Analysis of SAA1 gene polymorphisms in the Greek population: rheumatoid arthritis and FMF patients relative to normal controls. Homogeneous distribution and low incidence of AA amyloidosis.

OBJECTIVE: To address whether or not the rarity of amyloidosis in Greek patients with rheumatoid arthritis (RA) is related to specific alleles of single nucleotide polymorphisms (SNPs) in the 5'-flanking region and the exon 3 of the SSA1 gene. METHODS: The genotypes of the -13T/C SNP in the 5'-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 88 Greek patients with RA, 14 patients with familial Mediterranean fever (FMF) and 110 healthy controls. Linkage disequilibrium and haplotype frequencies involving -13T/C, 2995C/T and 3010C/T in these populations were tested and estimated, respectively. RESULTS: The genotypic distribution and allelic frequencies were similar in all groups tested. SNPs 2995 and 3010 were in linkage disequilibrium for all study populations (p < 0.05), whereas SNP -13 was not in linkage disequilibrium with either 2995 or 3010 (p > or = 0.05). Two major haplotypes presented in all patients with RA and FMF and controls: -13C; 2995T; 3010C (-13C; alpha) and -13C; 2995C; 3010T (-13C; beta). The -13T allele was linked with the gamma haplotype in Greek patients with RA and controls. The frequency of the -13T allele was found to be very rare in all groups tested. CONCLUSIONS: In conclusion, the rarity of the putative amyloidogenic -13T allele in Greek populations may be related to low prevalence of AA amyloidosis development in Greek RA patients.     

SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis

To investigate the precise modality of association between SAA1 gene polymorphisms and the development of AA amyloidosis in patients with rheumatoid arthritis (RA), Japanese patients with RA (n = 153), among whom 29 were histologically diagnosed as having amyloidosis, were genotyped for three single nucleotide polymorphisms (SNPs), C-13T, C2995T, and C3010T, in the SAA gene. Pairwise linkage disequilibrium coefficients between each pair of SNPs were calculated and estimated haplotype frequencies were compared between patients with and without amyloidosis. Possible associations between these SNPs and amyloidosis were analyzed by a case–control study and by the Kaplan–Meier method, in which the endpoint was defined as the time of diagnosis of AA amyloidosis. The -13T and 2995C alleles, which were in a tight linkage disequilibrium, were more frequent in the patients with amyloidosis, and the groups with the -13TT and 2995CC genotype had worse survival curves than patients without these genotypes, whereas C3010T was not associated with amyloidosis. Moreover, the haplotype containing −13C and 2995T was found to be protective. Both C-13T and C2995T were associated with the development of amyloidosis. Examining both polymorphisms may be more useful than examining only one of them for estimating the risk of the development of amyloidosis.     

SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis

Abstract

To investigate the precise modality of association between SAA1 gene polymorphisms and the development of AA amyloidosis in patients with rheumatoid arthritis (RA), Japanese patients with RA (n = 153), among whom 29 were histologically diagnosed as having amyloidosis, were genotyped for three single nucleotide polymorphisms (SNPs), C-13T, C2995T, and C3010T, in the SAA gene. Pairwise linkage disequilibrium coefficients between each pair of SNPs were calculated and estimated haplotype frequencies were compared between patients with and without amyloidosis. Possible associations between these SNPs and amyloidosis were analyzed by a case–control study and by the Kaplan–Meier method, in which the endpoint was defined as the time of diagnosis of AA amyloidosis. The -13T and 2995C alleles, which were in a tight linkage disequilibrium, were more frequent in the patients with amyloidosis, and the groups with the -13TT and 2995CC genotype had worse survival curves than patients without these genotypes, whereas C3010T was not associated with amyloidosis. Moreover, the haplotype containing ?13C and 2995T was found to be protective. Both C-13T and C2995T were associated with the development of amyloidosis. Examining both polymorphisms may be more useful than examining only one of them for estimating the risk of the development of amyloidosis.     

