The Journal of Rheumatology

Published by Journal of Rheumatology
Online ISSN: 1499-2752
Publications
Article
Axial involvement is the hallmark of ankylosing spondylitis (AS), and it is unique in many ways among inflammatory arthritides. By its very anatomical location, it is difficult to assess clinically. Laboratory investigations including inflammatory markers are often unrevealing, and simple imaging such as radiographs remain normal for several years after the onset of the disease and change very slowly — if at all — later in the disease course1. Unlike their efficacy in other inflammatory arthritides, traditional disease-modifying antirheumatic drugs (DMARD) have been ineffective in improving function or reducing signs and symptoms of spinal involvement in AS. The significant efficacy of anti-tumor necrosis factor (TNF) agents in axial disease of AS is therefore even more striking2–5. With the limited therapeutic armamentarium for the management of spinal disease in AS (e.g., physical therapy, nonsteroidal antiinflammatory drugs), the use of anti-TNF agents is likely to grow, although the biggest hurdle remains their cost. A systematic review along with an economic evaluation of the use of the original 3 anti-TNF agents approved for the treatment of AS (etanercept, adalimumab, and infliximab) by the National Institute of Clinical Excellence (NICE) of Britain showed that the incremental cost-effectiveness ratios (ICER) of etanercept and adalimumab were roughly similar, falling below the conventional £30,000 (US $50,000) threshold per quality-adjusted life-year (QALY). However, the ICER for infliximab (IFX) used in the “approved” dose of 5 mg/kg every 6 weeks was in the …
 
Article
To evaluate the safety and efficacy of civamide cream 0.075% for the treatment of osteoarthritis (OA) of the knee. We conducted a 12-week, multicenter, randomized, double-blind study with a 52-week open-label extension. Patients with OA of the knee received either civamide cream 0.075% or a lower dose of civamide cream, 0.01%, as the control. The 3 co-primary endpoints in the double-blind study were the time-weighted average (TWA) of change from baseline to Day 84 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, the WOMAC physical function subscale, and the Subject Global Evaluation (SGE). In the 52-week open-label extension study, the Osteoarthritis Pain Score and SGE were assessed. A total of 695 patients were randomized to receive civamide cream 0.075% (n = 351) or civamide cream 0.01% (control; n = 344) in the double-blind study. Significance in favor of civamide cream 0.075% was achieved for the TWA for all 3 co-primary efficacy variables: WOMAC pain (p = 0.009), WOMAC physical function (p < 0.001), and SGE (p = 0.008); and at Day 84 for these 3 variables (p = 0.013, p < 0.001, and p = 0.049, respectively). These analyses accounted for significant baseline-by-treatment interactions. In the 52-week open-label extension, efficacy was maintained. Civamide cream 0.075% was well tolerated throughout the studies. These studies demonstrate the efficacy of civamide cream for up to 1 year of continuous use. Civamide cream, with its lack of systemic absorption, does not have the potential for serious systemic toxicity, in contrast to several other OA treatments.
 
Article
Recent evidence suggests that pharmacological treatment may alter the rate of progression of cartilage damage in osteoarthritis (OA). However, a lack of accurate and precise noninvasive assessments of cartilage structure makes it difficult to answer this question directly with prospective clinical trials, prevents early diagnosis of OA and restricts assessment of treatment to evaluation of symptoms or joint function. It is important, therefore, to develop precise, noninvasive methods both for diagnosis of early OA before damage is extensive and irreversible and for evaluation of therapeutic effectiveness. Magnetic resonance imaging (MRI) allows for noninvasive, multiplanar body imaging which depends on proton density, flow, and the T1 and T2 relaxation times. Because these variables differ markedly among joint tissues, cartilage erosions are visible with MRI and it should be possible to quantify them. Our objective was to compare MRI with arthroscopy for assessing the depth of lesions in the articular cartilage of human knees to help develop and validate MRI for use in clinical trials designed to assess the effect of therapy on cartilage structure. In the first part of our study, the effect of the MRI pulse sequence variables on the images was evaluated by varying them systematically and comparing the anatomy seen with MRI with that seen at arthroscopy or arthrotomy and with the histology. In the second part, 31 patients were assessed with MRI before arthroscopy. The MRI were graded on a 4-point ordinal scale by 2 observers who were unaware of the clinical diagnosis and compared with findings at arthroscopy which were graded using the same scale.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Characteristics of patients with HSP. 
HLA-DRB1 phenotype frequencies in patients with HSP and controls. 
HLA-DRB1 phenotype frequencies in patients with HSP with and without a history of upper respiratory tract infection (URTI). 
Article
To examine the HLA-DRB1 phenotypes of patients with Henoch-Schönlein purpura (HSP) and determine if associations exist with disease susceptibility, clinical heterogeneity, or severe systemic complications. A retrospective study was performed on an unselected population of patients from Northwest Spain with HSP classified according to proposed criteria. Patients were included in this study if they had at least one year of followup. Fifty Caucasian patients (25 women), 11 of them older than 20 years, were studied. Patients and ethnically matched controls were HLA-DRB1 genotyped from DNA using molecular based methods. During the course of the disease, renal manifestations, especially hematuria, and severe gastrointestinal (GI) manifestations (bowel angina or GI bleeding) were observed in more than 60% of the patients. Twenty percent of patients had persistent renal involvement (renal sequelae). Patients with HSP had a significantly higher frequency of the HLA-DRB1*01 phenotype compared to matched controls. The HLA-DRB1*07 phenotype was also significantly reduced compared with controls. Patients with severe GI manifestations or with persistent renal involvement did not exhibit any specific HLA-DRB1 association other than the underlying association with HLA-DRB1*01. HSP in a population from Northwest Spain is significantly associated with HLA-DRB1*01.
 
Article
Objective: Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti-CCP-positive or -negative RA. Methods: All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression. Results: SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE-positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46-0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA-DRB1*04:05/*09:01. Conclusion: HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/ *09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently.
 
Article
To further investigate a clinical impression that patients with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) who carry HLA-DQw1 have more severe arthritis, we subtyped HLA-DQw1 in American midwestern patients with EOPA-JRA. The HLA-DQA1*0101 subtype was present in 10 of 19 patients who developed persistent polyarticular erosive disease compared with 18 of 92 healthy controls (chi 2 = 9.13, p = 0.003, RR = 4.6), and occurred more frequently in this polyarticular group than in patients without polyarticular erosive disease (chi 2 = 4.11, p = 0.040, RR = 3.0). The presence of HLA-DQA1*0101 was significantly lower in patients with chronic iridocyclitis than in patients without chronic iridocyclitis (chi 2 = 7.07, p = 0.008, RR = 0.21). In HLA-DQA1*0101 positive patients, DNA sequences of the beta-1 domain of the HLA-DQ alpha and HLA-DQ beta genes (HLA-DQA1*0101, HLA-DQB1*0501 and HLA-DQB1*0503) were identical to those in controls. In this midwestern EOPA-JRA population, HLA-DQA1*0101 or genes in linkage disequilibrium with it, are associated with a cohort of patients with EOPA-JRA with distinct clinical characteristics.
 
