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There is conflicting evidence in the literature concerning the role of circulating immune complexes (CIC) in the pathogenesis of erythema nodosum (EN). We investigated the possible involvement of CIC in 20 patients with EN, the majority of whom had idiopathic or uncomplicated disease. Immune complexes were detected by 3 complementary radioimmunoassays (the Clq, the mRF, and the anti-C3 solid phase assays). During the presence of the skin lesions, the only abnormalities noted were elevated concentrations of CIC detected by the anti-C3 assay in 5 of the 20 patients. None of the patients had elevated CIC by any of the 3 assays after resolution of skin lesions. These observations do not support a significant role for CIC in the pathogenesis of idiopathic or uncomplicated EN.

Trypanosome phagocytosis by normal polymorphonuclear leucocytes was studied in the presence of the pregnancy-associated alpha 2-glycoprotein (PAG). A serum fraction containing PAG at a concentration of 13.5 micrograms/ml significantly inhibited the uptake of Trypanosoma dionisii when contrasted with an identically obtained male serum fraction devoid of PAG (P less than .01). This finding of diminished trypanosome uptake in physiologic concentrations of PAG could account for the suggested increase in the frequency and severity of protozoal infections during gestation.

Acute rheumatic fever (ARF) in 53 adults was characterized by a severe, febrile migratory polyarthritis involving primarily large joints in the lower extremities, with evidence of an antecedent streptococcal infection. Carditis, present in only eight (15%) of the adults, was mild and transient. The characteristic abnormality in laboratory findings was an erythrocyte sedimentation rate (Westergren) greater than 100 mm/hr. Response to high-dose aspirin therapy was prompt and dramatic in all patients. Mild andevanescent abnormalities of both renal function and hepatic function (not aspirin-mediated) were detected in 51% and 64%, respectively. A common disorder in San Antonio, ARF has distinctive symptoms. It can be readily diagnosed and promptly treated. In the adult, it is almost exclusively a syndrome of events severe but transient in the joints, and mild and transient in the heart, kidneys, and liver.

The leukocyte adherence inhibition (LAI) test in arthritis can serve as an in vitro model for investigating cellular cooperation between mononuclear cells sensitized by cytophilic IgG rheumatoid factor(s) present in rheumatoid arthritis (RA) serum, normal synovial components, and polymorphonuclear cells. Since inflammatory and immunologic responses are altered during pregnancy, we studied the effect of pregnancy serum on the LAI. The adherence of normal leukocytes once sensitized in RA serum is inhibited by a synovial extract, but when these leukocytes are exposed to pregnancy serum prior to sensitization with RA serum, the cells are unresponsive to subsequent stimulation by the synovial extract (p less than 0.01). This blocking effect on sensitization is only present in serum obtained after the first trimester of pregnancy and can be detected even at serum dilutions of 1:100. Leukocytes obtained directly from pregnant subjects, washed, and then incubated with RA serum failed to react. Since pregnancy serum has been shown to mask certain cell membrane receptors, it is possible that our results are due to the blocking of IgG rheumatoid factor binding to mononuclear cells. This finding could contribute to the subsidence during pregnancy of some disorders such as rheumatoid arthritis.

Fracture of the cervical spine is a serious and often fatal complication of ankylosing spondylitis. An evaluation of eight patients and a review of 75 additional cases from the literature are presented. Although this complication is relatively uncommon, it is clear that people with advanced disease and complete ankylosis of the cervical spine are at increased risk of sustaining cervical fracture. When fracture occurs it usually stems from minor trauma resulting most commonly in disruption of the lower cervical segments (fifth through the seventh cervical vertebrae). Fracture is most likely the result of a hyperextension type injury, occurs through what was formerly an intervertebral space, and is unstable. Severe neurologic sequelae occur in 57 percent of the cases and the mortality rate (35 percent) is twice that observed with similar fracture involving normal spines. The majority of patients are best treated with closed reduction with halo traction together with body cast or jacket. Laminectomy is rarely indicted except in the event of an advancing neurologic deficit. With appropriate understanding and execution of management principles, the outcome in these patients can be favorable. Unfortunately, recognition of cervical fracture in patients with ankylosing spondylitis is often needlessly delayed. Distortion of normal anatomy in spondylitics, predominant fracture location in lower cervical spine segments and lack of obvious displacement make identification difficult. Thus, management is often inappropriate resulting in excessive neurologic injury and mortality.

