Объединения между хулиганскими пемфигоидами и коморбидами: шведское общенациональное когортное исследование 5,738 Пациенты.

Introduction

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder, primarily affecting the elderly, posing a significant burden due to its high morbidity and mortality rates.
1
The condition arises from autoantibodies against BP230 (BPAG1/Dystonin) and BP180 (BPAG2/Type XVII Collagen), proteins essential for dermo-epidermal cohesion.
2
The binding of these antibodies triggers inflammation and subepidermal blistering.
1
Clinically, BP presents as generalized tense, itchy blisters, sometimes involving mucous membranes. However, up to 20% of cases exhibit atypical symptoms such as mild pruritus, excoriations, and eczematous or urticarial lesions without frank blistering.
3

While the exact cause of BP remains unclear, several triggers have been linked to its onset. The incidence of BP varies widely, ranging from 2.6 to 42.8 cases per million across different populations. 4 – 6 In Sweden, the incidence has increased to 7 per 100,000 individuals, representing one of the highest rates in Europe.
7
Patients with BP have a higher mortality rate compared to healthy individuals, with 1-year mortality rates in Western populations reported at 6% to 41%. 6 , 8 , 9 Management varies but often involves long-term systemic corticosteroids alone or combined with other immunosuppressive agents.
10

BP has been significantly associated with a wide range of comorbidities such as hypertension, diabetes mellitus, chronic kidney disease, obstructive sleep apnoea, and psychiatric conditions such as schizophrenia and mood disorders.
11
Neurological disorders are particularly prevalent, with BP patients facing over a tenfold increased risk compared to the general population.
11
An American study revealed that a significant association exists between BP and neurological conditions, in which 36% of BP patients had a history of neurological diseases, with dementia and Parkinson’s disease being the most common.
12
Furthermore, BP patients exhibit higher prevalence rates of metabolic disorders. Specifically, 53% had hypertension, 40% had diabetes mellitus, and 73% had hyperlipidaemia.
11
The association between BP and malignancies has been inconsistent across studies. Some research indicates an increased risk of certain cancers in patients with BP, while other studies do not support this finding. 13 , 14

Effective management of BP requires addressing both the disease itself and its associated comorbidities to improve patient survival and quality of life; however, it remains unclear whether these comorbidities differ from those observed in other countries. Furthermore, there is limited information on the comorbidities associated with BP patients in Sweden. Therefore, this study investigates these associations on a national scale, leveraging comprehensive data from the Swedish National Patient Register (NPR) to quantify the burden of comorbidities in patients with BP and identify potential areas for targeted intervention.

Materials and methods

Study design

This study is a nationwide retrospective cohort analysis conducted in Sweden. It focuses on individuals aged 18 and older who have been diagnosed with BP, identified using the International Classification of Diseases (ICD) codes, specifically ICD-10: L12.0, L12.0A, L12.0B, L12.0W, L12.8, and L12.9. Data was obtained from the NPR, which contains comprehensive medical records for all residents of Sweden, covering the period from January 1, 2005, to December 31, 2016.

Patients were followed from the date of diagnosis until the earliest of three events: emigration, death, or the study’s end on December 31, 2016. Each resident’s unique personal identification number (PIN) allowed for seamless data linkage across multiple national databases. This electronic data linkage ensured comprehensive follow-up for both the BP cohort and the matched control cohort.

Matched control cohort

Statistics Sweden was used to collect data from the entire Swedish population, and a control cohort of individuals not diagnosed with BP was selected, up to three controls per case, matched by age, sex and county of residence. The control subjects had to be alive with no prior diagnosis of BP and contributing data at the time of the index date. We assigned a date of “pseudo diagnosis” to controls, which was the date of diagnosis of BP of the case they were matched to. This matching strategy aimed to minimize potential confounding effects from these demographic variables.

The Swedish National Patient Register

The NPR was established by the National Board of Health and Welfare in 1964 and has provided nearly complete coverage of all inpatient care in Sweden, both public and private, since 1987. The NPR includes detailed information about patients, such as their PIN, sex, age, county of residence, and hospital identification. It also contains medical data, including one primary and up to seven secondary diagnoses, coded using the ICD-10th Edition.

Reporting for inpatient care is nearly 100% complete, while specialized outpatient care reporting covering both public and private sectors stands at around 87%.
15
The PIN assigned to all Swedish residents allows for precise linkage of information across various registries, including the NPR. This enables the tracing of patient information both retrospectively, prior to a BP diagnosis, and prospectively, after the diagnosis. The NPR is known for its high-quality data, with a 92% positive predictive value for BP diagnoses.
16

Identification of comorbidities

During the study period, ICD-9 and ICD-10 codes were used to classify comorbid diseases. We included 21 diagnosis codes in the analysis, each identified by its respective ICD-9 and ICD-10 codes listed in Table 1 . These comorbidities were selected not only due to their potential shared pathophysiological mechanisms with BP, including autoimmune, inflammatory, metabolic, and systemic processes, but also based on their prevalence in older populations and their prevalence in previous literature examining disease clustering in BP. Table 1. ICD-9 and 10 codes for comorbidities included in the study. Comorbidities ICD-9 ICD-10 Diabetes Mellitus 250 E10-E14 Dementia 294 F03 Schizophrenia 295 F20 Unipolar/Bipolar Disease 296 F31 Parkinson’s Disease 332 G20 Amyotrophic lateral sclerosis 335 G12 Multiple Sclerosis 340 G35 Epilepsy 345 G40 Myasthenia Gravis 358 G70 Stroke 434 I60-I69 Psoriasis 696 L40 Lichen Planus 697 L43 Alopecia Areata 704 L63 Vitiligo 709 L80 Systemic Lupus Erythematosus 710.0 M32 Systemic Sclerosis 710.1 M34 Sjögrens Syndrome 710.2 M35 Dermatomyositis 710.3 M33 Polymyositis 710.4 M33.2 Rheumatoid Arthritis 714 M06 Suicide E950-E959 X60-X84 ICD: International Classification of Diseases.

