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Deaths Occurring During the First Year After Treatment Onset for Polyarteritis Nodosa, Microscopic Polyangiitis, and Churg-Strauss Syndrome

A Retrospective Analysis of Causes and Factors Predictive of Mortality Based on 595 Patients

Bourgarit, Anne MD; Toumelin, Philippe Le MD; Pagnoux, Christian MD; Cohen, Pascal MD; Mahr, Alfred MD; Guern, Véronique Le MD; Mouthon, Luc MD, PhD; Guillevin, Loïc MD for the French Vasculitis Study Group

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doi: 10.1097/01.md.0000180793.80212.17
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Abstract

INTRODUCTION

The prognoses of systemic necrotizing vasculitides have improved since the introduction of corticosteroids and immunosuppressants, mainly cyclophosphamide, to treat noninfectious vasculitis, and the combination of antiviral agents and plasma exchanges (PE) following short-term steroids for patients with hepatitis B virus-associated polyarteritis nodosa (HBV-PAN). The published 7-year survival rate is 79% for PAN, and the 5-year survival rates are 74% for microscopic polyangiitis (MPA) and 75% for Churg-Strauss syndrome (CSS)9. However, regardless of the treatment prescribed, some patients continue to have fulminating disease and die within the first days or months after diagnosis or starting therapy. We conducted the current study to identify factors predictive of early death and to analyze the responsibility of the vasculitis and/or treatment side effects in its occurrence.

This study was based on patients followed by members of the French Vasculitis Study Group. (See the article in this same issue by Guillevin et al18a for a report of the clinical characteristics of 115 patients with HBV-PAN from the French Vasculitis Study Group.)

PATIENTS AND METHODS

Patients and Treatment

Five hundred ninety-five patients were included in this retrospective analysis. Four hundred twenty-seven of them had participated in prospective, consecutive, multicenter therapeutic trials between 1981 and 1999. The other 168 were followed in our Department of Internal Medicine but had not been enrolled in prospective trials. These trials have previously been described in detail8,11,13-16,18 and are briefly summarized below.

Protocol 1: For 68 patients with PAN with or without HBV markers, MPA, or CSS (August 1980-December 1983)14, steroids and PE were prescribed, and 31 of them were subsequently randomized to receive cyclophosphamide (2 mg/kg per day) for 1 year.

Protocol 2: For 71 patients with non-HBV PAN, MPA, or CSS (December 1983-December 1988)13, steroids were prescribed for every patient and PE were randomized (a mean of 11 PE for each patient, 32 patients).

Protocol 3: Patients with non-HBV PAN, MPA, or CSS (January 1989-August 1993) were divided into 2 subgroups: 62 patients with factors of poor prognosis (five-factor score [FFS] ≥1; see below) were treated with steroids and a monthly pulse of cyclophosphamide for 1 year and, after randomization, 34 received 9 PE (3/week)15. In the other subgroup, 25 patients with good prognostic factors (FFS = 0)8 were treated with steroids and, after randomization, received oral cyclophosphamide (n = 15) or a monthly pulse of cyclophosphamide (n = 10) for 1 year.

Protocol 4: For 47 patients with HBV-PAN (beginning in 1983)16, treatment combined 2 weeks of steroids followed by an antiviral agent-vidarabine (n = 39) until 1987, then interferon-α (n = 8)-and PE. In the case of relapse, treatment was adapted to the severity of the symptoms: steroids, cyclophosphamide, or other immunosuppressive agents.

Protocol 5: For 82 patients with non-HBV PAN, MPA, or CSS (beginning in 1994) of good prognosis (FFS = 0), steroids were given alone until relapse and then patients were randomized to receive azathioprine or intravenous (IV) cyclophosphamide.

Protocol 6: For 72 patients with CSS or non-HBV PAN (beginning in 1994) with criteria of poor prognosis (FFS ≥1), treatment with IV steroids, then oral steroids combined with pulse cyclophosphamide, with patients being randomized to receive either 6 or 12 IV pulses11.

The steroid regimen in Protocols 1, 2, and 3 was the same. Prednisone was prescribed at a dose of 1 mg/kg per day for 1 month, decreased by 2.5 mg every 10 days for 1 month, then decreased by 2.5 mg each week until a level equal to half the initial dose was reached. This dose was maintained for 3 weeks, then further decreased by 2.5 mg every week until 20 mg/d, and finally decreased by 1 mg every week. In Protocol 4, steroids were given at the dose of 1 mg/kg per day during the first week and then rapidly tapered until stopped at the end of the second week. In Protocols 5 and 6, patients received a daily steroid pulse (15 mg/kg) for 3 days, then oral steroids (1 mg/kg per day) for 3 weeks; afterwards, the dose was tapered by 5 mg every 10 days until half the initial dose was reached, then diminished by 2.5 mg every 10 days until 15 mg/d; finally, it was lowered by 1 mg every 10 days until complete withdrawal.

