7 Other forms of vasculitis and pseudovasculitis

7 Other forms of vasculitis and pseudovasculitis Vedat Hamuryudan MD Associate Professor

Huri Ozdo{lan MD Professor

Hasan Yazlcl MD Professor and Chtef

Diwslon of Rheumatology, Department of Internal Medicine, University of Istanbul, Cerrahpa~a Medical Faculty, Cerrahpa~a, Istanbul 34303, Turkey

Beh£et's syndrome can mvolve all sizes and kinds of blood vessels. There ts an association between artenal involvement and venous thrombosis Pulmonary artenal aneurysms and neurologtcal ~nvolvement have a definite influence on mortahty. Male sex and young age are indicators of a more severe disease course. Immunosuppressive treatment early in the dtsease may affect the long term prognosis favourably. Patients with familial Mediterranean fever may develop mantfestations of vascuhtts The most common assoctatJons are w~th Sch6nlemHenoch purpura and polyarteritis nodosa. In some patients the d0agnosts of vascuhhs precedes that of famlhal Medtterranean fever. Kawasaki dtsease, although rare, can be seen in adults The coronary sequela of childhood dtsease can affect the prognosis later tn hfe. Many condlttons, hke myxoma, cholesterol embolism, and calciphylaxls may mlmtc vascuhhc syndromes These conditions should always be kept in mind because their pathophystology and treatment are different from true vasculittdes.

Key words: Vascuhtts; Beh£et's syndrome; famthal Medtterranean fever; relapsing polychondntis; pseudovascuhtts; Kawasak~ dtsease; cholesterol embohsm; myxoma, calciphylax~s, mfecttve endocardttJs Behget's syndrome Behqet's syndrome is not only the leading cause of acquired bhndness in certain countries hke Japan, but also leads to increased mortality. A survey of 10-year mortality in Behqet's syndrome patients aged 15-24 years Balll/#re's ChmcalRheumatology-Vol 11, No 2, May 1997 ISBN 0-7020-2266-7 0950-3579/97/020335 + 21 $12 00/00

335 Copyright © 1997, by Bailli~re Tindall All rights of reproduction in any form reserved

336

V, Hamuryudan et al

showed that of 152 (92 males, 60 females) had died; significantly more than expected in this age bracket when compared with the standard mortality tables (Yazlcl et al, 1996). The outcome for patients with specific organ involvement is even poorer. The mortality rate of those patients w~th neurological involvement was 20% at re-evaluation after 7 years (Akman-Demir et al, 1996), whereas 50% of 24 patients with pulmonary arterial involvement had &ed within 1 year after the onset of haemoptysis (Hamuryudan et al, 1994). Behqet's syndrome runs a more severe course among young males; all the fatal outcomes in these three reports were m males. The reason for this sex predilection is unknown. It is generally accepted that the disease severity &mmishes with age. The syndrome usually starts around the third decade, but its occurrence in children has become increasingly prevalent. It is associated with human lymphocyte antigen (HLA) B51, however familial occurrence is not pronounced and there is no consistent inheritance pattern. The association with HLA B51 shows a geographical variation and seems to be related to those patients attending hospital, wxth more severe disease. Clinical features

Many organ systems, including the skin, loints, blood vessels, central nervous system (CNS) and gastrointestinal tract can be affected (Table 1). Recurrent oral and gemtal ulcers along with eye involvement continue to be the hallmark of Beh~et's syndrome. Among the skin lesions, acne-like lesions are frequent and indistinguishable from ordinary acne; as they do not show vascuhtis, there is debate as to whether they are an integral part of Beh~et's syndrome (Jorizzo et al, 1995). Although some of the extraarucular features of Beh~et's syndrome resemble those of inflammatory bowel disease, back pain is uncommon and controlled studies have not shown an increased frequency ~)f sacrodlac joint involvement. Some features of Beh~et's syndrome show a geographical variation. Pathergy tests (formauon of an erythematous papule or pustule at the s~te of a sterile

Table 1. Frequency of clinical features of Beh£et's syndrome Lesions Oral ulceration Genital ulceratton Skin lesions Eye involvement Arthritis Subcutaneous thrombephlebltls Deep vein thrombosis Arterial involvement Central nervous system involvement Gastrointestinal involvement

Frequency (%) 97-100 80-90 -80 -50 -40 -25 -10 -4 5-15 0-25

Other forms of vascullt~s and pseudovasculitls

337

needle prick 48 hours after injection, usually at the forearm) and HLA B 51 assays are usually positive (about 70%) in patients from the Mediterranean countries and Japan but not in panents from the UK and USA. Gastrointestinal involvement, characterized by ulcers mostly in the terminal ileum and caecum, is frequent in Japanese, but rare in Turklsh patients (Yurdakul et al, 1996). Recurrent epidldymms affecting up to 6% of males, extragenital ulcers, which leave scars and show vasculitis when blopsled, and Sweet's syndrome-like papules are the usually under recogmzed manifestations.

Practice points •

The prognosis of Behqet's syndrome as more severe among young male pauents compared with elderly female patients

•

Genital scars are valuable diagnostic markers

•

Hypopyon mdacates severe eye involvement

•

Despite being a systemic vascuhtis, renal and peripheral nervous system involvement is rarely seen

Vascular involvement

Vascular involvement in Behqet's syndrome affects males more than females. Behqet's syndrome, together with systemic lupus erythematosus (SLE) and Buerger's disease, is one of the few vascuhtides that can revolve the venous side of the carculatory system along wath the arterial side (De, 1992). Furthermore, at can also involve the vena cavae. Characteristics of vascular involvement in Behqet's syndrome: •

Vessels of all sizes and kinds are involved with accentuation on the venous side

•

Vasa nervorum are usually spared

•

Anti-neutrophil cytoplasmic antibodies (ANCA) and other antibodies are absent

•

Immune complexes are absent.

