BLEEDING IN PATIENTS WITH LUPUS ANTICOAGULANT

868 INDUCTION OF EXPRESSION OF HLA-DR ANTIGENS IN HUMAN LEUKAEMIC CELLS IN LIQUID CULTURE BY TREATMENT WITH CYTARABINE AND 5-AZA-2’-DEOXYCYTIDINE

DRUG-INDUCED LUPUS

SIR,-Your editorial (Aug 25, p 441) states that predisposition to drug-induced systemic lupus erythematosus (SLE) is associated with the HLA-DR4 antigen. You cite a report of HLA-DR4 in 19 out of 26 (73%) patients with hydralazine-induced lupus compared with 33% of 113 controls. However, another study reported HLADR4 in only 5 out of 15 (33%) cases of hydralazine-induced lupus compared with 29% of 140 controls.2The numbers of patients in small. The relation between HLA-DR4 and is hydralazine lupus far from clear. On the other hand, there does seem to be a relation between idiopathic SLE and the histocompatibility complex. HLA-DR3 was found in 69% of SLE patients and this was in linkage disequilibrium with the null alleles of C4A and C4B which were present in 83%.3 Further, patients who are HLA-DR3 positive have impaired clearance of immune complexes, and this is associated with a reduction in Fc receptors for IgG on T cells.4HLA-DR3 has also been associated with However, in heightened immune 2 SLE, there appears to be no association with Dr Sim and co-workers (Aug 25, p 422) report a correlation between the ability of hydrazine derivatives to inhibit C4 binding and the likelihood of their causing SLE on prolonged administration. Although these are valuable in-vitro data, I do not agree that the concentrations at which inhibition occurred are similar to those found clinically in plasma. Sim et al cite a paper6in which the assay for hydralazine was nonspecific and did not distinguish hydralazine from its acid-labile metabolites. A later study in which hydralazine was measured by a specific high performance liquid chromatographic assay, plasma levels were always less than 1 f-tmol/l,7 well below the concentration range seen to cause inhibition of C4 binding. In patients with SLE on low doses of hydralazine,8 the plasma concentration would be expected to be lower still. This does not exlude the possibility that concentration of hydralazine in -the extravascular space may be higher. However, at this stage the relation between drug-induced SLE, the histocompatibility complex, and the complement system is a tenuous one.

both studies

were

responsiveness.

Data

percentage of cells reacting with monoclonal antibodies. Each sample contained than 70% blasts as determined by morphological examination. NT=not tested.

as

more

C=control; Aza=5azaCdR; Ara’--cytarabine.

(see table). In all the cells tested, the expression of all known allelic determinants to HLA-A, B, and C loci, assayed by means of at least three antisera for each specificity, remained unchanged after exposure to both drugs. Induction of DR antigen expression was not associated with morphological differentiation. This is the first time that cytidine analogues, such as ara-C and 5azaCdR, have been shown to induce the expression of HLA-DR antigens on myeloid leukaemia cells. Our data seem to agree with those of Reitz et al,6 who described expression of DR antigens induced by 5-azacytidine in human T-lymphocytic leukaemia cells.

Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria 3084, Australia

of membrane structures, such as HLA-DR molecules, involved in cell-to-cell recognition and/or regulation of blood cell growth and differentiation.

Supported in part by CNR grants 82.00434.96 and 82.00431.96 and CNR progetto finalizzato "oncologia". Department of Cellular and Molecular Biology and Pathology, Faculty of Medicine and Surgery II, University of Naples, 80131 Naples, Italy; and Section of Haematology TERE, USL 40, Naples

1107-09. 2. Brand C, Davidson A, Littlejohn G, Ryan P. Hydralazine-induced lupus: No association with HLA-DR4. Lancet 1984; i: 452. 3. Fielder AH, Walport MJ, Batchelor JR, et al. Family study of the major

human

4.

multipotential hematopoietic progenitor cells. Blood 1982; 59: 188-93. Broxmeyer HE. Relationships of cell-cycle expression of Ia-like antigenic determinants on normal and leukemic human granulocyte-macrophage progenitor cells to regulation in vitro by acidic isoferritins. J Clin Invest 1982; 69: 632-42. Fitchen JH, Ferrone S, Quaranta V, et al. Monoclonal antibodies to HLA-A,B and Ialike antigens inhibit colony formation by myeloid progenitor cells. J Immunol 1980;

125: 2004-08. der Reijden HJ, van Rhenen DJ, Lansdorp PM, et al. A comparison of surface marker analysis and FAB classification in acute myeloid leukemia. Blood 1983; 61: 443-48. 6. Reitz MS Jr, Mann DL, Eiden M, et al. DNA methylation and expression of HLA-DR. Mol Cell Biol 1984; 4: 890-97.

