Predictive value of uterine artery velocity waveforms in pregnancies complicated by systemic lupus erythematosus and the antiphospholipid syndrome.

The objective of this study was to see if determination of uterine artery velocity waveforms between 20 and 30 weeks in lupus pregnancy and the antiphospholipid syndrome (APS) have a good predictive value for later fetal distress before labor, intrauterine growth retardation, and preeclampsia. Uterine and umbilical artery blood flow velocity waveforms were determined in 21 pregnancies complicated by systemic lupus erythematosus (SLE): 12 with antiphospholipid antibodies (aPL), 9 without aPL. We also studied 7 pregnancies with APS. This retrospective study was running from January 1st 1986 to July 31st 1991, at the Port-Royal Maternity, Paris, France. Abnormal uterine artery blood flow velocity waveforms were found in 10 out of 28 pregnancies at the first examination performed between 20 and 30 weeks gestational age. All the later adverse fetal and neonatal events were predicted by an abnormal uterine artery blood flow velocity waveform. From the 7 cases of fetal distress diagnosed during pregnancy, 6 were predicted by abnormal uterine waveforms and all of these pregnancies resulted in induced delivery before 32 weeks of gestational age. Twelve pregnancies with aPL and normal uterine artery waveforms were uncomplicated. Only 1 out of 7 pregnancies with abnormal uterine artery waveform and aPL ended without complication. Determination of uterine artery flow velocity waveform is a good adjunct to the management of pregnancies complicated by SLE or aPL. This determination has a better predictive value than the presence of aPL.

Progesterone receptors in lymphocytes of liver-transplanted and transfused patients.

Previous data have shown that lymphocytes from pregnant women, but not from non-pregnant individuals, displayed progesterone receptors. These receptors are inducible in normal human lymphocytes in vitro by mitogenic or allogeneic stimuli. The present study was designed to test the role of in vivo allogeneic stimulation in inducing progesterone receptors in lymphocytes from transplanted and transfused patients. Receptors were detected by immunohistology using a progesterone receptor-specific MoAb and avidin-biotin system. Peripheral blood lymphocytes from 56 healthy pregnant women, 8 liver-transplanted patients and 15 transfused patients contained significantly more receptor-positive cells (P less than 0.001) than those of non-pregnant individuals. In transplanted and transfused patients no correlation was found between the percentage of positive lymphocytes and age, sex or transplant survival. Our results show that in these three groups the percentage of receptor-bearing lymphocytes was higher than in normal subjects.

Hepatocellular carcinoma after danazol therapy.

Danazol, an inhibitor of pituitary gonadotropin, has been proposed in the treatment of systemic lupus erythematosus (SLE). We report the case of a female patient with SLE in whom a hepatocellular carcinoma was discovered after 4 years of treatment with danazol. Except for 3 days of hypochondrium pain, there were neither clinical signs of liver tumor nor biological abnormalities. An ultrasonography showed 2 tumors of the liver. At histological examination after surgery, one of the tumors was found to be a benign adenoma, while the other was a well differentiated hepatocellular carcinoma. When longterm danazol therapy is required, ultrasonography may be useful for early tumor detection.

Mononuclear phagocytes from patients with active systemic lupus erythematosus down-regulate the specific in vitro reactivity of autologous lymphocytes to double-stranded DNA.

Peripheral mononuclear cells (MNC) from patients with systemic lupus erythematosus (SLE) are hyporesponsive in vitro. In order to study the role of mononuclear phagocytes (m phag) in regulating the in vitro responses of autologous lymphocytes, the MNC from 16 SLE patients (eight active, eight inactive) and 14 healthy controls were stimulated in vitro with PHA or dsDNA. The proliferative response to PHA was tested by 3H-thymidine incorporation on day 4 and the response to dsDNA using a specific haemolytic plaque assay. Indomethacin, an inhibitor of prostaglandin (PG) synthesis by m phag, was added into the cultures to test the presence of suppressive m phag acting through a PG-mediated pathway. Indomethacin augmented the proliferative response to PHA in active SLE cultures and not in inactive SLE or controls. In six of 13 SLE cultures, dsDNA totally or partly suppressed anti-dsDNA plaque-forming cell (PFC) generation. Indomethacin restored or enhanced the PFC response to dsDNA in active SLE and not in inactive SLE or controls. M phag depletion by plastic adherence prevented the effects of indomethacin. These results show that m phage exerting a suppressive activity on PHA-induced lymphocyte proliferation and on anti-dsDNA antibody production are found in cultures from active SLE and generally not in inactive SLE or healthy individuals. PHA being primarily a T-cell stimulator, the m phag suppressive activity observed in PHA-stimulated cultures is exerted on T cells. On the other hand, in two active SLE cultures depleted of T cells by OKT3 antibody, indomethacin still could enhance the PFC response to dsDNA, showing that in vitro suppressive m phag can act directly on B cells from patients with active SLE.

[Specific antibodies of soluble nuclear antigens in autoimmune vasculitis]. / Etude des anticorps spécifiques des antigènes nucléaires solubles au cours des vascularites auto-immunes.