Table 1. ICD-9 and 10 codes for comorbidities included in the study. Comorbidities ICD-9 ICD-10 Diabetes Mellitus 250 E10-E14 Dementia 294 F03 Schizophrenia 295 F20 Unipolar/Bipolar Disease 296 F31 Parkinson’s Disease 332 G20 Amyotrophic lateral sclerosis 335 G12 Multiple Sclerosis 340 G35 Epilepsy 345 G40 Myasthenia Gravis 358 G70 Stroke 434 I60-I69 Psoriasis 696 L40 Lichen Planus 697 L43 Alopecia Areata 704 L63 Vitiligo 709 L80 Systemic Lupus Erythematosus 710.0 M32 Systemic Sclerosis 710.1 M34 Sjögrens Syndrome 710.2 M35 Dermatomyositis 710.3 M33 Polymyositis 710.4 M33.2 Rheumatoid Arthritis 714 M06 Suicide E950-E959 X60-X84 ICD: International Classification of Diseases.

ICD-9 and 10 codes for comorbidities included in the study.

ICD: International Classification of Diseases.

In this study, BP was treated as the index disease. Accordingly, the term comorbidity is used to describe medical conditions occurring in relation to BP. When referring to disease burden independent of an index diagnosis, particularly in the control population or when discussing disease clustering in older individuals, the term multimorbidity is used. This distinction was applied consistently throughout the analyses and interpretation.

Statistics

The demographic data of the study population were analysed first. Continuous data are presented as the mean value and standard deviation (SD), and categorical variables are presented as percentages. Statistical analyses were conducted using three predefined analytical frameworks, pre-diagnosis, post-diagnosis, and overall post-diagnosis associations.

Pre-diagnosis analysis assessed the prevalence of selected conditions occurring before the BP index date. Univariable logistic regression models were used to estimate prevalence odds ratios (PORs) with 95% confidence intervals (CIs), comparing BP cases with matched controls. This analysis aimed to identify conditions potentially preceding or predisposing to BP.

Post-diagnosis analysis evaluated incident comorbidities after BP diagnosis using multivariable Cox proportional hazards regression models. Individuals with a diagnosis of the specific condition prior to the BP index date were excluded from the corresponding analysis. Hazard ratios (HRs) with 95% CIs were calculated, and analyses were stratified into events occurring within the first year after BP diagnosis and events occurring beyond one year.

Overall post-diagnosis association refers to the cumulative association between BP and incident comorbidities during the entire follow-up period after BP diagnosis, excluding individuals with a prior diagnosis of the condition of interest. Person-years at risk were calculated from the BP index date until first diagnosis of the outcome, death, emigration, or end of follow-up.

All models were adjusted for age, sex and county of residence. Standard errors in logistic regression were calculated using cluster-robust sandwich estimators. Statistical analyses were performed using STATA® version 15.1, and a two-sided significance level of 5% was applied.

Results

Study cohort characteristics

The study included 5,738 individuals diagnosed with BP in the NPR between 2005 and 2016, including 3,026 women (52.7%). The mean age of BP patients was 78.6 years (±12.2 SD). The total observation period for BP patients amounted to 18,022 person-years, with an average follow-up of 3.1 years (±2.9 SD). Most BP cases (83.2%, n = 4,772) were diagnosed in outpatient dermatology clinics. The control cohort comprised 17,167 randomly selected individuals from the Swedish general population. The mean age of this group was 78.7 years (±12.2 SD). Their mean follow-up duration was 4.2 years (±3.1 SD), covering a total observation period of 71,682 person-years ( Table 2 ). During follow-up, 38% of the controls (n=6,598 out of 17,167) and 56% of the patients with BP (n=3,192 out of 5,738) died. This resulted in an approximately one-year longer mean follow-up time for the control cohort compared to the BP patients. Table 2. Demographic data for patients diagnosed with bullous pemphigoid (BP) and control cohort from the general population. ​ BP Control cohort Subjects, n 5,738 17,167 Female, n (%) 3,026 (52.7) 9,064 (52.8) Follow-up time, mean±SD 3.1±2.9 4.2±3.1 Age, years, mean±SD 78.6±12.2 78.7±12.2 Patients-years of observation 18,022 71,682 SD: standard deviation.

Table 2. Demographic data for patients diagnosed with bullous pemphigoid (BP) and control cohort from the general population. ​ BP Control cohort Subjects, n 5,738 17,167 Female, n (%) 3,026 (52.7) 9,064 (52.8) Follow-up time, mean±SD 3.1±2.9 4.2±3.1 Age, years, mean±SD 78.6±12.2 78.7±12.2 Patients-years of observation 18,022 71,682 SD: standard deviation.

Demographic data for patients diagnosed with bullous pemphigoid (BP) and control cohort from the general population.

SD: standard deviation.