Efficacy of cyclophosphamide combined with prednisolone in patients with AA amyloidosis secondary to rheumatoid arthritis

Secondary amyloid A (AA) amyloidosis is an uncommon yet important complication of rheumatoid arthritis (RA). It is one of the most relentless of the extra-articular features of RA, and suitable treatments have not yet been found. We studied the efficacy of cyclophosphamide (CYC) combined with prednisolone (PSL) in amyloidotic patients who had serum amyloid A (SAA) 1.3 genotype, which is a risk factor for secondary amyloidosis in Japanese RA patients. Fifteen RA patients who were SAA1.3 homo- and heterozygotes with biopsy-confirmed AA amyloidosis were treated with a combination of CYC and PSL. Laboratory variables of C-reactive protein (CRP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), serum albumin (Alb), serum creatinine (Cre) and Lansburys index were carried out by statistical analysis of changes between before and during the medication. According to the Mann–Whitney rank test, CRP, RF, ESR, Alb and Cre levels improved significantly with the combination treatment (p<0.05). Also, paired t-tests showed significance in Lansburys index between before and during the medication (p=0.007). CYC combined with PSL ameliorated not only laboratory markers but also clinical rheumatoid activity in patients with amyloidosis secondary to RA, whose genotypes were SAA1.3 homo- and heterozygous. CRP, ESR, RF, Alb and Cre will be surrogate markers of therapeutic efficacy. The combination of CYC and PSL appears to be beneficial for Japanese RA patients who are SAA1.3 homo- and heterozygous carriers, associated with secondary AA amyloidosis.Abbreviations AA Amyloid A - CRP C-reactive protein - Ccr Creatinine clearance - CYC Cyclophosphamide - DMARD Disease-modifying antirheumatic drugs - ESR Erythrocyte sedimentation rate - NSAID Non-steroidal anti-inflammatory drugs - PCR Polymerase chain reaction - PSL Prednisolone - RA Rheumatoid arthritis - RF Rheumatoid factor - SAA Serum amyloid A     

Clinical strategies for amyloid A amyloidosis secondary to rheumatoid arthritis

Secondary amyloid A (AA) amyloidosis is an important complication of rheumatoid arthritis (RA) and has remarkable variation in frequency worldwide. It is a serious, potentially life-threatening disorder caused by deposition in organs of AA fibrils, which are derived from the circulatory, acute-phase-reactant, serum amyloid A protein (SAA). The SAA1.3 allele can serve not only as a risk factor for the association of AA amyloidosis but also as a poor prognostic factor in Japanese RA patients. Both the association of AA amyloidosis arising early in RA disease course and symptomatic variety and severity were found in amyloidotic patients carrying the SAA1.3 allele. Etanercept for patients with AA amyloidosis who carry the SAA1.3 allele showed the amelioration of rheumatoid inflammation, including marked reduction of SAA and improvement of renal function. In light of the SAA1.3 allele significance in Japanese RA patients, both a tight control by disease-modifying antirheumatic drugs and an early intervention of biologics for RA inflammation should be applied to suppress acute-phase response, thus preventing the association of AA amyloidosis. It is suggested that SAA plays not only an important role in the development of AA amyloidosis but also interacts with events closely involved in metabolic syndrome as a high- and low-grade inflammatory modulator, respectively.     

A case of AA amyloidosis associated with rheumatoid arthritis effectively treated with Infliximab

We report the case of a 55-year-old Japanese woman with reactive AA amyloidosis associated with rheumatoid arthritis, in which inflammatory disease was completely suppressed with infliximab. Nephrotic syndrome was observed and renal biopsy specimens revealed amyloidosis deposits. Treatment with infliximab normalized the serum amyloid A (SAA) protein level, and subsequently nephritic syndrome disappeared and her creatinine clearance improved. Serial gastrointestinal biopsy specimens showed marked lasting regression of amyloid deposits. Thus treatment with infliximab represents an important therapeutic strategy for AA amyloidosis associated with RA.     