Article
LF 15-0195 is an immunosuppressive agent obtained by organic synthesis, currently under clinical development for the treatment of vasculitis. We define the effects of LF 15-0195 in the murine collagen-induced arthritis (CIA) model, an experimental model of human rheumatoid arthritis. In our model, CIA was elicited in DBA/1 mice by immunization with bovine type II collagen (CII) in Freund's complete adjuvant, followed by a repeat injection 21 days later. Disease onset was observed 6 days after booster injection. In these experiments, mice were treated with 5 daily LF 15-0195 injections starting after the booster injection (days 21-25). The mice were observed for 40 days after the start of treatment, during which time arthritis was scored using clinical score and paw swelling assessment. Modulation of humoral immunity was documented by measuring the serum level of anti-CII IgG1 and IgG2a and cellular immunity by cytokines production by lymph node cells (LNC) and their proliferation in vitro. Short-term treatment of LF 15-0195 after booster injection prevented longterm development of CIA. LF 15-0195 inhibited B cell differentiation with a marked suppression of anti-CII IgG1 and IgG2a synthesis. Functional analyses of T lymphocytes showed that LF 15-0195 treatment reduces cytokine production by LNC after CII, anti-CD3, lipopolysaccharide stimulation. LF 15-0195 treatment during a short time period prevented development of arthritis, inhibited humoral-specific response longterm, induced a decrease in the number of LNC, and decreased cytokine production of T LNC after ex vivo stimulation.
 
Article
In rheumatoid arthritis (RA), many genetic markers, such as the shared-epitope (SE) alleles, are described in association with radiographic progression, but limited data are available on undifferentiated arthritis (UA). We investigated whether single-nucleotide polymorphisms (SNP) and haplotypes in immune response genes and HLA class II alleles are associated with radiographic progression in patients with early UA. Progression of radiographic damage was determined in white Dutch patients with early UA after 2 years of followup. Severe progression was defined as an increase in Sharp/van der Heijde Score > or = 5 points after 2 years of followup. The remainder was classified as mild. These SNP were genotyped by Taqman technology: tumor necrosis factor (TNF) -1031, -863, -857, -308, -238; lymphotoxin-alpha (LTA) +368, +252; interleukin 10 (IL10) -2849, -1082, -819; IL1A -889, IL1B -31, +3953; and IL1RN +2018. Carriage of SE alleles and HLA-DQA1*05-DQB1*02 haplotype was established. These markers were analyzed in relation to radiographic progression. Forty-eight out of 151 patients with early UA had severe radiographic progression. Severe radiographic progression was associated with an increased carrier frequency of SE alleles (OR 5.12, 95% CI 2.0-13.1, p < 0.001) and IL10 GGC haplotype (OR 2.8, 95% CI 1.4-5.8, p = 0.003). Mild radiographic progression was associated with the HLA-DQA1*05-DQB1*02 haplotype (OR 0.3, 95% CI, 0.1-0.8, p = 0.013) and with allele TNF -308A (OR 0.4, 95% CI, 0.2-0.9, p = 0.02). The SE and the IL10 GGC haplotype are associated with severe progression of radiographic damage, in contrast to the DQA1*05-DQB1*02 haplotype and the TNF -308A allele, which are associated with mild radiographic progression in early UA.
 
Article
To examine the respective role of the DRB1*, DQB1*, and DPB1* HLA alleles in primary Sjögren's syndrome (SS) and in the clinical and autoantibody profile of primary SS. HLA-DRB1*, DQB1*, and DPB1* alleles were analyzed in 42 patients with primary SS and 200 controls by reverse dot blot hybridization for DRB1* and DPB1* and by polymerase chain reaction-restriction fragment length polymorphism for DQB1*. We found a significant increase of the HLA-DRB1*15-*03 heterozygote genotype frequency (19% primary SS vs 3.5% controls; p<0.0006, OR=6.49) and especially for the HLA-DRBI*1501-*0301 genotype (16.7% primary SS vs 3% controls; p<0.002, OR=6.47). The DQB1*0201-*0602 genotype was also significantly increased in primary SS (17.1% primary SS vs 4% controls; p<0.006, OR=4.86). However, the higher risk to primary SS development was associated with the DRB1*1501-*0301 genotype (OR=6.47 vs 4.86). There were no differences between patients and controls in DPB1* allele frequencies. The HLA-DRB1*15-*03 heterozygote genotype was also associated with systemic features such as hematologic manifestations and Raynaud's phenomenon (RP) and with autoantibody production such as antinuclear, anti-Ro(SSA) or La(SSB) autoantibodies and rheumatoid factor. Our data suggest a role of the HLA-DRB1*1501-*0301 heterozygote genotype in susceptibility to primary SS. Moreover, the HLA-DRB1*1501-*0301 genotype was also found to be associated with a particular form of the disease characterized by RP, hematologic manifestations, and autoantibody production.
 
Article
To compare the HLA-DRB1 shared epitope (SE) alleles in Japanese patients with rheumatoid arthritis (RA) and amyloid A (AA) amyloidosis versus those without AA amyloidosis. The HLA-DRB1 alleles were genotyped for 91 RA patients without AA amyloidosis, 33 RA patients with AA amyloidosis, and 63 control subjects. HLA-DRB1 typing was performed by polymerase chain reaction, sequence-specific oligonucleotide probe hybridization method. Although a significant difference was not observed, the frequency of SE genotype was higher in RA patients with AA amyloidosis than in those without AA amyloidosis. All SE-positive RA patients with AA amyloidosis had *04 alleles (*0401, *0405, *0410), and a significant association of the presence of a double dose of *04 SE alleles with AA amyloidosis (OR 4.0, 95% CI 1.91-13.99) was observed. Our data suggest that presence of double *04 SE is associated with a higher risk of developing AA amyloidosis in Japanese patients with RA.
 
Article
To confirm the reported strong association between the HLA-DRB1*0401/0404 genotype and susceptibility to rheumatoid arthritis (RA), and to investigate the influence of sex, age at disease onset, and variables of disease severity on the strength of this association. A case control design was adopted comparing the frequency of specific HLA-DRB1 genotypes between 201 Caucasian patients with RA and 139 controls. HLA typing was performed using a polymerase chain reaction based oligonucleotide approach with HLA-DR4 subtyping using an amplification refractory mutation system RFLP technique. The risk of RA in those carrying a single shared epitope (SE) allele was 4 times, and in those carrying 2 SE alleles, 8 times that in the SE negative individuals. This increase was highest in individuals carrying 2 different SE alleles, with the risk in *0401/*0404 cases being 26 times higher. This genotype was associated with a 90-fold increased risk in men and this was more than doubled when age at disease onset was below 30. In all patients with RA, this genotype was associated with a substantially increased risk of being rheumatoid factor positive and having subcutaneous nodules and/or radiological erosion. Possession of the HLA-DRB1*0401/*0404 genotype carries a substantially high risk for RA development specifically in its more severe forms. The risks are particularly increased in young men.
 
Article
To determine the association of disease related HLA-DRB1 locus with disease severity and extraarticular features in Singaporean Chinese patients with rheumatoid arthritis (RA). 70 patients with RA and 80 controls were typed for HLA class II alleles by the polymerase chain reaction-sequence specific oligonucleotide probe method. 56 patients (80%) had erosive disease; 51 were seropositive (73%), and 16 had extraarticular features (23%). Patients with HLA-DRB1*0405 had significantly higher prevalence of extraarticular features (43 vs 10%; p = 0.001) and erosions (93 vs 71%; p = 0.022) compared to those without the allele. There was also a greater frequency of seropositivity and joint surgery, and a higher number of second line agents used by patients with HLA-DRB1*0405 in comparison to those without, although the difference was not statistically significant. HLA-DRB1*0405 is associated with the presence of extraarticular features and erosions in Singaporean Chinese patients with RA.
 
