A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study.

OBJECTIVE: To evaluate the efficacy and safety of subcutaneous blisibimod, an inhibitor of B cell activating factor, in patients with systemic lupus erythematosus (SLE) in a dose-ranging Phase 2b clinical trial. METHODS: 547 patients with SLE with anti-double stranded DNA or antinuclear antibodies and Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline were randomised to receive placebo or blisibimod at one of 3 dose levels. The primary end point, measured at Week 24, was the SLE Responder Index-5 (SRI-5, meeting established SRI criteria but with ≥5 point improvement in SELENA-SLEDAI). RESULTS: Although SRI-5 response rates were not significantly improved in the pooled blisibimod groups compared with placebo, they were higher in subjects randomised to the highest dose of blisibimod (200 mg once-weekly (QW)) compared with pooled placebo, from Week 16 to Week 24, reaching statistical significance at Week 20 (p=0.02). SRI response rates compared with placebo were higher still in subjects who attained SELENA-SLEDAI improvements of ≥8, and in a subgroup of patients with severe disease (SELENA-SLEDAI ≥10 and receiving corticosteroids at baseline). In subjects with protein:creatine ratios of 1-6 at baseline, significant reductions in proteinuria were observed with blisibimod. Significant (p<0.01) changes in anti-double stranded DNA antibodies, complement C3 and C4, and reductions in B cells were observed with blisibimod.No imbalances in serious adverse events or infections (4/280 and 3/266), deaths (4/280 and 3/266) and malignancies (2/280 and 2/266) were reported for blisibimod compared with placebo. CONCLUSIONS: This study successfully identified a safe, effective and convenient dose, study population and end point for evaluation of blisibimod effect in Phase 3. TRIAL REGISTRATION NUMBER: NCT01162681.

Therapeutic potential of interleukin-6 antagonism in bipolar disorder.

Bipolar disorder (BD) is a chronic, severe, and highly disabling psychiatric disorder. Its underlying neurobiology remains largely unclear. A significant body of evidence indicates that inflammatory activation expressed by increased cytokines is relevant in its pathophysiology. IL-6 is one of the most important cytokines involved in the pathogenesis of immune and inflammatory disorders. Several studies recently showed increased levels of IL-6 in manic and depressive episodes and also during euthymia in subjects with BD. Tocilizumab is an IL-6 receptor antagonist being marketed for the treatment of rheumatoid arthritis and Castleman's disease. In this article we discuss the possibility that tocilizumab may have a therapeutic role in treatment of BD through its anti-inflammatory action.

Rituximab in refractory autoimmune diseases: Brazilian experience with 29 patients (2002-2004).

OBJECTIVE: Rituximab, a monoclonal antibody against B-lymphocytes that express CD 20, is already available for the treatment of non-Hodgkin's lymphoma. Due to the increased relevance of B-cell regulation in the pathogenesis of autoimmune diseases, rituximab is being used in the treatment of patients whose condition is refractory to conventional therapy. METHODS: We retrospectively evaluated the short-term efficacy and tolerance of rituximab in patients with various autoimmune diseases who were treated at the Hospital Israelita Albert Einstein in the city of Sao Paulo. RESULTS: During the period 2002-2004, 29 patients with various autoimmune diseases were treated with rituximab 375 mg/m2 for 4 consecutive weeks, or two doses of 1 g 2 weeks apart. We observed remarkable short-term results in all cases, except for one patient with thrombocytopenic purpura. Of note, we describe the results in two patients with diseases not previously treated with rituximab (hypergammaglobulinemic purpura of Waldenstrom and eosinophilic fasciitis with hypergammaglobulinemia). Treatment was well tolerated, with no unexpected adverse events. We also observed a marked reduction in steroid dosage. CONCLUSION: Rituximab seems to be safe and effective in the treatment of patients with a variety of autoimmune diseases that are refractory to other modalities of treatment.

Serum vascular endothelial growth factor in late rheumatoid arthritis.

OBJECTIVES: To investigate the serum levels of VEGF in patients with rheumatoid arthritis of long duration. METHODS: Serum VEGF levels were measured in 118 patients with long-standing rheumatoid arthritis according to the ACR criteria (mean duration 12 years). The disease activity score was evaluated by the method of van der Heijde et al. RESULTS: Serum levels of VEGF in patients with RA were significantly higher than in healthy controls. VEGF levels showed no correlation with CRP, SAA amyloid protein, or the disease activity score. CONCLUSIONS: Our findings suggest that, contrary to the results reported in patients with early onset RA, where VEGF appears to play an active part in joint inflammation, in long-standing RA elevated VEGF serum levels may be an independent marker although its significance remain to be established.

Interleukin 6: a possible marker of disease activity in adult onset Still's disease.

OBJECTIVE: Adult onset Still's disease (AOSD) is an inflammatory disorder with elevated serum acute phase proteins. Interleukin-6 is a major contributor to the acute phase response. We therefore examined the serum levels of CRP, SAA and interleukin-6 in active and inactive AOSD. RESULTS: Active patients had significantly elevated CRP, SAA, and interleukin-6 values. After steroid treatment a marked reduction was observed in all three parameters. There was a close kinetics on the fluctuations of CRP and SAA, but not on IL-6. CONCLUSION: Acute phase proteins and IL-6 are useful markers of disease activity in AOSD.

