC assay may be used in follow-up of patients with SLE and, especially in combination with other routinely assessed laboratory tests, may help to predict flares and different clinical manifestations, including glomerulonephritis. Our results encourage further development of the PNC assay as a complementary laboratory tool in management of patients with SLE.
doi:10.1186/s13075-016-0941-1
PMCID: PMC4748567  PMID: 26860519
Systemic lupus erythematosus; Biomarkers; Diagnostic accuracy; Flow cytometry; Disease activity; Lupus nephritis
6.  Evaluation of the impact of fibromyalgia in disease activity and treatment effect in spondyloarthritis 
Background
Fibromyalgia (FM) can coexist with Spondyloarthritis (SpA) leading to diagnostic and treatment dilemmas, especially in the presence of enthesitis. With this study we aimed to estimate the prevalence of FM in SpA and to compare the clinical/disease features and TNF inhibitors (TNFi) in patients with/without FM.
Method
FM was defined by a score = > 5/6 of the Fibromyalgia Rapid Screening Tool (FiRST). SpA patients (according to the rheumatologist) and consecutively consulting in the day care hospital but also in the outpatient clinic at the rheumatology department of a tertiary care university hospital were included.
Demographics, disease characteristics, activity and severity and TNFi treatment were compared in patients with and without FM; retention rate of the first TNFi and associated factors were explored (Kaplan Meier and Cox regression).
Results
Of the 196 enrolled SpA patients, 42 (21.4 %) were positively screened for FM. No statistically significant differences in the prevalence of FM were found with regard to the fulfillment of the ASAS criteria for peripheral/axial SpA, nor with regard to the fulfillment of the imaging vs. clinical arm of the ASAS criteria. However, patients with coexisting FM presented significantly with more enthesitis, higher disease activity (BASDAI and VAS) and poorer function scores (BASFI). No differences were found with regard to the initiation of TNFi treatment (79.0 % vs. 70.0 %, respectively), but the retention rate of the first TNFi after 2 years was shorter in the group of patients with FM (28.1 % (95 % CI 12.5-44.0) vs. 41.7 % (95 % CI 32.2-51.3), p = 0.01).
Conclusion
This study confirms that coexistent FM in SpA might impact the patient-reported outcome indices for disease activity and function, and the retention rate of TNFi treatment.
doi:10.1186/s13075-016-0943-z
PMCID: PMC4748456  PMID: 26860612
Spondyloarhtritis; Fibromyalgia; TNF alpha blockers treatment
7.  Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis 
Background
The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious.
Methods
Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays.
Results
The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected ≥15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [α-enolase (CEP-1/Eno5–21)], fibrinogen (Fib)β36–52, Fibα580–600, filaggrin (CCP-1/Fil307–324) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001–0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development.
Conclusions
RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0940-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0940-2
PMCID: PMC4748586  PMID: 26860413
Rheumatoid arthritis; Rheumatoid factor; Anti-citrullinated peptide antibodies; Pre-symptomatic individuals; Anti-carbamylated protein antibodies; Anti-CCP2 antibodies
9.  The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem? 
In systemic sclerosis (SSc), peripheral vasculopathy is characterized by a progressive and irreversible loss of capillaries following endothelial cell injury, due to defects in both vascular repair and expected increase in new vessel growth (angiogenesis). The discovery of key molecular targets may help to develop the most effective therapeutic strategy for the SSc-related vasculopathy. A pathway worth targeting in SSc may include vascular endothelial growth factor, 165b isoform, an endogenous angiogenesis inhibitor abnormally expressed and released by different cell types, including activated endothelial cells and platelets.
doi:10.1186/s13075-016-0937-x
PMCID: PMC4743122  PMID: 26847365
10.  Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients 
Background
Fibromyalgia (FM) is a chronic, centralized pain condition characterized by alterations in the functional, chemical, and structural brain networks responsible for sensory and mood processing. Transcranial direct current stimulation (tDCS) has emerged as a potential treatment for FM. tDCS can alter functional connectivity (FC) in brain regions underneath and distant to the stimulating electrode, although the analgesic mechanisms of repetitive tDCS remain unknown. The aim of this study was to investigate how a clinically relevant schedule of tDCS sessions alters resting state FC and how these changes might relate to clinical pain.
