Umeå University's logo

Background

Psoriatic disease, encompassing skin psoriasis and psoriatic arthritis, is a common condition affecting 2-3% of the Western population associated with reduced quality of life and increased healthcare costs. To improve patients’ lives and the stewardship of societal resources, a nuanced understanding of the associations between patient characteristics and health outcomes are needed for optimal clinical and societal decision making. While randomised clinical trials play a central role in evidence-based medicine, they have limitations relating to patient selection, follow-up duration, and idealised clinical conditions. In recent years, the role of real-world evidence in health research has grown, including in dermatology, due in part to its ability to describe and compare patients in routine clinical care. This thesis contains four analyses using Swedish real-world data describing associations between patient characteristics and outcomes in psoriatic disease.

Methods

Data from several administrative population registers in Sweden and the clinical registry PsoReg were collected for those with psoriatic disease in routine clinical care and linked at the patient level. The data include diagnoses, pharmacy dispensed medications, mortality, socioeconomic information, quality of life, and clinical severity. A matched non-psoriatic control group was also extracted.

The first analysis assessed the association between disease severity (measured by the Psoriasis Area and Severity Index [PASI]) and health-related quality of life (measured the EuroQol 5-dimension instrument [EQ-5D]) in 2,674 patients with longitudinal follow-up in PsoReg, a fixed effects regression model was deployed adjusting for confounding factors including certain types of unobserved confounding. 

Second, the independent associations of skin psoriasis and somatic comorbidity with incident psychiatric illness were described across 93,239 psoriasis patients and 1.4 million controls. Their individual contributions and synergistic interaction were assessed using a time-to-event model. Diagnosis codes were used to construct the composite psychiatric illness outcome consisting of depression, anxiety, and suicidality. Diagnosis codes were also used to create the Elixhauser and Charlson comorbidity indexes to measure somatic comorbidity. 

The third analysis assessed age-related inequities in biologic prescriptions in 1,465 patients enrolled in PsoReg using a time-to-event analysis controlling for decision-making variables including disease severity. The analysis also described the non-parametric relationship between age and incident biologic prescriptions using a kernel regression.

Finally, the fourth analysis describes rates of non-persistence in individuals with psoriatic arthritis treated with adalimumab, ustekinumab, and secukinumab using a time-to-event model. A total of 4,649 drug exposure period across 3,918 patients were assessed. Non-persistence was defined as a treatment switch or discontinuation, the latter defined as a failure to refill an existing prescription within two times the days of drug supplied.

Results

The analysis found a statistically significant, negative association between PASI and the EQ-5D (                    =-0.0186, 95% confidence interval [CI]: -0.0360, -0.0201) which was non-linear (  =0.0003, 95% confidence interval [CI]: 0.0001, 0.0004). Incremental PASI improvements for those with less skin involvement were associated with larger increases in quality of life than in those with more skin involvement. 

Skin psoriasis was found to be independently associated with the onset of psychiatric illness (hazard ratio [HR]=1.32, 95% CI: 1.27-1.36) as was somatic comorbidity (HR=2.09, 95%CI: 2.06-2.13). However, the results were compatible with a lack of synergistic effect between skin psoriasis and somatic comorbidity on psychiatric illness (HR=0.93; 95% CI: 0.81-1.04).

Older psoriasis patients appeared less likely to initiate biologic therapies than their younger counterparts after controlling for disease severity and comorbidity (HR=0.97, 95% CI: 0.95-0.99).

Individuals with psoriatic arthritis treated with ustekinumab were found to have lower rates of non-persistence compared to adalimumab (HR=0.56, 95% CI: 0.49-0.64). Secukinumab and adalimumab appeared to have similar rates of non-persistence (HR=1.01, 95% CI: 0.88-1.15), although the results differed in biologic-naïve and biologic-experienced subgroups. The definition of discontinuation was sensitive and had material effects on the results.

