The phenomenon, syndrome and disease of Maurice Raynaud, JJF BELCH

Tags: blood flow, RP, SS, BRITISH JOURNAL OF RHEUMATOLOGY, vasoconstriction, blood vessel, Raynaud's phenomenon, RP patients, Rochester Minnesota, Stopford Building, constructive suggestions, blood coagulation, statistics, Population, Communicable diseases, cigarette smoking, sympathetic nervous system, vascular damage, cigarette smoke, central nervous system, Department of Health and Social Security, neurogenic mechanisms, nervous system, systolic blood pressure, England and Wales, subsequent development, vasodilatory, CREST, nifedipine, the CREST, side-effects, antiplatelet agent, scleroderma, Maurice Raynaud, Office of Population Censuses and Surveys, A. J. SILMAN ARC Epidemiology Research Unit, National Morbidity Study, HMSO, Royal College of General Practitioners, London, Morbidity statistics, University of Manchester
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data presented in these reviews of interest and constructive suggestions regarding the content and presentation of the data will be welcomed. A. J. SILMAN ARC Epidemiology Research Unit, Stopford Building, University of Manchester, Oxford Road, Manchester Ml 39PT REFERENCES 1. Office of Population, Censuses and Surveys. Cancer statistics: registrations, England and Wales. Series MBI (1971 onwards). London: HMSO. 2. Office of Population, Censuses and Surveys. Communicable diseases, statistics, England and Wales. Series MB2 (1974 onwards). London: HMSO. 3. Office of Population, Censuses and Surveys. Mortality statistics: England and Wales. Series DH1 (1974 onwards). London: HMSO. 4. Office of Population, Censuses and Surveys. Hospital in-patient enquiry England and Wales. Series MB4 (1974 onwards) London: HMSO. 5. Logan WPO, Cushion AA. Morbidity statistics from general practice. Vol I (general). London: HMSO, 1958.
6. Royal College of General Practitioners, Office of Population Censuses and Surveys, Department of Health and Social Security. Morbidity statistics from general practice. 2nd National Morbidity Study 1970-71. London: HMSO, 1979. 7. Royal College of General Practitioners, Office of Population Censuses and Surveys, Department of Health and Social Security. Morbidity statistics from general practice. 3rd National Morbidity Study 1981-82. London: HMSO, 1988. 8. Lawrence JS. Rheumatism in populations. London: Heinemann, 1977. 9. Linos A, Worthington JW, O'Fallon WM. The epidemiology of rheumatoid arthritis in Rochester Minnesota. A study of incidence, prevalence and mortality. Ann J Epidemiol 1980;lll:87-98. 10. Michet CJ, McKenna CH, Elveback LR, Kaslow RA, Kurland LT. Epidemiology of systemic lupus erythematous and other connective tissue diseases in Rochester Minnesota 1950 through 1979. Mayo Clin Proc 1985 ;60:105-13. 11. Lawrence RC, Hochberg MC, Kelsey JL, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol 1989;16:427-41.