Methods
Resting state functional magnetic resonance imaging data were collected from 12 patients with FM at baseline, after 5 days of sham treatment, and after 5 days of real tDCS with the anode over the left primary motor cortex (M1) and the cathode over the right supraorbital cortex. Seed to whole-brain FC analyses were performed with seed regions placed in bilateral M1, primary somatosensory cortices (S1), ventral lateral (VL) and ventral posterolateral (VPL) thalami, and periaqueductal gray (PAG).
Results
Stronger baseline FC between M1–VL thalamus, S1–anterior insula, and VL thalamus–PAG predicted greater analgesia after sham and real tDCS. Sham treatment (compared with baseline) reduced FC between the VPL thalamus, S1, and the amygdala. Real tDCS (compared with sham treatment) reduced FC between the VL thalamus, medial prefrontal, and supplementary motor cortices. Interestingly, decreased FC between the VL/VPL thalamus and posterior insula, M1, and S1 correlated with reductions in clinical pain after both sham and active treatments.
Conclusions
These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in FC that last beyond the stimulation period and may produce analgesia by altering thalamic connectivity.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0934-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0934-0
PMCID: PMC4741001  PMID: 26842987
Repetitive transcranial direct current stimulation (tDCS); Fibromyalgia; Functional connectivity; Resting state; Motor cortex; fMRI
11.  Tapering and discontinuation of TNF-α blockers without disease relapse using ultrasonography as a tool to identify patients with rheumatoid arthritis in clinical and histological remission 
Background
In this study, we assessed whether clinical and ultrasonography (US)-based remission could be used to select patients with rheumatoid arthritis (RA) eligible to taper and discontinue anti-TNF-α therapy after achievement of remission, looking at disease relapse.
Methods
Forty-two patients with RA in sustained remission who were receiving anti-TNF-α treatment (Disease Activity Score <1.6 at three visits 3 months apart) underwent US evaluation of synovial hypertrophy (SH) and power Doppler (PD) signal presence. Five SH+/PD− patients with RA underwent US-guided knee synovial tissue biopsy to assess histological features of residual synovitis (CD68, CD3 and CD20 immunostaining) after sustained clinical remission was achieved. All patients were enrolled to taper first then discontinue anti-TNF-α. They were followed every 3 months afterwards, and the relapse rate was recorded.
Results
Selected SH+/PD− patients showed low-grade synovitis as demonstrated by the presence of CD68+ cells in the lining layer and few infiltrating CD3+ and CD20+ cells at the time sustained clinical remission was achieved. After anti-TNF-α tapering, 13 patients (30.9 %) relapsed and 29 (69.1 %) SH+/PD− patients maintained disease remission after 3 months and discontinued anti-TNF-α treatment. Among them, 26 patients (89.7 %) maintained disease remission status after 6 months of follow-up. All patients who relapsed were retreated with the previous biologic, following the last effective therapeutic regimen, again reaching a good European League Against Rheumatism response within 3 months.
Conclusions
US evaluation using PD signalling allows the identification of patients with RA in clinical and histological remission after tapering and discontinuing biologics.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0927-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0927-z
PMCID: PMC4741059  PMID: 26842890
Rheumatoid arthritis; Synovial tissue; Ultrasonography assessment; Disease remission; Anti-TNF-α agents; Discontinuation; Disease relapse
12.  Evaluation of treatments for sacroiliitis in spondyloarthropathy using the Spondyloarthritis Research Consortium Canada scoring system 
Background
In this study, the Spondyloarthritis Research Consortium Canada (SPARCC) scoring method was used to compare treatment methods in patients with axial spondyloarthritis (SpA), a form of sacroiliitis. MRI abnormalities in bone marrow edema (BME) were compared before and after treatment in order to compare the efficacy of anti-TNF-α and DMARD, alone or in combination, as treatments for sacroiliitis.
Methods
Fifty-six Chinese patients with axial SpA (mean age 22.6 years) were recruited. Patients were divided into three groups according to different treatments (anti-TNF-α alone vs. DMARDs alone vs. combined anti-TNF-α and DMARDs). MRI examinations were performed before and after treatment. The SPARCC score, clinically relevant AS Disease Activity (ASDAS) indices, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analyzed.
Results
After treatment, ASDAS and SPARCC scores, ESR, and CRP were significantly improved (P < 0.05) in the anti-TNF-α monotherapy and combination groups; however, there were no statistically significant differences (P > 0.05) in clinical disease activity and radiological inflammation of sacroiliac joint (SIJ) in patients in the DMARDs alone group. SPARCC showed a correlation with ASDAS score pre-treatment, but not post-treatment. Furthermore, there were significant changes (P < 0.05) in these patients with axial SpA after only 3 months of treatment. Follow-up studies of patients who continued therapy for 4-6 months and 9-12 months revealed statistically significant differences from baseline (P < 0.05).
