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This study investigates the presence of antinuclear antibodies (ANA) in three primary synucleinopathies – Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), compared to healthy controls. Autoinflammatory disorders typically involve the immune system mistakenly attacking the body's own cells and start producing ANA. There is an increasing body of evidence that immune-mediated inflammation is a pathological feature linked to synucleinopathies. To investigate whether this could be autoimmune mediated we analyzed for ANA in the plasma of 25 MSA, 25 PD, and 17 DLB patients, along with 25 healthy controls, using the ANA HEp-2 indirect immunofluorescence antibody assay (ANA HEp-2 IFA). Contrary to initial expectations, results showed ANA HEp-2 positivity in 12% of PD, 8% of MSA patients, 18% of DLB patients, and 17% of healthy controls, indicating no increased prevalence of ANA in synucleinopathies compared to age-matched healthy individuals. Various ANA HEp-2 patterns were identified, but no specific pattern was associated with individual synucleinopathies. We conclude hereby that synucleinopathies are not associated with detectable presence of ANA in plasma. [ABSTRACT FROM AUTHOR]

Objectives To compare the tolerability and effectiveness of two different classes of biological DMARDs [IL-17 and IL-23(p19) inhibitors, IL-17i and IL-23(p19)i] relative to TNF inhibitors (TNFi) regarding the drug survival rates and treatment outcomes in patients with PsA. Methods We emulated a target trial on comparative effectiveness using observational data from a prospective cohort study based on the Parker Institute's PsA cohort (the PIPA cohort). All patients underwent interview and a clinical examination programme at baseline and at follow-up visits at 4 and 12 months. The primary endpoint, drug survival, was assessed up to 12 months from baseline. We estimated hazard ratios from proportional hazards model and used propensity score adjustment in an attempt to deconfound and emulate a random treatment assignment. Results We included a total of 109 patients in the intention-to-monitor population at baseline initiating either TNFi (75 patients), IL-17i (26 patients) or IL-23(19)i (8 patients). Hazard ratios in the propensity adjusted model comparing IL-17i and IL-23(p19)i with TNFi were 1.36 (95% CI 0.59–3.14) and 0.56 (95% CI 0.10–3.24), respectively. TNFi and IL-17i had comparable effects regarding response rates and changes in clinical outcomes after 12 months, whereas IL-23(p19)i tended to perform better overall. Conclusion No decisive differences between drugs were observed at group level regarding drug survival and clinical outcomes after 12 months. TNFi, IL-17i and IL-23(p19)i may all be considered equally effective in the treatment of patients with PsA, advocating for investigating more in personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Objectives To assess the effectiveness and tolerability of first- and second-line interleukin (IL)-17A inhibitor treatment in PsA patients from 2014 to 2021 using data from the Danish Rheumatology Registry (DANBIO) by investigating adherence to therapy. Method PsA patients recorded in the DANBIO who received a first- or second-line IL-17A inhibitor treatment were included in this study. All patients included had previously received one or more TNF inhibitor treatment. Baseline characteristics were analysed in subgroups as first-line IL-17A inhibitor treatment and second-line IL-17A inhibitor treatment. Adherence to therapy of first- or second-line IL-17A inhibitor treatments was reported as Kaplan–Meier plots. Results A total of 534 patients were included in the study, with 534 first-line switchers (secukinumab: 510, ixekizumab: 24) and 102 second-line switchers (secukinumab: 35, ixekizumab: 67). Baseline characteristics showed a similar HAQ and visual analogue scale (VAS) for pain. VAS global, 28-joint DAS with CRP and the previous number of biologic DMARD treatments were similar, with a greater value for second-line switchers. First-line ixekizumab-treated patients present a younger age, greater percentage of females, a lower disease duration and a lower CRP value. Concomitant MTX use was greater for the first-line secukinumab-treated patients. First- and second-line switchers had a similar adherence to therapy. Second-line secukinumab and second-line ixekizumab switchers showed a similar adherence to treatment. Conclusion PsA patients receiving first- or second-line IL-17A inhibitors showed homogeneous baseline characteristics and similar adherence to therapy. Treatment failure of the first IL-17A inhibitor treatment should not preclude a second-line IL-17A inhibitor treatment. [ABSTRACT FROM AUTHOR]