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THE PHENOMENON, SYNDROME AND DISEASE OF MAURICE RAYNAUD
MAN is a tropical animal, less able to retain heat than to lose it. His neutral environmental temperature is28°C and after a fall of only 8°C his metabolic rate must double or his body temperature will fall. Man's response to cold, the putting on of clothes, permits him to live in temperate areas. Despite this, some people respond abnormally to cold. The best recognized of the cold related disorders is Raynaud's phenomenon (RP). It was in 1862 that Maurice Raynaud first defined his clinical syndrome as episodic digital ischaemia provoked by cold, cyanosis and emotion. It is classically manifest by pallor of the digits followed by cyanosis and rubor. The pallor reflects vasospasm, cyanosis the deoxygention of static venous blood and the rubor reactive hyperaemia following the return of blood flow. RP affects 5-10% of the population and when severe can cause digital ulceration and gangrene [1]. Until recently, lack of knowledge in this area was reflected by the difficulties in the treatment and prediction of prognosis of RP. However, recent studies have investigated the extent of the vasospasm, its aetiology, progression and treatment and these 'moving points' in Raynaud's research are outlined below. One of the major problems is the question of terminology. In Europe, RP is the blanket term used to describe anyone suffering from cold-related digital vasospasm. RP is subdivided into secondary Raynaud's syndrome (RS) where there is an associated disorder and primary Raynaud's disease (RD) where there is not. This terminology has recently been ratified by the UK Raynaud's Working Group. Unfortunately this European classification is not globally accepted and,
additionally, other terms associated with the term 'Raynaud' are also used with different meanings by various authors resulting in a confusing overlap of synonyms. This confusion over nomenclature makes assessment of the literature difficult. Maricq [2] in her recent review concludes that the question of terminology will probably remain in a state of flux as long as the aetiology remains unknown and controversial. She stresses a most important point for all authors--all terminology attached to Raynaud's name should be carefully defined in each scientific paper so that useful comparisons within the literature can be made. Not only has the terminology used in RP been poorly defined but Raynaud's original definition of RP is now known to require significant modification. For example, the full triphasic colour change is not now thought to be essential for diagnosis. Furthermore, in addition to the digits, the tips of the ear lobes, tongue and the nose can also be involved. A recent hypothesis suggesting more widespread vasospasm in this disorder has been postulated. Workers have detected decreased oesophageal [3] and myocardial perfusion [4] after cold challenge. Some workers have speculated that the kidney and lung lesions [5] seen in severe RS associated with systemic sclerosis (SS) may be accounted for in the same way. It is interesting to speculate that abnormalities of the vasculature may exist throughout the whole RP patient. These may contribute to the wide spectrum of symptomatologies seen in RP. A further modification of Raynaud's definition is that other stimuli apart from cold and emotion can provoke an attack, for example, trauma, hormones [6] and chemicals such as
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those found in cigarette smoke. We know that cigarette smoking is harmful in general to the vasculature and a recent piece of work from Goodfield, Hume and Rowell [7] studied the effect of cigarette smoking in RP. The effects of smoking a single cigarette were profound and longlasting with a considerable reduction in finger blood flow. It seems that our advice to RP patients to stop smoking is based on sound scientific evidence. With the difficulties in the nomenclature and the changes in the original definition of RP, it is to be expected that controversy will also exist in the area of aetiology and this is so. We now know that a large number of factors are of aetiological importance and we can place them into three broad categories: neurogenic mechanisms, blood and blood vessel wall interactions and an abnormal immunological response. Neurogenic mechanisms include Raynaud's own hypothesis of hyperactivity of the sympathetic nervous system lately supported by work from Olsen and Petring [8] who investigated the effects of vibration on the fingers of patients with RP. The vibration induced vasoconstriction was abolished by a proximal nerve blockade. These along with previous data [9] showing that