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Objectives. Strong genetic association of rheumatoid arthritis (RA) with PADI4 (peptidyl arginine deiminase) has previously been described in Japanese, although this was not confirmed in a subsequent study in the UK. We therefore undertook a further study of genetic association between PADI4 and RA in UK Caucasians and also studied expression of PADI4 in the peripheral blood of patients with RA.Methods. Seven single-nucleotide polymorphisms (SNP) were genotyped using polymerase chain reaction (PCR)–restriction fragment length polymorphism in 111 RA cases and controls. A marker significantly associated with RA (PADI4_100, rs#2240339) in this first data set (P = 0.03) was then tested for association in a larger group of 439 RA patients and 428 controls. PADI4 transcription was also assessed by real-time quantitative PCR using RNA extracted from peripheral blood mononuclear cells from 13 RA patients and 11 healthy controls.Results. A single SNP was weakly associated with RA (P = 0.03) in the initial case–control study, a single SNP (PADI4_100) and a two marker haplotype of that SNP and the neighbouring SNP (PADI4_104) were significantly associated with RA (P = 0.02 and P = 0.03 respectively). PADI4_100 was not associated with RA in a second sample set. PADI4 expression was four times greater in cases than controls (P = 0.004), but expression levels did not correlate with the levels of markers of inflammation.Conclusion. PADI4 is significantly overexpressed in the blood of RA patients but genetic variation within PADI4 is not a major risk factor for RA in Caucasians.

Objectives. To examine the relationship between the severity of nail disease and characteristics of psoriatic arthritis (PsA). We also wished to assess the clinical management of nail disease in patients with PsA.Methods. We studied 69 patients with PsA at two visits. On the first visit, a rheumatology assessment of joint, skin and nail disease was made. On the second visit, a detailed dermatology assessment of skin and nails was made. Nail disease was analysed using a 20-nail psoriasis nail severity score (PNSS).Results..There were 57 (83%) patients with clinical evidence of psoriatic nail disease. Although 66 (96%) patients had been treated for skin disease, only one (1%) had received any treatment for nail disease. Severe nail disease measured by the PNSS correlated with severe skin psoriasis as indicated by the percentage of body surface area affected by psoriasis (r = 0.34, P = 0.004) and physician global assessment of psoriasis (r = 0.45, P<0.001). Patients with distal interphalangeal (DIP) joint disease had higher PNSS scores (P = 0.03). The PNSS was also associated with unremitting and progressive arthritis (P<0.001), and correlated with Stanford health assessment questionnaire (HAQ) (r = 0.34, P = 0.004), depression (r = 0.39, P<0.001) and anxiety (r = 0.34, P = 0.004) scores. Compared with dermatology assessment, the rheumatology examination of nail disease had a positive predictive value of 84% and negative predictive value of 83%.Conclusions. In patients with PsA, the severity of nail disease correlates with indicators of severity of both skin and joint disease. Although rheumatologists can adequately screen for nail disease, the management of this aspect of PsA is often overlooked.

Objectives. To determine whether genetic polymorphisms in or near the transforming growth factor β1 (TGFB1) locus were associated with susceptibility to or severity of ankylosing spondylitis (AS).Methods. Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index).Results. A weak association was noted between the rare TGFB1 +1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/+915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent–case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers.Conclusion. This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.

Objective. To determine the frequency and clinical predictors of sacroiliitis diagnosed by magnetic resonance imaging (MRI) in a psoriatic arthritis (PsA) population.Methods. The studied comprised 103 patients with PsA. A careful clinical assessment for sacroiliitis was made from history and examination, and HLA-B27 testing was performed. Sixty-eight patients underwent tilted coronal fat-saturated T1-weighted and STIR MRI of the sacroiliac joints.Results. Clinical features of moderate or severe sacroiliitis were found in 24/68 (35%) patients. MRI features of sacroiliitis were found in 26/68 (38%) patients. Clinical features of sacroiliitis were present in 14/42 (33%) with normal MRI scans and 10/26 (38%) with abnormal scans (normal vs abnormal scans, P = 0.7). The presence of sacroiliitis on MRI was associated with restricted spinal movements (P = 0.004) and the duration of PsA (P = 0.04). There was no correlation between HLA-B27 and sacroiliitis diagnosed by MRI.Conclusion. Sacroiliitis diagnosed by MRI occurs commonly in PsA but is difficult to detect clinically.

