Scl-86, a marker antigen for diffuse scleroderma.

More than 300 sera from patients with a connective tissue disease were analyzed with the immunoblotting technique. The presence of autoantibodies against an 86,000-mol wt marker antigen for diffuse scleroderma (Scl-86) was found in 14 out of 33 patients with scleroderma. The presence of anti-Scl-86 antibodies seemed to correlate with the diagnosis of diffuse scleroderma since they were found in 13 out of 22 diffuse scleroderma patients and in only one out of 11 patients with limited scleroderma. All scleroderma sera (33 patients' sera and 13 reference sera) were also tested for the presence of anti-Scl-70 antibodies. It was found that all anti-Scl-70 positive sera (n = 25) contained anti-Scl-86 antibody as well, suggesting a relationship between these two antigens. However, the Scl-86 antigen was shown to be an extremely insoluble nonchromosomal protein, resistant to boiling in sodium dodecyl sulfate. This contrasts with the Scl-70 antigen, which has been described as a thermolabile, soluble antigen present in the chromatin fraction. Together, our results are consistent with the idea that Scl-70 is a degradation product of Scl-86. The Scl-86 antigen is present in freshly prepared rabbit thymus, spleen, and liver nuclei as well as in nuclei from various cultured cell lines, but is not detectable in extractable nuclear antigen from rabbit thymus. In a limited retrospective study, the anti-Scl-86 antibodies were found in two sera from patients with Raynaud's phenomenon before the development of diffuse scleroderma. Therefore, it is possible that screening of patients' serum for this antibody might predict the development of diffuse scleroderma.     

Antimyenteric neuronal antibodies in scleroderma.

The pathogenesis of gastrointestinal (GI) dysmotility in scleroderma is incompletely understood, although previous studies have proposed a neuropathic mechanism. We studied patients with scleroderma as compared with other connective tissue disease patients and normal controls for the presence of circulating antibodies to myenteric neurons. Serial dilutions of sera were overlaid on rat intestine, double-labeled with antineurofilament antibody as a myenteric plexus marker, and imaged using indirect immunofluorescence techniques. High titer sera (> or = 1:50) from 19 out of 41 scleroderma patients stained myenteric neurons, whereas none of 22 normals or 5 patients with idiopathic GI dysmotility were positive. Although 6 out of 20 SLE and 6 out of 10 mixed connective tissue disease patients' sera stained myenteric plexus neurons, when positive sera were absorbed with calf thymus extract to remove antinuclear antibody, 15 scleroderma sera, 0 SLE, and 2 mixed connective tissue disease patients retained positive staining of myenteric neurons. Western blotting using actin and neuronal intermediate filament preparations failed to show immunoreactivity with scleroderma sera containing antimyenteric neuronal antibodies. Paraneoplastic sera associated with GI dysmotility stained myenteric neurons in a different pattern than seen with scleroderma sera. A positive correlation between the presence of Raynaud's phenomenon and antimyenteric neuronal antibodies was observed in scleroderma patients. Our results indicate that IgG antibodies reacting with myenteric neurons are present in many patients with scleroderma. Although the neuronal antigen has not yet been identified, the presence of myenteric neuronal antibodies in patients with GI dysmotility and scleroderma suggests a neuropathic process.     

Association of anti-centromere and anti-Scl 70 antibodies in scleroderma. Report of two cases

In testing for antinuclear antibodies the sera of 121 patients affected with scleroderma, we found in 2 of them the concurrent presence of anti-centromere and anti-Scl 70 antibodies. Since the association of these antibodies has never been reported, to the best of our knowledge, we report the clinical and serological features of the 2 patients. Both subjects were women with an incomplete CREST syndrome (RST), a relatively limited involvement of the skin, a mild pulmonary fibrosis without apparent signs of other visceral involvement. On the other hand, the clinical course of the disease was different in the 2 cases. One patient had a longer disease duration and up to date the clinical features appear to be unchanged; the other had a shorter disease duration, when suddenly she died of cardiac arrest.     