Despite a tendency to venous thrombosis, thromboembolism is rarely documented m Behqet's syndrome. In post-mortem examinations, there is a marked adherence of the thrombus to the diseased vessel wall. Thrombophlebitis and arterial aneurysms very frequently coexist. Thas suggests that a primary vessel wall pathology rather than a defect m coagulation is the primary vascular problem m Behqet's syndrome. Superficaal thrombophlebius is the most frequent type of vascular involvement and its development after vein punctures is common. It can be

338

V Harnuryudan et al

easdy misdiagnosed as erythema nodosum, one of the prevalent skin lesions of Behget's syndrome. In a series of 38 Behqet's syndrome panents with vascular involvement, superficial thrombophlebms was found to be a risk factor for deep vein thrombosis and vena cava inferior thrombosis (Ko9 et al, 1992). Deep vein thrombi are the second most common form of vascular involvement which mostly revolve the lower extremities and may end m chronic stasis dermamis and ulcers. Hepatic veto thrombosis leading to Budd-Chlari syndrome and involvement of venae cavae are seen less often. Symptoms of vena caval occlusion may subsxde gradually with the development of extensive collaterals. Even cerebral veins are not spared. In a survey of 40 cerebral venous thrombosis patients with diverse aetiologies, Beh~et's syndrome was the most frequent cause (Dalf et al, 1995). Virtually all arteries may be affected by aneurysm formation and/or occlusions. Arterial involvement usually occurs late in the course of the disease, the average duration being 3-8 years after the diagnosis of Beh~et's syndrome (Thi Huong et al, 1995). The main pathology is vascuhtis of the vasa vasarum. Aneurysms can occur both m the form of true and pseudoaneurysms and they carry more severe prognosis than occlusions. Even arterial punctures for diagnosuc procedures may carry a certain hazard of inciting an aneurysm. Behqet's syndrome is unique among the vascuhtides for the presence of pulmonary arterial aneurysms, a most dangerous form of arterial involvement. Haemoptysis ~s usually the presenting symptom. In a series of 24 patients, pulmonary arterial aneurysms were associated with a 88% frequency of thrombophlebius (Hamuryudan et al, 1994). The emergence of haemoptysis in a Behqet's syndrome pauent with thrombophlebltis may lead to a misdlagnosis of pulmonary thromboembolism and to potentially fatal anti-coagulation admimstration. Perfuslon-ventilation scans are not helpful m. the differential dlagnosks. Pulmonary arterial aneurysms, which are usually multiple involving both sides, are seer as nodular opaciues on radiographs. A defimte diagnosis can be made with angiography and computed tomography (CT) scans. Thrombosed aneurysms are best visualized with magnetic resonance imaging (MRI). Cardiac involvement of clinical significance is rare, however pericardlus, myocardltis, endocardlt~s, coronary artery vasculitis, myocardml infarction, and ventricular aneurysms have all been sporadically reported. Bizarre lesions such as intracardiac thrombi and endomyocardial fibrosis have also been observed. They usually involve the right ventricle and may lead to tricuspid valve regurgitation and heart failure. They seem to be associated with pulmonary arterial aneurysms. Recently, 36 Beh~et's syndrome patients were evaluated for the presence of silent myocardial lschaemia (oblectlve evidence of myocardial ischaemm occurring in the absence of symptoms). Evidence for sdent myocardial ischaemla was present in 25% of patients compared to 2.6% of controls. There was a slgmficant associauon with large vessel involvement, however, coronary ang:ography was normal m all evaluated patients. The authors Interpreted

Other forms of vascuhtls and pseudovascuhtls 339

this finding as possible evidence of myocardml microvascular disease (Giilhi et al, 1996). Neurological involvement

Neurological involvement was reported at 5% among Turkish patients in a prospective survey (Serdaro~lu et al, 1989) but there is much variation in the reported prevalence rates. The most common neurological pictures are brainstem and pyramidal syndromes, intracranial hypertension, aseptic meningitis, and medullary syndrome although symptoms mimicking multiple sclerosis have also been reported. Headaches, not accompanied by other neurological symptoms or s~gns, are usually considered as insignificant. A 7-year follow-up of 26 patients initially having headache as the only neurological symptom revealed that two developed apparent, and six subtle, neurological involvement (AkmanDemlr et al, 1996). Cerebrospmal fluid findings are usually non-specific and the levels of ohgoclonal immunoglobuhn's, IgA and IgM, may increase in active neurological involvement. MRI is valuable in the evaluation of patients with neurological involvement

Practice points •

Consider Beh~et's syndrome in a young patient with deep vem thrombosis

•

Headache in a Beh~et's syndrome patient might be a stgn of dural sinus thrombosis

•

Exclude first a pulmonary arterml aneury~m in a Behqet's syndrome patient with haemoptysis and deep vein thrombosis

Pathogenesis A defect in immunoregulauon triggered by an infectious agent(s) has been the mare proposltlon for the pathogenet~c mechamsm m Behqet's syndrome. An increased cellular and humoral response to mycobacterlal heat shock proteins (HSPs) has been demonstrated and a recent proposal suggests that this m~ght even be useful diagnostically (Hasan et al, 1996). These HSP peptides cause uve~tis in Lew~s rats suggesting a further role for these in the pathogenesis of Behqet's syndrome (Stanford et al, 1994). However, there are also many reasons why Behqet's syndrome might not be classified together with the 'autolmmune' diseases and these were recently discussed (Yazlcl, 1997). Behqet's syndrome patients have a heightened inflammatory response, which ~s best manifested by the pathergy reacuon. The inflammatory response to mtradermal injected urate crystals m Turkish, and the usually pathergy-negauve Bnush, patients ~s another example for this heightened

340

V. Hamuryudan et al

inflammation (Gakir et al, 1991). How this inflammatory response is initiated or maintained is, however, not clear. An lmmunohistological study of the pathergy test at 48 hours found that the characteristics of the mononuclear cells and keratinocytes in the perivascular infiltration were similar to those in a delayed-type hypersensitivity reaction. The expression pattern of adhesion molecules suggested antigen independent, direct epidermal injury, as the cause of this reaction (Gial et al, 1995). This finding was contradictory to that of another study, which found decreased pathergy positiwty when the skin was cleaned with disinfectants (surgical cleaning) before the introduction of the needle. The authors concluded that more than direct epidermal inlury is revolved m the producnon of the pathergy reaction (Fresko et al, 1993). Increased neutrophd hyperreactlvity has been found to be related to HLA B51 in a transgenic mouse model (Takeno et al, 1995). Abundance of monocyte and T-cell-derived cytokines in the sera of Behqet's syndrome patients may also be responsible for the increased neutrophil hyperreactivity (Mege et al, 1993). Treatment