Only weak association between disease severity and HLA-DRB 1 genes in a Swiss population of rheumatoid arthritis patients

This study analyses the prognostic value of HLA-DRB 1 genes for Swiss patients with rheumatoid arthritis (RA). HLA-DRB 1 genotyping was performed in 83 patients using the polymerase chain reaction and subsequent oligonucleotide hybridisation. They were categorised according to the presence of one or two putatively relevant genes (DRB 1^*01 and/or DRB 1^*04) and retrospectively evaluated for sex, age at disease onset, seropositivity, erosive disease and extraarticular manifestations. Sixty-one patients (73%) had disease-associated alleles. Twenty-four patients showed HLA-DRB 1^*04 variants on both alleles or combined an HLA-DRB 1^*04 variant with HLA-DRB 1^*01, while 37 patients expressed only one relevant allele. Interestingly, 22 patients did not express any relevant allele. Some 52% of patients had nodular disease, 88% were seropositive, 96% had joint erosions and I I% expressed vasculitis and/or rheumatoid organ disease. A significant difference was observed only for the number of seropositive individuals, which was slightly higher in the group of patients expressing a double dose of disease-associated alleles than in patients who had no relevant alleles. Moreover, patients expressing homozygous DRB 1 alleles had a significantly earlier onset of disease than those who were heterozygous. We conclude from these findings that HLA-DRB 1 genotyping in a Swiss population of RA patients only weakly identifies clinical subsets with distinct profiles of disease manifestations and is not of strong prognostic value to determine disease severity in individual patients.     

The prevalence of subclinical amyloidosis in Polish patients with rheumatoid arthritis

The aims of this study were to determine the proportion of rheumatoid arthritis (RA) patients attending hospital in whom amyloid deposits were present in abdominal fat aspiration (AFA) samples, and to assess possible risk factors for amyloid development in RA. One -hundred and twenty-one patients (16 males, 105 females) with RA referred to the Department of Rheumatology in Wroclaw between 1996 and 2001 were studied regardless of RA duration or laboratory findings. Abdominal subcutaneous fine-needle aspiration was performed, and samples of adipose tissue stained with alkaline Congo red then examined by polarized light microscopy. The presence or absence of amyloid fat deposits (AFD) was determined according to whether typical apple-green birefringence was observed. Amyloid deposits were found in 35 (29%) patients. Amyloidosis was significantly more common in males and in patients with longer disease duration. Patients with AFD had previously undergone less treatment with disease-modifying antirheumatic drugs (DMARDs) than those without AFD, and significantly fewer patients with AFD had previously taken methotrexate than those without AFD (25% vs 45%; p<0.01). Renal involvement was found in 12 of 35 patients with AFD (34%). Using the AFA technique, amyloid deposits were found commonly in RA patients, particularly in males with longer disease duration and in patients not treated intensively with DMARDs, especially methotrexate. AFA has potential useful application as a method for detecting amyloidosis before the overt occurrence of renal or other pathology related to amyloid deposits.Abbreviations AFA Abdominal fat aspiration - AFD Amyloid fat deposits - DMARDs Disease-modifying antirheumatic drugs - RA Rheumatoid arthritis     

Tocilizumab-induced hyperbilirubinemia in Japanese patients with rheumatoid arthritis: its association with UDP glucuronosyltransferase 1A1 gene polymorphisms

