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1.  A closer look at non‐Hodgkin's lymphoma cases in a national Swedish systemic lupus erythematosus cohort: a nested case‐control study 
Annals of the Rheumatic Diseases  2007;66(12):1627-1632.
To investigate risk factors for non‐Hodgkin's lymphoma (NHL) and analyse NHL subtypes and characteristics in patients with systemic lupus erythematosus (SLE).
A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case control study on SLE patients who developed NHL during this observation period was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed. Tissue specimens on which the lymphoma diagnosis was based were retrieved and reclassified according to the WHO classification. NHLs of the subtype diffuse large B cell lymphoma (DLBCL) were subject to additional immunohistochemical staining using antibodies against bcl‐6, CD10 and IRF‐4 for further subclassification into germinal centre (GC) or non‐GC subtypes.
16 patients with SLE had NHL, and the DLBCL subtype dominated (10 cases). The 5‐year overall survival and mean age at NHL diagnosis were comparable with NHL in the general population—50% and 61 years, respectively. Cyclophosphamide or azathioprine use did not elevate lymphoma risk, but the risk was elevated if haematological or sicca symptoms, or pulmonary involvement was present in the SLE disease. Two patients had DLBCL‐GC subtype and an excellent prognosis.
NHL in this national SLE cohort was predominated by the aggressive DLBCL subtype. The prognosis of NHL was comparable with that of the general lymphoma population. There were no indications of treatment‐induced lymphomas. Molecular subtyping could be a helpful tool to predict prognosis also in SLE patients with DLBCL.
PMCID: PMC2095297  PMID: 17517757
2.  [No title available] 
PMCID: PMC2095298
3.  Henoch–Schönlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria 
Annals of the Rheumatic Diseases  2007;66(12):1648-1650.
The aim of the present study on the occurrence of Henoch–Schönlein Purpura (HSP) in Dutch children is to give some insight into the epidemiology of HSP in the Netherlands, to record the diagnostic criteria used by Dutch paediatricians and to evaluate the accuracy of the latter using the presence of IgA in the skin when biopsies are available.
Each month in 2004, all Dutch paediatricians received an electronic card asking them to mention new diagnosed HSP. Paediatricians reporting one or more new patients with HSP were sent a list of questions concerning various parameters.
232 patients from 0 to 18 years of age (6.1/105) were reported as having contracted HSP in 2004. 29% presented renal symptoms. In accordance with the classification criteria of the American College of Rheumatology, 80% of paediatricians consider that isolated purpura (without haematological abnormalities) is sufficient to allow the diagnosis of HSP in children. From the 17 skin biopsies performed, only 9 (53%) presented IgA deposits. The follow‐up duration, considered as necessary, was longer in case of renal symptoms at presentation. However, 45% of patients without renal symptoms would be followed for more than 1 year.
Considering the recent (2006) EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides, HSP should have been diagnosed in only 160 of the 179 patients of our study. The use of isolated non‐thrombocytopenic purpura as the only criterion to diagnose HSP in children might therefore lead to over diagnosis and unnecessary follow‐up.
PMCID: PMC2095299  PMID: 17472987
4.  Comparison of composite measures of disease activity in an early seropositive rheumatoid arthritis cohort 
Annals of the Rheumatic Diseases  2007;66(12):1633-1640.
To evaluate concordance and agreement of the original DAS44/ESR‐4 item composite disease activity status measure with nine simpler derivatives when classifying patient responses by European League of Associations for Rheumatology (EULAR) criteria, using an early rheumatoid factor positive (RF+) rheumatoid arthritis (RA) patient cohort.
Disease‐modifying anti‐rheumatic drug‐naïve RF+ patients (n = 223; mean duration of symptoms, 6 months) were categorised as ACR none/20/50/70 responders. One‐way analysis of variance and two‐sample t tests were used to investigate the relationship between the ACR response groups and each composite measure. EULAR reached/change cut‐point scores were calculated for each composite measure. EULAR (good/moderate/none) responses for each composite measure and the degree of agreement with the DAS44/ESR‐4 item were calculated for 203 patients.
