The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis.
OBJECTIVE: To investigate the relative contribution of HLA antigens in the susceptibility to psoriasis and to localize additional genetic factors involved in psoriatic arthritis (PsA). METHODS: DNA from 45 patients with psoriasis, 65 with PsA, and 177 healthy control subjects was examined by polymerase chain reaction (PCR) using sequence-specific oligonucleotide probes to determine HLA-C. To examine whether MICA (class I major histocompatibility complex chain-related gene A) confers additional susceptibility, trinucleotide repeat polymorphism in the transmembrane region of the MICA gene was investigated by radioactive PCR. Further analysis of MICA was made by PCR-single-strand conformational polymorphism to determine the allelic variant corresponding to MICA transmembrane polymorphism. RESULTS: Our results reveal new findings: 1) the frequency of the Cw*0602 allele was significantly increased in both patient groups: psoriasis (corrected P [Pcorr] < 10(-5), relative risk [RR] 6.2), PsA (Pcorr < 10(-6), RR 6.3), 2) the trinucleotide repeat polymorphism MICA-A9 was present at a significantly higher frequency in PsA patients (Pcorr < 0.00035, RR 3.2), whereas a similar distribution was found in both the control and psoriasis population, 3) this polymorphism corresponds to the MICA-002 allele and was found to be overrepresented in patients with the polyarticular form (Pcorr < 0.0008, RR 9.35), 4) the increase in MICA-A9 in PsA patients is independent of linkage disequilibrium with Cw*0602, 5) this allele confers additional relative risk (RR 3.27, etiologic fraction 0.44; etiologic fraction is the proportion of disease cases among the total population that are attributable to 1 allele when the relative risk is > 1) in PsA patients who carry Cw*0602. CONCLUSION: The data obtained in this study are consistent with the polygenic inheritance of psoriasis. Cw*0602 appears to be the stronger genetic susceptibility factor for psoriasis. Independent of the HLA-C association, MICA-A9 polymorphism corresponding to the MICA-002 allele is a possible candidate gene for the development of PsA. (+info)
Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patients with early inflammatory arthritis.
OBJECTIVE: To examine the expression of the matrix metalloproteinase, MMP-1, and the cysteine proteases, cathepsin B (CB) and cathepsin L (CL), in the synovial membrane (SM) of patients with early inflammatory arthritis. METHODS: Samples of SM were obtained by blind needle biopsy or needle arthroscopy from inflamed knees of 28 patients with early inflammatory arthritis (mean disease duration 10.2 months, range 2 weeks-18 months). Sixteen patients had rheumatoid arthritis (RA), nine psoriatic arthritis and there was one each with ankylosing spondylitis, gout and an undifferentiated arthritis. Comparison was made with tissue from two patients with established erosive RA and three normal synovial tissue samples. In situ hybridization was performed using digoxigenin-labelled RNA probes. RESULTS: MMP-1, CB and CL were expressed in all patients with early arthritis and in established erosive RA, whereas normal synovium showed only scanty expression. The three proteases were prominent in perivascular infiltrates and endothelial cells of early arthritis tissue. MMP-1 was observed primarily in the lining layer, but was also evident in the sublining area. CB and CL were expressed to a lesser extent in the lining layer, and were present mainly in the subintima. The three proteases were not found in lymphoid aggregrates. No differences were observed between the disease categories. CONCLUSIONS: The detection of MMP-1, CB and CL in the synovium shortly after symptom onset implies that the potential for joint destruction exists at a very early stage in the disease. In addition, the perivascular and endothelial cell expression suggests a role for these proteases in mononuclear cell influx to the inflamed synovium and in angiogenesis. (+info)
Clinical and laboratory manifestations of elderly onset psoriatic arthritis: a comparison with younger onset disease.
