Internutional d
Journal
of Curdiology,
33 (1991) 253-258
1991 Elsevier
ADONlS
CARD10
Science Publishers 016752739100237E
B.V. All rights reserved
0167-5273/91/$03.50
01350
Acute aortitis and aortic incompetence due to systemic rheumatological disorders J.N. Townend
‘, P. Emery ‘, M.K. Davies ’ and W.A. Littler ’
lJt~iwr.s~ty of Birminghwn,Depurtments
of ’ Curdiolwscular Birmingham,
(Received
10 December
Medicine
md
’ Rheumatology.
Quern
Llixhcth
Hmpitul.
U.K.
1900; revision
accepted
Townend JN, Emery P. Davies MK, Littler WA. Acute aortitis rheumatological disorders. Int J Cardiol 1991;33:253-258.
20 May IYYI 1
and aortic
incompetence
due to systemic
We report the clinical, laboratory and echocardiographic features of five cases of aortic incompetence associated with ankylosing spondylitis, rheumatoid arthritis and undefined connective tissue diseases. lmmunosuppression with steroids and cytotoxic agents was used to suppress aortic root inflammation in four cases; in three the aortic root size stabilized and the patients remain well with no evidence of increasing aortic incompetence. In one case, control of the inflammatory process was never fully achieved for any length of time and the patient died shortly after aortic valve replacement. A fifth case required urgent valve replacement and remains well. A systemic rheumatological disorder should be considered in cases of apparent “lone” aortic incompetence and conversely aortic incompetence should not be overlooked in established systemic rheumatological disease. Immunosuppressive therapy may prevent or delay the need for aortic valve replacement in such cases. Key words:
Aortic
incompetence;
Aortitis;
Connective
Introduction The association of aortic incompetence with systemic rheumatological disease was first described by Mallory in 1936 [l]. Since then involvement of the aortic root or valve has been reported in many systemic rheumatological disorders including rheumatoid arthritis, seronegative spondyloarthropathies, connective tissue disor-
Correspondence to: Dr. J.N. Townend. University of Birmingham, Dept. of Cardiovascular Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH. U.K.
tissue disease;
Immunosuppressive
therapy
ders and a number of inflammatory disorders of uncertain aetiology. The inflammatory process causes aortic root dilatation and cusp retraction leading to valvular incompetence and haemodynamic compromise. All of these diseases arc thought to result from autoimmune mediated tissue damage involving both cell mediated and humoral immune processes. The immune mediated nature of these diseases suggests that it may be possible to reduce inflammation in the aortic root with the use of immunosuppressive agents. We present five cases which illustrate the difficulties of diagnosing and managing aortic incompetence due to inflammatory aortic root disease.
The response to immunosuppressive described in four cases.
regimens is
Case 1 A 29-year-old man was admitted with a short history of increasing dyspnoea and signs of congestive cardiac failure. There was also a six year history of low back pain and a previous surgical repair of a brachial artery aneurysm. Clinical and radiological cardiomegaly was noted together with signs of aortic incompetence; blood pressure was 145/70 mmHg. Restriction of lumbar spine movement was also observed. Echo and Doppler studies (Fig. 1) showed a dilated left ventricle with preserved systolic function, a normal aortic valve but dilated aortic root (4.1 cm) and evi-
dence of moderate aortic regurgitation. Bilateral sacro-ileitis was seen on X-ray. A polymorphonuclear leukocytosis, erythrocyte sedimentation rate of 84 mm/hr, polyclonal rise in immunoglobulins and a C-reactive protein of 204 mg/l suggested active inflammation. Complement levels were normal and an auto-antibody screen was negative. A raised factor VIII related antigen at 280 IU/dl (normal range < 200 IU/dl) indicated endothelial damage compatible with active arteritis. These clinical, radiological and laboratory features led to a diagnosis of active seronegative spondyloarthropathy with associated aortitis. Treatment with diuretics and digoxin was started together with pulsed intravenous cyclophosphamide (1.5 mg/kg) and methyl prednisolone (10 mg/kg) every two weeks. After three courses,
Fig. 1. Two-dimensional echocardiogram of the heart in case 1. Long axis parasternal view. The aortic root (Ao) is dilated at 4.1 cm. The left ventricle (LV) is also dilated and slightly hypertrophied. The characteristic “sub-aortic bump” [6] is also seen (arrow). There is a small posterior pericardial effusion.
