Tumor necrosis factor-alpha gene promoter methylation in Japanese adults with chronic periodontitis and rheumatoid arthritis.

BACKGROUND AND OBJECTIVE: Over-expression of tumor necrosis factor-alpha (TNF-α) plays a pathological role in chronic periodontitis (CP) and rheumatoid arthritis (RA), which might be regulated by the epigenetic mechanism. The aim of the present study was to evaluate whether there is a unique methylation profile of the TNF-α gene promoter in blood cells of individuals with CP and RA. MATERIAL AND METHODS: The study participants consisted of 30 Japanese adults with RA (RA group), 30 race-matched adults with CP only (CP group) and 30 race-matched healthy controls (H group). Genomic DNA isolated from peripheral blood was modified by sodium bisulfite and analyzed, by direct sequencing, to investigate DNA methylation of the TNF-α gene promoter region. The level of TNF-α produced in mononuclear cells stimulated with Porphyromonas gingivalis lipopolysaccharide was determined using ELISA. RESULTS: Twelve cytosine-guanine dinucleotide (CpG) motifs were identified in the TNF-α promoter fragment from -343 to +57 bp. The CP group showed a significantly higher methylation rate and frequency at -72 bp than the H group (p < 0.01). The RA group exhibited significantly higher methylation rates at seven CpG motifs (-302, -163, -119, -72, -49, -38 and +10 bp), and significantly higher methylation frequencies at six CpG motifs (-163, -119, -72, -49, -38 and +10 bp), than the H group (p < 0.01 for all comparisons). The levels of TNF-α produced were significantly different between individuals with and without methylation at -163 bp (p = 0.03). CONCLUSION: These results suggest that the hypermethylated status of CpG motifs in the TNF-α gene promoter in blood cells may be unique to Japanese adults with CP and RA.

Expression of anti-Porphyromonas gingivalis peptidylarginine deiminase immunoglobulin G and peptidylarginine deiminase-4 in patients with rheumatoid arthritis and periodontitis.

BACKGROUND AND OBJECTIVE: Autoimmunity against citrullinated proteins through peptidylarginine deiminase (PAD) may be involved in the pathophysiology of rheumatoid arthritis (RA). The present study evaluated the serum levels of antibodies to citrullinated proteins and to Porphyromonas gingivalis PAD (PPAD), and the endogenous expression of PAD-4, in individuals with and without RA, as well as before and after periodontal treatment. MATERIAL AND METHODS: The study participants consisted of 52 patients with RA (RA group) and 26 age-, gender- and smoking status-matched healthy controls (non-RA group). Of the 52 patients, 26 were randomly assigned to receive oral hygiene instruction and supragingival scaling (RA subgroup). After periodontal and rheumatologic assessments, the serum levels of anti-cyclic citrullinated peptide (CCP) immunoglobulin G (IgG), anti-PPAD IgG and PAD-4 were determined using ELISA. RESULTS: The serum levels of anti-CCP IgG and anti-PPAD IgG were significantly higher in the RA group than in the non-RA group (p < 0.001 and p = 0.03). A significant, positive correlation was observed between the serum levels of anti-PPAD IgG and anti-CCP IgG (p = 0.04), but not between the serum levels of PAD-4 and anti-CCP IgG. Multiple logistic regression analyses revealed a significant association between anti-PPAD IgG responses and RA after adjustment for age, gender and smoking (p = 0.004). Supragingival scaling significantly improved the periodontal condition and disease activity of RA (p < 0.05), but failed to decrease the serum levels of anti-CCP IgG, anti-PPAD IgG and PAD-4 after 2 mo of treatment. CONCLUSION: These results might suggest an association between anti-PPAD IgG and anti-CCP IgG responses, implicating a role for PPAD in protein citrullination in patients with RA and periodontitis.

Autoantibodies against oxidized low-density lipoprotein (LDL) and carotid atherosclerosis in patients with rheumatoid arthritis.