Overall comorbidity association after a BP diagnosis

Overall, 2,712 incidents of comorbidities occurred in the BP cohort, while 5,247 incidents were observed in the controls within the 1-11 year follow-up period. Patients with BP showed a significantly increased association with several comorbidities. Overall, BP patients exhibited a higher burden of comorbid conditions compared to controls, with an HR of 2.20 (95% CI: 2.08–2.33). Regarding specific types of comorbidities, neurological and psychiatric disorders, including dementia, were notably more prevalent in BP patients. Dementia revealed a higher association with an HR of 1.59 (95% CI: 1.43–1.77). Epilepsy showed a significantly higher association, with an HR of 2.21 (95% CI: 1.67–2.92). Unipolar/Bipolar diseases were also more common, with an HR of 2.47 (95% CI: 1.35–4.49). Suicide was significantly higher in BP patients (HR: 1.35, 95% CI: 1.04–1.76).

Dermatological and autoimmune diseases showed strong associations with BP. Psoriasis had an HR of 2.16 (95% CI: 1.45–3.20), systemic sclerosis was elevated at 2.10 (95% CI: 1.40–3.14), and lichen planus exhibited the highest association, with an HR of 5.55 (95% CI: 3.14–9.79). Diabetes was also more common in BP patients (HR of 1.66, 95% CI: 1.43–1.93). A few conditions, such as systemic lupus erythematosus, polymyositis, and dermatomyositis, had very low numbers of observed cases, making it difficult to draw firm conclusions ( Table 3 ). Table 3. Overall post-diagnosis hazard ratios (HR) between bullous pemphigoid (BP) and incident comorbidities during follow-up. Comorbidities Observed numbers of comorbidities HR overall (95% CI) BP cohort Control cohort All comorbidities 2,712 5,247
2.20 (2.08-2.33)
Diabetes Mellitus 240 633
1.66 (1.43-1.93)
Dementia 465 1417
1.59 (1.43-1.77)
Schizophrenia 7 11 2.19 (0.85-5.68) Unipolar/Bipolar Disease 18 27
2.47 (1.35-4.49)
Parkinson’s Disease 38 127 1.23 (0.85-1.78) Amyotrophic lateral sclerosis 9 28 1.49 (0.69-3.20) Multiple Sclerosis 3 4 2.60 (0.57-11.78) Epilepsy 77 144
2.21 (1.67-2.92)
Myasthenia Gravis 2 4 2.08 (0.37-11.67) Stroke 48 199 1.07 (0.78-1.48) Psoriasis 39 72
2.16 (1.45-3.20)
Lichen Planus 30 20
5.55 (3.14-9.79)
Alopecia Areata 5 7 2.87 (0.90-9.18) Vitiligo 2 3 2.89 (0.46-18.03) Systemic Lupus Erythematosus 1 0 ​ Systemic Sclerosis 37 72
2.10 (1.40-3.14)
Sjögrens Syndrome 9 19 1.96 (0.87-4.40) Dermatomyositis 1 4 ​ Polymyositis 0 0 ​ Rheumatoid Arthritis 1 0 ​ Suicide 74 224
1.35 (1.04-1.76)
Bold: 95% confidence interval (95% CI) does not include 1.00. ICD-10: International Classification of Diseases, tenth revision.

Table 3. Overall post-diagnosis hazard ratios (HR) between bullous pemphigoid (BP) and incident comorbidities during follow-up. Comorbidities Observed numbers of comorbidities HR overall (95% CI) BP cohort Control cohort All comorbidities 2,712 5,247
2.20 (2.08-2.33)
Diabetes Mellitus 240 633
1.66 (1.43-1.93)
Dementia 465 1417
1.59 (1.43-1.77)
Schizophrenia 7 11 2.19 (0.85-5.68) Unipolar/Bipolar Disease 18 27
2.47 (1.35-4.49)
Parkinson’s Disease 38 127 1.23 (0.85-1.78) Amyotrophic lateral sclerosis 9 28 1.49 (0.69-3.20) Multiple Sclerosis 3 4 2.60 (0.57-11.78) Epilepsy 77 144
2.21 (1.67-2.92)
Myasthenia Gravis 2 4 2.08 (0.37-11.67) Stroke 48 199 1.07 (0.78-1.48) Psoriasis 39 72
2.16 (1.45-3.20)
Lichen Planus 30 20
5.55 (3.14-9.79)
Alopecia Areata 5 7 2.87 (0.90-9.18) Vitiligo 2 3 2.89 (0.46-18.03) Systemic Lupus Erythematosus 1 0 ​ Systemic Sclerosis 37 72
2.10 (1.40-3.14)
Sjögrens Syndrome 9 19 1.96 (0.87-4.40) Dermatomyositis 1 4 ​ Polymyositis 0 0 ​ Rheumatoid Arthritis 1 0 ​ Suicide 74 224
1.35 (1.04-1.76)
Bold: 95% confidence interval (95% CI) does not include 1.00. ICD-10: International Classification of Diseases, tenth revision.

Overall post-diagnosis hazard ratios (HR) between bullous pemphigoid (BP) and incident comorbidities during follow-up.

Bold: 95% confidence interval (95% CI) does not include 1.00. ICD-10: International Classification of Diseases, tenth revision.