Article
Objective: Salmonella outer membrane proteins (OMP) are major immunogenic targets to synovial fluid lymphocytes of patients with reactive arthritis (ReA)/undifferentiated spondyloarthropathy (uSpA). Because these patients have genetic predisposition to HLA-B*27 and its subtype HLA-B*27:05, we sought to identify immunogenic HLA-B*27:05-binding salmonella OMP peptides in patients with ReA/uSpA. Methods: A total of 125 HLA-B*27:05-binding salmonella OMP peptides identified using ProPred-I software were synthesized and grouped in 23 pools. The peptide pools, along with crude enteric bacterial lysates and salmonella OMP, were cultured with synovial fluid (SF) or peripheral blood mononuclear cells (PBMC) from 23 patients with ReA/uSpA, 10 with rheumatoid arthritis (RA), and 10 healthy individuals in 96-well culture plates. Proliferation was measured by tritiated thymidine uptake and interferon-γ (IFN-γ) levels in culture supernatant. Individual peptides from pools having significant responses were retested with cryopreserved cells. Immunogenic peptides thus identified were further tested in 5 additional new patients with ReA/uSpA by flow cytometry. A Basic Local Alignment Search Tool program was used to search for similar peptides from a protein bank of arthritogenic bacteria and human protein. Results: Nineteen of 23 SFMC from ReA/uSpA showed a significant proliferative response to salmonella OMP, with minimal response of PBMC (1/10) from ReA/uSpA, SFMC from RA (1/10), or PBMC from controls (1/10). Nine salmonella OMP peptides, QRAEMLPTL, SRSGLNIAL, LRFLYAKSL, RLEGTWVKL, ARCIAPYAL, KLFLTTAAL, YRNSDFFGL, QRPAVRVKL, and YRVGPGDVL, were identified. Response to QRAEMLPTL was seen in 6/7 HLA-B*27:05-positive patients. All immunogenic peptides had sequence similarity with peptides from arthritogenic bacterial proteins, while 5 had similarity with peptides from human proteins. Conclusion: Nine novel immunogenic OMP peptides binding to HLA-B*27:05 were identified that showed sequence similarity with other arthritogenic bacteria.
 
Article
HLA class II encoded factors may influence the phenotype of ankylosing spondylitis (AS). These include HLA DRB1*07 for peripheral arthritis, and polymorphism of the HLA-linked LMP2 locus and HLA DRB1*08 for acute anterior uveitis (AAU). We studied the relationship between DRB1*08 and disease phenotype in additional populations of individuals with AS. The patient population included 385 unrelated HLA-B27 positive individuals with AS. These included 204 Caucasians and 2 populations of Mexican Mestizo with AS: 106 with predominately adult onset disease from Guadalajara and 75 with predominately juvenile onset disease from Mexico City. The control population of 428 individuals included 210 random and 36 HLA-B27 positive unrelated Canadian Caucasians and 173 random and 9 HLA-B27 positive Mexican Mestizo from Mexico City. DRB1*08 typing was by sequence specific polymerase chain reaction. A significantly higher prevalence of DRB1*08 was observed in Mexican patients with juvenile onset disease (44.9%) and especially those with undifferentiated spondyloarthropathy (55.6%) compared to normal unrelated Mexican Mestizo (25.4%) (p < 0.01 for both) and in patients with undifferentiated spondyloarthropathy versus B27 controls (11.1%) (p = 0.03), although no significant differences were observed in within patient group comparisons based on phenotypic features of disease such as AAU and age at onset. No significant relationship between DRB1*08 and disease phenotype was evident in Caucasian individuals. Our data suggest DRB1*08 may influence the phenotype of spondyloarthritis in Mexican Mestizo, but do not support the view that DRB1*08 influences the development of AAU, as reported in a Japanese population.
 
Article
To examine association of 8 candidate genes with susceptibility to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japanese patients. Little is known on the genetic background of AAV in Japanese patients mainly because of the difficulty in collecting a sufficient number of samples for the genetics study. Sixty-nine patients, including 50 with microscopic polyangiitis (MPA), were recruited in a multicenter study. Among them, 64 patients were positive for myeloperoxidase (MPO)-ANCA. Associations of HLA-DRB1, tumor necrosis factor-alpha promoter (TNF), TNF receptor 2 (TNFR2), Fcgamma receptor IIa (FCGR2A), IIb (FCGR2B), IIIa (FCGR3A), IIIb (FCGR3B), and CTLA-4 (CTLA4) polymorphisms were examined in a case-control analysis. A significant association of HLA-DRB1*0901 with MPA (p = 0.0037, OR 2.44, 95% CI 1.33-4.46), as well as with MPO-ANCA positivity (p = 0.0014, OR 2.44, 95% CI 1.41-4.22), was detected. There was no difference in the TNF promoter haplotype frequencies between patients with MPA and controls, excluding the possibility that the association of DRB1*0901 was secondarily caused by linkage disequilibrium with TNF. No association was observed for TNFR2, FCGR, or CTLA4 with MPA, nor with the presence of MPO-ANCA, although the combined genotype FCGR2A-131H/H and 3A-176F/F was increased in patients with MPA (p = 0.025). There was an association of HLA-DRB1*0901 with MPA and MPO-ANCA positive vasculitis in Japanese patients.
 
Article
The homologous upregulation produced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on vitamin D receptor (VDR) levels, and the effects produced by the heterologous agents hydrocortisone or deflazacort, alone or in conjunction with this vitamin D metabolite, were studied in rat osteoblastic UMR-106 osteosarcoma cells. VDR were determined by binding analysis (Bmax and dissociation constant). VDR mRNA expression levels were measured by Northern blot analysis. Incubation with 10 nM 1,25(OH)2D3 produced a significant increase in Bmax with respect to ethanol-treated cells (100.2 +/- 13.2 vs 11.4 +/- 4.8 fmol 3H-1,25(OH)2D3 bound/mg protein) together with a significant increase in VDR mRNA expression (483 +/- 170% vs 100%). The addition of 10 nM hydrocortisone to 1,25(OH)2D3 produced a significant decrease in Bmax (from 100.2 +/- 13.2 to 44 +/- 5.6), with mRNA levels similar to those of basal conditions (116 +/- 25% vs 100%). However, the addition of 10 nM deflazacort did not reduce the activation in Bmax produced by 1,25(OH)2D3 (92.4 +/- 16 vs 100.2 +/- 13.2), maintaining the increase in mRNA levels (430 +/- 10% vs 483 +/- 170%). If 10 nM hydrocortisone or 10 nM deflazacort was added to UMR-106 cells without 1,25(OH)2D3, a similar increase was observed in Bmax with respect to basal conditions (20.4 +/- 1.3 or 20.9 +/- 1.6 vs 11.4 +/- 4.8 in control cells), but hydrocortisone did not produce any significant variation in mRNA VDR levels, while deflazacort itself produced an increase in VDR mRNA expression. Our findings of different actions produced by hydrocortisone and deflazacort on the increase of VDR levels produced by 1,25(OH)2D3 could explain some of the different actions produced by both antiinflammatory medications on bone metabolism.
 