Immunological status of ENL (erythema nodosum leprosum) patients: its relationship to bacterial load and levels of circulating IL-2R.

Recent data suggest that the clinical course of reactional states in leprosy is closely related to the cytokine profile released locally or systemically by the patients. In the present study, patients with erythema nodosum leprosum (ENL) were grouped according to the intensity of their clinical symptoms. Clinical and immunological aspects of ENL and the impact of these parameters on bacterial load were assessed in conjunction with patients' in vitro immune response to mycobacterial antigens. In 10 out of the 17 patients tested, BI (bacterial index) was reduced by at least 1 log from leprosy diagnosis to the onset of their first reactional episode (ENL), as compared to an expected 0.3 log reduction in the unreactional group for the same MDT (multidrug therapy) period. However, no difference in the rate of BI reduction was noted at the end of MDT among ENL and unreactional lepromatous patients. Accordingly, although TNF-alpha (tumor necrosis factor) levels were enhanced in the sera of 70.6% of the ENL patients tested, no relationship was noted between circulating TNF-alpha levels and the decrease in BI detected at the onset of the reactional episode. Evaluation of bacterial viability of M. leprae isolated from the reactional lesions showed no growth in the mouse footpads. Only 20% of the patients demonstrated specific immune response to M. leprae during ENL. Moreover, high levels of soluble IL-2R (interleukin-2 receptor) were present in 78% of the patients. Circulating anti-neural (anti-ceramide and anti-galactocerebroside antibodies) and anti-mycobacterial antibodies were detected in ENL patients' sera as well, which were not related to the clinical course of disease. Our data suggest that bacterial killing is enhanced during reactions. Emergence of specific immune response to M. leprae and the effective role of TNF-alpha in mediating fragmentation of bacteria still need to be clarified.

[Natural history of systemic lupus erythematosus: the experience at the Arnaldo Vieira de Carvalho Cancer Institute]. / A história natural do lúpus eritematoso sistêmico: experiência do Instituto do Câncer "Arnaldo Vieira de Carvalho".

The authors present an evaluation of sixty patients with SLE who were observed at the "Arnaldo Vieira de Carvalho" Cancer Institute from 1980 to 1988. Their findings were compared to findings of other international series. Some differences were observed in the frequency of clinical manifestations, laboratory findings, and mortality.

Effect of tenoxican on inflammation and immune cellular function

1. We have shown that nonsteroidal anti-inflammatory drugs are potent inhibitors of neutrophil activation. tenoxican is a new compound of the oxican family which has been shown to be effective for routine clinical use. 2. In the present study we examined the immune pharmacological effects of this compound on lymphocyte function by determining its efffect on the expression of IL-2 receptors, on monocyte function by looking at chemotaxis and IL-1 release and on release and on neutrophil function by evaluating the chemotactic response to a standard stimulus. 3. The data show that Tenoxican inhibits the neutrophil and monocyte functional chemotactic response in vitro, and to some extent in vivo for monocytes, but has no effect onthe expression of IL-2 receptors or IL-1 release. Tenoxicam inhibits the mobilization of neutrophils and monocytes to inflamatory sites, even thought this effect was not clearly demonstrable when cells were tested after oral use

Amyloidosis secondary to gout. Identification with a monoclonal antibody to amyloid protein A.

A patient with amyloidosis secondary to polyarticular gout is presented in whom amyloid protein A (AA) was demonstrated in the kidney with a monoclonal antibody against protein A. The rarity of this association is discussed and a pathogenetic mechanism proposed.

The effect of gold salts on casein-induced macrophage activation and serum amyloid protein SAA levels.

Previous work from our laboratory has demonstrated a marked inhibitory activity of Auranofin (Au) and Gold Sodium Aurothiomalate (GST) on monocyte-macrophage function and an important role for macrophages in the pathogenesis of casein-induced experimental amyloidosis. In the present study we have looked at the in vivo effect of Au and GST on the inhibition of casein-induced macrophage activation and serum SAA levels. Au and GST markedly inhibited casein-induced macrophage activation while only Au reduced serum SAA levels to a significant degree. The present data raises the possibility that Au may be helpful in the treatment of secondary amyloid disease.

Chemical classification of hereditary amyloidosis in Brazilian families and identification of gene carriers.

Plasma prealbumin was isolated from individuals in 3 kindreds from Brazil with biopsy proven heredofamilial amyloidosis as well as from a number of asymptomatic family members. The prealbumin samples were cleaved with cyanogen bromide and the resulting peptide mixtures separated by reverse phase high performance liquid chromatography. The peptide elution pattern seen for the individuals with confirmed amyloidosis is consistent for the presence of a prealbumin variant with a methionine for valine at position 30 of the molecule. Sequence analysis of the isolated peptides confirms this observation and shows that the 3 Brazilian families investigated in our study have the same prealbumin variant as individuals with amyloidosis of Swedish/American, Portuguese and Japanese origins.