vibration of one hand induces vasoconstriction of the other suggests the existence of a vibration elicited central sympathetic vasoconstrictor reflex. Conversely, Freedman et al. [10] compared finger blood flow responses to brachial artery infusions of substances effecting a- and (3-adrenergic receptors. Their findings do not support a theory of elevated central sympathetic nervous system activity in RP as patients and controls did not differ in responses to reflex cooling or to indirect heating. Their work suggests that the same catecholamine levels in RD and in controls will produce greater digital vasoconstriction in RD suggesting an increased a-adrenergic responsiveness in these patients, more along the lines of Lewis' hypothesis of a 'local fault' [11]. The apparent dichotomy of these results is not easily explained either in terms of methodology or patient type. They serve once more to remind us that the exact pathophysiology of vasospasm is still uncertain and probably multifactorial. Another abnormality of the nervous system in RS secondary to SS has also recently been suggested by Klimiuk et al. [12] who postulated an autonomic dysfunction as detected by alteration in systolic blood pressure on standing. However, Suarez-Almazor et al. [13] using six standard tests of autonomic function report normal testing in the other five. In normal subjects systolic BP and heart rate increase rapidly after standing due to an increase in sympathetic activity caused by the initial decrease in peripheral resistance. The vascular damage in RS complicated by SS could cause an alteration in the normal variation in peripheral resistance owing to loss of elasticity of vessels. As the other cardiac reflexes are normal the central nervous system autonomic control is probably intact in these patients. With the above controversies in the literature it is pleasant to see a clearer consensus developing regarding the abnormalities in blood and blood vessel wall in RP. Flow in the microcirculation is critically dependent
on the properties of both the cellular elements of blood and plasma. Hard red cells, activated platelets and white cells have all been reported in RP as having increased plasma viscosity and decreased fibrinolysis [14]. Recent work on one of the platelet release products, serotonin, has confirmed the increased platelet activation in RS secondary to the CREST variant of SS [15]. In addition to providing another marker for platelet activation, an increased plasma serotonin level may contribute to further vascular damage via vasoconstriction, platelet aggregation and direct vascular damage. Most abnormalities in blood are best seen in patients with RS particularly those with RS secondary to SS. This is also true of the endothelial cell injury which contributes to the RS. The exception to this is factor VIII von Willebrand Factor Antigen (f VIII vWFAg, previously f VIII RAG) which is made and released by vascular endothelium. Damage to the vasculature will elevate plasma levels and such an elevation has been reported in RP [16]. This elevation occurs in both RD and RS with the levels appearing to predict transformation from RD to RS [17]. Greaves et al. [18] have extended this work byfindinghigher levels in patients with SS and visceral damage than in patients with RS and scleroderma alone. The mechanisms whereby this vascular damage occurs are multifactorial and include ischaemic damage, reperfusion Free radical induced injury and possibly the presence of cytotoxic activity in RP serum [19]. The suggestion that a circulating factor is involved in the endothelial cell injury and in the pathology of RP is supported by the reported temporary improvement in symptoms following plasmapheresis associated with a decrease in serum endothelial cell cytotoxicity [20]. Endothelial damage is an important feature in RS. The endothelium is a functioning organ, important not only in blood coagulation but in mediating various inflammatory and immune responses. Kahaleh et al. [21] have recently investigated the role of tumour necrosis factor (TNF) and lymphotoxin (LT) on the growth and function of vascular cells. TNF and LT inhibit endothelial cell growth and stimulate fibroblast growth and collagen synthesis. They also promote the release of f VIII vWFAg and can thus be linked theoretically to the abnormalities seen in RS. LeRoy et al. [22] reviewed this possible role of TNF in vascular injury and it is likely that the importance of this and growth factors such as transforming growth factor 8 and platelet derived growth factor in RP will be more fully realized in the future. The presence of autoantibodies in the blood of patients with RP has been well documented. Recent work concentrates on the prognostic and diagnostic abilities of these antibodies with the prediction of those who will progress from RD to RS being a most important consideration. RP may precede the development of the systemic illness, usually a connective tissue disease, by over 20 years [23]. A test with predictive power for the evolution of an associated disorder would, therefore, be very useful. Recent interest has centred on the antinuclear antibodies (ANAs), particularly the anticentromere
