OBJECTIVE:A self-management app, Urika, was developed to remotely monitor and support patients when initiating urate-lowering therapy (ULT). The objective was to test the overall feasibility of a future randomized controlled trial of a digital treat-to-target gout-care approach using Urika in secondary care. METHOD:Feasibility was tested among patients with gout in specialized healthcare over 3 months. The predefined set of feasibility criteria included aspects of technical, operational, and trial feasibility, as well as the feasibility of collecting clinical outcomes. Overall feasibility would be deemed acceptable if ≥ 70% of the predefined criteria were achieved. Patient participants entered their measured serum urate, ULT medication, start dose, and flare medication into the app. The app provided instructions about dose escalations. Patient characteristics and patient-reported outcome measures were collected by digital questionnaires, and app experiences were collected in semi-structured telephone interviews. RESULTS:The study included 21 males aged 29-71 years. In total, 27/31 (87%) of the predefined feasibility criteria were achieved, 85% of patients rated their satisfaction with the app ≥ 8 on a 0-10 numeric rating scale, and 90% reported being satisfied/very satisfied with the gout treatment. Ten patients were interviewed, giving mainly positive feedback on the Urika app. No safety issues were identified in this small sample. CONCLUSION:The overall feasibility of the Urika app and the study logistics were satisfactory. The study results have been used to improve the app functions and decide study logistics in an ongoing randomized controlled trial of a digital treat-to-target gout-care approach.Trial Registration Number: ClinicalTrials.gov: NCT06211322, registered 18 January 2024.
OBJECTIVE:To define the demographics of Kawasaki disease (KD) in Sweden during a 32 year period. METHOD:Routinely collected administrative and healthcare data from nationwide Swedish registers were collected for this population-based cohort study. The case definition was individuals under the age of 25 and diagnosed with KD from 1987 to 2018. Main measures included incidence rate, year and month of diagnosis, sex and age at diagnosis, patient's and parents' world region of birth, and home county. RESULTS:In total, 1917 cases were identified. Median age at diagnosis was 2.82 years (interquartile range 1.47-5.13) and 62% were males. Relative incidence rates in winter [1.29, 95% confidence interval (CI) 1.14-1.47] and spring (1.21, 95% CI 1.07-1.38) were higher than in the reference season (summer), while incidence over the study period varied geographically across counties, with no discernible pattern. The incidence rate in the population increased during the 32 year period from 3.6 to 12.1 (95% CI 9.1-15.2) per 100 000 under-5-year-olds during the last 5 years of the study. This increase related mainly to cases with one or two parents of non-Swedish, predominantly Asian and African, origin. Two significant peaks in incidence rates in 2008 and 2015 were also observed, mainly relating to cases with two Swedish-born parents. CONCLUSION:Our study confirms the age and sex distribution as well as seasonal variation and occurrence of peak years of KD. Migration patterns were associated with increasing numbers of KD, which is important to consider for healthcare planning and for defining risk groups.
OBJECTIVES:To compare Sámi and non-Sámi patients with psoriatic arthritis (PsA) and evaluate potential differences in treatment and joint damage. METHOD:A total of 424 adult PsA patients meeting the ClASsification for Psoriatic ARthritis (CASPAR) criteria were recruited from the Norwegian Arthritis Registry and hospitals in northern Norway. A questionnaire from the SAMINOR (a study in regions with Sámi and Norwegian populations) was used to identify Sámi and non-Sámi patients. Demographic and clinical characteristics, joint damage, and disease-modifying anti-rheumatic drug treatment data were compared between the groups. Binary logistic regression was used to adjust for age and gender differences. RESULTS:Sixty Sámi and 364 non-Sámi patients were identified, and the groups were comparable in demographic characteristics and disease activity measurements. Sámi patients experienced more joint damage than non-Sámi patients (42% vs 26%, p = 0.010), and the highest rate was observed among Sámi men (p = 0.005). Sámi patients also had a higher prevalence of arthritis and axial involvement (92% vs 76%, p = 0.007 vs 32% vs 20%, p = 0.033). In addition, Sámi men showed significant underutilization of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) (83% vs 92%, p = 0.031), particularly methotrexate (68% vs 90%, p = 0.002). CONCLUSION:Sámi PsA patients show higher rates of axial involvement, arthritis, and joint damage than their non-Sámi peers. Furthermore, Sámi patients demonstrate underutilization of csDMARDs. These findings underscore the importance of implementing culturally adapted healthcare strategies to improve treatment outcomes for Sámi patients with PsA.
