Masashi Akizuki

Sjögren-Type Syndrome After Allogeneic Bone-Marrow Transplantation

Four patients, treated for hematologic disorders with bone-marrow transplants from HLA-identical siblings, spontaneously complained of dry eyes 8 to 12 months after transplantation. Four allograft recipients and two recipients of autologous bone-marrow transplants were evaluated for xerophthalmia and xerostomia. Three allogeneic marrow recipients had evidence of keratoconjunctivitis sicca, and two had decreased parotid gland function. All four allograft recipients had minor salivary gland histopathology identical to that of Sjögrens syndrome. The severity of symptoms and histologic lesions corresponded with the severity of chronic graft-versus-host disease. In addition, one patient developed sclerodermatous skin changes, another had discoid lupus erythematosus, and two patients had laboratory evidence of cholestasis. None of the patients had autoantibodies but all had hypergammaglobulinemia. In contrast, none of the recipients of autologous bone marrow had clinical, laboratory, or histologic findings resembling Sjögrens syndrome.

Methotrexate treatment in patients with adult onset Still's disease—retrospective study of 13 Japanese cases

OBJECTIVE To evaluate methotrexate treatment in patients with active adult onset Still’s disease (AOSD). METHODS Methotrexate was initially given as a single weekly oral dose of 5 mg and adjusted individually afterwards in 13 patients with active AOSD. Symptoms and laboratory findings were investigated. RESULTS Signs of AOSD activity disappeared (remission) in eight patients between 3 and 16 weeks after starting methotrexate. In these patients, significant improvements in C reactive protein, erythrocyte sedimentation rate, white blood count, and serum ferritin were observed at 8, 12, 14, and 16 weeks after starting methotrexate, respectively. In six of these eight patients, steroids or non-steroidal anti-inflammatory drugs could be reduced or discontinued. In four patients methotrexate was not effective despite 12 or 16 weeks of treatment, and one patient discontinued treatment after 2 weeks because of severe nausea. Five patients suffered from adverse reactions, including acute interstitial pneumonia (one patient) and liver toxicity (two patients). Five out of eight patients successfully treated with methotrexate were HLA-DR4 positive (four homozygotes), and all the unsuccessfully treated patients were DR2 positive. CONCLUSIONS Methotrexate is useful for controlling disease activity in AOSD, not only for refractory patients but also for patients who have never taken steroids or for those with steroid associated toxicity. However, serious adverse reactions can occur, as with rheumatoid arthritis. It is important to determine the critical factors, such as the immunogenetic background, that are associated with response to methotrexate treatment.

Autoantibodies to DEK oncoprotein in human inflammatory disease.

OBJECTIVE To evaluate the specificity of anti-DEK antibodies for juvenile rheumatoid arthritis (JRA). METHODS Anti-DEK autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA) using affinity-purified his6-DEK fusion protein. Sera from 639 subjects (417 patients with systemic autoimmune disease, 13 with sarcoidosis, 44 with pulmonary tuberculosis, 125 with uveitis, and 6 with scleritis, and 34 healthy control subjects) were screened. Reactivity was verified by immunoblotting and immunoprecipitation studies using baculovirus-expressed human DEK. RESULTS Anti-DEK activity was found at the following frequencies: JRA 39.4% (n = 71), systemic lupus erythematosus (SLE) 25.1% (n = 216), sarcoidosis 46.2% (n = 13), rheumatoid arthritis 15.5% (n = 71), systemic sclerosis 36.0% (n = 22), polymyositis 6.2% (n = 16), and adult Stills disease 0% (n = 21). Autoantibodies also were detected in 9.1% of tuberculosis sera (n = 44), but were undetectable in sera from the 34 healthy controls. Western blot and immunoprecipitation assay results correlated well with the ELISA findings. In general, levels of anti-DEK autoantibodies were higher in SLE than in other patient subsets, including JRA. CONCLUSION Anti-DEK autoantibodies are less specific for JRA than previously believed. They are produced in association with a variety of inflammatory conditions, many of which are associated with granuloma formation and/or predominant Thl cytokine production. Anti-DEK antibodies may be a marker for a subset of autoimmunity associated with interferon-gamma production rather than a particular disease subset.

Antibody to a soluble acidic nuclear antigen in Sjögren's syndrome.

Abstract The presence of a precipitating antibody to an extractable nuclear antigen, termed Ha, was examined by immunodiffusion in gel in three subpopulations of patients with Sjogrens syndrome (SS): (1) those with sicca complex alone, (2) those with SS and rheumatoid arthritis (SS-RA) and (3) those with SS and systemic lupus erythematosus (SS-SLE). Control populations included patients with rheumatoid arthritis (RA) alone and systemic lupus erythematosus (SLE) alone, and normal age-matched blood donors without a history of SS or other connective tissue disease. The results demonstrate the high incidence of anti-Ha antibody in sicca complex (68 per cent) versus the low incidence of the antibody in SS-RA (5 per cent) (p No correlations were found between anti-Ha antibody positivity and clinical parameters, such as serum immunoglobulin concentration, degree of abnormality of parotid scan, titer of rheumatoid factor or focal score of labial biopsy in the patients with SS. However, a correlation between anti-Ha antibody titer and clinical disease activity was noted in two patients examined. The appearance of the anti-Ha antibody was correlated with the development of pseudolymphoma in a third patient. The presence of the anti-Ha antibody may identify a subpopulation of patients with SS at greater risk of rapid progression of the disease and/or the development of pseudolymphoma.