5.

van

histocompatibility complex in patients with systemic lupus erythematosus: Importance of null alleles of C4A and C4B in determining disease susceptibility. Br Med J 1983; 286: 425-28. Lowley TJ, Hall RP, Fauci AS, Katz SI, Hamburger MI, Frank MM. Defective Fc-receptor functions associated with the HLA-B8/DRW3 haplotype: Studies in patients with dermatitis herpetiformis and normal subjects. N Engl J Med 1981; 304: 185-92.

5.

6. 7.

1. Winchester RJ, Kunkel HG. The human Ia system. Adv Immunol 1979; 28: 221-92. 2. Fitchen JH, Fèvre CL, Ferrone S, et al. Expression of Ia-like and HLA-A,B antigens on 3.

4.

by

ANTONIO PINTO MICHELE MAIO VINCENZA ATTADIA SERAFINO ZAPPACOSTA RENATO CIMINO

N. CHRISTOPHIDIS

1. Batchelor JR, Welsh KI, Mansilla Tinoco R, et al. Hydralazine-induced systemic lupus erythematosus: Influence of HLA-DR and sex on susceptibility. Lancet 1980; i:

These results may suggest that the in vivo effects of low-dose

therapy with cytidine analogues could also be due to the modulation

drug-induce HLA-DR3.2

8.

Christophidis N, Huskisson EC, Wolf E, Cudworth AG. HLA-DR and MT antigens and penicillamine induced nephropathy in rheumatoid arthritis. Aust NZ J Med 1984; 14: (suppl 1): 361-62. Zacest R, Koch-Weser J. Relation of hydralazine plasma concentration to dosage and hypotensive action. Clin Pharmacol Ther 1972; 13: 420-25. Reece PA, Cozamanis I, Zacest R. Kinetics of hydralazine and its main metabolites in slow and fast acetylators. Clin Pharmacol Ther 1980; 23: 769-78. Cameron HA, Ramsay LE. The lupus syndrome induced by hydralazine: a common complication with low dose treatment. Br Med J 1984; 289: 410-12.

BLEEDING IN PATIENTS WITH LUPUS ANTICOAGULANT

SIR,-The most frequent clinical manifestations of lupus anticoagulant (LA) are thrombosis and habitual abortion.I Paradoxically, spontaneous bleeding and bleeding after surgery are rare. So far these have invariably been associated with clotting factor deficiency, severe thrombocytopenia, or vascular abnormality.l,2 But Dr Manoharan and Dr Gottlieb (July 21, p 171) described a patient with LA and haemorrhage after surgery who did not have any associated abnormality. The haemorrhage was stopped with plasma exchange. These authors wondered if the improvement was due to the action on LA or another plasma factor. 20 of our series of

869 PRESENCE OF LA MEASURED BY COAGULATION TESTS

patients with LA underwent surgery, and 2 had substantial haemorrhage postoperatively. Nevertheless, an earlier operation on 1 of these 2 patients, before which he had been treated with steroids, did not result in haemorrhage. A 42year-old man with a history of an accidental fracture of the right femur in 1978 was operated on and had heavy bleeding requiring the transfusion of 3 litres of fresh blood. Postoperatively he contracted hepatitis B, and a circulating anticoagulant was detected. In 1981 a new bleeding occurred after a tooth extraction, even though 2 units of fresh plasma had been transfused before the extraction. On June 18, 1984, he was admitted to our hospital with a strangulated inguinal hernia. A study of the clotting profile showed 59

the presence of LA (table) with no other associated abnormality. Before surgery he was treated with 1 mg/kg/day ofprednisone. At 21 days LA was almost undetectable (table), and there was no

haemorrhage during operation or postoperatively. The lack of bleeding during surgery with steroid cover suggests the immunoglobulin itself causes bleeding. The difficulty is that laboratory tests do not identify patients with LA who will bleed during an operation. In the absence ofa history of thrombosis and/or abortions, there will be no indication of the danger. Is it better to give immunosuppressive treatment to every patient with LA who is going to undergo surgery, or should postoperative plasma exchange be given as an emergency measure if bleeding occurs? Laboratory tests are needed to indicate which patients with LA will bleed during an operation. For the moment, we think that preoperative prednisone is the most appropriate treatment. J. ORDI M. VILARDEL