OBJECTIVES: To examine the relationship between autoantibodies against oxidized low-density lipoprotein (oxLDL-Abs) and the progression of carotid atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Fifty RA patients without evidence of risk factors for atherosclerosis (RA group) and 30 healthy volunteers (normal group) were investigated. The mean intima-media thickness of the common carotid artery (mean CCA-IMT) was measured by high-resolution B-mode ultrasonography. The titer of IgG oxLDL-Abs was measured by enzyme-linked immunosorbent assay. The relationships among mean CCA-IMT, IgG oxLDL-Ab titer and patient factors such as body mass index, systolic blood pressure, diastolic blood pressure, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum lipid levels were examined. RESULTS: Mean CCA-IMT, CRP, ESR and titer of IgG oxLDL-Abs were significantly higher in the RA group than in the normal group. Although mean CCA-IMT showed a positive correlation only with age in multivariate analysis, IgG oxLDL-Ab titers in the RA group were positively associated with mean CCA-IMT and independently with age and sex by multiple regression analysis. CONCLUSIONS: IgG oxLDL-Abs appear to be associated with the degree of carotid atherosclerosis in patients with RA, and are independent of traditional risk factors for atherosclerotic diseases. These results suggest a possible link between autoimmune mechanisms and accelerated atherosclerosis in RA.

Localization of human glucocorticoid receptor in rheumatoid synovial tissue of the knee joint.

OBJECTIVE: This study was conducted to investigate the localization of human glucocorticoid receptors (GCRs) in the knee synovium of patients with rheumatoid arthritis (RA) and to evaluate the correlation between GCR expression and the clinical profiles. METHODS: Twenty synovial specimens from RA knees, six from knees with osteoarthritis (OA), and five from knees with traumatic arthritis (TA) were obtained at surgery. The GCRs were stained immunohistochemically. The immunopositive cells were counted at random in the lining (synoviocytes) and sublining layers (fibroblastic and lymphoid cells). The relationship between the GCR-expressing cells and clinical profiles was analysed statistically. RESULTS: GCRs were expressed in the nuclei of synoviocytes and the fibroblastic and lymphoid cells in the sublining layer. The GCR-positivity rate of synoviocytes was 67.1+/-18.4% in RA, 58.7+/-13.5% in OA, and 49.4+/-19.7% in TA, differences between the three groups being statistically insignificant. There was a significant difference in the GCR-positivity rate of sublining fibroblastic cells (p = 0.029), but not synoviocytes or sublining lymphoid cells, from RA patients treated with and without prednisolone, while there was no correlation between the rate for synoviocytes and that for sublining fibroblastic cells from RA patients treated with prednisolone. CONCLUSIONS: GCRs are localized not only on inflammatory lymphoid cells but also on synoviocytes, suggesting that glucocorticoids could act directly on these cells. Furthermore, the rate of GCR expression on synoviocytes and sublining lymphoid cells is less suppressed with low-dose prednisolone, regardless of the duration of treatment.

Comparison of gastroduodenal, renal and abdominal fat biopsies for diagnosing amyloidosis in rheumatoid arthritis.

The aim of the study was to determine the frequency of amyloidosis detected by gastroduodenal biopsy in rheumatoid arthritis (RA) patients, and to investigate correlations between the results of gastroduodenal biopsy and abdominal fat and renal biopsies. A total of consecutive 1006 RA patients underwent gastroduodenal biopsy. The 71 patients who tested positive for gastrointestinal (GI) amyloidosis were asked to undergo renal and abdominal fat biopsies, and 21 did so. Renal biopsies were also performed on 12 patients with no amyloidosis but indicators of drug-induced renal damage, and abdominal fat biopsies were performed on 50 RA patients with no indication of amyloidosis. The prevalence of GI amyloidosis was 7.1%. Urinary abnormalities and GI symptoms were common in GI amyloidisis, and inflammatory markers were elevated. Sixty-one (86%) had either depressed creatinine clearance or urinary symptoms. Nineteen of the 21 patients (91%) with GI amyloidosis who underwent renal biopsies also had renal amyloid deposits. Eleven of the 21 (52%) had amyloidosis on abdominal fat biopsy. None of the 12 patients without GI amyloidosis had renal amyloidosis on renal biopsy, and none of the 50 patients without GI amyloidosis had amyloidosis on abdominal fat biopsy. Gastroduodenal biopsy reveals a high prevalence of amyloidosis in RA patients. Amyloidosis is often associated with signs of renal impairment. Results of GI biopsy are highly correlated with those of renal biopsy, but the results of fat biopsy are not. We recommend GI biopsy for RA patients for the screening of systemic amyloidosis.

