Finnish case-control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis

Several studies have identified the PTPN22 allelic variant 1858 C/T that encodes the R620W amino-acid change as a putative susceptibility factor in autoimmune diseases. The current study was undertaken to examine a large cohort of Finnish rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) subjects using both population control and, importantly, family-based association methods. The latter is particularly important when, as is the case for the 1858 C/T polymorphism, the frequency of the variant allele (T) differs in both major ancestral populations and in subpopulations. The analysis of rheumatoid factor-positive 1030 RA probands from Finland provides strong support for association of this variant in both population studies (allele specific odds ratio (OR)=1.47, 95% confidence interval (CI)=1.27-1.70, P=3 x 10(-7)) and in family studies (P<10(-6)). In contrast, no allelic association was seen with JIA (230 probands) and only weak evidence for a genotypic effect of 1858T homozygotes was observed in this population.     

Prediction of disease progression in early rheumatoid arthritis by ICTP, RF and CRP. A comparative 3-year follow-up study

OBJECTIVE: To test the predictive value of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP; a marker of type I collagen degradation), rheumatoid factor (RF) and C-reactive protein (CRP) for disease progression in patients with early rheumatoid arthritis (RA) METHOD: We tested the value of baseline values of RF, CRP and ICTP for the prediction of radiological joint progression over 3 yr in 63 consecutive patients with early RA who were treated with the 'saw-tooth strategy'. RESULTS: Age- and sex-adjusted risks as odds ratios (95% confidence intervals) of elevated serum ICTP, RF positivity and increased CRP for progressive joint disease (defined as an increase of > 20 in Larsen's index on radiographs of the hands and feet) were 3.9 (1.3, 11.9), 3.9 (1.0, 15.5) and 2.6 (0.9, 7.5), respectively. Better prediction was achieved when the tests were used in combination, and where there was both elevated ICTP and positive RF the odds ratio was 9.1 (2.5, 32.9). This test combination showed good sensitivity and specificity (71 and 77%, respectively), with a positive predictive value of 65% and a likelihood ratio of 3.1. CONCLUSION: This kind of risk profile, in which the tests used reflect different aspects of the disease process, may be useful in early disease assessment to find patients who will need the most active drug therapy.     

Osteonecrosis in children treated for acute lymphoblastic leukemia

The purpose of the study was to find out the prevalence of osteonecrosis in children with acute lymphoblastic leukemia (ALL) in complete bone marrow remission at the end of the treatment. Twenty-eight children with ALL underwent MRI of the upper and/or lower extremities. Bone marrow signal intensity was analyzed on T1-weighted images, where cir-cumscribed lesions with a rim of low signal intensity were considered typical of osteonecrosis. Osteonecrosis was found in 9 of the 28 children (32%, 95% CI 16% to 52%). Five of them were asymptomatic. They had been treated with high risk and intermediate risk protocols, both of which include a delayed intensification phase with dexamethasone. None of the patients with standard risk ALL were found to have developed osteonecrosis. Osteonecroses occurred unexpectedly in symptomless patients and in patients with mild transient symptoms treated with high risk and intermediate risk protocols. Our study suggests that the intensification phase of the treatment protocols with intensive dexamethasone medication might be responsible for the development of osteonecrosis. Med. Pediatr. Oncol. 29:260–265, 1997. © 1997 Wiley-Liss, Inc.     

Influence of antineoplastic therapy on function of the masticatory system,tooth development,and cariogenic status: A case report

Antineoplastic therapy causes developmental disturbances in the dental enamel and root if children are treated during tooth development. Increased caries activity has also been reported. The effect of anticancer therapy on the function of the masticatory system (i.e., jaws, dentition, masticatory muscles) is not well known. A case report of a 9-year-old girl with right auricular rhabdomyosarcoma is presented. She received irradiation of 50 Gy to the right auricular area and chemotherapy. A year and a half after cessation of cancer therapy, she was disease free and the clinical stomatognathic examination combined with electromyogram (EMG) registration of the masseter and temporal muscles and magnetic resonance imaging (MRI) examination of the temporomandibular joints (TMJ) revealed a strongly restricted mouth opening capacity, painful right TMJ, and flattened head of the right mandibular condyle. Muscle atrophy in the right masseter muscle was clearly visible but EMG activities of the masseter and temporal muscles, however, were higher on the right than on the left. More severe developmental defects, and worse gingival and cariological health were observed on the right side than on the left side. She developed 12 carious lesions and all the lesions were on the right maxilla or mandible or on anterior teeth. The left side was not affected. Intensive prophylactic dental care after cancer treatment is important in order to prevent caries and gingival inflammation. Stomatognathic treatment (i.e., management of occlusal and dysfunctional problems) may improve the mouth opening capacity and relieve pain. © 1996 Wiley-Liss, Inc.     