The classic skin and internal organ system manifestations of systemic sclerosis developed in 4 individuals, each with an erosive, destructive chronic polyarthritis characteristic of rheumatoid arthritis. All had serum rheumatoid factors, anti-nuclear antibodies, hypergammaglobulinemia and circulating immune complexes. Each of the 4 has been resistant to treatment. The features of these patients, together with an analysis of this unusual coexistence of two connective tissue disorders, are presented.

The influence of pregnancy serum on the directional migration of normal human polymorphonuclear leukocytes (PMN) in response to a standard chemotactic attractant was studied. Using the Boyden chamber method for quantitating directional migration, both gestational and control sera in the unmodified state were found to have comparable actions on neutrophil chemokinesis and chemotaxis. Activation of these sera with endotoxin generated equivalent amounts of chemotactic factors. However, pregnancy serum in direct contact with normal PMN, inhibited their response to a standard chemoattractant (p less than 0.001). The suppressive effect was present in sera obtained during the third trimester of gestation. Sera obtained one month post partum contained less of the inhibitor of PMN directional migration. Since neutrophils are essential to the development of rheumatoid arthritis and certain other inflammatory diseases, the subsidence of these disorders during gestation and their exacerbation post partum could be related to the inhibitory effects of pregnancy serum on leukocyte functions.

The concentration of the acute phase serum protein C-reactive protein (CRP) is used as an index of disease activity in patients with rheumatoid arthritis and with other disorders associated with rheumatoid factor (RF). When CRP was determined by the latex agglutination method, RF caused both increased titers for CRP and false positive reactions for CRP. These effects of RF were abrogated by pretreatment of test samples with 2-mercaptoethanol. Detection of CRP by radial immunodiffusion was not affected by RF. Therefore, the clinical relevance of CRP detected in RF positive sera by latex agglutination can be ascertained only following pretreatment of sera with 2-mercaptoethanol or by the use of radial immunodiffusion to circumvent interference by RF.

The development of immune complexes (IC) and rheumatoid factors (RF) during normal, uncomplicated pregnancy is a controversial issue. Discrepancies in previous reports are due most likely to the different methods used to detect both IC and RF. Using four sensitive radioimmunoassays for immune complexes employing both Clq and mRF and employing sensitive and specific radioimmunoassays for the detection of IgM-RF and IgG-RF, we examined the sera of 35 normal subjects in their third trimester of pregnancy. Immune complex concentrations as measured by four assays were not increased during gestation. However, both IgM-RF and IgG-RF were significantly elevated even though the concentrations of immunoglobulins M and G were virtually identical to the controls. These observations provide further insight into the immunological changes associated with pregnancy. (Am J Reprod Immunol. 2:208-211.)

Third trimester pregnancy serum caused a dose-dependent inhibition of the one-way allogeneic mixed leukocyte reaction (MLR) through an effect that occurred during the first 48 hours of culture. Pregnancy serum also inhibited the mitogenic responsiveness of normal mononuclear leukocytes to concanavalin A (Con A) while the responses to phytohemagglutinin (PHA) and pokeweed mitogen (PWM) were less affected. Preincubation of normal peripheral blood mononuclear cells (PBMC) for 48 hours with 10% pregnancy serum enhanced a suppressor activity transferable with cells. These pregnancy serum-induced effector cells suppressed the MLR only when they were autologous to the responder population (p less than 0.05). The same suppressor cell preparation inhibited the proliferative responses of autologous PBMC to Con A (p less than 0.001) and PWM (p less than 0.05). These data suggest that one or more factors in pregnancy serum can induce or enhance suppressor cell activity in vitro. A comparable increase in suppressor cell activity in vivo may be responsible for blocking maternal rejection of the fetus and for the observed improvement in clinical activity of rheumatoid arthritis during pregnancy.

