Rituximab therapy for multisystem autoimmune diseases in pediatric patients.

OBJECTIVE: To evaluate the effects of rituximab (anti-CD20 monoclonal antibody) on the disease course in pediatric patients with multisystem autoimmune diseases. METHODS: Four patients with multisystem autoimmune diseases refractory to conventional immunosuppressive medications, each with central nervous system (CNS) involvement, were treated with four weekly infusions of rituximab. Their clinical and laboratory responses were evaluated. RESULTS: Each of the patients had improvement in clinical symptoms and laboratory parameters. One patient with autoimmune cytopenias and autoimmune CNS and peripheral nervous system disease had resolution of the cytopenias and marked improvement in neurologic symptoms; he currently receives no immunosuppressive medications. Two half-siblings with lymphoplasmacytic colitis, pulmonary nodules, and CNS disease had improvement of their symptoms. A fourth patient with chorea and seizures secondary to primary antiphospholipid antibody syndrome had improvement in fine and gross motor function and reduced seizure frequency. There were no serious adverse events. CONCLUSIONS: The biologic response modifier rituximab, designed to eliminate B lymphocytes, was safe and effective in four pediatric patients with multisystem autoimmune disorders. It appears to be beneficial in autoimmune conditions presumably mediated by a variety of B-cell-related mechanisms, and may decrease or eliminate the need for other immunosuppressive medications.

Impaired postprandial glucose utilization in non-insulin-dependent diabetes mellitus.

The importance of impaired glucose utilization in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) is controversial. Three methods were used to assess glucose utilization following ingestion of a mixed meal in 18 NIDDM and 12 nondiabetic subjects. Dual glucose isotopes were used to determine first-pass splanchnic glucose uptake, suppression of endogenous glucose production, and systemic glucose utilization. Leg balance was used to evaluate skeletal muscle glucose metabolism, and systemic and limb indirect calorimetry were used to assess glucose and lipid oxidation. NIDDM subjects had marked postprandial hyperglycemia as compared with nondiabetics (15.35 +/- 0.72 v 5.83 +/- 0.28 mmol, P < .001), accompanied by lower postprandial insulin (179 +/- 25 v 253 +/- 46 pmol, P < .01) and elevated plasma free fatty acids ([FFA] 569 +/- 34 v 314 +/- 20 mumol/L, P < .001). Cumulative postprandial glucose appearance was nearly twofold greater in NIDDM (82.2 +/- 4.7 v 48.7 +/- 4.9 g.5h, P < .001) due to increased endogenous glucose production (56.4 +/- 4.8 v 24.5 +/- 1.9 g, P < .001), whereas first-pass splanchnic uptake of ingested glucose was normal in NIDDM. Cumulative postprandial glucose utilization in NIDDM, after correction for urinary glucose, was unchanged from postabsorptive rates, a pattern also found for postprandial glucose oxidation. Cumulative leg glucose uptake was somewhat less in NIDDM subjects (123 +/- 18 v 173 +/- 14 mumol/100 mL leg tissue.5 h, P = .06), whereas lactate and alanine net release across the leg were nevertheless twofold greater in NIDDM (P = .04) and accounted for nearly half of the leg glucose metabolism in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance.

BACKGROUND: Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. METHODS: We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. RESULTS: After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. CONCLUSIONS: Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.

Chemical shift imaging of human brain: axial, sagittal, and coronal P-31 metabolite images.

Multivoxel magnetic resonance (MR) spectroscopy and novel data analysis techniques were developed to obtain high-quality phosphorus-31 metabolite images from the human brain and to overlay each metabolite distribution directly onto corresponding hydrogen-1 MR images. The P-31 MR spectroscopic data were acquired by means of three-dimensional chemical shift imaging (phase encoding in three spatial dimensions) on a 1.5-T clinical instrument equipped with a specially designed quadrature P-31 birdcage coil constructed in the authors' laboratory. Axial, sagittal, and coronal metabolite images based on the area for any one of five peak regions (phosphodiester; phosphocreatine; gamma, alpha, and beta adenosine triphosphate) were generated from 8 X 8 X 8 or 12 X 12 X 8 CSI arrays with voxel sizes of 27 cm3 and 12 cm3, respectively. The positions of these images were aligned with anatomic features by means of the voxel-shifting capability of the Fourier transform. Direct overlays of these metabolite images on corresponding proton images demonstrated excellent correlation with anatomy, factors indicating the utility of this technique for viewing P-31 metabolite levels in all areas of the brain simultaneously.

Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM.

To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), we administered an oral glucose load enriched with [14C]glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose, lactate, alanine, O2, and CO2 (with forearm calorimetry). In addition, we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd), suppression of endogenous glucose output, and splanchnic glucose sequestration. During the initial 1-1.5 h after glucose ingestion, plasma glucose increased by approximately 8 mM in NIDDM vs. approximately 3 mM in nondiabetic subjects (P less than 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects (45.1 +/- 2.3 vs. 34.4 +/- 1.5 g, P less than 0.01), but glucose Rd was not significantly different in NIDDM (35.1 +/- 2.4 g) and nondiabetic (33.3 +/- 2.7 g) subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 +/- 1.1 vs. 6.8 +/- 1.0 g, P less than 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 +/- 1.5 vs. 27.5 +/- 0.9 g, P less than 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 +/- 3.5 vs. 41.0 +/- 2.5 g/5 h), a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 +/- 1.0 vs. 5.2 +/- 0.3 g in nondiabetic subjects, P less than 0.01), and less was stored (11.7 +/- 1.3 vs. 16.9 +/- 1.5 g, P less than 0.05). We conclude that increased systemic glucose delivery, due primarily to reduced suppression of endogenous hepatic glucose output and, to a lesser extent, reduced splanchnic glucose sequestration, is the predominant factor responsible for postprandial hyperglycemia in NIDDM.