Patients were mostly female (78%) with moderate to high disease activity. A centile‐based nomogram compared equivalent composite measure scores. Changes from baseline in the composite measures in patients with ACRnone were significantly less than those of ACR20/50/70 responders, and those for ACR50 were significantly different from those for ACR70. EULAR reached/change cut‐point scores for our cohort were similar to published cut‐points. When compared with the DAS44/ESR‐4 item, EULAR (good/moderate/none) percentage agreements were 92 with the DAS44/ESR‐3 item, 74 with the Clinical Disease Activity Index, and 80 with the DAS28/ESR‐4 item, the DAS28/CRP‐4 item and the Simplified Disease Activity Index.
The relationships of nine different RA composite measures against the DAS44/ESR‐4 item when applied to a cohort of seropositive patients with early RA are described. Each of these simplified status and response measures could be useful in assessing patients with RA, but the specific measure selected should be pre‐specified and described for each study.
PMCID: PMC2095300  PMID: 17472996
5.  EULAR evidence‐based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases 
Annals of the Rheumatic Diseases  2007;66(12):1560-1567.
To develop evidence‐based recommendations for the management of systemic glucocorticoid (GC) therapy in rheumatic diseases.
The multidisciplinary guideline development group from 11 European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist–epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference.
The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy (ie, non‐steroidal anti‐inflammatory drugs, gastroprotection and cyclo‐oxygenase‐2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice (ie, adrenal insufficiency, pregnancy, growth impairment).
Ten key recommendations for the management of systemic GC‐therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence (ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC‐replacement) and need further research; therefore also a research agenda was composed.
PMCID: PMC2095301  PMID: 17660219
6.  Tumour necrosis factor receptor 2 (TNFRSF1B) association study in Sjögren's syndrome 
Annals of the Rheumatic Diseases  2007;66(12):1684-1685.
PMCID: PMC2095302  PMID: 17998218
Sjögren syndrome; tumour necrosis factor receptor 2; association
7.  [No title available] 
PMCID: PMC2095303
8.  Isolated knee monoarthritis heralding resectable non‐small‐cell lung cancer. A paraneoplastic syndrome not previously described 
Annals of the Rheumatic Diseases  2007;66(12):1672-1674.
To describe isolated knee monoarthritis as a paraneoplastic syndrome heralding non‐small cell lung cancer (NSCLC), and to discuss its clinical characteristics.
Clinical records of all consecutive, new outpatients with isolated knee monoarthritis observed from January 2000 to December 2005 were reviewed. A systematic review of Medline and Cochrane Library databases was performed to identify English‐language articles related to rheumatological paraneoplastic syndromes associated with NSCLC.
Over 6 years, 6654 new outpatients with different rheumatic disorders were observed. Of these, 296 (4.4%) presented with isolated monoarthritis of the knee. In five out of 296 patients (1.7%) this feature represented the initial manifestation of NSCLC. All five patients were middle‐aged men, with a long history of heavy cigarette smoking, who had a non‐erosive, isolated knee monoarthritis, with mild articular fluid collection of non‐inflammatory type. NSCLC was resectable in all patients, and knee monoarthritis remitted with no relapse confirming its paraneoplastic nature. All five patients are in good condition after a median follow up of 41 months. The literature review revealed that paraneoplastic knee monoarthritis has not previously been reported.
Knee monoarthritis may in some cases represent a paraneoplastic syndrome heralding NSCLC at an early stage.
PMCID: PMC2095304  PMID: 17768172
9.  Bone mineral density in patients with hand osteoarthritis compared to population controls and patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(12):1594-1598.
Several studies have revealed increased bone mineral density (BMD) in patients with knee or hip osteoarthritis, but few studies have addressed this issue in hand osteoarthritis (HOA). The aims of this study were to compare BMD levels and frequency of osteoporosis between female patients with HOA, rheumatoid arthritis (RA) and controls aged 50–70 years, and to explore possible relationships between BMD and disease characteristics in patients with HOA.
190 HOA and 194 RA patients were recruited from the respective disease registers in Oslo, and 122 controls were selected from the population register of Oslo. All participants underwent BMD measurements of femoral neck, total hip and lumbar spine (dual‐energy x ray absorptiometry), interview, clinical joint examination and completed self‐reported questionnaires.
Age‐, weight‐ and height‐adjusted BMD values were significantly higher in HOA versus RA and controls, the latter only significant for femoral neck and lumbar spine. The frequency of osteoporosis was not significantly different between HOA and controls, but significantly lower in HOA versus RA. Adjusted BMD values did not differ between HOA patients with and without knee OA, and significant associations between BMD levels and symptom duration or disease measures were not observed.
