Department of Internal Medicine, Rheumatology Unit, University of Pisa,
1 Division of Pathology, Santa Chiara Hospital,
2 CNR Institute of Clinical Physiology and
3 Nephrology and Transplant Unit, Santa Chiara Hospital, Pisa, Italy
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Abstract |
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Methods. Nineteen ChurgStrauss syndrome patients were selected from the medical records of all vasculitis patients attending the Immunology Unit at the Department of Internal Medicine of the University of Pisa in the decade between 1989 and 2000. Data were obtained retrospectively.
Results. All the patients had asthma and hypereosinophilia. As in other case series, the lungs, skin and peripheral nervous system were the most commonly involved organs. The majority of our patient received i.v. pulses of methylprednisolone followed by i.v. pulses of cyclophosphamide. The outcome and long-term follow-up were good. There were no fatalities observed in this series during the follow-up period.
Conclusions. ChurgStrauss syndrome is a systemic vasculitis occurring in patients with a history of asthma and allergic rhinitis. The positive results of the treatment protocol used in this preliminary study deserve to be tested in controlled multicentre studies.
KEY WORDS: ChurgStrauss syndrome, Retrospective study, Treatment, Long-term follow-up, Italian centre.
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Introduction |
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Due to the rarity of the disease, few large, single-centre studies of CSS patients have been published [3, 69]. In this paper we describe the clinical features, treatment and long-term follow-up of a series of 19 patients who were followed at our clinic during the period 19892000.
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Patients and methods |
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Nineteen cases of CSS were selected out of a total of 104 case records of systemic vasculitis patients. The diagnosis was based on the presence of asthma, hypereosinophilia (>1500/mm3 or >10%) and clinical manifestations consistent with systemic vasculitis. In 12/19 (63%) patients the diagnosis had been confirmed by the biopsy of an involved organ or tissue (muscle, n=1; sural nerve, n=1; liver, n=1; omentum, n=1; skin, n=4; lung, n=1; heart, n=2; kidney, n=1). Biopsy findings were considered to be consistent with the diagnosis of CSS when necrotizing vasculitis of the small to medium-sized vessels, with or without eosinophilic infiltrates and extravascular eosinophilic granulomas, was detected.
In the absence of a histological examination the following criteria were considered as the basis for a diagnosis.
Heart involvement. Heart manifestations occurring in the absence of pre-existing risk factors such as hypertension, hyperlipidaemia, diabetes, valvulopathy or lesions caused by toxic or infectious agents.
Gastrointestinal involvement. Unexplained abdominal pain, acute abdomen or other GI complaints (hepatitis, cholecystitis) occurring during a vasculitic flare with no other pathogenic explanation.
Renal involvement. Unexplained increase in serum creatinine or decrease in creatinine clearance, proteinuria >1 g/24 h, or abnormal urinary sediment.
A patient was considered to be in remission when the clinical manifestations disappeared for a period of at least 6 months. Prolonged remission was defined as the absence of CSS-related symptoms for at least 1 yr. A relapse was defined as the recurrence of CSS-related symptoms other than asthma.
Methods
Antineutrophil cytoplasmic antibodies (ANCA) were detected using an enzyme-linked immunosorbent assay (ELISA) against proteinase 3 and myeloperoxidase (MPO), as reported previously [10].
The treatment modality was as follows. In cases of severe, life-threatening multisystem involvement (i.e. heart failure, severe GI involvement or severe peripheral polyneuropathy) the treatment of choice consisted of the administration of pulse 6-methylprednisolone (6-MP) (750 mg/m2) followed by pulse cyclophosphamide (750 g/m2), which represented a slight modification of past protocols [11, 12]. All patients received intravenous (i.v.) pulses of methylprednisolone for three consecutive days, followed by rapid tapering to a mean dose of 20 mg/day by the end of the first week and a mean dose of 48 mg by the end of the third month of treatment. Seven days after the last methylprednisolone pulse, i.v. cyclophosphamide (750 mg/m2 body surface area) was started following the schedule of two pulses at 15- or 30-day intervals (depending upon the severity of organ involvement) followed by four pulses at 1-month intervals, giving a total of six pulses. According to the clinical status of the patient, further pulses could be administered once every 3 months.
