RESUMEN
Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD.
RESUMEN
Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we performed an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed 2 distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug-related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing patients with ILD, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a noninvasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.
Asunto(s)
Indoles , Proteómica , Fibrosis Pulmonar , Animales , Indoles/uso terapéutico , Indoles/farmacología , Ratones , Humanos , Proteómica/métodos , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/patología , Antifibróticos/farmacología , Antifibróticos/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Masculino , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/metabolismo , Matriz Extracelular/metabolismoRESUMEN
OBJECTIVE: Clinical observation suggests that vascular activation and autoimmunity precede remodelling of the extracellular matrix (ECM) in systemic sclerosis (SSc). We challenge this paradigm by hypothesising that ECM biomarkers are already disturbed in patients with very early SSc (veSSc) when fibrosis is not yet clinically detectable. METHODS: 42 patients with veSSc, defined as the presence of Raynaud's phenomenon and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, not meeting the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc, were compared with healthy controls (HCs, n=29). ECM degradation (BGM, C3M, C4M and C6M) and ECM formation biomarkers (PRO-C3, PRO-C4 and PRO-C5) were measured in serum using ELISAs. A cross-sectional analysis at baseline and a longitudinal analysis was performed. RESULTS: Compared with HC, veSSc patients showed a strongly dysregulated turnover of type III and IV collagens (higher C3M, C4M, both p<0.0001 and PRO-C3, p=0.004, lower turnover ratios PRO-C3/C3M and PRO-C4/C4M, both p<0.0001). The biglycan degradation biomarker BGM was higher in veSSc than in HC (p=0.006), whereas the degradation biomarker for type VI collagen, C6M, was lower (p=0.002). In an ROC analysis, biomarkers of type III and IV collagen excellently distinguished between veSSc and HC: C3M, AUC=0.95, p<0.0001; C4M, AUC=0.97, p<0.0001; turnover ratios PRO-C3/C3M, AUC=0.80, p<0.0001; PRO-C4/C4M, AUC=0.97; p<0.0001. CONCLUSION: These findings indicate ECM remodelling as a very early phenomenon of SSc occurring in parallel with microvascular and autoimmune changes. Biomarkers of type III and IV collagens distinguished between veSSc patients and HC, indicating them as potential biomarkers for the detection of veSSc.
Asunto(s)
Biomarcadores , Esclerodermia Sistémica , Humanos , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/diagnóstico , Biomarcadores/sangre , Femenino , Masculino , Persona de Mediana Edad , Adulto , Matriz Extracelular/metabolismo , Colágeno/metabolismo , Estudios de Casos y Controles , Estudios Transversales , Curva ROC , Anciano , Biglicano/sangre , Biglicano/metabolismo , Colágeno Tipo III/sangre , Colágeno Tipo III/metabolismoRESUMEN
Objectives: To derive segmental cut-off values and measures of diagnostic accuracy for the intima-media thickness of compressed temporal artery segments for the diagnosis of giant cell arteritis (GCA) on the patient level. To examine the influence of cardiovascular risk. Methods: Retrospectively, patients evaluated for GCA with an ultrasound of the temporal arteries and an MRI of the head, including a T1-fatsat-black blood (T1-BB) sequence, were identified and classified based on cardiovascular risk and a dual reference standard of T1-BB on the segmental level and the clinical diagnosis on the patient level. Intima-media thickness of the common superficial temporal artery (CSTA), frontal and parietal branches (FB, PB) were measured by compression technique. Statistically and clinically optimal (specificity of approx. 90% for the patient level) cut-offs were derived. Diagnostic accuracy was evaluated on the patient level. Results: The population consisted of 144 patients, 74 (51.4%) with and 70 (48.6%) without GCA. The statistically optimal cut-offs were 0.86 mm, 0.68 mm and 0.67 mm for the CSTA, the FB and PB, respectively. On the patient level sensitivity and specificity were 86.5 and 81.4%. Clinically optimal cut-offs were 1.01 mm, 0.82 mm and 0.69 mm and showed a sensitivity of 79.7% and a specificity of 90.0%. For patients without high cardiovascular risk, statistically optimal cut-offs showed a sensitivity of 89.6% and a specificity of 90.5%. Conclusion: Newly derived ultrasound intima-media thickness cut-offs with a dual reference standard show high diagnostic accuracy on the patient level for the diagnosis of GCA, particularly in patients without high cardiovascular risk.
RESUMEN
OBJECTIVES: Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. METHODS: Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. RESULTS: A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. CONCLUSION: Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.