OBJECTIVE:Positron emission tomography/computed tomography (PET/CT) enables the visualization of vascular inflammation in Takayasu arteritis (TAK). However, the prognostic significance of PET/CT-based arterial involvement remains unclear. This study aimed to classify the distribution patterns of vascular lesions in treatment-naïve TAK using PET/CT and evaluate their association with clinical outcomes. METHOD:Patients with TAK who underwent PET/CT before treatment initiation were retrospectively analysed. Hierarchical clustering was performed based on the distribution of arterial 18F-fluorodeoxyglucose uptake. The clinical outcomes, including relapse and large-vessel complications, were analysed according to the resulting clusters using survival analyses. Longitudinal changes in PET/CT findings and clinical activity were assessed. RESULTS:Thirty patients (90% women) were included, with a median follow-up of 4.8 years and median age at diagnosis of 48 years. Three distinct PET/CT-based clusters were identified: thoracic (43%), diffuse (30%), and localized (27%). The diffuse type showed the highest relapse rate 24.1/100 person-years, p = 0.04), whereas the thoracic type tended to be associated with more vascular complications (13.9/100 person-years, p = 0.12). The Numano classification did not always correspond to PET/CT-based clusters or predict clinical outcomes. A PET Vascular Activity Score ≥ 7 was associated with relapse but not with vascular complications. PET/CT activity persisted despite clinical inactivity in some cases, which may cause future relapse. CONCLUSION:PET/CT-based classification suggested three distinct TAK subtypes with different clinical outcomes. The diffuse type was significantly associated with relapse, whereas the thoracic type caused vascular complications. PET/CT provided superior risk stratification compared to the conventional classification.
OBJECTIVE:To determine whether serum immunoglobulin A (IgA) identifies an extra-articular-prone phenotype in axial spondyloarthritis (axSpA) and assess its clinical utility. METHOD:We retrospectively analysed 402 patients with axSpA. Elevated IgA was defined as > 4.0 g/L. Associations with extra-articular manifestations (EAMs) were evaluated by logistic regression, and time to first EAM by Kaplan-Meier and Cox models. Discrimination and clinical utility were assessed. RESULTS:During follow-up, 45.5% of patients developed ≥1 EAM and 8.7% developed ≥2. Elevated IgA occurred in 15.0% overall but was more common in patients with multiple EAMs (40.6%) than in those without (10.9%) or with a single EAM (14.7%); corresponding odds ratios were 5.57 (95% CI 2.41-12.89, p < 0.001) and 3.98 (1.66-9.54). Elevated IgA predicted ≥2 EAMs with 40.6% sensitivity, 89.0% specificity, and an area under the curve of 0.65, rising to 0.78 when combined with C-reactive protein (CRP). Kaplan-Meier analysis showed reduced EAM-free survival with elevated IgA (p = 0.008). In Cox models, elevated IgA independently predicted incident EAMs (hazard ratio 2.28, 95% CI 1.18-4.40, p = 0.014). Decision-curve analysis indicated a positive net benefit. Crohn's disease was overrepresented among patients with elevated IgA (33.3% vs 11.4%, p < 0.0001). CONCLUSION:Elevated serum IgA delineates an intestinally biased, extra-articular-prone axSpA phenotype and provides actionable information beyond CRP, supporting the integration of IgA-based risk stratification into EAM surveillance.
OBJECTIVE:To describe the epidemiology, organ involvement, histopathological patterns, and clinical management of immunoglobulin G4-related disease (IgG4-RD) in Stockholm County, Sweden. METHOD:Patients with an International Classification of Diseases, 10th revision, Swedish Edition (ICD-10-SE) diagnosis of IgG4-RD recorded between 2019 and 2023 were identified from the Swedish National Patient Register, encompassing all diagnoses recorded in inpatient and specialist outpatient care. Clinical data, laboratory results, histopathology reports, and treatment information were obtained through systematic medical record review. RESULTS:In total, 112 patients with a registered IgG4-RD diagnosis were identified, of which 95 diagnoses were confirmed after medical record review. The cohort was predominantly male (68%), and 60% had disease involvement of two or more organs. Elevated serum IgG4 was present in 71% of patients. The pancreas, hepatobiliary system, and kidneys were the most frequently affected organs, while salivary gland involvement was comparatively uncommon. Among patients who underwent biopsy (76%), a majority showed histopathological features supportive of IgG4-RD, although only a minority fulfilled multiple histopathological criteria. Comorbidities at the time of diagnosis were similar to those observed in the general older population, although an elevated prevalence of nasal polyposis and asthma was observed. Most patients received systemic glucocorticoids, either alone or in combination with rituximab. Overall, the prognosis was favourable, with high remission rates. CONCLUSION:IgG4-RD in Stockholm County shows a pancreatohepatobiliary-renal dominant pattern, with relatively few glandular cases compared to Asian and US cohorts. Histopathological confirmation was supportive in most biopsied patients, although many affected organs were not biopsied.