Cocaine and scleroderma

I have described a patient with scleroderma whose sex, age at onset of symptoms, and history of long-term intravenous use of cocaine suggest a possible causative role of cocaine in his disease.     

Cloning and characterization of the cDNA coding for a polymyositis- scleroderma overlap syndrome-related nucleolar 100-kD protein

About 50% of patients with the polymyositis-scleroderma overlap syndrome are reported to have autoantibodies to a nucleolar particle termed PM/Scl. The particle consists of several polypeptides of which two proteins of 75 and 100 kD have been identified as the major antigenic components. Here we report on the cDNA cloning and partial epitope mapping of the 100-kD autoantigen from human placenta and HeLa lambda gt11 libraries. The deduced amino acid sequence encodes a protein of 885 amino acid residues with a molecular mass of 100.8 kD. Rabbit antibodies raised against a recombinant protein fragment reacted in immunofluorescence and immunoblotting in the same manner as human autoantibodies directed against the nucleolar 100-kD protein. Sequence analysis shows close homology to a consensus sequence of 12 amino acids from serine/threonine kinases, suggesting a possible function for this autoantigen. A major antigenic region is found to be located within the NH2-terminal third of the polypeptide.     

Monoclonal antibodies currently in Phase II and III trials for multiple myeloma

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option.

Areas covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options.

Expert opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.     

原发性胆汁性肝硬化患者抗SP100抗体与核点型抗核抗体的检测

目的探讨抗SP100抗体与核点型抗核抗体对原发性胆汁性肝硬化(PBC)患者的临床意义。方法选取PBC患者100例,60例自身免疫性肝炎(AIH)患者、50例慢性乙型肝炎(HB)患者和50例慢性丙型肝炎(HC)患者作为疾病对照组,50例献血员(BD)作为健康人对照组。间接免疫荧光法(IFA)检测自身抗体,免疫印迹法检测抗SP100抗体。结果IFA法检测结果,抗核抗体(ANA)阳性57例,抗线粒体抗体(AMA)阳性100例,抗平滑肌抗体(SMA)阳性3例,细胞骨架抗体(CS)阳性5例。免疫印迹法检测PBC患者抗SP100阳性16例(阳性率16.0%),AIH患者抗SP100阳性4例(6.7%),HB、HC、BD对照均阴性。PBC患者抗SP100阳性组与阴性组ANA滴度比较,差异无统计学意义;抗SP100阳性组93.8%(15/16)表现核点型ANA,其次表现核点合并核膜型,而抗SP100阴性组主要表现核膜型(70.7%),其次为着丝点型、颗粒型等。PBC患者抗SP100阳性患者与阴性患者ALT、AST、TB il、GGT、ALP、IgG、IgA、IgM水平差异均无统计学意义(P>0.05)。结论抗SP100抗体阳...     

Myenteric neuronal antibodies in scleroderma: passive transfer evokes alterations in intestinal myoelectric activity in a rat model.

Although the mechanism for neuropathic gastrointestinal motility disturbances in scleroderma is unknown, we have previously described anti-myenteric antibodies in some patients with scleroderma. The aim of this study was to screen patients with scleroderma who had gastrointestinal symptoms for the presence of anti-myenteric neuronal antibodies and then purify the immunoglobulin G (IgG) fraction from serum samples for passive immunization into a rat model and observe for intestinal motility effects. Patients with scleroderma were screened, a serum sample from a patient with high titer anti-myenteric neuronal antibodies was obtained, and IgG was purified. Using a rat model with chronic indwelling intestinal electrodes to measure intestinal myoelectric activity, we passively transferred the IgG from either control subjects or this patient with scleroderma. We immunosuppressed the rats and intraperitoneally injected IgG from control subjects and this patient with scleroderma daily for 7 days. Recordings of myoelectric activity in control injected rats revealed no difference from baseline, but a prolongation in the activity front duration and interval and a disruption were seen after scleroderma IgG injections. IgG from a patient with scleroderma with antimyenteric neuronal antibodies, when passively immunized into a rat model, evokes intestinal myoelectric activity alterations. We hypothesize that these antibodies could account for the gastrointestinal neuropathic motility disturbances seen in scleroderma.     