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antibody (ACA) found in the CREST variant of SS and the scleroderma-70 antibody (Scl 70) found in patients with diffuse SS. Both can be found in patients with RD and recent work has shown that in patients initially presenting with RD alone, ACA had a predictive value for the development of CREST (sensitivity 60%, specificity 98%) and Scl 70 for SS (sensitivity 38%, specificity 100%) [24]. Once the clinical syndromes are established, however, the ANAs lose their prognostic value [25]. Another factor suggested as a potential predictor for disease progression is the finding of abnormal nailfold capillary vessels on microscopy. Both the prospective study of Fitzgerald et al. [26] and the study of Wong et al. [27] found that an abnormal nailfold capillary pattern is strongly associated with the subsequent development of SS or CREST. This is supported by studies of RP in childhood [28] showing also the value of abnormal nailfold vessels as a predictor for those developing a later connective tissue disorder. These recent observations in combination with sensitive laboratory assays are now leading to a shrinkage in the true RD population and an expansion in potential RS patients. This is particularly so in the group of patients severe enough to require referral to a hospital clinic. The recent hypotheses regarding TNF and other mediators have not yet been extended to the therapeutic stage. Treatment of RP remains symptomatic, directed towards vasospasm or the blood constituents which contribute to decreased flow. Most of the blood abnormalities are likely to be a consequence rather than a cause of the disorder; however, this may be therapeutically unimportant as adherent hard cells and viscous plasma may contribute to impaired blood flow and their correction may produce clinical improvement. Nifedipine, the calcium channel blocker, is currently the gold standard of RP treatment. Its mechanism of action is predominantly vasodilatory but it is also an antiplatelet agent and may have other antithrombotic effects. A major problem with nifedipine, as with all vasodilators used in RP, is that in order to obtain a significant therapeutic effect intolerable vasodilatory side-effects may be induced [29]. Most recent research has concentrated on the attenuation of the side-effects [30, 31] or exploring the beneficial effects of other calcium channel blockers [32]. The slow release preparation of nifedipine is already used by most clinicians and Challenor et al. [33] showed benefit from both 10 mg and 20 mg slow release preparations given twice a day, although side-effects were more common with the high dose. A further concern regarding the use of nifedipine is that it is contraindicated in pregnancy. This recommendation is due to lack of data although successful pregnancy outcomes on nifedipine have been reported [34]. As patients with RP have an increased risk of abortion and pre-eclampsia possibly related to their tendency to vasospasm [35], the mode of action of nifedipine could possibly benefit RP patients. However, mutagenic and teratogenic effects of the drug must first be excluded. Studies of analogues of the vasodilator antiplatelet agent prostacyclin continue to benefit RP patients [36]. The side-effects of Iloprost are vasodilatory but occur only during the 3-day infusion.
The good tolerance of this drug prompted Rademaker et al. [37] to compare intravenous Iloprost with oral nifedi- pine in RS secondary to SS. Both drugs were effective but the side-effects seen with nifedipine were considered to be more troublesome. In the same way nifedipine has been compared to ketanserin, a serotonin antagonist [38]. Both treatments are beneficial but significantly fewer side-effects occurred with ketanserin. The defini- tive data on ketanserin itself have just recently been pub- lished in the form of a multicentre study of 222 patients [39]. A significant reduction in frequency of vasospastic attacks similar to that seen with nifedipine was wit- nessed. This was, however, not supported by any objec- tive increase in finger blood flow. The interaction of ketanserin with potassium-losing diuretics, plus the lack of objective increase in blood flow makes ketanserin a second-line choice of