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- PATIENTS AND METHODS
Demographics. Two hundred seventy-eight patients with a mean ± SD age of 53.8 ± 15.1 years at the time of diagnosis were included in the study; 54.3% were men and 45.7% were women. Regardless of the disease, no difference was noted between male and female patients in terms of clinical symptoms and causes of death. Of this total group, 64 had CSS, 58 had MPA, 93 had non–HBV-related PAN, and 63 had HBV-related PAN. Two hundred sixty-two of the patients (94.2%) were European Caucasians, 10 were born in North Africa, 3 were born in Asia, and 3 were black (2 Caribbean and 1 African). The patients were treated in different centers in France (see Acknowledgments). Nine patients were lost to followup after a mean of 82.3 months. The mean ± SD followup of the entire series of patients was 88.3 ± 51.9 months (range 3 days to 192 months).
The sex ratio, mean age, mean FFS and BVAS scores, deaths, and relapses for the different clinical forms of vasculitis are shown in Table 1. For the 64 patients with CSS, the ENT and chest manifestations accounted, respectively, for 3.52 ± 1.6 and 2.6 ± 1.1 BVAS points (mean ± SD). The mean BVAS, excluding ENT and chest signs (with the exception of hemorrhagic alveolitis), was 16 ± 6.4.
Table 1. Demographics and vasculitis scores of the 278 patients with CSS, MPA, and PAN
|Parameter||CSS (n = 64)||MPA (n = 58)||Non–HBV-related PAN (n = 93)||HBV-related PAN (n = 63)|
|Sex, no. females/no. males||35/29||28/30||46/47||22/41|
|Mean age, years||51.1||59.5||53.4||51.9|
|FFS, mean ± SD*||0.75 ± 0.9||1.86 ± 1.3||0.72 ± 1||0.95 ± 1|
|BVAS, mean ± SD†||22.1 ± 6.3||23.4 ± 8.4||15.1 ± 6.4||18.6 ± 7.3|
|Deaths, no. (%)‡||20 (31.3)||22 (37.9)||22 (23.7)||21 (33.3)|
|Deaths due to vasculitis, no.||4||7||5||6|
|Patients with relapses, no. (%)§||13 (20.3)||20 (34.5)||18 (19.4)||5 (7.9)|
ANCA were sought in 118 of the 278 patients and were positive by immunofluorescence assay in 40 (14 of 30 CSS patients, 19 of 30 MPA, 7 of 35 non–HBV-related PAN, and 0 of 23 in HBV-related PAN).
Outcome. As shown by the Kaplan-Meier survival curves (Figure 1), the overall death rate of the study patients exceeded that of the general population of France, regardless of their age (P < 0.0004). A sharp drop in survival was observed within the first 18 months of followup. Afterwards, the curves tended to be parallel.
Figure 1. Survival of vasculitis patients (Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa with and without hepatitis B virus markers; n = 278) as compared with the general population of France (P < 0.0004).
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The mean ± SD FFS score for the entire cohort was 1 ± 1.13. The numbers of patients in each FFS group were 126 for an FFS of 0, 60 for an FFS of 1, 63 for an FFS of 2, 20 for an FFS of 3, 7 for an FFS of 4, and 2 for an FFS of 5. The mean ± SD BVAS score for the entire group was 19.1 ± 7.8, which was distributed as follows: 32 for a BVAS of ≤10, 130 for a BVAS of 10 to ≤20, 91 for a BVAS of 20 to ≤30, and 25 for a BVAS of >30.
Mortality was significantly associated with disease severity, as assessed by the FFS (P = 0.004) (Figure 2A) and the BVAS (P < 0.0002) (Figure 2B). Despite a tendency toward increased mortality in the MPA patients, no statistically significant difference was observed among the 4 clinical forms of vasculitis (Table 1 and Figure 3). Nevertheless, we observed more deaths during the followup of the MPA patients. Patients in this group were older at the time of diagnosis, 2 of them experienced severe relapses (108 and 120 months, respectively, after the diagnosis of vasculitis), and 2 CS-dependent patients developed sepsis due to severe immunosuppression. A correlation was established between the FFS and BVAS scores (r = 0.69, P < 0.01) (Figure 4).
Figure 2. Survival of vasculitis patients (Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa with and without hepatitis B virus markers; n = 278) as a function of A, their Five-Factors Scores (FFS) (P = 0.004) and B, their Birmingham Vasculitis Activity Scores (BVAS) (P < 0.0002).
