Max I. Hamburger

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.

Sjögren's Syndrome (Sicca Syndrome): Current Issues

This paper outlines the clinical, serologic, and immunogenetic differences and similarities of Sjögrens syndrome alone (primary) and Sjögrens syndrome associated with rheumatoid arthritis and systemic lupus erythematosus (secondary). The immunoregulation in Sjögrens syndrome is discussed and the incidence of immune complex-like material, its nature, pathophysiology, and clearance by the Fc recptor of the reticuloendothelial system presented.

Defective Fc-Receptor Functions Associated with the HLA-B8/DRw3 Haplotype: Studies in Patients with Dermatitis Herpetiformis and Normal Subjects

Dermatitis herpetiformis is associated with the HLA-B8/DRw3 haplotype in over 90 per cent of patients, and various percentages have been reported to have circulating immune complexes. Since removal of immune complexes from the circulation is thought to depend on the Fc-receptor function of tissue macrophages, we studied this function by measuring the clearance of IgG-sensitized autologous erythrocytes in 16 patients with dermatitis herpetiformis, in normal controls with the HLA-B8/DRw3 haplotype, and in randomly selected controls. All patients were HLA-B8 positive, and all of 12 patients tested were HLA-DRw3 positive. Erythrocyte clearance was reduced in eight of the 16 patients, but did not correlate with immune-complex levels. Four of eight controls with HLA-B8/DRw3 also had delayed Fc-receptor-mediated clearance as compared with normal controls. In addition, both patients and HLA-B8/DRw3-positive controls had decreased percentages and total numbers of T cells bearing Fc receptors for IgG. These findings indicate a functional Fc-receptor defect associated with the HLA-B8/DRw3 antigens.

Opsonic Requirements for Intravascular Clearance after Splenectomy

We investigated the opsonic requirements for intravascular clearance of pneumococci in guinea pigs and of sensitized erythrocytes in human beings after splenectomy. The impaired clearance of injected pneumococci in splenectomized guinea pigs was corrected by immunization. This improvement in clearance was due to increased hepatic sequestration of organisms. There was a significant delay in antibody-mediated clearance of autologous erythrocytes sensitized with IgG (P < 0.001), although the rate of complement-mediated clearance in splenectomized patients was normal. A fourfold increase in sensitizing antibody resulted in a significant improvement in clearance that was due to increased hepatic sequestration (P < 0.005). One patient who had an intact spleen and who had previously received Thorotrast (thorium oxide) had impaired antibody-mediated clearance despite increased sensitization. These observations suggest that, after splenectomy the remaining macrophages of the reticuloendothelial system require increased amounts of antibody to mediate efficient intravascular clearance of opsonized particles.

Immunoglobulin G Fc Receptor-Mediated Clearance in Autoimmune Diseases

The reticuloendothelial system is thought to play an important role in removing immune complexes and other immunologically active substances from the circulation via interaction with specific cell-surface receptors. The function of the reticuloendothelial system in humans with autoimmune diseases was studied in vivo by measuring the rate of removal of IgG-coated, radio-labeled autologous erythrocytes. Such cells are removed by phagocytic cells of the spleen, and the process depends on the presence of an intact IgG Fc fragment. Studies in patients with active systemic lupus erythematosus show a profound defect in Fc-receptor-specific clearance that correlates with disease activity. Patients with other autoimmune diseases have defects in Fc receptor functional activity when their illness is characterized by tissue deposition of immune complexes. Normal patients with HLA-B8/DRw3, an HLA type associated with an increased incidence of autoimmune disease, also have an increased incidence of defective Fc receptor-specific functional activity, suggesting that this defect may predispose patients with this haplotype to develop manifestations of immune complex-mediated disease.

2011 Recommendations for the diagnosis and management of gout and hyperuricemia.

Abstract Gout is a major health problem in the United States; it affects 8.3 million people, which is approximately 4% of the adult population. Gout is most often diagnosed and managed in primary care physician practices. Primary care physicians have a significant opportunity to diagnose and manage patients with gout and improve patient outcomes. Following publication of the 2006 European League Against Rheumatism (EULAR) gout guidelines, significant evidence on gout has accumulated and new treatments for patients with gout have become available. It is the objective of these 2011 recommendations for the diagnosis and management of gout and hyperuricemia to update the 2006 EULAR guidelines, paying special attention to the needs of primary care physicians, who manage most patients with gout. The revised 2011 recommendations are based on the Grading of Recommendations Assessment, Development, and Evaluation approach as an evidence–based strategy for rating quality of evidence and grading strength of recommendation in clinical practice. A total of 26 key recommendations for diagnosis (n = 10) and management (n = 16) were evaluated. Presence of tophus (proven or suspected) and response to colchicine had the highest clinical diagnostic value (likelihood ratio [LR], 15.56 [95% CI, 2.11–114.71] and LR, 4.33 [95% CI, 1.16–16.16], respectively). The key aspect of effective management of an acute gout attack is initiation of treatment within hours of onset of first symptoms. Low–dose colchicine is better tolerated than and is as effective as high–dose colchicine (number needed to treat [NNT], 5 [95% CI, 3–13] and NNT, 6 [95% CI, 3–72], respectively). For urate–lowering therapy, allopurinol in combination with probenecid was shown to be more effective than either agent alone (effect size [ES], 5.51 for combination; ES, 4.46 for probenecid; and ES, 2.80 for allopurinol). Febuxostat, also a xanthine oxidase inhibitor, has a slightly different mechanism of action and can be prescribed at unchanged doses for patients with mild–to–moderate renal or hepatic impairment. Febuxostat 40 mg versus 80 mg (NNT, 6 [95% CI, 4–11]) and 120 mg (NNT, 6 [95% CI, 3–26]) both demonstrated long–term efficacy. The target of urate–lowering therapy should be a serum uric acid level of # 6 mg∕dL. For patients with refractory and tophaceous gout, intravenous pegloticase is a new treatment option.