Conclusions
SPARCC can be used to assess severity of disease pre-treatment. Anti-TNF-α treatment resulted in effective reduction of disease activity and BME of SIJ after 3 months of therapy.
doi:10.1186/s13075-016-0916-2
PMCID: PMC4734856  PMID: 26832154
spondyloarthritis; sacroiliitis; imaging studies; scoring; biologics; disease-modifying anti-rheumatic drugs
13.  Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis 
Background
Age, C-Reactive Protein (CRP) and autoantibodies (Abs) are associated with worse prognosis in patients with recent-onset inflammatory polyarthritis (EPA). Serum 14-3-3η protein is a joint-derived biomarker that up-regulates cytokines and enzymes that perpetuate local and systemic inflammation and may contribute to joint damage. Our objective was to evaluate, over a 5-year prospective period of observation, the additional prognostic potential of serum 14-3-3η protein in EPA patients.
Methods
Clinical variables, serum and radiographs (scored according to the Sharp/van der Heijde (SvH) method) were collected serially. Relationships between serum 14-3-3η protein and other biomarkers were computed with Spearman correlations. Outcomes were Simple Disease Activity Index (SDAI) scores and joint damage progression: ΔSvH for SvH score and ΔErosion for its Erosive component. The additional predictive contribution of 14-3-3η was defined using generalized estimating equations (GEE) and generalized linear mixed models (GLMM).
Results
Among 331 patients, baseline 14-3-3η was ≥0.19 and ≥0.50 ng/ml in 153 (46.2 %) and 119 (36.0 %), respectively; CRP was >8.0 mg/L in 207 (62.5 %), and at least one Ab (Rheumatoid Factor, anti-CCP2 or anti-Sa/citrullinated vimentin) was positive in 170 (51.5 %). Elevated 14-3-3η levels moderately correlated with positive Abs, but not with elevated CRP. Baseline 14-3-3η ≥0.19 ng/ml was associated with more radiographic progression over 5 years. The optimal levels of baseline 14-3-3η to predict radiographic progression was defined by ROC curves at 0.50 ng/ml. Levels of 14-3-3η ≥0.50 ng/ml at baseline were associated with lower likelihoods of ever reaching SDAI remission (RR 0.79 (95 % CI 0.64–0.98), p = 0.03) and higher subsequent progression of Total and Erosion SvH scores. Elevated levels of 14-3-3η during follow-up also predicted higher subsequent progression, even in patients in SDAI remission. Decreases of 14-3-3η levels by at least 0.76 ng/ml and reversion to negative during follow-up associated with less subsequent radiographic progression. In multivariate models, elevated 14-3-3η interacted with positive Abs, elevated CRP and older age to predict subsequent radiographic progression.
Conclusions
Levels of 14-3-3η protein ≥0.50 ng/ml predict poorer clinical and radiographic outcomes in EPA, both at baseline and after initiation of treatment, even in SDAI remitters. 14-3-3η, CRP, age and Abs represent independent predictors of subsequent joint damage.
Trial registration
ClinicalTrials.gov ID: NCT00512239. Registered August 6, 2007.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0935-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0935-z
PMCID: PMC4736641  PMID: 26832367
Recent-onset inflammatory arthritis; 14-3-3η; Radiographic progression; Anti-CCP2 antibodies; Anti-Sa/citrullinated vimentin antibodies; Rheumatoid factor; CRP; SDAI remission
14.  Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study 
Background
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented.
Methods
Study A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate. Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID. Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted. Primary endpoints were adverse events, laboratory parameters and vital signs. Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Safety and efficacy data were assessed throughout the study.
Results
A total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study. Median (range) duration of treatment in this extension study was 1185 (5–2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity. The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %). For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer). Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib. ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion.
Conclusions
Tofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis. The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population.
Trial registration
Clinicaltrials.gov NCT00661661. Registered 7 February 2008.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0932-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0932-2
PMCID: PMC4730592  PMID: 26818974
Tofacitinib; Japanese; Rheumatoid arthritis; Long-term extension
15.  Co-morbidity in patients with early rheumatoid arthritis - inflammation matters 
Background
Patients with rheumatoid arthritis (RA) suffer from co-morbidities that contribute to a shortened lifespan. Inflammation is important for the development of cardiovascular disease, but little is known on its relationship with other co-morbidities. We investigated the role of inflammation for the development of new comorbidities in early RA.
