Rheumatoid Arthritis: Griffiths B

Griffiths B, Situnayake RD, Clark B, Tennant A, Salmon M, Emery P. · Rheumatology and Rehabilitation Research Unit, University of Leeds, City Hospital, Dudley Road, Birmingham, University of Birmingham, UK. · Rheumatology (Oxford). · Pubmed #10952739 links to  free full text

Abstract: OBJECTIVE: There are a significant number of patients with rheumatoid arthritis (RA) of North Indian or Pakistani origin (Asian) now living in the UK. RA has been poorly studied in this racial group. The aim of this study was to compare RA in this Asian group with RA in the indigenous northern European (European) population. It was hypothesized that these two racial groups would have different disease expressions and immunogenetics that could be relevant to pathogenesis, prognosis and therapy. METHODS: One hundred and seven Asian RA patients, who fulfilled the 1987 American College of Rheumatology criteria, were stringently matched for age, sex and disease duration with 107 European RA patients, and were fully assessed. RESULTS: The Asian RA patients had significantly fewer bony erosions [median Larsen score 58.5 (interquartile range 45.5-77.8) vs 68 (52-93) for European patients; P: = 0.0066, Mann-Whitney U:-test] and rarely had nodules (5.7 vs 20%, P: = 0. 0019, Fisher's exact test). The two groups had the same prevalence of rheumatoid factor positivity, number of swollen joints and level of inflammation (C-reactive protein). The Asian RA patients had a reduced prevalence of the conserved third allelic hypervariable region (3AHVR) (45 vs 82%, P: < 0.0001, Fisher's exact test), particularly DRB1*0401 (4.5 vs 55%). However, the prevalence of the conserved 3AHVR was significantly increased in the Asian RA patients compared with Asian controls. By contrast, the Asian patients had more tender joints [13.5 (7-22) vs 5.5 (2-11.8); P: < 0.0001 Mann-Whitney U:-test]. The Health Assessment Questionnaire score was also significantly worse in the Asians compared with the Europeans [median 2.0 (1.13-2.63) vs 1.25 (0.5-2.13), P: = 0.0001). CONCLUSIONS: The Asian patients had similar levels of inflammation and less damage but more pain and disability than the matched European RA patients. Of the known prognostic factors for erosions (rheumatoid factor, conserved 3AHVR, swollen joints and C-reactive protein), only the conserved 3AHVR was reduced in the Asian RA patients, and this was consistent with their less erosive disease. These data also indicate the importance of pain as well as erosive damage in determining disability in Asian patients and stress the importance of adequate pain relief, in addition to disease suppression, when treating Asian RA patients.

Proudman SM, Conaghan PG, Richardson C, Griffiths B, Green MJ, McGonagle D, Wakefield RJ, Reece RJ, Miles S, Adebajo A, Gough A, Helliwell P, Martin M, Huston G, Pease C, Veale DJ, Isaacs J, van der Heijde DM, Emery P. · University of Leeds, UK. · Arthritis Rheum. · Pubmed #10943871 links to  free full text

Abstract: OBJECTIVE: To determine whether a regimen of methotrexate, cyclosporin A, and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis (RA) can produce a significant improvement in outcome compared with standard monotherapy with sulfasalazine (SSZ). METHODS: Eighty-two consecutive patients presenting with new, untreated RA of less than 12 months' duration who fulfilled criteria for poor long-term outcome were randomized to receive either combination therapy (n = 40) or SSZ alone (n = 42). The primary outcome measures were remission and American College of Rheumatology (ACR) criteria for 20% improvement at 48 weeks. RESULTS: After 48 weeks, the numbers of patients who met the ACR criteria for 20% improvement were not significantly different between the two groups (combination 58% versus SSZ 45%), and similar numbers of patients had persisting clinical remission (approximately 10% both groups). During the first 3 months, there were significantly greater reductions in parameters of disease activity in the combination group. By 24 weeks, the swollen and tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates had fallen significantly in both groups, with a greater improvement in the swollen and tender joint count in the combination group. At 48 weeks, the radiographic damage score had increased by a median of 1 (range 0-42.5) in the combination group and 1.25 (range 0-72.5) in the SSZ group (P = 0.28; although there were significant differences in the scores for the right hand). There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group (1 of 40 versus 10 of 42; P = 0.007). In the combination group, dose reduction was needed in 22.5% because of hypertension and in 22.5% because of elevated creatinine levels. Over 48 weeks, serum creatinine increased in both groups, but particularly in the combination arm. CONCLUSION: In poor-prognosis RA patients, "aggressive" combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates. This suggests that in poor-prognosis disease, an approach based on identifying patients with poor treatment responses before extra therapy is added ("step-up" approach) may be more appropriate than the use of combination therapy in all patients from the outset.