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Figure 3. Survival of vasculitis patients (Churg-Strauss syndrome [CSS], microscopic polyangiitis [MPA], and polyarteritis nodosa [PAN] with and without hepatitis B virus [HBV] markers; n = 278) as a function of the type of vasculitis, adjusted to the Five-Factors Score (P = 0.53) and to the Birmingham Vasculitis Activity Score (P = 0.79).
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Figure 4. Correlation between the Five-Factors Score (FFS) and the Birmingham Vasculitis Activity Score (BVAS) in 278 patients with vasculitis (Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa with and without hepatitis B virus markers) (r = 0.69, P < 0.01).
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Relapses. Fifty-six patients (20.1%) experienced 84 relapses. No relationship was observed between the initial disease severity and the occurrence of relapse (mean ± SD FFS 0.94 ± 1.1 and BVAS 18.8 ± 8 in the group with relapses and FFS 1.05 ± 1.1 and BVAS 19 ± 7.8 in the group without). The first relapse occurred a mean ± SD of 31.6 ± 26.9 months after the initiation of first-line therapy. Treatment with cytotoxic agents did not prevent relapses: among the 215 patients treated with CS and CYC for CSS, MPA, or non–HBV-related PAN, 23.4% experienced a relapse, compared with 24.2% among those treated with CS alone. The time to relapse for the group treated with CYC and CS was 33.6 ± 20.8 months, and the time to relapse or uncontrolled disease for those treated with CS alone was 26.9 ± 24 months. It should be noted that the 6 patients whose disease became uncontrollable before the end of this initial treatment, between the sixth and eighth months, had received CS alone. No patient receiving CS and CYC had uncontrolled disease during the treatment period.
The number of relapses differed according to the type of vasculitis: 5 (7.9%) of the 63 patients with HBV-related PAN, 18 (19.4%) of the 93 patients with non–HBV-related PAN, 13 (20.3%) of the 64 CSS patients, and 20 (34.5%) of the 58 MPA patients experienced at least 1 relapse (P = 0.004 for the comparison of relapses versus no relapses among the 4 groups, by chi-square test with 3 degrees of freedom). The time to the first relapse was comparable for all the vasculitides: 24.6 ± 18 months in CSS, 37 ± 26 months in MPA, 29.4 ± 20.5 months in non–HBV-related PAN, and 36.6 ± 60.1 months in HBV-related PAN.
Deaths. The causes of the 85 deaths that were recorded are shown in Table 2. Four sudden deaths of unknown cause were noted during the first 6 months after the start of treatment and were considered to be related to the disease. Three patients died of heart-related conditions (sequelae of specific cardiomyopathy in 2, hypertensive heart disease in 1). Two occurrences of pulmonary emboli were observed during the first 4 months of treatment. Thirteen patients died of cancers that developed in the following sites: lung (n = 3), throat (n = 2), GI tract (2 colon, 1 stomach), liver (n = 1), prostate (n = 1), lymphatic system (n = 2), unknown (n = 1). These patients were older than the rest of the study patients at the time of study inclusion (60.3 ± 10 years); their mean ± SD duration of followup was 71.9 ± 57.6 months. One patient developed breast carcinoma but died of cardiac failure secondary to cardiomyopathy that was specifically associated with CSS.
Table 2. Causes of the 85 deaths of the vasculitis patients
|Cause of death||No. (%) of patients|
|Progressive vasculitis||22 (25.9)|
| Bowel infarction||10|
| Cardiac failure||5|
| Multivisceral involvement||3|
| Renal failure||3|
|Infectious side effects of treatment||11 (12.9)|
| Bacterial pneumonia||5|
|Sudden deaths||9 (10.6)|
|Heart disease||8 (9.4)|
|Pulmonary embolism||3 (3.5)|
|Chronic respiratory disease||3 (3.5)|
|Fulminant viral hepatitis||2 (2.4)|
Two patients were treated for malignancies during followup. One had bladder cancer secondary to CYC therapy, and the other had uterine cancer considered to be independent of the vasculitis and its treatment. Both are still alive and in remission of both the vasculitis and the malignancy. The patient who had uterine cancer also developed thrombotic thrombocytopenic purpura 16 years after HBV-related PAN; the condition was attributed to the radiotherapy that had been used to treat the cancer.
Among the total of 15 patients who developed cancers, 7 received CS plus CYC, and 8 received CS alone. One of the 2 lymphoma patients received CYC.