This study aimed to examine the changes in biomarker levels in responders and non-responders to tumor necrosis factor alpha inhibitor (TNFi) and interleukin-17A inhibitor (IL-17Ai) in psoriatic arthritis (PsA) patients over a 4-month period after treatment initiation. A total of 68 PsA patients initiating either TNFi, IL-17Ai, or methotrexate treatment were included. Blood plasma and clinical outcome measures were collected adjacent to treatment initiation and after four months. A commercially available multiplex immunoassay was included to evaluate 54 biomarkers. Mean changes were used to evaluate change over time. A statistically significant decrease in pro-inflammatory cytokines IL-6 (log-transformed mean change −0.97, 95%CI −4.30; 2.37, [p = 0.032]) and an increase in anti-inflammatory IL-10 (0.38, 95%CI 1.74; 2.50 [p = 0.010]) were seen in TNFi responders. Meanwhile, a statistically significant increase in the target cytokine IL-17A was seen in both IL-17Ai responders (2.49, 95%CI −1.84; 6.85 [p = 0.031]) and non-responders (2.48, 95%CI −1.46; 6.41 [p = 0.001]). This study demonstrated differing changes in cytokine levels when comparing treatment responders and non-responders, highlighting the need to improve the understanding of the different immune response mechanisms explaining different responses to medical treatment in PsA patients. [ABSTRACT FROM AUTHOR]

Acute mixed cellular and antibody-mediated rejection (MR) has an estimated prevalence of 7.8%. However, knowledge of MR immune pathogenesis in cardiac graft rejection remains sparse. We report a case of acute MR in a heart transplant patient with a mutation in the MYH7 gene encoding the protein b-myosin heavy chain, resulting in familial hypertrophic cardiomyopathy. The patient presented with substantial eosinophilic infiltration and extensive production of Human Leukocyte Antigen (HLA)-antibodies associated with shared epitopes. Eosinophilic infiltration in the endo- and myocardium was diagnosed in routine post-transplant biopsies stained with hematoxylin-eosin on day 6 after transplantation. On day 27, the patient presented with dyspnea, weight gain, increased pro-brain natriuretic peptide, and was hospitalized due to suspected acute rejection. Endomyocardial biopsies showed eosinophils in endo- and myocardium with additional lymphocytes and hyperplastic endothelium. Immunohistochemistry, including CD31/CD68 double stain confirmed endothelium-associated macrophages in capillaries and severe C4d positivity in the capillaries and endocardial endothelium. Lymphocytes were identified as primarily CD45+/CD3+ T cells with a concomitant few CD45+/CD20+ B cells. HLA-antibody analysis demonstrated a significant increase in 13 HLA-antibodies present in pre-transplant-serum, of which anti-B7 was donor-specific, and 23 strong de-novo HLA-class I antibodies of which anti-B62 was donor-specific. 72% of HLA-antibodies, including the two donor-specific antibodies, shared the same HLA antigen epitope; 43P+69A or 163L+167W. This is a case reporting both HLA-antibody and pathohistological data indicating the need for better understanding of interactions between cellular and antibody-mediated immune response mechanisms in graft rejection, and the significance of pretransplant donor-specific antibodies during immunological pre-transplant risk assessment. [ABSTRACT FROM AUTHOR]

This study aimed to explore the dynamic interactions between 32 cytokines and biomarkers in Psoriatic Arthritis (PsA) patients to compare cytokine signatures of treatment responders and non-responders. Biomarkers were measured before and after four months of treatment in 39 PsA patients initiating either Tumor Necrosis Factor alpha inhibitor (TNFi) or Interleukin-17A inhibitor (IL-17Ai). Response to treatment was defined by the composite measure, Disease Activity in Psoriatic Arthritis (DAPSA). A two-component principal component analysis (PCA) was implemented to describe cytokine signatures comparing DAPSA50 responders and non-responders. The cytokine signature of TNFi responders was driven by the correlated cytokines interferon γ (IFNγ) and IL-6, additionally associated with IL-12/IL-23p40, TNFα, and CRP, while the cytokine signature of TNFi non-responders was driven by the correlated cytokines IL-15, IL-8, and IFNγ. IL-17Ai responders were characterized by contributions of strongly correlated Th17 inflammatory cytokines, IL-17A, IL-12/IL-23p40, IL-22 to the cytokine signature, whereas IL-17A and IL-12/IL-23p40 did not demonstrate significant contribution in IL-17Ai non-responders. Based on PCA results it was possible to differentiate DAPSA50 responders and non-responders to treatment, endorsing additional examination of cytokine interaction models in PsA patients and supporting further PsA patient immune stratification to improve individualized treatment of PsA patients. [ABSTRACT FROM AUTHOR]