The effect of activity and type of rheumatoid arthritis on the flexible implant arthroplasty of the metacarpophalangeal joint.

A retrospective study was performed on 184 Swanson flexible implant arthroplasties of the metacarpophalangeal joint in 75 hands of 64 patients with rheumatoid arthritis, to investigate the influence of systemic factors on the clinical and radiological results. The mean follow-up period was 6 years. The postoperative serum C-reactive protein level was found to affect postoperative pain, and there was a larger extension lag and more subsidence of the implant in those with the mutilating type of the disease.

Interleukin-2 levels are elevated in the bone marrow serum of patients with mutilans-type rheumatoid arthritis.

In order to investigate the pathogenesis of mutilans-type rheumatoid arthritis (RA), we measured cytokine levels in the bone marrow serum of patients with RA. We studied 35 patients with non-mutilans RA, 19 with mutilans RA, and 20 patients with osteoarthritis (OA) undergoing joint surgery. At the time of surgery, iliac bone marrow and peripheral blood were sampled from all 74 patients and cytokine levels measured. The serum levels of five cytokines (IL-1beta, IL-2, IL-3, IL-6 and GM-CSF) were measured by ELISA. Haematologic and inflammatory factors were also measured. Levels of IL-2, IL-6 and GM-CSF in bone marrow serum were significantly higher in all RA patients than in those with OA. Mean (+/-SD) IL-2 levels were significantly higher in patients with mutilans-type RA (309.8+/-686.3 pg/ml) than in patients with other types of RA (66.5+/-173.1 pg/ml; P<0.01). IL-2 was detected significantly more often in patients with mutilans-type RA than in patients with other types of RA (P < 0.01). Inflammatory factors were higher in all RA groups than in OA patients. However, the haematologic and immunologic variables were no different between mutilans RA and other types of RA. No correlations were observed between IL-1beta, IL-2, IL-3, IL-6 and GM-CSF levels and these laboratory variables. In patients with mutilans-type RA, IL-2 levels in the bone marrow serum were significantly higher than in patients with other types of RA or with OA. This elevation does not appear to be related to systemic inflammation, as there was no correlation with other inflammatory factors.

Effectiveness of omeprazole for the treatment of upper gastrointestinal lesions in rheumatoid arthritis patients.

Abstract We evaluated the efficacy of omeprazole (OPZ) for the treatment of upper gastrointestinal (UGI) lesions in rheumatoid arthritis (RA) patients. Fourteen RA patients with H2 receptor antagonist- (H2RA-) resistant UGI lesions (1 stomal, 11 gastric, and 2 esophageal with reflux esophagitis ulcers) were treated with OPZ at 20 mg/day (study A). New untreated UGI lesions (1 stomal and 12 gastric ulcers) were treated with OPZ (study B). Three patients who showed renal dysfunction during H2RA treatment for UGI lesion were treated with OPZ (study C). Nonsteroidal antiinflammatory drugs (NSAIDs) were not discontinued. The stage of each ulcer was determined by gastrointestinal fiberscopy (GIF). In study A, during the first 8 weeks of OPZ treatment, 1 esophageal and 7 gastric ulcer patients were completely cured. Six patients showing partial response were treated further with OPZ for another 8 weeks. During this second period, 1 stomal and 3 gastric ulcer patients were completely cured, and 1 gastric and 1 esophageal ulcer patient showed only partial response. In study B, after an 8-week OPZ treatment, all except 2 patients showed complete healing. One patient developed mild eruption at 4 weeks and was shifted to H2RA. One patient showed complete healing after 4 weeks. No patient in study C showed renal dysfunction with OPZ. Our results suggest that OPZ is an effective treatment for UGI lesions in RA patients using NSAIDs.