Forty-one patients died as a consequence of their vasculitis or its treatment: 22 died of uncontrolled vasculitis, 11 of treatment side effects (sepsis), 6 of early sudden death, and 2 of sequelae of cardiomyopathy, representing 14.7% of the total population and 48.2% of all the deaths (Table 3). Eighteen of the 22 patients who died of uncontrolled vasculitis had poor prognostic factors. The mean followup of this group was 39 ± 17.4 months. Thirty (73.2%) of the 41 deaths due to the disease or its consequences occurred during the first 18 months after starting treatment.
Table 3. Patient characteristics and vasculitis scores, according to outcome*
|Parameter||Study population (n = 278)||Survivors (n = 193)||Deaths|
|Overall (n = 85)||Uncontrolled vasculitis (n = 22)||Sepsis (n = 11)|
|Age, years||53.6 ± 15.5||51.3 ± 15.3||58.9 ± 13.6||52.1 ± 16.2||63.5 ± 9.2|
|FFS||1 ± 1.1||0.9 ± 1||1.3 ± 1.2||2.3 ± 1.3||1.5 ± 1.1|
|BVAS||19.1 ± 7.7||17.9 ± 7.5||21.9 ± 7.6||25.2 ± 9.2||22.1 ± 6.3|
|Followup, months||88.5 ± 51.7||106 ± 42.5||49 ± 42.5||26.6 ± 40.4||17.9†|
Influence of treatment. Survival was comparable for the 215 patients receiving either CS or CS plus CYC (Figure 5). When these patients were stratified according to FFS, those with scores ≥2 who received CYC (n = 91) benefited from significantly prolonged survival (P = 0.044). No difference was observed between the overall population and those with an FFS score of 0 or 1 (P = 0.46 and P = 0.31, respectively). Stratification according to the BVAS failed to reveal a difference in survival. Nevertheless, among the 25 patients for whom the BVAS was >30, a tendency toward significance was observed in favor of CYC (P = 0.069). Fifteen of the 22 patients who died of severe vasculitis had been treated with CS alone.
Figure 5. Survival of patients with vasculitis (Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa without hepatitis B virus markers; n = 215) as a function of treatment with corticosteroids (CS) versus CS plus cyclophosphamide (CYC) as first-line therapy (P not significant).
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Treatment side effects. Only moderate and severe side effects were recorded; mild side effects were not taken into account because they were not always reported. One hundred seventy-five treatment side effects (Table 4) were reported in 93 of the 278 patients; 79 of the 93 patients (84.9%) had received CYC. The distribution of side effects among the protocols and forms of diseases were as follows: 41% in protocol 1, 9.8% in protocol 2, 64.2% in protocol 3, and none in protocol 4 (only mild effects due to antiviral agents); 37.5% of the CSS patients, 58.6% of MPA, 29% of non–HBV-related PAN, and 7.9% of HBV-related PAN. Among the 185 patients who did not experience side effects, only 53 (28.6%) had received CYC (P < 0.0001). The mean ± SD ages of the patients with and without side effects were, respectively, 56.5 ± 12.7 years and 52.4 ± 15.5 years.
Table 4. Distribution of side effects as a function of treatment with CS with and without CYC*
|Side effect||No. of events (n = 175)||No. of patients with side effects|
|Total (n = 93)||No. taking CYC (n = 79)|
| Bacterial pneumonia||8|
| Acute bronchitis||6|
| Pneumocystis carinii pneumonia||1|
| Urinary tract infections||2|
| Herpes zoster infections||5|
| Osteomyelitis, arthritis||2|
| Aspergillosis, candidiasis, cryptococcosis||5|
Infectious diseases and osteoporotic fractures were the 2 major events, respectively, in 13.3% and 8.6% of the entire study population. In protocol 3, in which all patients received CS and CYC, infections occurred in 28.6% (mean ± SD age 61.8 ± 10 years), and osteoporotic fractures occurred in 19% of the whole group and in 35% of the women in the group. The 11 patients who died of sepsis had taken CYC (6 oral doses and 5 intravenous pulse doses) and were older than the other patients in the series (63.5 years versus 53.6 years). Side effects were observed in 59% of patients receiving oral CYC and in 62% of those receiving pulse doses.
Sequelae were noted in 58 patients. The main sequelae were end-stage renal failure necessitating hemodialysis (n = 8; 2 of whom subsequently received renal allografts), moderate renal insufficiency (n = 7), peripheral neuropathy (n = 10), congestive heart failure (n = 5), hypertension (n = 4), chronic respiratory disease (n = 5), hemiplegia (n = 1), visual impairment (n = 1), amputation (n = 2), marked weight gain (n = 2), pain from vertebral fractures (n = 11), and inability to get out of bed (n = 2).