Morgan AW, Barrett JH, Griffiths B, Subramanian D, Robinson JI, Keyte VH, Ali M, Jones EA, Old RW, Ponchel F, Boylston AW, Situnayake RD, Markham AF, Emery P, Isaacs JD. · Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK. · Arthritis Res Ther. · Pubmed #16356189 links to  free full text

Abstract: The Fcgamma receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A-FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13-8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44-17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.

Lawson CA, Donaldson IJ, Bowman SJ, Shefta J, Morgan AW, Gough A, Isaacs JD, Griffiths B, Emery P, Pease CT, Boylston AW. · Molecular Medicine Unit, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #15708895 links to  free full text

Abstract: OBJECTIVE: To analyse T cell receptor beta variable (TCRBV) gene polymorphisms (insertion/deletion related polymorphism (IDRP) and BV6S7) in primary Sjögren's syndrome (PSS). METHODS: Genomic DNA was extracted from blood samples from patients fulfilling the modified European criteria for PSS (n = 61). Healthy control blood samples were obtained from the Blood Transfusion Service (n = 121). As a disease control group, samples from patients with systemic lupus erythematosus (n = 42) were analysed. BV6S7 was genotyped using an established PCR/RFLP method. The IDRP was determined by comparison of the intensity of PCR product bands from within BV9S2 and an internal control region (BV9S1), to ascertain whether 0, 1, or 2 copies of the insertion were present. RESULTS: There was a decrease (p = 0.018) in the proportion of PSS patients with the deleted/deleted genotype. There was no association with specific BV6S7 alleles or genotypes with either the PSS group or the hypergammaglobulinaemic subgroup. There were no significant differences in haplotype frequencies after Bonferroni correction. CONCLUSIONS: A reduced proportion of patients with PSS have the deleted/deleted genotype. Eighty nine per cent of PSS patients have at least one extra germline copy of BV13S2*1. This may relate to previous observations of increased BV13 specific T cells and mRNA in the salivary glands.

Küçükdeveci AA, Sahin H, Ataman S, Griffiths B, Tennant A. · Ankara University, Ankara, Turkey. · Arthritis Rheum. · Pubmed #14872450 links to  free full text

Abstract: OBJECTIVE: Guidelines have been established for cross-cultural adaptation of outcome measures. However, invariance across cultures must also be demonstrated through analysis of Differential Item Functioning (DIF). This is tested in the context of a Turkish adaptation of the Health Assessment Questionnaire (HAQ). METHODS: Internal construct validity of the adapted HAQ is assessed by Rasch analysis; reliability, by internal consistency and the intraclass correlation coefficient; external construct validity, by association with impairments and American College of Rheumatology functional stages. Cross-cultural validity is tested through DIF by comparison with data from the UK version of the HAQ. RESULTS: The adapted version of the HAQ demonstrated good internal construct validity through fit of the data to the Rasch model (mean item fit 0.205; SD 0.998). Reliability was excellent (alpha = 0.97) and external construct validity was confirmed by expected associations. DIF for culture was found in only 1 item. CONCLUSIONS: Cross-cultural validity was found to be sufficient for use in international studies between the UK and Turkey. Future adaptation of instruments should include analysis of DIF at the field testing stage in the adaptation process.