HOA patients have a higher BMD than population‐based controls, and this seems not to be limited to patients with involvement of larger joints. The lack of correlation between BMD and disease duration or severity does not support the hypothesis that higher BMD is a consequence of the disease itself.
PMCID: PMC2095305  PMID: 17502356
10.  Joint‐specific hand symptoms and self‐reported and performance‐based functional status in African–Americans and Caucasians: The Johnston County Osteoarthritis Project 
Annals of the Rheumatic Diseases  2007;66(12):1622-1626.
To assess associations between joint‐specific hand symptoms and self‐reported and performance‐based functional status.
Participants were from the population‐based Johnston County Osteoarthritis Project. Symptoms in the distal interphalangeal (DIP), proximal interphalangeal (PIP), first carpometacarpal (CMC), and metacarpophalangeal (MCP) joints were assessed on a 30‐joint diagram of both hands. Self‐reported function was assessed by Health Assessment Questionnaire (HAQ) and performance‐based function by timed repeated chair stands and 8‐foot walk time. Separate multiple logistic regression models examined associations between symptoms in specific hand joint groups, symptoms in ⩾2 hand joint groups and number of symptomatic hand joints, and functional status measures, controlling for age, race/ethnicity, sex, body mass index, radiographic knee and hip OA, knee and hip symptoms and depressive symptoms.
Those with symptomatic hand joint groups were more likely than those without these complaints to report more difficulty and require longer times for performance measures. Those with 2 or more symptomatic hand joint groups were more likely to have higher HAQ scores (OR = 1.97 (1.53 to 2.53)) and require more time to complete 5 chair stands (OR = 1.98 (1.23 to 3.18)) and the 8 foot walk test (OR = 1.49 (1.12 to 1.99)).
Joint‐specific hand symptoms are associated with difficulty performing upper‐ or lower‐extremity tasks, independent of knee and hip OA and symptoms, suggesting that studies examining functional status in OA should not ignore symptomatic joints beyond the joint site of interest, even when functional measures appear to be specific for the joint site under study.
PMCID: PMC2095306  PMID: 17504840
11.  [No title available] 
PMCID: PMC2095307
12.  [No title available] 
PMCID: PMC2095308
14.  Scleroderma lung study (SLS): differences in the presentation and course of patients with limited versus diffuse systemic sclerosis 
Annals of the Rheumatic Diseases  2007;66(12):1641-1647.
Pulmonary fibrosis is a leading cause of death in systemic sclerosis (SSc). This report examines the differences at baseline and over 12 months between patients with limited versus diffuse cutaneous SSc who participated in the Scleroderma Lung Study.
SSc patients (64 limited; 94 diffuse) exhibiting dyspnoea on exertion, restrictive pulmonary function and evidence of alveolitis on bronchoalveolar lavage and/or high‐resolution computed tomography (HRCT) were randomised to receive cyclophosphamide (CYC) or placebo and serially evaluated over 12 months.
Baseline measures of alveolitis, dyspnoea and pulmonary function were similar in limited and diffuse SSc. However, differences were noted with respect to HRCT‐scored fibrosis (worse in limited SSc), and to functional activity, quality of life, skin and musculoskeletal manifestations (worse in diffuse SSc) (p<0.05). When adjusted for the baseline level of fibrosis, both groups responded similarly to CYC with regard to lung function and dyspnoea (p<0.05). Cyclophosphamide was also associated with more improvement in skin score in the diffuse disease group more than in the limited disease group (p<0.05).
After adjusting for the severity of fibrosis at baseline, CYC slowed the decline of lung volumes and improved dyspnoea equally in the limited and the diffuse SSc groups. On the other hand, diffuse SSc patients responded better than limited patients with respect to improvements in skin thickening.
PMCID: PMC2095310  PMID: 17485423
15.  HLA‐DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(12):1588-1593.
To test whether HLA‐DR alleles influence the production of particular autoantibodies in rheumatoid arthritis (RA) patients, we screened synovial proteins with sera of RA patients homozygous for different HLA‐DR alleles by using 2D blots. We found that sera of RA patients homozygous for HLA‐DRB1*0404 recognised a 100‐kDa synovial protein identified as calpastatin. We studied B and T cell epitopes on calpastatin and their association with HLA‐DRB1*0404.