2.55
therapy was given orally (cyclophosphamide 5 mg/kg and prednisolone 3.3 mg/kg for 3 days) at three weekly intervals. A rapid clinical improvement in both cardiac and spondylitic symptoms and signs was associated with a reduction in laboratory disease markers. The echocardiographic aortic root size fell to 3.7 cm and left ventricular dimensions returned to normal. After nine pulses of cyclophosphamide and prednisolone he was converted to daily oral steroids and azathioprine. Naproxen was given continuously from the time of diagnosis. At 16 months from presentation he is currently well with a normal effort tolerance. The clinical and echocardiographic signs suggest mild aortic incompetence and the aortic root size is stable at 3.6 cm. Case 2 A 44-year-old man with long standing severe nodular, seropositive erosive rheumatoid arthritis, cutaneous small vessel vasculitis and interstitial lung disease was noted to have signs consistent with mild aortic incompetence during a routine clinic visit. His arthritis and vasculitis had been worsening and had responded only partially to the introduction of oral steroids. An echocardiogram revealed a dilated aortic root (4.5 cm), normal aortic valve morphology and normal left ventricular dimensions. The erythrocyte sedimentation rate was 25 mm/hr but the C-reactive protein was raised at 62 mg/l, the rheumatoid latex, Rose-Waaler (1: 128) and anti nuclear factors were positive (1: 400) and circulating immune complexes were detected at a titre of 1: 2560. C, and C, complement levels were normal. Therapy was converted from oral steroids, sulphasalazine and a non-steroidal agent to pulsed oral cyclophosphamide (5 mg/kg) and prednisolone (100 mg) daily for three days at intervals of four weeks, increasing to six weeks after one year. This was continued for a further year before reverting to low dose oral steroids and sulphasalazine. Three years after the diagnosis of aortitis the aortic root diameter remains at 4.5 cm with normal left ventricular dimensions and no evidence of increasing aortic incompetence.
Case 3 A 33-year-old lady presented two months after the delivery of her second child with increasing dyspnoea associated with a worsening of long standing iritis and arthritis affecting the joints of her hands and feet. Signs of severe aortic incompetence were noted (blood pressure was 150/50 mmHg) and echocardiography revealed a dilated left ventricle, normal aortic valve morphology and an aortic root which measured 2.5 cm at the valve ring but dilated to 4.2 cm in diameter 3 cm above the valve. The PR interval was 0.24 set and left ventricular hypertrophy on voltage criteria was present in the electrocardiogram. The erythrocyte sedimentation rate (80 mm/hr), C-reactive protein (75 mg/l) and a polyclonal rise in immunoglobulins indicated active inflammatory disease. Factor VIII related antigen was raised at 373 IU/dl. Autoantibodies and HLA B27 were negative. A diagnosis of an undefined connective tissue disorder with acute aortitis was made and immunosuppressive therapy was commenced using oral prednisolone (60 mg/dayI and azathioprine (2.5 mg/kg/day). A rapid improvement in her clinical status with an associated reduction in acute phase markers was obtained. There was also a concomitant fall in the PR interval to 0.18 sec. The steroid dose was reduced gradually to 20 mg/day. After only 6 weeks a florid relapse occurred and therapy was changed to pulsed intravenous methyl prednisolone and cyclophosphamide (5 mg/kg) given daily for three days at two weekly intervals. Once again a period of improvement was followed by relapse this time after four months. Over the succeeding 12 months various regimens were used employing steroids, methotrexate and azathiocyclophosphamide, prine. Whilst these resulted in some improvement of her clinical status and laboratory markers of inflammation, short periods of apparent resolution were invariably followed by relapse. Following an episode of acute pulmonary oedema fourteen months after presentation she underwent an urgent aortic valve replacement but died 36 hours later. At operation there was gross aortic valve cusp shortening and evidence of inflammation of
256
the aortic root. Unfortunately aorta is not available.
