Evelyn V. Hess

Association of Antibodies to Ribonucleoprotein and Sm Antigens with Mixed Connective-Tissue Disease, Systemic Lupus Erythematosus and Other Rheumatic Diseases

Extractable nuclear antigen contains ribo-nuclease-sensitive (ribonucleoprotein) and ribonuclease-resistant (Sm) components. To determine the diagnostic usefulness of antibodies to these antigens, a multicenter study was undertaken in which serums were analyzed for these antibodies and the findings compared with clinical and other laboratory characteristics of the patients. Of 100 patients with hemagglutinating antibodies to ribonuclease-sensitive extractable nuclear antigen, and only the same antibodies by immunodiffusion, 74 per cent had typical features of mixed connective-tissue disease; 12 features of systemic lupus erythematosus, eight those of scleroderma and six an undifferentiated mild connective-tissue disease. Of 27 patients with hemagglutinating antibodies to ribonuclease-resistant extractable nuclear antigen (and Sm antibodies by immunodiffusion), 85 per cent had typical systemic lupus. Thus, antibodies to nuclear ribonucleoprotein and Sm are of diagnostic use; if the serum contains only ribonucleoprotein antibody in high titer, it is likely that the patient has mixed connective-tissue disease.

A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia

PURPOSE To assess the efficacy of fluoxetine in the treatment of patients with fibromyalgia. SUBJECTS AND METHODS Sixty outpatients (all women, aged 21-71 years) with fibromyalgia were randomly assigned to receive fluoxetine (10-80 mg/d) or placebo for 12 weeks in a double-blind, parallel-group, flexible-dose study. The primary outcome measures were the Fibromyalgia Impact Questionnaire total score (score range, 0 [no impact] to 80) and pain score (score range, 0-10). Secondary measures included the McGill Pain Questionnaire, change in the number of tender points, and total myalgic score. RESULTS In the intent-to-treat analysis, women who received fluoxetine (mean [+/- SD] dose, 45 +/- 25 mg/d) had significant (P = 0.005) improvement in the Fibromyalgia Impact Questionnaire total score compared with those who received placebo, with a difference of -12 (95% confidence interval [CI]: -19 to -4). They also had significant (P = 0.002) improvement in the Fibromyalgia Impact Questionnaire pain score (difference, -2.2 [95% CI: -3.6 to -0.9]), as well as in the Fibromyalgia Impact Questionnaire fatigue (P = 0.05) and depression (P = 0.01) scores and the McGill Pain Questionnaire (P = 0.01), when compared with subjects who received placebo. Although counts for the number of tender points and total myalgic scores improved more in the fluoxetine group than in the placebo group, these differences were not statistically significant. CONCLUSIONS In a 12-week, flexible-dose, placebo-controlled trial, fluoxetine was found to be effective on most outcome measures and generally well tolerated in women with fibromyalgia.

In vitro studies in reproductive immunology. 1. Suppression of cell-mediated immune response by human spermatozoa and fractions isolated from human seminal plasma.

Abstract Components of the male mammalian genital tract are capable of inhibiting in vitro cell-mediated immune responses. In the current study, intact human spermatozoa in a concentration of 10 7 cells/ml inhibited both spontaneous and PHA-M- and Con A-induced blast transformation of normal human peripheral blood lymphocytes. Similar inhibitory properties were found in human seminal plasma using concentrations of 100 and 400 μg/ml. Sephadex G-100 chromatography of seminal plasma yielded five fractions (F 1 - F 5 ) which were qualitatively assessed by SDS-polyacrylamide disc gel electrophoresis. Fractions 1 and 4 inhibited spontaneous blast transformation while fractions 1 and 3 inhibited mitogen-induced blastogenesis. Normal leukocyte migration was not affected by fractions. It is concluded that suppression of blast transformation might be due to a spermatozoal or seminal plasma component(s) able to bind receptors on lymphocytes specific for PHA-M and Con-A.

Lupus-Erythematosus-Like Disease in Three Unrelated Women with Hereditary Angioneurotic Edema

Excerpt Inherited deficiencies of components of complement have been reported in association with connective tissue disorders, including lupus erythematosus. In hereditary angioneurotic edema serum...

Prospective study of the evolution of Raynaud's phenomenon☆

Seventy-four patients with Raynauds phenomenon and no associated illness were followed prospectively to determine whether a secondary disease would develop, and clinical and laboratory assessments were performed at study entry to determine their association with the subsequent development of disease. After an average of 2.7 years of follow-up (range 0.5 to 5.7 years), outcome information was available on 58 persons (78.4 percent). A connective tissue disease developed in 11 (19.0 percent): three systemic sclerosis and eight CREST syndrome. The two variables at entry most strongly associated with the subsequent development of a connective tissue disease were an abnormal nailfold capillary pattern (adjusted odds ratio = 26.82, 95 percent confidence interval = 4.69, 153.2) and an abnormal pulmonary function test result (odds ratio = 4.78, 95 percent confidence interval = 1.02, 22.41). The positive association of an abnormal barium esophagram, presence of antinuclear antibodies, and cutaneous abnormalities did not reach statistical significance. The development of connective tissue diseases in this group of patients is not rare. An abnormal nailfold capillary pattern is strongly associated with the subsequent development of systemic sclerosis or CREST syndrome in patients with Raynauds phenomenon.