OBJECTIVE:To describe the clinical features of six patients diagnosed with both rheumatoid arthritis (RA) and granulomatosis with polyangiitis (GPA), as well as their anti-neutrophil cytoplasmic antibody (ANCA) status and human leucocyte antigen (HLA) phenotypes. METHOD:Patients diagnosed with both RA and GPA were identified among people followed at our department for ANCA-associated vasculitis. Genomic HLA typing was performed using routine methods. RESULTS:We identified six patients diagnosed with both RA and GPA. All patients were women, five were myeloperoxidase (MPO)-ANCA positive, one was proteinase 3 (PR3)-ANCA positive, five had erosive joint disease, and all patients were immunoglobulin M-rheumatoid factor and/or anti-cyclic citrullinated peptide antibody positive. Five had localized GPA, one had systemic GPA, four had subglottic stenosis, and three had saddle nose deformity. The median time between the two diagnoses was 13 (range 7-17) years. Four patients had RA before GPA, while two had GPA before RA. The MPO-ANCA-positive patients all had an HLA-DR4/DQ8/DPB1*04:01 phenotype. CONCLUSION:In this case series of patients diagnosed with both RA and GPA, a long latency period between the two diagnoses was observed in all cases. All patients were women, the majority had erosive arthritis, and many patients were affected by saddle nose deformity and/or subglottic stenosis. MPO-ANCA was present in the majority of patients, which has not been described before. All patients were HLA-DR4/DQ8/DPB1*04:01 positive. These findings may contribute to our understanding of the underlying pathogenesis and the clinical recognition of this rare disease overlap.
OBJECTIVE:Avacopan (AVAC), an oral selective C5a receptor inhibitor, has been approved for treatment in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Outside randomized controlled studies, real-world data are scarce. The aim of this study was to provide further insight into the clinical experience of AVAC. METHOD:We analysed data from 16 patients with severe AAV included in an AVAC compassionate use programme. Disease activity was estimated with the Birmingham Vasculitis Activity Score (BVAS). Fatigue was assessed using the Multidimensional Assessment of Fatigue (MAF). RESULTS:Thirteen patients (81%) were diagnosed with granulomatosis with polyangiitis (GPA) and three (19%) with microscopic polyangiitis. The mean age at AVAC initiation was 51 (range 16-74) years. The median [interquartile range (IQR)] BVAS score was 10 (3.25-13.25) at baseline and 0 (0-0) at 6 months (p < 0.0001). All but one reached clinical remission. Prednisolone was tapered from a median (IQR) dose of 25 (20-60) to 2.5 (0-5) mg/day at 6 months (p = 0.0001). Eight patients discontinued prednisolone [median time 2.5 month1 week to 10 months)]. The median (IQR) estimated glomerular filtration rate in patients with renal AAV (n = 10) increased from 50 (13-75) to 58 (15.5-88) mL/min/1.73 m2 at 6 months (p = 0.055). One patient progressed to end-stage kidney disease, while another was able to discontinue haemodialysis. Serious adverse events were seen in five of the 16 patients (31.3%). The MAF score decreased, with a mean difference of 6.65 (p = 0.05) at 6 months. CONCLUSION:The use of AVAC in a case series with mainly GPA patients led to rapid clinical improvement, reduction of corticosteroid doses, and improvement in fatigue. The findings demonstrate beneficial effects of AVAC as add-on therapy in severe AAV.
OBJECTIVE:Kruppel-like factor 15 (KLF15) is a transcription factor that promotes anabolic pathways and suppresses catabolic signalling in joint tissues. KLF15 regulates adipocyte differentiation through peroxisome proliferator-activated receptor-γ (PPARγ), which suppresses inflammation via the nuclear factor-κB pathway. This study aimed to clarify the effects of KLF15 in a mouse model of collagen antibody-induced arthritis (CAIA). METHOD:Tamoxifen-induced cartilage-specific KLF15 knockout (KO) mice were generated. Ten-week-old male KO mice (KO group) and wild-type mice (WT group) were treated intraperitoneally with anti-type II collagen antibody to create CAIA mice. At 0, 1, 2, and 4 weeks after antibody administration, the knee joints were collected for histological (safranin-O, haematoxylin-eosin) and immunohistological [PPARγ, phosphor-IκB kinase complex (pIKK) α/β, interleukin-1β (IL-1β), matrix metalloproteinase-3 (MMP3) and MMP13] evaluation and compared. Chondrocytes from KLF15 KO and WT mice were evaluated for KLF15, PPARγ, MMP3, and MMP13 mRNA expression by quantitative polymerase chain reaction, and for pIKKα/β by Western blotting. RESULTS:The arthropathy score was significantly higher in the KO group at 4 weeks, while the synovitis score showed no difference. Positive cell ratios for PPARγ were decreased in the KO group, and pIKKα/β, IL-1β, MMP3, and MMP13 were significantly increased. Western blotting showed significantly increased pIKKα/β expression in KO cells compared to WT cells. CONCLUSION:Arthritis induced in cartilage-specific KLF15 KO mice may cause articular cartilage destruction by decreasing PPARγ expression and increasing inflammatory cytokines and MMPs via IKKα/β. Modulation of KLF15 could be a potential therapeutic strategy for the treatment of arthritis, including rheumatoid arthritis.