Inadequately low serum levels of steroid hormones in relation to interleukin‐6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis

Objective

To compare levels of steroid hormones in relation to cytokines and to study levels of cortisol or dehydroepiandrosterone (DHEA) in relation to other adrenal hormones in untreated patients with early rheumatoid arthritis (RA) and reactive arthritis (ReA) compared with healthy controls.

Methods

In a retrospective study with 34 RA patients, 46 ReA patients, and 112 healthy subjects, we measured serum levels of interleukin‐6 (IL‐6), tumor necrosis factor (TNF), adrenocorticotropic hormone (ACTH), cortisol, 17‐hydroxyprogesterone (17‐OH‐progesterone), androstenedione (ASD), DHEA, and DHEA sulfate (DHEAS).

Results

RA patients had higher serum levels of IL‐6, TNF, cortisol, and DHEA compared with ReA patients and healthy subjects, but no difference was noticed with respect to ACTH and DHEAS. However, in RA and ReA patients compared with healthy subjects, levels of ACTH, cortisol, ASD, DHEAS, and 17‐OH‐progesterone were markedly lower in relation to levels of IL‐6 and TNF. Furthermore, the number of swollen joints correlated inversely with the ratio of serum cortisol to serum IL‐6 in RA (R_Rank = −0.582, P = 0.001) and, to a lesser extent, in ReA (R_Rank = −0.417, P = 0.011). In RA patients, the mean grip strength of both hands was positively correlated with the ratio of serum cortisol to serum IL‐6 (R_Rank = 0.472, P = 0.010). Furthermore, in these untreated patients with RA and ReA, there was a relative decrease in the secretion of 17‐OH‐progesterone, ASD, and DHEAS in relation to DHEA and cortisol. This indicates a relative predominance of the nonsulfated DHEA and cortisol in relation to all other measured adrenal steroid hormones in the early stages of these inflammatory diseases.

Conclusion

This study indicates that levels of ACTH and cortisol are relatively low in relation to levels of IL‐6 and TNF in untreated patients with early RA and ReA compared with healthy subjects. The study further demonstrates that there is a relative increase of DHEA and cortisol in relation to other adrenal hormones, such as DHEAS. This study emphasizes that adrenal steroid secretion is inadequately low in relation to inflammation. Although changes in hormone levels are similar in RA and ReA, alteration of steroidogenesis is more pronounced in RA patients than in ReA patients.

     

Ultrasonography in the quantification of arterial involvement in Takayasu's arteritis

OBJECTIVE: To evaluate the accuracy of ultrasonography (US) in the detection and quantification of arterial involvement in Takayasu's arteritis (TA). METHODS: The common carotid and subclavian arteries, and the abdominal aorta of 15 patients with TA were studied by Color Doppler (CD) US and Doppler spectral analysis and compared with angiography. RESULTS: The mean difference (+/-SD) between the percent luminal stenoses measured at angiography and by CD US was 2.0+/-10.3% for the common carotid artery, 4.0+/-23.6% for the subclavian artery and -1.3+/-16.8% for the abdominal aorta. The differences were not statistically significant. However, the agreement of the methods was less than satisfactory as shown by the wide standard deviations. CONCLUSIONS: More efforts are needed to improve the less than optimal agreement of US with angiography regarding the severity of individual stenoses. The technique performs best in the study of carotid arteries.     