Asunto(s)
Antirreumáticos , Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Humanos , Inmunosupresores/uso terapéutico , Rituximab/uso terapéutico , Metotrexato/uso terapéutico , Ácido Micofenólico/uso terapéutico , Estudios Prospectivos , Suiza , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inducido químicamente , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/diagnóstico , Fibrosis , Antirreumáticos/uso terapéuticoRESUMEN
A diagnosis of interstitial lung diseases (ILD) can be challenging, and the identification of an associated connective tissue disease (CTD) is crucial to estimate prognosis and to establish the optimal treatment approach. Diagnostic delay, limited expertise, and fragmented care are barriers that impede the delivery of comprehensive health care for patients with rare, complex, and multiorgan diseases such as CTD and ILD. In this article, we present our perspective on the interdisciplinary diagnosis and interprofessional treatment of patients with ILD and suspected CTD or CTD at risk of ILD. We outline the structure of our service, delineating the roles and responsibilities of the team members. Additionally, we provide an overview of our patient population, including diagnostic approaches and specific treatments, and illustrate a patient case. Furthermore, we focus on specific benefits and challenges of joint interdisciplinary and interprofessional patient consultations. The importance of rheumatology and pulmonology assessments in specific patient populations is emphasized. Finally, we explore future directions and discuss potential strategies to improve care delivery for patients with CTD-associated ILD.
Asunto(s)
Enfermedades del Tejido Conjuntivo , Enfermedades Pulmonares Intersticiales , Grupo de Atención al Paciente , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/terapia , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades del Tejido Conjuntivo/complicaciones , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/terapia , Grupo de Atención al Paciente/organización & administración , Manejo de la Enfermedad , Comunicación InterdisciplinariaRESUMEN
OBJECTIVE: To investigate the clinical phenotype and treatment response in patients with rheumatoid arthritis (RA) with and without concomitant Sjögren's disease (SjD). METHODS: In this observational cohort study, patients with RA from the Swiss Clinical Quality Management in Rheumatic Diseases registry were categorised according to the presence or absence of SjD. To assess treatment effectiveness, drug retention of tumor necrosis factor-α-inhibitors (TNFi) was compared to other mode of action (OMA) biologics and Janus kinase-inhibitors (JAKi) in RA patients with and without SjD. Adjusted hazard ratios (HR) for time to drug discontinuation were compared in crude and adjusted Cox proportional regression models for potential confounders. RESULTS: We identified 5974 patients without and 337 patients with concomitant SjD. Patients with SjD were more likely to be female, to have a positive rheumatoid factor, higher disease activity scores, and erosive bone damage. For treatment response, a total of 6781 treatment courses were analysed. After one year, patients with concomitant SjD were less likely to reach DAS28 remission with all three treatment modalities. Patients with concomitant SjD had a higher hazard for stopping TNFi treatment (adjusted HR 1.3 [95% CI 1.07-1.6]; OMA HR 1.12 [0.91-1.37]; JAKi HR 0.97 [0.62-1.53]). When compared to TNFi, patients with concomitant SjD had a significantly lower hazard for stopping treatment with OMA (adjusted HR 0.62 [95% CI 0.46-0.84]) and JAKi (HR 0.52 [0.28-0.96]). CONCLUSION: RA patients with concomitant SjD reveal a severe RA phenotype, are less responsive to treatment, and more likely to fail TNFi.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Humanos , Femenino , Masculino , Antirreumáticos/uso terapéutico , Suiza/epidemiología , Factor de Necrosis Tumoral alfa , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Resultado del Tratamiento , BiomarcadoresRESUMEN
OBJECTIVES: To investigate the diagnostic accuracy of a pattern recognition approach for the evaluation of MRI scans of the head with diffusion-weighted imaging (DWI) in suspected giant cell arteritis (GCA). METHODS: Retrospectively, 156 patients with suspected GCA were included. The 'DWI-Scrolling-Artery-Sign' (DSAS) was defined as hyperintense DWI signals in the cranial subcutaneous tissue that gives the impression of a blood vessel when scrolling through a stack of images. The DSAS was rated by experts and a novice in four regions (frontotemporal and occipital, bilaterally). The temporal, occipital and posterior auricular arteries were assessed in the T1-weighted black-blood sequence (T1-BB). The diagnostic reference was the clinical diagnosis after ≥6 months of follow-up. RESULTS: The population consisted of 87 patients with and 69 without GCA; median age was 71 years and 59% were women. The DSAS showed a sensitivity of 73.6% and specificity of 94.2% (experts) and 59.8% and 95.7% (novice), respectively. Agreement between DSAS and T1-BB was 80% for the region level (499/624; kappa(κ)=0.59) and 86.5% for the patient level (135/156; κ=0.73). Inter-reader agreement was 95% (19/20; κ=0.90) for DSAS on the patient level and 91.3% (73/80; κ=0.81) on the region level for experts. For expert versus novice, inter-reader agreement for DSAS was 87.8% on the patient level (137/156; κ=0.75) and 91.2% on the region level (569/624; κ=0.77). CONCLUSIONS: The DSAS can be assessed in less than 1 min and has a good diagnostic accuracy and reliability for the diagnosis of GCA. The DSAS can be used immediately in clinical practice.