Repeated determination for antinuclear antibody (ANA) were negative in a patient with systemic lupus erythematosus (SLE) and severe multisystem involvement including diffuse proliferative glomerulonephritis and the nephrotic syndrome. However, concentration of urinary protein, of pleural fluid and subsequently of serum revealed ANA. This case demonstrates another cause of a false negative ANA in SLE--a low concentration of the antibody in serum and loss in body fluids.

A distinguishing feature of the mixed connective tissue disease (MCTD) syndrome is the presence in the serum of antibody in high titer to ribonucleoprotein (RNP). To determine whether this was an exclusive observation, a large rheumatic disease population was surveyed for the presence of antibody in high titer to extractable nuclear antigens (ENA) including RNP. Of 650 sera examined, 440 (from 240 patients) had antinuclear antibody. Only 39 patients had serum antibody to ENA in titers greater than or equal to 1:200 dilution. In 16 the anti-ENA was shown by RNAse digestion to be anti-RNP. Although many clinical and laboratory characteristics were similar in these two groups, the patients more closely resembled the previously described MCTD syndrome and, importantly, less often had severe renal and central nervous system disease manifestations. Thus the presence of serum antibodies to ENA that are predominantly RNAse-sensitive (anti-RNP) helps to identify a rheumatic disease syndrome and also appears to have prognostic value.

Lysosomal membrane stabilization has been proposed as a mechanism for the anti-inflammatory action of corticosteroid hormones. This hypothesis was based on studies with liver organelles. We studied the action of steroids on intact lysosomes isolated from human peripheral blood polymorphonuclear (PMN) leukocytes. Both androstenedione and progesterone, 10(-3)-10(-5) M, caused leakage of acid hydrolase markers from these organelles, thus resembling their effects on liver lysosomes. But none of the anti-inflammatory steroids tested protected organelle membranes from either detergent lysis (Triton X-100) or heat incubation (37 degrees C, 90 min). Hydrocortisone (HC), HC sodium succinate, HC acetate, HC hemisuccinate, prednisone, and dexamethasone were without detectable stabilizing activity at concentrations of 10(-3)-5 x 10(-8) M. Release of the lysosomal marker, beta-glucuronidase, was not retarded by any of the compounds studied. In addition, PMN leukocyte lysosomes isolated from human volunteers receiving prednisolone were not more stable than control organelles, nor did serum from steroid-treated humans protect intact lysosomes from detergent lysis. Variations in cholesterol and phospholipid contents of liver and PMN leukocyte lysosome membranes could possibly account for the different reactivity to corticosteroids observed. We believe that the anti-inflammatory activity of adrenal corticosteroids can best be explained by their inhibitory effects on cellular metabolism rather than by their direct interaction with lysosomal membranes.

Since the number of polymorphonuclear leukocytes (PMN) responding to a chemotactic stimulus in the Boyden chamber is influenced by the cell density, we studied whether this variable was important in determining chemotaxis under agarose. The chemotactic index was determined by summing the product of each cell that had migrated from the chemotactic well by its distance and correcting this sum for random migration. Cell density (number of PMN per mm2 surface area of the agarose plate well) influenced the number of cells responding to the chemotactic stimulus. Only when more than 1.8 x 10(2) PMN/mm2 were used was chemotaxis then detected. For cell densities greater than this number, there was a highly positive correlation between cell density and chemotactic index (P less than 0.001). These findings are consistent with previous reports and indicate that PMN density is a critical variable when using the agarose method. In addition, these studies provide further evidence for cellular cooperation in the initial phases of the chemotactic response.

The precise factor responsible for the altered immunological reactivity and diminished inflammatory responses occurring in pregnancy is unknown. Recent observations implicate the pregnancy-associated alpha-2 glycoprotein (PAG). Using rosette assays for the detection of cells carrying Fc receptors and for the demonstration of surface HLA-DR antigens, we demonstrate that a serum protein fraction rich in PAG inhibits these surface markers on human monocytes. Brief exposure of normal peripheral blood monocytes to physiological concentrations of PAG led to almost total loss of Fc receptor expression, an effect that was concentration-related. Using a monoclonal anti-HLA-DR antibody linked to red cells, physiological concentrations of PAG also significantly inhibited the detection of HLA-DR on monocytes. As controls, we used a protein fraction isolated in identical fashion from male sera devoid of PAG, and an alpha-2 macroglobulin isolate. These findings suggest that PAG, by masking monocyte surface markers, could be responsible for the suppression of some cell functions during pregnancy.