Orthodontic treatment need from eight to 12 years of age in an early treatment oriented public health care system: a prospective study

The aim of this study was to investigate the effects of an early treatment oriented orthodontic program on treatment need at age 12 years in a public health care system. The subjects consisted of one whole age cohort in a municipality in Finland, 87 children in total. All children were examined at ages eight, 10, and 12 years. Treatment need was assessed on casts using a modified Dental Health Component of the Index of Orthodontic Treatment Need and a 10-Grade Scale based on the Treatment Priority Index. Early treatment was started on children having definite treatment need according to both indices. The agreement between indices was good at ages eight and 12 years and moderate at age 10 years. Treatment need changed significantly from eight to 12 years. Of the 29 children with definite treatment need at age eight years, only two had treatment need at age 12 years. Of the 38 children with no treatment need at age eight years, 28 remained in this category and only two children had definite need for treatment at age 12 years. The duration of treatment ranged from one to 61 months, although 59% of the treatments lasted two years or less. We conclude that systematically planned early orthodontic treatment may have contributed to the significant reduction in treatment need from eight to 12 years of age.     

HLA-DRB1, TAP2/TAP1, and HLA-DPB1 haplotypes in Finnish juvenile idiopathic arthritis: more complexity within the MHC

This study further defines genetic susceptibility to JIA in the region centromeric to HLA-DRB1. DNA from 234 Finnish JIA nuclear families and 639 elderly Finnish control individuals was genotyped for five functional SNPs within the TAP2 and TAP1 loci ( approximately 200 kb centromeric of HLA-DRB1). Subsets of the controls (186) and patients (145) that had been previously typed for HLA-DRB1 were also genotyped by sequence for the HLA-DPB1 locus. Case/control and transmission disequilibrium test (TDT) methods revealed an association with the DPB1(*)030101 allele for JIA (OR 2.3, 95% CI 1.5-3.5). Notably, a detailed haplotypic analysis of the TAP2/TAP1 loci and their interaction with the HLA-DPB1(*)030101 and DRB1(*)08 and (*)11 alleles showed a variety of over-represented and under-represented TAP2/TAP1 haplotypes not evident in the single marker analysis. The strongest effect was observed in the polyarticular RF negative JIA subgroup for the 2-2-1-2-1 TAP2/TAP1 haplotype (TAP2B and TAP1A alleles) which showed an independent effect from both DRB1(*)08 and (*)11 (P<0.000003) and DPB1(*)030101 (P=0.02). We have provided evidence that the extended haplotypes (including HLA-DRB1, TAP2/TAP1, and HLA-DPB1) of pauciarticular and polyarticular RF negative disease are distinct. This observation may have implications for functional etiological differences between the pauciarticular and polyarticular JIA patients.     

Antibacterial and antipeptide antibodies in Japanese and Finnish patients with rheumatoid arthritis

It has been suggested that Proteus infection may be involved in the pathogenesis of rheumatoid arthritis (RA). Bacterial and peptide immune responses in patients with RA and other control subjects were investigated in two geographically different populations. Serum samples from Finnish patients with early (n=72) and advanced (n=27) RA and 30 Finnish healthy controls, as well as from Japanese RA patients from two different locations: Tokyo (n=30) and Otsu (n=30), 18 patients with systemic lupus erythematosus (SLE) and 23 Japanese healthy controls were all screened for the total, and class-specific (IgG, IgA and IgM) antibodies against Proteus mirabilis, Escherichia coli and Serratia marcescens by indirect immunofluorescence assay. These samples were also tested for the determination of levels of isotypic antibodies against the shared epitope involving 16-mer synthetic peptides containing the EQRRAA or ESSRAL sequences and compared to scrambled control peptide by using an enzyme-labeled immunosorbent assay method. Significantly elevated levels of IgG and IgM antibodies to P. mirabilis and antibodies against both EQRRAA and ESSRAL peptides were detected in sera of Finnish patients with early and advanced RA, and in Japanese patients from Otsu or Tokyo compared to their corresponding control groups. In contrast, no difference either in the total or in any of the isotypic antibodies were observed between these groups when serum samples were screened against each of E. coli and S. marcescens or against the control peptide. Furthermore, there was a significant correlation between the antibody levels against Proteus bacteria only and both EQRRAA and ESRRAL peptides. Our findings support the possibility for specific involvement of P. mirabilis in the etiopathogenesis of RA even in early cases.Abbreviations ELISA Enzyme linked immunosorbent assay - IIF Immunofluorescence - RA Rheumatoid arthritis - SLE Systemic lupus erythematosus