Asunto(s)
Arteritis de Células Gigantes , Humanos , Femenino , Anciano , Masculino , Arteritis de Células Gigantes/diagnóstico por imagen , Arterias Temporales/diagnóstico por imagen , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , ArteriasRESUMEN
OBJECTIVES: We investigated the potential of serum proteins to distinguish clinical and molecular subtypes in patients with giant cell arteritis (GCA). METHODS: Proximity extension assays were used to analyse 1463 proteins in serum samples from patients with new-onset GCA (n = 16) and after achieving remission (n = 13). Unsupervised and supervised cluster analyses were performed. RESULTS: Unsupervised cluster analysis identified three distinct clusters based on the protein signature. Compared with cluster 2, patients of cluster 1 had less polymyalgia rheumatica symptoms, increased levels of macrophage migration inhibitory factor (MIF) and pronounced NF-kB, STAT5 and interleukin-1 signalling. The changes in serum proteins upon remission differed between cluster 1 and 2.Patients with cranial GCA were characterised by altered endothelial and Th17 signalling whereas patients not responding to treatment within the GUSTO-trial showed increased Th1 and diminished B cell signalling. Patients with anterior ischemic optic neuropathy displayed higher levels of CHI3L1 (YKL40), MMP12 and reduced levels of TIMP3. CONCLUSIONS: Protein profiling identifies patient clusters in GCA with distinct proteomic features and therefore likely different pathophysiology. These unique proteomic footprints might lead to more targeted treatments in future.
RESUMEN
AIM: To explore if patient global assessment (PGA) is associated with inflammation over time and if associations are explained by other measures of disease activity and function in patients with idiopathic inflammatory myopathies (IIM). METHODS: PGA and systemic inflammatory markers prospectively collected over five years were retrieved from the International MyoNet registry for 1200 patients with IIM. Associations between PGA, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and creatine kinase (CK) were analyzed using mixed models. Mediation analysis was used to test if the association between PGA and inflammatory markers during the first year of observation could be explained by measures of disease activity and function. RESULTS: PGA improved, and inflammatory markers decreased during the first year of observation. In the mixed models, high levels of inflammatory markers were associated with worse PGA in both men and women across time points during five years of observation. In men, but not in women, the association between elevated ESR, CRP and poorer PGA was explained by measures of function and disease activity. With a few exceptions, the association between improved PGA and reduced inflammatory markers was partially mediated by improvements in all measures of function and disease activity. CONCLUSION: Increased levels of systemic inflammation are associated with poorer PGA in patients with IIM. In addition to known benefits of lowered inflammation, these findings emphasize the need to reduce systemic inflammation to improve subjective health in patients with IIM. Furthermore, the results demonstrate the importance of incorporating PGA as an outcome measure in clinical practice and clinical trials.
Asunto(s)
Miositis , Masculino , Humanos , Femenino , Estudios Longitudinales , Miositis/complicaciones , Inflamación , Evaluación de Resultado en la Atención de Salud , Sedimentación SanguíneaRESUMEN
BACKGROUND: Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment. RESULTS: 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively). CONCLUSIONS: Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation.
Asunto(s)
Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Humanos , Pulmón , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inducido químicamente , Inmunosupresores/uso terapéutico , Inflamación/inducido químicamenteRESUMEN
OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.