The number of polymorphonuclear leukocytes (PMN) responding to a chemotactic stimulus is influenced by the cell density. Evidence is presented that the cytoplasmic fraction of PMN augments the response of neutrophils to endotoxin-activated serum but the activator of chemotaxis (CACh) in cytosol is not chemotactic itself. This cytoplasmic neutrophil cytosol is not present in nuclear, microsomal or large granular fractions. Preliminary characterization studies suggest that CACh is nondialyzable, has a molecular weight of less than that of albumin, is heat stable (56 degrees C for 30 min) but is destroyed by trypsin. Studies on intracellular concentrations of cAMP and cGMP following incubation of PMN with various subcellular fractions suggest that CACh causes the loss of intracellular cAMP, a finding which could account for its chemokinetic action. As expected, the lysosomal fraction of PMN was chemotactic and reduced the net negative surface charge of neutrophils. CACh, however, was neither chemotactic nor did it alter the charge density on PMN surfaces. These studies provide evidence for cellular cooperation in the initial phases of the chemotactic response. The clustering of PMN along endothelial surfaces could provide the necessary local cell density for this augmented response to take place.

The density of neutrophils influences the number of cells that will respond to a chemoattractant, endotoxin-activated serium. When fewer than 3 x 10(5) polymorphonuclear leukocytes (PMN) were placed in the top compartment of a modified Boyden chemotaxis chamber, the cellular response was weak. Complete membrane penetration by activated neutrophils rarely was observed. When this number of PMN was exceeded, however, both the number of cells and the percentage of neutrophils responding to the leukoattractant increased. The density of cells required for effective chemotactic response to occur was such that intimate cell-to-cell contact was suggested. This indicated that PMN exerted a kinetic influence upon one another. Extracts of disrupted PMN induced an otherwise insufficient number of neutrophils to respond to the chemotactic stimulus. The active component was isolated in the cytoplasmic fraction (postcentrifugation, 100,000 x g, 60 min) of PMN, but was not present in other subcellular fractions. This cytoplasmic augmentor of chemotaxis (CACh) increased random mobility of neutrophils, but was not, itself, a chemotactic factor. These findings suggest that PMN cooperate in their response to a leukotactic stimulus.

The phagocytosis of S. aureus by normal human PMN leukocytes was inhibited by pregnancy serum. Control sera from normal adult nulliparous women, from men, and from cord blood all functioned normally in support of phagocytosis. However, particle ingestion was reduced significantly (p less than 0.001) when leukocytes were in 15% pregnancy serum obtained at term. To determine at what stage in pregnancy the inhibition of phagocytosis could first be detected, sera were obtained from multiple pregnant donors and pooled according to week of gestation. Significantly fewer bacteria were ingested in each of the serum pools obtained after week 16 of pregnancy and the inhibitory effect persisted through gestation. Following delivery, less inhibition was detected as early as 2 days post partum. Phagocytosis assays were performed in six matched maternal and cord serum pairs. Five of the six maternal sera showed inhibition of phagocytosis; one pregnancy and all cord sera functioned normally in support of bacterial ingestion by normal granulocytes. Since neutrophils are essential to the development of rheumatoid arthritis and certian other inflammatory disorders, the subsidence of these diseases during gestation and their exacerbation post partum could be related, at least in part, to the inhibitory effects of pregnancy serum on leukocyte functions.

By use of a microlymphocytotoxic assay to detect 32 HLA antigens of the A and B series, we examined 49 Mexican-American adults with acute rheumatic fever and contrasted the findings with 100 ethnically identical controls. Eighty-nine percent of the total possible antigens were identified. Strong associations between HLA antigens from either locus and acute rheumatic fever were not detected. These findings serve to emphasize the importance of nongenetic factors in the pathogenesis of acute rheumatic fever and help clarify the role of HLA antigens in rheumatic diseases.

The frequencies of 32 HLA antigens of the A and B series were determined in a previously unstudied population of Mexican-Americans in South Texas. The phenotype and gene frequencies for this group are presented and are contrasted with those determined in studies of Mexican/Mexican--American populations from two different locales. The statistically significant differences observed emphasize the need for indigenous controls when evaluating racially heterogeneous populations for disease-associated HLA antigens.

