John D. Clough

Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease

PURPOSE Methotrexate (MTX), when used to treat malignancy or psoriasis, has been implicated in anecdotal reports as a teratogen or abortifacient in the first trimester of pregnancy. We are unaware of any previous reports that describe the course of gestation and the effect on subsequent offspring in patients treated with low-dose oral MTX for rheumatoid arthritis, and therefore present our experience. PATIENTS AND METHODS We report on eight women experiencing 10 pregnancies. Mean number of weeks of gestation while taking MTX was 7.5 (range 2 to 20 weeks). Outcome of pregnancies included five full-term babies (FTB), three spontaneous abortions (SAB), and two elective abortions. RESULTS There were no significant differences in either the FTB or SAB group when considering risk factors including smoking, alcohol, concomitant medications, and age. One of three in the SAB group had recurrent abortions prior to MTX therapy. All five of the FTB group had uncomplicated pregnancies and deliveries. All offspring were of normal height and weight at birth with no physical abnormalities. All children reached growth, development, and intellectual stages normally, and their present mean age is 11.5 years. No observed learning disabilities or medical abnormalities have occurred in any of these children. CONCLUSION In this uncontrolled study we failed to demonstrate tertogenicity of MTX. However, the possibility of abortion due to MTX use remains.

Ocular Involvement in the Respiratory Vasculitides

The respiratory vasculitides are idiopathic inflammatory syndromes, characteristically involving the pulmonary vasculature as well as that of several other organ systems. The inflammatory response in these diseases is uniformly granulomatous. There are three distinct, recognized respiratory vasculitides: Wegeners granulomatosis, Churg-Strauss syndrome (allergic granulomatosis and angiitis), and lymphomatoid granulomatosis. Each of these entities may have ophthalmic manifestations, and ocular involvement may, in fact, be the presenting sign. The systemic and ocular manifestations, as well as the differential diagnosis and management of each of these entities are discussed.

Serum C3 Levels Are Diagnostically More Sensitive and Specific for Systemic Lupus Erythematosus Activity Than Are Serum C4 Levels

To determine whether serum C3 or C4 is more likely to be normal during systemic lupus erythematosus (SLE) remission and abnormal during SLE relapse we studied twelve SLE patients who presented with severe nephritis. The patients were followed long term (12 to 77 months) through multiple relapses (N = 41) and remissions (N = 13) defined by protocol. A total of 471 serum samples were obtained at defined intervals during these relapses and remissions and were analyzed for C3 and C4 levels by two different methods: nephelometry (N) and radial immunodiffusion (R). During SLE remission (defined by protocol and without reference to serum complement levels), C3 measured by N-assay (C3N) and by R-assay (C3R) tended to be normal (specificity of 93% and 71%, respectively). By contrast, C4 measured by N-assay (C4N) and by R-assay (C4R) showed no such tendency (specificity of 50% for both C4N and C4R). During SLE relapse (defined by protocol and without reference to serum complement levels), C3N and C3R were more likely to be abnormal (sensitivity 95% and 85%, respectively) compared with C4N and C4R (sensitivity 56% and 54%, respectively, P less than 0.001 compared with corresponding values for the C3 assay). Analysis by receiver-operator characteristic (ROC) curves demonstrated that the reduced diagnostic sensitivity of C4 versus C3 is not explained by use of an inappropriate lower limits of normal (LLN) for C4.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of antinuclear antibodies during acebutolol therapy

Eleven patients were studied while taking the beta blocker acebutolol for a period ranging from 12 to more than 24 wk. Control titers for fluorescent antinuclear antibody (ANA) were obtained in all. Serial testing was performed over the duration of the therapy and following its discontinuation. Additional immunologic testing was performed in most patients. The patients were observed closely for the development of clinical autoimmune disease. Using a sensitive assay, fluorescent ANA developed in 8 of 9 patients with negative values in the control period. In no patient has evidence of clinical autoimmune disease developed. In general, the titers of ANA tended to rise with increasing duration of therapy and decline after its discontinuation. Positive lupus erythematosus cell preparations were also observed in several patients. These data suggest that autoantibodies are frequently induced by acebutolol and, although no evidence of clinical autoimmune disease has been reported, immunologic surveillance is warranted.

Folate supplementation in methotrexate-treated rheumatoid arthritis patients

Two hundred rheumatoid arthritis (RA) patients taking low dose methotrexate (MTX) were evaluated for adverse effects. During a mean follow up of 41.5 months, the mean cell volume (MCV) was elevated at some time during the course of treatment in 42 patients. The MCV was normal in the remaining 158 patients. One hundred ninety-eight patients were treated simultaneously with oral folic acid. With the exception of heartburn, which was seen more often in the high MCV group, there was no difference in the frequency of adverse effects attributable to MTX between groups. Severity of side effects and the frequency of MTX dose reduction and MTX discontinuation due to toxicity were also similar between groups. This analysis suggests that elevation of MCV in RA patients treated simultaneously with MTX and folate does not predict MTX toxicity. The authors also discuss the mechanism of action of MTX with regard to folate metabolism.