OBJECTIVES:Pneumocystis pneumonia (PCP) is a serious fungal infection in immunocompromised patients. We investigated the prevalence of Pneumocystis jirovecii (PJ) colonization using oral wash polymerase chain reaction (PCR) in Danish rheumatoid arthritis (RA) patients with respiratory symptoms or recurrent pneumonia, and assessed its diagnostic utility for PCP. METHOD:This secondary analysis of the AURORA study included 76 consenting adults (aged ≥ 18 years) with RA and respiratory symptoms or recurrent pneumonia. Oral wash samples were tested for PJ using a validated PCR assay. All patients underwent pulmonary assessment, including high-resolution computed tomography (HRCT). Medical records were audited for PCP diagnoses after 2 years. RESULTS:The mean age was 65.6 years, 63% were female, 24% received biological disease-modifying anti-rheumatic drug treatment, and 8% had received biological treatment of >3 years' duration. Only one patient (1%), treated with methotrexate and rituximab and presenting with recurrent pneumonia, cough, and dyspnoea, tested positive for PJ. HRCT showed pneumonia, interstitial lung disease (usual interstitial pneumonia pattern), bronchiectasis, and emphysema. PCP was confirmed by a respiratory physician based on clinical presentation. No other patients developed PCP during follow-up. CONCLUSION:Oral colonization with PJ was rare in this cohort of Danish RA patients with respiratory symptoms. The low prevalence of colonization and the absence of PCP in PJ-negative patients suggest that routine screening for oral PJ colonization is not warranted in this population.
OBJECTIVE:Primary Sjögren's disease (pSjD) is one of the most common autoimmune connective tissue diseases. Sicca symptoms are a hallmark of pSjD. Up to 80% of patients have immunoglobulin G (IgG) anti-Ro52 autoantibodies in their plasma. This study investigates the frequency of IgG and IgA anti-Ro52 autoantibodies in plasma and saliva from pSjD patients, and assess the associations between disease activity and autoantibody titers. METHOD:The study was conducted on a Norwegian cross-sectional SjD cohort (n = 113). IgA and IgG anti-Ro52 autoantibodies were measured in plasma and saliva by an indirect in-house enzyme-linked immunosorbent assay (ELISA). ELISA results were correlated with clinical data using relative risk and Spearman's correlation coefficients. RESULTS:Measuring plasma, 73% of the cohort were positive for IgG anti-Ro52 and 47% for IgA anti-Ro52 autoantibodies. In saliva, 34% were positive for IgA anti-Ro52 and 17% for IgG anti-Ro52 autoantibodies. We observed an inverse correlation between plasma IgG anti-Ro52 autoantibodies and disease activity. Patients with a low plasma titre of IgG anti-Ro52 autoantibodies had a higher probability of reporting pain, as indicated by the EULAR Sjögren's Syndrome Patient Reported Index score (relative risk = 0.48, 95% confidence interval 0.29-0.80, p = 0.002). Furthermore, plasma IgA anti-Ro52 correlated significantly with the focus score. CONCLUSION:IgA and IgG anti-Ro52 autoantibodies in saliva and plasma showed an inverse correlation with disease activity but significant positive association with immune activity in patients with SjD. Our findings do not support the use of salivary IgA and IgG anti-Ro52 autoantibodies as biomarkers of disease activity in SjD.