histology of the
Case 4 A 60-year-old man was admitted with presumed infective endocarditis on a mitral valve prosthesis inserted two years previously to replace a severely regurgitant floppy valve. The features of his illness were fever, weight loss, polyarthritis, haematuria and proteinuria, mild anaemia, polymorphonuclear leukocytosis, an erythrocyte sedimentation rate of over 100 mm/hr and a C-reactive protein of 1.51 mg/l. There was also a four year history of intermittent scleritis which had required steroid therapy and ‘flitting’ arthritis affecting both the large and small joints. All cultures were negative and there was no improvement on antibiotics. A new murmur of aortic incompetence was detected and although an echocardiogram showed no abnormality of the aortic valve the aortic root was slightly dilated to 3.7 cm in diameter. Further investigation demonstrated a weakly positive antineutrophil cytoplasmic antibody titre (the rest of the autoantibody screen was negative) and a slight polyclonal rise in immunoglobulins. Radiology of the lumbar spine and sacroiliac joints was normal and he was HLA B27 negative. No evidence of Wegener’s granulomatosis was found after examination of the upper respiratory tract and sinus X-rays. A diagnosis of an undefined connective tissue disease with an associated aortitis was made and high dose oral steroids (60 mg/day) were commenced. The systemic symptoms rapidly resolved with a concurrent fall in laboratory markers of inflammation which reached normal values after six weeks. The prednisolone was gradually reduced but at 5 mg per day the scleritis returned. He is currently well controlled on oral prednisolone (10 mg on alternate days) and azathioprine (150 mg/day) three years after diagnosis. The aortic regurgitation remains mild and aortic root size is stable at 3.9 cm. Case 5 A 3%year-old man presented with a two month history of intermittent chest pains and signs of
severe aortic regurgitation with a blood pressure of 1lo/40 mmHg. One year earlier he had developed an effusion of the right knee associated with a raised erythrocyte sedimentation rate (74 mm/hour) and a positive Rose-Waaler test. There was no history of conjunctivitis or urethritis. On this occasion the erythrocyte sedimentation rate was 47 mm/hour, a Rose-Waaler test was weakly positive (1 : 161, syphilis serology was negative and tissue typing was HLA B27 negative. Radiology of the lumbar spine and sacro-iliac joints was normal and there were no erosive changes in the
Fig. 2. Section of the aortic wall from case 5. There is gross thickening and fibrosis of the intima. The elastica is disrupted and the media infiltrated by inflammatory cells which are mainly lymphocytes and plasma cells although there is a neutrophil component. There are inflammatory cells surrounding the vasa vasora which are affected by an arteritis. A florid endarteritis obliterans is seen affecting an arteriole in the adventitia.
757
joints of the knees, hands or feet. Echocardiography revealed a dilated aortic root (4.1 cm>, thickening of the aortic valve and a dilated, volume loaded left ventricle. Following cardiac catheterization the patient underwent an uncomplicated aortic valve replacement at which time the aortic root was reported as inflamed and the aortic valve cusps thickened and shortened. Subsequent histology showed mucoid degeneration of the valve with no evidence of inflammation but aortic biopsies (Fig. 2) showed features of an inflammatory aortitis indistinguishable from syphilitic aorwith rheumatoid or other titis but “consistent connective tissue disease”. Nine years post operatively he has no cardiovascular problems but remains troubled by persistent arthritis.
Discussion In a United Kingdom series of 100 consecutive cases of isolated aortic regurgitation requiring valve replacement the incidence of inflammatory aortitis or aortic valvulitis was 8% compared to 26% for rheumatic heart disease [2]. In a similar American series 7 out of 100 cases were associated with spondyloarthropathies and a further 6 with various connective tissue diseases [3]. As the incidence of syphilis and rheumatic fever declines in developed countries it is likely that systemic rheumatological disorders will become a relatively more important cause of aortic incompetence. Most cases of aortic incompetence due to systemic rheumatological disorders will present after the acute inflammatory phase of the illness but recognition of active aortitis allows the possibility of early immunosuppressive therapy to reduce systemic, and in particular aortic root, disease activity. The diagnosis can be made by recognition of the physical signs of aortic incompetence in combination with clinical and laboratory evidence of systemic inflammatory disease. Aortic incompetence occurs in approximately 5% of cases of ankylosing spondylitis and probably less frequently in the other seronegative spondyloarthropathies [4]. The underlying pathology as well as clinical. electrocardiographic and echocardiographic features have been fully described [5-