Fatigue is a common symptom reported by patients with chronic immunoinflammatory diseases and with profound negative implications on health-related quality of life. This study aimed to delineate underlying components contributing to fatigue in patients with inflammatory bowel disease (IBD) receiving biologic therapy. Cross-sectional questionnaire study of all patients with IBD receiving any biologic therapy at a tertiary IBD center. Fatigue was assessed by Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F). Disease activity and quality of life were evaluated by generic questionnaires. Principal component analysis (PCA) was used to identify components of variables explaining fatigue. Three hundred patients with IBD were included. Moderate-to-severe fatigue defined as FACIT-F ≤ 39 was present in half of the included patients. PCA condensed variables associated with fatigue into three main components contributing to 49% of observed fatigue. The first component, explaining 21% of fatigue, included factors related to disease chronicity, e.g., long disease duration, high number of previously used biologic therapies, presence of previous intestinal surgery, and increasing age. The second component explained 14% of fatigue and comprised disease activity-related aspects, e.g., disease activity indices and C-reactive protein. The third explained 14% of fatigue and comprised various nutritional deficiencies. Fatigue can partly be explained by chronicity, disease activity, and nutritional deficits. However, the cause of fatigue is unexplained in approximately half of the patients with IBD supporting that fatigue can be an independent, systemic extraintestinal disease manifestation in IBD. [ABSTRACT FROM AUTHOR]

Objective The objective was to investigate interplay and physical and mental component scores between change (Δ) in health-related quality of life (HRQoL) quantified by the physical component score (PCS) and mental component score (MCS) retrieved from short-form health survey (SF-36), change in disease activity (ΔDAS28CRP) and manifestations of PsA. Methods PsA patients initiating new medical therapy were enrolled. Independent disease measures evaluating disease activity, enthesitis, psoriasis, pain and fatigue were collected at treatment initiation and after 4 months. Interplay between independent disease measures and dependent outcome measures, ΔPCS and ΔMCS, was described with univariate regression analyses. Multivariate regression analyses were applied to assess the impact of independent variables, such as individual disease outcome measures vs ΔDAS28CRP on ΔPCS and ΔMCS. Results One hundred and eight PsA patients were included. In the univariate regression analyses, improvement in fatigue, pain and disability were associated with improvement in ΔPCS (β; −2.08, −0.18 and −13.00, respectively; all P < 0.001) and ΔMCS (β; −1.59, −0.12 and −6.07, respectively; P < 0.001, P < 0.001 and P = 0.003, respectively). When patient-reported outcomes were included in the final multivariate models, improvements in ΔPCS and ΔMCS were associated with improvements in pain, fatigue and disability (P < 0.001). Improvement in enthesitis impacted ΔPCS positively (β −0.31, P < 0.001). No association was found between change in skin psoriasis, ΔPCS and ΔMCS (β 0.15, P = 0.056 and β 0.05, P = 0.561, respectively). Conclusion In this PsA patient cohort, diminishing pain, disability and fatigue improved PCS and MCS significantly. Changes in enthesitis and psoriasis did not grossly impact HRQoL compared with DAS28CRP. Individual PsA manifestations influence HRQoL differently, which is important clinically when targeting treatment. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov , NCT02572700. [ABSTRACT FROM AUTHOR]