Suppressor cell function defect in idiopathic systemic lupus erythematosus

Abstract Six normals and 12 patients with idiopathic systemic lupus erythematosus (SLE) who had received no therapy other than nonsteroidal, anti-inflammatory medication were studied for suppressor cell function. In vitro immunoglobulin synthesis by normal B cells was suppressed by concanavalin A (Con A)-stimulated allogeneic normal lymphocytes, whereas Con A-stimulated lymphocytes from patients with SLE mediated significantly less suppression of normal lymphocytes. In addition, although B cells from patients with SLE synthesized less immunoglobulin in the presence of normal T cells than did normals, T cells from patients with SLE mediated significantly less allogeneic suppression of immunoglobulin synthesis by normal B lymphocytes than did T cells from normal individuals. SLE B cells are, nonetheless, sensitive to T-cell-mediated suppression. This suppressor cell defect might contribute to the pathogenesis of SLE. Several plausible causes for this defect are considered.

Lack of Relationship Between the Cleveland Health Quality Choice Project and Decreased Inpatient Mortality in Cleveland

The Cleveland Health Quality Choice (CHQC) project was previously suggested to have been responsible for declines in inpatient mortality in Cleveland hospitals during the first years of the project (1992-1993). We sought to (a) verify this decline in mortality and (b) better understand its possible relationship to CHQC. We employed regression analysis to compare mortality rate trends for Cleveland versus the rest of Ohio using Ohio Hospital Association inpatient mortality data. We found that the rate of decline in mortality in Cleveland (-.218% per 6 months; 95% confidence limits, -.278% to -.159% per 6 months) was statistically indistinguishable from that in the rest of the state (-.188% per 6 months; 95% confidence limits, -.234% to -.143% per 6 months) ( P = .35). We could not demonstrate a significant beneficial effect of the CHQC project on hospital mortality in Cleveland. Inpatient mortality was simultaneously declining at a statistically indistinguishable rate throughout the state.

Relationship of renal histopathology in SLE nephritis to immunoglobulin class of anti-DNA☆

Using a newly-developed solid-phase radioimmunoassay for DNA-binding immunoglobulins, immunoglobulin M (IgM), immunoglobulin G (IgG) and immunoglobulin A (IgA) anti-DNA were measured in serums from 11 patients with active untreated systemic lupus erythematosus (SLE) with nephritis. All patients underwent renal biopsy and were classified according to standard criteria as having diffuse or focal proliferative glomerulonephritis. Although both groups had almost identical total anti-DNA (13.1 versus 13.9 micrograms/ml, respectively), the IgM to IgG ratio was significantly higher (p less than 0.01) in the group with DPGN (7.51) than in the group with FPGN (1.10). We suggest that the switchover mechanism from IgM to IgG antibody production is more profoundly impaired in SLE with severe renal disease than in SLE with mild renal disease.

Measurement of DNA-binding immunoglobulins in systemic lupus erythematosus.

A radioimmunoadsorbant assay for quantitating DNA antibody in the IgM, IgG, and IgA classes is described. The method was standardized allowing expression of results in absolute terms. Effects of rheumatoid factor on the results were investigated. The new assay was found to correlate well with the Farr assay for DNA antibody. Serum levels of DNA antibody in all three immunoglobulin classes reflected the degree of clinical activity of SLE.

Two distinct subsets of patients with systemic lupus erythematosus

This study was undertaken to examine the levels and function of peripheral blood immunoregulatory T cell subpopulations in systemic lupus erythematosus (SLE). T cell subpopulations can be distinguished by the T cell differentiation antigens CD4 (recognized by the monoclonal antibodies OKT4 or Leu3) and CD8 (recognized by the monoclonal antibodies OKT8 or Leu2). All SLE patients tested had normal percentages of CD8 cells in their peripheral blood. The SLE patients, however, fell into two groups based on their CD4 cell numbers. Fifty-five percent of the SLE patients had normal levels of CD4 cells (Group A) and therefore normal CD4/CD8 cell ratios, whereas 45% of the SLE patient population had markedly depressed CD4 cell levels (Group B) and significantly low CD4/CD8 cell ratios. T cells from normal donors and SLE patients were further examined for their ability to stimulate allogeneic normal B/M phi cells to secrete IgM in the presence of pokeweed mitogen (PWM). Utilizing this assay system two forms of immunosuppression were observed: (1) that mediated by high concentrations of purified CD4 cells and (2) that mediated by CD8 cells. High concentrations of purified CD4 cells, added to a constant number of allogeneic normal B/M phi cells, suppressed PWM-stimulated IgM synthesis. Group B SLE patients, with significantly low CD4 cell numbers, had defective CD4 cell-mediated suppression which was concentration dependent. This result was confirmed in a study using identical twins discordant for SLE. In this case CD4 cells from the SLE twin did not induce immunosuppression at a high concentration of CD4 cells whereas similar concentrations of CD4 cells from the normal twin resulted in suppression. SLE patients (Group A) with normal levels of CD4 cells had normally immunosuppressive CD4 cells. Suppression mediated by CD8 cells was demonstrated by the fact that removal of CD8 cells resulted in enhanced IgM synthesis induced by the remaining CD4 cells. Although all the SLE patients in this study had normal peripheral blood levels of CD8 cells, SLE Group A patients had defective CD8 cell suppression whereas CD8 function appeared to be normal in Group B patients. These results suggest that in SLE patients with depressed CD4 cell numbers (Group B) there is a corresponding defect in CD4 cell function. We demonstrate that in SLE Group B patients, defective suppression is due to a subset of T cells that bear the CD4 antigen. The SLE patient population (Group A) with normal CD4/CD8 ratios and normally functioning CD4 cells, however, appear to have normal CD4 cell-mediated suppression but defective CD8 suppressor cell function.