Tai Muryoi

Rheumatoid arthritis after human parvovirus B19 infection

Polyarthropathy associated with human parvovirus B19 (B19) is usually transient, but often resembles rheumatoid arthritis (RA).1-3 However, B19 DNA screened by polymerase chain reaction (PCR) may be positive not only in autoimmune diseases, but also in non-arthropathy.4 To study whether or not RA occurs after acute B19 infection, we conducted a prospective study of patients with acute onset polyarthritis. Sixty seven cases showing acute inflammatory polyarthritis from January 1990 to June 1990 were examined and followed up for six years. Among them, 12 (9 female and 3 male) exhibited IgM anti-B19 antibodies.5 PCR, followed by a Southern blot analysis6 also showed the presence of B19 DNA in all 12 cases with IgM anti-B19 antibodies, but did not in the remainder. Initially, rheumatoid factor (RF) was negative in all B19 positive cases except one, but became positive in four, two to four months after the infection (table 1). Among RF …

Circulating anti-DNA immune complexes in active lupus nephritis

PURPOSE The role that circulating anti-DNA immune complexes play in autoimmunity has not yet been elucidated in humans. The aim of this study was to relate circulating anti-DNA immune complexes to a variety of renal histologic features and to immunoglobulin deposits in active lupus nephritis. PATIENTS AND METHODS The study population consisted of 47 patients with active lupus nephritis, 28 with active systemic lupus erythematosus (SLE) in the absence of renal lesions, and 40 with other categories of the disease. All patients were examined for anti-DNA circulating immune complexes (CIC) and their anti-DNA idiotype expression by an isoelectrofocusing analysis. Patients with renal lesions were also examined for renal histologic and immunofluorescent findings in renal biopsy specimens. RESULTS Anti-DNA CIC expressing an anti-DNA idiotype termed 0-81 Id occurred in patients with active lupus nephritis but not in acute episodes lacking renal involvement or in remission. Positive test results for anti-DNA CIC were associated with the incidence of diffuse proliferative glomerulonephritis (DPGN). Patients with anti-DNA CIC were also found to have a statistically significant increase in the prevalence of immunoglobulin immune deposits in the subendothelial area of the renal glomeruli. CONCLUSION The findings suggest that anti-DNA CIC preferentially occurred in lupus patients with DPGN. Examination for anti-DNA CIC may be a useful predictor of renal lesions, and therefore may contribute to the management of SLE. The results also indicate that anti-DNA CIC may be associated with immunoglobulin deposition in the subendothelial area of the renal glomeruli.

Monoclonal human anti-DNA antibodies from EB virus-transformed lymphocytes of systemic lupus erythematosus (SLE) patients

Sixteen monoclonal human anti-DNA antibodies were obtained from Epstein-Barr virus-transformed lymphoblastoid cells of patients with systemic lupus erythematosus (SLE) and were studied in terms of antigenic specificity. All of the antibodies showed polyspecificity to polynucleotides. Among them, some antibodies had a specificity to single-stranded (ss) DNA. Especially, O-8 antibodies showed a preference for polynucleotides with pyrimidine bases. The binding specificity of the antibody was also studied using different sizes of dT oligomers in order to assess the size of the epitope. It was revealed that oligonucleotides with a size of more than 25–30 nucleotides are required for inhibition of the antibody to ss-DNA. Other studies also demonstrated that anti-ss-DNA (O-8) antibody and anti-double-stranded (ds) DNA (NE-28) antibody bound to different combining sites in the same polynucleotides, poly(dT). These results suggest that some anti-ss-DNA antibodies are directed to the conformational structure related to the base sequence and that nucleic acids, therefore, might be responsible for the possible immunogenic stimulus causing the anti-DNA immune response. We also indicate that this type of antibody would be popular among serum anti-DNA antibodies in SLE.

Somatic mutation in autoantibody-associated VH genes of circulating IgM+IgD+ B cells.