Objectives To explore the prognostic value of pre-specified comorbidities on treatment outcomes in PsA, and to compare baseline data with cutaneous psoriasis without arthritis and healthy controls (HC). Methods Patients initiating conventional synthetic/biological disease-modifying antirheumatic drugs were enrolled in this clinical observational cohort study, and data on comorbidities, and clinical and patient-reported outcomes were retrieved at baseline and after 4 months. Pearson's chi-squared tests were performed to investigate the prognostic value of pre-specified comorbidities and achievement of ACR20, DAPSA50 and MDA. Mann–Whitney U tests were used to compare OMERACT PsA Core Outcome Set (COS) measures at baseline and follow-up for the pre-specified comorbidities. Results A total of 100 PsA patients were included at baseline. Statistically significantly fewer patients with obesity achieved DAPSA50 compared with patients without obesity (P  =0.035), and fewer patients with hypertension (P  =0.034) and Charlson Comorbidity Index (CCI) ≥1 (P  =0.027), respectively, achieved MDA compared with patients without these comorbidities. Patients with obesity, hypertension, widespread pain, and CCI ≥1 had significantly worse COS measures at follow-up compared with patients without these comorbidities. At baseline, patients with PsA had higher disease burden compared with patients with cutaneous psoriasis and HC, including higher pain (P  <0.001) and fatigue (P  <0.001) scores, and more widespread pain (P  =0.002). Conclusion Obesity, hypertension and CCI ≥1 were prognostic factors for poorer treatment outcome rates in PsA. Pain and fatigue were more frequently reported among patients with PsA compared with patients with cutaneous psoriasis and HC. Trial registration The Danish National Committee on Health Research Ethics: H-15009080; Data Protection Agency: 2012-58-0004; ClinicalTrials.gov: NCT02572700. [ABSTRACT FROM AUTHOR]

Purpose: Optic disc drusen (ODD) are calcified optic nerve head deposits. Objectives of this study were to examine the prevalence of ODD in eyes removed by enucleation and to describe related histopathological signatures of ODD and surrounding tissues. Methods: The study was a retrospective observational case series study assessing and re‐evaluating enucleated eyes in Denmark from 1980 to 2015 by microscopy. Individual ODD were described based on size, number and location (superficial and/or deep) within the optic nerve. Optic nerve heads with ODD were assessed for elevated discs, retinal nerve fibre layer (RNFL) thickness, oedematous axons and presence of localized peripapillary axonal distension (LPAD) equivalent to the peripapillary hyperreflective ovoid mass‐like structures seen on optical coherence tomography. Results: Microscopy of 1713 eyes revealed ODD in 31 eyes equivalent to a prevalence of 1.8%. Optic disc drusen (ODD) were seen as circular shapes of different sizes and varying number. Elevated discs were present in 15 (54%) of the cases. Thickening of the superficial RNFL was present in eyes with large deeply located ODD. For more superficial ODD of approximately same size, the RNFL was thinner. Oedematous axons were present in three eyes. Localized peripapillary axonal distension (LPAD) was seen in five eyes. Conclusions: Prevalence of ODD in this study of histopathological signatures was higher than the prevalence found in clinical studies. Our results suggest that large, deep ODD might cause crowding and herniation of axons in the optic nerve head leading to a thickened superficial nerve fibre layer, pseudopapilledema and LPAD. [ABSTRACT FROM AUTHOR]

Objective: To assess the importance of trial characteristics as contextual factors when evaluating the treatment effect of targeted therapies for patients with psoriatic disease.Methods: We identified randomized controlled trials (RCTs) evaluating targeted therapies approved for psoriatic arthritis (PsA) and psoriasis (8 biologics and apremilast). The effect of targeted therapies was analyzed in the 2 psoriatic conditions combined by using drug retention as a common outcome, and separately by using the American College of Rheumatology 20% improvement criteria (ACR20) for PsA and the Psoriasis Area Severity Index 75% improvement score (PASI75) for psoriasis. We explored potential effect modification of trial characteristics in stratified and meta-regression analyses. Odds ratios (ORs) were calculated and compared among the trial eligibility criteria via the ratio of ORs.Results: Forty-eight PsA and psoriasis trials (51 comparisons; 17,737 patients) were eligible. Overall retention was OR 2.16 (95% confidence interval [95% CI] 1.70-2.75) with higher odds for PsA trials