Methods
Since 1995, all patients with early RA in Northern Sweden are included in a prospective study on co-morbidities, with a total of 950 patients being included. At the time for this study, 726 had been ill for ≥5 years. Data on co-morbidities, clinical and laboratory disease activity and pharmacological therapy were collected from patient records and further validated using a questionnaire at RA onset (T0) and after 5 years (T5).
Results
Of the patients, 53.2 % of the patients had one or more co-morbidity at onset, the commonest being: hypertension (27.3 %), obstructive pulmonary disease (13.9 %), diabetes (8.0 %), hypothyroidism (6.3 %) and malignancy (5.0 %). After 5 years, 41.0 % had developed at least one new co-morbidity, the most common being: hypertension (15.1 %), malignancy (7.6 %), stroke/transient ischemic accident (5.1 %), myocardial infarction (4.3 %) and osteoporosis (3.7 %). Age at disease onset, a raised erythrocyte sedimentation rate (ESR) at inclusion, previous treatment with glucocorticoids (GC; p < 0.001 for all), extra-articular RA (Ex-RA; p < 0.01), DAS28 (area under the curve) at 24 months (p < 0.05), previous smoking at inclusion (p = 0.058) and male gender (p < 0.01) were associated with a new co-morbidity overall at T5. Treatment with biologics (p < 0.05) reduced the risk. In multiple logistic regression modelling, ESR (p = 0.036) at inclusion was associated with a new co-morbidity after 5 years, adjusted for age, sex, smoking and GC treatment. In a similar model, Ex-RA (p < 0.05) was associated with a new co-morbidity at T5. In a third model, adjusted for age and sex, a new pulmonary co-morbidity was associated with a smoking history at inclusion (p < 0.01), but not with ESR.
Conclusion
There was substantial co-morbidity among early RA patients already at disease onset, with considerable new co-morbidity being added during the first five years. Measures of disease activity were associated with the occurrence of a new co-morbidity indicating that the inflammation is of importance in this context.
doi:10.1186/s13075-016-0928-y
PMCID: PMC4730785  PMID: 26818851
Early rheumatoid arthritis; Co-morbidity; Inflammation
16.  Sex disparities in systemic sclerosis-associated pulmonary arterial hypertension: a cohort study 
Background
The impact of male sex as a determinant of health outcomes in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is controversial. The primary objective of this study was to evaluate the effect of sex on survival in patients with SSc-PAH. The secondary objectives were to evaluate the effect of sex on age of PAH diagnosis, time from SSc diagnosis to PAH diagnosis, and SSc disease manifestations.
Methods
Sex-based disparities were evaluated in a cohort of SSc-PAH patients with a primary outcome of time from PAH diagnosis to all-cause mortality. Secondary outcomes were differences in age of diagnosis, disease duration, and SSc manifestations. Survival differences were evaluated using Kaplan-Meier and Cox proportional hazard models.
Results
We identified 378 SSc-PAH (58 males, 320 females) patients, with a female:male ratio of 5.5:1. Males had a shorter mean ± standard deviation time from SSc diagnosis to PAH diagnosis (1.7 ± 14 versus 5.5 ± 14.2 years); shorter PAH duration (3.5 ± 3.1 versus 4.7 ± 4.2 years), increased frequency of renal crisis (19 % versus 8 %, relative risk (RR) 2.33, 95 %CI 1.22, 4.46), interstitial lung disease (67 % versus 48 %, RR 1.41, 95 %CI 1.14, 1.74), and diffuse subtype (40 % versus 22 %, RR 1.84, 95 %CI 1.26, 2.69). Males appeared to have decreased 1-, 2-, 3-, and 5-year survival (83.2 %, 68.7 %, 53.2 %, 45.6 %) compared to females (85.7 %, 75.7 %, 66.4 %, 57.4 %). However, there was no difference in mortality between sexes (HR 1.43 (95 %CI 0.97, 2.13).
