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ischaemic heart disease, or who died unknown casualties of the Gulf war.

suddenly

are

the

REFERENCES A, Berman DS. Silent myocardial ischaemia. I. Pathophysiology, frequency of occurrence and approaches toward detection. Am Heart J 1987; 114: 615-26. 2. Mason JW. Emotion as reflected in patterns of endocrine integration. In: 1. Rozanski

Levi L, ed. Emotions: their parameters and measurement. New York: Raven Press, 1975: 143-81. 3. Frankenhaeuser M. Experimental approaches to the study of catecholamines and emotion. In: Levi L, ed. Emotions: their parameters and measurement. New York: Raven Press, 1975: 209-34. 4. Dimsdale JE, Moss J. Plasma catecholamines in stress and exercise. JAMA 1980; 243: 340-42. 5. Rebeca G, Wagner R, Zebede T, et al. Pathogenetic mechanisms causing transient myocardial ischemia with mental arousal in patients with coronary artery disease. Clin Pres 1986; 34: 338A (abstr). 6. Gordon JB, Zebede J, Wayne RR, Mudge GH, Ganz P, Slawyn AP. Coronary constriction with exercise: possible role for endothelial dysfunctionand alpha tone. Circulation 1986; 73 (suppl 2): II-481

(abstr). January

Daily incidence of acute myocardial infarction in ICCU during Jan 8-25, 1991 (closed columns), compared with same period in 1990 (open columns). Large arrow=beginning of Gulf war; small arrows= missile attacks on

Israel.

Rozanski

all demonstrated the induction of silent myocardial ischaemia after mild mental stress in patients with coronary artery disease. A personally relevant, emotionally stressful task induced more ischaemic changes than did non-personal, cognitive challenges. In the same patients, the magnitude of the emotionally induced ischaemia was not significantly different from that induced by vigorous physical exercise. Increased afterload due to the rise in systolic and diastolic blood pressure, increased catecholamine secretion during stress, 2-4 transient coronary vasoconstriction during mental stressand exerciseare some of the implicated mechanisms. During the first few missile attacks on Israel fear was intense because of the dread of mass destruction by non-conventional weapons. The gas masks donned by most citizens may have contributed to the aggravation of cardiac ischaemia by reducing air flow, causing a cycle of fright, ischaemia, and possibly a reduction in oxygen supply. Such a huge fear reaction seems to explain the sharp transient rise in the number of patients presenting with acute MI as well as a two-fold increase in the incidence of sudden out-ofhospital death. Our data correlate well with an apparant nationwide increase in cardiac morbidity and mortality according to unofficial data gathered from most medical centres in Israel, which strongly suggests that our observations are valid and do not constitute a publication bias. To our knowledge, such an increase in incidence of MI and sudden death rate in a civilian population during wartime has not been previously recorded. There may be a lack of such documentation because cardiac morbidity may have been masked by the huge number of war injuries-eg, in London during the blitz in the 1939-45 war-or because modern nonconventional warfare conveys the possibility of annihilation. The cardiac effects of extreme emotional stress may have been present in other wars in which the civilian population was involved. However, in those situations the vast number of war casualties probably overshadowed the cardiac casualties. Patients who had an acute MI or exacerbation of

ADDRESSES.

Department of Cardiology, Meir General Hospital, Sapir Medical Center affiliated to the Tel-Aviv, University Sackler School of Medicine (S. R Meisel, MD, K. I. Dayan, MD, H. Pauzner, MD, I. Chetboun, MD, Y Arbel, MD, D David, MD), and Psychiatric Service, Sapir Medical Center and Shalvatah Psychiatric Hospital (I. Kutz, MD), Kfar Saba, Israel. Correspondence to Dr D. David, Department of Cardiology, Meir General Hospital, Sapir Medical Center, Kfar Saba 44281, Israel

et

Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis

75 systemic sclerosis patients were independently tested for pulmonary fibrosis, autoantibodies, and MHC class II genes. 24 of 42 (57%) patients with pulmonary fibrosis had either HLA DR3/DRw52a or anti-Scl-70 vs 2 of 33 (6%) patients without pulmonary fibrosis. The presence of DR3/DRw52a or anti-Scl-70 gives a relative risk of 16·7 for the development of pulmonary fibrosis in a patient with scleroderma—a risk substantial enough to require careful monitoring of these patients and treatment at an early stage of disease.