compared with psoriasis trials (ratio of ORs 2.55 [95% CI 1.64-3.97]). The eligibility criteria "targeted therapy history," "minimum required disease duration," "required negative rheumatoid factor," and "required Classification Criteria for Psoriatic Arthritis criteria" were of importance for achieving ACR20 in PsA. The eligibility criterion "minimum required disease duration" was of importance for achieving PASI75 in psoriasis. A total of 7 PsA trials had rescue before time-point-of-retention reporting (adaptive trials).Conclusion: From this exploratory meta-epidemiologic study, we now have evidence from RCTs to support the notion that patients with PsA are more likely to adhere to targeted therapies compared to patients with psoriasis. Furthermore, we identified a few contextual factors of importance in regard to achieving ACR20 in PsA trials and PASI75 in psoriasis trials. [ABSTRACT FROM AUTHOR]

Objective: The objective of this population-based cohort study was to investigate the impact of comorbidities on disease activity, treatment response, and persistence with the first-tried tumor necrosis factor inhibitor (TNFi) in patients with psoriatic arthritis (PsA).Methods: Data on patient characteristics, disease activity, and treatment response and persistence were obtained from the DANBIO registry. Information on comorbidities according to the Charlson Comorbidity Index (CCI) was obtained through linkage with the Danish National Patient Register. Kaplan-Meier plots and Cox proportional hazard regression analyses were performed. Percentages of patients achieving relevant clinical responses were calculated.Results: We identified 1,750 patients eligible for analyses. Patients with higher CCI scores had higher disease activity measures at baseline and increased occurrence of depression and/or anxiety. Kaplan-Meier curves showed shorter persistence with treatment for patients with a CCI score ≥2 (log-rank P < 0.001) and for patients with depression and/or anxiety (P = 0.027) compared to patients without comorbidities. In multivariate analysis, a CCI score ≥2 was associated with reduced TNFi persistence compared with patients without comorbidities (hazard ratio 1.72 [95% confidence interval 1.26-2.37]; P = 0.001). A smaller proportion of patients with a CCI score ≥2 achieved European League Against Rheumatism (EULAR) good response (P < 0.001) and EULAR good-or-moderate response (P < 0.001) at 6 months compared with patients without comorbidities.Conclusion: The presence of comorbidities was associated with higher baseline disease activity, shorter TNFi persistence, and reduced clinical response rates in a cohort of Danish patients with PsA. [ABSTRACT FROM AUTHOR]

Background It has been demonstrated that weight loss improves symptoms in obese subjects with knee osteoarthritis (KOA). A parallel change in cartilage morphology remains to be demonstrated. Purpose To demonstrate a parallel change in cartilage morphology. Material and Methods Obese patients with KOA were examined before and after weight loss over 16 weeks. Target knee joints were radiographically assessed by the Kellgren/Lawrence grading (KLG) system. Patients with KLG-1 and 2 changes in the lateral compartment were included. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) was performed using intra-articular contrast. Results Nine patients with lateral KLG-1 and ten patients with lateral KLG-2 were studied. There were no group differences regarding the lateral compartment baseline dGEMRIC T1 values: median = 497 ms (KLG-1) and 533 ms (KLG-2) ( P = 0.12), or regarding reduction in body mass index (BMI) after 16 weeks: 12.8% versus 11.4% ( P = 0.74). In the KLG-1 group, several cases of increased dGEMRIC T1 values were seen and median value decreased significantly less than in KLG-2 group (15 ms versus 41 ms, P = 0.03) after weight loss. Conclusion Improvement of cartilage quality, assessed with dGEMRIC, after weight loss might be possible in early stage KOA (KLG-1), but not in later stage KOA (KLG-2). The results may suggest a point of no return for improvement of cartilage quality that should be tested in larger trials. [ABSTRACT FROM AUTHOR]