OBJECTIVE: Although the influence of age on clinical and laboratory features has been widely demonstrated in many arthropathies, studies on elderly onset (> 60 years) psoriatic arthritis (EOPsA) are rare. This study compares manifestations at onset and two year outcome of EOPsA with those of younger onset PsA (YOPsA). PATIENTS AND METHODS: Sixty-six consecutive PsA patients with disease duration < 1 year, 16 EOPsA (> 60 years) and 50 YOPsA (< or = 60 years) were admitted to a prospective study. Clinical, laboratory, and radiographic assessment were carried out at admission and after two years. HLA class I and bone scintigraphy were also recorded. In 10 patients with EOPsA and 24 with YOPsA it was possible to obtain synovial fluid, which was subsequently analysed for local inflammatory indices, including interleukin (IL) 1 beta, IL6, and IL8. RESULTS: Presenting manifestations of EOPsA differed from YOPsA in number of active joints (mean (SD)) (12.2 (6.3) v 6.7 (4.6), p < 0.001), foot bone erosions (2.7 (1.2) v 1.1 (1.1), p < 0.001), erythrocyte sedimentation rate (64.2 (35.3) v 30.5 (30.0) mm 1st h, p < 0.001), C reactive protein (3.9 (2.0) v 1.3 (1.3) mg/dl, p < 0.001) and synovial fluid IL1 beta (8.0 (4.7) v 3.0 (3.0) pg/ml, p < 0.001) and IL6 (828.2 (492.6) v 469.3 (201.4) pg/ml, p < 0.005). No differences were found in the number of subjects with dactylitis, pitting oedema, HLA-B27, or signs of sacroiliac and sternoclavicular joint involvement at bone scintigraphy. After two years, progression was more evident in EOPsA than in YOPsA, as the number of new erosions in the hands and also the C reactive protein were higher in EOPsA patients. CONCLUSION: PsA has a more severe onset and a more destructive outcome in elderly people (onset > 60 years) than in younger subjects. This behaviour may be influenced by immune changes associated with aging, as suggested by the higher concentrations of IL1 beta and IL6 found in the synovial fluid of EOPsA than in YOPsA. (+info)
Excessive paternal transmission in psoriatic arthritis.
OBJECTIVE: The differential expression of a disease according to the sex of the disease-transmitting parent has been demonstrated in several autoimmune disorders. The purpose of the present study was to determine whether there are differences in the transmission and expression of psoriatic arthritis (PsA) that are dependent on the sex of the affected parent. METHODS: All probands (patients with PsA) were identified from among the patients attending the University of Toronto Psoriatic Arthritis Clinic. A self-reported family history of psoriasis or PsA was noted for each proband. Differences in parental and offspring transmission with respect to the proband were evaluated. In addition, the expression of PsA according to the sex of the affected parent was assessed at the time of the proband's presentation to the clinic. RESULTS: Ninety-five probands had affected parents: 62 (65%) had an affected father, and 33 (35%) had an affected mother. Thus, the proportion of paternal transmission (0.65) was significantly greater than was expected (0.5) (P = 0.001). Twelve of 74 offspring from male probands (16.2%) were affected with psoriasis or PsA, as compared with 9 of 108 offspring from female probands (8.3%) (P = 0.10). Probands whose fathers were affected had a higher frequency of skin lesions prior to arthritis (P = 0.047), an erythrocyte sedimentation rate > 15 mm/hour (P = 0.044), and a lower incidence of rheumatoid factor (P = 0.044). No differences were noted with respect to age at the onset of psoriasis or PsA, the severity of the PsA, or the frequency of HLA antigens. CONCLUSION: There appears to be excessive paternal transmission in PsA. Further clinical confirmation and elucidation of its genetic basis is warranted. (+info)
A comparative quantitative morphometric study of cell apoptosis in synovial membranes in psoriatic, reactive and rheumatoid arthritis.
OBJECTIVES: Inflammatory arthritides/synovitides such as psoriatic (PsA), reactive (ReA) and rheumatoid (RA) arthritis share numerous immunopathological features, but develop different patterns of joint involvement. To investigate whether distinctive cell apoptosis may play a role in this context, we have assessed synovial cell apoptosis in situ in PsA and ReA, and compared it with RA and 'non-inflammatory' controls. METHODS: TdT-mediated dUTP nick end-labelling (TUNEL) of DNA breaks complemented immunoperoxidase staining for CD68 or LCA as the specific cell markers. RESULTS: The proportion of apoptotic synovial lining cells was high in PsA, ReA and RA compared to values in controls (P < 0.05). No differences existed between these inflammatory arthritides in numbers or type of apoptotic lining cells. In RA, however, in contrast to PsA and ReA, apoptotic lining cells were clustered or, in a small subset of samples, were very low in number. Prominent apoptosis of inflammatory cells in the sublining in ReA has accounted for higher overall apoptotic cell numbers in synovial stroma (sublining + perivascular inflammatory cell infiltrates) in this condition than in RA or PsA (P < 0.05). CONCLUSIONS: No disease-specific pattern in the phenotype of apoptotic synovial lining cells could be suggested in any of the inflammatory arthritides studied. However, topological differences in the lining and quantitative differences in the inflammatory cell apoptosis in synovial stroma may in part explain the occurrence of the prominent synovial lining cell hyperplasia distinguishing RA from ReA and PsA. On the other hand, relatively frequent inflammatory cell apoptosis may contribute both to the downregulation of synovial inflammation and to the control of synovial lining hyperplasia in ReA. (+info)
SAPHO syndrome or psoriatic arthritis? A familial case study.
