SNV are a heterogeneous group of diseases. Despite some shared characteristics, their differences have been clearly identified since classification systems and testing for antineutrophil cytoplasmic antibodies (ANCA) have become available. Notably, the outcome and prognosis of each of the SNV can be different. In the past, treatments were applied in a uniform manner, regardless of the vasculitis diagnosed. The results of therapeutic trials12,15,33 showed that outcomes and prognoses vary among the 4 SNV groups.
In addition to those variable outcomes, disease severity also has proven therapeutic implications. Several scores have been designed and used in prospective trials,27,36 mainly to follow the impact of treatment on the disease course. Establishing a uniform score for vasculitis assessment is not easy, and that was the BVAS objective. That score has been mainly studied in ANCA-associated vasculitides but needs to be validated for other groups of vasculitides. A universal assessment system was the OMERACT goal30 but it too focuses mainly on ANCA-associated vasculitides and has to be extended to other vasculitides.
The 2009 FFS was calculated for those 3 SNV and, for the first time, WG was also included. Moreover, this new prognostic score has been validated on a larger patient population. Because vasculitis treatment regimens have become more effective, thereby improving outcomes, mortality decreased from 1953 to 2005. However, because only 33 patients were included during the cohort's first period (1953-1974), their impact on overall mortality and identification of prognostic factors was diluted in the >1000+ patients added since then. But it must be kept in mind that all 1108 patients included in this analysis received the best treatment available at the time of diagnosis, and that corticosteroids and immunosuppressants were already being prescribed in the 1970s. Moreover, the 50% mortality rate in the earliest period was not too bad for that era. Today, we have improved regimens and better adapted supportive care that have limited adverse events.
The FFS takes into account only clinical symptoms present at the time of diagnosis. Symptom changes over time are also parameters that clinicians consider in making first-line treatment decisions or modifying ongoing regimens. But those aspects are beyond the scope of this study. The creation of an evolving prognostic parameter, by integrating the progressive kinetics of symptoms initially present, would surely be useful and could achieve another objective that has not been obtained to date, to our knowledge.
Results of FVSG prospective trials previously demonstrated the therapeutic impact of the 1996 FFS.3,9,35 In a retrospective study,8 we showed that the most severe forms of necrotizing PAN without HBV and CSS should be treated with combined steroids and cyclophosphamide. Conversely, our findings obtained in a prospective study35 indicated that patients without poor-prognosis factors could be treated initially with steroids alone, and that only a quarter of them required a cytotoxic agent to control their SNV. This use of the prognostic 1996 score to guide treatment changes is not valid for WG. Published results of therapeutic trials based on the impact of treatment stratification using the 1996 FFS would favor treatment adapted for patients with CSS, PAN, or MPA without poor-prognosis factors. Survival of patients initially treated with corticosteroids alone was excellent. However, subsequent relapses were frequent, and then about half of the patients required the adjunction of an immunosuppressant to control their disease.34 Therapeutic strategies based on prognostic factors will probably have to be adapted to some SNV and validated in other studies, also comparing the benefits/risks of the regimens prescribed.
The current revisitation analysis established the reliability of the 2009 FFS, compared to the 1996 version, despite the introduction and deletion of some items. When the 1996 FFS was applied to the present SNV population, no difference in the mortality rates was observed. Pertinently, the FFS is based on mortality and not on morbidity. Morbidity also has a major impact on outcome and quality of life, but it was not taken into account in the formulation of this score.
The cohort used to establish the score was amassed over several decades. During that time, treatments obviously changed and the general care of patients was certainly improved, which could have modified patients' general outcomes. Our objective was not to analyze the influence of treatments but to evaluate the impact of some clinical symptoms on mortality. Hogan et al14 evaluated the effect of cyclophosphamide on their patient cohort and found that odds ratios decreased when a cytotoxic agent was compared to steroids. A combination of steroids and another immunosuppressant is the optimal treatment for severe SNV. This combination needs to be assessed in patients with less severe SNV, as identified by prognostic scores, and ANCA-independent vasculitis in an attempt to achieve steroid-sparing. Because our analysis was made on a cohort of French patients, the 2009 FFS should be validated on other international cohorts to confer to this score a broader impact.