Patients' data were recorded in a computerized database and analyzed retrospectively for those who died within the first year following diagnosis.

Because the vasculitides had been classified according to the classification of Fauci et al4 in Protocols 1-3, diagnoses for this analysis were revised, independently of therapeutic trials, and patients were classified according to the Chapel Hill nomenclature for PAN and MPA20. All diagnoses also satisfied the American College of Rheumatology criteria for PAN23 and CSS25.

We compared data for the patients who died during the first year following treatment onset and those who survived the first year. The definition of early death was chosen arbitrarily, according to notions found in literature2,3,9,26 and because both groups of patients were treated similarly during this initial phase of therapy.

We included the 3 vasculitides-PAN, MPA, and CSS-because they have already been shown to have the same 10-year survival rate9 and the regimens prescribed for the first months of therapy were almost the same.

Methods

For each patient, the following data were recorded: clinical features, laboratory and immunologic parameters at the time of diagnosis, outcome, treatment, and cause of death. A weight-loss ratio was calculated as the initial weight loss claimed by the patient divided by weight at diagnosis. Renal involvement consisted of renal insufficiency, proteinuria, and/or hematuria.

Two assessment scores were applied. The FFS17, which is a marker of prognosis, comprises the following items: serum creatinine ≥140 μmol/L, proteinuria (≥1 g/d), presence of severe gastrointestinal (GI) tract involvement (defined as bleeding, perforation, infarction, and/or pancreatitis but not appendicitis or cholecystitis), cardiomyopathy (infarction or cardiac insufficiency), and central nervous system (CNS) involvement; the presence of each factor is accorded 1 point.

We also retrospectively applied the Birmingham Vasculitis Activity Score (BVAS)24 in its first presentation at baseline to test its ability to predict prognosis and compare it with FFS. BVAS is a clinical index of disease activity based on symptoms and signs in 9 separate organ categories (systemic signs, skin, mucous membranes and eyes, ear-nose-throat, chest, heart and vessels, GI, kidney, nervous system). Maximum points were accorded to each category; the maximum possible score is 63. Disease features are only considered when they are attributable to active vasculitis.

Response to treatment was recorded in detail for the first-year nonsurvivors and classified as improvement, worsening after beginning treatment, or new events. The latter comprised new flares occurring after initial improvement, treatment side effects, or intercurrent events such as infection, hemorrhage, etc.

The causes of death were classified into 3 different subgroups: vasculitis-related, treatment side effects, and miscellaneous. Only 15 (25%) first-year nonsurvivors had autopsies; for the 45 others, we retained the last event before death as its cause.

Statistical Analysis

Statistical analyses were conducted using SAS v. 8.2 (SAS Institute Inc, Cary, NC). The baseline characteristics of the study patients are expressed as numbers and percentages for categorical variables and as means ± standard deviations (SD) for continuous variables. For univariate analysis, the chi-square and Fisher exact tests were used for categorical variables, and the Student t-test was used for continuous variables. Analysis of variance was performed for multiple comparisons of means with Bonferroni t-test corrections27. Patient survival was assessed by life-table analysis using the Kaplan-Meier method21. Survival time was calculated from the date of treatment onset and ended at the date of censoring or the time of death. All survival curves were constructed according to the Kaplan-Meier method and were compared using the log-rank test. All parameters found to be significantly associated based on our univariate analysis were entered into the multivariate Cox proportional hazards model using SAS Proc PHREG to search for the independent predictors of first-year survival. Results are reported as hazard ratio (HR) and 95% confidence intervals (95% CI). For all statistical analyses, p < 0.05 was considered significant.

RESULTS

Demographics

Between 1953 and 1999, 60/595 (10%) patients with vasculitis died during the first year following treatment onset. Their mean age was 57.5 ± 17.6 years compared with 51.6 ± 16.2 years for first-year survivors. Their respective male-to-female sex ratios were 34:26 (1.31) and 318:217 (1.47) (not significant [NS]). Age and weight-loss ratio at diagnosis were significantly higher (p < 0.05) for first-year nonsurvivors.

