Bruton's tyrosine kinase inhibition limits endotoxic shock by suppressing IL-6 production by marginal zone B cells in mice.

Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.

Successful transition from intravenous epoprostenol to oral selexipag and inhaled iloprost in a case of severe pulmonary arterial hypertension associated with systemic lupus erythematosus.

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

Infliximab for reversible dementia in acute onset of neuro-Behçet's disease: A case report and cytokine analysis.

We describe a 49-year-old female patient with neuro-Behçet's disease (NBD) with acute onset of fever and symptoms of dementia. High-dose glucocorticoid was partially effective for cognitive impairment, and infliximab, an anti-TNF-α antibody, gradually improved the symptoms. An analysis of cytokines showed that IP-10 in the cerebrospinal fluid was higher than that in the peripheral blood, and both decreased after treatment. This is the first known case of NBD wherein the patient with acute onset of dementia responded to a treatment with infliximab. In glucocorticoid-resistant patients, it is important to consider the introduction of infliximab to prevent irreversible brain dysfunction.

A case of systemic lupus erythematosus with marked ascites due to idiopathic non-cirrhotic portal hypertension.

A 43-year-old-woman admitted to our department because of abdominal pain, abdominal distension, pain on both inner thighs and blurred vision lasting for 3 months. Pancytopenia and positive anti-double stranded DNA (dsDNA) antibodies were noted 5 years prior to her hospitalisation. On admission, the patient was diagnosed with systemic lupus erythematosus (SLE) with retinal vasculitis, panniculitis, cholecystitis and enteritis. The ultrasound test revealed a large amount of ascites, splenomegaly, a hypoechoic band in the liver, and portal hypertension with mildly elevated hepatic venous wedge pressure (15 mmHg). Liver biopsy showed no evidence of hepatitis, cholangitis or liver cirrhosis, leading to the diagnosis of idiopathic non-cirrhotic portal hypertension (INCPH). Prednisolone (PSL) at a daily dose of 50 mg and intravenous cyclophosphamide pulse therapy (IVCY) were initiated for SLE, while diuretics were administered for transudative ascites associated with INCPH. Although these symptoms temporarily improved, 2 months later, SLE and ascites effusion aggravated again, and portal vein thrombosis was confirmed by computed tomography. After increasing the dose of IVCY and adding an anticoagulant agent, all symptoms improved, allowing a reduction of the PSL dose. In the present case, the exacerbation of INCPH was associated with the exacerbation of SLE and the occurrence of portal thrombosis, suggesting an autoimmune and thrombotic mechanism of INCPH. On the other hand, splenomegaly, oesophageal varices, the hypoechoic band remained unchanged, suggesting the established organised INCPH was refractory to immunosuppressive agents.