Lung involvement at presentation predicts disease activity and permanent organ damage at 6, 12 and 24 months follow - up in ANCA - associated vasculitis

Antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening condition[1]. The introduction of immunosuppressive therapy has transformed this condition from an outcome of 80% mortality at one year to a survival of 55% and 75% in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) respectively at 10 years[2, 3]. Very active disease at presentation, continuous disease activity, relapse and drug toxicity may cause irreversible damage leading to considerable burden of disease. Therefore, studies to stratify prognostic indicators of AAV and identify high-risk subjects are crucial[4, 5].

Pulmonary involvement (PI) is a major characteristic feature of both GPA and Churg-Strauss syndrome (CS), but less common in MPA[6]. Diffuse alveolar hemorrhage (DAH) is one of the most severe pulmonary manifestations. The prognostic value of PI in AAV remains controversial. One study reported that DAH at presentation in MPA was associated with a relative risk (RR) of 8.65 for mortality[7]. Reinhold-Keller reported that PI was associated with a RR of 3.75 for mortality in GPA[8]. Another study showed that the early death risk was 15 times higher in subjects presenting with cough in GPA[9]. However, a more recent study concluded that DAH alone is not predictive of a poor prognosis[10]. Meanwhile, the revised Five-Factor Score (FFS), a score designed to predict survival concluded that ENT manifestations were associated with favorable outcomes in GPA[11].

Although survival rates have improved, disease activity and subsequent burden of disease remain important outcomes in assessing the overall well being of AAV individuals. The objective of this study was to determine the relationship between disease activity and damage in subjects presenting with PI and lung involvement (LI) using the Birmingham Vasculitis Activity Score v.3 (BVAS3) and Vasculitis Damage Index (VDI) respectively.

AAV represents a very heterogeneous group of diseases with disease-specific and overlapping clinical features[6]. Although current therapies have reduced the rate of mortality, the quality of life remains poor. Therefore, recent studies to identify high-risk clinical features have enhanced categorization of AAV using accurate stratification for future therapeutic, epidemiological and basic research[4, 13].

BVAS and VDI are clinical tools that may provide an accurate description of the current status of an individual patient in a standardized manner. Studies evaluating long-term prognosis and risk factors have reported organ-specific involvement as important indicators. GI involvement at initial presentation in subjects with CSS is associated with a high rate of relapse whilst the presences of renal disease and pANCA positivity are associated with lower rate of relapse[14]. Damage has been a major concern with regard to patient outcome in AAV. Since 1997, the VDI has been the only validated tool for damage in AAV[15].

The role of LI at initial presentation remains controversial[13]. A recent study with 80 subjects presenting with DAH in AAV showed that AAV was not associated with increased deaths compared to renal insufficiency[10]. In addition, ENT manifestations were associated with a better outcome in GPA[11]. In a study with 155 subjects with GPA that were followed-up for a median of 7 years, LI at diagnosis was predictive of a >3-fold higher mortality[8]. Another study showed that DAH in MPA was associated with 8.65 RR of mortality[7]. PI was also a predictor of survival with renal involvement. A later study by the same group showed that in 350 subjects with renal AAV, lung and ENT involvement were associated with RR of 1.7 for relapse[16]. The authors postulated that the likelihood of pulmonary infection and/or colonization is increased due to previous disease activities leading to structural damages such as cavitating lesions and further infection. This may lead to changes in vascular flow trauma and adaptations responsible for future relapses. External agents have been shown to increase relapse such as nasal colonization with S. aureus in GPA[17].

Our present study investigated the association of damage and disease activity with PI at initial presentation in subjects with AAV. There were no differences in BVAS3 and VDI between the PI and non-PI group. However, when the subjects were subcategorized into LI and non-LI groups, there were significant differences for both BVAS3 and VDI between the two groups at almost all time points. It is to be noted that discrepancy of symptoms existed in this study. 64% of subjects with PI were diagnosed with GPA. Interestingly, the overall upper respiratory tract or ENT involvement was less common at 20%. Tracheobronchial disease was also less common even though studies have reported up to 50-60%[18, 19]. This is likely due to the design of the study which does not include subjects attending the ENT service due to isolated upper respiratory tract problems. In MPA, PI was not as common as GPA, however half of these were diagnosed radiologically in which radiographic infiltrates were the most common finding. We had a smaller number of subjects presenting with PI that were subsequently diagnosed with CSS. One of these subjects had minor infiltrates on the presenting chest radiograph. 2 subjects in the PI group were diagnosed with IPIPC in which one presented with limited alveolar hemorrhage. Therefore, we conclude that though discrepancy of symptoms existed in this cohort, the prevalence of different diseases represent the overall prevalence of these diseases in other AAV studies.