8]. Rheumatoid arthritis causing aortitis and valvulitis is almost always severe, seropositive, nodular rheumatoid disease with associated extra articular vasculitic manifestations 19,101. Although clinically evident aortic incompetence during life is rare affecting less than 1% of patients with rheumatoid arthritis [o] recent necropsy data suggest that aortitis and aortic valvulitis might be present in up to 15%1 of cases [ll]. Progression of aortic incompetence due to rheumatoid arthritis may be rapid with up to 50%’ of cases requiring valve replacement within one year of diagnosis [9]. The list of connective tissue and other inflammatory disorders known to be associated with aortitis and or valvulitis is long and includes systemic lupus crythematosus [ 131, giant cell arteritis 1131, Behcet’s disease [ 141, scleroderma [ 151, Takayasu’s disease [ 161, relapsing polychondritis [ 171 and Cogan’s syndrome [ 181. Idiopathic aortitis is also well described [2,19]. The difficult combination of sometimes silent ventricular dysfunction as a result of aortic incompetence and systemic inflammatory disease necessitates joint cardiological and rheumatological management. We suggest that in cases of active aortitis, immunosuppressive therapy should be considered at an early stage in an effort to control inflammation in the aortic root and thereby reduce further dilatation. Response to treatment can be measured using clinical and echocardiographic indices and standard laboratory markers of inflammation and disease activity. In addition, we have found factor VIII related antigen levels to be useful. This glycoprotein is synthesized by endothelial ceils and released in conditions characterized by vascular damage. Levels have been shown to be raised in the systemic vasculitides and serial estimations form an index of disease activity which is independent of the acute phase response [20]. The use of immunosuppression to treat acute aortitis and valvulitis has not been subjected to a controlled trial and as few cases present during the acute inflammatory phase, such a trial would be difficult. However, immunosuppressive regimens using principally steroids and cyclophosphamide are of proven benefit in the systemic vasculitides [21,22] and as aortitis and aortic
258
valvulitis are vasculitic processes, a response to immunosuppression might be expected. Immunosuppressive regimens cause significant morbidity and mortality but if the need for aortic valve replacement in a young person can be avoided or delayed the risks may be outweighed. Should surgery be required, it is likely to be technically easier and more successful if the aortic root inflammation is effectively suppressed [23]. We suggest that the results obtained in this small series are sufficiently encouraging to merit consideration of immunosuppressive therapy when such patients are encountered. References 1 Mallory TB. Case records of the Massachusetts General Hospital. N Engl J Med 1936;214:690-698. 2 Davies MJ. Pathology of cardiac valves. London: Butterworths, 1980. 3 Qaiyumi S, Ul Hassan Z, Toone E. Seronegative spondyloarthropathies in lone aortic insufficiency. Arch Intern Med 1985;145:822-824. 4 Graham DC, Smythe HA. The carditis and aortitis of a&losing spondylitis. Bull Rheum Dis 1958;IX:171-174. 5 Bulkley BH, Roberts WC. Ankylosing spondylitis and aortic regurgitation. Description of the characteristic cardiovascular lesion from eight necropsy patients. Circulation 1973;XLVIII:1015-1027. 6 Tucker CR, Fowles RE, Calin A, Popp RL. Aortitis in a&losing spondylitis: early detection of aortic root abnormalities with two dimensional echocardiography. Am J Cardiol 1982;49:680-686. 7 LaBresh KA, Lally EV, Sharma SC, Ho G. Two dimensional echocardiographic detection of preclinical aortic root abnormalities in rheumatoid variant diseases. Am J Med 1985;78:908-912. 8 Weed CL, Kulander BJ, Mazzarella JA, Decker JL. Heart block in ankylosing spondylitis. Arch Int Med 1966;117: 800-806. 9 Cosh JA, Lever JV. The Aortic Valve. In: Ansell BM, Simkin PA, eds. The Heart and rheumatic disease 1984.