Article
To investigate the effects of vitamin D3 [1,25-(OH)2D3] metabolites on interleukin 1 beta (IL-1 beta) stimulated secretory activities and on the proliferation of human synovial fibroblasts in culture. Dose dependent effects on IL-1 beta actions were determined in nonproliferating cultures containing 1% fetal calf serum (FCS) in the culture medium. Production of prostaglandin E (PGE), collagenase and hyaluronic acid (HA) was measured respectively by radioimmunoassay, enzymatic degradation of radiolabelled collagen gels after collagenase activation and 14C-glucosamine incorporation. Effects on cell growth in 10% FCS were monitored colorimetrically, by staining cells with crystal violet. 1,25-(OH)2D3 inhibited the effects of IL-1 beta on PGE production by up to 90%, with half maximal inhibition at 2.0 x 10(-10) M. Inhibitory effects on stimulated collagenase and HA production and cell growth were also found but were less marked. At 10(-7) M 1,25-(OH)2D3 inhibition was 50, 21 and 50%, respectively. 24,25-dihydroxyvitamin D3 was a less potent inhibitor than 1,25-(OH)2D3. Neither metabolite influenced IL-1 beta effects on PGE or sulfated glycosaminoglycan production in human articular cartilage in tissue culture. Our results suggest that the active metabolites of vitamin D3 may modulate the behavior of synovial fibroblasts in articular inflammatory processes.
 
Article
Ninety-four patients with seropositive rheumatoid arthritis (RA) were typed for HLA-A, B, C and DR antigens and for immunoglobulin G (Gm) allotypes. Isolated IgG from patient serum was used to avoid interference of IgM rheumatoid factor (RF) with Gm typing in sera with high IgM-RF titer. Besides the association of seropositive RA with the antigen DR4 and an earlier disease onset in DR3/DR4 heterozygotes, we found the uncommon Gm phenotype Gm(1,2;21) significantly more often in our patient group than in healthy controls. Combination of HLA-DR and Gm data shows that individuals with both DR4 and Gm(1,2;21) are at a particularly high disease risk.
 
Article
The mechanisms controlling the recruitment of T helper type 1 (Th1) cells to the inflamed synovium are not fully understood. Here, we focus on alpha(1,3)-fucosyltransferase-VII (FucT-VII), an enzyme responsible for the generation of functional P- and E-selectin ligands that is upregulated in Th1 cells. Expression of transcripts encoding FucT-VII, interferon-gamma (IFN-gamma), and interleukin 12Rbeta2 (IL-12Rbeta2) were analyzed in T cells purified from synovial fluid (SF) and from peripheral blood (PB) of children with juvenile idiopathic arthritis (JIA) using kinetic reverse transcriptase polymerase chain reaction analysis. Binding of SF and PB T cells to P-selectin was determined by flow cytometry using a soluble P-selectin/IgG1 fusion molecule. Recruitment of T cells to synovial tissue in vivo was studied by analyzing the migration of FucT-VII transfected Jurkat T cells into human rheumatoid synovial tissue grafted into SCID mice. In patients with JIA, the mRNA levels of FucT-VII, as well as of IFN-gamma and IL-12Rbeta2, were up-regulated in SF T cells compared to paired PB T cells. A higher expression of FucT-VII mRNA in SF T cells was associated with increased binding of T cells to P-selectin. Moreover, FucT-VII expression and increased P-selectin binding capacity of T cells were associated with a polyarticular course of oligoarticular JIA. Expression of FucT-VII in Jurkat T cells resulted in an increased accumulation of these cells in human rheumatoid synovial tissue grafted into SCID mice. Our data indicate an important role of FucT-VII in the enhanced homing of T cells to the inflamed synovium.
 
Article
We studied the pain, Stanford Health Assessment Questionnaire functional disability, pain/disability ratio, and psychological scores in 1,522 patients with rheumatic disease with 7 distinct disorders. Individual differences between patients were more striking than differences among diagnostic groups. Patients with rheumatoid arthritis (RA) had the greatest disability, least pain, lowest pain/disability ratio, and least abnormal psychological scores. Highest pain and psychological distress was noted in low back pain, neck pain, and fibromyalgia (axial disorders). Disability in activities of daily living was as high in fibromyalgia as in RA, but low in axial skeletal disorders. There appears to be a continuum for disability that begins with axial but not articular disease (neck and back pain) and ends with multiple articular and periarticular involvement (RA and fibromyalgia).
 
Article
To assess the prevalence of rheumatoid arthritis (RA) in a representative study of the South Transdanubian region of Hungary. Ten thousand individuals aged between 14-65 years were interviewed. The stratified sample was representative for age, sex and urban/rural residence structure of the regional population of the South-West Hungarian region. As a second step, all individuals with possible RA were asked to undergo a clinical investigation to confirm the diagnosis of RA according to the American Rheumatism Association (ARA) 1987 criteria. Of 10,000 interviewed individuals, 632 reported having RA or symptoms including digital pain, stiffness, and/or swelling. Two hundred and twenty-four individuals were investigated clinically. Individuals fulfilling the 1987 ARA criteria were considered as having definite RA, and their clinical data were evaluated. RA was confirmed in 13 cases. The male/female ratio was 3/10. The prevalence of RA among individuals aged 14-65 years was 0.37% (95% confidence interval, CI: 0.26-0.51), 0.23% (95% CI: 0.15-0.35) in men and 0.48% (95% CI: 0.35-0.64) in women. The prevalence of RA in the South Transdanubian region of Hungary is similar to those of other recent studies from other regions around the world.
 
Article
There is controversy whether older-onset systemic lupus erythematosus (SLE) is associated with a different, more benign disease course than in younger-onset SLE. Our objective was to characterize the clinical features and prognosis of late-onset SLE in a large, multicenter cohort. We studied adult-onset lupus in the 1000 Canadian Faces of Lupus cohort (n = 1528) of whom 10.5% had onset at age > or = 50 years versus a control group with onset at < 50 years. Disease duration was different in early- and late-onset groups (15 yrs in early vs 9.3 yrs in late; p < 0.001). Caucasians were represented more in the later-onset SLE group (55.6% vs 74.5%), while Asians and Blacks were more prevalent in the younger group. Younger-onset SLE subjects fulfilled more American College of Rheumatology criteria for SLE (< 50 yrs: 5.98 +/- 1.68; > or = 50 yrs: 5.24 +/- 1.44; p < 0.0001). Despite an equal prevalence of anti-dsDNA, the younger-onset group more often had positive anti-Smith autoantibody, ribonucleoprotein, and hypocomplementemia, and more nephritis, rash, and cytopenias than the older-onset group. However, disease activity and damage accrual were higher in the older-onset group. The older patients received less prednisone and immunosuppressives (current and ever-use). As expected, comorbidity was higher in the older-onset SLE group. This study suggests that older age-onset SLE is not benign. There may be an interaction between lupus and age in which, although there is less lupus nephritis in the elderly, more disease activity and damage are present.
 
