Effective plasma concentrations of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in the remission-maintenance phase

What is known and Objective: Mycophenolate mofetil (MMF) has been reported recently to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) in SLE in the remission‐maintenance phase remains to be clarified. The aim of this study was to evaluate the therapeutic efficacy of MMF and predose plasma concentrations of MPA and its phenolic glucuronide (MPAG) in patients with SLE in the remission‐maintenance phase. Methods: Thirty‐one patients with SLE receiving a fixed dosage regimen of MMF (median and interquartile range, 1500 and 1000–2000 mg/day) for at least 1 month and who had not experienced any adverse drug reactions for more than 3 months were enrolled. Results: Significant improvement was observed after MMF administration in total haemolytic complement CH₅₀ and its fractions C3 and C4, immunoglobulins IgG, IgA and IgM, anti‐dsDNA antibody, serum concentration of albumin and red blood cell count, even though the mean daily dose of prednisolone was significantly reduced (P = 0·02). Median predose plasma concentrations of MPA and MPAG were 1·95 and 26·2 μg/mL (interquartile ranges, 0·94–2·96 and 18·6–53·7 μg/mL). Predose plasma concentrations of MPA and MPAG correlated significantly with MMF dose (r = 0·64, P < 0·01 and r = 0·39, P = 0·03). What is new and Conclusions: MMF improved clinical laboratory markers and reduced prednisolone dosage in SLE patients with predose plasma concentration of MPA and MPAG in the interquartile ranges of 0·94–2·96 and 18·6–53·7 μg/mL, respectively.     

Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain–containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-γ and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-γ and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients.     

Nephritis in systemic lupus erythematosus

Summary Nephritis in systemic lupus erythematosus is a prototype for immune complex mediated renal disease in man. The renal manifestations are pleomorphic in their expression. In the past 25 years, the natural history of the disease and its response to treatment have been related to the renal histology seen when the patient was initially studied. Patients with normal kidneys and those with membranous nephropathy have five-year survivals that are excellent and uninfluenced by treatment. Patients with mesangial disease may be a heterogeneous population — those with deposits doing comparatively worse; focal and diffuse proliferative nephritis carry a poorer prognosis. Extensive studies in the relatively homogeneous NZB/NZW F1 hybrid mouse have led to a better understanding of human lupus nephritis. Critical factors in getting a good response involve not only selection of the appropriate drug but also its mode of administration and timing in relation to the course of the disease. Intelligent treatment must be based on an understanding of etiopathogenesis. Recent studies have cast some light on the role of the mediators of inflammation, e.g. platelets, fibrinolysis, and the modulating role of the reticuloendothelial system. Future studies must take these into account in the discovery and evaluation of new forms of therapy. This work was supported in part by National Institutes of Health, grants AM 17196 and AM 20711.     

Advances in systemic lupus erythematosus

To help to understand recent progresses in studies on systemic lupus erythematosus (SLE), the essence of the Fifth International Conference on SLE that was successfully held at Cancun, Mexico on April, 1998 is reviewed. Among more than 400 papers, most highlighted topics were (1) relationship between hyperprolactinemia and SLE, (2) molecular mechanisms of antiphospholipid syndrome, (3) roles of anti-endothelial cell antibodies, (4) apoptosis in pathogenesis, (5) autoimmunity against nucleosomes, (6) penetration of autoantibodies into living cells, and so on. Clinical studies on adverse effects of current therapies, pioneer cases of autologous stem cell transplantation for refractory SLE, and other numerous cases that were full of suggestiveness were also reported by physicians from many countries.     

Neuropsychiatric systemic lupus erythematosus

The systemic lupus erythematosus (SLE) patients with neuropsychiatric complaints requires a comprehensive and timely diagnostic approach. Despite the obvious difficulties in diagnosing neuropsychiatric SLE, the neurologic complications of SLE can be approached in a careful, logical manner with gratifying results.     

儿童系统性红斑狼疮

儿童系统性红斑狼疮，是指儿童包括青春期前后起病的系统性红斑狼疮。其临床特点、诊断及治疗既与成人大体相似，又有其自身的特点。本文介绍了儿童系统性红斑狼疮的临床特点及诊疗要点。     

Diagnosis of systemic lupus erythematosus

Systemic lupus erythematosus is a multisystem inflammatory disease that is often difficult to diagnose. Before the diagnosis can be established, four of 11 clinical and laboratory criteria must be met. Antinuclear antibody titer is the primary laboratory test used to diagnose systemic lupus erythematosus. Because of the low prevalence of the disease in primary care populations, the antinuclear antibody titer has a low predictive value in patients without typical clinical symptoms. Therefore, as specified by the American College of Rheumatology, this titer should be obtained only in patients with unexplained involvement of two or more organ systems. Patients with an antinuclear antibody titer of 1:40 and characteristic multiorgan system involvement can be diagnosed with systemic lupus erythematosus without additional testing; however, patients with an antibody titer of 1:40 who fail to meet full clinical criteria should undergo additional testing, including tests for antibody to double-stranded DNA antigen and antibody to Sm nuclear antigen. While an antinuclear antibody titer of less than 1:40 usually rules out systemic lupus erythematosus, patients with persistent, characteristic multisystem involvement may be evaluated for possible antinuclear antibody-negative disease.     

Amyloidosis in systemic lupus erythematosus]

Based on the authors' experience from 1982 to 1990 it was noted that out of 26 cases of renal amyloidosis in the presence of nonpurulent and purulent conditions 2 patients (7%) demonstrated the association with systemic lupus erythematosus (SLE). It was also noted that amyloidosis developed in the patients with a long history of the disease. Long-course immunosuppression treatment could be regarded as the other factor-of-risk for amyloidosis development. Histochemical examination of both patients demonstrated that amyloid deposits in the renal glomeruli were resistant to the potassium permanganate effect and consisted of AL-protein. The results obtained indicated the possibility of appearance of immunoglobulins AL--the proteins of the primary amyloidosis--synthesized in the spectrum in the SLE presence as well as their deposition in the renal glomeruli. As a possible cause of proteinuria and the nephrotic syndrome in SLE patients amyloidosis should be diagnosed in the life time and be regarded in the choice of therapeutic policy as well as in the assessment of pulse immunosuppressive therapy practicability.     

Aortal defects in systemic lupus erythematosus

Five patients with significant lupus erythematosus (SLE) are described. The use of ECG, PCG and ultracardiosonography made it possible to verify the diagnosis of aortal valvular disease. On recognition of the damage to the aortal valves the question arises as to the genesis of its occurrence: does it occur because of the lupoid process proper or superaddition of bacterial endocarditis? The similar signs of SLE and bacterial endocarditis are described as are differential and diagnostic criteria. The main mechanisms by which the aortal valvular disease develops in SLE are depicted. Four out of the 5 patients described had bilateral sacroileitis and were not HIA-B27 carriers.