Among patients who died during the first year, 38 had PAN, 20 of whom had HBV markers; 13 had MPA; and 9 had CSS. Among first-year survivors, 271 had PAN, 89 of them with HBV infection; 140 had MPA; and 124 had CSS. The distribution of vasculitides differed between groups, with more CSS and fewer HBV-PAN in the group of first-year survivors (p < 0.005). At the time of diagnosis, signs of vasculitis had been present for 128.3 ± 139 days (mean ± SD) in first-year nonsurvivors compared with 220.6 ± 785 days in survivors (NS). Median survival for first-year nonsurvivors was 95 days (range, 4-294 d) and 1,887 days (range, 449-10,281 d) for first-year survivors who subsequently died. Figure 1 and Table 1 show the overall survival rates of patients and their outcomes according to the period of treatment onset. The survival curves show the dramatic improvement of survival since 1990 but, pertinently, the percentages of early deaths have remained unchanged over the decades.

F1-7
FIGURE 1:
Overall survival rates of patients according to the period of treatment onset.
T1-7
TABLE 1:
Mortality, Expressed as n (%), Observed Among 595 Patients According to the Time of Treatment Onset*

Clinical Findings

The clinical findings are summarized in Tables 2 and 3. Cardiovascular involvement (cardiomyopathy and/or cardiovascular disease), renal insufficiency, severe GI tract involvement, or CNS involvement, as defined in the FFS, were more frequent (p < 0.005) in patients who died early than in survivors.

T2-7
TABLE 2:
Clinical Characteristics at the Time of Vasculitis Diagnosis for the 595 Patients*
T3-7
TABLE 3:
Main Clinical Findings at Diagnosis for the Different Vasculitides as a Function of First-Year Death or Survival*

Considering visceral involvement, some differences were observed between early nonsurvivors and survivors, and as a function of the vasculitis (see Table 3). For CSS patients, cardiac involvement and GI involvement were significantly more frequent in first-year nonsurvivors (p < 0.005), as was renal insufficiency in patients diagnosed with MPA (p < 0.005). All the FFS parameters were more frequent in first-year nonsurvivors with non-HBV PAN, while GI and CNS involvement were more frequent in nonsurvivors with HBV-PAN.

Prognostic Factors

The BVAS at baseline was significantly higher for first-year nonsurvivors than for survivors (p < 0.005) (see Table 2). At diagnosis, 25 (42%) first-year nonsurvivors had FFS ≤1 and 10 (16%) of them had FFS = 0 compared with 407 (76%) first-year survivors with FFS ≤1 and 250 (47%) with FFS = 0 (p < 0.005).

No significant differences were found between the clinical findings or BVAS at diagnosis for the 10 early fatalities (16 ± 6) and first-year survivors (14 ± 6) with FFS = 0. For this subgroup of 10 early deaths, we also calculated BVAS at the time of death: it had increased dramatically to 22 ± 10, which made it significantly higher than the BVAS for first-year survivors (p < 0.0001).

The factors tested by univariate analysis are listed in Table 2. Cox multivariate analysis retained the following factors as being independently associated with early death: age at diagnosis (HR, 1.04; 95% CI, 1.02-1.05) and the clinical manifestations included in the FFS (HR, 1.6, 95% CI, 1.3-1.7).

The multivariate analysis for survival showed that, for CSS patients, cardiomyopathy was an independent factor associated with early death (HR, 3.39; 95% CI, 1.6-7.3), as was renal insufficiency in MPA (HR, 3.69; 95% CI, 1.006-13.4) and cardiac (HR, 2.47; 95% CI, 1.3-4.8) and CNS involvement (HR, 3.4; 95% CI, 1.4-8.2) in non-HBV PAN. For patients with HBV-PAN, cardiomyopathy (HR, 3.54; 95% CI, 1.2-10.7) and CNS involvement (HR, 6.7; 95% CI, 2.9-15.5) were retained as independent factors predictive of early death, but GI tract involvement was not.

Treatment and Outcome

The distribution of patients among the different therapeutic protocols is given in Table 4. Because each protocol usually had 2 arms, we compared the patients according to the treatment scheme in Table 5. The percentages of patients assigned to receive each treatment were comparable for first-year survivors and nonsurvivors (see Tables 4 and 5), except for antiviral therapy, which was prescribed more frequently for first-year nonsurvivors because of the higher percentage of HBV-PAN patients who died. Concerning HBV-PAN, 14% (9/66) of the patients treated with short-term steroids followed by antiviral agents and PE died during the first year compared with 26% (11/43) of the patients treated with steroids with or without immunosuppressants (NS).

T4-7
TABLE 4:
Distribution of First-Year Nonsurvivors and Survivors as a Function of Treatment Protocol*
T5-7
TABLE 5:
Comparison of Treatment Regimens for First-Year Nonsurvivors and Survivors*

Early deaths of patients with FFS ≥2 were more frequent (p < 0.05) when steroids were prescribed alone.