OBJECTIVE: To discuss the relationships between SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome and the group of spondylarthropathies. METHODS: Few reports of familial SAPHO have been published. We describe three children, two sisters and one brother, whose clinical and radiological presentation was in accordance with SAPHO syndrome. RESULTS: Two children developed psoriasis, and one child palmoplantar pustulosis. Both sacroiliac and sternoclavicular joints were involved in these three cases. Some features in our observations are also common to psoriatic arthritis. No association was found with HLA antigens, but a history of trauma preceding the onset of symptoms was present in all three children. CONCLUSIONS: We can consider that SAPHO is nosologically related to spondylarthropathies. Psoriatic arthritis could be the missing link between SAPHO and spondylarthropathies. It is likely that both genetic and environmental factors are involved. (+info)
Chromosomal analysis of peripheral lymphocytes of patients before and after radiation synovectomy with samarium-153 particulate hydroxyapatite.
OBJECTIVE: Radiation synovectomy may be indicated for the treatment of chronic synovitis. A number of factors may affect its current use, including availability, limited evidence for its efficacy compared to intra-articular glucocorticoid, and concerns regarding the potential long-term effects of radiation exposure, particularly in younger patients. Specific chromosome-type abnormalities in peripheral lymphocytes can be useful indicators of whole-body radiation exposure. The frequency of these aberrations has been shown to increase in patients who have had radiation synovectomy using yttrium-90 by up to five times compared to baseline levels. Samarium-153 particulate hydroxyapatite (Sm-153 PHYP) is a new radiopharmaceutical currently on trial which appears to have less extra-articular leakage than yttrium-90 compounds. The aim of this study was to identify any increase in specific chromosome-type abnormalities, using published criteria, in patients following Sm-153 PHYP synovectomy of the knee. The 10 patients (five men, five women) in whom the analyses were performed had a mean age of 47 yr (range 28-70 yr). RESULTS: There was no increase in scored chromosome-type abnormalities after Sm-153 PHYP synovectomy. CONCLUSION: This study further supports the relative safety of Sm-153 PHYP compared to other radiopharmaceuticals. (+info)
Clinical, radiographic and HLA associations as markers for different patterns of psoriatic arthritis.
OBJECTIVE: The aim of this study was to examine whether the five clinical forms of psoriatic arthritis (PsA) identified by Moll and Wright (Semin Arthritis Rheum 1973;3:55-78) could be clearly distinguished, especially as the disease evolved over time, to analyse whether radiographic features or HLA associations could define subsets with greater precision and to identify predictors of disease outcome. METHODS: Seventy-three patients (37 males and 36 females) were followed for a median time of 8 yr (range 1-16 yr). A standard clinical protocol was used to assess patients at each visit and two clinical scores. based on the joint areas involved, were defined to evaluate the mode of onset and the evolution of arthritis. X-ray films of the hands, feet and sacroiliac joints were taken and the patients were divided into two categories according to the presence or absence of erosions and an X-ray erosion score was also used. Three classification methods were used to define the different clinical subsets. HLA-A, B and DR antigens were tested by standard microlymphocytotoxicity assays. A multiple linear regression model was used in the statistical analysis. RESULTS: The five classical clinical subsets defined by Moll and Wright did not remain since distinct peripheral arthritis patterns tended to evolve over time. Only two discrete groups were identified, axial disease (AD) (sacroilitis with or without peripheral arthritis) in 29% of cases and peripheral disease (PD) without sacroilitis in 71%. AD was positively associated with the duration of arthritis (P < 0.04), presence of mutilation (P < 0.02) and the joint area score over disease evolution (JASE) (P < 0.02). There were erosions in 71% of the patients. Erosions correlated with the presence of mutilation (P < 0.007) and with the JASE (P < 0.0005). HLA-B27 was found in 43% of patients with AD, but only in 11% of PD patients (P < 0.01). No other clear HLA correlations were found. CONCLUSIONS: Despite the relatively small number of patients, this longitudinal study suggests that only two clinical subsets can be clearly defined in PsA, AD and PD; these are primarily determined on clinical grounds although HLA-B27 is strongly associated with AD. The evolution of PD pattern with time means that narrower peripheral arthritis subsets are of little clinical use. (+info)