Current treatment of Behqet's syndrome vanes from reassurance and topical treatment to high doses of immunosuppresslve drugs depending on the presence and seventy of symptoms (Table 2). The lack of

Table 2. Treatment of Beh(}et's syndrome Lesions

Suggested treatment

Orogenltal ulcers, skin lesions Mild Topical treatment, ¢olchicme 1 5 n~g/day. Severe AzatNopnne 2 5 mg/kg/day,thalidomide 100--300 mg/day, prednisolone -20 mg Arthritis Mild Severe Eye involvement Mild Severe

"~Non-sterotdal anti-inflammatory drugs Sulphasalazme 2-3 g/day, steroids -20 mg/day, azatNopnne 2 5 rng/kg/day, interferon-c~5 MU/3 times a week Local treatment with mydnatics and steroids under close follow-up Azathlopnne 2 5 mg/kg/day, cyclosporm A 5 mg/kg/day, chlorambucll 0 1 mg/kg/day, ~mterferon-~

Deep vein thrombophlebitts

~Antl-coagulatlon, aspmn, azathtopnne

Arterial involvement

Prednlsolone 1 mg/kg with cyclophosphamide 2 5 mg/kg/day or monthly 1 g boluses, surgery

Neurological involvement

Boluses of predntsolone 1 g/day followed by oral prednisolone and cyclophosphamtde 2.5 mg/kg/day

Gastrointestinal involvement Predmsolone 30-60 mg/day, sulphasalazme 3-6 gm/day, surgery Reproduced from Yaz~cl et al (1995, ChmcalImmunotherapeutlcs3: 102-107) with permission

Other forms of vascuhtls and pseudovasculltis

341

reliable activity measures, prognostic markers, and longitudinal studies as well as the limited number of controlled studies, leave unanswered questions about the optimal time for the initiation, duration, and intensity of treatment, as well as its effect on the long-term prognosis. Colchicine is recommended by some authorities for all patients, but this drug was of value only in the treatment of arthralgia and erythema nodosum m a controlled trial (Aktulga et al, 1980). A further trial of colchicine by our group is almost complete. Several reports suggest that thalidomide is highly effective m the treatment of the mucocutaneous lesions of Behqet's syndrome. A double-blind study of thalidomide by our group is finished and the results will be available soon. Eye disease, as a rule, is treated with immunosuppressives. Cyclosporin A and azathioprine are the only agents that have been studied in controlled trials. Cyclosporm A seems to be the most rapidly effective agent (Masuda et al, 1989). Its usual dosage is 5 mg/kg/day which needs to be lowered when nephrotoxiclty occurs. Azathioprine, on the other hand, when used at 2.5 mg/kg/day, is effective in preserving visual acuity and perhaps in preventing the emergence of new eye disease (Yazml et al, 1990). Although there Is no formal evidence, a combination of azathioprine and cyclosponn A in doses mentioned above, can be effective m patients who are resistant to single agent treatment. Corticosteroids are probably not effecnve, ff not harmful, in the long-term treatment of eye inflammation. They are used less and less in large centres dealing with Behqet's syndrome. Chlorambucil is an alternative immunosuppressive, but toxmity limits Its use. Cyclophosphamide (CP), m the form of monthly 1 gram boluses or 2.5 mg/kg/day orally, alone or in combination with high dose steroids, is used in the treatment of arterial and CNS involvement of Behqet's syndrome. Unfortunately, there are again no controlled stu&es addressing the efficacy of this regimen. The treatment of deep veto thrombosis is far from satisfactory and it is not clear whether ann-coagulants are of any value in its treatment. In general, for any serious organ involvement, treatment can be stopped after 2 years of clinical remission, but there are exceptions to this rule. Recently, panents who had taken part in a controlled study of azathioprlne were re-evaluated after an average of 8 years after the trial had ended. Th~s study found that patients allocated to azathmprme m the controlled trial had a better outcome in terms of emergence of blindness, drop in visual acmty, and extraocular complications in the long term, compared to patients allocated to placebo despite a comparable length of lmmunosuppress~ve treatment during follow-up. The outcome was even better for patients allocated to azathloprme within 2 years of eye involvement than patients who entered the trial after 2 years of eye involvement. This study opens the question as to whether young male Behqet's syndrome panents should be treated w~th lmmunosuppressives without waiting for the emergence of any comphcations of Behget's syndrome (Hamuryudan et al, 1997).

342

V. Hamuryudan et al

Research agenda •

Why ;Ire p:mems with Beh~'ct'~ s)ndrome prone to thronlbt torntatloLl?

•

l)ocs early treatmcn! \~lth llmntlllO.Mlpprc~Sl~,t's mlprove the longif'i'm OtltCOnle?

•

Should p;llient~ ~lth venous nlvolvclncnt receive antico:~gulants/antlthrombotlc agents/fibrmol.~ tics?

•

What Js the treatment for the central nervous system mvolvcmenr?

•

ls n~terl'cron alpha an
Familial Mediterranean fever

Familial Mediterranean fever IS an autosomal recessive disorder characterized by intermittent attacks of fever with peritonitis, pleuritls and/or synovltis, affecting certain ethnic groups originating from the Mediterranean and Middle East, for example, Sephardlc Jews, Arabs, Armenians, and Turks. The responsible gene in Sephardic Jews has been mapped to the short arm of chromosome 16 (Pras et al, 1992). The pathogenesls of the disease is unknown. Several mechanisms, such as an inborn error of catecholamlne metabolism and lack of CSa-inhlbltor which also inhibits interleukin 8 (IL8) in peritoneal and synovial fluids of patients with familial Mediterranean fever, have been proposed (Ayesh et al, 1993). No association of familial Mediterranean fever with any HLA loci has been shown. The disease first appears in childhood or adolescence (Gedalla et al, 1992). The male to female sex ratio is 3:2. There is a positive family history in about 30-50% ,of the patients. Fever and abdominal pain are the most common features of the disease. About 90°70 of the patients experience a peritoneal attack compared with 20--40% who suffer pleural attacks. Articular manifestations occur in approximately 50-70% of cases with familial Mediterranean fever, with a wide variation in clinical presentation and course, causing diagnostic difficulties. Acute monoarthrms is observed in the malonty of the cases. Skin involvement in the form of erysipelas-like erythema, subcutaneous nodules, urticaria, non-specific purpura, and oedema of the scalp, palms, and soles is observed in 20-50% of patients. Amyloldosis of the AA type is a common fatal manifestation of famlhal Mediterranean fever In untreated~patients. A non-specific, transient acute phase response is detected in almost all patients during an attack. The efficacy of colchiclne in familial Mediterranean fever has been well estabhshed. Regardless of age, weight, and disease severity the recommended daily dose of prophylactic colchicine is 1 to 1.5 mg. Although abdominal and pleural attacks respond almost completely, articular attacks are more resistant. Besides preventing acute attacks of familial Mediterranean fever, continuous treatment with colchicine also prevents the development of amyloidosis.

