Autoantibody to scaffold attachment factor B (SAFB): A novel connective tissue disease-related autoantibody associated with interstitial lung disease.

OBJECTIVE: To identify and characterize a novel connective tissue disease (CTD)-related autoantibody (autoAb) directed against scaffold attachment factor B (SAFB). METHODS: AutoAb specificity was analyzed using RNA and protein-immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. RESULTS: By immunoprecipitation assay, 10 sera reacted with a protein with a molecular weight of approximately 160 kDa. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot-based analyses revealed that the Ab specifically recognized SAFB. Anti-SAFB Abs were detected in 2 of 646 patients with systemic sclerosis (SSc) (0.3%), 1 of 1570 patients with polymyositis/dermatomyositis (0.06%), 4 of 270 patients with interstitial lung disease (ILD) (1.5%), 1 of 43 patients with overlap syndrome (2.3%) and 2 patients with other diseases including primary Raynaud's disease and eosinophilic pneumonia. Five patients with anti-SAFB Abs had Raynaud's phenomenon and 3 had nail fold punctate hemorrhage. Of note, 8 of the 10 patients (80%) suffered from ILD. None of the patients with anti-SAFB Abs had pulmonary arterial hypertension, heart disease, or renal involvement. CONCLUSIONS: Anti-SAFB Ab is a novel CTD-related autoAb possibly associated with ILD.

A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency.

Neutrophil-specific granule deficiency (SGD) is a rare autosomal recessive primary immunodeficiency characterized by neutrophil dysfunction, bilobed neutrophil nuclei and lack of neutrophil-specific granules. Defects in a myeloid-specific transcription factor, CCAAT/enhancer binding protein-ε (C/EBPε), have been identified in two cases in which homozygous frameshift mutations led to loss of the leucine zipper domain. In this study, we report a 55-y-old woman affected with SGD caused by a novel homozygous 2-aa deletion (ΔRS) in the leucine zipper domain of the C/EBPε gene. The patient showed characteristic neutrophil abnormalities and recurrent skin infections; however, there was no history of deep organ infections. Biochemical analysis revealed that, in contrast to the two frameshift mutations, the ΔRS mutant maintained normal cellular localization, DNA-binding activity, and dimerization, and all three mutants exhibited marked reduction in transcriptional activity. The ΔRS mutant was defective in its association with Gata1 and PU.1, as well as aberrant cooperative transcriptional activation of eosinophil major basic protein. Thus, the ΔRS likely impairs protein-protein interaction with other transcription factors, resulting in a loss of transcriptional activation. These results further support the importance of the leucine zipper domain of C/EBPε for its essential function, and indicate that multiple molecular mechanisms lead to SGD.

Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome.

OBJECTIVE: To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). METHODS: This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. RESULTS: Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. CONCLUSION: Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the "anti-synthetase syndrome."

Two young-adult female cases of dermatomyositis with antibodies for transcriptional intermediary factor 1-γ.

A variety of myositis-specific autoantibodies (MSAs) have been detected in patients with dermatomyositis (DM). We analyzed MSAs in 20 cases with DM. Eleven of the 20 cases were positive. Out of those 11 cases, 3 were positive for antibodies against aminoacyl-tRNA synthetase and 3 had antibodies to anti-melanoma differentiation-associated gene 5 detected using an immunoprecipitation assay and/or a specific enzyme-linked immunosorbent assay. One case had anti-NXP-2 antibodies and 4 cases had anti-transcriptional intermediary factor 1 (TIF1)-α/γ antibodies detected by immunoprecipitation and Western blotting. Two of those 4 cases had antibodies for both TIF1-α and TIF1-γ, and the 2 other cases had antibodies for TIF1-γ alone. We report the 2 cases with antibodies for TIF1-γ only, who were young-adult females without an internal malignancy or interstitial pneumonia. Those 2 cases had clinically amyopathic DM. Among DM patients with antibodies against TIF1 family proteins, there seems to be a subgroup of young-adult cases who have clinically amyopathic DM and show good prognosis without malignancy.

Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) are useful tools for identifying clinically homogeneous subsets and predicting prognosis of patients with idiopathic inflammatory myopathies (IIM) including polymyositis (PM) and dermatomyositis (DM). Recent studies have shown that anti-NXP2 antibody (Ab) is a major MSA in juvenile dermatomyositis (JDM). In this study the frequencies and clinical associations of anti-NXP2 Ab were evaluated in adult patients with IIM. METHODS: Clinical data and serum samples were collected from 507 adult Japanese patients with IIM (445 with DM and 62 with PM). Eleven patients with JDM, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with idiopathic pulmonary fibrosis were assessed as disease controls. Serum was examined for anti-NXP2 Ab by immunoprecipitation and western blotting using polyclonal anti-NXP2 Ab. RESULTS: Seven patients (1.6%) with adult DM and one (1.6%) with adult PM were positive for anti-NXP2 Ab. Except for two patients with JDM, none of the disease controls were positive for this autoantibody. Among eight adult patients with IIM, three had internal malignancies within 3 years of diagnosis of IIM. Another patient with DM also had a metastatic cancer at the diagnosis. All of the carcinomas were at an advanced stage (stage IIIb-IV). CONCLUSIONS: While less common than in juvenile IIM, anti-NXP2 Ab was found in adult IIM. Anti-NXP2 Ab may be associated with adult IIM with malignancy.

Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins.

OBJECTIVE: To identify the 140-kd autoantigen recognized by anti-155/140 autoantibodies that are associated with adult cancer-associated dermatomyositis (DM) and juvenile DM and to determine the clinical relevance of anti-155/140 antibodies in a large cohort. METHODS: Sera from 456 DM patients were assessed for the presence of anti-155/140 antibodies by immunoprecipitation using K562 cell extracts as substrate. Using immunoprecipitation and Western blotting, we then examined whether anti-155/140-positive sera recognized transcription intermediary factor 1α (TIF-1α), TIF-1ß, and TIF-1γ. The clinical associations of antigen reactivity were also evaluated. RESULTS: Anti-155/140-positive sera reacted with 140-kd TIF-1α in addition to 155-kd TIF-1γ. Among sera from 456 DM patients, 52 were reactive with both TIF-1α and TIF-1γ, while another 25 were reactive with TIF-1γ alone. Additionally, 7 were reactive with TIF-1ß. Malignancy was more frequently found in adult patients with both anti-TIF-1α and anti-TIF-1γ antibodies than in those with anti-TIF-1γ antibodies alone (73% versus 50%; P < 0.05). In addition to juvenile DM patients and middle-aged and older DM patients with high percentages of malignancy, 8 "young adult" DM patients without malignancy had these autoantibodies. CONCLUSION: Anti-155/140 antibodies target TIF-1 family proteins, TIF-1α and TIF-1ß, in addition to TIF-1γ. Since TIF-1 proteins have significant roles in oncogenesis, these antibodies may be produced during misdirected antitumor immunity.

Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study.

OBJECTIVE: To clarify the association of clinical and prognostic features with dermatomyositis (DM)-specific autoantibodies (Abs) in adult Japanese patients with DM. DESIGN: Retrospective study. SETTING: Kanazawa University Graduate School of Medical Science Department of Dermatology and collaborating medical centers. Patients A total of 376 consecutive adult Japanese patients with DM who visited our hospital or collaborating medical centers between 2003 and 2008. MAIN OUTCOME MEASURES: Clinical and laboratory characteristics of adult Japanese patients with DM and DM-specific Abs that include Abs against Mi-2, 155/140, and CADM-140. RESULTS: In patients with DM, anti-Mi-2, anti-155/140, and anti-CADM-140 were detected in 9 (2%), 25 (7%), and 43 (11%), respectively. These DM-specific Abs were mutually exclusive and were detected in none of 34 patients with polymyositis, 326 with systemic sclerosis, and 97 with systemic lupus erythematosus. Anti-Mi-2 was associated with classical DM without interstitial lung disease or malignancy, whereas anti-155/140 was associated with malignancy. Patients with anti-CADM-140 frequently had clinically amyopathic DM and rapidly progressive interstitial lung disease. Cumulative survival rates were more favorable in patients with anti-Mi-2 compared with those with anti-155/140 or anti-CADM-140 (P < .01 for both comparisons). Nearly all deaths occurred within 1 year after diagnosis in patients with anti-CADM-140. Conclusion Dermatomyositis-specific Abs define clinically distinct subsets and are useful for predicting clinical outcomes in patients with DM.

Intractable genital ulcers from herpes simplex virus reactivation in drug-induced hypersensitivity syndrome caused by allopurinol.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS/DRESS) is a severe adverse systemic reaction. Reactivation of human herpesvirus (HHV) family members other than HHV-6 has been reported in patients with DIHS. Reactivation of HHV family members is generally characterized by increased serum antibody titers against the virus. By contrast, clinical symptoms caused by viral reactivation are relatively rare. METHOD: We report a case of DIHS with intractable genital ulcers from reactivation of herpes simplex virus (HSV) in accordance with reactivation of HHV-6 and cytomegalovirus (CMV). RESULT: Twenty-two days after the onset of the rash, the patient developed intractable genital ulcers that were resistant to treatment. Histological examination of the ulcers revealed necrotic degeneration in the epidermal cells, with giant cells containing inclusion bodies and marked lymphocytic infiltration in the upper dermis. Immunohistochemical staining with antibodies reactive to HSV or CMV showed that these giant cells were positive for HSV but negative for CMV. CONCLUSION: Genital herpes is a common skin disease. However, our case was considered to be a DIHS-associated symptom, not an accidental complication, as the symptoms were severe and resistant to treatment.