Conclusions
Sex disparities appear to exist in the frequency of PAH, time to PAH diagnosis, PAH disease duration and SSc disease burden. However, male sex does not independently impact SSc-PAH survival.
doi:10.1186/s13075-016-0933-1
PMCID: PMC4729129  PMID: 26819137
Systemic sclerosis; Scleroderma; Pulmonary arterial hypertension; Sex; Survival; Scleroderma renal crisis
17.  Targeting oxidative stress to reduce osteoarthritis 
Osteoarthritis (OA) is the commonest chronic disease, with an estimated 9.6 % of men and 18.0 % of women aged over 60 years having symptomatic OA according to the World Health Organisation. Despite this prevalence, no therapies to slow disease progression are currently available. Oxidative stress has been described as an important factor in various diseases, and more recently in OA. Evidence for using antioxidants to reduce OA severity is slowly accumulating but further understanding of their chondroprotective mechanisms in joint tissues is still required to demonstrate potential benefit to patients. A new study implicates the transcriptional repressor Bach-1 and its downstream target HO-1 as important players in this process.
doi:10.1186/s13075-015-0908-7
PMCID: PMC4730642  PMID: 26818766
18.  Correlates of knee bone marrow lesions in younger adults 
Background
Subchondral bone marrow lesions (BMLs) play a key role in the pathogenesis of osteoarthritis (OA) and are associated with pain and structural progression in knee OA. However, little is known about clinical significance and determinants of BMLs of the knee joint in younger adults. We aimed to describe the prevalence and environmental (physical activity), structural (cartilage defects, meniscal lesions) and clinical (pain, stiffness, physical dysfunction) correlates of BMLs in younger adults and to determine whether cholesterol levels measured 5 years prior were associated with current BMLs in young adults.
Methods
Subjects broadly representative of the Australian young adult population (n = 328, aged 31–41 years, female 48.7 %) underwent T1- and proton density-weighted fat-suppressed magnetic resonance imaging (MRI) in their dominant knee. BMLs, cartilage defects, meniscal lesions and cartilage volume were measured. Knee pain was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and physical activity was measured by the International Physical Activity Questionnaire (IPAQ). Cholesterol levels including high-density lipoprotein (HDL) were assessed 5 years prior to MRI.
Results
The overall prevalence of BML was 17 % (grade 1: 10.7 %, grade 2: 4.3 %, grade 3: 1.8 %). BML was positively associated with increasing age and previous knee injury but not body mass index. Moderate physical activity (prevalence ratio (PR):0.93, 95 % CI: 0.87, 0.99) and HDL cholesterol (PR:0.36, 95 % CI: 0.15, 0.87) were negatively associated with BML, while vigorous activity (PR:1.02, 95 % CI: 1.01, 1.03) was positively associated with medial tibiofemoral BMLs. BMLs were associated with more severe total WOMAC knee pain (>5 vs ≤5, PR:1.05, 95 % CI: 1.02, 1.09) and WOMAC dysfunction (PR:1.75, 95 % CI: 1.07, 2.89), total knee cartilage defects (PR:2.65, 95 % CI: 1.47, 4.80) and total meniscal lesion score (PR:1.92, 95 % CI: 1.13, 3.28).
Conclusions
BMLs in young adults are associated with knee symptoms and knee structural lesions. Moderate physical activity and HDL cholesterol are beneficially associated with BMLs; in contrast, vigorous physical activity is weakly but positively associated with medial tibiofemoral BMLs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0938-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0938-9
PMCID: PMC4730612  PMID: 26817452
Young adults; Cholesterol; Physical activity; Bone marrow lesions; Cartilage defects; Meniscal lesions
19.  Anti-RANKL treatment inhibits erosive joint destruction and lowers inflammation but has no effect on bone formation in the delayed-type hypersensitivity arthritis (DTHA) model 
Background
The aims of the present study were to determine the relationship between bone destruction and bone formation in the delayed-type hypersensitivity arthritis (DTHA) model and to evaluate the effect of receptor activator of nuclear factor κB ligand (RANKL) blockade on severity of arthritis, bone destruction, and bone formation.
Methods
DTHA was induced in C57BL/6 mice. Inflammation, erosive joint damage, and new bone formation were semiquantitatively scored by histology. Osteoclast activity was assessed in vivo, and messenger RNA (mRNA) expression of mediators of bone destruction and bone formation were analyzed by mRNA deep sequencing. Serum concentrations of tartrate-resistant acid phosphatase 5b, carboxy-terminal telopeptide I (CTX-I), matrix metalloproteinase 3 (MMP3), and serum amyloid P component (SAP) were determined by enzyme-linked immunosorbent assay. Anti-RANKL monoclonal antibody treatment was initiated at the time of immunization.