Flexible hinge toe implant arthroplasty for rheumatoid arthritis of the first metatarsophalangeal joint: long-term results.

We report the long-term clinical results and survival rate of the implant in flexible hinge toe implant arthroplasty of the first metatarsophalangeal joint, combined with a shortening oblique osteotomy of the metatarsal neck in the lateral toes, in patients with rheumatoid arthritis. Between 1983 and 1990, arthroplasty was performed on 97 feet in 66 patients. Twenty-seven patients died; follow-up information was available for 60 feet in the remaining 39 patients, who were followed for an average of 12 years. Twenty-nine patients (74%) were satisfied with the outcome after surgery, 7 were satisfied but had some pain or recurrent deformities, and 3 were unsatisfied. Radiologically, visible fracture was identified in nine implants. Four implants were removed because of infection (n = 2) or recurrent deformity (n = 2); no implant was removed because silicone synovitis developed. With revision as the endpoint, the implant survival rate was 93% at 10 years, and with radiographic implant fracture as the endpoint, the implant survival rate was 87% at 10 years. Shortening oblique osteotomy of the lateral toes appeared to decrease the rate of implant fracture and should be performed concomitantly with implantation when rheumatoid forefoot deformities are being reconstructed.

Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient.

A 75-year-old female rheumatoid arthritis patient who was positive for hepatitis B surface antigen and for antibodies to hepatitis Be antigen showed liver dysfunction, and therefore methotrexate (MTX) therapy was discontinued. Her drug lymphocyte stimulation test indicated positivity for MTX. Her liver dysfunction improved briefly, but she developed fulminant hepatitis with elevated levels of hepatitis B virus (HBV)/DNA polymerase and subsequently died. HBV/DNA analysis performed with polymerase chain reaction-mutation site-specific assay revealed that the fulminant hepatitis was caused by a precore mutant virus. Sudden reactivation of the immune system by discontinuation of MTX may have led to the attack on infected cells. Even when hepatitis Be antibodies are present, MTX should not be used in patients who have chronic infection with HBV.

Systemic sclerosis in two second cousins: a case report.

Abstract We describe two second cousins who developed systemic sclerosis. These patients had major histocompatibility complex (MHC) class I alleles in common, including A2, A26(10), B60(40), and Cw7 as well as class II allele DR2. This DR2 was thought to be associated with the onset of the disease. Our patients both experienced a limited type of systemic sclerosis, but the expression of autoantibodies was different.

The Senami Wrist Supporter for patients with rheumatoid arthritis.

Abstract One of the wrist orthoses, the Senami Wrist Supporter (SWS), was applied to 203 rheumatoid wrists in 112 patients who had persistent wrist pain and restricted forearm rotation due to synovitis and instability at the distal radioulnar joint (DRUJ). The study was performed by sending out a questionnaire to the patients about the use of the SWS at home, and examining grip strength and forearm rotation with and without the use of the SWS. The average age of the patients was 61 years, and the average follow-up period was 18 months. The rate of compliance of wearing the SWS at home was 73% on average. It was higher in wrists of Larsen-Dale-Eek (LDE) grades 0, I, and II (normal, slight, and definite early abnormality) than in those of grades III, and IV (medium and severe destructive abnormality). Decreased pain was noted in 52% of the wrists at the time of applying the SWS. The SWS was not used in 10% of the wrists because of remission of pain at follow-up. Grip strength increased significantly (P < 0.01) and so did forearm rotation (P < 0.05) by the stabilizing effect of the SWS on the unstable DRUJ. The use of the SWS was confirmed to be an efficient measure to treat painful rheumatoid wrists with early stages of disease at the DRUJ.