Cellular Immunity to Nuclear Antigens in Systemic Lupus Erythematosus

Cellular immune repsonses were determined by skin testing and mitogen- and antigen-induced blastic transformation of peripheral blood lymphocyte cultures in 24 patients with systemic lupus erythematosus (SLE) and 24 normal subjects. The incidence of positive skin tests with Candida albicans, PPD (tuberculin-purified protein derivative) intermediate strength, Trichophyton and histoplasmin was not significantly different in the two groups nor was lymphocyte stimulation by the mitogen phytohemagglutinin-M (PHA-M), implying that cellular immunity is normal in SLE. However, the SLE patients had a significantly increased incidence of positive skin tests and stimulated lymphocyte cultures to a number of nuclear antigens compared with normal subjects. No correlation could be made between the test results and the activity of the SLE at the time of study except for a significant association between lymphocyte culture stimulation by rabbit thymus native DNA and active SLE nephritis. Patients with a membranous antinuclear factor (ANF) pattern had positive skin tests with rabbit thymus native DNA and usually had active disease.

Drug-Related Lupus

SummaryAdverse side effects to drugs and chemicals in which immune mechanisms may be responsible have been described in drug-related lupus (DRL). The spectrum of drugs that may elicit DRL includes such classes as the hydrazines, arylamines, and chemicals that can be metabolised to amines. The 2 major pathways of metabolism — acetylation and N-hydroxylation — are described in detail.The events leading to autoantibody production are not well understood; however, specific consideration of the genetic makeup of patients who are candidates for treatment with these drugs may help identify those at risk of developing DRL.

Immunologic findings in idiopathic cardiomyopathy: A prospective serial study

Abstract Thirty-two patients with idiopathic cardiomyopathy were followed for 51.6 patient years and evaluated for evidence of immunologic disease. Serologic and immunologic variables were correlated with exacerbation and remission of the underlying disease. Twenty-eight per cent of patients had H.R.F. and 28 per cent had positive latex tests. Nineteen per cent had positive thyroid antibody tests. There was no correlation between positive tests and the clinical course, or between positive tests and the severity of the disease. The results suggest that idiopathic cardiomyopathy is a disease in which secondary immunologic mechanisms are present but that they do not play a role in etiology or pathogenesis.

Induction of antibodies to nuclear antigens in rabbits by immunization with hydralazine-human serum albumin conjugates.

The antihypertensive drug hydralazine can induce in man a syndrome similar to spontaneous systemic lupus erythematosus (SLE). The pathogenesis of this drug-induced syndrome is not understood. In this investigation, five groups of rabbits were studied: group I, 10 rabbits hyperimmunized with hydralazine conjugated to human serum albumin (HSA) in complete Freunds adjuvant (CFA); group II, four rabbits with HSA in CFA; group III, four rabbits with CFA alone; group IV, five rabbits with hydralazine conjugated to rabbit serum albumin (RSA); and group V, four rabbits with a major metabolite of hydralazine conjugated to HSA. The rabbits immunized with hydralazine-HSA developed rising titers of antibodies to hydralazine and progressively increasing amounts of antibodies to both single-stranded and native DNA. The antibodies to DNA were cross-reactive with hydralazine as determined by inhibition of DNA binding and DNA hemagglutination tests. Similar results were obtained in rabbits immunized with the metabolite-HSA compound except the major hapten antibody response was to the metabolite. The DNA antibodies in this group were also capable of being absorbed by metabolite-HSA as well as hydralazine-HSA, indicative of the cross-reactivity between hydralazine and its metabolite. Immunization with hydralazine-RSA caused rabbits to produce antibodies to hydralazine but not to DNA, indicating the requirement for an immune response to the carrier protein in order for antibodies reactive with DNA to be produced. Thus, hyperimmunization of rabbits with hydralazine-protein conjugates may provide a useful animal model of SLE. The data suggests that an immune response to hydralazine may be important in human hydralazine-induced SLE.

In vitro studies in reproductive immunology — 2 demonstration of the inhibitory effect of male genital tract constituents on PHA-stimulated mitogenesis and E-rosette formation of human lymphocytes

The effect of male genital tract components (human spermatozoa, intact and chromatographed seminal plasma fractions) on in vitro cell-mediated immune reactions was examined. Their addition to PHA-containing lymphocyte cultures resulted in a marked degree of inhibition of DNA synthesis, the response varying with the fractions employed. The interference by such components with a terminal cell event during blast transformation was suggested by the failure of stimulated cultures to incorporate thymidine irrespective of the time during the incubation period at which the constituents were added. Seminal plasma and sperm extracts were also shown to inhibit T-cell associated E-rosette formation. The inhibitory properties of genital fractions remained unaltered after repetitive freeze-thaw cycling when tested in the transformation and E-rosette assays. Heating to 100 degrees C modified the response with some of the fractions.