Robert P. Kimberly

Increased Risk of Lymphoma in Sicca Syndrome

The risk of cancer was ascertained in 136 women with sicca syndrome followed at the National Institutes of Health (NIH). Seven patients developed non-Hodgkins lymphoma from 6 months to 13 years after their first admission to NIH. This was 43.8 times (P less than 0.01) the incidence expected from the rates of cancer prevailing among women of the same age range in the general population during this time. In addition, three cases of Waldenströms macroglobulinemia occurred in this study group. Eight patients developed cancers other than lymphoma, similar to the number expected based on the rates prevailing in the general population. Patients with a history of parotid enlargement, splenomegaly, and lymphadenopahy had an increased risk of lymphoma. These clinical conditions did not appear to be early manifestations of undiagnosed lymphoma but rather seemed to identify a subgroup of patients with sicca syndrome with marked lymphoid reactivity, who had a particularly high risk of subsequently developing lymphoma.

Defective Reticuloendothelial System Fc-Receptor Function in Systemic Lupus Erythematosus

To determine whether reticuloendothelial-system immunospecific Fc-receptor function is abnormal in patients with systemic lupus erythematosus, we studied the clearance of IgG-sensitized 51Cr-labeled erythrocytes by these splenic macrophage membrane receptors in 15 untreated patients. Fc-specific clearance rates were strikingly abnormal in 13 of 15 patients (half-times ranging from 80 to 2256 minutes, P less than 0.001 as compared to controls). Abnormal clearances correlated with immune-complex levels (as measured by the C1q-binding assay) and with disease activity. C1q-binding activity and anti-DNA titers also correlated with disease activity. The correlations of C3, C4, CH50 and factor B with abnormal clearance and disease activity were weaker or nonexistent. The significant correlations among clearance, disease activity and C1q-binding activity suggest that the defect in Fc-receptor function may lead to the prolonged circulation of immune complexes, thereby contributing to tissue deposition and damage.

Aspirin-induced depression of renal function.

We observed elevation of serum creatinine and blood urea nitrogen and decrease in creatine clearance in patients taking anti-inflammatory doses of aspirin. In 13 of 23 patients with systemic lupus erythematosus increases in serum creatinine ranged from 27 to 163 per cent, and those in urea nitrogen from 42 to 270 per cent. Sequential creatinine-clearance studies, available in 11 of the 13 patients, demonstrated decreases up to 58 per cent. Patients with aspirin-induced changes in renal function were more likely to have active renal disease (P =0.035) or hypocomplementemia (P =0.030). Four of 22 patients with rheumatoid arthritis and two of three normal volunteers also demonstrated biochemical changes. The rate of aspirin-induced alterations was significantly higher in systemic lupus erythematosus (P =0.007) than in rheumatoid arthritis. Aspirin, and other nonsteroidal anti-inflammatory agents, can have a major reversible effect on renal function that may influence the interpretation of clinical data.

Elevated Urinary Prostaglandins and the Effects of Aspirin on Renal Function in Lupus Erythematosus

We studied the urinary excretion of immunoreactive prostaglandin E-like material (iPGE) and renal function in seven women with systemic lupus erythematosus to evaluate the relation between urinary iPGE and the increase in serum creatinine in patients taking aspirin. The mean pretreatment excretion of urinary iPGE in patients with lupus erythematosus, 42.7 +/- 6.4 ng/h, was significantly higher than the value of 29.0 +/- 1.9 ng/h for normal subjects (P less than 0.02). With aspirin, the urinary iPGE decreased an average of 45% (P less than 0.001). Increases in serum creatinine and blood urea nitrogen confirmed our previous clinical observations. The concomitant mean fall in creatinine clearance of 18% (P less than 0.001) was accompanied by a 14% decrease in inulin clearance (P less than 0.005); p-aminohippurate clearance fell 29% (P less than 0.005). The decline in urinary iPGE preceded the fall in creatinine clearance but was significantly correlated with it (r = 0.78; P less than 0.001). The observed changes reversed rapidly when aspirin was stopped. These data show that, in these patients with high urinary iPGE excretion, aspirin causes significant changes in renal function that may be mediated by the inhibition of prostaglandin synthesis.

Defective Fc Receptor-Mediated Function of the Mononuclear Phagocyte System in Lupus Nephritis

To determine whether patients with systemic lupus erythematosus and nephritis have more profound defects in mononuclear phagocyte system clearance than their counterparts without renal disease, we studed Fc receptor-mediated splenic clearance function in 32 patients. Clearance half-times were prolonged in patients with lupus erythematosus compared with those in normal controls (p less than 0.0001) and longer in patients with renal disease than in those without (p less than 0.025). Both renal (tau = 0.45, p less than 0.0002) and nonrenal (tau = 0.35, p less than 0.003) disease activity were significantly but independently associated with clearance half-times. When matched for nonrenal activity, patients with nephritis had greater clearance dysfunction than their counterparts without renal disease. Circulating immune complexes did not correlate with clearance for all patients. Neither B8 nor DR3 histocompatibility antigen markers differentiated the renal and nonrenal disease subgroups. The greater Fc receptor-mediated clearance dysfunction, which occurs in patients with lupus erythematosus and nephritis, could lead to enhanced glomerular deposition of immune complexes as a primary event, or as a secondary event amplifying previously established lesions.

Fcγ Receptor Polymorphisms

Two decades ago, seminal studies from the National Institute of Health identified impairment of in vivo Fc receptor specific function in patients with systemic lupus erythematosus (SLE) (1). Further work demonstrated that this receptor dysfunction correlated with immune complex levels measured by complement-independent assays (2), varied with disease activity both within individual patients and across patient cohorts (2–5), and also occurred in patients with various types of immune complex disease (6,7). Efforts to understand the molecular basis of these findings accelerated with the cloning of eight distinct genes, grouped in three highly homologous families, for human Fcγ receptors. Through intrinsic differences in each gene and through alternative splicing, these genes yield 10 or so distinct protein products (8–14).

Letter: Effect of salicylates on creatinine clearance.

history-namely, Bellergal (belladonna alkaloids with ergotamine and phenobarbitone), amitriptyline, Stelabid (isopropamide and trifluoperazine), orphenadrine, and phenytoin. Two patients had been on a combination of Bellergal and amitriptyline. All of these drugs have an anticholinergic effect and will produce a decrease in bladder contractility. There were seven patients with a slow stream. Their aetiology is shown in the table; one of them has gone into retention but subsequently has been relieved. Of the total cases, 15 were found to have a neurological componentnamely, multiple sclerosis, prolapsed intervertebral disc, laminectomy, tethered cord, and ependymoma of the spinal cord. I am unable to support your contention that hysteria is not a common cause as six patients were found to be suffering from this.

Hemophilia, Antineoplastic Factor, and Immune Complexes

Excerpt To the editor: To explain immunologic abnormalities resembling the acquired immunodeficiency syndrome in patients receiving several blood transfusions and factor VIII concentrates, Gascon a...