Following treatment, the patients were placed on maintenance therapy. Azathioprine (2 mg/kg) or methotrexate (7.515 mg once a week) were the drugs of choice; only one patient received cyclosporin instead. Oral cyclophosphamide (0.72 mg/kg/day) was reserved for cases of major flares or the failure to achieve remission.
In patients with moderate to mild organ involvement (i.e. peripheral neuropathy, cutaneous involvement) the administration of steroids at medium to low doses (0.10.7 mg/kg) was the treatment of choice, sometimes in combination with azathioprine or methotrexate.
Disease activity was assessed as the Birmingham Vasculitis Activity Score (BVAS) [13] at disease onset and after treatment.
Statistical analyses of the results were carried out using the 2 test, the MannWhitney test, and Spearman's correlation coefficient to determine the correlations between the clinical and serological parameters. Qualitative variables were compared using contingency table analysis and Fisher's exact test.
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Results |
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In 11/19 patients (57.8%) a history of atopy was recorded, defined as the presence of at least one of the following manifestations: allergic rhinitis, allergic asthma, drug-induced allergy (particularly antibiotics), food allergy urticaria and inhalant allergy (dust mites, pollen).
Clinical features
Systemic complaints. Non-specific symptoms consisting of malaise, low-grade fever, weight loss and arthromyalgias marked the early stages of vasculitis in 17/19 patients (89.4%).
Lungs. By definition, all the patients had asthma. This symptom was the most frequent manifestation at presentation. The mean time lapse between the appearance of asthma and the onset of vasculitis was 79 months (range 030 years). In 13 patients the asthma began when the patient was an adult (mean age at onset 33 yr, range 2070 yr). In 12 patients (63.1%) the asthma was of recent onset (<6 months).
The upper airways were affected in 11/19 cases (57.8%); the manifestations included, in various combinations: allergic rhinitis, hyperaemic turbinates and recurrent sinusitis. Three patients required upper respiratory tract surgery for nasal polyposis. Alveolar haemorrhage was detected in one patient, who suffered from recurrent haemoptysis. One patient had eosinophilic pneumonitis diagnosed by endoscopic transbronchial lung biopsy. Transient pulmonary infiltrates were detected by chest X-ray in 7/19 patients (36.8%). The radiological aspect of these infiltrates was patchy or diffuse interstitial infiltrates without a lobar or segmental distribution. Two patients had pleural effusion.
Skin. Thirteen of 19 patients (68.4%) had cutaneous lesions. The skin manifestations observed were highly heterogeneous, although half of the cases showed palpable purpura. This manifestation typically involves the distal limbs, most frequently the legs, with a calf stocking distribution.
Urticarial lesions, livedo reticularis, papules, cutaneous infarctions, bullae/vesicles and subcutaneous nodules were also observed. Figure 1 shows a skin biopsy specimen taken during the acute stage of the disease (from patient MG) from one of multiple papular lesions involving the lower third of the limbs. The patient had similar lesions on his palms. Histology showed perivascular histiocytic granulomatous infiltrates in the dermis with conspicuous eosinophils.
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Peripheral nervous system. Eleven of 19 (57.8%) patients showed signs of peripheral nerve involvement (Table 1). The majority of these cases (7/11) had sensorymotor mononeuritis multiplex neuropathy. Two of the patients (AA, FA) demonstrated severe functional impairment and cranial nerve involvement (facial palsy). One of these patients (FA) also had optic ischaemic neuritis. In one case (AA) the peripheral involvement was extremely severe, with tetraparesis and complete loss of strength (the patient was unable to move even in the absence of gravity); electroneurography revealed a complete denervation pattern. Sensory impairment and muscle involvement were restricted to the distal limbs. The nerves involved most frequently in our series were the deep peroneal nerve (n=8), followed by the posterior tibial (n=4), sural (n=3), ulnar (n=2) and median (n=1) nerves.