Naive B cells expressing IgM and IgD on their surface have no or little somatic mutations in V genes. We have demonstrated that the human IgM+IgD+B cell clone (0 – 81), which expresses nephritogenic idiotypes, produces IgM anti‐DNA antibodies which show monospecificity to DNA. Using a DNA probe which specifically links to the VH gene of antibody 0 – 81, we identified the counterpart germ‐line V gene of 0 – 81, V3‐7, which appears to be used by pathogenic autoantibodies in humans. Clone 0 – 81, which may belong to naive B cells in terms of cell phenotype, uses a somatically mutated V3‐7 gene. We further studied DNA sequences of V3‐7 genes in circulating IgM+IgD+B cells from normal subjects and patients with systemic lupus erythematosus (SLE). The results revealed that rearranged V3‐7 genes in IgM+IgD+B cells from patients with SLE contained somatically mutated sequences at significantly increased frequencies. These data indicate an abnormal maturation of B cells in autoimmune states that may be associated with an escape of self‐reactive B cells from the elimination process in the germinal center.

Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group

Abstract Objective: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). Methods: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. Results: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. Conclusions: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

Incidence of anti-DNA idiotype-positive cells in human peripheral blood

Human anti-DNA idiotype (Id)-bearing cells in peripheral blood were sought using mouse monoclonal anti-Id antibodies to human monoclonal anti-DNA antibodies. Pretreatment with acid pH or pronase P or preincubation in human serum-free medium markedly decreased the number of anti-Id-reactive cells. Pronase P-treated cells were able to bind to anti-Id once more after incubation for 18 hr at 37° C, indicating the resynthesis of internal idiotypic determinants on the cells. Antiidiotype-reactive cells retained the same idiotypes in their cytoplasma. The cells expressing anti-DNA idiotypes, termed 0-81 and NE-1, were detected in the circulation of most patients with active lupus nephritis but not in those of inactive systemic lupus erythematosus (SLE) and healthy subjects. The idiotype-positive cells occurred in up to 5–10% of B cells from some patients with SLE in the active stage but became undetectable in remission. A limited number of anti-DNA Id-positive cells responsible for anti-DNA production might be preferentially expanded during acute episodes of the disease in some patients with SLE.

Epstein-Barr virus-transformed B cells bearing idiotypes of anti-DNA autoantibodies

Epstein-Barr virus (EBV)-transformed B cells obtained from healthy subjects had the same idiotypes of anti-DNA autoantibodies on their surface as those obtained from patients suffering from systemic lupus erythematosus. These clones secreted anti-single-stranded or antidouble-stranded DNA antibodies. Among them, some produced anti-DNA idiotype-positive antibodies but failed to bind DNA. This was confirmed by a competitive inhibition radioimmunoassay. It was then considered whether or not the expression of anti-DNA idiotype on B-cell clones related to the anti-DNA antibody activityin vivo. The amounts of anti-DNA antibodies were not associated with the incidence of idiotype-positive B cells in the EBV-transformed cell lines from normals. The results indicate that the clones committed to the synthesis of anti-DNA idiotype-positive antibodies commonly exist at a resting state in the circulation of healthy subjects, probably through the self-tolerance regulatory system.

Is Methotrexate (MTX) Necessary in Combination Therapy with Tocilizumab and MTX for Rheumatoid Arthritis in Remission? Cohort Study Carried by the Michinoku Tocilizumab Study Group

Objectives: To determine the necessity of methotrexate (MTX) in patients with rheumatoid arthritis (RA) achieving clinical remission treated by tocilizumab (TCZ) and MTX (TCZ+MTX). Methods: A 3 year, multicenter, observational cohort study was performed. RA patients were treated by TCZ with or without MTX depending on the attending doctor’s decision. Of the patients treated with TCZ+MTX, the patients who discontinued MTX after achieving clinical remission (discontinued group: DISC) were compared with those who maintained the same dose of MTX after achieving clinical remission (maintained group: MAIN). Results: The DISC and MAIN consisted of 33 patients and 37 patients, respectively. The mean DAS28-ESR was significantly lower in the DISC than in the MAIN at 3 months, 6 months and 9 months (3 months: 1.8 ± 0.8 and 2.4 ± 1.0, p=0.018, 6 months: 1.5 ± 0.7 and 2.2 ± 1.0, p=0.009 and 9 months: 1.4 ± 0.6 and 2.0 ± 1.0, p=0.008, respectively). The DAS28-ESR remission rate and Boolean remission rate were significantly higher in the DISC than in the MAIN (93.8% and 64.5%, respectively in the DAS28-RSR, p=0.04; 51.6% and 17.2%, respectively in the Boolean, p=0.005) at 6 months. Conclusions: RA patients treated by the combination of TCZ and MTX who achieved deep remission (DAS28- ESR ≤ 1.98) at as early as 3 months could discontinue taking MTX.