OBJECTIVE:Patients with inflammatory bowel disease (IBD) and concomitant spondyloarthritis (SpA) experience substantial pain burden. We examined long-term trends in chronic opioid use (COU) among patients with IBD with and without SpA in Denmark. METHOD:Using nationwide Danish health registers, we identified patients with Crohn's disease or ulcerative colitis between 2000 and 2023. SpA was defined using validated International Classification of Diseases, 10th Revision (ICD-10) codes. COU was defined as the dispensing of three or more opioid prescriptions within a 12 month period, with prescriptions separated by at least 30 days. Annual proportions of COU were calculated for patients with IBD with SpA (IBD + SpA) and IBD without SpA. A subgroup analysis evaluated chronic use of strong opioids exclusively. Temporal trends were assessed descriptively and comparisons between groups were performed using logistic regression with robust variance. RESULTS:The IBD population increased from 13 417 patients in 2000 to 51 230 in 2023, while the proportion with SpA increased from 1.6% to 5.5%. COU declined over time in both groups. Among patients without SpA, COU decreased from 9.8% in 2000 to 5.7% in 2023. In contrast, COU remained substantially higher in IBD + SpA patients, declining from 27.0% to 13.7% over the same period (p < 0.001). Chronic strong opioid use remained stable in patients without SpA but increased in IBD + SpA patients from 3.6% to 6.2% (p < 0.001). CONCLUSION:Despite overall reductions in opioid prescribing, COU, particularly strong opioid use, remains disproportionately high among patients with IBD + SpA. These findings suggest persistent unmet needs in pain management for this high-risk population.
Objectives: Cigarette smoke (CS) increases the risk of seropositive rheumatoid arthritis (RA), particularly in individuals carrying HLA-DR4 (Human Leukocyte Antigen-DR4) shared epitope (SE) alleles, though the underlying mechanisms remain unclear. This study aimed to investigate the interaction between these 2 key risk factors-CS and HLA-DR4-and their effect on T cell responses to citrullinated antigens in early RA and in HLA-DR4 transgenic mice. Methods: Major histocompatibility complex (MHC)-II tetramer technology was used to detect CD4+ T cells specific for citrullinated antigens in patients with early SE+ RA and in HLA-DR4 transgenic mice. Mice were exposed to CS or immunised with citrullinated alpha-enolase (Cit-ENOL) to assess T cell responses. Systemic interleukin (IL)-23 overexpression was induced by hydrodynamic injection of IL-23-enhanced episomal vector. Results: CS exposure enhanced T cell reactivity to citrullinated peptides, including Cit-ENOL, in the lungs of both patients and mice. While Cit-ENOL T cells, either induced by CS or immunisation, did not directly trigger arthritis development, IL-23 overexpression unleashed their arthritogenic potential in immunised HLA-DR4 mice. Interestingly, CS exposure and Cit-ENOL immunisation led to gamma 8-T cell activation strongly correlating with Cit-ENOL T cell responses. Furthermore, gamma 8-T cell-deficient HLA-DR4 mice exhibited an aggravated arthritis phenotype, mirrored by altered functional Cit-ENOL T cell responses. Conclusions: These findings reveal a selective impact of CS on pulmonary T cell subsets and suggest that gamma 8 T cells act as gatekeepers of HLA-DR4-mediated autoimmune responses in RA pathogenesis. They also highlight a potential 2-hit model involving IL-23 in driving T cell-mediated arthritis.
Objectives Most mammalian tissues have limited regenerative capacity. It has been speculated that the brain might regulate tissue regeneration, while this concept has yet to be experimentally addressed. Using cartilage, a tissue with limited regenerative capacity as an example, we investigated this hypothesis. Methods We employed magnetic resonance imaging, polysynaptic retrograde tracing, chemogenetic/optogenetic manipulations, and single-cell RNA sequencing to characterise a functional brain-cartilage neural circuit regulating cartilage regeneration in human and mouse models. Results We found that fractional anisotropy and amplitude of low-frequency fluctuations values of the paraventricular nucleus (PVN) are elevated, and correlate with Western Ontario and McMaster Universities Arthritis Index scores and synovial fluid norepinephrine (NE) concentrations in patients with osteoarthritis. We further demonstrate the existence of a functional trans-neuronal circuit to regulate cartilage regeneration, which originates from PVNCRH neurons to sympathetic nerves in the synovium of joint. Inhibition of the circuit is sufficient to strongly promote the production of stable mature articular cartilage instead of fibrocartilage. This process fosters the regeneration of articular cartilage by inhibiting the pathways mediated by NE/articular cartilage via the beta 2-adrenergic receptor (ADRB2) in Proteoglycan 4(+) cells. Furthermore, treatment with an ADRB2 inverse agonist prevented cartilage degradation in human articular cartilage explants. Conclusions Our findings unveil a brain-cartilage circuit that regulates cartilage regeneration, providing valuable insights into the inherent limitations of tissue regeneration and suggesting a promising treatment strategy for enhancing cartilage regeneration.