Gallstones in patients with rheumatoid arthritis.

OBJECTIVE: We performed abdominal ultrasonography (US) on patients with rheumatoid arthritis (RA) to investigate the frequency and characteristics of gallstones (GS). METHODS: Patients with RA (n = 224; 42 male and 182 female) underwent abdominal US. RESULTS: The incidence of GS (including post-chorecystectomy patients) was significantly higher in female patients with RA (15.4%) than in female controls (5.2%, p < 0.01). There was no significant difference in GS incidence between male patients with RA (9.5%) and male controls (3.8%). The percentage of cholesterol stones was 100% in patients with RA with GS but only 66.7% in controls with GS (p < 0.01). Compared to patients with RA without GS, patients with RA with GS were older and had lower C-reactive protein levels, a decreased creatinine clearance and urinary calcium excretion, and an increased incidence of hypercholesterolemia. CONCLUSION: We observed a high incidence of GS in female patients with RA. With our previous observation of a high incidence of renal stones in patients with RA, these results suggest the importance of US as a diagnostic tool in the management of RA.

Arthroplasty for rheumatoid forefoot deformities by a shortening oblique osteotomy.

Seventy-five feet in 47 patients (46 women, 1 man) who had rheumatoid arthritis were observed for an average of 6 years (range, 4-11 years) after an operation on the forefoot that included a shortening oblique osteotomy of the metatarsal neck of the lateral toes. In addition, patients underwent either flexible hinge toe implant arthroplasty or Mitchell's osteotomy in the first metatarsophalangeal joint. Forty-two feet (56%) looked normal with no valgus or dorsal displacement of the toes. Recurrence of callosities occurred in 9 feet (12%) with moderate pain in 3 feet. Thirty-nine (83%) patients were satisfied with the outcome after surgery. Resection arthroplasty often is recommended for management of forefoot deformities. However, as shown in this series, the improvement in deformities, function, and cosmesis of metatarsophalangeal joint preservation may be better with an osteotomy of the metatarsal neck than with a resection arthroplasty. Because of the development of combined drug therapy, the benefits of synovectomy, osteotomy, and shortening in length should be reconsidered. The authors' studies suggest that the shortening oblique osteotomy should be considered 1 of the surgical reconstruction options for patients with rheumatoid arthritis who have forefoot deformities.

Renal stones in patients with rheumatoid arthritis.

OBJECTIVE: Renal stones are reported to be one of the causes of hematuria in patients with juvenile rheumatoid arthritis (RA). We performed abdominal ultrasonography on patients with RA to investigate the frequency of renal stones and whether renal stones are related to hematuria. METHODS: We conducted abdominal ultrasonography in 224 patients with RA (42 men, 182 women). Mean age was 61.4 years, and the mean duration of disease was 13.5 years. RESULTS: Renal stones were defined as hyperechoic spots with acoustic shadows, and they were observed in 37 patients. We also noticed hyperechoic spots without acoustic shadows in 50 patients. Five of these 50 patients also had renal stones. Twenty-one patients showing hyperechoic spots without acoustic shadows underwent computed tomographic scans, and apparent calcifications were observed in 10 patients. Age and sex matched controls had a significantly lower incidence of renal stones and hyperechoic spots without acoustic shadows than did patients with RA. Hematuria was more frequently observed in patients with RA with renal stones than in those without renal stones or hyperechoic spots without acoustic shadows. Urinary calcium/creatinine (Ca/Cr) ratios were elevated in patients compared to controls. Urinary Ca/Cr ratios in patients taking vitamin D3 were higher than those of patients not receiving the vitamin. Administration of vitamin D3 also was associated with increased incidence of renal stones. CONCLUSION: We observed a high incidence of renal stones in patients with RA. Hematuria was more prevalent in patients with RA with renal stones than in those without. These results suggest the importance of performing abdominal ultrasonography on patients with RA.