Collagenase in scleroderma.

Collagenase activity was measured by direct assay in skins from 12 patients afflicted with systemic sclerosis. In seven of those cases where extensive involvement of the forearm and trunk skin existed, collagenase activity of the involved skin was minimal or absent. Moreover, in the same patient, regions of marked skin involvement (e.g., forearm) showed no collagenase activity, when clinically uninvolved areas (thigh) exhibited normal or nearly normal levels of enzyme activity. In other patients where clinical symptoms were systemic and not associated significantly with the skin, collagenase activity approximated normal levels. Measurements of collagenase activity and tensile strength in another condition (basal cell carcinoma) that includes changes in mechanical properties of skin that any be regarded as the opposite end of the spectrum from those of sclerodermatous skin support a general correlation between collagenase activity and tensile strength. These studies indicate that the major defect responsible for the hidebound skin lesions of scleroderma may be decreased collagenase activity.     

Efficacy and Tolerability of Amlodipine Camsylate/Losartan 5/100-mg Versus Losartan/Hydrochlorothiazide 100/12.5-mg Fixed-Dose Combination in Hypertensive Patients Nonresponsive to Losartan 100-mg Monotherapy

Purpose

The aim of this study was to determine whether the efficacy and tolerability of amlodipine camsylate/losartan 5/100 mg/d (AML/LOS) are noninferior to those of losartan/hydrochlorothiazide 100/12.5 mg/d (LOS/HCTZ) fixed-dose combination in hypertensive patients unresponsive to losartan 100-mg/d monotherapy.

Methods

Male and female patients aged ≥18 years with hypertension despite 4-week, stable treatment with losartan 100-mg/d monotherapy were eligible for inclusion in this multicenter, randomized, double-blind study. Patients were randomly assigned to receive AML/LOS or LOS/HCTZ once daily for 8 weeks. The primary end point was the change from baseline to week 8 in sitting diastolic blood pressure (ΔsiDBP), and the secondary end points were the changes from baseline to 4 weeks in siDBP and sitting systolic BP (ΔsiSBP) and changes from baseline to 4 and 8 weeks in BP response rate. Tolerability was evaluated by physical examination, including vital sign measurement; laboratory analysis; and ECG.

Findings

Of 275 patients screened at 9 cardiovascular centers, 199 were enrolled (AML/LOS, n = 101; LOS/HCTZ, n = 98), and 183 completed the study. The demographic characteristics were similar between the 2 groups (mean age, 51.56 [9.97] years; men, 70.53%). At 8 weeks, the mean ΔsiDBP values were –11.54 (7.89) and –9.05 (6.57) mm Hg in the AML/LOS and LOS/HCTZ groups, respectively (both, P < 0.0001 vs baseline). The mean difference between the 2 groups was –2.57 mm Hg, a nonsignificant difference, meaning that AML/LOS was noninferior to LOS/HCTZ with regard to the primary end point. At 8 weeks, the mean uric acid level was changed significantly from baseline in the LOS/HCTZ group (+0.41 [0.80] mg/dL; P < 0.0001) but not in the AML/LOS group (–0.12 [0.82] mg/dL), representing a significant intergroup difference (P < 0.0001). Nineteen patients each in the AML/LOS (18.81%) and LOS/HCTZ (20.00%) groups experienced ≥1 adverse event, with 4 (3.96%) and 3 (3.16%) patients, respectively, experiencing 1 or more events considered by the investigators to have been treatment related.

Implications

The efficacy and tolerability of AML/LOS 5/100 mg/d was found to have been noninferior to those of LOS/HCTZ 100/12.5 mg/d in these hypertensive patients nonresponsive to losartan 100-mg/d monotherapy.