The 2009 FFS still comprises 5 factors and 5 points, but only 4 of them are associated with a poor prognosis (age, renal insufficiency, cardiac involvement, and gastrointestinal manifestations), each accorded +1 point, while the fifth factor, ENT manifestations, is associated with a better outcome, and their absence is scored +1 point. ENT symptoms should be a part of the FFS used only for patients with WG or CSS. ENT signs were also present in a minority of MPA patients, but their ENT involvement was usually minor and we did not consider it a significant marker of prognosis. The favorable impact of ENT manifestations on survival had been shown previously1 and could embody the different pathogenic mechanisms at work in WG, probably pleading in support of different WG phenotypes.22
Cardiac involvement, as in the 1996 FFS version, is still associated with a poor prognosis. Not surprisingly, it is more frequently present in CSS and it is the first cause of death for this SNV. One limitation is that the link between cardiac manifestations and vasculitis is indirect in some patients, based on the coexistence of both diseases and the absence of a cause other than vasculitis to explain the occurrence of cardiac manifestations.
The mortality rate was higher for patients with HBV-PAN than for PAN patients without HBV. However, the poor-prognosis factor, as defined by multivariable analysis, was not HBV itself, but rather some symptoms associated with poor prognosis, like those comprising the FFS.34,35 For HBV-PAN patients, they were renal insufficiency and gastrointestinal involvement, which are already FFS items.
Compared to the 1996 version, age is now included among the factors predictive of prognosis, reflecting the severity of vasculitis in the elderly;31 this probably argues for different therapeutic approaches, at least to limit the number and severity of infectious side effects. Steroids and cytotoxic drugs favor the occurrence of infections, as demonstrated by the results of several prospective trials,2,6,10,15 especially in the elderly,31 that explored different therapeutic strategies, for which infectious side effects are less frequent when drugs are prescribed at a lower cumulative dose or are switched rapidly from intensive induction to less aggressive maintenance therapy.
Among the items included in the 1996 and 2009 versions of FFS, we did not modify the definitions for gastrointestinal and cardiac involvements. Kidney manifestations counted for 2 points in the 1996 FFS, with proteinuria >1 g/d being considered but not microscopic hematuria. Those parameters were evaluated separately in this analysis and were not retained as being associated with a poor prognosis.
According to our multivariable analysis, only peak creatininemia was a prognostic factor, and it overwhelmed the other renal parameters. Proteinuria and microscopic hematuria, signs of glomerulonephritis, had little impact on prognosis, probably because its recognition implies treating the patient with steroids and immunosuppressants, and the therapeutic decisions are made early, before renal insufficiency can occur.
Few studies regrouping a large number of patients with alveolar hemorrhage have been published,18,23 and 1 was published several decades ago.13 When the patient was hospitalized in an intensive care unit because of alveolar hemorrhage, those investigations focused on the subgroup comprising the most severely ill patients. Even for this subgroup of patients, at higher risk of mortality, the outcome was better than would be expected for some authors20 and better management techniques improved prognosis.21
One of the major changes in the 2009 FFS is the absence of CNS involvement as a parameter of poor prognosis. We had arbitrarily introduced it into the 1996 FFS, considering its impact on prognosis, but its rarity prevented it from reaching statistical significance because of the small size effect. For the analysis of this larger cohort, we had decided not to include items that were not significantly associated with a poorer outcome in univariable analysis. That does not mean that CNS involvement is a benign manifestation. We confirmed that peripheral neuropathy has no effect on vital prognosis, even though its impact on function and quality of life is important.
We did not examine the impact of ANCA on prognosis, because some patients were diagnosed before the era of ANCA, and, hence, their antibodies were not systematically sought at the time of SNV diagnosis. However, Hogan et al14 found that a cytoplasmic versus perinuclear ANCA-labeling pattern increased the relative risk of mortality. In our study, mortality was higher for MPA patients than for those with WG, which is contradictory to the findings of Hogan et al,14 if we consider cytoplasmic and perinuclear labeling to correspond, respectively, to WG and MPA.
The 2009 FFS, one of the simplest scores for clinicians to use to predict the prognosis of their SNV patients, now needs to be validated as a tool to help clinicians make therapeutic choices. When the 1996 FFS was applied to therapeutic options, we showed that SNV patients with FFS = 0 could receive steroids alone as first-line treatment,35 and that those with PAN or CSS given first-line steroids and cyclophosphamide were overtreated.8 For WG, the combined immunosuppressant and steroid regimen is universally accepted, thus probably conferring less usefulness to the 2009 FFS for therapeutic choices. Pertinently, the new therapeutic strategies for the management of the 3 ANCA-associated SNV now being investigated could modify these dogmas in the near future. For SNV without poor-prognosis factors, the respective advantages and disadvantages of treating patients with steroids alone need to be reinvestigated in terms of morbidity and relapse prevention, even though our present results showed lower mortality when poor-prognosis factors were absent.
Although we have not yet tested the 2009 FFS on other vasculitides, it could probably be adapted to cryoglobulinemic vasculitis or Henoch-Schönlein purpura, but adaptation is unlikely for Takayasu arteritis, which has characteristics that differ markedly from those of ANCA-associated vasculitides.
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