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In three patients with severe acute abdominal pain (AA, CMR, FA), an emergency laparotomy was required. In the first case a necrotizing cholecystitis, liver eosinophilic infiltrates and diffuse bowel perforation were found. In the second case, omental resection showed the presence of endoluminal thrombosis and a chronic inflammatory infiltrate of the small-sized mesenteric vessel walls. In the third case laparotomy revealed a bowel perforation and pyogenic peritonitis.
Heart. Six of the 19 patients (31.5%) had heart involvement ranging in severity from mild pericarditis to severe heart failure due to myocarditis. All of the patients underwent a standard ECG and echocardiography at enrolment (Table 2). Two showed only minor pericardial effusion with no other abnormalities.
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During the follow-up, two of the patients with congestive heart involvement due to CSS underwent a second echocardiogram and NH3 positron emission tomography (PET) in order to study the local and overall flow in the microcirculation. The third patient was lost to follow-up. In patient 1 (AA), the second echocardiogram showed a striking improvement (44%) in left ventricular function (LVEF), with persistence of hypokinesis of the anterior and lateral walls. PET showed decreased regional flow of the lateral wall, consistent with the echocardiographic findings, and a normal mean flow (1.04 ml/min/g; normal value > 0.8). In patient 14 (CF) the repeat electrocardiogram was unchanged. PET showed decreased regional flow of the anterior and lateral walls, including the apex, and severely decreased mean flow (0.6 ml/min/g). During the follow-up, AA showed continued improvement (an electrocardiogram at the end of follow-up showed normal LVEF with persistence of mild hypokinesis of the anterior and lateral walls). Patient CF, despite partial remission of the disease, showed progressive worsening of heart function and relapsing pulmonary oedema, and has been placed on the waiting list for a heart transplant. The electrocardiogram performed at the end of follow-up showed an LVEF of 42% and PET showed that hypokinetic areas in the same sites were involved.
Kidney. Three out of 19 patients (15%) had chronic renal failure (creatinine >1.5 mg/dl), although none required dialysis. In these three cases a kidney biopsy was not necessary because ultrasound showed clear signs of sclerosis and poor corticomedullary differentiation. One patient exhibited increasing proteinuria with microhaematuria and casts despite treatment with cyclophosphamide pulses. He was admitted to hospital and a renal biopsy was done. Histology showed glomerulonephritis with matrix and mesangial proliferation and the formation of mixed crescents, as well as small areas of hyalinosis, interstitial lymphocytes and small fibrin aggregates (WHO class IIIIV) (Fig. 2a and b). Immunofluorescence showed the scattered mesangial deposition of immunoglobulin A (IgA).
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Other clinical features. One patient experienced jaw claudication and one had recurrent thrombophlebitis of the lower limbs.
Laboratory parameters. All of the patients had blood eosinophilia (eosinophil count >1500/mm3, range 160023 000/mm3) during the vasculitic phase of the disease. Moreover, most of the patients (18/19, 94.7%) had an elevated erythrocyte sedimentation rate (ESR) and/or an elevated C-reactive protein (CRP) concentration during the acute stage of the disease. However, neither the ESR and CRP values nor the absolute number of eosinophils were correlated with one another or with the disease activity as calculated by BVAS (P not significant).
Three patients had raised liver enzymes. Markers of hepatitis B and C viruses were negative, so that hepatitis infection could be ruled out. In two patients the rise in enzyme levels could be attributed to vasculitic liver involvement (demonstrated by biopsy in one; see above). In the third patient this change appeared during cyclophosphamide treatment (cumulative dose 8 g over 12 months). Liver biopsy was unremarkable in all three patients. After stopping cyclophosphamide, enzyme levels returned to normal within 4 weeks.
ANCA were investigated in 18/19 patients and were present in 7/18 (35%). All of these patients had antibodies against MPO. One patient had a borderline proteinase 3 result that was not confirmed in subsequent testing.
Table 3 summarizes the clinical manifestations in this case series.