Objectives: Exploring patients' perspectives for significant factors of relevance in living with a chronic disease is important to discover unmet needs and challenges. The primary objective of this study was to explore disease-related and treatment-related issues and concerns experienced by adults with spondyloarthropathies (SpA) and associated diseases. As a secondary objective, we wanted to explore whether these factors were generic or disease dependent., Design: We used group concept mapping (GCM), a validated qualitative method, to identify disease-related and treatment-related issues and concerns. Participants generated statements in the GCM workshops and organised them into clusters to develop concepts. Furthermore, participants rated each statement for importance from 1: 'not important at all' to 5: 'of great importance'., Setting: Participants were recruited during routine care at the outpatient clinic at the hospitals in the period from May 2018 to July 2022., Participants: Eligible participants were adults ≥18 years and diagnosed with axial spondyloarthritis (AxSpA), psoriatic arthritis (PsA), psoriasis (PsO) or inflammatory bowel disease -split into Crohn's disease (CD) and ulcerative colitis (UC)., Results: 52 patients participated in the 11 workshops divided into groups according to their diagnosis. They created a total of 1275 statements that generated 10 AxSpA concepts, 7 PsA concepts, 7 PsO concepts, 10 CD concepts and 11 UC concepts. The highest rated concepts within each disease group were: AxSpA, 'lack of understanding/to be heard and seen by healthcare professionals' (mean rating 4.0); PsA, 'medication (effects and side effects)' (mean rating 3.8); PsO, 'social and psychological problems, the shame' (mean rating 4.0); CD, 'positive attitudes' (mean rating 4.3) and UC; 'take responsibility and control over your life' (mean rating 4.0)., Conclusion: People with SpA and associated diseases largely agree on which concepts describe their disease-related and treatment-related issues and concerns with a few of them being more disease-specific., Competing Interests: Competing interests: ZRS: none to declare. MS: has received research funding from Pfizer and Lilly. KRC: has served as speaker for Janssen and Pfizer and received funding from Pfizer and Gilead Nordic. MAA: Consultancy for Janssen and AbbVie. RLH: None to declare. SFT: Speaker or advisor for Sanofi, AbbVie, LEO Pharma, Pfizer, Eli Lilly, Novartis, UCB Pharma, Almirall and Janssen Pharmaceuticals, and received research support from Sanofi, AbbVie, LEO Pharma, Novartis, UCB Pharma, and Janssen Pharmaceuticals, outside the submitted work. MM: None to declare. LD: support for attending conferences from Janssen, UCB and Boehringer Ingelheim. Research grant from BMS, outside the submitted work. LEK: has served as a speaker and consultant for Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen and received research grants from Pfizer, AbbVie, UCB, Biogen, Novartis, Eli Lilly, and Janssen, outside the submitted work. TSJ: has served as a speaker and consultant for AbbVie, Pfizer, Roche, Novartis, UCB, Biogen, Gilead and Eli Lilly, outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Physicians tend to focus on biomedical targets while little is known about issues important to patients. We aimed to identify critical concepts impacting patients with inflammatory bowel disease (IBD)., Design: We performed a survey of patients with IBD in biologic therapy (n=172) and used a validated qualitative method called group concept mapping (GCM) in patient workshops. The survey included 13 questions on attitudes toward symptoms and issues related to IBD. In the eight workshops, patients (n=26) generated statements later clustered into concepts identifying issues impacting a patient's life. Patients ranked the statements., Results: In the survey, patients' mean age were 40 years (SD 13), 53% were women, and 38% had ulcerative colitis. They identified fatigue (57%) and stool frequency (46%) as the most critical symptoms impacting their daily lives regardless of disease activity. In the GCM workshops with Crohn's disease (n=13) (median age 42 years (IQR 39-51) and 62% were women), 335 statements divided among 10 concepts were generated, and the three most important concepts were 'Positive attitudes', 'Accept and recognition', and 'Sharing knowledge and experiences in life with Crohn's disease'. In the workshops with ulcerative colitis (n=13) (median age 43 years (IQR 36-49) and 69% were women), 408 statements divided into 11 concepts were generated; the most important concepts were 'Take responsibility and control over your life', 'Medication', and 'Everyday life with ulcerative colitis'., Conclusion: Focusing solely on IBD symptoms, patients identified fatigue and stool frequency to impact daily life the most. However, when investigating the disease burden in a broader