Other forms of vascuhtis and pseudovascuhtis

343

There is a close association between some vascuhtic conditions such as Sch6nlein-Henoch purpura and polyarterins nodosa, and familial Mediterranean fever (Table 3), (Pras et al, 1996). These three disease entities share a number of clinical signs and symptoms such as attacks of abdominal pain, fever, arthritis, rash, haematuria, and occult blood in stool. The frequency of HSP was 7.2% among 207 Turkish familial Mediterranean fever panents compared to 0.8 % among a general paediatric clinic population seen during the same 10-year period (Ozdo~an et al, 1997). A delayed diagnosis of familial Mediterranean fever follows that of HSP m about half of the patients. Although we have not observed any significant difference with regard to disease manifestations and severity of HSP between patients with and without famihal Mediterranean fever, a more severe and protracted course has been described by others in HSP associated with familial Mediterranean fever (Figure 1) (Schlesinger et al,

1985). Table 3. Vasculitlc conditions associated wtth familial Mediterranean fever • • • •

Schonlein-Henoch purpura Polyartentis nodosa Protracted febrile myalgla Subcutaneous nodules

Figure 1. Penrenal haematoma at ultrasonograph~c examination Jn a patient with familial Mediterranean fever and polyartentls nedosa who presented with severe flank pain

344

V. Harnuryudan et al

Polyarteritis nodosa has a yearly incidence of six to seven cases per million in the general population (Michet, 1990). The frequency of polyarteritis nodosa among our famlhal Mediterranean fever patients was 1%. Others have reported a prevalence of 1-2/1000 patients with familial Mediterranean fever (Glikson et al, 1989). Even these figures indicate an association of familial Mediterranean fever and polyarteritis nodosa more common than one would expect by chance alone. The mean age of polyartentis nodosa coexisting with famihal Mediterranean fever is usually around 20, while isolated polyarteritis nodosa is more prevalent in the fourth and fifth decades. Most clinical mamfestatlons of polyarterltis nodosa in patients with familial Mediterranean fever resemble those of polyartentis nodosa in general. A rare, but well known, complication of classic polyarteritis nodosa, perlrenal haematoma, (Figure 2), has been reported m more than half of the patients with familial Mediterranean fever

Figure 2, Presence of m~croaneurysrns in a patient with familial Mediterranean fever and associated polyartent~s nodosa

Other forms of vascuhtls and pseudovascuht~s 345

who developed polyarteritis nodosa. Corticostenods and, m some cyclophosphamide treatment are indicated. Recently, a new clinical entity probably associated with vasculius, called 'protracted febrile myalgia' has been reported in patients with famihal Mediterranean fever (Langevitz et al, 1994). Pronounced myalgia with increased erythrocyte sedimentation rate (ESR), leukocytosis and polyclonal hyperglobulinaemia are the characteristics of this entity. Another finding suggestive of vasculitis is the presence of occult blood in the first stool specimens obtained after an abdominal attack in about half of the patients (Ozdo~an et al, 1997). Practice points •

Be alert for familial Mediterranean fever in a child with Sch6nleinHenoch purpura in areas and races where familial Mediterranean fever is prevalent

•

A perirenal haematoma is usually associated with polyarteritis nodosa secondary to familial Mediterranean fever

•

Occult blood in stools, during an attack, is common in familial Mediterranean fever

Familial Mediterranean fever has been considered as one of the neutrophilic dermatoses with associated vascular changes (Jorizzo, 1988). The histopathologlcal findings of the involved skin range from non-specific perivasculitis to fully developed leukocytoclastic vasculitis. Histological examination of subcutaneous nodules has been described as neutrophllic vasculitis of small veins and/or acute septal and lobular pannicuhtis in occasional case reports (Danar et al, 1987).

Relapsing polychondritis Relapsing polychondrms, is a rarely diagnosed recurrent, systemic disorder of unknown aetiology characterized by inflammation of camlage, mainly affecting the ears, nose, larynx, trachea, and joints. The most common clinical manifestation is a destructive auricular chondritis with sparing of the ear lobule (Herman, 1991). Nasal chondrltis can cause a saddle nose deformity (Figure 3). Laryngeal and/or tracheobronchlal cartilage involvement may result m airway obstruction, accounting for 10% of all fatalities. Articular symptoms are reported to be the second most frequent feature of relapsing polychondrms detected m about 70% of cases. A non-erosive, self-limited ohgo- or polyamcular involvement with peripheral arthritis is common. Arthralgla and costochondritls are other frequent findings. The presence of arthmis is associated with generalized disease and poor prognosis (Balsa et al, 1995). Conjunctivitis, eplscleritis, keratltis, tinnltus,

346

V Hamuryudan et al

Figure 3. Swelhng of cartilaginous part of the external ear, sparing the Iobule in relapsing polychondrltls

vertigo, deafness, and skin lesions are other features of the disease. Both small and large vessels may be involved in less than 10% of the patients. Leukocytoclastic vascuhtis causing vascuhtic skin lesions and/or aneurysms of the thoracic-abdominal aorta, and cerebral artery can occur. Neurological and psychiatric &sturbances may be observed secondary to vasculins of the nervous system (Hanslik et al, 1994). In a quarter of the cases, an abnormal urinalysis is found but only few patients develop severe renal mvolvement. The proposed criteria for the diagnosis of recurrent polychondntis (McAdam et al, 1976) is given m Table 4. The associanon of recurrent polychondntis with a number of other &seases like seroposltive rheumatoid arthritis (RA), Sjbgren's syndrome, Wegener's granulomatosls, microscopm polyarteritis nodosa, pustular psoriasis, Behqet's syndrome, and malignancies including myeloprohferative disorders, Hodgkin's disease, and carcinoma of lung, breast, and colon have been recogmzed (Herman, 1991). These are detected in over 30% of the cases, with chondrms following the onset of the associated &sease.