10
11
12
13 14
15 16
17
18
19
20
21
22
23
Cornwall: Buttetworths International Medical ReviewsRheumatology 2, 83- 119. Weintraub AM, Zvaifler NJ. The occurrence of valvular and myocardial disease in patients with chronic joint deformity. A Spectrum. Am J Med 1963;35:145-162. Gravallese EM, Corson JM, Coblyn JS, Pinkus GS, Weinblatt ME. Rheumatoid aortitis: a rarely recognized but clinically significant entity. Medicine 1989;68:95-106. Libman E, Sacks B. A hitherto undescribed form of valvular and mural endocarditis. Arch Intern Med 1924;33:701737. Klinkhoff AV, Reid GD, Moscovich M. Aortic regurgitation in giant cell arteritis. Arth Rheum 1985;28:582-585. Chikamori T, Doi YL. Yonezawa Y, Takata J, Kawamura M. Ozawa T. Aortic regurgitation secondary to Behcet’s disease. A case report and review of the literature. Em Heart J 1990;11:572-576. Yunnus MB, Radford CM, Masi AT et al. Aortic regurgitation in scleroderma. J Rheumatol 1984;11:384-386. Ishikawa K. Natural history and classification of occlusive thromboaortopathy (Takayasu’s disease). Circulation 1978;57:27-35. Pearson CM, Kroening R, Verity MA, Getzen JH. Aortic insufficiency and aortic aneurysm in relapsing polychondritis. Trans Assoc Am Physicians 1967;80:71-89. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan’s syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature. Medicine 1980; 59:426-441. McGuire J, Scott RC, Gall EA. Chronic aortitis of undetermined cause with severe and fatal aortic insufficiency. Am J Med Sci 1958;235:394-404. Woolf AD, Wakerley G, Wallington TB, Scott DGI. Dieppe PA. Factor VIII related antigen in the assessment of vasculitis. Ann Rheum Dis 1987;46:441-447. Fauci AS. Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 1979;301:235-238. Scott DGI, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in the treatment of systemic rheumatoid vasculitis. Am J Med 1984;76:377-384. Isomura T. Hisatomi K, Yanagi 1 et al. The surgical treatment of aortic incompetence secondary to aortitis. Ann Thoracic Surg 1988;45:181-185.
Journal
of Curdiology,
33 (1991) 253-258
1991 Elsevier
ADONlS
CARD10
Science Publishers 016752739100237E
B.V. All rights reserved
0167-5273/91/$03.50
01350
Acute aortitis and aortic incompetence due to systemic rheumatological disorders J.N. Townend
‘, P. Emery ‘, M.K. Davies ’ and W.A. Littler ’
lJt~iwr.s~ty of Birminghwn,Depurtments
of ’ Curdiolwscular Birmingham,
(Received
10 December
Medicine
md
’ Rheumatology.
Quern
Llixhcth
Hmpitul.
U.K.
1900; revision
accepted
Townend JN, Emery P. Davies MK, Littler WA. Acute aortitis rheumatological disorders. Int J Cardiol 1991;33:253-258.
20 May IYYI 1
and aortic
incompetence
due to systemic
We report the clinical, laboratory and echocardiographic features of five cases of aortic incompetence associated with ankylosing spondylitis, rheumatoid arthritis and undefined connective tissue diseases. lmmunosuppression with steroids and cytotoxic agents was used to suppress aortic root inflammation in four cases; in three the aortic root size stabilized and the patients remain well with no evidence of increasing aortic incompetence. In one case, control of the inflammatory process was never fully achieved for any length of time and the patient died shortly after aortic valve replacement. A fifth case required urgent valve replacement and remains well. A systemic rheumatological disorder should be considered in cases of apparent “lone” aortic incompetence and conversely aortic incompetence should not be overlooked in established systemic rheumatological disease. Immunosuppressive therapy may prevent or delay the need for aortic valve replacement in such cases. Key words:
Aortic
incompetence;
Aortitis;
Connective
Introduction The association of aortic incompetence with systemic rheumatological disease was first described by Mallory in 1936 [l]. Since then involvement of the aortic root or valve has been reported in many systemic rheumatological disorders including rheumatoid arthritis, seronegative spondyloarthropathies, connective tissue disor-
Correspondence to: Dr. J.N. Townend. University of Birmingham, Dept. of Cardiovascular Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH. U.K.
tissue disease;
Immunosuppressive
therapy
ders and a number of inflammatory disorders of uncertain aetiology. The inflammatory process causes aortic root dilatation and cusp retraction leading to valvular incompetence and haemodynamic compromise. All of these diseases arc thought to result from autoimmune mediated tissue damage involving both cell mediated and humoral immune processes. The immune mediated nature of these diseases suggests that it may be possible to reduce inflammation in the aortic root with the use of immunosuppressive agents. We present five cases which illustrate the difficulties of diagnosing and managing aortic incompetence due to inflammatory aortic root disease.