Bruynesteyn K, Van Der Heijde D, Boers M, Saudan A, Peloso P, Paulus H, Houben H, Griffiths B, Edmonds J, Bresnihan B, Boonen A, Van Der Linden S. · Division of Rheumatology, Maastricht University, Maastricht, The Netherlands. · J Rheumatol. · Pubmed #12415585 No free full text.

Abstract: OBJECTIVE: To evaluate whether knowledge of the chronological sequence influences the sensitivity and specificity of the Sharp/van der Heijde (SvH) and Larsen/Scott (LS) scoring method to detect clinically important progression of joint damage caused by rheumatoid arthritis (RA) in the individual patient and assess whether scoring in chronological order leads to better sensitivity at the cost of lower specificity. METHODS: For both scoring methods, progression scores obtained with (chronological) and without knowledge of the sequence of the films (paired) were compared with the judgment of an international expert panel. This panel assessed whether progression of joint damage seen on films with 1 year intervals was clinically relevant (defined as progression of joint damage that would make clinicians change therapy). The applied thresholds for clinical relevance were (1) the progression scores with the highest accuracy by receiver operating characteristics analyses for the expert opinion, and (2) the smallest progression score that can be detected apart from interobserver measurement error by the scoring method, i.e., the smallest detectable difference (SDD). RESULTS: Progression scores that detected clinically relevant progression most accurately (chronological: 3.0 SvH units and 2.0 LS units; paired: 2.5 SvH units and 1.5 LS units) were smaller than the SDD (chronological 5.0 SvH units and 5.8 LS units; paired 13.8 SvH units and 9.7 LS units). With the SDD as threshold, the sensitivity to detect clinically relevant progression increased significantly from 20 to 60% for the SvH method and from 23 to 33% for the LS method if the sequence of the films was known. The specificity remained good when scoring chronologically: 88% for the SvH and 100% for the LS. CONCLUSION: Our results suggest that knowing the chronological sequence leads to an increase in detecting clinically relevant changes in the patient without serious overestimation of nonrelevant differences. Analyzing a clinical trial should be done preferably by reading films in chronological order.

Bruynesteyn K, van der Heijde D, Boers M, Saudan A, Peloso P, Paulus H, Houben H, Griffiths B, Edmonds J, Bresnihan B, Boonen A, van der Linden S. · Maastricht University, Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #11953967 No free full text.

Abstract: OBJECTIVE: To assess the minimal clinically important difference (MCID) in joint damage on hand and foot radiographs of patients with early rheumatoid arthritis (RA) as assessed with the Sharp/van der Heijde and Larsen/Scott methods, and to study how the smallest detectable difference (SDD) relates to the MCID for each method. METHODS: The judgments of an international panel of experts on the clinical relevance of progression of joint damage as seen on sets of radiographs obtained at 1-year intervals in 4 clinical settings (early versus late RA and mild versus high disease activity) were used as the external criterion, which was compared with the progression scores as determined by the 2 scoring methods. Progression scores with the highest combined sensitivity and specificity for detecting clinically relevant progression represented the MCID. Subsequently, the sensitivity and specificity of the scoring methods were determined when using the SDD as the threshold for relevant progression, and these were compared with the sensitivity and specificity of the MCID. RESULTS: The panel judged changes in joint damage around the level of the SDD (5.0) of the Sharp/van der Heijde method as minimal clinically important, resulting in satisfactory sensitivity (mean 79%) and specificity (mean 84%) for detecting clinically important progression in the 4 clinical settings when using the SDD as the threshold value. The MCID (mean 2.3) of the Larsen/Scott method was much smaller than its SDD (5.8), and the sensitivity for detecting clinically important progression by applying the SDD as threshold was consequently low (mean 51%), accompanied by high specificity (mean 99%). CONCLUSION: This study suggests that the SDD of the Sharp/van der Heijde method can be used as the MCID, i.e., as the threshold level for individual response criteria. The SDD of the Larsen/Scott method, however, turned out to be too insensitive to use as the threshold for individual clinically relevant change.

McKibbin M, Clark B, Isaacs JD, Morrell AJ, Griffiths B, Morgan AW, Gooi HC. · Department of Ophthalmology, St James's University Hospital, Leeds, UK. · Eye. · Pubmed #11767025 No free full text.