- Top of page
- PATIENTS AND METHODS
Several studies (6–12) have demonstrated an overall improvement in the prognosis of vasculitis and, recently, scores predicting the prognosis have been devised (19). However, to date, the impact of therapeutic strategies on subgroups of vasculitides according to the prognostic factors and the occurrence of long-term side effects has not been evaluated. We demonstrated in the present study that the overall mortality was significantly higher than that observed in the general population of France, despite the improvement in treatments. Deaths usually occurred early, within the first 18 months of followup. Later, survival curves tended to be parallel despite the occurrence of late relapses. Survival reflected the initial disease severity (Figures 2A and B), and in our opinion prognostic scores should be used in clinical trials to guide the initial treatment choice as a function of disease severity in the individual patient.
We observed a few discrepancies between the BVAS and the FFS. Although the scores were correlated (r = 0.69), for CSS the BVAS (20) overestimated the disease severity (Table 1) as a consequence of the points attributed to ENT involvement and chest involvement, despite the fact that neither maxillary sinusitis nor asthma has ever been demonstrated to be a factor of poor prognosis in CSS (19). Based on these data, the FFS was easier to use and better adapted for comparing the initial severity of the different types of vasculitides. However, the BVAS is a more precise measurement of the dissemination of the disease and could be used to evaluate followup (21), which is not the case for the FFS. The 2 scores are therefore complementary and are useful for decision-making and treatment followup.
Figure 6. Survival of patients with vasculitis (Churg-Strauss syndrome, microscopic polyangiitis, and polyarteritis nodosa without hepatitis B virus markers and Five-Factors Scores [FFS] of ≥2; n = 91) as a function of treatment with corticosteroids (CS) versus CS plus cyclophosphamide (CYC) as first-line therapy (P = 0.044).
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In our opinion, deaths due to vasculitis or its complications did not reflect the type of vasculitis but, rather, the extent of organ involvement, e.g., kidney, GI tract, or heart, or the patient's age at the time of diagnosis (in terms of treatment-related sepsis). The increased, but not significant, number of late deaths of MPA patients was partly due to more severe disease (with kidney involvement in nearly all patients), to their tendency to relapse more frequently (and thus require more treatments, which are potentially responsible for a higher number of side effects), and to their older age at study entry. Considering the entire cohort of patients, we did not observe that patients receiving CS plus CYC had better outcomes. Careful analysis of survival stratified according to prognostic factors showed that CS plus CYC significantly prolonged the survival of the more severely ill patients, who had FFS scores ≥2 (P = 0.044). A tendency toward prolonged survival was also observed for patients who received CYC and had BVAS scores >30.
Also, 15 patients taking CS alone died of uncontrolled disease. We found that CYC in combination with CS did not prevent the occurrence of the first relapse, which seemed more often to be related to the type of vasculitis and its spontaneous tendency to relapse than to the first-line therapy prescribed. Nevertheless, only patients who were being treated with CS alone had uncontrolled disease.
The causes of death in a previous French cohort of 149 patients (for the years 1958–1983) (4) were nearly identical to those seen in the present group, except for sepsis, which was lower in the present study (26.5% versus 12.9%, respectively), and can be attributed to the improved management of infections.
Side effects were frequent, being reported in at least 33.5% of the patients. Infectious events were strongly associated with the combination of CS and CYC, were more frequent in patients older than 65 years, and were responsible for 11 deaths. The increased frequency of infections in patients taking the combination of CS and CYC has previously been reported (2, 28). In a few of our patients, the vasculitis was controlled by this combination, but the treatment was responsible for infection-related deaths. Although no difference was observed between oral and pulse administration of CYC, hematuria was predominantly observed with the oral form (6 of 7 cases).
Despite recommendations to prescribe calcium and vitamin D supplements to all patients, we observed a high frequency of osteoporotic fractures, higher than that which would be expected in the general population of France (annual incidence of femoral fractures 170/100,000 females, 62/100,000 males; no data concerning vertebral fractures are available) (29). Bone demineralization can be explained by the prolonged and high-dose CS regimen given in these prospective trials, the mean age of the patients at the time of diagnosis, and the high number of menopausal women without hormone replacement therapy and/or women with CYC-induced amenorrhea. Indeed, a lower CS dose, close to that used in National Institutes of Health and European trials (30), is prescribed in the ongoing trials in an attempt to lower the frequency of osteoporosis. We also recommend preventing osteoporosis in different manners: hormone replacement therapy for menopausal women, and/or calcium, vitamin D, and bisphosphonates.