Comorbidities before BP diagnosis

The total number of comorbidities observed among BP patients before they were diagnosed with BP is higher (n=3392) than among controls (n=4790). Overall, BP patients exhibit a significantly higher prevalence of comorbid conditions, with the POR at 2.72 (95% CI: 2.56-2.90) for all comorbidities combined. For specific comorbidities, the POR varies. Some of the most notable associations include neurological disorders such as Parkinson’s disease (POR: 3.73, 95% CI: 3.05-4.56), epilepsy (POR: 2.55, 95% CI: 2.10-3.10), dementia (POR: 2.75, 95% CI: 2.51-3.02), amyotrophic lateral sclerosis (ALS) (POR: 2.25, 95% CI: 1.46-3.47), and multiple sclerosis (MS), which presents the highest overall POR at 7.56 (95% CI: 4.95-11.56). Metabolic and cerebrovascular comorbidities revealed increased prevalence for diabetes (POR: 1.89, 95% CI: 1.74-2.06) and stroke (POR: 2.51, 95% CI: 1.99-3.16).

Additionally, psychiatric conditions such as schizophrenia (POR: 1.63, 95% CI: 1.06-2.50) and unipolar/bipolar disorder (POR: 1.61, 95% CI: 1.17-2.22) also show increased prevalence. Suicide risk is notably higher in BP patients, with a POR of 1.82 (95% CI: 1.52-2.18).

Interestingly, dermatological conditions such as psoriasis (POR: 2.54, 95% CI: 2.11-3.07) and lichen planus (POR: 3.51, 95% CI: 2.53-4.86) are strongly associated with BP, particularly in the period leading up to diagnosis, where the POR for lichen planus reaches 20.46 (95% CI: 8.00-52.33). Moreover, vitiligo (POR: 4.50, 95% CI: 2.17-9.34) was positively associated with BP before diagnosis, especially one year before the onset of BP (POR 26.96, 95% CI: 3.42-212.87). Additionally, alopecia areata showed a strong association before BP diagnosis (POR: 2.53, 95% CI: 1.13–5.66).

Autoimmune diseases, such as systemic lupus erythematosus (POR: 3.59, 95% CI: 1.10-11.78) and systemic sclerosis (POR: 1.34, 95% CI: 1.09-1.65), also exhibit an increased prevalence.

The likelihood of having a comorbidity within one year prior to BP diagnosis was higher for several conditions, including psoriasis (POR 7.93, 95% CI: 4.67-13.46), lichen planus (POR 20.46, 95% CI: 8.00-52.33), vitiligo (POR 26.96, 95% CI: 3.42-212.87), and amyotrophic lateral sclerosis (POR 5.99 (95% CI: 1.50-23.95) .

In other cases, the sample size was insufficient to conduct a robust analysis, as seen in dermatomyositis, polymyositis, and rheumatoid arthritis ( Table 4 ). Table 4. Pre-diagnosis prevalence odds ratios (PORs) for comorbidities occurring ≤1 year and >1 year before bullous pemphigoid (BP) diagnosis. Comorbidities Observed no. of comorbidities POR overall (95% CI) POR ≤ 1 year before BP (95% CI) POR > 1 year before BP (95% CI) BP Control cohort All comorbidities 3392 4790
2.72 (2.56-2.90)

2.83 (2.50-3.20)

2.45 (2.29-2.61)
Diabetes Mellitus 1035 1789
1.89 (1.74-2.06)

2.15 (1.69-2.73)

1.82 (1.67-1.99)
Dementia 936 1136
2.75 (2.51-3.02)

2.62 (2.16-3.18)

2.65 (2.40-2.94)
Schizophrenia 32 59
1.63 (1.06-2.50)
1.50 (0.27-8.17)
1.64 (1.05-2.55)
Unipolar/Bipolar Disease 58 108
1.61 (1.17-2.22)
1.20 (0.38-3.82)
1.65 (1.19-2.31)
Parkinson’s Disease 217 179
3.73 (3.05-4.56)

2.77 (1.59-4.83)

3.87 (3.12-4.80)
Amyotrophic lateral sclerosis 36 48
2.25 (1.46-3.47)

5.99 (1.50-23.95)

2.00 (1.26-3.18)
Multiple Sclerosis 75 30
7.56 (4.95-11.56)
1.0 (1.0-1.0)
7.16 (4.67-10.98)
Epilepsy 189 226
2.55 (2.10-3.10)

3.60 (2.12-6.13)

2.41 (1.95-2.97)
Myasthenia Gravis 5 14 1.07 (0.38-2.97) 1.00 (1.00-1.00) 1.25 (0.44-3.54) Stroke 134 162
2.51 (1.99-3.16)

2.03 (1.13-3.64)

2.60 (2.02-3.34)
Psoriasis 203 244
2.54 (2.11-3.07)

7.93 (4.67-13.46)

2.06 (1.68-2.54)
Lichen Planus 79 68
3.51 (2.53-4.86)

20.46 (8.00-52.33)

2.15 (1.46-3.15)
Alopecia Areata 11 13
2.53 (1.13-5.66)
1.50 (0.14-16.50)
2.72 (1.16-6.41)
Vitiligo 18 12
4.50 (2.17-9.34)

26.96 (3.42-212.87)

2.45 (1.01-5.91)
Systemic Lupus Erythematosus 6 5
3.59 (1.10-11.78)
2.99 (0.19-47.84) 3.74 (1.00-13.94) Systemic Sclerosis 134 300
1.34 (1.09-1.65)
1.62 (0.83-3.19)
1.32 (1.06-1.64)
Sjögrens Syndrome 27 72 ​ 1.00 (0.20-4.94) 1.13 (0.71-1.80) Dermatomyositis 2 0 ​ ​ ​ Polymyositis 1 0 ​ ​ ​ Rheumatoid Arthritis 1 3 ​ ​ ​ Suicide 193 322
1.82 (1.52-2.18)

2.05 (1.27-3.31)

1.78 (1.46-2.16)
Bold: 95% confidence interval (95% CI) does not include 1.00.