perspective beyond classic IBD symptoms, patients identified concepts with focus on emotional health to be most important., Trial Registration: The Copenhagen University Hospital, Herlev and Gentofte approved the questionnaire and methodology (work-zone no: 18015429)., Competing Interests: Competing interests: KRC participated in an advisory board for Gilead Nordic and received unrestricted grants from Pfizer and Gilead Nordic, and served as a speaker for Janssen Pharmaceuticals. MS received research funding from Eli Lilly and Pfizer. CS served as a speaker and advisory board member for MSD. JB has been a consultant and/or an advisory board member and received fees and/or research grants from AbbVie, Pfizer, MSD, Takeda, Janssen, and Gilead. TSJ served as a speaker and consultant for AbbVie, Pfizer, Roche, Novartis, UCB, Biogen, Gilead, and Eli Lilly. LEK served as a speaker and consultant for Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen and received research grants from Pfizer, AbbVie, UCB, Biogen, Novartis, Eli Lilly, and Janssen. MAA and SB declare no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The development of digital health solutions for current health care settings requires an understanding of the complexities of the health care system, organizational setting, and stakeholder groups and of the underlying interplay between stakeholders and the technology. The digital health solution was founded on the basis of an information and communication technology platform and point-of-care devices enabling home-based monitoring of disease progression and treatment outcome for patients with rheumatoid arthritis (RA)., Objective: The aim of this paper is to describe and discuss the applicability of an iterative evaluation process in guiding the development of a digital health solution as a technical and organizational entity in three different health care systems., Methods: The formative evaluation comprised the methodologies of contextual understanding, participatory design, and feasibility studies and included patients, healthcare professionals, and hardware and software developers. In total, the evaluation involved 45 patients and 25 health care professionals at 3 clinical sites in Europe., Results: The formative evaluation served as ongoing and relevant input to the development process of the digital health solution. Through initial field studies key stakeholder groups were identified and knowledge obtained about the different health care systems, the professional competencies involved in routine RA treatment, the clinics' working procedures, and the use of communication technologies. A theory-based stakeholder evaluation achieved a multifaceted picture of the ideas and assumptions held by stakeholder groups at the three clinical sites, which also represented the diversity of three different language zones and cultures. Experiences and suggestions from the patients and health care professionals were sought through participatory design processes and real-life testing and actively used for adjusting the visual, conceptual, and practical design of the solution. The learnings captured through these activities aided in forming the solution and in developing a common understanding of the overall vision and aim of this solution. During this process, the 3 participating sites learned from each other's feed-back with the ensuing multicultural inspiration. Moreover, these efforts also enabled the consortium to identify a 'tipping point' during a pilot study, revealing serious challenges and a need for further development of the solution. We achieved valuable learning during the evaluation activities, and the remaining challenges have been clarified more extensively than a single-site development would have discovered. The further obstacles have been defined as has the need to resolve these before designing and conducting a real-life clinical test to assess the outcome from a digital health solution for RA treatment., Conclusions: A formative evaluation process with ongoing involvement of stakeholder groups from 3 different cultures and countries have helped to inform and influence the development of a novel digital health solution, and provided constructive input and feedback enabling the consortium to control the development process., (©Anne Lee, Marianne Sandvei, Hans Christian Asmussen, Marie Skougaard, Joanne Macdonald, Jakub Zavada, Henning Bliddal, Peter C Taylor, Henrik Gudbergsen. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 16.07.2018.)