The response to immunosuppressive described in four cases.
regimens is
Case 1 A 29-year-old man was admitted with a short history of increasing dyspnoea and signs of congestive cardiac failure. There was also a six year history of low back pain and a previous surgical repair of a brachial artery aneurysm. Clinical and radiological cardiomegaly was noted together with signs of aortic incompetence; blood pressure was 145/70 mmHg. Restriction of lumbar spine movement was also observed. Echo and Doppler studies (Fig. 1) showed a dilated left ventricle with preserved systolic function, a normal aortic valve but dilated aortic root (4.1 cm) and evi-
dence of moderate aortic regurgitation. Bilateral sacro-ileitis was seen on X-ray. A polymorphonuclear leukocytosis, erythrocyte sedimentation rate of 84 mm/hr, polyclonal rise in immunoglobulins and a C-reactive protein of 204 mg/l suggested active inflammation. Complement levels were normal and an auto-antibody screen was negative. A raised factor VIII related antigen at 280 IU/dl (normal range < 200 IU/dl) indicated endothelial damage compatible with active arteritis. These clinical, radiological and laboratory features led to a diagnosis of active seronegative spondyloarthropathy with associated aortitis. Treatment with diuretics and digoxin was started together with pulsed intravenous cyclophosphamide (1.5 mg/kg) and methyl prednisolone (10 mg/kg) every two weeks. After three courses,
Fig. 1. Two-dimensional echocardiogram of the heart in case 1. Long axis parasternal view. The aortic root (Ao) is dilated at 4.1 cm. The left ventricle (LV) is also dilated and slightly hypertrophied. The characteristic “sub-aortic bump” [6] is also seen (arrow). There is a small posterior pericardial effusion.
2.55
therapy was given orally (cyclophosphamide 5 mg/kg and prednisolone 3.3 mg/kg for 3 days) at three weekly intervals. A rapid clinical improvement in both cardiac and spondylitic symptoms and signs was associated with a reduction in laboratory disease markers. The echocardiographic aortic root size fell to 3.7 cm and left ventricular dimensions returned to normal. After nine pulses of cyclophosphamide and prednisolone he was converted to daily oral steroids and azathioprine. Naproxen was given continuously from the time of diagnosis. At 16 months from presentation he is currently well with a normal effort tolerance. The clinical and echocardiographic signs suggest mild aortic incompetence and the aortic root size is stable at 3.6 cm. Case 2 A 44-year-old man with long standing severe nodular, seropositive erosive rheumatoid arthritis, cutaneous small vessel vasculitis and interstitial lung disease was noted to have signs consistent with mild aortic incompetence during a routine clinic visit. His arthritis and vasculitis had been worsening and had responded only partially to the introduction of oral steroids. An echocardiogram revealed a dilated aortic root (4.5 cm), normal aortic valve morphology and normal left ventricular dimensions. The erythrocyte sedimentation rate was 25 mm/hr but the C-reactive protein was raised at 62 mg/l, the rheumatoid latex, Rose-Waaler (1: 128) and anti nuclear factors were positive (1: 400) and circulating immune complexes were detected at a titre of 1: 2560. C, and C, complement levels were normal. Therapy was converted from oral steroids, sulphasalazine and a non-steroidal agent to pulsed oral cyclophosphamide (5 mg/kg) and prednisolone (100 mg) daily for three days at intervals of four weeks, increasing to six weeks after one year. This was continued for a further year before reverting to low dose oral steroids and sulphasalazine. Three years after the diagnosis of aortitis the aortic root diameter remains at 4.5 cm with normal left ventricular dimensions and no evidence of increasing aortic incompetence.
Case 3 A 33-year-old lady presented two months after the delivery of her second child with increasing dyspnoea associated with a worsening of long standing iritis and arthritis affecting the joints of her hands and feet. Signs of severe aortic incompetence were noted (blood pressure was 150/50 mmHg) and echocardiography revealed a dilated left ventricle, normal aortic valve morphology and an aortic root which measured 2.5 cm at the valve ring but dilated to 4.2 cm in diameter 3 cm above the valve. The PR interval was 0.24 set and left ventricular hypertrophy on voltage criteria was present in the electrocardiogram. The erythrocyte sedimentation rate (80 mm/hr), C-reactive protein (75 mg/l) and a polyclonal rise in immunoglobulins indicated active inflammatory disease. Factor VIII related antigen was raised at 373 IU/dl. Autoantibodies and HLA B27 were negative. A diagnosis of an undefined connective tissue disorder with acute aortitis was made and immunosuppressive therapy was commenced using oral prednisolone (60 mg/dayI and azathioprine (2.5 mg/kg/day). A rapid improvement in her clinical status with an associated reduction in acute phase markers was obtained. There was also a concomitant fall in the PR interval to 0.18 sec. The steroid dose was reduced gradually to 20 mg/day. After only 6 weeks a florid relapse occurred and therapy was changed to pulsed intravenous methyl prednisolone and cyclophosphamide (5 mg/kg) given daily for three days at two weekly intervals. Once again a period of improvement was followed by relapse this time after four months. Over the succeeding 12 months various regimens were used employing steroids, methotrexate and azathiocyclophosphamide, prine. Whilst these resulted in some improvement of her clinical status and laboratory markers of inflammation, short periods of apparent resolution were invariably followed by relapse. Following an episode of acute pulmonary oedema fourteen months after presentation she underwent an urgent aortic valve replacement but died 36 hours later. At operation there was gross aortic valve cusp shortening and evidence of inflammation of
256
the aortic root. Unfortunately aorta is not available.