Conclusions

Patient characteristics appear to play an important role in a variety of health outcomes in psoriatic disease, demonstrated across four real-world settings. The utilisation of data from routine clinical care enabled the investigation of research questions that are not suitable for clinical trial contexts, providing relevance for patients in everyday clinical practice. The study designs and methodologies applied in this thesis are associated with a variety of strengths and limitations, many of which are closely linked to the observational nature of the data, which have material importance for the interpretation of the results and implications for healthcare and policy. Understanding the associations between patient characteristics and subsequent outcomes is an important element in the delivery of holistic, personalised healthcare.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with allergic comorbidities. However, studies examining comorbidities in childhood AD are incomplete, which may contribute to suboptimal care.

Objective: The objective was to compare the risk of developing different allergic and non-allergic comorbidities among children with AD to that of a matched non-AD reference cohort in Sweden.

Methods: This was a nationwide population-based cohort study using longitudinal data from primary and specialist care registers. Patients with AD were identified by confirmed diagnosis in primary or specialist care. The non-AD reference cohort was randomly drawn from the general population and matched 1:1 with the AD patients. The risk of developing the following conditions was evaluated: hypersensitivity and allergic disorders, neurological disorders, psychiatric disorders, infections, immunological and inflammatory disorders, Type 1 diabetes (T1D), endocrine and metabolic disorders, skeletal disorders, ocular disorders and malignancies.

Results: This study included 165,145 patients with AD (mild-to-moderate [n = 126,681] and severe [n = 38,464]) and an equally sized reference cohort. Patients with AD displayed a higher risk of developing comorbid conditions for all investigated categories, except for T1D and skeletal disorders, compared with the reference cohort. The highest risk compared with the reference cohort was observed for hypersensitivity and allergic disorders (hazard ratio [HR]: 3.87), followed by malignancies (HR: 2.53) and immunological and inflammatory disorders (HR: 2.36). Patients with AD also had higher risk of developing multiple comorbidities (≥2). The risk of comorbidity onset increased alongside AD severity and patients with active AD were associated with increased risk of comorbidity onset compared with patients in remission.

Conclusions: The clinical burden of AD is substantial for children with AD and patients are at an increased risk of developing several comorbid conditions extending beyond the atopic march. Our results also showed a positive association between worsening severity of AD and an increased risk of comorbidity onset.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that has been shown to be associated with allergic comorbidities. However, studies examining comorbidities in patients with AD are incomplete, which may contribute to suboptimal care.

Objectives: The objective was to compare the risk of developing different allergic and nonallergic comorbidities among adult patients with AD to that of a matched reference cohort in Sweden.

Methods: This was a nationwide population-based cohort study using longitudinal data from primary and specialist care registers. AD patients were identified by confirmed diagnosis in primary or specialist care. A non-AD reference cohort was randomly drawn from the general population and matched 1:1 with the AD patients on age, gender, and geographical region. The risk of developing the following conditions was evaluated: asthma, food hypersensitivity, allergic rhinitis, neurological disorders, psychiatric disorders, infections, immunological & inflammatory disorders, type 1 diabetes (T1D), type 2 diabetes (T2D), endocrine & metabolic disorders, skeletal disorders, ocular disorders, cardiovascular diseases, and malignancies.

Results: This study included 107,774 AD patients [mild-to-moderate (n = 92,413) and severe (n = 15,361)] and an equally-sized reference cohort. AD patients displayed a higher risk of developing comorbid conditions for all investigated categories, except for T1D, compared with the reference cohort. The highest risk compared with the reference cohort was observed for allergic comorbidities followed by immunological & inflammatory disorders (hazard ratio: 2.15) and infections (hazard ratio: 2.01). Patients with AD also had higher risk of developing multiple comorbidities (2 or more). The risk of comorbidity onset increased alongside AD severity and patients with active AD were associated with increased risk of comorbidity onset compared with patients in remission.