Sjögren's syndrome: a defect in reticuloendothelial system Fc-receptor-specific clearance.

To determine the functional status of reticuloendothelial system Fc receptors in patients with Sjögrens syndrome, we studied the rate of clearance from the circulation of 51Cr-labeled IgG-sensitized autologous erythrocytes in 19 patients. Fc-receptor-mediated clearance was abnormal in 12 of the 19 patients, with half-lives ranging from 80 to 356 min. There was a significant correlation between clearance rates and clinical manifestations of disease. Clearance rates tended to be normal in patients with disease limited to exocrine glands and abnormal in patients with widespread disease. In contrast, there were no correlations between the rate of clearance of IgG-sensitized erythrocytes and serum immune complex levels, serum complement component levels, or rheumatoid factor titers. The striking correlation between clearance rates and disease manifestations suggests that decreased clearance of immune complexes by defective reticuloendothelial system Fc receptors may contribute to disease pathogenesis.

2011 Recommendations for the Diagnosis and Management of Gout and Hyperuricemia

Abstract Gout is a major health problem in the United States; it affects 8.3 million people, which is approximately 4% of the adult population. Gout is most often diagnosed and managed in primary care practices; thus, primary care physicians have a significant opportunity to improve patient outcomes. Following publication of the 2006 European League Against Rheumatism (EULAR) gout guidelines, significant new evidence has accumulated, and new treatments for patients with gout have become available. It is the objective of these 2011 recommendations to update the 2006 EULAR guidelines, paying special attention to the needs of primary care physicians. The revised 2011 recommendations are based on the Grading of Recommendations Assessment, Development, and Evaluation approach as an evidence-based strategy for rating quality of evidence and grading the strength of recommendation formulated for use in clinical practice. A total of 26 key recommendations, 10 for diagnosis and 16 for management, of patients with gout were evaluated, resulting in important updates for patient care. The presence of monosodium urate crystals and/or tophus and response to colchicine have the highest clinical diagnostic value. The key aspect of effective management of an acute gout attack is initiation of treatment within hours of symptom onset. Low-dose colchicine is better tolerated and is as effective as a high dose. When urate-lowering therapy (ULT) is indicated, the xanthine oxidase inhibitors allopurinol and febuxostat are the options of choice. Febuxostat can be prescribed at unchanged doses for patients with mild-to-moderate renal or hepatic impairment. The target of ULT should be a serum uric acid level that is ≤ 6 mg/dL. For patients with refractory and tophaceous gout, intravenous pegloticase is a new treatment option. This article is a summary of the 2011 clinical guidelines published in Postgraduate Medicine. This article provides a streamlined, accessible overview intended for quick review by primary care physicians, with the full guidelines being a resource for those seeking additional background information and expanded discussion.

Influence of an Educational Seminar on Use of Disease Activity Measurements by Rheumatologists in Treatment of Rheumatoid Arthritis

Objective. To determine the variables underlying clinical decisions made by rheumatologists when treating patients with rheumatoid arthritis (RA), and to determine the effect of an educational seminar on the use of quantitative disease activity measurements in clinical practice in this population of physicians. Methods. Practicing rheumatologists were surveyed on the variables affecting their clinical management of patients with RA by questionnaire. Physicians were divided into 2 groups: the first comprised attenders (Group A) to an educational seminar in the use of the quantitative disease activity measurements in patient management, while the second group comprised nonattenders (Group NA). Both groups were surveyed on their practice behavior before (Survey 1) and 2 to 3 months after (Survey 2) the seminar. Results. Fifty-two rheumatologists in clinical practice from across the US completed and returned 364 surveys. A significantly greater number of rheumatologists in Group A reported use of disease activity measures following the training seminar (Survey 2), compared to their use pre-meeting and compared to Group NA (p < 0.0001). Conclusion. Our results support employment of an educational seminar on the use of disease activity measurements to increase the use of these quantitative measures in rheumatologic practice.

Visual evoked potentials altered by serum IgG of patients with multiple sclerosis

Immunoglobulin G, isolated from serum of patients with multiple sclerosis was repeatedly injected into guinea pigs and serial visual evoked potentials were recorded. Latency changes indicated a reversible delay in conduction velocity in the central visual pathways. This finding suggests that some component of immunoglobulin plays a role in the pathogenesis of multiple sclerosis.