Table 4. Pre-diagnosis prevalence odds ratios (PORs) for comorbidities occurring ≤1 year and >1 year before bullous pemphigoid (BP) diagnosis. Comorbidities Observed no. of comorbidities POR overall (95% CI) POR ≤ 1 year before BP (95% CI) POR > 1 year before BP (95% CI) BP Control cohort All comorbidities 3392 4790
2.72 (2.56-2.90)

2.83 (2.50-3.20)

2.45 (2.29-2.61)
Diabetes Mellitus 1035 1789
1.89 (1.74-2.06)

2.15 (1.69-2.73)

1.82 (1.67-1.99)
Dementia 936 1136
2.75 (2.51-3.02)

2.62 (2.16-3.18)

2.65 (2.40-2.94)
Schizophrenia 32 59
1.63 (1.06-2.50)
1.50 (0.27-8.17)
1.64 (1.05-2.55)
Unipolar/Bipolar Disease 58 108
1.61 (1.17-2.22)
1.20 (0.38-3.82)
1.65 (1.19-2.31)
Parkinson’s Disease 217 179
3.73 (3.05-4.56)

2.77 (1.59-4.83)

3.87 (3.12-4.80)
Amyotrophic lateral sclerosis 36 48
2.25 (1.46-3.47)

5.99 (1.50-23.95)

2.00 (1.26-3.18)
Multiple Sclerosis 75 30
7.56 (4.95-11.56)
1.0 (1.0-1.0)
7.16 (4.67-10.98)
Epilepsy 189 226
2.55 (2.10-3.10)

3.60 (2.12-6.13)

2.41 (1.95-2.97)
Myasthenia Gravis 5 14 1.07 (0.38-2.97) 1.00 (1.00-1.00) 1.25 (0.44-3.54) Stroke 134 162
2.51 (1.99-3.16)

2.03 (1.13-3.64)

2.60 (2.02-3.34)
Psoriasis 203 244
2.54 (2.11-3.07)

7.93 (4.67-13.46)

2.06 (1.68-2.54)
Lichen Planus 79 68
3.51 (2.53-4.86)

20.46 (8.00-52.33)

2.15 (1.46-3.15)
Alopecia Areata 11 13
2.53 (1.13-5.66)
1.50 (0.14-16.50)
2.72 (1.16-6.41)
Vitiligo 18 12
4.50 (2.17-9.34)

26.96 (3.42-212.87)

2.45 (1.01-5.91)
Systemic Lupus Erythematosus 6 5
3.59 (1.10-11.78)
2.99 (0.19-47.84) 3.74 (1.00-13.94) Systemic Sclerosis 134 300
1.34 (1.09-1.65)
1.62 (0.83-3.19)
1.32 (1.06-1.64)
Sjögrens Syndrome 27 72 ​ 1.00 (0.20-4.94) 1.13 (0.71-1.80) Dermatomyositis 2 0 ​ ​ ​ Polymyositis 1 0 ​ ​ ​ Rheumatoid Arthritis 1 3 ​ ​ ​ Suicide 193 322
1.82 (1.52-2.18)

2.05 (1.27-3.31)

1.78 (1.46-2.16)
Bold: 95% confidence interval (95% CI) does not include 1.00.

Pre-diagnosis prevalence odds ratios (PORs) for comorbidities occurring ≤1 year and >1 year before bullous pemphigoid (BP) diagnosis.

Bold: 95% confidence interval (95% CI) does not include 1.00.

Comorbidities after BP diagnosis

In this study, we examined comorbidities that occur after the diagnosis of BP. The findings indicate a significantly elevated association of various comorbidities in patients diagnosed with BP compared to the matched control cohort. The overall HR for developing any comorbidity within the first year of BP diagnosis is 2.88 (95% CI: 2.68-3.10), which declines but remains elevated beyond one year at 1.57 (95% CI: 1.44-1.71). Specific conditions show varying degrees of association, with some conditions exhibiting a particularly high association with BP ( Table 5 ). Table 5. Post-diagnosis hazard ratios (HR) for comorbidities occurring ≤1 year and >1 year after bullous pemphigoid (BP) diagnosis. Comorbidities Observed no. of comorbidities ≤ 1 year HR overall (95% CI) Observed no. of comorbidities > 1 year HR overall (95% CI) BP Control BP Control All comorbidities 1649 2070
2.88 (2.68-3.10)
1063 3177
1.57 (1.44-1.71)
Diabetes Mellitus 103 150
2.47 (1.92-3.18)
137 483
1.35 (1.11-1.63)
Dementia 153 300
1.94 (1.59-2.36)
312 1117
1.46 (1.29-1.66)
Schizophrenia 3 4 2.33 (0.52-10.40) 4 7 2.11 (0.61-7.25) Unipolar/Bipolar Disease 8 7
3.75 (1.36-10.36)
10 20 1.96 (0.91-4.21) Parkinson’s Disease 15 24
2.09 (1.09-3.98)
23 103 0.98 (0.62-1.55) Amyotrophic lateral sclerosis 3 4 2.43 (0.54-10.86) 6 24 1.26 (0.51-3.14) Multiple Sclerosis 1 2 1.60 (0.14-17.63) 2 2 3.71(0.51-27.19) Epilepsy 33 32
3.44 (2.11-5.60)
44 112
1.77 (1.24-2.52)
Myasthenia Gravis 0 2 0.00 (0.00-0.00) 2 2 4.90(0.66-36.40) Stroke 11 39 0.96 (0.49-1.88) 37 160 1.11 (0.77-1.60) Psoriasis 15 17
3.01 (1.50-6.03)
24 55
1.84 (1.13-3.00)
Lichen Planus 19 5
12.51(4.67-33.52)
11 15
3.00 (1.37-6.55)
Alopecia Areata 2 2 3.21 (0.45-22.78) 3 5 2.71(0.64-11.53) Vitiligo 2 1 6.86 (0.62-75.79) 0 2 ​ Systemic Lupus Erythematosus 1 0 ​ 0 0 ​ Systemic Sclerosis 11 19 2.06 (0.98-4.33) 26 53
2.12 (1.31-3.42)
Sjögrens Syndrome 1 5 0.61 (0.07-5.18) 8 14
2.62 (1.08-6.39)
Dermatomyositis 0 0 ​ ​ ​ ​ Polymyositis 0 0 ​ ​ ​ ​ Rheumatoid Arthritis 0 0 ​ ​ ​ ​ Suicide 22 41
1.77 (1.06-2.98)
52 183 1.23 (0.90-1.69) Bold: 95% confidence interval (95% CI) does not include 1.00.