Background. Rheumatoid arthritis (RA) is strongly associated with a series of HLA‐DRB1 alleles that encode a conserved sequence of amino acids (70Q/R K/R R A A74) in the DRβ1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE‐negative. Exposure to these alleles as non‐inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA.Methods. One hundred families, including the RA proband and both parents, were recruited. HLA‐DRB1 genotyping was performed using an allele‐specific polymerase chain reaction by standard methods. The frequencies of NIMA and non‐inherited paternal antigens (NIPA) were compared using contingency tables and a two‐tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined dataResults. We identified 36 families in which the proband was DRB1*04‐negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non‐inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non‐inherited SE allele (P=0.03).Conclusion. A role for HLA NIMA in RA is suggested by these results.

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda  1.6) at the TCRA/D locus was excluded (LOD score &lt; -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.

&lt;it>Objectives&lt;/it>. To confirm the association of a functional single-nucleotide polymorphism (SNP), C1858T (rs2476601), in the &lt;it>PTPN22&lt;/it> gene of British Caucasian rheumatoid arthritis (RA) patients and to evaluate its influence on the RA phenotype. &lt;it>Methods&lt;/it>. A total of 686 RA patients and 566 healthy volunteers, all of British Caucasian origin, were genotyped for C1858T polymorphism by PCR–restriction fragment length polymorphism assay. Data were analysed using SPSS software and the χ2 test as applicable. &lt;it>Results&lt;/it>. The &lt;it>PTPN22&lt;/it> 1858T risk allele was more prevalent in the RA patients (13.9&percnt;) compared with the healthy controls (10.3&percnt;) (&lt;it>P&lt;/it>&equals;0.008, odds ratio 1.4, 95&percnt; confidence interval 1.09–1.79). The association of the T allele was restricted to those with rheumatoid factor (RF)-positive disease (&lt;it>n&lt;/it>&equals;524, 76.4&percnt;) (&lt;it>P&lt;/it>&equals;0.004, odds ratio 1.5, 95&percnt; confidence interval 1.1–1.9). We found no association between &lt;it>PTPN22&lt;/it> and the presence of the HLA-DRB1 shared epitope or clinical characteristics. &lt;it>Conclusions&lt;/it>. We confirmed the previously reported association of &lt;it>PTPN22&lt;/it> with RF-positive RA, which was independent from the HLA-DRB1 genotype.

&lt;it>Objective&lt;/it>. To identify HLA class II associations with anti &lt;it>β&lt;/it>&lt;inf>2&lt;/inf>&hyphen;glycoprotein I &lpar;&lt;it>β&lt;/it>2GPI&rpar; antibodies in a cohort of Caucasian patients with systemic lupus erythematosus &lpar;SLE&rpar; and to determine whether these &lt;it>HLA&lt;/it> genotypes act as restriction elements for lymphocyte proliferation to native human &lt;it>β&lt;/it>2GPI &lt;it>in vitro&lt;/it>. &lt;it>Methods&lt;/it>. Anti&hyphen;&lt;it>β&lt;/it>2GPI antibodies were detected in patient sera using enzyme&hyphen;linked immunosorbent assays &lpar;ELISAs&rpar;. &lt;it>HLA&lt;/it> class II alleles &lpar;&lt;it>DRB1&lt;/it>, &lt;it>DQB1&lt;/it>&rpar; were determined by polymerase chain reaction&hyphen;based DNA genotyping. &lt;it>In vitro&lt;/it> peripheral blood mononuclear cell &lpar;PBMC&rpar; responses to native human &lt;it>β&lt;/it>2GPI were measured in a 7&hyphen;day proliferation assay. &lt;it>Results&lt;/it>. We identified three groups of Caucasian SLE patients using these ELISAs. In group 1, 16 out of 18 SLE patients &lpar;89&percnt;&rpar; with anti&hyphen;&lt;it>β&lt;/it>2GPI antibodies were positive for HLA&hyphen;DRB1*0401&sol;4&sol;8, DR11 or DRB1*1302 &lpar;&lt;it>P&lt;/it>&equals;0.001 &lt;it>vs&lt;/it> controls&rpar; compared with 23 out of 53 patients &lpar;43&percnt;&rpar; in group 2 with anti&hyphen;cardiolipin antibodies only, 57 out of 151 patients &lpar;38&percnt;&rpar; in group 3 &lpar;SLE patients without anticardiolipin antibodies&rpar; and 109 out of 225 controls &lpar;48&percnt;&rpar;. Fourteen patients with anti&hyphen;&lt;it>β&lt;/it>2GPI antibodies had greater median stimulation indices to &lt;it>β&lt;/it>2GPI &lt;it>in vitro&lt;/it> compared with the 15 controls studied &lpar;&lt;it>P&lt;/it>&equals;0.04&rpar;. &lt;it>Conclusion&lt;/it>. The &lt;it>HLA&lt;/it> class II and PBMC proliferation data suggest that &lt;it>β&lt;/it>2GPI may be both a T&hyphen; and B&hyphen;cell autoantigen in SLE.