Article
To examine the agreement between and compare the sensitivity to change of the Arthritis Impact Measurement Scale (AIMS2) and AIMS2 Short Form (AIMS2-SF) in a large sample of rheumatoid arthritis (RA) patients examined within the framework of a longitudinal observational study. Data were collected from patients in a community based RA register by a postal survey in April 1994 (1,030 respondents) and again in 1996 (1,153 respondents), comprising AIMS2, Modified Health Assessment Questionnaire (MHAQ), Medical Outcome Survey SF-36, and other commonly used health status measures. The degree of agreement was examined by plotting differences between AIMS2 and AIMS2-SF against the mean of the 2 scores for the 5 main components. The upper and lower limits of agreement (mean diff. +/- 1.96 SD) were calculated and plotted. The intraclass correlation coefficients were computed by repeated measurement ANOVA. Validity was assessed on the basis of external indicators of health status, and responsiveness on the basis of standardized response means. The AIMS2 and AIMS2-SF showed substantial to near-perfect agreement. Best agreement was seen for the physical and affect components. Better agreement for the symptom component was obtained when replacing item 42 with item 38. Internal consistency was high in all components. The 2 forms correlated similarly with scores from other instruments within the same domains, showing similar construct validity. There was no difference in responsiveness between the 2 forms when using changes in patient assessed global disease activity as external indicator of change in health status, and responsiveness for the physical and symptom dimension was similar to other instruments (SF-36, MHAQ). The AIMS2-SF is amenable for use in large surveys with a modification of one item in the symptom scale.
 
Article
To describe disease expression and damage accrual in systemic lupus erythematosus (SLE), and determine the influence of ethnicity and socioeconomic factors on damage accrual in a large multiethnic Canadian cohort. Adults with SLE were enrolled in a multicenter cohort. Data on sociodemographic factors, diagnostic criteria, disease activity, autoantibodies, treatment, and damage were collected using standardized tools, and results were compared across ethnic groups. We analyzed baseline data, testing for differences in sociodemographic and clinical factors, between the different ethnic groups, in univariate analyses; significant variables from univariate analyses were included in multivariate regression models examining for differences between ethnic groups, related to damage scores. We studied 1416 patients, including 826 Caucasians, 249 Asians, 122 Afro-Caribbeans, and 73 Aboriginals. Although the overall number of American College of Rheumatology criteria in different ethnic groups was similar, there were differences in individual manifestations and autoantibody profiles. Asian and Afro-Caribbean patients had more frequent renal involvement and more exposure to immunosuppressives. Aboriginal patients had high frequencies of antiphospholipid antibodies and high rates of comorbidity, but disease manifestations similar to Caucasians. Asian patients had the youngest age at onset and the lowest damage scores. Aboriginals had the least education and lowest incomes. The final regression model (R2=0.27) for higher damage score included older age, longer disease duration, low income, prednisone treatment, higher disease activity, and cyclophosphamide treatment. There are differences in lupus phenotypes between ethnic populations. Although ethnicity was not found to be a significant independent predictor of damage accrual, low income was.
 
Article
To investigate the results and feasibility of available scales to measure minimal disease activity (MDA) and remission in rheumatoid arthritis (RA) in the clinic. We studied 849 consecutive patients with RA seen in a community rheumatology practice for routine RA care by 4 rheumatologists, beginning in March 2007 and ending in August 2007. Patients and physicians completed a simple form at each visit. We calculated the Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI), physician assessment of global activity, and the Patient Activity Scale (PAS-II). From these we calculated remission and MDA prevalence in this community practice. The DAS28 could not be determined in more than 50% of patients because of referring physician and insurance company restrictions. Remission prevalences differed by assessment method: DAS28 28.5%, CDAI 6.5%-8.1%, physician global 12.5%, PAS 13.7%. MDA was 26.9% using the American College of Rheumatology core set variables, 34.7% using the DAS28, and 26.8% using the PAS-II. The kappa statistic was only fair (0.2 to 0.4) for most comparisons between assessment methods. No significant differences were noted for remission and MDA according to biologic therapy. The CDAI and/or physician global and PAS-II are simple acceptable ways to measure RA activity in the clinic, but results differ strikingly according to method. Further standardization appears to be required for full implementation of the CDAI. Caution is urged before using these methods for regulatory purposes.
 
Article
To describe the clinical and immunologic characteristics of a large series of patients with systemic autoimmune diseases (SAD) associated with chronic hepatitis C virus (HCV) infection. The HISPAMEC Registry is a multicenter international study group dedicated to collecting data on patients diagnosed with SAD with serological evidence of chronic HCV infection. The information sources are cases reported by physicians of the HISPAMEC Study Group and periodic surveillance of reported cases by a Medline search updated up to December 31, 2007. One thousand twenty HCV patients with SAD were included in the registry. Patients were reported from Southern Europe (60%), North America (15%), Asia (14%), Northern Europe (9%), South America (1%), and Australia (1%). Countries reporting the most cases were Spain (236 cases), France (222 cases), Italy (144 cases), USA (120 cases), and Japan (95 cases). The most frequently reported SAD were Sjögren's syndrome (SS; 483 cases), rheumatoid arthritis (RA; 150 cases), systemic lupus erythematosus (SLE; 129 cases), polyarteritis nodosa (78 cases), antiphospholipid syndrome (59 cases), inflammatory myopathies (39 cases), and sarcoidosis (28 cases). Twenty patients had 2 or more SAD. Epidemiological data were available in 677 cases. Four hundred eighty-seven (72%) patients were female and 186 (28%) male, with a mean age of 49.5 +/- 1.0 years at SAD diagnosis and 50.5 +/- 1.1 years at diagnosis of HCV infection. The main immunologic features were antinuclear antibody (ANA) in 61% of patients, rheumatoid factor (RF) in 57%, hypocomplementemia in 52%, and cryoglobulins in 52%. The main differential aspect between primary and HCV-related SAD was the predominance of cryoglobulinemic-related markers (cryoglobulins, RF, hypocomplementemia) over specific SAD-related markers (anti-ENA antibodies, anti-dsDNA, anti-cyclic citrullinated peptide) in patients with HCV. In the selected cohort, the SAD most commonly reported in association with chronic HCV infection were SS (nearly half the cases), RA and SLE. Nearly two thirds of SAD-HCV cases were reported from the Mediterranean area. In these patients, ANA, RF and cryoglobulins are the predominant immunological features.
 
Concurrent medication during 1072 methotrexate treatment episodes. 
Methotrexate withdrawal and reasons in 1072 treatment episodes (1022 patients). 
Factors related to methotrexate discontinuation-univariate and multivariate analysis (Cox regression analysis; p ≤ 0.05). 
Article
To study which factors are associated with longterm methotrexate (MTX) use in rheumatoid arthritis (RA). All patients with RA who had started MTX after January 1, 1993, were selected from a regional hospital based registration system. Data on demographic and clinical features were retrieved through chart review. By means of life table analysis and Cox regression analysis, MTX survival and the relation between demographic variables, clinical features, and MTX survival were studied. A total of 1072 MTX treatment episodes in 1022 patients were analyzed. The cumulative MTX survival probability after 5 years was 64%, and after 9 years was 50%. Univariate analysis showed a significant relation between MTX survival probability and folic acid supplementation, attending rheumatologist, concurrent prednisolone use, concurrent sulfasalazine use, and the number of previous disease modifying drugs. In the multivariate analysis folic acid supplementation, attending rheumatologist, and concurrent prednisolone use remained significantly related to MTX survival. Age, disease duration, and creatinine clearance were not. In this retrospective study of 1022 patients with RA the cumulative MTX survival probability was 64% after 5 years and 50% after 9 years. Folic acid supplementation and to a lesser extent prednisolone were associated with a longer MTX survival. In addition, treatment strategies of individual rheumatologists influenced MTX survival.
 