The spectrum of scleroderma ranges from morphoea, in which there is only dermal fibrotic disease, through to limited cutaneous and diffuse cutaneous systemic sclerosis,’ in which internal organ involvement is common. These diseases are characterised by the production of excessive amounts of normal extracellular matrix proteins, principally collagen. The lungs are affected by interstitial fibrosis in many patients with systemic sclerosis, but not in morphoea. Since the treatment of renal systemic sclerosis has improved, pulmonary fibrosis is the major cause of death in the

662

MARKERS ASSOCIATED WITH PULMONARY FIBROSIS

Scl-70 antibody was detected in 10 patients (13%), and 7 of these have the diffuse cutaneous form of the disease (p=0 15). All patients with anti-Scl-70 had pulmonary fibrosis (p 0 002). 6 of the 10 patients with anti-Scl-70 had DR3/DRw52a (p=0025, pc=0-45). 24 of 42 (57%) patients with pulmonary fibrosis had either DR3/DRw52a or anti-Scl-70 compared with 2 of 33 (6%) patients without evidence of pulmonary fibrosis (pe= 0-0000018). The relative risk for development of pulmonary fibrosis in patients with DR3/DRw52a or anti-Scl-70 vs those without is 16.7 (4-0 to 69-2). These data show clearly that knowledge of MHC type and autoantibody profile has the potential to predict development of pulmonary fibrosis in patients with systemic sclerosis. Since both DR3/DRw52a and anti-Scl-70 are associated with pulmonary fibrosis, it is not clear whether the expression of the antibody is dependent on this MHC type. The presence of either DR3/DRw52a or anti-Scl-70 gives the maximum probability of predicting pulmonary fibrosis, and we believe justifies the use of intensive pulmonary investigation at the earliest opportunity. It is only at the prefibrotic stage that existing therapy is likely to slow progression and improve the quality and length of life. A previous study2 showed a serologically defined but weaker DR3 association. It is the ability of the DNA techniques to distinguish the DR3/DRw52a haplotype that makes the observation clinically applicable. Formal proof of the predictive potential of anti-Scl-70 expression in relation to pulmonary fibrosis will be obtained only in a prospective study. Others have shown that antibodies with this specificity both predict the development of systemic sclerosis in patients with Raynaud’s disease (initially without other symptoms of connective tissue disease) and =

Statistical significance for comparisons within groups between those with and without PF (pulmonary fibrosis): *p < 05; tp < 0,005; :t:p < 0,0005; pc = 0.02

disorder. Early detection and management of pulmonary fibrosis are a major challenge to clinicians; typically pulmonary fibrosis is only apparent when the process has advanced to a stage at which there is no effective therapy. The ability to predict pulmonary fibrosis is therefore desirable. Lynch and colleagues2 found a higher frequency of the MHC class II allele DR3 in systemic sclerosis patients with pulmonary fibrosis than in those without the complication (43% vs 20%). The predictive value of their findings is limited by the incidence of DR3 in the latter group, but it is now known that there is substantial heterogeneity of DR3-bearing haplotypes. We have investigated DR3 at the level of DNA in systemic sclerosis. We also studied the Scl-70 autoantibody (specific for topoisomerase I) which also associates with pulmonary fibrosis.3 MHC type and autoantibody status were assessed in 75 patients with systemic sclerosis. All attended the same clinic and are British caucasoids. No selection process was used for inclusion in this study other than availability of sufficient blood for DNA study. Pulmonary fibrosis was diagnosed in 42 patients and excluded in the remainder by the following criteria:4 no other known causes of alveolar wall fibrosis; bilateral persisting radiographic shadows; and a restrictive pulmonary deficit and/or reduced gas transfer measurements. In 26 of the 42 patients, the presence of pulmonary fibrosis was confirmed by high-resolution computerised