The frequency of positive sera in patients expressing different RA‐associated HLA‐DR allele combinations was calculated by inhouse ELISA using purified synovial calpastatin or calpastatin peptides encompassing the entire calpastatin protein as immunosorbent. Interaction between calpastatin peptides and HLA‐DR alleles was tested by a direct binding assay. T cell responses to calpastatin were measured in RA patients and controls.
We found that RA‐associated HLA‐DR alleles are associated with presence of autoantibodies to synovial calpastatin in RA patients' sera. HLA‐DRB1*0404 is strongly associated with antisynovial calpastatin in RA sera. One linear B cell epitope is preferentially associated with HLA‐DRB1*0404. Multiple peptides from calpastatin bind every tested HLA‐DR allele associated or not with RA. Peptides from domain 1 and 4 of calpastatin are the best HLA‐DR allele binders. The T cell response to calpastatin is frequent in RA patients and independent of the HLA‐DR background.
HLA‐DRB1*0404 is strongly associated with anticalpastatin antibodies in rheumatoid arthritis.
PMCID: PMC2095311  PMID: 17324966
16.  Microscopic measurement of inflammation in synovial tissue: inter‐observer agreement for manual quantitative, semiquantitative and computerised digital image analysis 
Annals of the Rheumatic Diseases  2007;66(12):1656-1660.
To evaluate inter‐observer agreement for microscopic measurement of inflammation in synovial tissue using manual quantitative, semiquantitative and computerised digital image analysis.
Paired serial sections of synovial tissue, obtained at arthroscopic biopsy of the knee from patients with rheumatoid arthritis (RA), were stained immunohistochemically for T lymphocyte (CD3) and macrophage (CD68) markers. Manual quantitative and semiquantitative scores for sub‐lining layer CD3+ and CD68+ cell infiltration were independently derived in 6 international centres. Three centres derived scores using computerised digital image analysis. Inter‐observer agreement was evaluated using Spearman's Rho and intraclass correlation coefficients (ICCs).
Paired tissue sections from 12 patients were selected for evaluation. Satisfactory inter‐observer agreement was demonstrated for all 3 methods of analysis. Using manual methods, ICCs for measurement of CD3+ and CD68+ cell infiltration were 0.73 and 0.73 for quantitative analysis and 0.83 and 0.78 for semiquantitative analysis, respectively. Corresponding ICCs of 0.79 and 0.58 were observed for the use of digital image analysis. All ICCs were significant at levels of p<0.0001. At each participating centre, use of computerised image analysis produced results that correlated strongly and significantly with those obtained using manual measurement.
Strong inter‐observer agreement was demonstrated for microscopic measurement of synovial inflammation in RA using manual quantitative, semiquantitative and computerised digital methods of analysis. This further supports the development of these methods as outcome measures in RA.
PMCID: PMC2095312  PMID: 17604286
17.  MRI of enthesitis of the appendicular skeleton in spondyloarthritis 
Annals of the Rheumatic Diseases  2007;66(12):1553-1559.
Entheses are sites where tendons, ligaments, joint capsules or fascia attach to bone. Inflammation of the entheses (enthesitis) is a well‐known hallmark of spondyloarthritis (SpA). As entheses are associated with adjacent, functionally related structures, the concepts of an enthesis organ and functional entheses have been proposed. This is important in interpreting imaging findings in entheseal‐related diseases. Conventional radiographs and CT are able to depict the chronic changes associated with enthesitis but are of very limited use in early disease. In contrast, MRI is sensitive for detecting early signs of enthesitis and can evaluate both soft‐tissue changes and intraosseous abnormalities of active enthesitis. It is therefore useful for the early diagnosis of enthesitis‐related arthropathies and monitoring therapy. Current knowledge and typical MRI features of the most commonly involved entheses of the appendicular skeleton in patients with SpA are reviewed. The MRI appearances of inflammatory and degenerative enthesopathy are described. New options for imaging enthesitis, including whole‐body MRI and high‐resolution microscopy MRI, are briefly discussed.