therapy. Work with y-linoleic acid, an essential fatty acid, appeared, like ketanserin, to produce subjective benefit in RP without objectively improving blood flow [40]. Fish oil has also been studied [41] but benefit, probably mediated through vasodilatory and antiplatelet effects, appears to be limited to primary RD. Although drugs without serious side-effects are always attractive, the small numbers of studies in this area combined with the expense of such preparations means further work is required before such treatments can be recommended. JILL J. F. BELCH Department of Medicine, Nine Wells Hospital and Medical School, Dundee, Scotland REFERENCES 1. Porter JM, Rivers SP, Anderson CJ, Baur GM. Evaluation and management of patients with Raynaud's syndrome. Am J Surg 1981; 142: 183-9. 2. Maricq HR. Raynaud's phenomenon and microvascular abnormalities in scleroderma (systemic sclerosis). In: Jayson MIV, Black CM, eds. Systemic sclerosis: scleroderma. Chichester: John Wiley & Sons, 1988; Chapter 10: 151-66. 3. Belch JJF, Land D, Park RHR, McKillop JH, McKenzie JF. Decreased oesophageal blood flow in patients with Raynaud's phenomenon. Br J Rheumatol 1988; 27: 426-30. 4. Gustafsson R, Mannting F, Kazzam E, Waldenstrom A, Hallgren R. Cold-induced reversible myocardial ischaemia in systemic sclerosis. Lancet 1989; ii: 475-9. 5. Barr WG, Fahey PJ. Reduction of pulmonary capillary blood volume following cold exposure in patients with Raynaud's phenomenon. Chest 1988; 94: 1195-9. 6. Lafferty K, De Trafford JC, Potter C, Robert VC, Cotton LT. Reflex vascular responses in the finger to contralateral thermal stimuli during the normal menstrual cycle: a hormonal basis to Raynaud's phenomenon? Clin Sci 1985; 68: 10-15. 7. Goodfield MJD, Hume A, Rowell NR. The acute effects of cigarette smoking on cutaneous blood flow in smoking and non-smoking subjects with and without Raynaud's phenomenon. Br J Rheumatol 1990; 29: 89-91. 8. Olsen N, Petring OU. Vibration elicited vasoconstriction reflex in Raynaud's phenomena. BrJInd Med 1988; 45: 413-19. 9. Olsen N, Petring OU, Rossing N. Exaggerated pos-
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tural vasoconstrictor reflex in Raynaud's phenomenon. Br Med J 1987; 294: 1186-8. 10. Freedman RR, Subharwal SC, Desai N, Wenig P, Mayes M. Increased a-adrenergic responsiveness in idiopathic Raynaud's disease. Arthritis Rheum 1989; 32: 61-5. 11. Lewis T. Raynaud's disease and pre-ganglionic sympathectomy. Clin Sci 1938; 3: 320-36. 12. Klimiuk PS, Taylor L, Baker RD, Jayson MW. Autonomic neuropathy in systemic sclerosis. Ann Rheum Dis 1988; 47: 542-5. 13. Suarez-Almazor ME, Bruera E, Russell AS. Normal cardiovascular autonomic function in patients with systemic sclerosis. (CREST variant). Ann Rheum Dis 1988; 47: 672-4. 14. Belch JJF, Drury J, McLaughlin K, Anderson J, Lowe GDO, Forbes CD. Abnormal biochemical and cellular parameters in the blood of patients with Raynaud's phenomenon. Scot Med J1987; 32:12-13. 15. Klimiuk PS, Grennan A, Weinkove C, Jayson MIV. Platelet serotonin in systemic sclerosis. Ann Rheum Dis 1989; 48: 586-9. 16. Kahaleh MB, Osborn I, LeRoy EC. Increased factor VHIVvon Willebrand Factor antigen and von Willebrand Factor activity in scleroderma and in Raynaud's phenomenon. Ann Intern Med 1981; 94: 482-4. 17. Belch JJF, Zoma A, Richards I, Forbes CD, Sturrock RD. Vascular damage and factor VIII related antigen in the rheumatic diseases. Rheumatol Int 1987; 7: 107-11. 18. Greaves M, Malia RG, Milford Ward A, et al. Elevated von Willebrand factor antigen in systemic sclerosis: relationship to visceral disease. BrJRheumatol 1988; 27: 281-5. 19. Kahaleh MB, Le Roy EC. Vascular factors in the pathogenesis of systemic sclerosis. In: Jayson MIV, Black CM, eds. Systemic sclerosis: scleroderma. Chichester: John Wiley & Sons, 1988; Chapter 7: 107-18. 20. Dau AC, Kahaleh MB, Sagebiel RW. Plasmapheresis and immunosuppressive drug therapy in scleroderma. Arthritis Rheum 1981; 24: 1128-36. 21. Kahaleh MB, Smith EA, Soma Y, Le Roy EC. Effect of lymphotoxin and tumour necrosis factor on endothelial and connective tissue cell growth and function. Clin Immunol Immunopathol 1988; 49: 261-72. 22. Le Roy EC, Smith EA, Kahaleh MB, Trojanowska M, Silver RM. A strategy for determining the pathogenesis of systemic sclerosis. Arthritis Rheum 1989; 32: 817-25. 23. Youinou P, Pennec Y-L, Katsikis P, Jonquan J, Fauquert P, Le Goff P. Raynaud's phenomenon in primary Sjogren's syndrome. Br J Rheumatol 1990; 29: 205-7. 24. Kallenberg CGM, Wouda AA, Hoet MH, van Venrooij WJ. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six year follow-up with emphasis on the predictive value of antinuclear anitbodies as detected by immunoblotting. Ann Rheum Dis 1988; 47: 634-41.