We investigated the effects of chemotaxins on the surface charge of isolated human PMN. Chemotaxis was ascertained using Boyden chambers. Surface charge was calculated using data derived from cell mobility as measured in a cytophorometer. The electrophoretic mobility of cells exposed to all chemotactic agents studied was altered. Endotoxin-activated serum containing C5a, PMN lysosomal extracts from "resting" and from crystal-stimulated cells, and Gly-His-Gly, a synthetic tripeptide, all significantly reduced the net negative surface charge of isolated neutrophils. Only chemotactically active substances effected this change; controls including heat-inactivated serum, other subcellular fractions, and an inert tripeptide, Gly-Gly-Gly, did not alter cell mobility in an electric field. These findings are consistent with studies by others on the effects of chemotactic factors on cation fluxes and cell aggregation and suggest a possible mechanism by which PMN directional migration is regulated.

Forty-eight patients with definite of classical rheumatoid arthritis (RA) were studied for the presence of tarsal tunnel syndrome (TTS). Nerve conduction velocities and distal latencies were determined in a constant temperature room and the findings compared with a group of 35 normal, age-matched subjects. After excluding four patients with peripheral neuropathy, a definite delay in the distal motor latency of the tibial nerve was documented in 11 subjects (25%). Two of the 11 had foot symptoms suggestive of TTS. These 11 patients with prolonged distal motor latencies did not otherwise differ from RA patients without TTS in terms of disease duration or severity, treatment, or the presence of foot deformity. Thus, compressive neuropathy of the branches of the posterior tibial nerve is a relatively frequent finding in patients with definite or classical RA.

Serum C1q concentrations were studied in 78 patients with definite and classical rheumatoid arthritis (RA). No correlation could be made either with disease activity, with erythrocyte sedimentation rate or with rheumatoid factor titers. In contrast to these findings in RA, however, serial determinations of this complement component were of value in predicting the response to therapy in four patients with immunologically-mediated vasculitis. Initially both C1q and C3 were depressed in two patients with SLE, one with cryoglobulinemic purpura and one with HbsAg-positive serum sickness, each with acute vasculitis. Sequential studies following the institution of treatment showed in each case that C1q returned to normal while C3 remained low. These observations suggest that analysis of serum C1q is preferable to C3 in these disorders when used to predict clinical change and the response to treatment.

Since the successful introduction of injectable gold compounds for the treatment of rheumatoid arthritis over 50 years ago, numerous studies on the possible mechanism of action have been performed. This heavy metal has been show to possess a bewildering array of biological effects. Studies using gold performed both in vitro and in vivo can be grouped into anti-microbial, anti-immunologic, anti-inflammatory, anti-enzymatic and other effects. In this survey, we have analyzed these multiple approaches to the study of the mechanism of action of injectable gold preparations and apply the findings to rheumatoid arthritis.

Rheumatoid arthritis is associated with circulating and intra-articular immune complexes and rheumatoid factors. The clinical activity of rheumatoid arthritis improves during pregnancy in the majority of women, with exacerbation following delivery. Concentrations of immune complexes, as detected by the Clq-binding assay, the Clq-solid phase assay, and the monoclonal rheumatoid factor-solid phase assay, decreased during gestation, with elevations following delivery. Concentrations of IgM-rheumatoid factor and IgG-rheumatoid factor, analyzed by radioimmunoassay, changed variably during pregnancy, increasing in some patients and decreasing in others. When examined serially before, during, and following pregnancy, changes in the concentration of circulating immune complexes and/or rheumatoid factors corresponded with the clinical changes in three patients. These observations document the significant effect of gestation on the concentration of circulating immune complexes in patients with rheumatoid arthritis. They also support the role of these laboratory tests in monitoring the clinical course of rheumatoid arthritis.

Lesions of the costovertebral (CV) and costotransverse (CT) joints are distinctly unusual in rheumatoid arthritis. The patient presented had dramatic changes in these joints with destruction, ankylosis, and bony overgrowth. This led to a moderate respiratory impairment and a distinctive radiological presentation.