tomography.s

DQA alleles were identified by restriction fragment length polymorphism analysis. This procedure allows identification of the broad DR alleles equivalent to the serological specificities and their further subdivision.6 Taq I restriction fragment patterns allow assignment of alleles of the DRB1, DRB3, and DRB4 loci. DR3 (DRB 1 *0301 ) is associated with either DRw52a or DRw52b owing to linkage of DRBI*0301 with DRB3*0101 or DRB3*0201, respectively. Antibodies specific for Scl-70 were detected by DRB and

immunodiffusion.7 Genetic factors were assigned independently of the clinical assessment. Statistical analysis for comparison of frequencies of MHC alleles and autoantibodies used Fisher’s exact test. A correction factor (18, the number of alleles assessed) was applied to each p value except where we reassessed the individual associations of DR3 and Scl-70 with pulmonary fibrosis.

Analysis of the MHC class II loci DRB and DQA showed significant differences between systemic sclerosis patients with and without pulmonary fibrosis (table). The association with DR3 (p = 0-012) was confirmed. A more important observation was the association of pulmonary fibrosis with the combination DR3/DRw52a (p 000012, pc 0-0022). This association was found in both the major subsets of systemic sclerosis but was strongest in the patients =

=

with the limited cutaneous form.

are

persistent.8

We thank the Scleroderma Research Foundation (San Francisco, and the Arthritis Research Council (UK) for financial support.

USA)

REFERENCES 1.

Leroy EC, Black CM, Fleischmajer J, et al. Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J Rheumatol 1982;

2.

Lynch CJ, Singh G, Whiteside TL, et al. Histocompatibility antigens in progressive systemic sclerosis (scleroderma). J Clin Immunol 1982; 2:

15: 202-12.

314-18. 3. Steen VD, Powell DL, Medsger TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988; 31: 196-203. 4. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax 1980; 35: 171-80. 5. Harrison NK, Glanville AR, Strickland B, et al. Pulmonary involvement in systemic sclerosis: the detection of early changes by thin CT scan, bronchoalveolar lavage and 99m Tc-DTPA clearance. Respir Med 1989; 83: 404-14. 6. Bidwell J. DNA-RFLP analysis and genotyping of HLA-DR and DQ antigens. Immunol Today 1988; 9: 18-23. 7. Catoggio LJ, Bernstein RM, Black CM, et al. Serological markers in progressive systemic sclerosis: clinical correlations. Ann Rheum Dis 1983; 42: 23-27. 8. Weiner ES, Hilderbrandt S, Senecal J-L, et al. Prognostic significance of anticentromere antibodies and anti-topoisomerase I antibodies in Raynaud’s disease. Arthritis Rheum 1990; 34: 68-77.

ADDRESSES: Department of Immunogenetics, Guy’s Hospital, London, UK (D. C. Briggs, MSc, R W. Vaughan, MSc, K. I. Welsh, PhD); Temple University Health Services Centre, Philadelphia, USA (A Myers, MD); Department of Thoracic Medicine, Royal Brompton Hospital (R. M. duBois, FRCP); and Department of Rheumatology, Royal Free Hospital, London, UK (C. M. Black, FRCP). Correspondence to Mr D. C. Briggs, Tissue Typing Laboratory, Guy’s Hospital, St Thomas Street, London SE1 9RT, UK

Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis.

75 systemic sclerosis patients were independently tested for pulmonary fibrosis, autoantibodies, and MHC class II genes. 24 of 42 (57%) patients with ...
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