histology of the
Case 4 A 60-year-old man was admitted with presumed infective endocarditis on a mitral valve prosthesis inserted two years previously to replace a severely regurgitant floppy valve. The features of his illness were fever, weight loss, polyarthritis, haematuria and proteinuria, mild anaemia, polymorphonuclear leukocytosis, an erythrocyte sedimentation rate of over 100 mm/hr and a C-reactive protein of 1.51 mg/l. There was also a four year history of intermittent scleritis which had required steroid therapy and ‘flitting’ arthritis affecting both the large and small joints. All cultures were negative and there was no improvement on antibiotics. A new murmur of aortic incompetence was detected and although an echocardiogram showed no abnormality of the aortic valve the aortic root was slightly dilated to 3.7 cm in diameter. Further investigation demonstrated a weakly positive antineutrophil cytoplasmic antibody titre (the rest of the autoantibody screen was negative) and a slight polyclonal rise in immunoglobulins. Radiology of the lumbar spine and sacroiliac joints was normal and he was HLA B27 negative. No evidence of Wegener’s granulomatosis was found after examination of the upper respiratory tract and sinus X-rays. A diagnosis of an undefined connective tissue disease with an associated aortitis was made and high dose oral steroids (60 mg/day) were commenced. The systemic symptoms rapidly resolved with a concurrent fall in laboratory markers of inflammation which reached normal values after six weeks. The prednisolone was gradually reduced but at 5 mg per day the scleritis returned. He is currently well controlled on oral prednisolone (10 mg on alternate days) and azathioprine (150 mg/day) three years after diagnosis. The aortic regurgitation remains mild and aortic root size is stable at 3.9 cm. Case 5 A 3%year-old man presented with a two month history of intermittent chest pains and signs of
severe aortic regurgitation with a blood pressure of 1lo/40 mmHg. One year earlier he had developed an effusion of the right knee associated with a raised erythrocyte sedimentation rate (74 mm/hour) and a positive Rose-Waaler test. There was no history of conjunctivitis or urethritis. On this occasion the erythrocyte sedimentation rate was 47 mm/hour, a Rose-Waaler test was weakly positive (1 : 161, syphilis serology was negative and tissue typing was HLA B27 negative. Radiology of the lumbar spine and sacro-iliac joints was normal and there were no erosive changes in the
Fig. 2. Section of the aortic wall from case 5. There is gross thickening and fibrosis of the intima. The elastica is disrupted and the media infiltrated by inflammatory cells which are mainly lymphocytes and plasma cells although there is a neutrophil component. There are inflammatory cells surrounding the vasa vasora which are affected by an arteritis. A florid endarteritis obliterans is seen affecting an arteriole in the adventitia.
757
joints of the knees, hands or feet. Echocardiography revealed a dilated aortic root (4.1 cm>, thickening of the aortic valve and a dilated, volume loaded left ventricle. Following cardiac catheterization the patient underwent an uncomplicated aortic valve replacement at which time the aortic root was reported as inflamed and the aortic valve cusps thickened and shortened. Subsequent histology showed mucoid degeneration of the valve with no evidence of inflammation but aortic biopsies (Fig. 2) showed features of an inflammatory aortitis indistinguishable from syphilitic aorwith rheumatoid or other titis but “consistent connective tissue disease”. Nine years post operatively he has no cardiovascular problems but remains troubled by persistent arthritis.