Other forms of vascuhtls and pseudovasculitis

347

Table 4. Diagnostic cr~tena for relapsing polychondritls, requmng three or more to confirm the diagnosis • • • • • • •

Bilateral auricular chondntls Non-erosive, seronegatlve inflammatory polyarthntls Nasal chondntis Ocular inflammation (con]unctMtls, kerat)tls, sclent~s/eplsclentls, uveltls) Respvatory tract chondntls (laryngeal and/or tracheal cartilages) Cochlear and/or vestibular dysfunction (neurosensory heanng loss, tlnnltus, and/or vertigo) Cartilage bLopsy confirmation of a compatible h)stologlcal picture

There is no laboratory test specific for recurrent polychondrltis. Positive results for rheumatoid factor, anti-nuclear antibodies (ANA) and ANCA have been reported in conjunction with the underlying autolmmune or vasculitic condmon. For assessment of disease acuwty, a serum 148 kDa non-collagenous cartilage matrix protein has been identified in recurrent polychondrms but also in RA (Saxne and Hemegard, 1995). The medical treatment of recurrent polychondrms is based on the use of non-stero:dal antfinflammatory drugs, steroids, and immunosuppresslves, the latter being spared for severe cases. Once airway damage has occurred, tracheostomy ~s necessary to treat a subglomc stenosls. Successful use of expandable intrabronchml metal stents in the treatment of bronchial collapse in recurrent polychondritis has been reported (Shah et al, 1995).

Adult Kawasaki disease

Kawasaki disease is an acute febrile vasculitxs primardy affecting mfants and young children. Since its first description in Japan in 1967, both endemic and epidemic forms have been reported with an estimated incidence of 150 per 100 000 in Japan and 5 to 8 per 100 000 in chddren under the age of 4 in North America (Yanagawa and Nakamura, 1986). Although the aetlology of Kawasakl disease is unknown, reported associations suggest an infectious cause. Kawasak] disease has features m common with staphylococcal toxic shock syndrome, scarlet fever, and viral exanthema. Similar disease mechanisms have been suggested for Kawasakl disease and the toxic shock syndrome (Leung, 1993). Antibodies against vascular endothelial cell antigens and neutrophil cytoplasmic anugens (c-ANCA) support the role of neutrophils and endothelial lnlury in acute Kawasakl disease. At least five of the six mamfestauons outlined m Table 5, proposed by the Kawasaki Disease Research Committee, should be present for diagnosis (Dillon, 1996). Only four criteria are sufficient if coronary artery aneurysms are detected. Table 6 gives the other chmcal features associated with Kawasaki disease. Abnormal cardiac findings consisting of myocarditls, pericarditis, arrhythmla during the acute phase, and coronary artery aneurysms, stenosis, and myocardial infarction later in the course,

348

V. H a m u r y u d a n et al Table 5. Dlagnosttc crltena for Kawasakt disease • • • • • •

Fever persisting for 5 days or more Changes of lips and oral cawty (reddening of hps, strawberry tongue diffuse mjectton of oral and pharyngeal mucosa) Bdateral conjunctival rejection Changes in the penpheral extremities (reddening of palms and soles, indurative oedema in intttal stage and membranous desquamatton of the fingertips Jn the convalescent phase) Polymorphous exanthema Acute non-purulent cervtcal lymphadenopathy

Table 6. Other chn~cal features associated with Kawasaki disease. Body system

Chnlcal features

Cardiovascular system

Heart murmurs, gallop rhythm, ECG changes, cardtemegaly, twodimensional ECHO fmdtngs of pencardlal effuston, coronary artery aneurysms, aneurysms of peripheral arteries, angina pectons and myocardtal infarction

Gastrointestinal tract

Diarrhoea, vomiting, abdominal pare, hydrops of the gallbladder, deus, jaundtce

Blood

Leukocytosis, thrombocytosis, increased ESR, increased CRP, hypoalbummaemia, anaemia

Urine

Protelnurla, increased leukocytes in sediment

Skin

Transverse furrows of fingernails

Respiratory tract

Cough, rhlnorrhoea

Joints

Pare and swelling

Neurological system

Pleocytosis m CSF, convulsions, factal palsy

ECG = electrocardiographic, ECHO = echocardtographic, ESR = erythrocyte sedimentation rate, CRP = Creactive protein, CSF = cerebrospmal fluid

make up the most important aspects of the disease, because long-term morbidity 'is related to these complkzations. Kawasakl disease ]s a disease of interest m the adult population for two reasons. F]rst, Kawasaki d]sease, although rare, can be diagnosed during adulthood, second, the coronary sequela of childhood Kawasaki disease can affect prognos~s later in hfe. A review of the literature on adult Kawasaki disease showed that the mean age of onset was 25.6 years (Jackson et al, 1994). The frequency of diagnostic manifestations was the same in both adults and children. Sterde pyuria was more common in chddren while arthralgia and hepatitis were more prevalent in adults. Electrocardiographic abnormahues and heart fa]lure in adult cases were as common as in chddhood series. On the other hand, coronary artery aneurysms were less frequent compared with chddren, but was still the mare cause of mortality (Phllhps and Marsden, 1993). It has been suggested that echocardiographlc examination m detecting adult coronary artery aneurysms may not be as sensitive as in children (Jackson et al, 1994). Aspirin and high dose intravenous gammaglobuhn e]ther as five daily doses of 400 mg/kg/day or a single dose of 2 g/kg (Newburger et al, 1991)

Other

forms

of vasculttis

and pseudovasculrtrs

349

are recommended for adults and children. The risk of developing coronary artery aneurysms decreases from 15 to 25% to 3% by the early administration of the latter treatment. The data on adult survivors of childhood Kawasaki disease who had coronary artery disease IS accumulating in recent years. It has been reported that even after the regression of aneurysms, localrzed stenosis can progress and cause ischaemic myocardial sequelae later m life (Tatara et al, 1996). Another question of interest IS the development of premature atherosclerotic coronary artery disease secondary to previous damage of the coronary arteries from Kawasaki disease. Although there is no sufficient evidence, it has been stated that there might be an increased risk (Ross, 1995). Kawasaki disease is also being considered among the causes of silent myocardial ischaemia and sudden death in asymptomatic middle aged men (Fazzmi et al, 1993). In view of the data summarized above, it is important to consider Kawasaki disease in patients of any age and start treatment within the first 10 days after onset to minimize the short- and long-term complications of the disease.