Among the first-year nonsurvivors, 23 (38%) initially improved; the 37 (62%) others deteriorated despite therapy. A new flare, intercurrent infection, or treatment side effects (diabetes, hematuria, and/or hypokalemia) occurred, respectively, in 17, 3, and 3 patients who had initially improved, with a mean time from treatment onset of 66 days. The initial responses to treatment according to the type of vasculitis are detailed in Table 6. First-line treatment was modified for 41/60 patients because of inefficacy: the immunosuppressant dose was increased for 15/41 (37%) patients and tapered or withdrawn for 13/41 (32%). Six patients suffered major side effects: pancytopenia (n = 2), hemorrhagic cystitis (n = 1), GI perforation under steroids (n = 2), fulminant hepatitis while on PE with antiviral treatment (n = 2). Anti-infectious agents and/or surgery were prescribed for 10 (24%) and 11 (27%) of these 41 patients, respectively.

T6-7
TABLE 6:
Response to Treatment According to the Vasculitis Diagnosed for Patients Who Died During the First Year*

Among non-HBV PAN patients, the 4 (22%) who initially improved developed flares 5, 6, 54, and 59 days, respectively, after starting treatment (mean, 31 ± 29 d). For MPA patients, 8 (62%) of the 13 initially improved, but all of them developed flares at a mean of 62 ± 29 days after treatment onset. The time to a new event differed significantly between these 2 vasculitides (p < 0.05). Eleven (85%) of these MPA patients needed treatment modification: adjunction of antibiotics for 4 (36%), GI tract surgery for 2, associated or not with intensification of immunosuppression (n = 3) or treatment withdrawal (n = 4).

Causes of Death

The causes of the 60 early deaths are reported in Table 7. These deaths were predominantly vasculitis-related, explaining 33/57 (58%) of them and comprised the following: septic shock complicating GI perforation or digestive bleeding for 16, hepatic vasculitis for 3 (2 with HBV-PAN-related fulminant hepatitis and 1 with intrahepatic aneurysm rupture), acute cardiac insufficiency or myocardial infarct for 4, intraalveolar hemorrhage for 1, CNS vasculitis for 4, and multivisceral involvement for 5. Among the 15 autopsies performed, 9 attributed death to vasculitis; for the remaining 45 deaths, the last event was retained as the cause.

T7-7
TABLE 7:
Causes of Death of First-Year Nonsurvivors and Survivors Who Subsequently Died*

Treatment side effects were responsible for 15/57 (26%) of the early deaths attributed to infection: pulmonary for 6, septicemia for 7, and CNS infection for 2. Two of these 15 patients were neutropenic <500/mm3 or pancytopenic at the time of death. Nine of the first-year nonsurvivors died from miscellaneous causes: 1 CSS patient died of fulminant hepatocarcinoma, probably not related to the vasculitis or its treatment; 2 patients had pulmonary emboli; 3 died sudden deaths; 1 had a fatal acute myocardial infarction with no known cardiac involvement of vasculitis; 1 developed cerebral deep vein thrombosis; and 1 had end-stage cirrhosis.

The duration of survival of patients who died during the first year varied as a function of the vasculitis diagnosed: shorter for patients with non-HBV PAN and HBV-PAN than for patients with MPA and CSS: 71 and 103 days compared with 118 and 136 days, respectively (p < 0.05 between non-HBV PAN and MPA).

Most first-year nonsurvivors with non-HBV PAN, HBV-PAN, or CSS died of vasculitis (66%, 70%, and 66% of the deaths, respectively): diffuse vasculitis for patients with non-HBV PAN, GI vasculitis for those with HBV-PAN, and cardiac vasculitis for patients with CSS. In contrast, MPA patients died predominantly of infections (8/13, 62%).

For first-year survivors who subsequently died, the causes were active vasculitis for 26/70 (37%) and malignancies for 17/70 (24%): lung (n = 6), prostate (n = 2), ear-nose-throat (n = 2), lymphoma (n = 2), GI (n = 1), stomach (n = 1), unknown primary (n = 2) or hepatocarcinoma (n = 2). Miscellaneous causes of deaths, including sequelae of the vasculitis, were more frequent (56%) than active vasculitis (see Table 7).