Table 5. Post-diagnosis hazard ratios (HR) for comorbidities occurring ≤1 year and >1 year after bullous pemphigoid (BP) diagnosis. Comorbidities Observed no. of comorbidities ≤ 1 year HR overall (95% CI) Observed no. of comorbidities > 1 year HR overall (95% CI) BP Control BP Control All comorbidities 1649 2070
2.88 (2.68-3.10)
1063 3177
1.57 (1.44-1.71)
Diabetes Mellitus 103 150
2.47 (1.92-3.18)
137 483
1.35 (1.11-1.63)
Dementia 153 300
1.94 (1.59-2.36)
312 1117
1.46 (1.29-1.66)
Schizophrenia 3 4 2.33 (0.52-10.40) 4 7 2.11 (0.61-7.25) Unipolar/Bipolar Disease 8 7
3.75 (1.36-10.36)
10 20 1.96 (0.91-4.21) Parkinson’s Disease 15 24
2.09 (1.09-3.98)
23 103 0.98 (0.62-1.55) Amyotrophic lateral sclerosis 3 4 2.43 (0.54-10.86) 6 24 1.26 (0.51-3.14) Multiple Sclerosis 1 2 1.60 (0.14-17.63) 2 2 3.71(0.51-27.19) Epilepsy 33 32
3.44 (2.11-5.60)
44 112
1.77 (1.24-2.52)
Myasthenia Gravis 0 2 0.00 (0.00-0.00) 2 2 4.90(0.66-36.40) Stroke 11 39 0.96 (0.49-1.88) 37 160 1.11 (0.77-1.60) Psoriasis 15 17
3.01 (1.50-6.03)
24 55
1.84 (1.13-3.00)
Lichen Planus 19 5
12.51(4.67-33.52)
11 15
3.00 (1.37-6.55)
Alopecia Areata 2 2 3.21 (0.45-22.78) 3 5 2.71(0.64-11.53) Vitiligo 2 1 6.86 (0.62-75.79) 0 2 ​ Systemic Lupus Erythematosus 1 0 ​ 0 0 ​ Systemic Sclerosis 11 19 2.06 (0.98-4.33) 26 53
2.12 (1.31-3.42)
Sjögrens Syndrome 1 5 0.61 (0.07-5.18) 8 14
2.62 (1.08-6.39)
Dermatomyositis 0 0 ​ ​ ​ ​ Polymyositis 0 0 ​ ​ ​ ​ Rheumatoid Arthritis 0 0 ​ ​ ​ ​ Suicide 22 41
1.77 (1.06-2.98)
52 183 1.23 (0.90-1.69) Bold: 95% confidence interval (95% CI) does not include 1.00.

Post-diagnosis hazard ratios (HR) for comorbidities occurring ≤1 year and >1 year after bullous pemphigoid (BP) diagnosis.

Bold: 95% confidence interval (95% CI) does not include 1.00.

Among metabolic disorders, diabetes presents an increased association, with an HR of 2.47 (95% CI: 1.92-3.18) within the first year and a lower but still significant HR of 1.35 (95% CI: 1.11-1.63) beyond one year. Stroke, in contrast, does not show a significant increase. Neurological disorders also show notable associations, with dementia having an HR of 1.94 (95% CI: 1.59-2.36) within the first year and 1.46 (95% CI: 1.29-1.66) after one year. Parkinson’s disease shows an increased association initially (HR: 2.09, 95% CI: 1.09-3.98), but this association diminishes beyond the first year. Epilepsy has an HR of 3.44 (95% CI: 2.11-5.60) within the first year and remains elevated thereafter at 1.77 (95% CI: 1.24-2.52).

Psychiatric conditions display mixed association levels. Unipolar/Bipolar diseases have elevated HRs, with HRs of 3.75 (95% CI: 1.36-10.36), although wide confidence intervals suggest a degree of uncertainty. Suicide risk is significantly elevated within the first year (HR: 1.77, 95% CI: 1.06-2.98), though this association weakens over time and becomes insignificant (HR: 1.23, 95% CI: 0.90-1.69).