Survivorship analysis of total knee arthroplasty with the kinematic prosthesis in patients who have rheumatoid arthritis.

Eighty-eight primary total knee arthroplasty procedures in 61 patients with rheumatoid arthritis were performed using the Kinematic total knee prosthesis (Howmedica, Rutherford, NJ) with cement between 1980 and 1985. No patients were lost to follow-up evaluation. Thirty-one of 61 patients died during the study period. Survivorship for all patients by life-table method was estimated as 56% at 10 years. This was shorter than the expected survival rate of a sex- and age-matched control group. Fifty procedure outcomes in 34 patients (27 women, 7 men) who were followed for more than 10 years were available for clinical evaluation. Complications occurred in 11 cases; in 4 of these, revision surgery was required. With revision as the endpoint, the survival rate of the prostheses was estimated as 93% at 10 years.

The use of grommets for flexible hinge toe implants. A case report.

The postmortem examination of bilateral first metatarsophalangeal flexible hinge toe implants in a 66-year-old woman with rheumatoid arthritis is reported. The prosthesis had been inserted with grommets in 1 joint and without grommets in the other 2.5 years before her death. The implants were removed, and the bone/implant interfaces were examined microscopically by hematoxylin eosin stains and an electron probe microanalyzer. Surfaces of the implants were examined by scanning electron microscopy. Silicone particles within the fibrous tissue at the bone/implant interface, and a tear and significant scuffing of the implant surface, were detected in the joint without grommets. Such changes were not detected in the joint with grommets. These findings suggest that grommets may improve implant durability and preventing silicone synovitis.

Early blood-brain barrier disruption after high-dose single-fraction irradiation in rats.

We studied the effect of high-dose single-fraction irradiation on the permeability of the blood-brain barrier (BBB) in rat brains. Immunohistochemistry with an antibody to serum albumin was used as a sensitive method for detecting the extravasation of endogenous serum components. Extravasation of albumin was detected as early as 1 day after irradiation with 20 or 40 Gy. Immunoreactivity reached its maximum after 3 days, gradually decreased during the following few weeks and had disappeared by day 30. Extravasation was much greater after irradiation with 80 Gy and continued to increase during the whole period of the experiment (6 days). Disruption of BBB this early after irradiation has not been previously documented. The time course of observed serum albumin extravasation, however, agrees well with the previous ultrastructural evidence for increased BBB permeability after irradiation with 27 Gy in monkey brains. This transient impairment of BBB may contribute to the reversible neurological symptoms after radiosurgery. It may also allow drugs that normally not pass the BBB to do so and thus disperse in the brain when administered at this time.

Diagnosis and treatment of patients with meningeal carcinomatosis.

The records of thirty-four patients with meningeal carcinomatosis treated at our hospital between 1984 and 1990 were reviewed. The sources, histologies, metastatic lesions outside the central nervous system, the history of the treatment of primary lesions and intraparenchymal of metastatic brain tumors and the period from the diagnosis of primary lesions and the treatment of intraparenchymal metastatic brain tumors to the diagnosis of meningeal carcinomatosis were investigated. Meningeal carcinomatosis was diagnosed and by neurological signs, CSF cytology, CT scan and MRI. Each patient was given a 5 mg single dose of methotrexate (MTX) alone or combined with 20 mg cytosine arabinoside (Ara-C) administered by intrathecal injection via an Ommaya reservoir and standard lumbar puncture with or without radiotherapy. Following intrathecal chemotherapy 22 of 29 patients showed symptomatic improvement of meningeal irritation and in 10 of 29 patients with cranial nerve impairment amelioration of symptoms was also observed. Moreover, CSF cytology became negative in 10 of 29 patients after a full course of intrathecal chemotherapy. Neurotoxicity Leukoencephalopathy, a neurotoxic effect of intrathecal chemotherapy was not observed in any of the patients. From these results, MTX in small doses is recommended for intrathecal chemotherapy of meningeal carcinomatosis to prevent neurotoxicity.