Results
Bone destruction (MMP3 serum levels, cathepsin B activity, and RANKL mRNA) peaked at day 3 after arthritis induction, followed by a peak in cartilage destruction and bone erosion on day 5 after arthritis induction. Periarticular bone formation was observed from day 10. Induction of new bone formation indicated by enhanced Runx2, collagen X, osteocalcin, MMP2, MMP9, and MMP13 mRNA expression was observed only between days 8 and 11. Anti-RANKL treatment resulted in a modest reduction in paw and ankle swelling and a reduction of serum levels of SAP, MMP3, and CTX-I. Destruction of the subchondral bone was significantly reduced, while no effect on bone formation was seen.
Conclusions
Anti-RANKL treatment prevents joint destruction but does not prevent new bone formation in the DTHA model. Thus, although occurring sequentially during the course of DTHA, bone destruction and bone formation are apparently not linked in this model.
doi:10.1186/s13075-016-0931-3
PMCID: PMC4724155  PMID: 26801240
Arthritis; Joint inflammation; Bone destruction; Bone formation; Osteoclast; RANKL
20.  Reduced pro-inflammatory profile of γδT cells in pregnant patients with rheumatoid arthritis 
Background
During pregnancy, many patients with rheumatoid arthritis (RA) experience disease improvement, whereas patients with ankylosing spondylitis often suffer from persistent active disease. Here we investigated whether pregnancy-related changes in disease activity were associated with changes in the proportion and function of γδT cells.
Methods
The study population comprised 55 patients with RA, 31 patients with ankylosing spondylitis, and 35 healthy controls. Among these participants, 28 RA patients, 21 ankylosing spondylitis patients, and 23 healthy controls were investigated once before conception when possible, at each trimester of pregnancy, and at 8 weeks postpartum. Data were compared with age-matched non-pregnant patients to obtain disease-related background. In all subjects, peripheral Vδ1 and Vδ2 T cells were analyzed for cell frequencies, the activation marker CD69, the cytotoxicity markers NKG2D and NKG2A, and the intracellular cytokines tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-17 and IL-10.
Results
Pregnant patients showed a decreased Vδ2/Vδ1 ratio in the third trimester, which resulted from a slightly reduced proportion of Vδ2 cells. Changes in RA disease activity during pregnancy and postpartum were not associated with numerical proportions of γδT cells but with changes of the cell activation marker CD69 on Vδ1 and Vδ2 cells. Only RA patients showed reduced proportions of TNFα-positive Vδ1and Vδ2 cells and IFNγ-positive Vδ2 cells at the third trimester of pregnancy, a finding that was not apparent in the entire population of CD3 T cells. The proportions of IL-17-positive γδT cells and IL-10-positive γδT cells did not differ between pregnant and non-pregnant women of the different groups.
Conclusions
Changes of disease activity in pregnant RA patients were associated with functional changes in both γδT cell subsets. This reduced pro-inflammatory profile of γδT cells might contribute to the immunomodulation resulting in pregnancy-induced improvement of RA.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0925-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0925-1
PMCID: PMC4722716  PMID: 26795030
Pregnancy; rheumatoid arthritis; ankylosing spondylitis; disease improvement; gammadelta T cells
21.  Content validity of the Dutch Rheumatoid Arthritis Impact of Disease (RAID) score: results of focus group discussions in established rheumatoid arthritis patients and comparison with the International Classification of Functioning, Disability and Health core set for rheumatoid arthritis 
Background
The Rheumatoid Arthritis Impact of Disease (RAID) score was developed as a European League Against Rheumatism initiative to obtain a patient reported outcome score for clinical trials in patients with rheumatoid arthritis (RA), based on patients’ perception of the impact of the disease on several domains of health. The objective of this study was to assess the content validity of this score in Dutch RA patients.
Methods
During three focus group discussions (n = 23), patients with RA reflected on comprehensiveness of the RAID to measure impact of RA on their life, relevance of the RAID domains and formulation of questions. Also, the domains of the RAID score were compared to the comprehensive International Classification of Functioning, Disability and Health core set for RA.
Results
Patients confirmed that RA had impact on five domains already incorporated in the RAID score: emotional well-being, pain, performing daily activities, fatigue and coping. There was variation in interpretation of some of the items of the RAID score, suggesting problems in comprehension. Patients indicated that the domains work, relationships with others (such as family and friends) and spare time/hobbies were missed in the RAID and could be added to obtain a more ‘complete’ picture of the impact of the disease.