Dermatological diseases such as psoriasis (HR: 3.01, 95% CI: 1.50-6.03) and lichen planus (HR: 12.51, 95% CI: 4.67-33.52) show strong associations with BP in the first year, with a reduced but still significantly elevated beyond one year (HR: 1.84, 95% CI: 1.13-3.00) and (HR: 3.00, 95% CI: 1.37-6.55) respectively.

Some conditions, such as systemic sclerosis and Sjögren’s Syndrome, maintain an elevated association beyond the first year, with HRs of 2.12 (95% CI: 1.31-3.42) and 2.62 (95% CI: 1.08-6.39), respectively. Several conditions, including dermatomyositis, polymyositis, and rheumatoid arthritis, lack sufficient data to determine any associations.

Discussion

This nationwide population-based cohort study demonstrates that BP is associated with a broad spectrum of systemic diseases, highlighting that BP extends beyond a skin-limited condition. Patients with BP exhibited a markedly higher burden of both pre-existing and incident comorbidities compared with age, sex and county of residence matched controls. These findings support the concept that BP occurs within a broader context of multimorbidity, particularly in older individuals, and emphasize the importance of viewing BP as part of a complex systemic disease profile.

Our findings confirm a substantially increased overall burden of systemic disease in patients with BP, consistent with previous large-scale epidemiological studies.
17
The elevated prevalence of conditions prior to BP diagnosis and the increased incidence after diagnosis together indicate that BP occurs within a broader context of immune dysregulation and age-related multimorbidity rather than as an isolated dermatologic entity.

The temporal distinction between conditions occurring before and after BP diagnosis provides important clinical insight. Comorbidities identified prior to BP may represent shared pathophysiological mechanisms, immune priming, or systemic vulnerability that predisposes to BP development. In contrast, conditions arising after diagnosis may reflect the combined effects of chronic inflammation, treatment exposure, functional decline, or increased healthcare contact. The stronger associations observed within the first year after diagnosis suggest a period of heightened systemic vulnerability, emphasizing the need for closer clinical monitoring during early disease phases.

Diabetes showed consistent associations both before and after BP diagnosis, supporting prior evidence of a bidirectional relationship. 18 , 19 Chronic systemic inflammation may contribute to metabolic dysregulation, while corticosteroid therapy may exacerbate glucose intolerance. In addition, previous research has linked dipeptidyl peptidase-4 inhibitors (DPP-4i) to increased BP risk, 20 , 21 suggesting that pharmacologic exposure may partly contribute to this association. Although medication data were not available in our registry analysis, these findings underscore the complex interplay between metabolic disease and BP pathogenesis.

Our analysis highlights a significant association between BP and neurological disorders, reinforcing previous findings that suggest a link between neurodegenerative conditions and BP. Dementia emerged as one of the most prominent neurological associations, with increased prevalence prior to BP diagnosis and sustained incidence afterward. These findings align with prior research demonstrating a strong association between BP and neurodegenerative disorders. A recent systematic review and meta-analysis found a substantially elevated association of all-cause dementia in BP patients, with pooled odds ratios of 4.25 (95% CI 2.73–6.61) in case-control studies and HR of 1.41 (95% CI 1.20–1.66) from cohort studies.
22
The association between BP and dementia has been documented before, with proposed mechanisms including neuro-inflammation, shared autoantibodies, and blood-brain barrier dysfunction.
23
Additionally, Parkinson’s disease demonstrated a similar pattern, supporting the growing evidence of a bidirectional relationship between neurodegeneration and BP.
24

Another comprehensive study highlighted that 26.4% to 55.8% of BP patients present with at least one neurological condition, such as stroke, dementia, or Parkinson’s disease, compared to 9.1% to 20.5% in control groups.
25

The relationship between BP and epilepsy also remains a subject of interest. This is consistent with previous research showing a heightened prevalence of epilepsy in BP patients, particularly among those with preexisting neurodegenerative conditions.
23
The role of neuro-inflammation in both conditions also supports the hypothesis that autoantibodies in BP may contribute to neuronal damage, reinforcing the need for neurological monitoring in BP patients.
26

We observed that the HR for MS was elevated but with wide confidence intervals, and the number of observed cases was small, making this result inconclusive. These contrasts with previous large-scale studies that have consistently reported a strong association between MS and BP.
27

Nonetheless, the elevated POR for MS suggests a strong association, with individuals diagnosed with BP being more than seven times as likely to have a history of MS compared to matched controls. Notably, this association remains substantial and statistically significant when examining diagnoses that occur more than one year before BP onset. The elevated POR values before BP onset suggest that MS may act as a predisposing factor or early autoimmune marker in BP pathogenesis. In a large population based case–control study from the UK, MS was strongly associated with the subsequent development of BP, with an adjusted odds ratio of 10.7 (95% CI: 2.8–40.2).
28
The hypothesized mechanism involves chronic neuroinflammation and the presence of cross-reactive autoantibodies targeting both myelin and skin basement membrane components.
27

We found an association between ALS and BP, particularly with ALS appearing before the onset of BP. Our findings align with earlier reports, such as those by Chosidow et al. (2000), who identified BP in 3 out of 168 ALS patients, and Nakane et al. (2016), who described six additional cases where BP developed, on average, 5.6 years after ALS diagnosis. 29 , 30 Other case reports have proposed that damage to the nervous system in ALS might trigger an autoimmune response due to cross-reactivity with BP antigen 1.
29
While these observations suggest a possible link between the two conditions, larger epidemiological studies are still necessary to confirm this association.