PMCID: PMC2095313  PMID: 17526551
18.  [No title available] 
PMCID: PMC2095314
19.  [No title available] 
PMCID: PMC2095315
20.  [No title available] 
PMCID: PMC2095316
21.  [No title available] 
PMCID: PMC2095317
22.  Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis 
Annals of the Rheumatic Diseases  2007;66(12):1599-1603.
To examine the relationship between longitudinal fluctuations in synovitis with change in pain and cartilage in knee osteoarthritis.
Study subjects were patients 45 years of age and older with symptomatic knee osteoarthritis from the Boston Osteoarthritis of the Knee Study. Baseline and follow‐up assessments at 15 and 30 months included knee magnetic resonance imaging (MRI), BMI and pain assessment (VAS) over the last week. Synovitis was scored at 3 locations (infrapatellar fat pad, suprapatellar and intercondylar regions) using a semiquantitative scale (0–3) at all 3 time points on MRI. Scores at each site were added to give a summary synovitis score (0–9).
We assessed 270 subjects whose mean (SD) age was 66.7 (9.2) years, BMI 31.5 (5.7) kg/m2; 42% were female. There was no correlation of baseline synovitis with baseline pain score (r = 0.09, p = 0.17). The change in summary synovitis score was correlated with the change in pain (r = 0.21, p = 0.0003). An increase of one unit in summary synovitis score resulted in a 3.15‐mm increase in VAS pain score (0–100 scale). Effusion change was not associated with pain change. Of the 3 locations for synovitis, changes in the infrapatellar fat pad were most strongly related to pain change. Despite cartilage loss occurring in over 50% of knees, synovitis was not associated with cartilage loss in either tibiofemoral or patellofemoral compartment.
Change in synovitis was correlated with change in knee pain, but not loss of cartilage. Treatment of pain in knee osteoarthritis (OA) needs to consider treatment of synovitis.
PMCID: PMC2095318  PMID: 17491096
23.  Hypoglycaemia after initiation of treatment with etanercept in a patient with type 2 diabetes mellitus 
PMCID: PMC2095319  PMID: 17998221
type 2 diabetes mellitus; etanercept; hypoglycaemia
24.  International survey on the diagnosis and management of gout 
Annals of the Rheumatic Diseases  2007;66(12):1685-1686.
PMCID: PMC2095320  PMID: 17998219
25.  Epigenetic regulation of leptin affects MMP‐13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention 
Annals of the Rheumatic Diseases  2007;66(12):1616-1621.
To investigate whether epigenetic mechanisms can regulate leptin's expression and affect its downstream targets as metalloproteinases 3,9,13 in osteoarthritic chondrocytes.
DNA methylation in leptin promoter was measured by DNA bisulfite sequencing, and mRNA expression levels were measured by real‐time quantitative PCR in osteoarthritic as well as in normal cartilage. Osteoarthritic articular cartilage samples were obtained from two distinct locations of the knee (n = 15); from the main defective area of maximum load (advanced osteoarthritis (OA)) and from adjacent macroscopically intact regions (minimal OA). Using small interference RNA, we tested if leptin downregulation would affect matrix metalloproteinase (MMP)‐13 activity. We also evaluated the effect of the demethylating agent, 5′‐Aza‐2‐deoxycytidine (AZA) and of the histone deacetylase inhibitor trichostatin A (TSA) on leptin expression in chondrocyte cultures. Furthermore, we performed chromatin immunoprecipitation in leptin's promoter area.
We found a correlation between leptin expression and DNA methylation and also that leptin controls MMP‐13 activity in chondrocytes. Leptin's downregulation with small interference RNA inhibited MMP‐13 expression dramatically. After 5‐AZA application in normal chondrocytes, leptin's methylation was decreased, while its expression was upregulated, and MMP‐13 was activated. Furthermore, TSA application in normal chondrocyte cultures increased leptin's expression. Also, chromatin immunoprecipitation in leptin's promoter after TSA treatment revealed that histone H3 lysines 9 and 14 were acetylated.
We found that epigenetic mechanisms regulate leptin's expression in chondrocytes affecting its downstream target MMP‐13. Small interference RNA against leptin deactivated directly MMP‐13, which was upregulated after leptin's epigenetic reactivation, raising the issue of leptin's therapeutic potential for osteoarthritis.
PMCID: PMC2095321  PMID: 17502362

Results 1-25 (11689)