Pseudovasculitis There are many conditions which obstruct the blood flow in vessels without an accompanying inflammation of the vessel wall. These are collectively called ‘vascuhtis likes’ or ‘pseudovasculitis’. Pseudovasculitis is usually the result of four different mechanisms (Table 7). Table 7. Causes

and examples

of pseudovasculrtrs

Mechanrsm

Examples

Embolrsm

Myxoma,

Drugs

Methersygrde,

Thrombosrs

Antr-phospholrprd syndrome, thrombocytopenrc purpura

Vessel

wall pathology

Cholesterol

(non-mflammatory)

cholesterol

Calciphylaxis,

embolt,

mfecttve

endocardrtrs

ergot suckle cell drsease,

thrombotrc

amylotdosis

embolism

Cholesterol embolism is a syndrome that results from the shedding away of cholesterol crystals from atheromatous plaques (Coppiello et al, 1989). It is most commonly seen among elderly males. When cholesterol emboh occlude small arteries they cause many symptoms indistmguishable from those seen m a true systemic vascuhtis. The common presence of an augmented acute phase response and abnormalities in immunological tests compound the problem.

350

V Hamuryudan et al

Cholesterol embohsm usually occurs in a patient with diffuse atherosclerosis and not uncommonly after a triggering affect like abdominal surgery or diagnostic angiography, during which the emboli become dislodged. The syndrome has also been reported after anti-coagulation therapy. The emboh usually emerge from the plaques in the abdominal aorta, and livedo reticularis in the lower extremity is a frequent finding. Sometimes frank gangrene can be seen. More serious manifestations are intestinal or coronary artery occlusion. A progressive renal failure can occur. Amaurosis fugax (in the course of which cholesterol crystals can be seen in retinal vessels), various CNS pathology, and a peripheral neuropathy are also seen. Mononeurltis multiplex and arthrms are unusual. Myalgla along with muscle tenderness, on the other hand, is frequent. The ESR is almost always quite elevated and in many cases there is leukocytosis with eosinophilia. Emboli in skeletal muscles will cause an elevation of muscle enzymes. ANAs and rheumatoid factor can be positive. As in other pseudovasculltic syndromes, the first step in diagnosis is the clinical suspicion. Histological demonstration of cholesterol emboli as narrow 'clefts' In tissue sections or, If one is lucky, observation of cholesterol crystals during examination of the retina are the only ways of making a positive diagnosis. Treatment is by excision of the causative atheromatous plaque. Steroids are of no value. Anti-coagulation, if already started for a suspected true vasculitls, should be stopped.

Myxoma Myxomas are benign cardiac tumours that are more common in the left atrium. They can be silent or may cause symptoms of an 'intermittent' mltral stenosls. They can also cause extracardiac symptoms and thus may be confused with a vascuhtis (Abraham et al, 1995). The most frequent site of embolism is the brain causing a myriad of symptoms ranging from a progressive loss of cognitive function to true pyramidal symptoms. Peripheral pathology, including petechial skin rashes, Raynaud's phenomenon, glomerulonephrins, arthritis, myositls, pleurisy, and perlcar&tis can also be observed. There is, most of the time, an accompanying fever. In fact myxoma can be a cause of a fever of unknown origin. As in the case of cholesterol embolism, there is very commonly a heightened acute phase response with an elevated ESR, increased C-reactive protein (CRP) levels and a leukocytosis. Hyperglobuhnaemia and elevated aDNA levels have been described as well as thrombocytopenla, hypocomplementenaemla and, occasionally, a polycythaemla. The mechanism behind any of these findings are far from clear. Urinalyses are also frequently abnormal showing a haematurla and protemurla. The diagnosis is made by demonstrating the cardiac tumour by echocardiography (Navarro et al, 1995) and searching for a tissue diagnosis of the peripheral emboh. Whenever an embolectomy is done the removed embolus should always be sent for histology.

Other forms of vasculitls and pseudovasculltls

351

Calciphylaxis Calciphylax]s is a rare and potentially lethal syndrome almost always assooated w~th chromc renal failure (CRF). Many patients with CRF develop medial calcification. This is usually of no clinical consequence. However, a small minority also develop a severe devastating condition characterized by skin necrosis and gangrene of the extremities (Meliko~lu et al, 1996). Organ involvement, as recently described for myocardium (MacLean and Brahn, 1995), although rare, can occur. Calchlphylaxls, as distinct from calcinosis, is not a simple deposition of calcium, it is thought to be the result of a hypersensmvity reaction m the presence of parathyroid hormone, vitamin D and hypercalcaemia (Bargman, 1995). Histologically, apart from the me&al calcification, there is fibrous intimal proliferation and thrombus formation (Figure 4). Treatment is mainly directed at local ulcer management with debridement and fighting secondary refection. Parathyroldectomy can be life saving. ,..,,.

. .7~ •

k t,

Figure 4. Medial calcification and occlus=on of the vessel lumen in calclphylaxls

Infective endocarditis Infective endocardius is assooated both with a true vascuhtis and embohc phenomenon. The true vasculitlc lesions are either due to an immune complex vasculitis secondary to the prolonged Immunological response, to the infectious agent or to mycotic aneurysms caused by sepuc emboli. In the

352

V. Hamuryudan et al

latter case there is d:rect bacterial or fungal invasion of the vessel wall. However, s:mple emboli occluding the vessel lumen are also another cause of tissue injury m bacterial endocardins. Fungal endocarditis is especially known to occlude large vessels, i.e. the femoral vein, with large bits of embolic vegetation. Skin, brain, spleen, and kidney are the organs that are frequently revolved in bacterial endocarditis resulting in petechiae, strokes, splenic infarcts, and glomerulonephntis. The patients also frequently have lmmunologically-mediated arthralgias and occasional arthritis. The accompanying brisk acute phase response, hyperglobuhnaemia and presence of rheumatoid factors also cause the panent with infective endocardins to be misdiagnosed as a true systemic vasculitis or vascuhtis secondary to SLE, especially in the light of the qmte common presence of valvular disease in the latter condinon (Roldan et al, 1996).