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Disease course and long-term follow-up
The majority of our patients had a single acute episode, with severe multisystem involvement in a few cases that could have led to widespread life-threatening vasculitis if it had not been treated promptly.
Apart from a few such extreme cases, most of our patients experienced long-term remission after immunosuppressive treatment. During a mean follow-up of 42.4 months (range 5132 months), only three (15%) patients experienced a disease flareone case of glomerulonephritis, one of cutaneous manifestations and one case of lung involvement. In all patients the disease relapse was accompanied by worsening of respiratory tract symptoms and the eosinophil count. The administration of corticosteroids was sufficient to treat the minor manifestations (see above), but the patient with glomerulonephritis required the continuous administration of cyclophosphamide (100 mg/day) for 6 months followed by maintenance therapy with methotrexate.
Our remaining patients experienced remission of the disease. In six patients remission was sustained (>12 months). In nine patients, residual symptoms persisted; these consisting of neurological symptoms (paraesthesias and dysaesthesias, muscle weakness), generalized complaints (disabling weakness, malaise), cardiac symptoms (relapsing pulmonary oedema), respiratory tract symptoms (asthma, allergic rhinitis) and muscle/joint complaints (arthralgias/myalgias) in varying combinations. Figure 3 summarizes the therapeutic modalities and disease course of the 19 patients.
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Discussion |
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Table 4 shows the main clinical manifestations in our patients in comparison with the largest series in the literature. The age of our patients at disease onset (46.3 yr) was similar to that in series described previously. The duration of asthma ranged from 0 to 30 yr, again in agreement with previous reports [3, 6, 1317]. Peripheral nerve involvement was the most frequent manifestation (57%), its frequency being comparable to that in other series [18, 19]. Nerve involvement responded well to immunosuppressive therapy in the majority of our patients. In some cases residual symptoms, such as paraesthesias and dysaesthesia of the involved limbs, sometimes associated with mild motor deficit, persisted but in no case were these symptoms severe. In the patient with complete denervation, improvement was very slow, reflecting the rate of fibre regeneration, which does not exceed 2 mm/day [19].
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Another common manifestation in CSS is cardiac involvement [2123]. In approximately one-third of our patients heart involvement was present, but only in three was it demonstrated to be due to the disease. Two of the three patients underwent catheterization with a heart biopsy which showed eosinophilic myocarditis. In two patients an extensive work-up was performed, including serial follow-up echocardiography and analysis of the blood flow in the microcirculation with N13 ammonium. It is worth noting that the patient whose heart symptoms responded to immunosuppressive therapy had a normal global blood flow, while the patient who failed to respond had a reduction in global blood flow. It is not known whether this difference should be attributed to the duration of cardiac involvement before therapy or to a true difference in cardiac involvement between the patients. As both patients had a normal angiogram, this test is not sufficient to rule out the possibility of abnormal flow in the microcirculation of patients with signs of heart damage. This demonstrates the urgent need for more sophisticated examination in patients affected by systemic vasculitis. PET has so far been employed only to evaluate myocardial viability in patients with Kawasaki's disease [24, 25], but could be useful in the follow-up of patients with CSS or other systemic vasculitides.
Cardiac involvement is the primary cause of mortality in CSS [3, 6, 18, 21] and is invariably associated with a poor outcome, although on occasion it is fully reversible [21], as occurred in one of our patients.
Renal involvement has been reported in 1649% of CSS patients [1317], the prevalence being higher only in the series of Gaskin et al. [8], whose patients were all drawn from a kidney disease unit. It generally takes the form of focal segmental glomerulonephritis with crescents and the course is mild, although sometimes it may be associated with renal failure requiring dialysis [15]. Approximately 22% of our patients showed some signs of (generally mild) kidney involvement. Only in one case was histology available; it showed glomerulonephritis with mesangial deposition of IgA (Fig. 2). This finding has been reported only rarely and it is not known whether it represents an overlap between ANCA vasculitides and IgA nephropathy or a new type of glomerulonephritis that may appear in CSS [26, 27]. IgA nephropathy has been associated with ANCA IgA [28], but this antibody subtype was not detected in our patient. He suffered a relapse during the administration of pulse cyclophosphamide and was placed on oral cyclophosphamide, to which he responded well with a marked decrease in proteinuria. Moreover, he maintained normal renal functioning.