In order to assess the clinical value of antinuclear antibody (ANA) assays in classifying vasculitis, 136 sera from 28 patients with cutaneous vasculitis alone, and 80 patients with vasculitis associated with a connective tissue disease or an unclassified arthritis were tested. ANAs were assayed by indirect immunofluorescence, anti-ENA and anti-histone antibodies were tested by immunodiffusion. ANAs are seldom in patients with cutaneous vasculitis alone (1 positive serum/28 = 3.5%). ANAs are more generally observed in vasculitis associated with systemic lupus erythematosus (SLE) (15 positive sera/16 vasculitis associated with SLE = 94%), rheumatoid arthritis (RA) (8 positive/30 RA with vasculitis = 27%), or a Sjögren syndrome (SS) (9 positive/19 vasculitis with SS = 47%). ANAs in SS are correlated with vasculitis or Raynaud's phenomenon. ANAs are not detected in vasculitis associated with other connective tissue diseases or unclassified arthritis. Anti-ENA antibodies are only found in vasculitis associated with SLE (11 positive sera/13 = 85%) or SS (3 positive sera/19 = 16%). Contrasting with the findings of other groups, our results show no anti-ENA antibodies in RA with vasculitis. Anti-RNP in SLE are correlated with cutaneous vasculitis (p less than 0.005). An antibody different from anti-Ro (SS-A) antibodies but precipitating with a trypsinized human spleen extract was observed in 2/11 sera from RA with vasculitis and not in other sera. Its significance is not established yet; this antibody would have a clinical interest only if further studies showed a high prevalence in rheumatoid vasculitis.

Cellular control of antinuclear antibody production. Anti-dsDNA and anti-Sm plaque forming cells in SLE patients and normal individuals.

The in vitro response of lymphocytes to dsDNA, Sm, and Pokeweed Mitogen (PWM) and the role of monocytes in the control of this response were studied in 21 SLE and 14 healthy individuals. Specific hemolytic plaque assays were used to enumerate peripheral blood B lymphocytes secreting anti-dsDNA and anti-Sm antibodies. After 7 days in tissue culture without stimulation, anti-dsDNA or anti-Sm Plaque Forming Cells (PFC) were observed in 75% of SLE patients and 45% of normals. PWM, dsDNA, and Sm stimulation raised the levels of anti-dsDNA PFC in 25%, 37%, and 83% of SLE cultures respectively, and in all but one normal culture. PWM and dsDNA induced a decrease in anti-dsDNA PFC in 50% and 62% of SLE cultures. This suppressive effect was mainly exerted on spontaneous high producers of anti-dsDNA PFC. Monocyte depletion from cultures resulted in a decrease in PFC formation in all normals studied and in 7 SLE cultures. In 2 SLE cultures with no stimulation and one dsDNA stimulated culture, the number of anti-nuclear PFC increased after monocyte depletion. In cocultures of allogeneic, HLA-DR identical mononuclear cells, dsDNA pulsed SLE monocytes appeared more efficient than pulsed normal monocytes in helping to generate anti-dsDNA PFC. SLE lymphocytes responded less well than normals to dsDNA. These results suggest that: nuclear antigens may act as stimulators or suppressor of the specific autoimmune response, depending on the immune status of the SLE patient; and that abnormalities in both monocyte and lymphocyte responses lead to the excessive secretion of anti-dsDNA and anti-Sm antibodies by SLE B lymphocytes.

Use of nuclear antigen-coated red cells in hemolytic plaque assays.

By studying antinuclear antibody production at the cellular level, we can better understand the problems of immunoregulation in individuals with systemic lupus erythematosus. To date, the use of hemolytic plaque assays to detect B cells secreting antinuclear antibodies has been hampered by an inability to achieve reliable coating of red cells by nuclear antigens. Because the chromic chloride technique has proved ineffective for coupling nucleic acids and/or nuclear antigens to sheep red blood cells (SRBC) in our laboratory, we have developed a method of coupling SS DNA, DS DNA, poly(I).poly(C), Sm, and ENA to red cells pretreated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ECDI) and poly(L-lysine) (PLL). Coated red cells were agglutinated by specific antisera and not by normal sera and were then used in hemolytic plaque assays to detect antinuclear plaque-forming cells (PFC) in spleens from various strains of mice with lupus-like syndromes. PFC specific for SS DNA, DS DNA, poly(I).poly(C), Sm, and ENA were found in MRL/lpr and NZB x W mice, and the number of anti-SS DNA and anti-DS DNA PFC correlated with the age of the animals. Indirect (IgG) PFC specific for nuclear antigens increased dramatically in female NZB x W mice between 11 and 13 months, a time when more than 50% of the animals usually die. Preliminary studies have shown that PFC specific for nuclear antigens can be detected in peripheral blood from patients with lupus erythematosus. Pretreatment of sheep red cells with ECDI and PLL thus allowed the coupling of selected nuclear antigens to these cells and provided the first demonstration of IgM and IgG PFC specific for a variety of nuclear antigens.

The anti-anaphylactic action of tiaramide hydrochloride.

Tiaramide hydrochloride (THC) is a new basic, non-steroidal, anti-flammatory drug. Its anti-anaphylactic action has been investigated using rat mast cells. It was found that THC exerts a strong inhibitory action on antigen-induced and compound 48/80-induced histamine release from rat peritoneal mast cells in a fluorometric assay. Compound 48/80-induced vasodilatation in rat skin is inhibited by prior intradermal injection of THC, as measured by blueing of skin due to intravascular Evans blue dye. THC also inhibits radio-labeled serotonin release from compound 48/80-challenged rat mast cells. In these experimental systems a similar action was exerted by disodium cromoglycate, but higher drug concentrations were needed. Further studies are needed to determine the exact mode of action of this drug and its eventual clinical use in the field of allergic diseases.