RESUMEN
OBJECTIVES: To investigate the diagnostic performance of diffusion-weighted imaging (DWI) of the superficial cranial arteries in the diagnosis of giant cell arteritis (GCA). METHODS: Retrospectively, 156 patients with clinically suspected GCA were included. A new 4-point ordinal DWI rating scale was developed. A post-contrast, fat-suppressed, T1-weighted "black-blood" sequence (T1-BB) was rated for comparison. Ten arterial segments were assessed: common superficial temporal arteries, temporal and parietal branches, occipital and posterior auricular arteries bilaterally. The expert clinical diagnosis after ≥ 6 months of follow-up was the diagnostic reference standard. Diagnostic accuracy was evaluated for different rating methods. RESULTS: The study cohort consisted of 87 patients with and 69 without GCA. For DWI, the area under the curve was 0.90. For a cut-off of ≥ 2 consecutive pathological slices, DWI showed a sensitivity of 75.9%, a specificity of 94.2% and a positive likelihood ratio of 13.09. With a cut-off of ≥ 3 consecutive pathological slices, sensitivity was 70.1%, specificity was 98.6%, and the positive likelihood ratio was 48.38. For the T1-BB, values were 88.5%, 88.4% and 7.63, respectively. The inter-rater analysis for DWI with a cut-off of ≥ 2 pathological slices showed a kappa of 1.00 on the patient level and 0.85 on the arterial segment level. For the T1-BB the kappa was 0.78 and 0.79, respectively. CONCLUSION: DWI of the superficial cranial arteries demonstrates a good diagnostic accuracy and reliability for the diagnosis of GCA. DWI is widely available and can be used immediately in clinical practice for patients with suspected GCA.
RESUMEN
Background: The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. Aims and methods: To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. Results: In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. Conclusions: Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging.
RESUMEN
Dermatomyositis (DM) is an inflammatory multisystem disease of unknown etiology, which can already occur in children but first onset can also be in older adulthood. Myalgia and muscle weakness can occur later in the course of the disease or even be completely absent in some forms. Classical signs on the skin include heliotrope rash, facial erythema, Gottron's papules and nailfold capillary abnormalities. For the diagnosis, screening for the presence of myositis-specific autoantibodies has become increasingly more relevant. Muscle enzymes may be elevated but not in approximately one third of patients. In the absence of typical clinical or serologic findings, additional examination methods such as nailfold capillaroscopy, magnetic resonance imaging, electromyography, skin or muscle biopsies may help to establish the diagnosis. Depending on the clinical and serological subtype, additional screening for gastrointestinal or cardiopulmonary involvement should be considered. In adults, an age-appropriate tumor screening should also be performed. Apart from corticosteroids as induction therapy, biologics and small molecule inhibitors are gaining in importance in addition to conventional disease-modifying anti-rheumatic drugs and intravenous immunoglobulins. The prognosis for DM and juvenile DM (JDM) has improved. Most patients recover at least to some extent; however, a few patients die and a minority develop persisting muscle atrophy or severe calcinosis.
Asunto(s)
Dermatomiositis , Miositis , Niño , Adulto , Humanos , Anciano , Dermatomiositis/tratamiento farmacológico , Piel/patología , Miositis/diagnóstico , Corticoesteroides/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéuticoRESUMEN
AIMS: Myocardial involvement is common in patients with systemic sclerosis (SSc) and causes myocardial fibrosis and subtle ventricular dysfunction. However, the temporal onset of myocardial involvement during the progression of the disease and its prognostic value are yet unknown. We used cardiovascular magnetic resonance (CMR) to investigate subclinical functional impairment and diffuse myocardial fibrosis in patients with very early diagnosis of SSc (VEDOSS) and established SSc and examined whether this was associated with mortality. METHODS AND RESULTS: One hundred and ten SSc patients (86 established SSc, 24 VEDOSS) and 15 healthy controls were prospectively recruited. The patients were followed-up for a median duration of 7.0 years (interquartile range 6.0-7.3 years). Study subjects underwent CMR including assessment of myocardial fibrosis [native T1 and extracellular volume (ECV)] and measurement of global longitudinal (GLS) and circumferential (GCS) myocardial strain. Native T1 values and ECV were elevated in VEDOSS and SSc patients compared with controls (P < 0.001). GLS was similar in VEDOSS and controls but significantly impaired in patients with established SSc (P < 0.001). GCS was similar over all groups (P = 0.88). There were 12 deaths during follow-up. Elevated native T1 [hazard ratio (HR) 5.8, 95% confidence interval (CI): 1.7-20.4; P = 0.006] and reduced GLS (HR 6.1, 95% CI: 1.3-29.9; P = 0.038) identified subjects with increased risk of death. Only native T1 was predictive for cardiovascular mortality (P < 0.001). CONCLUSION: Subclinical myocardial involvement first manifests as diffuse myocardial fibrosis identified by the expansion of ECV and increased native T1 in VEDOSS patients while subtle functional impairment only occurs in established SSc. Native T1 and GLS have prognostic value for all-cause mortality in SSc patients.