Article
To study, in patients with rheumatoid arthritis (RA), the association between the tumor necrosis factor (TNF)-alpha -1031 T/C polymorphism and quantitative and qualitative low density lipoprotein (LDL) characteristics. From a sample of 100 patients with RA and 100 controls, we used the strategy of "recruit by genotype" to select 30 patients with RA: 15 carriers of the rare allele (C) and 15 homozygous for the more frequent allele (T). These were matched with 30 controls. Plasma lipoprotein profile including size distribution of lipoproteins was determined using nuclear magnetic resonance spectrometry. LDL susceptibility to oxidation was assessed by diene formation. The LDL affinity for extracellular matrix was determined using electrophoretic mobility shift assay. Genotyping was performed by SnapShot. Compared to TT patients with RA, carriers of the C allele had (1) LDL particles significantly smaller [20.74 (0.68) nm vs 21.18 (0.52), p < 0.02]; (2) LDL particles with a greater affinity for the proteoglycans (i.e., with a lower Kd) [197.26 (123.98) nmol/l vs 259.26 (139.31), p = 0.05]; and (3) LDL particles with significantly greater susceptibility to oxidation [shorter lag phase: 47 (20.01) min vs 74 (41.8), p < 0.03, and higher maximal rate of diene production: 3.1 (0.5) mol/min vs 2.6 (0.95), p < 0.05]. None of these differences was observed in the control group. In patients with RA, genetic variability in the TNF-alpha gene is associated with smaller LDL particles that have a greater affinity for extracellular matrix and higher susceptibility to oxidation. Because these characteristics are associated with a greater risk of atherosclerosis, identification of such predisposition in patients with RA could help in implementing early preventive intervention measures against cardiovascular disease.
 
Article
Of 105 cases seen over 12 years with mean 4 years followup, there were 69 with polymyositis (PM) and 36 with dermatomyositis (DM). and in 43 this complicated another connective tissue disease (CTD). Primary PM had onset a decade later than others and most severe myopathy occurred in DM. Earliest symptoms were polyarthritis and Raynaud's phenomenon with frequent sicca syndrome (51%). The less than universal prevalence of elevated muscle enzymes (68%), myopathic electromyography (86%). and abnormal muscle biopsy (78%) emphasizes the need for complete evaluation in all cases. Improvement occurred in 69% overall, including all 23 given no therapy or low dose corticosteroids and 59% of the remainder who received high dose corticosteroids with added cytotoxics in one-quarter. Outcome was worse in older patients and in those where weakness exceeded 4 months before diagnosis. Eight of 19 deaths were due to myositis or its therapy which also caused considerable morbidity. Malignancy in 16 cases was temporally related to myositis in half of these cases.
 
Article
To determine the effects of SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5] decane-2-propanamine dihydrochloride) on the arthritic lesions in the tibiotarsal joint of adjuvant arthritic (AA) rats. Inhibition of hindpaw inflammation was measured by water displacement. The protective effects on joint integrity were determined by measuring radiographic and histological changes and by scanning electron microscopy. Compared to AA control rats, SK&F 105685 suppressed hindpaw edema 64% or 41-54% in AA rats receiving 30 or 20 mg/kg/day, respectively. Radiographic evaluation showed marked decreases in soft tissue swelling and in the severity of skeletal tissue loss at the tibiotarsal joint in both dose groups. Histologically SK&F 105685 markedly attenuated the extent and severity of the inflammatory lesion and preserved the basic integrity of bone and cartilaginous tissues, including the content and distribution of proteoglycans of the articular cartilages. Cellular changes included decreases in the inflammatory infiltrate and in the number of osteoclasts and chondroclasts. Whereas AA control rats exhibited marked to severe loss (41-70%) of skeletal tissue mass, the loss in rats given 30 mg/kg SK&F 105685 was mild (< 20%). Scanning electron microscopy of the talus revealed only slight erosion of the articular cartilage and general preservation of the underlying bone. In contrast, in AA controls, there was marked erosion of the talar articular cartilage and severe loss of subchondral bone. Spleen cells from SK&F 105685 treated rats had a reduced capacity to respond to concanavalin A and contained suppressor cell activity as measured in a coculture assay. Our studies show that SK&F 105685 has remarkable protective effects on the joints of AA rats and suggests that it may attenuate the overall inflammatory process and retard the degenerative loss of skeletal tissue in rheumatoid arthritis in humans.
 
Article
We evaluated the rheumatic manifestations in 106 patients with AIDS whose risk factor is intravenous drug addiction. All were intravenous drug addicts and carriers of the human immunodeficiency virus (HIV). Their average age was 28.36 years; 83 were men and 23 were women; 73 were in stage IV of the HIV infection; 12 were in stage III and 21 in stage II. Rheumatic manifestations were found in 21 patients (20%). Specifically, 13 had arthralgias/myalgias, 2 demonstrated oligoarthritis, 1 had tuberculous arthritis of the knee, and 1 patient showed systemic necrotizing vasculitis. Finally, 6 patients had a history of septic arthritis. There was an absence of the Reiter syndrome/reactive arthritis, a low frequency of symptoms of articular swelling, and the marked presence of histories of septic arthritis. The practices that lead to HIV infection may play a decisive role in the appearance of rheumatic manifestations in patients with AIDS, even more than the presence of the virus itself or the immunological alterations thereby produced.
 
Article
To determine prognostic factors for mortality in a cohort of 667 patients with systemic lupus erythematosus (SLE) including those variables associated with the presence of antiphospholipid antibodies (aPL) as well as antiphospholipid syndrome (APS) itself. Analysis of the cohort under a nested case control design by means of Cox proportional hazards regression with and without stepwise method. During the 2039 person-years of followup, there were 49 deaths (cases). Thrombocytopenia, arterial occlusions, and hemolytic anemia were the aPL related manifestations that were associated with decreased survival in univariate analyses. The first 2 were also selected among risk factors for mortality in stepwise Cox multivariate analysis. The syndrome itself was also associated with increased mortality rates, independently of other variables. APS is among the variables that confer decreased survival on patients with SLE. This decreased survival is due to some (e.g., thrombocytopenia or arterial occlusions), but not all, of the manifestations of APS.
 
Article
Patients with rheumatoid arthritis (RA) have reduced life expectancy; however, there are few data on the changing pattern of causes of death with longterm followup, or on the longterm effect of early presentation. The objectives of this study were (1) to examine the effect of early presentation on subsequent mortality; (2) to compare the causes of death early and late in the followup period; and (3) to compare survival of the cohort with that of the general population (adjusted for age and sex) over a followup period of up to 27 years. A cohort of 448 patients with RA (inpatients and outpatients), assembled 1968-74, were followed to December 31, 1990. Death certificates were obtained for all who had died and coded using the International Classification of Diseases. Kaplan-Meier survival curves were constructed. By the end of the study, 266 patients (59%) had died. The standardized mortality ratio (SMR) was 2.7 (95% CI 2.4-3.1). Patients who presented early continued to do well. Most excess deaths were due to cardiovascular disease. SMR due to infection, renal failure, and non-Hodgkin's lymphoma rose with disease duration. Patients with RA should be referred early, and those with chronic disease should be closely monitored for evidence of infection and renal impairment.
 