In our patients, malignancies were not clearly attributable to CYC, except for 1 case of bladder cancer. Those who developed cancer were older at the time of the diagnosis of vasculitis, the mean interval between the two diagnoses was rather long, and 5 of them had risk factors (smokers and/or heavy drinkers). Comparison of the frequencies of cancers in this series with those of the general population is difficult because there is no exhaustive registry of cancers in France. They are recorded in some districts of France and extrapolated to the entire population (31). Nevertheless, the incidence of lymphomas was higher than that of the general population.
It has been reported that, in Wegener's granulomatosis, long-term treatment with CYC was the cause of a dramatically increased number of bladder cancers, with a long latency period between the first exposure and the diagnosis of cancer (32–35). The presence of microscopic hematuria is an independent risk factor for the development of cancer. Although the total CYC dose and the duration of therapy were not clearly associated with the development of cancers, most of them occurred in patients who had received a cumulative dose that exceeded 100 gm (32). In our patients, the duration of CYC treatment did not exceed 12 months, and, since 1987, pulses have been predominantly prescribed, thereby lowering the total dose, with the systematic use of hydration and mesna. The relatively short duration of CYC therapy compared with that in Wegener's granulomatosis and the use of pulses to lower the total CYC dose could explain the low number of bladder cancers observed in our patients.
Based on the results of these studies, our group has undertaken new trials that aim to specify the indications for CYC and other immunosuppressive agents and to lower the CYC dose in patients with severe vasculitis. We also intend to establish a strategy adapted to the type of vasculitis, its severity, and its predicted (according to the FFS) outcome.
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- PATIENTS AND METHODS
This research was conducted with the help of The Société Nationale Française de Médecine Interne (SNFMI). The following investigators participated in the study: M. Alcalay and P. Roblot (Poitiers); P. Amarenco, J. Cabane, P. Cacoub, J. Cadranel, B. Christoforov, P. Deblois, G. Deray, P. Druet, P. Even, M. Gayraud, P. Godeau, M. Krulik, F. Lioté, D. Molle, P. Pasquier, J. C. Piette, J. M. Visy, B. Wechsler, and J. M. Ziza (Paris); K. S. Ang, G. Dien, and P. Simon (St. Brieuc); P. Arlet, P. Bayle, P. Carles, O. Pourrat, and S. Ollier (Toulouse); P. Babinet and F. Lhote (St. Denis); J. Baillet, J. P. Ducroix, A. Fournier, R. Madkassi and S. Smaïl (Amiens); G. Baralis (Arles); J. Barrier and J. Y. Grolleau (Nantes); P. Bironne and J. Glowinski (Gonesse); J. P. Bouchon (Ivry); E. Bercoff, O. Deshayes, B. Desrumeaux, X. Le Loët, and B. Pinel (Rouen); P. Canton and M. Maignan (Nancy); J. P. Cassuto, P. Dujardin, J. G. Fuzibet and J. F. Quaranta (Nice); B. Coevoet (St. Quentin); P. Casassus, P. Cohen, D. Daupleix, P. Dreyfus, L. Guillevin, B. Jarrousse, P. Le Toumelin, and J. N. Hugues (Bobigny); G. Desproges-Gotteron, F. Liozon, R. Treves, and E. Vidal (Limoges); J. F. Desson (Caen); P. Doumovo (Eaubonne); Y. Echard (Montfermeil); A. Fischer (Evry); J. L. Debru, A. Franco, B. Imbert, and P. Micoud (Grenoble); B. Godeau, A. Schaeffer, J. C. Roujeau, and A. Sobel (Créteil); G. Janin (Mâcon); J. Jouquan (Brest); M. Kerjean (St. Malo); M. Imler (Strasbourg); S. Lassoued (Cahors); J. Mallecourt (Dreux); J. Maupetit (Libourne); O. Maurisset (La Roche-sur-Yon); P. Mornet (St. Germain-en-Laye); M. Mougeot Martin (Creil); J. Ninet, J. Pasquier, C. Trépo, and D. Vital-Durand (Lyon); O. Patey (Villeneuve St. Georges); A. M. Piette (Suresnes); M. Pointud (Montluçon); F. Rossi (Vendôme); H. Rousset (St. Etienne); M. Ruel (Senlis); M. Sigal Nahum (Argenteuil); and P. Veyssier (Compiègne). The coordinating center is at the Department of Internal Medicine, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris-Nord, Bobigny, France.