Laboratory features were largely non-specific and included raised ESR, CRP and eosinophil levels, as already observed in other studies. In all of the relapsing patients the eosinophil count rose shortly before the episode. ANCA were demonstrated only in 35% of our patients and were all of MPO specificity; this is in agreement with the other series described in the literature [1317]. We did not find any correlation between laboratory parameters and disease activity. In particular, BVAS did not correlate with the eosinophil count or with the inflammation indexes, suggesting that other factors may play a more important role in the pathogenesis of the disease. Whatever the role of ANCA in CSS, the present study demonstrates that they cannot be used to monitor the disease course [29].
The treatment of CSS remains an unresolved problem; given the rarity of the disease, there is no established protocol whose efficacy has been documented in randomized controlled studies [for a review see reference 29]. In general, as with the other systemic vasculitides, the therapeutic approach relies on the use of corticosteroids, alone or in association with one or more immunosuppressive drugs, such as cyclophosphamide, methotrexate, azathioprine and (more rarely) cyclosporin A. However, the schedules, modalities and length of treatment adopted vary from report to report.
CSS is characterized by an abrupt onset and often by life-threatening manifestations. The latter is reflected in the mortality rate, which may range from 25 to 50% [3, 6, 1317]. Disease-related mortality ranges from 53 to 55% and is mainly due to severe heart and GI involvement. Iatrogenic mortality, on the other hand, may range from 28 to 47% and is usually linked to the adverse effects of long-term immunosuppression (i.e. opportunistic infections) [6]. The prognosis in our series seemed to be better, for no deaths were observed during the follow-up period (mean 44 months, range 5132 months) and almost all patients did well after immunosuppressive therapy. Three of our patients experienced a single relapse during the follow-up and no patient suffered multiple relapses. All relapses occurred within the first year of follow-up.
In the remaining cases only minor manifestations persisted, including neurological symptoms (paraesthesias and dysaesthesia, muscle weakness), generalized complaints (asthenia, malaise), respiratory tract symptoms (asthma, allergic rhinitis) and muscle/joint complaints (arthralgias/myalgias) in varying combinations. This, in part, confirms the findings by Guillevin et al. [16], who reported that relapses occurred either very soon or long after the clinical remission, 45% during the first year of therapy.
We do not have a clear-cut explanation for the striking difference in outcome between our patients and others. We can reasonably rule out the hypothesis that only patients with milder symptoms were included in our series, as the clinical features did not differ significantly from those in other reported series and a similar proportion of our patients had severe multisystem involvement with potentially life-threatening manifestations. We are therefore more inclined to believe that the favourable outcome in our patients can be ascribed, at least in part, to the immunosuppressive treatment used. It is not surprising that in a condition characterized by acute onset, the early administration of pulse corticosteroid therapy could be safer and more effective in controlling the disease than the long-term administration of medium or high doses of the same drug, and with a lower relapse rate. This positive finding contrasts with the less favourable results achieved in other systemic immune-mediated vasculitides, such as Wegener's granulomatosis. The fact that our protocol consisted of 6-methylprednisolone pulses followed by cyclophosphamide pulses could explain the very low number of severe infective complications seen (a frequent side-effect of drastic immunosuppression). A similar form of combination therapy has already been successfully used by us to treat a series of systemic lupus erythematosus patients with renal involvement [30].
Our findings are in line with the results of a multicentre study by the French vasculitis group, which reported a 6.5 yr actuarial survival rate of 72%, with an initial clinical remission being achieved in 91% of the patients [16]. Twenty-two out of 96 patients (22.9%) suffered a total of 28 relapses; only three patients had multiple relapses.
The positive results of the treatment protocol used in this preliminary Italian study deserve to be tested in controlled multicentre studies.
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Notes |
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References |
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