Discussion In a United Kingdom series of 100 consecutive cases of isolated aortic regurgitation requiring valve replacement the incidence of inflammatory aortitis or aortic valvulitis was 8% compared to 26% for rheumatic heart disease [2]. In a similar American series 7 out of 100 cases were associated with spondyloarthropathies and a further 6 with various connective tissue diseases [3]. As the incidence of syphilis and rheumatic fever declines in developed countries it is likely that systemic rheumatological disorders will become a relatively more important cause of aortic incompetence. Most cases of aortic incompetence due to systemic rheumatological disorders will present after the acute inflammatory phase of the illness but recognition of active aortitis allows the possibility of early immunosuppressive therapy to reduce systemic, and in particular aortic root, disease activity. The diagnosis can be made by recognition of the physical signs of aortic incompetence in combination with clinical and laboratory evidence of systemic inflammatory disease. Aortic incompetence occurs in approximately 5% of cases of ankylosing spondylitis and probably less frequently in the other seronegative spondyloarthropathies [4]. The underlying pathology as well as clinical. electrocardiographic and echocardiographic features have been fully described [5-
8]. Rheumatoid arthritis causing aortitis and valvulitis is almost always severe, seropositive, nodular rheumatoid disease with associated extra articular vasculitic manifestations 19,101. Although clinically evident aortic incompetence during life is rare affecting less than 1% of patients with rheumatoid arthritis [o] recent necropsy data suggest that aortitis and aortic valvulitis might be present in up to 15%1 of cases [ll]. Progression of aortic incompetence due to rheumatoid arthritis may be rapid with up to 50%’ of cases requiring valve replacement within one year of diagnosis [9]. The list of connective tissue and other inflammatory disorders known to be associated with aortitis and or valvulitis is long and includes systemic lupus crythematosus [ 131, giant cell arteritis 1131, Behcet’s disease [ 141, scleroderma [ 151, Takayasu’s disease [ 161, relapsing polychondritis [ 171 and Cogan’s syndrome [ 181. Idiopathic aortitis is also well described [2,19]. The difficult combination of sometimes silent ventricular dysfunction as a result of aortic incompetence and systemic inflammatory disease necessitates joint cardiological and rheumatological management. We suggest that in cases of active aortitis, immunosuppressive therapy should be considered at an early stage in an effort to control inflammation in the aortic root and thereby reduce further dilatation. Response to treatment can be measured using clinical and echocardiographic indices and standard laboratory markers of inflammation and disease activity. In addition, we have found factor VIII related antigen levels to be useful. This glycoprotein is synthesized by endothelial ceils and released in conditions characterized by vascular damage. Levels have been shown to be raised in the systemic vasculitides and serial estimations form an index of disease activity which is independent of the acute phase response [20]. The use of immunosuppression to treat acute aortitis and valvulitis has not been subjected to a controlled trial and as few cases present during the acute inflammatory phase, such a trial would be difficult. However, immunosuppressive regimens using principally steroids and cyclophosphamide are of proven benefit in the systemic vasculitides [21,22] and as aortitis and aortic
258
valvulitis are vasculitic processes, a response to immunosuppression might be expected. Immunosuppressive regimens cause significant morbidity and mortality but if the need for aortic valve replacement in a young person can be avoided or delayed the risks may be outweighed. Should surgery be required, it is likely to be technically easier and more successful if the aortic root inflammation is effectively suppressed [23]. We suggest that the results obtained in this small series are sufficiently encouraging to merit consideration of immunosuppressive therapy when such patients are encountered. References 1 Mallory TB. Case records of the Massachusetts General Hospital. N Engl J Med 1936;214:690-698. 2 Davies MJ. Pathology of cardiac valves. London: Butterworths, 1980. 3 Qaiyumi S, Ul Hassan Z, Toone E. Seronegative spondyloarthropathies in lone aortic insufficiency. Arch Intern Med 1985;145:822-824. 4 Graham DC, Smythe HA. The carditis and aortitis of a&losing spondylitis. Bull Rheum Dis 1958;IX:171-174. 5 Bulkley BH, Roberts WC. Ankylosing spondylitis and aortic regurgitation. Description of the characteristic cardiovascular lesion from eight necropsy patients. Circulation 1973;XLVIII:1015-1027. 6 Tucker CR, Fowles RE, Calin A, Popp RL. Aortitis in a&losing spondylitis: early detection of aortic root abnormalities with two dimensional echocardiography. Am J Cardiol 1982;49:680-686. 7 LaBresh KA, Lally EV, Sharma SC, Ho G. Two dimensional echocardiographic detection of preclinical aortic root abnormalities in rheumatoid variant diseases. Am J Med 1985;78:908-912. 8 Weed CL, Kulander BJ, Mazzarella JA, Decker JL. Heart block in ankylosing spondylitis. Arch Int Med 1966;117: 800-806. 9 Cosh JA, Lever JV. The Aortic Valve. In: Ansell BM, Simkin PA, eds. The Heart and rheumatic disease 1984.
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