Conclusion
The RAID score has fairly good content validity. If confirmed as important in other patient groups, items in the above mentioned areas should be considered in a future upgrade.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0911-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0911-z
PMCID: PMC4722755  PMID: 26794406
Rheumatoid arthritis; RAID score; WHO ICF; qualitative study; COSMIN standard
22.  Stress granules and RNA processing bodies are novel autoantibody targets in systemic sclerosis 
Background
Autoantibody profiles represent important patient stratification markers in systemic sclerosis (SSc). Here, we performed serum-immunoprecipitations with patient antibodies followed by mass spectrometry (LC-MS/MS) to obtain an unbiased view of all possible autoantibody targets and their associated molecular complexes recognized by SSc.
Methods
HeLa whole cell lysates were immunoprecipitated (IP) using sera of patients with SSc clinically positive for autoantibodies against RNA polymerase III (RNAP3), topoisomerase 1 (TOP1), and centromere proteins (CENP). IP eluates were then analyzed by LC-MS/MS to identify novel proteins and complexes targeted in SSc. Target proteins were examined using a functional interaction network to identify major macromolecular complexes, with direct targets validated by IP-Western blots and immunofluorescence.
Results
A wide range of peptides were detected across patients in each clinical autoantibody group. Each group contained peptides representing a broad spectrum of proteins in large macromolecular complexes, with significant overlap between groups. Network analyses revealed significant enrichment for proteins in RNA processing bodies (PB) and cytosolic stress granules (SG) across all SSc subtypes, which were confirmed by both Western blot and immunofluorescence.
Conclusions
While strong reactivity was observed against major SSc autoantigens, such as RNAP3 and TOP1, there was overlap between groups with widespread reactivity seen against multiple proteins. Identification of PB and SG as major targets of the humoral immune response represents a novel SSc autoantigen and suggests a model in which a combination of chronic and acute cellular stresses result in aberrant cell death, leading to autoantibody generation directed against macromolecular nucleic acid-protein complexes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0914-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0914-4
PMCID: PMC4724133  PMID: 26801089
Systemic sclerosis; Scleroderma; Autoantibody; RNA processing bodies; Stress granules
23.  Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study) 
Background
Early suppression of disease activity in (rheumatoid) arthritis (RA) patients may result in drug-free remission and prevent damage. We assessed 2-year clinical and radiological outcomes of two disease activity score (DAS)-remission-steered treatment strategies in early arthritis patients.
Methods
Patients (n = 610) with early RA or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (44/53 joints DAS <1.6) after 4 months tapered and stopped medication. Patients who did not achieve early DAS-remission were randomized to either MTX plus hydroxychloroquine plus sulphasalazine plus low dose prednisone (arm 1) or to MTX + adalimumab (arm 2). At four-monthly intervals, medication was tapered and stopped if DAS was <1.6 but restarted, increased or switched if DAS was ≥1.6. Proportions of (drug-free) DAS-remission (DFR) after 2 years and Sharp-van der Heijde scores (SHS) were analyzed separately for the treatment strategies and patients with RA and UA.
Results
After 2 years, 301/610 (49 %) patients were in DAS-remission and 131/610 (21 %) in DFR. In the early remission group 241/387 patients (62 %) were in DAS-remission and 111/387 (29 %) DFR. In arm 1 22/83 (27 %) and in arm 2 24/78 (31 %) were in DAS-remission, and 6/83 (7 %) and 7/78 (9 %), respectively, were in DFR. RA and UA patients achieved DAS-remission in comparable percentages (RA: 234/479 (49 %), UA: 64/122 (52 %), p = 0.25). More UA patients achieved DFR (41/122 (34 %)) compared to RA patients (89/479 (19 %), p<0.001). Mean (SD) DAS over time was 1.74 (0.58) across all patients, and median (IQR) SHS progression was 0 (0–0).
Conclusions
After 2 years remission-steered treatment in early RA and UA patients, DAS-remission and DFR percentages were relatively low. Patients who achieved early remission more often achieved (drug-free) remission after 2 years than patients who needed additional treatment steps in the randomization arms, and more UA than RA patients achieved DFR. Overall, disease activity and radiologic damage progression in all patients were well suppressed.