Abstract

This study was performed to explore the possibility of an association between polymorphisms within the uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) and hyperbilirubinemia arising during tocilizumab therapy. We examined the distributions of 3 variant alleles, UGT1A1*6, *28, and *27, in 46 Japanese patients with rheumatoid arthritis (RA) who had received tocilizumab therapy for at least 24 weeks, grouped the patients according to their carriage status of these UGT1A1 variants, and determined the frequency of hyperbilirubinemia in each of the groups. Of the 46 patients treated with tocilizumab, 34 maintained normal bilirubin levels after 24 weeks, whereas the remaining 12 developed mild or moderate hyperbilirubinemia. Patients carrying 2 copies of UGT1A1*28 (*28/*28) were more likely to develop hyperbilirubinemia than those without UGT1A1*28. In addition, patients carrying 2 copies of variant alleles, either as homozygotes (UGT1A1*6/*6 or *28/*28) or as compound heterozygotes (UGT1A1*6/*28), were at higher risk of hyperbilirubinemia as compared with those without either UGT1A1*6 or UGT1A1*28 (odds ratio [OR] 28.33; 95% confidence interval [CI] 2.39–336.00; p = 0.005). Multivariate logistic regression analysis confirmed the strong association of tocilizumab-induced hyperbilirubinemia with the presence of 2 copies of variant alleles (OR 25.51; 95% CI 2.35–276.53; p = 0.008), yielding an area under the receiver operating characteristics curve of 0.78 (95% CI 0.60–0.95, p = 0.005). Tocilizumab can induce hyperbilirubinemia in RA patients, especially those carrying UGT1A1*6/*6, *6/*28, and *28/*28 genotypes. Considering this genetic association, it may be unnecessary to withdraw this drug from RA patients in the absence of other signs of hepatic injury. Given that tocilizumab has the potential to inhibit UGT1A1-mediated glucuronidation, however, it may inhibit not only bilirubin metabolism but also UGT1A1-dependent detoxification of drugs, thereby increasing the risk of unwanted adverse events during RA therapy.     

HLA-DRB1 alleles in Egyptian rheumatoid arthritis patients: Relations to anti-cyclic citrullinated peptide antibodies,disease activity and severity

BackgroundHuman leukocyte antigen HLA-DRB1 alleles encoding a common amino acid sequence called shared epitope in the third hypervariable region of DRB1 molecule have been identified as risk alleles for rheumatoid arthritis (RA).Aim of the workThe aim was to study HLA-DRB1 01, 04 and 10 alleles in Egyptian RA patients and determine their relation with anticyclic citrullinated peptide (anti-CCP) antibody level, disease activity, clinical and radiological severity.Patients and methodsThe study involved 40 RA patients and 20 control. Simplified disease activity index (SDAI) was calculated, clinical severity was assessed using the mechanical joint score (MJS) and radiological severity evaluated using the simple erosion narrowing score (SENS). HLA-DRB1 genotyping and anti-CCP antibodies were detected.ResultsThe mean patients’ age was 41.6 ± 12.7 years and disease duration 8.9 ± 7.7 years. The frequency of HLA DRB1 01, 04 and 10 in patients was 42.5%, 60% and 25% respectively. Of them 04 was significantly higher than in controls (p = 0.013) and was associated with anti-CCP positive cases (p = 0.0008) while the absence of HLA-DRB1 alleles was significantly associated with negative anti-CCP negative RA (p = 0.0008). There were significant associations between HLA-DRB1 01 and 04 with SDAI (p = 0.0002 and p = 0.005, respectively); between HLA-DRB1 04 and 10 with SENS (p = 0.002 and p = 0.001 respectively) and between HLA-DRB1 01, 04 and 10 with MJS (p = 0.02, p = 0.03 and p = 0.02, respectively).ConclusionHLA-DRB1 04 is associated with RA in Egyptian patients and is strongly associated in the production of elevated titers of anti-CCP antibodies which contribute to the development, severity and activity of the disease.     

Successful treatment of protein-losing enteropathy due to AA amyloidosis with octreotide in a patient with rheumatoid arthritis

Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. This excessive protein loss across the gut epithelium can be explained by several mechanisms, such as augmentation of the intestinal mucosal capillary permeability, mucosal disruption, intestinal or mesenteric vasculitis, and lymphangiectasia. However, these pathophysiologic alterations of the gut are closely linked to the underlying cause, and primary treatment for PLE should be directed at the underlying condition. Here, we report a female patient with rheumatoid arthritis who developed severe PLE due to AA amyloidosis and was successfully treated with octreotide. She had been suffered from rheumatoid arthritis for 18 years, and her arthritic symptoms at the time of presentation were not definite but manifested as severe diarrhea and general edema with hypoalbuminemia. PLE due to gastrointestinal amyloidosis was confirmed by increased fecal α₁-antitrypsin clearance and a colonoscopic biopsy that was positive for amyloid deposits. The diarrhea dissipated with conventional treatment, but the general edema resolved only after introducing a long-acting somatostatin analog (octreotide), along with a gradual recovery of the serum albumin level. This case teaches us that in the case of PLE due to AA amyloidosis that is refractory to conventional treatment, the administration of octreotide should be considered.     

Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis

The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues.

A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens.

In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log₁₀%amyloid). The results of sex-, age-, and Log₁₀%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group.

There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.     

Tumor necrosis factor-alpha and Interleukin-10 gene promoter polymorphisms in Turkish rheumatoid arthritis patients

Tumor necrosis factor and interleukin 10 have been implicated in the pathogenesis of rheumatoid arthritis (RA). Certain single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-10 and TNF genes have been associated with altered levels of circulating IL10 and TNF. We aimed to explore the association of IL-10 and TNF-alpha polymorphisms in Turkish RA patients. We analyzed the association of TNF-alpha (-308G/A, -238G/A, -376G/A) and IL10 (-1082G/A, -819C/T, -592C/A) polymorphisms in 98 Turkish patients with rheumatoid arthritis and 122 healthy subjects using ARMS-PCR. The correlation of these findings with RF positivity and erosive disease in RA patients was also sought. A significant association was found between having RA and -1082 G allele (p = 0.008; OR = 1.44, 95% CI 1.11-1.86). There was no association between RA and -819C/T polymorphism. Significant differences were observed in IL10 GCC and ACC haplotypes distribution between RA and control subjects (p = 0.006; OR = 1.46, 95% CI 1.13-1.89 and p = 0.011; OR = 1.43, 95% CI 1.09-1.88, respectively). No statistically significant association was found between TNF-alpha 308G/A, -238G/A, -376G/A polymorphisms and RA. No significant association was found between RF positivity and erosive disease and TNF-alpha, IL10 gene polymorphisms. In addition, when combined genotypes were analyzed, no significant difference was found between RA patients and healthy controls. Our findings suggest that IL-10 1082 G/A polymorphism or GCC, ACC haplotypes may be associated with RA in Turkish patients.     

Interleukin-1 receptor antagonist gene polymorphism and rheumatoid arthritis

The aim of this study was to evaluate the association of polymorphism in IL-1 receptor antagonist (IL-1RA) gene intron 2 with susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and their clinical features. Polymerase chain reaction of a genomic DNA was used to determine genotypes of the IL-1RA in 138 RA, 93 SLE, and 127 healthy control subjects. The frequency of IL-1RA allele 2 (IL-1RN*2) was lower in RA patients (2.5%) than in control subjects (7.1%) (odds ratio 0.34, 95% confidence interval 0.13–0.88, P=0.02). There was a significant difference in genotype and allele distribution between RA patients and controls. However, it did not differ between SLE patients and controls. In SLE and RA patients, there was no significant difference in clinical and laboratory findings concerning IL-1RA polymorphisms. In conclusion, our data suggest that IL-1RA gene polymorphism is not responsible for specific clinical characteristics in RA and SLE but that IL-1RN*2 is relevant in the susceptibility to RA, suggesting a protective role of IL-1RN*2 in the pathogenesis of RA.     