Article
Patients with rheumatoid arthritis (RA), a chronic inflammatory disease, have increased cardiovascular morbidity and mortality. We investigated whether early markers of RA inflammatory disease activity could predict later increased levels of pulse-wave velocity (PWV) and augmentation index (AIx), 2 measures of arterial stiffness. In total 238 patients with early RA were followed longitudinally and 108 were available for the 15-year followup examination. Comprehensive baseline clinical and radiographic data were collected in 1992. Arterial stiffness, measured as AIx and PWV (Sphygmocor apparatus), was recorded at the 15-year followup. Adjusted logistic univariate and multivariate analyses were performed with levels of AIx and PWV as the dependent variables, and variables reflecting baseline RA disease activity as possible predictors. The validity of the final models was examined in linear regression analyses. Baseline C-reactive protein (CRP) above the median predicted increased AIx (OR 3.52, 95% CI 1.04-11.90) and PWV (OR 4.84, 95% CI 1.39-16.83) at the 15-year assessment in multivariate models. Patients with elevated baseline CRP had significantly higher AIx (ß = 2.67, 95% CI 0.06-5.31, p = 0.045) and lnPWV (ß = 0.08, 95% CI 0.01-0.14, p = 0.02) after 15 years, after adjustments for age, sex, heart rate (AIx only) and mean arterial pressure. Inflammation early in the RA disease course was associated with increased AIx and PWV after 15 years. These findings support the importance of early control of the inflammatory process in patients with RA.
 
Article
Polymyositis (PM) and dermatomyositis (DM) are inflammatory muscle diseases of presumed autoimmune origin. Many possible interventions are available to treat these patients: corticosteroids, immunosuppressive drugs, plasmapheresis, and total body irradiation. But these therapies are not always effective and may be responsible for certain serious side effects. Polyvalent intravenous immunoglobulin (IVIG) has been tried with success in inflammatory myopathies after failure of traditional treatment. An attempt was made to evaluate the efficacy of IVIG as first line therapy in patients with PM or DM. Eleven Caucasian patients [6 women, 5 men, mean age 55.6 (SD 10.1) years], with active recent inflammatory myopathy, were treated by high doses of IVIG as first choice. The average duration of inflammatory myopathy before IVIG was 9.6 months (SD 10.2 months, with a range of 1 month to 3 years). Five patients had PM and 6 had DM. None had myositis associated with connective tissue disease. Two patients had a history of malignant disease: 1 lymphoma and 1 breast tumor with relapse of the malignancy during the study. One patient had a probable lung carcinoma and in another patient, ovarian carcinoma was diagnosed a few months after the onset of IVIG. We used preparations of polyvalent human i.v. gamma globulins with intact IgG. All patients received 1 g/kg daily for 2 days each month. The mean course of treatment was 4 months. Clinical assessment, evaluated by proximal muscle power and biochemical tests, was carried out before each treatment period. Significant clinical improvement was noted in only 3 of the 11 patients (one with acute coxsackie virus B infection, and one with possible drug induced myopathy). Mean muscle power estimated for the 11 patients before and after IVIG therapy was not significantly improved. Eight patients showed significant biochemical improvement (more than 50%). Mean CK levels for the 11 patients showed a statistically significant decrease during IVIG therapy (p < 0.01). Minor IVIG side effects were noted in one patient. IVIG therapy seems effective rarely as first therapy in patients with inflammatory myopathy but may be considered especially in viral or drug induced myopathy. IVIG therapy as the first treatment may also be tried in patients with contraindication for steroids, and in mild myopathy, especially in the elderly, to avoid steroid induced side effects.
 
Article
![Figure][1] ### OMERACT 11 — International Consensus Conference on Outcome Measures in Rheumatology Clinical Trials The biennial OMERACT 11 meeting was held in Pinehurst, North Carolina, USA, from May 12 to 17, 2012, with participants from North America, Europe, Asia, and
 
Article
The Outcome Measures in Rheumatology (OMERACT) initiative works to develop core sets of outcome measures for trials and observational studies in rheumatology. At the OMERACT 11 meeting, substantial time was devoted to discussing a conceptual framework and a proposal for a more explicit working process to develop what we now propose to term core outcome measurement sets, collectively termed "OMERACT Filter 2.0." Preconference work included a literature review, and discussion of preliminary proposals through face-to-face discussions and Internet-based surveys with people within and outside rheumatology. At the conference, 5 interactive sessions comprising plenary and small-group discussions reflected on the proposals from the viewpoint of previous and ongoing OMERACT work. These considerations were brought together in a final OMERACT presentation seeking consensus agreement for the Filter 2.0 framework. After debate, clarification, and agreed alterations, the final proposal suggested all core sets should contain at least 1 measurement instrument from 3 Core Areas: Death, Life Impact, and Pathophysiological Manifestations, and preferably 1 from the area Resource Use. The process of core set development for a health condition starts by selecting core domains within the areas ("core domain set"). This requires literature searches, involvement (especially of patients), and at least 1 consensus process. Next, developers select at least 1 applicable measurement instrument for each core domain. Applicability refers to the original OMERACT Filter and means that the instrument must be truthful (face, content, and construct validity), discriminative (between situations of interest) and feasible (understandable and with acceptable time and monetary costs). Depending on the quality of the instruments, participants formulate either a preliminary or a final "core outcome measurement set." At final vote, 96% of participants agreed "The proposed overall framework for Filter 2.0 is a suitable basis on which to elaborate a Filter 2.0 Handbook." Within OMERACT, Filter 2.0 has made established working processes more explicit and includes a broadly endorsed conceptual framework for core outcome measurement set development.
 
Article
The newly formed Outcome Measures in Rheumatology (OMERACT) Myositis Special Interest Group (SIG) was established to examine patient-reported outcome measures (PROM) in myositis. At OMERACT 11, a literature review of PROM used in the idiopathic inflammatory myopathies (IIM) and other neuromuscular conditions was presented. The group examined in more detail 2 PROM more extensively evaluated in patients with IIM, the Myositis Activities Profile, and the McMaster-Toronto Arthritis Patient Preference Disability Questionnaire, through the OMERACT filter of truth, discrimination, and feasibility. Preliminary results from a qualitative study of patients with myositis regarding their symptoms were discussed that emphasized the range of symptoms experienced: pain, physical tightness/stiffness, fatigue, disease effect on emotional life and relationships, and treatment-related side effects. Following discussion of these results and following additional discussions since OMERACT 11, a research agenda was developed. The next step in evaluating PROM in IIM will require additional focus groups with a spectrum of patients with different myositis disease phenotypes and manifestations across a range of disease activity, and from multiple international settings. The group will initially focus on dermatomyositis and polymyositis in adults. Qualitative analysis will facilitate the identification of commonalities and divergent patient-relevant aspects of disease, insights that are critical given the heterogeneous manifestations of these diseases. Based on these qualitative studies, existing myositis PROM can be examined to more thoroughly assess content validity, and will be important to identify gaps in domain measurement that will be required to develop a preliminary core set of patient-relevant domains for IIM.
 