This is the first study evaluating BVAS3 in discriminating PI. The two main concerns flagged from BVAS version 2 were that two sub-scores were produced to reflect active and persistent disease respectively[20]. In BVAS3, subjects with purely persistent disease will generate a BVAS value on the same scale as those with ‘new/worse’ disease. The earlier BVAS2 has been shown to have prognostic value and correlates with the validated 5-factor prognostic score[21]. BVAS3 demonstrates concordance with BVAS2, treatment decision, physician global assessment and C-reactive protein[21], however, further studies are required to determine if BVAS3 correlates with mortality and/or health related quality of life. We have shown here that BVAS3 correlates with VDI. Accumulation of even a single VDI item is associated with reduced response to treatment and survival[22]. A 6-month VDI score >4 has been associated with increased risk of mortality[23].

We have not shown a correlation between PI and/or LI with risk of relapses or mortality. This provides additional data supporting recent studies looking at the low impact of LI on the overall AAV prognosis. However, the impact on the overall morbidity remained unanswered. Interestingly, the BVAS and VDI have been weakly correlated with patient health-related quality of life (HRQOL) reinforcing that quality of life cannot be generalized to biological effects of the disease only[24, 25]. Future studies should examine the effects of LI in both physical and functional quality of life using objective assessment tools.

We showed a weak but statistically significant correlation between PI and the presence of musculoskeletal, renal and cardiovascular involvement within 2-years of follow up. Renal involvement was expected due to the high prevalence of pulmonary-renal syndrome in this cohort. Myalgia is included in the analysis of musculoskeletal involvement and therefore, may not impact on the overall prognosis. However, cardiovascular involvement was unexpected. This may relate to 4 and 6 subjects respectively reported to have pulmonary hypertension and coronary artery diseases in the PI group compared to 0 and 4 in the non-PI group respectively. Therefore, this correlation could be related to the differences in prevalence of coronary artery disease that may or may not be related to active vasculitis.

Interestingly, we also identified a significant relationship between pulmonary fibrosis and AAV. Although these parameters were recorded within 6 months to two years of follow-up, we cannot determine that pulmonary fibrosis is secondary to damage of previous lung involvement or a new, unusual manifestation of AAV itself. A few retrospective studies reported that pulmonary fibrosis is an underestimated manifestation of AAV, which often predates the development of vasculitis[26, 27].

There are several limitations to this study. The overall number for specific diseases are small however, this study emphasized the long-term impact of LI in AAV as a single entity. Interestingly, there were differences in VDI when subjects were subcategorized into disease-specific populations, demonstrating that LI individuals with GPA and MPA had higher VDI compared to their counterparts. This observation could be mirrored due to the partly distinct clinical manifestations which may reflect the differences between active vasculitis and granulomatous inflammation. This reinforces the concept of AAV especially in regards to MPA and GPA that are a phenotypic continuum. Meanwhile, CS has distinct features related to atopy and eosinophilia despite shared features of pauci-immune glomerulonephritis and positive MPO-ANCA. AAV is recruited and those that were may be selected leading to bias. For example, as subjects were not recruited from all clinical services, other localized forms of AAV such as localized cardiac or intracranial vasculitis are not represented. Additionally, this study did not take into account the possible effects of different immunosuppressive regimens on damage scores and complications.

Despite its limitations, this study is important as it highlights another issue in the natural history and prognosis of AAV. Although the outcome of AAV has improved significantly with the introduction of immunosuppressive therapy, subsequent disease course remains unsatisfactory for most subjects, due to low-grade active disease, relapse and the effects of damage due to established disease or drug toxicity. This study shows that subjects presenting with LI suffered considerable burden of disease which should drive the search to improve current management strategies in AAV. An important measure of future therapeutic approaches will be their ability to reduce the damage accrued over time.