Comparison of single nucleotide polymorphisms in the human interleukin-10 gene promoter between rheumatoid arthritis patients and normal subjects in Malaysia

Abstract

In this study, three single nucleotide polymorphisms (SNPs) located within the promoter of the human interleukin (IL)-10 gene [rs1800896 (position: ?1087G > A), rs1800871 (position: ?824C > T) and rs1800872 (position: ?597C > A)] were investigated in 84 rheumatoid arthritis (RA) patients and 95 age- and sex-matched healthy subjects using polymerase chain reaction-restriction fragment length polymorphism method. Production of IL-10 by peripheral blood lymphocytes from the RA patients and healthy subjects cultured in the presence of Concanavalin A (Con A) was determined by using enzyme-linked immunosorbent assay. The results show that the distribution of the IL-10 genotypes did not differ significantly between RA patients and healthy subjects (P > 0.05). However, a significant difference was observed in allele frequencies of ?824CT, ?824TT, ?597CA, and ?597AA between the RA patients and healthy volunteers (P = 0.04). The ?1087A/?824T/?597A (ATA) haplotype, which comprises all mutant alleles, was associated with lower IL-10 production when compared with the other haplotypes. In contrast, the RA patients who did not display the ATA haplotype produced significantly higher levels of IL-10 when compared with those carrying either one (P = 0.012) or two (P = 0.005) ATA haplotypes. Our findings suggest that there is an association between SNPs in the promoter of the human IL-10 gene and susceptibility to RA.     

Comparison of single nucleotide polymorphisms in the human interleukin-10 gene promoter between rheumatoid arthritis patients and normal subjects in Malaysia

In this study, three single nucleotide polymorphisms (SNPs) located within the promoter of the human interleukin (IL)-10 gene [rs1800896 (position: −1087G > A), rs1800871 (position: −824C > T) and rs1800872 (position: −597C > A)] were investigated in 84 rheumatoid arthritis (RA) patients and 95 age- and sex-matched healthy subjects using polymerase chain reaction-restriction fragment length polymorphism method. Production of IL-10 by peripheral blood lymphocytes from the RA patients and healthy subjects cultured in the presence of Concanavalin A (Con A) was determined by using enzyme-linked immunosorbent assay. The results show that the distribution of the IL-10 genotypes did not differ significantly between RA patients and healthy subjects (P > 0.05). However, a significant difference was observed in allele frequencies of −824CT, −824TT, −597CA, and −597AA between the RA patients and healthy volunteers (P = 0.04). The −1087A/−824T/−597A (ATA) haplotype, which comprises all mutant alleles, was associated with lower IL-10 production when compared with the other haplotypes. In contrast, the RA patients who did not display the ATA haplotype produced significantly higher levels of IL-10 when compared with those carrying either one (P = 0.012) or two (P = 0.005) ATA haplotypes. Our findings suggest that there is an association between SNPs in the promoter of the human IL-10 gene and susceptibility to RA. An erratum to this article is available at .     

An autopsy case of acute pancreatitis with a high serum IgG4 complicated by amyloidosis and rheumatoid arthritis

We report an autopsy case of acute pancreatitis with a high serum IgG4 concentration complicated by systemic amyloid A amyloidosis and rheumatoid arthritis (RA). The patient was a 42-year-old Japanese female with a 22-year history of rheumatoid arthritis. She was diagnosed with myasthenia gravis when she was 31-year old. At the onset of pancreatitis, the patient was anti-nudear antibody-positive, and had high serum gamma globulin and IgG4 levels. Dexamethasone and conventional therapy induced clinical remission and significantly decreased the serum IgG4 and gamma globulin. However, despite the decreased disease parameters, the patient developed a bleeding pseudocyst and died of cardiac failure. In the autopsy examination, it was determined that pancreatitis was probably caused by ischemia due to vascular obstruction caused by amyloid deposition in the pancreas. Even though acute pancreatitis is a rare complication in RA patients, we speculate that an autoimmune pancreatitis-related mechanism and ischemia due to vascular obstruction by amyloid deposition might be attributable to a single source that leads to acute pancreatitis in our particular case.     