Article
The OMERACT Rheumatoid Arthritis (RA) Flare Group (FG) is developing a data-driven, patient-inclusive, consensus-based RA flare definition for use in clinical trials, longterm observational studies, and clinical practice. At OMERACT 11, we sought endorsement of a proposed core domain set to measure RA flare. Patient and healthcare professional (HCP) qualitative studies, focus groups, and literature review, followed by patient and HCP Delphi exercises including combined Delphi consensus at Outcome Measures in Rheumatology 10 (OMERACT 10), identified potential domains to measure flare. At OMERACT 11, breakout groups discussed key domains and instruments to measure them, and proposed a research agenda. Patients were active research partners in all focus groups and domain identification activities. Processes for domain selection and patient partner involvement were case studies for OMERACT Filter 2.0 methodology. A pre-meeting combined Delphi exercise for defining flare identified 9 domains as important (> 70% consensus from patients or HCP). Four new patient-reported domains beyond those included in the RA disease activity core set were proposed for inclusion (fatigue, participation, stiffness, and self-management). The RA FG developed preliminary flare questions (PFQ) to measure domains. In combined plenary voting sessions, OMERACT 11 attendees endorsed the proposed RA core set to measure flare with ≥ 78% consensus and the addition of 3 additional domains to the research agenda for OMERACT 12. At OMERACT 11, a core domain set to measure RA flare was ratified and endorsed by attendees. Domain validation aligning with Filter 2.0 is ongoing in new randomized controlled clinical trials and longitudinal observational studies using existing and new instruments including a set of PFQ.
 
Article
This module reflected work within the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) to develop and validate composite disease activity measures in psoriatic arthritis (PsA). At the Outcome Measures in Rheumatology (OMERACT) 8 Meeting, a core set of domains to be assessed in randomized controlled trials (RCT) and longitudinal observational studies of PsA was agreed upon. At OMERACT 10, 5 proposed composite responder definitions for PsA were reviewed and discussed, including new data from the GRACE (GRAppa Composite Exercise) study. At OMERACT 11, ongoing retrospective analyses of RCT data using the 3 proposed measures (Composite Psoriatic Disease Activity Index, Psoriatic Arthritis Disease Activity Score, and Arithmetic Mean of the Desirability Function) were discussed in detail. There was agreement that developing composite outcome measures for use in RCT and longitudinal observational studies in PsA was important. Concerns were expressed regarding development of a single measure that encompassed diverse domains, such as joint counts, quality of life (QOL), and disability measures. It was emphasized that the use of any composite measure should include the ability to differentiate between activity in individual domains, such as enthesitis or psoriasis, such that the effect of each could be assessed independently. It was also agreed that patients would be systematically involved in further development and refinement of composite measures. Future plans include qualitative work with patients to explore their experience of disease activity and statistical modeling to explore how each of the proposed measures will perform in different disease subgroups.
 
Article
In a study of 222 patients with vasculitis, we identified 11 who had an associated neoplasia. Seven had hematological neoplasia and 4 had solid malignant tumors. In 4 patients vasculitis gave the first evidence of the neoplasia or of its recurrence. Nine of our patients had cutaneous vasculitis. The other 2 had vasculitis involving the intestine and resulted in acute abdomens. These 2 patients needed prednisone treatment for the vasculitis. Neoplasia should be considered in patients with vasculitis without an apparent cause.
 
Characteristics of patients with RA who continued or dropped out. 
Crude attrition rates in various ARAMIS databanks sorted in ascending order. 
Length of followup and attrition rates of patients by calendar year of entering the study. 
Attrition rates and sociodemographic characteristics adjusted for center effects. 
Multivariate Weibull models of factors associated with attrition. 
Article
Patient dropout (attrition) can bias and threaten validity of databank-based studies. Although there are several databanks of rheumatoid arthritis (RA) in operation, this phenomenon has not been well studied. We studied the attrition patterns of patients with RA in 11 long-running databanks where patients were followed using semiannual Health Assessment Questionnaires. Attrition rates were calculated as the proportion of living patients who were in active followup at the cutoff date. Mantel-Haenszel methods and Weibull regression were used to model the relationship between attrition and age, sex, race, education, disease duration, functional disability, and other characteristics. Overall, 6346 patients with RA were recruited into the study cohorts and followed for 32,823 person-years with 65,649 observations. The crude attrition rate was 3.8% per cycle. Rates were lowest in community-based databanks. Smaller size of the centers, inner-city location, and university clinic settings were associated with worse attrition. In multivariable analyses, younger age, lower levels of education, and non-Caucasian race predicted attrition. Level of disability and disease duration were not associated with attrition. Conclusion. In terms of person-years of followup and observation-points, this may be the largest study on attrition to date. While it is possible to have very high overall retention rates, certain types of databanks (smaller, inner-city-based, and university-based) are more likely to be biased due to selective retention of older, more educated Caucasian patients.
 
Article
To summarize the work performed by the Outcome Measures in Rheumatology (OMERACT) Ultrasound (US) Task Force on the validity of different US measures in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) presented during the OMERACT 11 Workshop. The Task Force is an international group aiming to iteratively improve the role of US in arthritis clinical trials. Recently a major focus of the group has been the assessment of responsiveness of a person-level US synovitis score in RA: the US Global Synovitis Score (US-GLOSS) combines synovial hypertrophy and power Doppler signal in a composite score detected at joint level. Work has also commenced examining assessment of tenosynovitis in RA and the role of US in JIA. The US-GLOSS was tested in a large RA cohort treated with biologic therapy. It showed early signs of improvement in synovitis starting at Day 7 and increasing to Month 6, and demonstrated sensitivity to change of the proposed grading. Subsequent voting questions concerning the application of the US-GLOSS were endorsed by > 80% of OMERACT delegates. A standardized US scoring system for detecting and grading severity of RA tenosynovitis and tendon damage has been developed, and acceptable reliability data were presented from a series of exercises. A preliminary consensus definition of US synovitis in pediatric arthritis has been developed and requires further testing. At OMERACT 11, consensus was achieved on the application of the US-GLOSS for evaluating synovitis in RA; and work continues on development of RA tenosynovitis scales as well as in JIA synovitis.
 
Article
The Outcome Measures in Rheumatology (OMERACT) community strives to develop core outcome sets for rheumatologic conditions to specify, for each condition, the minimum set of outcomes necessary to provide consistent estimates of the benefits of an intervention. The original and successful OMERACT filter of "truth, discrimination, and feasibility" requires development and updating because of application to a widening range of conditions by an expanding group, particularly patients. It should more explicitly identify the relevant core outcomes that might be universal to all randomized controlled trials within rheumatology. Working from first principles, comparing proposals against actual procedures adopted by OMERACT working groups, and seeking a broad consensus over several major sessions at the OMERACT 11 meeting, a new version has emerged, OMERACT Filter 2.0, which will form the central theme of the intended OMERACT handbook and offers an approach to core outcome set development in many areas of healthcare.
 
Top-cited authors
Daniel Furst
  • University of California; University of Washington; University of Firenze(Italy) Los Angeles
Peter A Lachenbruch
  • Oregon State University
David Collier
Richard W Martin
  • Michigan State University
Thomas A Medsger, Jr.
  • University of Pittsburgh