Amyloidosls Primary systemic amyloidosxs can sometimes masquerade as a vasculitis (Salvarini et al, 1994) and can be accompanied by polymyalgia rheumatica and or giant cell arteritis-associated symptoms like scalp tenderness, and claudication of the jaw and legs. True muscle weakness can also occur. The vascular histology shows amyloid deposits in the vessel wall, compromising the lumen. Occasionally, a true granulomatous giant cell arteritis can coexist. The syndrome seems to be confined to primary amyloidosis. A useful mnemonic to recall the more frequently seen pseudovasculitic conditions is MACEC (myxoma, amyloidosis, cholesterol emboli, endocarditis, and calclphylaxis).

Pracnce points •

Always obtain blood cultures in a patient presenting as systemm vascuhtis

•

Always obtain an echocar&ogram in a patient presenting as systemic vascuhtis

•

Be alert for cholesterol emboh in an aged person being treated for a presumed thrombosis and who is deteriorating under anticoagulation therapy. Do not [orget to examine the retinas

•

After an embolectomy, always send the embolus for pathological examination preferably with a culture for bacteria and fungi

•

Always ask for an amylold stain after a temporal artery biopsy

•

Be alert for 'calchlphylaxls' m a patient with renal failure presenting as a systemic vasculitis

Other forms of vascuhtls and pseudovascuhtls

353

References Abraham Z, Rozenbaum M, Rosner I et al (1995) Cutanoeus eruption m a patient with cardiac myxoma. Journal of Dermatology 22: 276-278. Akman-Demir G, Kurt BB, Serdaro~lu P e t al (1996) Seven year follow up of neurological involvement m Behqet's syndrome . Archwes of Neurology 53: 691-694. Aktulga A, Altac M, Mufruo~lu AU et al (1980) A double bhnd study of colchicme m Beh~et's disease. Haematologzca 65: 399-402. Ayesh SK, Azar Y, Bablor BM & Matzner Y (1993) Inactlvanon of IL 8 by the C5a mactwatmg protease from serosal fluids. Blood 81: 1424-1427. Balsa A, Espmosa A, Cuesta M e t al (1995) Joint symptoms m relapsing polychondrms. Chmcal and Experimental Rheumatology 13: 425-430. Bargman JM (1995) Calclphylaxls, calcmosls, and calcergy--separate but not equal. Journal of Rheumatology 22: 5-6. (~akir N, Yazlcl H, Chamberla,n MA et al (1991) Response to mtradermal mlectlon of monosodmm urate crystals m Behqet's syndrome . Annals of the Rheumatic Diseases 50:

634-636. "Coppiello RA, Espmoza LR, Adelman H et al (1989) Cholesterol embohsm: a pseudovascuhuc syndrome. Seminars zn Arthritis and Rheumatism 18: 240-246. Daif A, Awada A, al Raleh Set al (1995) Cerebral venous thrombosis m adults: a study of 40 cases from Saudl Arabia. Stroke 26: 1193-1195. Danar DA, Kwan TH, Stern RS et al (1987) Panmculms m famflml Mediterranean fever: Case report wlth hlstopathologlc findings. American Journal of Medicine. 82: 829832. Dillon MJ (1996) Kawasakl syndrome. In Ansell BM, Bacon PA, Ll JT & Yazlcl H (eds) The Vascuhudes, pp 384-391 London- Chapman & Hall. Fazzini FP, Pratl PL, Rovelh F et al (1993) Epldemmlogy of silent myocardml lschemm m asymptomatlc middle-aged men. AmericanJournal of Cardiology 72: 1383-1388. Fresko I, Yazlcl H, Bayramlqh M e t al (1993) Effect of surgical clean,ng of the skin on the pathergy phenomenon m Behqet's syndrome . Annals of the Rheumatic Diseases 52: 619-620. Gedalia A, Adar A & Goro&scher R (1992) Famflml Mediterranean fever m children. Journal of Rheumatology 19 (supplement 35): 1-7. "Glikson M, Galun E, Schlezlnger M e t al (1989) Polyarterms nodosa and familial Me&terranean fever: A report of 2 cases and rewew of the hterature. Journal of Rheumatology 16: 536-539. ~'Gul A, Esln S, Dfl~en N e t al (1995) Immunohlstology of skin pathergy reacnon m Beh~et's disease. British Journal of Derrnatology 132: 901-907. Gullu IH, Benekh M, Muderrlso~lu H et al (1996) Silent myocardml lschemm m Behqet's disease Journal of Rheumatology 23: 323-327. Hamuryudan V, Yurdakul S, Moral F et al (1994) Pulmonary arterml aneurysms in Behqet's syndrome : a report of 24 cases. Brlttsh Journal of Rheumatology 33: 48-51. " Hamuryudan V, Ozyazgan Y, Hlzll N e t al (1997) Azathloprme m Behqet's syndrome • effects on the long term prognosis. Arthrztis and Rheumatism 40: 769-774. Hanslik T, Wechsler B, Plette JC et al (1994) Central nervous system involvement m relapsing polychondrms. Clmzcal and Experimental Rheumatology 12: 539-541. '~Hasan A, Fortune F, Wilson A et al (1996) Role of gamma delta T cells m pathogenesls and dmgnosls of Beh~et's disease Lancet 347:789-793 Herman JH (1991) Polychondrlns. Current Opznlon in Rheumatology, 3: 28-31. Jackson JL, Kunkel MR, Llbow L & Gates RH (1994) Adult Kawasakl disease: report of two cases treated with intravenous gamma globuhn. Archzves of Internal Medtcme 154: 1398-1405. '"Jorizzo JL (1988) Neutrophlhc dermatoses: Sweet's syndrome and pyoderma gangrenosum. In Galhn JI, Goldstem MI & Synderman R (eds) Inflammatzon: Basic principals and Ckmcal Correlates pp 785-802. Raven Press: New York. Jorizzo JL, Abernethy JL, White WL et al (1995) Mucocutaneous cnterm for the dmgnosls of Beh~et's &sease: an analysis of chmcopathologlc data from multiple international centers. Journal of the American Academy of Dermatology 32: 968-976.