25. Steen VD, Powell DL, Medsger TA Jnr. Clinical correlations--prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988; 31: 196-203. 26. Fitzgerald O, Hess EV, O'Connor GT, SpencerGreen G. Prospective study of the evolution of Raynaud's phenomenon. Am J Med 1988; 84: 718-26. 27. Wong ML, Highton J, Palmer DG. Sequential nailfold capillary microscopy in scleroderma and related disorders. Ann Rheum Dis 1988; 47: 53-61. 28. Duffy CM, Laxer RM, Lee P, Ramsay C, Fritzler M, Silerman ED. Raynaud syndrome in childhood. J Pediat 1989; 114: 73-8. 29. Coulter DM. Eye pain with nifedipine and disturbance of taste with captopril: a mutally controlled study showing a method of postmarketing surveillance. Br Med J1988; 296: 1086-8. 30. Friedman El, Taylor LM, Porter JM. Late-onset Raynaud's syndrome: diagnostic and therapeutic considerations. Geriatrics 1988; 43: 59-70. 31. Miller FW, Love LA. Prevention of predictable Raynaud's phenomenon by sublingual nifedipine. N Engl J Med 1987; 317: 1476. 32. Leppert J, Jonasson T, Nilsson H, Ringqvist I. The effect of isradipine, a new calcium-channel antagonist, in patients with primary Raynaud's phenomenon. Cardiovasc Drug Ther 1989; 3: 397^01. 33. Challenor VF, Waller DG, Hayward RA, Griffin MJ, Roath OS. Vibrotactile sensation and response to nifedipine dose titration in primary Raynaud's phenomenon. Angiology 1989; 40:122-8. 34. Baethge BA, Wolfe RE. Successful pregnancy with scleroderma renal disease and pulmonary hypertension in a patient using angiotensin converting enzyme inhibitors. Ann Rheum Dis 1989; 48:776-8. 35. Silman AJ, Black C. Increased evidence of spontaneous abortion and infertility in women with scleroderma before disease onset: a controlled study. Ann Rheum Dis 1988; 47: 441^t. 36. Yardumian DA, Isenberg DA, Rustin M, et al. Suc- cessful treatment of Raynaud's syndrome wth Iloprost, a chemically stable prostacyclin analogue. Br J Rheumatol 1988; 27: 220-6. 37. Rademaker M, Cooke ED, Almond NE, et al. Com- parison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's pheonomenon in patients with systemic sclerosis: a double blind randomized study. Br Med J19$); 298:561^. 38. Codella O, Caramaschi P, Olivieri O, et al. Controlled comparison of ketanserin and nifedipine in Raynaud's phenomenon. Angiology 1989; 40: 114-21. 39. Coffman JD, Clement DL, Creager MA, etal. International study of ketanserin in Raynaud's phenomenon. Am J Med 1989; 87: 264-8. 40. Belch JJF, Shaw B, O'Dowd A, Saniabadi A, Sturrock RD, Forbes CD. Evening primrose oil (Efamol) in the treatment of Raynaud's phenomenon: a double-blind study. Thrombosis Haemostas 1985; 54:490-4. 41. DiGiacomo RA, Kremer JM, Shah DM. Fish-oil dietary supplementation in patients with Raynaud's phenomenon: a double -blind controlled, prospective study. Am J Med 1989; 86:158-64.

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