Conclusions: AD patients are at an increased risk of developing many comorbidities that extend beyond allergic conditions. This study highlights the need for interdisciplinary follow-up of comorbidities in the management of AD patients to reduce overall patient burden.

Background: Real-life evidence on prevalence and management of severe asthma is limited. Nationwide population registries across the Nordic countries provide unique opportunities to describe prevalence and management patterns of severe asthma at population level. In nationwide register data from Sweden, Norway and Finland, we examined the prevalence of severe asthma and the proportion of severe asthma patients being managed in specialist care.

Methods: This is a cross-sectional study based on the Nordic Dataset for Asthma Research (NORDSTAR) research collaboration platform. We identified patients with severe asthma in adults (aged ≥18 years) and in children (aged 6-17 years) in 2018 according to the European Respiratory Society/American Thoracic Society definition. Patients managed in specialist care were those with an asthma-related specialist outpatient contact (only available in Sweden and Finland).

Results: Overall, we identified 598 242 patients with current asthma in Sweden, Norway and Finland in 2018. Among those, the prevalence of severe asthma was 3.5%, 5.4% and 5.2% in adults and 0.4%, 1.0%, and 0.3% in children in Sweden, Norway and Finland, respectively. In Sweden and Finland, 37% and 40% of adult patients with severe asthma and two or more exacerbations, respectively, were managed in specialist care; in children the numbers were 56% and 41%, respectively.

Conclusion: In three Nordic countries, population-based nationwide data demonstrated similar prevalence of severe asthma. In children, severe asthma was a rare condition. Notably, a large proportion of patients with severe asthma were not managed by a respiratory specialist, suggesting the need for increased recognition of severe asthma in primary care.

Background: There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma.

Methods: We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018.

Results: Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma.

Conclusions: Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma.

Background: Atopic dermatitis (AD) is a complex disease with variations in severity and healthcare utilization. Examining patient pathways through analyses of longitudinal patient data provides an opportunity to describe real-world clinical patient care and evaluate healthcare access and treatment.

Objective: To describe longitudinal care pathways including health care management, treatment patterns and disease progression (by proxy measures) in patients with AD.

Materials and methods: This was a longitudinal observational study, which used linked data from national and regional healthcare registers in Sweden. Patients with AD were identified through diagnosis in primary or secondary care or by dispensed medications. Descriptive statistics for number of healthcare visits, type of dispensed drug class, rate of - and time to - referral to secondary care and treatment escalation were calculated.

Results: A total of 341 866 patients with AD distributed as 197 959 paediatric (age < 12), 36 133 adolescent (age ≥ 12- < 18) and 107 774 adult (age ≥ 18) patients were included in this study. Healthcare visits to primary and secondary care and dispensation of AD-indicated treatments were more common during the year in which managed AD care was initiated. Topical corticosteroids (TCSs) and emollients were the most frequently used treatments across all age cohorts while systemic treatment was uncommon in all age cohorts. Among patients who initiated treatment with TCSs, 18.2% escalated to TCSs with higher potency following the start of managed AD care.

Conclusions: We found that healthcare contacts and use of AD-indicated treatments were concentrated in the year during which managed AD care was initiated and decreased significantly thereafter. Since a significant proportion of patients with AD have flares and persistent AD, our results suggest that patients with AD may be monitored infrequently and are undertreated. There is a need to inform practitioners about adequate treatment options to provide individualized care, in particular for patients with persistent severe AD.

Background: Psoriasis is a chronic, autoimmune-mediated inflammatory disorder. Drug persistence is a composite measure of effectiveness, safety, and treatment satisfaction, often estimated using data from administrative databases and clinical registries. Persistence rates calculated from these two data sources appear to be systematically different.

Objective: Review and compare persistence rates of psoriasis-indicated biologics reported in registry and database studies.