Abstract: PURPOSE: To investigate the role of the shared epitope alleles in determining susceptibility to and the phenotype of corneal melting in patients with rheumatoid arthritis (RA). METHODS: The HLA class 1 and 2 genotype was determined for 17 patients with rheumatoid-associated comeal melting by the phototyping method. HLA-DR4 subtyping was performed by PCR sequence-based typing. The frequency of all the shared epitope alleles and, in particular, of the higher-risk *0401 and *0404 alleles, was compared with healthy controls and unrelated RA patients, with and without extra-articular manifestations. A comparison was also made between the shared epitope genotype of the corneal melt patients and local, ocular disease characteristics. RESULTS: Thirteen (76%) patients with corneal melt possessed at least one shared epitope allele and 5 (29%) possessed two alleles. The dominant alleles were variants of the DR4 family, notably the *0401, *0404 and *0408 alleles. Both the allele frequency and a double dose of shared epitope alleles were more common in the three RA patient groups than in the healthy, control group (p < 0.005). Although the frequency of the higher-risk alleles was similar in the three RA patient group, a trend existed for a double dose of higher-risk alleles to be more common in the patients with either corneal melt or other extra-articular manifestations (p > 0.2). No association was found between the number or type of shared epitope alleles and any of the ocular disease characteristics studied. CONCLUSIONS: The results of this study suggest that the shared epitope alleles do not influence the ocular disease phenotype of corneal melt in RA patients. Shared epitope determination of RA patients may help to identify those susceptible to either corneal melt or other extra-articular disease. RA patients with a double dose of higher-risk alleles may have an increased risk of corneal melt.

Morgan AW, Griffiths B, Ponchel F, Montague BM, Ali M, Gardner PP, Gooi HC, Situnayake RD, Markham AF, Emery P, Isaacs JD. · University of Leeds, UK. · Arthritis Rheum. · Pubmed #11037893 links to  free full text

Abstract: OBJECTIVE: To investigate a possible association between a functional polymorphism in the intermediate-affinity receptor for IgG called Fc-gamma receptor type IIIA (FcgammaRIIIA [CD16]) and rheumatoid arthritis (RA). METHODS: This was an allelic association study in which a single nucleotide polymorphism in FcgammaRIIIA was examined as a susceptibility and/or severity factor for RA. The FcgammaRIIIA-158V/F polymorphism was genotyped by direct sequencing in 2 well-characterized ethnic groups, UK Caucasians (141 RA patients and 124 controls) and North Indians and Pakistanis (108 RA patients and 113 controls). RESULTS: The FcgammaRIIIA-158V/F polymorphism was associated with RA in both ethnic groups (P = 0.028 for UK Caucasians, P = 0.050 for North Indians and Pakistanis, and P = 0.003 for both groups combined). FcgammaRIIIA-158VF and -158W individuals had an increased risk of developing RA in both populations (UK Caucasians odds ratio [OR] 1.6, P = 0.050; North Indians and Pakistanis OR 1.9, P = 0.023; and combined groups OR 1.7, P = 0.003). In the UK Caucasian group, the highest risk was for nodular RA, a more severe disease subset, associated with homozygosity for the FcgammaRIIIA-158V allele (OR 4.4, P = 0.004). There was also evidence for an interaction between the RA-associated HLA-DRB1 allele and the presence of at least 1 FcgammaRIIIA-158V allele in predicting susceptibility to RA (OR 5.5, P = 0.000). CONCLUSION: We have demonstrated that the FcgammaRIIIA-158V/F polymorphism is a susceptibility and/or severity marker for RA in 2 distinct ethnic groups. This finding may ultimately provide additional insights into the pathogenesis of RA and other autoantibody/immune complex-driven autoimmune diseases.

Kirby A, Kumar N, Saravanan V, Griffiths B, Mitchison H. · No affiliation provided · Rheumatology (Oxford). · Pubmed #18413344 No free full text.

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Raftery G, Griffiths B, Kay L, Kane D. · No affiliation provided · Rheumatology (Oxford). · Pubmed #17567635 links to  free full text

This publication has no abstract.