Hepatitis with bridging fibrosis and reversible hepatic insufficiency in a woman with rheumatoid arthritis taking methotrexate.

A patient with seropositive rheumatoid arthritis developed ascites while taking weekly doses of methotrexate (MTX). Her serum transaminase and albumin levels were normal. A liver biopsy revealed chronic hepatitis with bridging fibrosis and piecemeal necrosis. Upon discontinuation of MTX, her ascites resolved, and her arthritis became more active. This is the third report of reversible hepatic decompensation associated with prolonged MTX therapy in patients with rheumatoid arthritis.

IgM rheumatoid factor in Lyme disease: correlation with disease activity, total serum IgM, and IgM antibody to Borrelia burgdorferi.

We tested the sera of 50 patients with Lyme disease for IgM-rheumatoid factor (IgM-RF) using a sensitive ELISA. Levels of IgM-RF greater than 3 SD above the mean of normal subjects were found in 2 of 15 patients with erythema chronicum migrans, 7 of 10 with neurologic abnormalities, and 7 of 25 with Lyme arthritis (p = 0.038). Only 2 of these sera were positive by latex agglutination. In contrast, none of the 23 control patients with osteoarthritis, ankylosing spondylitis, or Reiter's syndrome had positive tests. The levels of IgM-RF correlated with disease activity (p = 0.002), total serum IgM levels (p = 0.002), and specific IgM antibody titers to Borrelia burgdorferi (p = 0.006). IgM-RF reactivity was absorbed with heat aggregated IgG (HAGG), but the titer of specific IgM antibody was insignificantly affected by this procedure. Thus, small amounts of RF are produced at certain times in many patients with Lyme disease, and IgM-RF production appears to be linked to the specific IgM response.

Rapid immune adherence reactivity of nascent, soluble antibody/DNA immune complexes in the circulation.

Immune complex disease in humans and experimental animals can occur as a consequence of the binding of specific antibodies to exogenous or endogenous antigens. If this reaction occurs in the circulation, the fate of the resulting immune complex may depend upon many factors including the ability of the immune complex to fix complement and bind to complement receptors on circulating cells (immune adherence). We studied the in vivo formation and immune adherence of soluble antibody/dsDNA immune complexes in the circulation of both a nonprimate and a primate model. The fact that this sequence of biological recognition reactions is completed in less than 2 min suggests that the immune adherence phenomenon may play a crucial role in the clearance of nascent complement-fixing immune complexes from the circulation.

Clearance kinetics and immunochemistry in rabbits of soluble antibody/DNA immune complexes. Effects of antibody class and DNA conformation.

We examined the clearance kinetics in rabbits of soluble antibody/DNA immune complexes (IC) containing either IgG or IgM anti-DNA antibodies. Differences in the complement-mediated binding of these IC to rabbit blood cells (platelets) were also studied. Complexation of either double-stranded (ds) or single-stranded (ss) DNA with IgG anti-DNA tends to preclude in vivo DNA recognition mechanisms; the DNA is cleared as part of an IC at a rate slower than that of free DNA. Binding of ds- or ssDNA by IgM anti-DNA antibodies leads to formation of IC which are cleared more like free DNA, and this effect is most evident for ssDNA. However, although both IgG- and IgM-containing IC bound rapidly to blood cells in vivo, significant differences in their immunochemistry were apparent. For example, the DNA in IgM-containing IC was more susceptible to both in vivo and in vitro degradation. In addition, the binding of IgM-containing IC to rabbit platelets and human red blood cells was considerably more labile. Based on this systematic investigation of the soluble antibody/DNA IC that can potentially form in the circulation of a patient with systemic lupus erythematosus, it should be possible to formulate predictions regarding the relative pathogenic potential of these IC.

The interaction of antibody/DNA immune complexes with complement. Influence of antibody class and DNA conformation.

In 28 serum and plasma samples from patients with systemic lupus erythematosus, we examined the importance of antibody class with respect to complement-mediated binding to human red blood cells (RBC) of antibody/DNA immune complexes (IC) prepared with anti-DNA antibodies. We used both 3H-double-stranded DNA and 3H-single-stranded DNA (ssDNA). Generally, double-stranded DNA IC showed considerably higher binding than did ssDNA IC in the RBC binding assay. Further analysis indicated that although ssDNA IC fix complement, it is necessary that these IC contain IgM anti-DNA antibodies in order for them to bind to RBC. The results suggest that the mechanisms of clearance and pathogenic potential of these IC may depend upon both the DNA conformation and antibody class. In particular, complement-fixing IC which contain IgG anti-DNA antibodies and ssDNA may not be cleared via the erythrocyte clearance mechanism, and therefore, could be more likely to deposit in certain tissues and initiate inflammatory reactions.

Clearance of human antibody/DNA immune complexes and free DNA from the circulation of the nonhuman primate.

The present study evaluated the participation of the primate erythrocyte immune complex (IC) clearing mechanism in the clearance and organ uptake of double-stranded DNA (dsDNA) and of soluble ICs formed with human anti-DNA antibodies and dsDNA (dsDNA-ICs). Five baboons received 51Cr-labeled autologous erythrocytes and after a period of equilibration received separate intraarterial injections of [125I]free dsDNA and [125I]dsDNA-IC. Four of these five baboons were studied on a second occasion. To assess clearance from the arterial circulation and organ uptake, multiple blood samples were obtained from aorta, hepatic vein, and renal vein after injection of each probe. Two minutes after injection, a mean of 85% of dsDNA-ICs were bound to erythrocytes. By contrast, free dsDNA did not bind significantly to blood cells. The clearance rate of dsDNA-ICs from the arterial circulation was significantly faster than that of free dsDNA in all animals but one. Erythrocyte-bound dsDNA-ICs were cleared at a rate similar to that of total dsDNA-ICs. The liver was the major site of uptake of free dsDNA and of dsDNA-ICs. The hepatic uptakes of free dsDNA (17 +/- 8%/5 min) and dsDNA-ICs (27 +/- 8%/5 min) were not significantly different. 51Cr-labeled erythrocytes were not sequestered in the liver. There was not detectable uptake of free dsDNA or dsDNA-ICs by the kidney but with one exception. Thus, the primate erythrocyte IC clearing mechanism is involved in the clearance of dsDNA-ICs from the circulation but not in the clearance of free dsDNA.