Prognostic factors for mortality in patients with bullous pemphigoid: a meta-analysis

In this meta-analysis of 14 studies that included 2499 subjects, we found that older age, presence of circulating antibodies regardless of detection method, co-existing dementia, and stroke were associated with an increased risk of BP mortality. No significant association was observed for gender, disease extent, mucosal involvement, or IIF result and survival.

In consistence with most studies included in the current analysis, we found no survival difference based on sex. However, age at diagnosis was associated with increased risk of death, with advanced age being a poor prognostic factor. Stratification of studies based on age cut-off value demonstrated that the effect size was more significant when the cutoff was lower, suggesting that the truly younger patients may have a better prognosis. Discrepancies in the age cut-off values, patient baseline characteristics, and treatment approaches between studies might contribute to the high level of heterogeneity. The pooled result did not remain comparable after “trim and fill” adjustment, suggesting that publication bias might have led to an overestimation of the effect of age on survival. However, the asymmetry in funnel plot may also simply be the play of chance, since only ten studies were included, or true heterogeneity existed because cut-off age varied greatly. Of note, the two outlier investigations by Roujeau et al. [29] and Cortés et al. [5] were small studies with less than 100 participants. Nevertheless, the above finding indicates that younger age at the diagnosis of BP does not necessarily denote a lower risk of mortality, and physicians should be more cautious about patients’ general health condition and comorbidity profile.

As reported previously, more extensive form of BP did not significantly increase the risk on mortality. Although the extent and distribution of disease are a variable susceptible to high variability between centers and may introduce information bias, especially in retrospective studies, heterogeneity between the included studies was low. The presence of mucosal lesion was also not predictive of poor survival outcome in our analysis. Of the other factors related to BP activity that were not included in this meta-analysis due to insufficient data for statistical pooling, such as pruritus [15, 29] and eosinophilia [1, 15, 22, 29], no mortality difference was found by previous investigations. These findings suggest that inherent factors such as age and gender, as well as disease severity at the time of diagnosis, may not influence mortality as much as general condition and concomitant morbidities.

Our analysis corroborated previous finding that IIF is not a sensitive indicator of BP clinical activity [18], but suggested that the presence of circulating antibodies regardless of detection method increased mortality risk, pointing to a predictive role of ELISA test. Unfortunately, since only three studies investigated survival prognosis based on ELISA result, we did not perform statistical pooling for this. To date, IIF plays a key role in the detection of circulating antibodies and is often used as the routine test. However, the circulating autoantibodies can also be detected by more accurate serological assays, including immunoblotting and ELISA [18]. Of note, ELISA has been demonstrated as a useful tool to detect circulating antibodies in BP with its high sensitivity and specificity, particularly to recombinant BP180 antigen [18]. Moreover, it has the ability to reflect the severity of bullous pemphigoid, presumably because autoantibody against BP180 is believed to be pathogenic in BP [10]. It is noteworthy that this represents an intrinsic risk factor that correlates with BP mortality.

Severe concomitant morbidities at the time of diagnosis of bullous pemphigoid, such as neurological disorders, cardiac insufficiency, diabetes, and malignancies, increase the risk of mortality [3, 12, 21]. Interestingly, there is a strong link between BP and neurological diseases. In this study, we evaluated the impact of two most common neurological diseases in BP patients, dementia, and stroke, on the survival of BP patients. Our pooled data indicated a roughly two-fold higher mortality risk for BP patients with dementia or stroke. The exact mechanism underlying the link between neurological diseases and BP has not yet been fully elucidated, but a putative autoimmune reaction against BP antigens in the brain, via a compromised blood–brain barrier, that cross react with the skin have been speculated as a possible cause [20]. Neurological diseases may be responsible for the poor prognosis of some patients with BP because of their altered general condition. However, patients with neurodegenerative disorders are known to have increased blood–brain barrier permeability that may facilitate the generation and crossing of BP autoantibodies into the periphery, worsening skin damage, and clinical outcome [8]. A recent study revealed that in a group of patients with Alzheimer’s disease but no bullous pemphigoid, their sera contained much higher level of BP180 autoantibody than neurologically healthy controls. Furthermore, increased levels of the autoantibody were associated with more severe dementia [19]. Thus, it remains unclear whether neurological disease itself could increase the mortality risk, or the increased risk is conferred by functional impairment and decreased autonomy resulting from neurological disease. Future prospective studies should assess patient’s functional status at initial presentation and employ a multivariate analysis to answer this question.

Meta-analysis of some other prognostic factors was not conducted, because the data were too sparse or heterogeneous to combine analytically. Poor general condition, low karnofsky scale, or being bedridden has been repeatedly reported to be associated with unfavorable outcome [3, 15, 32], with the exception of one study conducted by Lee et al. [21], which did not find a significant association between karnofsky scale and BP mortality after multivariate analysis. Low serum albumin level and high erythrocyte sedimentation rate (ESR) were found to be associated with elevated mortality risk in BP [22, 30]. High ESR may be a surrogate marker for more severe inflammatory status and more severe disease. Serum albumin level is related to patient’s nutritional condition, or underlying diseases, or extensive cutaneous erosions. However, these two factors are easily influenced by various factors, such as other acute and chronic illnesses, so they do not represent intrinsic biological variables of bullous pemphigoid.

Steroid is the first line therapy in both localized and generalized BP [17]. High dosage of systemic corticosteroid or immunosuppressive agents correlates with higher mortality and increased side effects especially in patients at risk, as early deaths in BP patients are mainly of infectious or cardiovascular origin [16]. However, we were not in an optimal situation to validly investigate this issue, because (1) treatment modalities had not been predetermined and controlled in most studies in our analysis; (2) the average dosage of steroid used in different studies varied greatly; (3) dosage and route of administration were largely determined by patients’ disease status; and (4) patients were often administered a combination of systemic steroid, topical steroid, and adjunctive immunomodulators.

Potential limitations need to be considered when interpreting the results of our meta-analysis. First, since most included studies were retrospective and conducted in referral centers, a potential unidentified confounding, information, and selection bias may exist, causing us to interpret our results with caution. Second, the follow-up time varied from 1 to 5 years among studies, which may influence the comparability of the results between component studies. Third, pooled results for some factors, such as mucosal involvement and positive IIF, were based on a limited number of studies. Therefore, we cannot rule out the possibility that insufficient statistical power is present. Finally, we could not evaluate all of the predictive factors for BP mortality in this meta-analysis.