DISCUSSION

Despite the overall improvement of the prognoses for systemic vasculitides, early death remains a concern, and the characteristics of the patients with early poor prognoses deserve to be analyzed. Frohnert and Sheps7 showed that only 13% of untreated PAN patients survived, but 48% of those who received steroids were still alive at 5 years. Leib et al22 showed that combining immunosuppressants with steroids further improved the prognosis and that 80% of the treated patients were alive at 5 years. In 1980, when Cohen et al3 studied the influence of clinical factors and treatment on prognosis, the 5-year survival rate was 55%, and GI and renal involvement affected prognosis most adversely. But unlike the results of Leib et al22, the outcome was the same for both groups. Early deaths were usually due to complications directly related to the vasculitis, and late deaths were often due to CNS or cardiovascular involvement3.

The prognosis of systemic vasculitides improved when immunosuppressants were prescribed in combination with steroids5 for patients who were not controlled with steroids alone. However, adjunction of immunosuppressants was not able to prevent early death of patients with vasculitides of the so-called PAN group4.

The prospective trials organized by the French Vasculitis Study Group showed that the outcome of vasculitides had improved13-16,18 but also that immunosuppressant use should be modulated according to the type of vasculitis and its prognostic factors17, and that only the most severely ill patients benefited over the long term from the combination of steroids and immunosuppressants9.

The rates of early death of PAN, MPA, and CSS patients have remained stable, and we attempted to identify symptoms predictive of early death and treatment potentially able to prevent it. The time defining early death was chosen arbitrarily as 1 year, but the median survival of first-year nonsurvivors was only 3 months, indicating that therapeutic efforts should focus on this period. Unfortunately, because clinical symptoms at diagnosis were the same for first-year nonsurvivors and survivors, we were unable to identify any specific characteristics of the patients who died early, and thus were unable to select a subpopulation of patients who should be treated differently to prevent a fatal outcome, except for the HBV-infected patients who had been treated before the etiology-adapted antiviral strategy had been devised. Although pooling 3 different vasculitides that have heterogeneous features could limit the sensitivity of this analysis, it was necessary because of the small numbers of patients with these uncommon diseases.

Patient's age was the only factor associated with early death in addition to the parameters comprising the FFS17. Weight-loss ratio was prognostic for early death in our univariate analysis but was not retained by multivariate analysis. Although FFS was able, in different patient cohorts, to predict the overall prognosis9, and BVAS paralleled the decline of patients with active vasculitis19, neither score was predictive of early death. Indeed, not all patients who died early had FFS ≥2. Our search for specific factors predictive of early death was unfruitful, except for GI involvement, which alone is strongly associated with early mortality.

Factors associated with early mortality differed among the different vasculitides. We observed that each of the vasculitides studied had specific clinical manifestations associated with early death. Cardiovascular involvement was a major cause of death of CSS patients6,10 and we demonstrated here that it occurred mainly within the first few months following diagnosis. Cardiac involvement was the cause of early death but, after disease recovery, its sequelae could sometimes be responsible10. The same can be said for renal insufficiency in MPA patients1,12,26. GI involvement was a predominant cause of death of HBV-PAN patients16, but was not retained as an independent factor of early death in this study.

Patients who died early had received the same treatment as first-year survivors but, sometimes, treatment was not adapted to the vasculitis etiology. This could explain why a higher percentage (26%) of HBV-PAN patients who had been treated with steroids and immunosuppressants died, but not significantly, than of those given the antiviral regimen (14%). A treatment poorly adapted to disease severity9 or generating side effects can cause death, but not necessarily early death. Pertinently, we also observed that survival was shorter after starting therapy for non-HBV PAN and HBV-PAN patients than for MPA and CSS patients. We previously found9 that the most severely ill patients (FFS ≥2) who received steroids alone had a higher overall mortality rate (60% vs 35%).

Notably, the causes of death differed significantly between first-year nonsurvivors and survivors: the former mainly died from active vasculitis, whereas the latter succumbed to vasculitis (uncontrolled disease and flares) but also died from chronic complications or malignancies. This finding confirmed the relationship between the time of death and vasculitis activity2. The second cause of early death was infection (27 patients), but 12 of these patients also had active vasculitis at the time of death. Septic shock as a consequence of GI perforation was a major cause of death. The types of infections did not differ from those described previously2. Two of these 27 patients had cyclophosphamide-induced cytopenia. Even if, according to our univariate analysis, deaths were not significantly associated with treatment and the intensity of immunosuppression, patients may have been victims of iatrogenic complications.

The mortality rate has declined since the 1990s; this can be attributed to improved supportive care and treatment adapted to disease severity. However, the early death rate has not changed since our first prospective trial in 1980, and therapeutic strategies are needed to improve early outcome. This task remains difficult despite the accuracy of assessment scores, which help guide treatment choice but are not predictive of early death for patients with severe vasculitis.

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