Tristetraprolin (TTP) gene polymorphisms in patients with rheumatoid arthritis and healthy individuals

Abstract

Tristetraprolin (TTP) is an intracellular protein that modulates the production of cytokines, including TNFα, by binding to and destabilizing the mRNAs of these cytokines. Therefore, differences in TTP gene expression may affect the severity of inflammatory diseases, such as rheumatoid arthritis (RA). We searched for polymorphisms in the human TTP gene and for this purpose, we sequenced the entire TTP gene in 20 Japanese individuals (ten with RA and ten healthy volunteers) and found one single nucleotide polymorphism (SNP) in the promoter region. We analyzed this SNP (A/G) by restriction fragment length polymorphism method in 155 RA patients and 100 control subjects. While the frequency of A allele in this SNP was similar in RA patients (74.5%) and controls (76.0%), the disease duration in RA patients with genotype GG was shorter than that of patients with genotypes AA/AG and RA patients with genotype GG had a higher probability of being treated with infliximab. We studied the difference in promoter activity between the two alleles by luciferase assay and found that the promoter activity of TTP promoter region with allele A was around two-fold higher than that with allele G. We conclude that this SNP in the promoter region of the TTP gene mildly affects promoter activity, and thus, may influence the disease activity of inflammatory disorders including RA.     

HLA DRB1* alleles in rheumatoid nodulosis: a comparative study with rheumatoid arthritis with and without nodules

Rheumatoid nodulosis (RN) is a rare condition associating rheumatoid nodules, episodes of arthritis, cystic bone lesions and, generally, positive rheumatoid factors (RF). It is considered a benign variant of rheumatoid arthritis (RA). In this study, we determined the HLA DRB1^* alleles of our RN patients and compared the distribution of these alleles to those of 74 healthy controls and 104 RA patients with and without nodules. Four RN patients were observed. All had subcutaneous nodules and RF were negative in three patients. Of the 104 RA patients, 18 had nodules (nodRA). Systemic manifestation (including vasculitis, peripheral neuropathy or lung involvement) were found in seven of these nodRA cases (33.8%) and most had positive RF and erosive changes on X-rays. Only one RN patient had a RA-associated allele (DRB1^*0101). The frequencies of the HLA DRB1^* alleles encompassing the “rheumatoid” shared epitope were similar to those of other RA series: ^*0101, 34.6% (P=0.03 compared with controls); ^*0401, 26.9% (P<0.0001); ^*0404, 12.5% (P=0.04); ^*0405, 4.8% (P=0.8); ^*1001, 8.6% (P=0.5). Of the nodRA and seronegative RA patients, 77.7% and 53.3%, respectively, presented the shared epitope. Thus, there was a tendency to decreased expression of the RA-associated alleles in RN (25%) compared with nodRA and seronegative RA patients. This study is restricted by the small number of tested RN patients, but the results suggest that the RA-associated alleles are poorly expressed in RN. Received: 29 September 1997 / Accepted: 13 February 1998     

Tristetraprolin (TTP) gene polymorphisms in patients with rheumatoid arthritis and healthy individuals

Tristetraprolin (TTP) is an intracellular protein that modulates the production of cytokines, including TNFα, by binding to and destabilizing the mRNAs of these cytokines. Therefore, differences in TTP gene expression may affect the severity of inflammatory diseases, such as rheumatoid arthritis (RA). We searched for polymorphisms in the human TTP gene and for this purpose, we sequenced the entire TTP gene in 20 Japanese individuals (ten with RA and ten healthy volunteers) and found one single nucleotide polymorphism (SNP) in the promoter region. We analyzed this SNP (A/G) by restriction fragment length polymorphism method in 155 RA patients and 100 control subjects. While the frequency of A allele in this SNP was similar in RA patients (74.5%) and controls (76.0%), the disease duration in RA patients with genotype GG was shorter than that of patients with genotypes AA/AG and RA patients with genotype GG had a higher probability of being treated with infliximab. We studied the difference in promoter activity between the two alleles by luciferase assay and found that the promoter activity of TTP promoter region with allele A was around two-fold higher than that with allele G. We conclude that this SNP in the promoter region of the TTP gene mildly affects promoter activity, and thus, may influence the disease activity of inflammatory disorders including RA.