Methods: A structured literature search of studies published during 2009-2019 was performed in PubMed and American Academy of Dermatology records to identify research describing persistence with biologic treatments in psoriasis patients. English language retrospective or prospective persistence studies based on database or registry data, and reporting on at least two psoriasis-indicated biologics, of which at least one was ustekinumab, secukinumab, ixekizumab or guselkumab, were included. Single-arm studies, randomized control trials, systematic literature reviews, and studies presenting stratified results only were excluded.

Results: A total of 37 studies (22 registry- and 15 database-derived) comprising 76,000 patients were included. On average, drug persistence collected from registry studies was 18% higher than database studies.

Conclusion: The findings of this study may be used by practitioners to make meaningful comparisons between persistence data derived from registries and databases, and thereby improve clinical decision making.

Background: Atopic dermatitis (AD) is a common inflammatory skin disease while the economic burden of AD by severity is not adequately understood.

Objective: To estimate the societal economic burden and to identify cost determinants of AD.

Methods: In this population-based, controlled cohort study in Sweden, patients with AD were identified through diagnosis codes in primary or secondary care or by dispensed medications using administrative healthcare registers. A reference cohort without AD was randomly selected from the general population. Healthcare costs (primary/secondary care visits and dispensed medication) and indirect costs (care for sick children and long-term sick leave for adults) were calculated annually. AD patients were stratified by age (paediatric [age < 12], adolescent [12 ≤ age < 18] or adult [age ≥ 18]), and severity (mild-to-moderate [M2M] or severe AD) and matched to the reference cohort.

Results: Compared with controls, the annual mean per-patient direct healthcare costs in the first year following diagnosis were €941 and €1259 higher in paediatric patients with M2M and severe AD, respectively. In the first year following diagnosis, the mean indirect cost for care of sick children was €69 and €78 higher per patient in M2M and severe AD, respectively. In adolescents with M2M and severe AD, direct healthcare costs were €816 and €1260 higher, respectively. In adults, healthcare costs were €1583 and €2963 higher in patients with M2M and severe AD, respectively and indirect costs were €148 and €263 higher compared with controls. Management of comorbid medical conditions was an important driver of incremental healthcare costs. Total incremental societal economic burden for AD was €351 and €96 million higher in patients with M2M and severe AD, respectively, compared to controls.

Conclusion: AD is associated with a significant societal economic burden primarily driven by the cost burden of M2M AD due to the high prevalence of this population. Regardless of severity level, management of non-AD comorbidities is a major driver of total costs.

Introduction: The use of real-world data offers a possibility to perform large-scale epidemiological studies in actual clinical settings. Despite their many advantages, administrative databases were not designed to be used in research, and the validation of diagnoses and treatments in administrative databases is needed. The primary objective of this study was to validate an existing algorithm based on dispensed prescriptions and diagnoses of skin conditions to identify pediatric patients with atopic dermatitis (AD), using a diagnosis of AD in primary care as a gold standard.

Methods: Retrospective observational data were collected from nation-wide secondary care and pharmacy-dispensed medication databases and two regional primary care databases in Sweden. An existing algorithm and a Modified algorithm, using skin-specific diagnoses from secondary care and/or pharmacy-dispensed prescriptions to identify patients with AD, were assessed. To verify the presence of AD, diagnoses from primary care were used in the base case and complemented with diagnoses from secondary care in a sensitivity analysis.

Results: The sensitivity (30.0%) and positive predictive value (PPV) (40.7%) of the existing algorithm were low in the pediatric patient population when using primary care data only but increased when secondary care visits were also included in the Modified algorithm (sensitivity, 62.1%; PPV, 66.3%). The specificity of the two algorithms was high in both the base case and sensitivity analysis (95.1% and 94.1%). In the adult population, sensitivity and PPV were 20.4% and 8.7%, respectively, and increased to 48.3% and 16.9% when secondary care visits were also included in the Modified algorithm.

Conclusion: The Modified algorithm can be used to identify pediatric AD populations using primary and secondary administrative data with acceptable sensitivity and specificity, but further modifications are needed to accurately identify adult patients with AD.