Psychiatric comorbidities, including unipolar/bipolar disease and suicide risk, were also elevated in BP patients. Research done by Egeberg et al. (2020) demonstrated a significantly increased prevalence of major depressive disorder and suicide attempts in BP patients.
31
A recent systematic review and meta-analysis demonstrated that individuals with BP have a significantly higher risk of developing psychiatric disorders, including schizophrenia, with an odds ratio of 2.63 (95% CI: 2.03–3.39), further supporting the association between BP and severe psychiatric comorbidities.
32
The reasons for this association may include chronic pain, pruritus, reduced quality of life, and potential psychiatric comorbidities.

The increased prevalence of stroke prior to BP diagnosis suggests that cerebrovascular events may act as potential triggers rather than merely consequences of systemic inflammation. A study from Taiwan reported that BP patients had a significantly increased risk of ischemic stroke compared to matched controls, with an adjusted hazard ratio of 2.37 (95% CI: 1.78–3.15), suggesting a potential role of endothelial dysfunction and systemic inflammation in BP pathogenesis.
33
A study of stroke patients and matched controls revealed that anti-BP180 autoantibodies were detectable in 14% of stroke patients, compared to 5% of healthy controls, suggesting that post-stroke immune dysregulation may lead to basement membrane autoantibody formation and potentially trigger bullous pemphigoid.
34
This aligns with our finding of a markedly increased stroke risk in the year preceding BP diagnosis, reinforcing the hypothesis that stroke may act as a predisposing factor for BP rather than solely being a consequence of chronic inflammation in BP patients. This finding is consistent with research indicating that chronic inflammatory skin diseases, including BP, are associated with an increased risk of thromboembolic events, likely due to persistent systemic inflammation and vascular endothelial dysfunction.
35

Psoriasis, lichen planus, vitiligo, and alopecia areata were more prevalent in BP patients, suggesting potential shared autoimmune mechanisms and inflammatory pathways. These findings align with previous research that has linked BP to other skin diseases. An extensive population-based study found that psoriasis was significantly associated with an increased risk of BP, with an adjusted hazard ratio of 3.05 (95% CI: 2.10–4.43).
36
Furthermore, our findings align with previous studies, including a recent case series, which reported an increased occurrence of BP-like disease in patients with lichen planus, particularly in the form of lichen planus pemphigoides. This overlap is thought to result from shared autoimmune mechanisms involving T-cell activation and basal keratinocyte injury.
37

Furthermore, a study revealed that patients with vitiligo have an increased risk of developing BP, possibly due to autoantibody cross-reactivity against melanocyte and keratinocyte antigens.
38
In our study, we observed a significant association between alopecia areata and BP prior to BP diagnosis. However, the current literature on this relationship is limited, with only a few isolated case reports suggesting possible overlap, and no large-scale epidemiological studies have confirmed this association to date. Among systemic autoimmune diseases, systemic sclerosis showed an influential association with BP. A relationship that has previously only been described in isolated case reports.
39
While these individual cases suggest a possible clinical overlap, our findings provide broader support for a potential link between the two conditions, which may share underlying autoimmune mechanisms. Although rare, bullous lesions can occur in SLE through bullous SLE, and up to seven cases have been reported where SLE and classic BP coexisted.
40
We observed an association between BP and the subsequent development of Sjögren’s Syndrome, particularly emerging more than one year after BP diagnosis. Current evidence on this relationship is limited to isolated case reports.
41
To date, no large-scale epidemiological studies have established a consistent population-level association.

The present findings have direct implications for clinical practice. Dermatologists should recognize BP as a condition frequently embedded within a broader multimorbid profile, particularly in elderly patients. Baseline assessment at diagnosis should therefore extend beyond cutaneous evaluation and include structured review of neurological history, metabolic status, and psychiatric well-being.

Strengths and limitations

This study has several limitations. Comorbidities were identified using registry-based diagnostic codes without access to detailed clinical records, which may result in misclassification. Information on disease severity, medication exposure, seasonality, and lifestyle factors was not available and could not be adjusted for, leaving the possibility of residual confounding. The retrospective design relies on the accuracy of registry data, and heterogeneity in disease severity may have influenced the results. Despite the high positive predictive value of BP diagnoses in the NPR, coding errors may occur.
16
Additionally, the findings may not be directly generalizable to healthcare systems with different population structures or access to care.

Despite these limitations, the study’s strengths include its large, population-based design and use of validated national data. It is the most extensive study to explore comorbidities both before and after BP diagnosis, allowing for assessment of prodromal factors and long-term disease burden. The extended follow-up and focus on incident cases further strengthen the reliability of the findings.

Furthermore the Swedish healthcare setting provides a unique epidemiological context for studying BP-associated disease burden. Sweden has one of the highest reported incidences of BP in Europe, an aging population, and universal access to specialist care. The near-complete national coverage and high diagnostic validity of the NPR allow for comprehensive assessment of multimorbidity patterns at the population level. These features strengthen the generalizability of our findings within similar healthcare systems and underscore their relevance for healthcare planning and multidisciplinary management.

Conclusion

This nationwide study demonstrates that BP is associated with a broad spectrum of systemic comorbidities occurring both before and after diagnosis. These findings support the view that BP represents a systemic disease embedded within age-related multimorbidity rather than a purely cutaneous disorder. Recognition of BP as part of a complex clinical profile should encourage proactive screening, interdisciplinary collaboration, and individualized follow-up strategies. Future research should clarify causal mechanisms and explore whether targeted preventive strategies can reduce morbidity and mortality in this vulnerable population.