Association of Takayasu arteritis with HLA-B*67:01 and two amino acids in HLA-B protein

OBJECTIVE Takayasu arteritis (TAK) is a rare autoimmune arteritis that affects large arteries. Although the association between TAK and HLA-B 52:01 is established, the other susceptibility HLA-B alleles are not fully known. We performed genetic association studies to determine independent HLA-B susceptibility alleles other than HLA-B 52:01 and to identify important amino acids of HLA-B protein in TAK susceptibility. METHODS One hundred patients with TAK and 1000 unrelated healthy controls were genotyped for HLA-B alleles in the first set, followed by a replication set containing 73 patients with TAK and 1000 controls to compare the frequencies of HLA-B alleles. Step-up logistic regression analysis was performed to identify susceptibility amino acids of HLA-B protein. RESULTS Strong associations of susceptibility to TAK with HLA-B 52:01 and HLA-B 67:01 were observed (P = 1.0 × 10(-16) and 9.5 × 10(-6), respectively). An independent susceptibility effect of HLA-B 67:01 from HLA-B 52:01 was also detected (P = 1.8 × 10(-7)). Amino acid residues of histidine at position 171 and phenylalanine at position 67, both of which are located in antigen binding grooves of the HLA-B protein, were associated with TAK susceptibility (P ≤ 3.8 × 10(-5)) with a significant difference from other amino acid variations (ΔAIC ≥ 9.65). CONCLUSION HLA-B 67:01 is associated with TAK independently from HLA-B 52:01. Two amino acids in HLA-B protein are strongly associated with TAK susceptibility.

Development of anti-Sm and anti-DNA antibodies followed by clinical manifestation of systemic lupus erythematosus in an elderly woman with long-standing Sjögren's syndrome

A 69-year-old Japanese women who had been followed up for 10 years as a primary Sjögrens syndrome, is reported. She suddenly developed serological and clinical characteristics of systemic lupus erythematosus (SLE): anti-Sm and anti-dsDNA antibodies followed by nephrotic syndrome and pancytopenia. This case suggests that the diagnosis of primary Sjögrens syndrome should be considered as tentative in certain cases and that the development of serological characteristics precede and are associated with the development of clinical symptoms of SLE.

Recurrent annular erythema associated with anti-SS-B/La antibodies: analysis of the disease-specific epitope

We have found that anti‐SS‐B/La antibodies are present in a group of patients with a characteristic recurrent annular erythema, and immunological abnormalities. The presence of a disease‐specific epitope for this entity has been examined by comparing immunological reactivity of anti‐SS‐B/La antibodies between these patients and patients with classical Sjögrens syndrome who have anti‐SS‐B/La antibodies hut do not have this characteristic erythema.

Systemic lupus erythmatosus associated with autoimmune hepatitis two cases with novel autoantibodies to transfer RNA-related antigens

SummaryTwo cases of systemic lupus erythematosus (SLE) with autoimmune hepatitis are reported. Both patients had a mild form of SLE without central nervous system or renal involvement and showed a rapid response to corticosteroid therapy. Neither of them had antibodies to mitochondria, smooth muscle, and liver/kidney microsome-1 related to autoimmune hepatitis. Instead, novel autoantibodies which react with transfer RNA-related antigen were detected. These autoantibodies could be a useful marker for classification of SLE associated with autoimune hepatitis.

What is the definition for coexistent rheumatoid arthritis and systemic lupus erythematosus

We have recently published a report on a patient with rheumatoid arthritis(RA) complicated by serological and clinical characteristics of systemic lupus erythematosus (SLE) 1, i.e. a case of classical RA with bony ankylosis and nodules which developed anti-Sm antibodies, biological false positive result for serological test for syphillis, leukopenia and pericarditis, 19-years after the onset of RA. While reviewing the previously published articles on coexistent RA and SLE2-5, we asked the basic question ’What is the definition for coexistent RA and SLE?’.

Clinical Activity After 12 Weeks of Treatment with Nonbiologics in Early Rheumatoid Arthritis May Predict Articular Destruction 2 Years Later

Objective. To investigate earlier prediction of future articular destruction in patients with early rheumatoid arthritis (RA). Methods. We randomly allocated patients with RA with disease duration < 2 years to different nonbiologic disease modifying antirheumatic drug (DMARD) therapies in a double-blind trial. Progression of articular destruction over the 96-week treatment period was assessed using the modified Sharp method. Results. Progression of articular destruction correlated more strongly with the American College of Rheumatology (ACR) core set measures after 12 weeks of treatment than with pretreatment values. Multiple regression analysis of data after 12 weeks yielded a correlation coefficient of 0.711. The sensitivity and specificity to predict articular destruction over the 75th percentile of the cohort were 78.6% and 84.6%, respectively. Patients who showed articular destruction over the 75th percentile of the cohort had low response to treatment at 12 weeks, and continued to have high clinical disease activity thereafter. Contrasting data were found in patients with slow progression of articular destruction. Conclusion. In patients with early RA, ACR core set measures after 12 weeks of nonbiologic DMARD treatment may predict articular destruction 2 years later. Low response to treatment at 12 weeks and continuing high disease activity thereafter were found in patients with rapid radiological progression. These data can be used to determine the appropriateness of treatment at 12 weeks and aid the decision to introduce biologic DMARD.