J. ORISTRELL

A = Laboratory

Department of

Internal Medicine, Valle Hebron General Hospital,

Barcelona, Spain

Y. MONASTERIO P. FLORES

1. Editorial. Lupus anticoagulant. Lancet 1984; i: 1157-58. 2. Shaulian E, Shoenfeld Y, Berliner S, Shaklao M, Pinkhas J. Surgery in circulating lupus anticoagulant. Int Surg 1981; 66: 157-59.

for

dllldren

spontaneous fractures.

laboratory methods vary considerably and the normal ranges are poorly established for this weight group. If the alkaline phosphatase level is very high, the infant is likely to have radiological changes but, as the figure shows, some infants with very high levels have radiologically normal wrists and some infants with definite radiological changes have surprisingly low enzyme levels. often

N. MCINTOSH Neonatal Unit and Department of St George’s Hospital, London SW170RE

Radiology,

J. E. WILLIAMS A. J. LYON K. A. WHEELER

1. Kovar

patients with

DIAGNOSIS OF RICKETS OF PREMATURITY

SIR,-There is no agreement on the best way to diagnose rickets of some workers use biochemical criterial and some

prematurity;

radiological.2

limit of normal

Comparison of maximum serum alkaline phosphatase (log scale) and radiological grading of rickets. Alkaline phosphatase was measured in the routine chemical pathology laboratory and the radiological grading followed the method of Koo et awl.4 Grade 1;= osteopenia, grade 2=classical rickets, grade 3=rickets with

M. VALDES A. KNOBEL

J. ALIJOTAS

upper

This probably accounts in part for the differing reported incidences. The incidence is inversely related to birthweight and gestation and rickets is more common if there have been neonatal complications.3 Over 3 years (1981-83) we have monitored prospectively the radiological appearance at the wrist in babies whose birthweight was less than 1000 g and who survived for more than 28 days. 47 infants had both X-rays and repeated measurements of serum alkaline phosphatase. The illustration shows the correlation between these two indices. Our feeding policy is to establish enteral expressed breast milk feeding as soon as possible and to give vitamin D 2000 units daily for 7 days. Over the first few days intravenous nutrition is given, supplementing oral breast milk. We accept the diagnosis of rickets for grades 2 and 3radiological changes, which would give a frequency of 54% in infants weighing less than 1000 g at birth. We believe this is a more objective approach than serum alkaline phosphatase measurements because

I, Mayne P, Barltrop D. Plasma alkaline phosphatase activity: A screening test for rickets in preterm neonates. Lancet 1982; i: 308-10. 2. Kulkarni PB, Hall RT, Rhodes PG, et al. Rickets in very low birthweight infants. J Pediatr 1980; 96: 249-52. 3. McIntosh N, Livesey A, Brooke OG. Plasma 25 hydroxyvitamin D and rickets in infants of extremely low birthweight. Arch Dis Child 1982; 57: 848-50. 4. Koo WWI, Gupta JM, Nayanar W, Wilkinson M, Posen S. Skeletal changes in preterm infants. Arch Dis Child 1982; 57: 447-52.

INCIDENCE OF INFANTILE HYPERTROPHIC PYLORIC STENOSIS IN FUNEN COUNTY, DENMARK

SIR,-Your editorial request for data on infantile hypertrophic stenosis (IHPS)1 prompted us to examine the incidence in our area over a long period. Studies from the United Kingdom suggesting an increasing incidence of IHPS include two 7-year studies (1974-80)2,3 and two 10-year studies (1970-79).4,s Only one study includes both medically and surgically treated cases.2 A study from Australia reported no significant variation in incidence during the period 1966-77.6 Earlier reports suggested declining incidences in Northern Ireland and Sweden.7,8

pyloric

The county of Funen can be considered as a geographically welldelineated and demographically representative 9% sample of the whole of Denmark and is especially suitable for incidence studies. Our study covers the years 1950-1983. The population was 395 535 in 1950 and 453 773 in 1983. To avoid loss of patients with IHPS as the result of incorrect diagnostic coding,3we reviewed all