Trial registration
http://www.controlled-trials.com/ISRCTN11916566 Registered 07/11/2006 and EudraCT number 2006-06186-16 Registered 16/07/2007.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0912-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0912-y
PMCID: PMC4721018  PMID: 26794605
Rheumatoid arthritis; Methotrexate; Remission steered treatment; Radiology; Joint damage; Progression
24.  Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration 
Background
One potential mechanism for early superficial cartilage wear in normal joints is alteration of the lubricant content and quality of synovial fluid. The purpose of this study was to determine if the concentration and quality of the lubricant, hyaluronan, in synovial fluid: (1) was similar in left and right knees; (2) exhibited similar age-associated trends, whether collected postmortem or antemortem; and (3) varied with age and grade of joint degeneration.
Methods
Human synovial fluid of donors (23–91 years) without osteoarthritis was analyzed for the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5–7 MDa, 1–2.5 MDa, 0.5–1 MDa, and 0.03–0.5 MDa. Similarity of data between left and right knees was assessed by reduced major axis regression, paired t-test, and Bland-Altman analysis. The effect of antemortem versus postmortem collection on biochemical properties was assessed for age-matched samples by unpaired t-test. The relationships between age, joint grade, and each biochemical component were assessed by regression analysis.
Results
Joint grade and the concentrations of protein, hyaluronan, and hyaluronan in the molecular weight ranges of 2.5–7 MDa, 1–2.5 MDa, and 0.5–1 MDa in human synovial fluid showed good agreement between left and right knees and were similar between age-matched patient and cadaver knee joints. There was an age-associated decrease in overall joint grade (–15 %/decade) and concentrations of hyaluronan (–10.5 %/decade), and hyaluronan in the molecular weight ranges of 2.5–7 MDa (–9.4 %/decade), 1–2.5 MDa (–11.3 %/decade), 0.5–1 MDa (–12.5 %/decade), and 0.03–0.5 MDa (–13.0 %/decade). Hyaluronan concentration and quality was more strongly associated with age than with joint grade.
Conclusions
The age-related increase in cartilage wear in non-osteoarthritic joints may be related to the altered hyaluronan content and quality of synovial fluid.
doi:10.1186/s13075-016-0922-4
PMCID: PMC4721052  PMID: 26792492
Hyaluronan; Synovial fluid; Aging; Degeneration
25.  Randomized controlled studies on the efficacy of antiarthritic agents in inhibiting cartilage degeneration and pain associated with progression of osteoarthritis in the rat 
Background
As an initial step in the development of a local therapeutic to treat osteoarthritis (OA), a number of agents were tested for their ability to block activation of inflammation through nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), subchondral bone changes through receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclastogenesis, and proteolytic degradation through matrix metalloproteinase (MMP)-13 activity. Candidates with low toxicity and predicted efficacy were further examined using either of two widely accepted models of OA joint degeneration in the rat: the monoiodoacetic acid (MIA) model or the medial meniscal tear/medial collateral ligament tear (MMT/MCLT) model.
Methods
Potential therapeutics were assessed for their effects on the activation of nuclear factor (NF)-κB, RANKL-mediated osteoclastogenesis, and MMP-13 activity in vitro using previously established assays. Toxicity was measured using HeLa cells, a synovial cell line, or primary human chondrocytes. Drugs predicted to perform well in vivo were tested either systemically or via intraarticular injection in the MIA or the MMT/MCLT model of OA. Pain behavior was measured by mechanical hyperalgesia using the digital Randall-Selitto test (dRS) or by incapacitance with weight bearing (WB). Joint degeneration was evaluated using micro computed tomography and a comprehensive semiquantitative scoring of cartilage, subchondral bone, and synovial histopathology.
Results
Several agents were effective both in vitro and in vivo. With regard to pain behavior, systemically delivered clonidine was superior in treating MIA-induced changes in WB or dRS, while systemic clonidine, curcumin, tacrolimus, and fluocinolone were all somewhat effective in modifying MMT/MCLT-induced changes in WB. Systemic tacrolimus was the most effective in slowing disease progression as measured by histopathology in the MMT/MCLT model.
Conclusions
All of the agents that demonstrated highest benefit in vivo, excepting clonidine, were found to inhibit MMP-13, NF-κB, and bone matrix remodeling in vitro. The MIA and MMT/MCLT models of OA, previously shown to possess inflammatory characteristics and to display associated pain behavior, were affected to different degrees by the same drugs. Although no therapeutic was remarkable across all measures, the several which showed the most promise in either model merit continued study with alternative dosing and therapeutic strategies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0921-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-016-0921-5
PMCID: PMC4721142  PMID: 26794830
Osteoarthritis; Arthritis; Monoiodoacetic; Meniscal; Therapeutics; Degeneration; Pain; NF-κB; RANKL; Bone remodeling

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