354

V. Hamuryudan et al

'~Koq Y, Gullu I, Akpek G e t al (1992) Vascular involvement m Beh~et's disease. Journal of Rheumatology 19: 402-410. Langevitz P, Zemer D, Llvneh A & Pras M (1994) Protracted febrile myalgla m panents with famlhal Mediterranean fever. Journal of Rheumatology 21: 1708-1709. Leung DYM (1993) Kawasakl disease Current Opinion m Rheumatology 5: 41-50. Lie JT (1992) Vascular mvolvement m Beh~et's disease: arterial and venous and vessels of all sizes Journal of Rheumatology 19: 341-343. McAdam LP, O'Hanlan MA, Bluestone R et al (1976) Relapsing polychondrms: prospecnve study of 23 panents and a review of the hterature. Medicine 55: 193-215. MacLean C & Brahn E (1995) Systemic lupus erythematosus: Calclphylaxls induced cardlomyopathy. Journal of Rheumatology 22: 177-179. Masuda K, Nakallma A, Urayama A, et al (1989) Double-masked trial of cyclosporm versus colchlcme and long-term open study of cyclosporm in Behcet's disease. Lancet 1: 1093-1096. Mege JL, Ddsen N, Sanguedolce V e t al (1993) Overproducnon of monocyte derived tumor necrosis factor alpha, mterleukm (IL) 6, IL-8 and increased neutrophll superoxide generanon m Behcet's disease. A comparanve study with famlhal Mediterranean fever and healthy subjects. Journal of Rheumatology 20:1544-1549 Meliko~lu M, Apaydm S, Hamuryudan V e t al (1996) Calclphylaxis: A condmon mimicking necrotlzmg vascuhns. Ckmcal Rheumatology 15: 498-500. Michet CJ (1990) Epidemiology of vascuhns. Rheumatic Disease Ckmcs of North Amerzca 16: 261-268. Navarro PH, Bravo FP, Beltran GG et al (1995) Atrial myxoma with hvedold macules as the sole cutaneous manifestation. Journal of the American Academy of Dermatology 32: 381-385. Newburger JW, Takahashi M, Beiser AS et al (1991) A single intravenous infusion of gammaglobuhn as compared w~th four infusions m the treatment of acute Kawasaki syndrome. New England Journal of Medicine 324:1633-1639. '~Ozdo~an H, Ansoy N, Kasap~apur O et al (1997) Vascuhns in familial Mediterranean fever. Journal of Rheumatology 24: 323-327. Phillips WG & Marsden JR (1993) Adult Kawasaki syndrome. Br~tzshJournal of Dermatology 129: 330-333. '~Pras E, Askennyevich I, Gruberg L e t al (1992) Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. New England Journal of Medicine 326: 1509-1513. Pras M, Langevitz P, Livneh A & Zemer D (1996) Vascuhns in familial Mediterranean fever. In Ansell BM, Bacon PA, Lie JT & Yazici H (eds) The Vascuktzdles. pp 412-416. London: Chapman & Hall. Roldan CA, Shlvely BK & Crawford MH (199-6) An echocardiographlc study of valvular heart disease associated with systemic lupus erythematosus. New England Journal of Medzcme 335: 1424-1430. Ross BA (1995) Kawasakl disease- Unsafe at any age? American College of Cardsology 25: 1425-1427. Saxne T & Hemegard D (1995) Serum concentrations of two cartilage matrix proteins reflecting different aspects of cartilage turnover m relapsing polychondrlns. Arthrzt~s Rheumatism 38: 294-296. Schlesinger M, Vardy PA & Rubmow A (1985) Henoch-Schonlem purpura and famflml Mediterranean fever. Israel Journal of Medzcal Sczences 21: 83-85. Serdaro~lu P, Yazlcl H, Ozdemir C et al (1989) Neurologlc involvement in Beh~et's syndrome a prospective study Archwes of Neurology 46: 265-269. Shah R, Sabanathan S, Mearns AJ et al (1995) Self-expanding tracheobronchial stents in the management of malor airway problems. Journal of Cardiovascular Surgery (Tormo) 36: 343-348. Stanford MR, Kasp E, Whiston R et al (1994) Heat shock protein peptldes reactive in panents with Beh~et's disease are uveitogemc in Lewis rats. Ckmcal and Expertmental Immunology 97: 226-231. Takeno M, Kanyone A, Yamashlta N e t al (1995) Excessive function of peripheral blood neutrophlls from patients with Beh~et's disease and from HLA B51 transgemc mice Arthr~tls and Rheumatzsm 38: 426-433.

Other forms of vascuhtls and pseudovascuhtls

355

Tatara K, Murata M, Itoh K et al (1996) Management of severe coronary sequelae of Kawasakl disease. American Heart Journal 131: 576-581. Thi Huong DL, Wechsler B, Papo T et al (1995) Arterial lesions m Behqet's disease: a study m 25 patients. Journal of Rheumatology 22:2103-2113 Yanagawa H & Nakamura Y (1986) Nationwide epidemic of Kawasakl &sease m Japan during winter of 1985-1986. Lancet 2,. 1138-1140. Yazlcl H (1997) The place of Behqet's syndrome among the autolmmune &seases. International Revtews of Immunology 14: 1-10. Yazlcl H, Pazarh H, Barnes CG et al (1990) A controlled trial of azathioprme m Behqet's syndrome. New England Journal of Medicine 322: 281-285. Yazlcl H, Yurdakul S & Hamuryudan V (1995) Behqet's syndrome: How should we treat st? Ckmcal Immunotherapeutzcs 3: 102-107. Yaztcl H, Ba~aran G, Hamuryudan V et al (1996) The ten year mortahty m Behqet's syndrome. Br~tlsh Journal of Rheumatology 35: 139-141. Yurdakul S, Tuzuner N, Yurdakul I e t al (1996) Gastrointestinal involvement m Behqet's syndrome: a controlled study. Annals of the Rheumatic Diseases 55: 208-210.