Clinical and pathological findings of interstitial lung disease patients with anti-aminoacyl-tRNA synthetase autoantibodies.

OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics of interstitial lung disease (ILD) patients with anti-aminoacyl-tRNA synthetase (anti-ARS) autoantibodies. Patients and Methods We examined 14 ILD patients with anti-ARS autoantibodies between 2004 and 2007 and retrospectively investigated their clinical, radiographic, and pathological findings. RESULTS: Anti-Jo-1 antibodies were the most common (10 of 14), followed by anti-OJ, anti-KS, and anti-EJ (1 each for 3 patients); 1 patient with polymyositis had both anti-Jo-1 and anti-PL-12 antibodies. Ten patients had a chronic clinical course, whereas 4 presented with subacute deterioration. Of 8 patients with myositis, 1 (12.5%) had myositis-preceding ILD, 3 (37.5%) had ILD-preceding myositis, and 4 (50%) had simultaneous onset. Chest high-resolution computed tomography frequently showed lung-base predominant ground glass opacities (GGO) with volume loss. The results of surgical lung biopsies indicated that 4 patients had nonspecific interstitial pneumonia (NSIP) and/or organizing pneumonia (OP) patterns. All but 1 received corticosteroid therapy, and 6 patients were also given cyclosporin. The mean duration of follow-up was 22 months (range, 5-47 months). ILD improved in 9 patients and stabilized in 3; however, in 1 patient, it initially improved during 6 months, then progressively worsened despite treatment, and finally resulted in death. CONCLUSION: These results indicate that ILD patients with anti-ARS antibodies usually have a chronic clinical course, lung-base predominant GGO with volume loss, NSIP and/or OP patterns, and a good response to corticosteroid treatment; however, some have a rapidly worsening course and recurrence, despite therapy.

Drug eruption due to intravesical instillations of both epirubicin and mitomycin C.

We present the first patient to develop drug eruption due to intravesical instillations of both epirubicin and mitomycin C. A 58-year-old-man underwent transurethral resection (TUR) for superficial bladder carcinoma followed by instillations of intravesical chemotherapy. Immediately after TUR, the first instillation of epirubicin was performed. Two days after the first instillation, the patient developed generalized erythema of the face, trunk, upper and lower limbs. Two days after the second instillation, the patient developed severe generalized erythema and was diagnosed as having drug eruption due to intravesical instillations of epirubicin by the dermatologist. Instead of epirubicin, mitomycin C was instilled 2 weeks postoperatively. Two days after the first instillation of mitomycin C, the patient again developed severe generalized erythema and was diagnosed as having drug eruption due to intravesical instillation of mitomycin C. Drug eruption after the first instillation of epirubicin might have been due to drug toxicity of the agent. However, drug eruptions after the second instillation of epirubicin and the first instillation of mitomycin C might have been due to allergic reactions to the drugs. The patient has not received any further intravesical chemotherapy and has not demonstrated any such a drug eruption again.

Reduced red blood cell velocity in nail-fold capillaries as a sensitive and specific indicator of microcirculation injury in systemic sclerosis.

OBJECTIVE: To assess red blood cell velocity in finger nail-fold capillaries using video capillaroscopy in patients with SSc and other collagen diseases. METHODS: This study included 127 patients with SSc as well as patients with SLE (n = 33), DM/PM (n = 21), RA (n = 13) and APS (n = 12), and 20 healthy subjects. Red blood cell velocity was evaluated using frame-to-frame determination of the position of capillary plasma gaps. RESULTS: The mean red blood cell velocity was significantly decreased in patients with SSc compared to healthy controls (63.0% reduction) and patients with other conditions. Mean blood velocity was similar between patients with dcSSc and lcSSc. Importantly, even SSc patients with normal or non-specific nail-fold video capillaroscopic (NVC) patterns or a scleroderma early NVC pattern exhibited a significantly lower red blood cell velocity compared to healthy controls (51.7 and 61.4% reduction, respectively) or patients with other conditions, despite normal or mild capillary changes. Patients with the scleroderma active and late NVC pattern showed a more decreased blood velocity (65.5 and 66.2% reduction, respectively). This reduced blood velocity was significantly associated with NVC findings, including capillary ramification and capillary loss. Although remarkably reduced velocity was observed in SSc patients with intractable digital ulcers (72.1% reduction), it was significantly improved by lipo-prostaglandin E(1) (lipo-PGE(1)) infusion. CONCLUSION: Our results suggest that reduced blood velocity is a hallmark of SSc. Furthermore, measurement of red blood cell velocity may be useful in evaluating therapeutic effects on microcirculation.

Antigen specificity of antihistone antibodies in connective tissue disease patients with anti-U1RNP antibodies.

To determine the prevalence of antibodies to individual histone components in collagen disease patients with anti-U1RNP antibodies. Serum samples were examined by enzyme-linked immunosorbent assay. Patients with mixed connective tissue disease (MCTD) and systemic sclerosis (SSc) showed similar levels and patterns of antihistone antibody (AHA) reactivities to individual histones: IgG responses to H2B or H3 and IgM responses to H2B were highest. However, both IgG and IgM AHAs against outer portion of chromatin (H1, H2A, or H2B) were generally higher in SLE compared with other diseases. SLE or SSc patients with anti-U1RNP antibodies showed generally higher AHA levels than in those without them. Thus, the pattern of reactivities to each histone component was dependent on the disease, while the intensity was dependent on both the disease and anti-U1RNP antibodies. The antigenic stimulus in SLE may be different from other connective tissue diseases and is more likely to be native chromatin.

Clinical evaluation of anti-aminoacyl tRNA synthetase antibodies in Japanese patients with dermatomyositis.

OBJECTIVE: To investigate the distribution of anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies among patients with autoimmune diseases, and to analyze the clinical features of patients with dermatomyositis (DM) with anti-ARS antibodies. METHODS: Serum samples from 315 patients with autoimmune diseases or related disorders who had visited Kanazawa University Hospital or affiliated facilities were assessed for anti-ARS antibodies by immunoprecipitation. In particular, the association between anti-ARS antibodies and clinical features was investigated in detail in patients with DM. RESULTS: Anti-ARS antibody was positive in 16 (29%) of 55 patients with DM, 2 (22%) of 9 patients with polymyositis, and 7 (25%) of 28 patients with idiopathic pulmonary fibrosis. Although anti-ARS antibody was detected with high frequency (63%, 15/24) in DM patients with interstitital lung disease (ILD), the incidence of anti-ARS antibody was very low (3%, 1/31) in DM patients without ILD. Anti-ARS antibody-positive patients with DM had significantly higher incidences of ILD (94% vs 23%) and fever (64% vs 10%) than the antibody-negative patients. Some immunosuppressive agents, in addition to oral corticosteroids, were required more frequently in the antibody-positive patients with DM than the antibody-negative patients (88% vs 26%). Although 60% of DM patients with ILD simultaneously developed ILD and myositis, ILD preceded myositis in 33% of patients. CONCLUSION: Among patients with DM, anti-ARS antibodies are found in a subset with ILD. DM patients with anti-ARS antibodies appear to have a more persistent disease course that requires additional therapy compared to those without anti-ARS antibodies.

Scleroderma renal crisis in a patient with anticentromere antibody-positive limited cutaneous systemic sclerosis.

We have encountered a 68-year-old Japanese woman with limited cutaneous systemic sclerosis who developed de novo onset of accelerated hypertension and renal dysfunction; thus we diagnosed scleroderma renal crisis. Anticentromere antibody alone was identified, and not anti-DNA topoisomerase I antibody, anti-RNA polymerase antibodies, anti-Th/To antibodies, or antiribonucleoprotein antibodies, even with use of immunoprecipitation assay. She was successfully treated with angiotensin-converting enzyme inhibitor. This case, scleroderma renal crisis with detection of anticentromere antibody, is thought to be extremely uncommon.

Multiple small pulmonary emboli associated with transient antiphospholipid syndrome in human Parvovirus B19 infection.

Antiphospholipid antibodies (aPL) have been reported to occur in several conditions other than antiphospholipid syndrome, including infections. We herein report the case of a 21-year-old Japanese woman with Parvovirus B19 infection, who developed multiple pulmonary emboli associated with aPL, a lupus anticoagulant and IgM anticardiolipin antibody. Eight weeks later, antiphospholipid antibodies spontaneously disappeared and normal pulmonary flow was observed. Considering the high prevalence of Parvovirus B19 infection, we should be aware of thrombosis associated with transient aPL antibodies in this infectious disease.