Asunto(s)
Cardiomiopatías , Esclerodermia Sistémica , Humanos , Pronóstico , Función Ventricular Izquierda , Estudios Prospectivos , Cardiomiopatías/patología , Miocardio/patología , Fibrosis , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico por imagen , Imagen por Resonancia Cinemagnética/métodos , Valor Predictivo de las PruebasRESUMEN
OBJECTIVES: The first objective of this study was to implement and assess the performance and reliability of a vision transformer (ViT)-based deep-learning model, an 'off-the-shelf' artificial intelligence solution, for identifying distinct signs of microangiopathy in nailfold capilloroscopy (NFC) images of patients with SSc. The second objective was to compare the ViT's analysis performance with that of practising rheumatologists. METHODS: NFC images of patients prospectively enrolled in our European Scleroderma Trials and Research group (EUSTAR) and Very Early Diagnosis of Systemic Sclerosis (VEDOSS) local registries were used. The primary outcome investigated was the ViT's classification performance for identifying disease-associated changes (enlarged capillaries, giant capillaries, capillary loss, microhaemorrhages) and the presence of the scleroderma pattern in these images using a cross-fold validation setting. The secondary outcome involved a comparison of the ViT's performance vs that of rheumatologists on a reliability set, consisting of a subset of 464 NFC images with majority vote-derived ground-truth labels. RESULTS: We analysed 17 126 NFC images derived from 234 EUSTAR and 55 VEDOSS patients. The ViT had good performance in identifying the various microangiopathic changes in capillaries by NFC [area under the curve (AUC) from 81.8% to 84.5%]. In the reliability set, the rheumatologists reached a higher average accuracy, as well as a better trade-off between sensitivity and specificity compared with the ViT. However, the annotators' performance was variable, and one out of four rheumatologists showed equal or lower classification measures compared with the ViT. CONCLUSIONS: The ViT is a modern, well-performing and readily available tool for assessing patterns of microangiopathy on NFC images, and it may assist rheumatologists in generating consistent and high-quality NFC reports; however, the final diagnosis of a scleroderma pattern in any individual case needs the judgement of an experienced observer.
Asunto(s)
Esclerodermia Localizada , Esclerodermia Sistémica , Enfermedades Vasculares , Humanos , Inteligencia Artificial , Angioscopía Microscópica/métodos , Reumatólogos , Reproducibilidad de los Resultados , Uñas/irrigación sanguínea , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/diagnóstico por imagen , Capilares/diagnóstico por imagenRESUMEN
OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.
Asunto(s)
Enfermedades Autoinmunes , Miositis , Polimiositis , Humanos , Miositis/genética , Enfermedades Autoinmunes/genética , Predisposición Genética a la Enfermedad , HaplotiposRESUMEN
Background: Interstitial lung disease (ILD) defines a group of parenchymal lung disorders, characterized by fibrosis as their common final pathophysiological stage. To improve diagnosis and treatment of ILD, there is a need for repetitive non-invasive characterization of lung tissue by quantitative parameters. In this study, we investigated whether CT image patterns found in mice with bleomycin induced lung fibrosis can be translated as prognostic factors to human patients diagnosed with ILD. Methods: Bleomycin was used to induce lung fibrosis in mice (n_control = 36, n_experimental = 55). The patient cohort consisted of 98 systemic sclerosis (SSc) patients (n_ILD = 65). Radiomic features (n_histogram = 17, n_texture = 137) were extracted from microCT (mice) and HRCT (patients) images. Predictive performance of the models was evaluated with the area under the receiver-operating characteristic curve (AUC). First, predictive performance of individual features was examined and compared between murine and patient data sets. Second, multivariate models predicting ILD were trained on murine data and tested on patient data. Additionally, the models were reoptimized on patient data to reduce the influence of the domain shift on the performance scores. Results: Predictive power of individual features in terms of AUC was highly correlated between mice and patients (r = 0.86). A model based only on mean image intensity in the lung scored AUC = 0.921 ± 0.048 in mice and AUC = 0.774 (CI95% 0.677-0.859) in patients. The best radiomic model based on three radiomic features scored AUC = 0.994 ± 0.013 in mice and validated with AUC = 0.832 (CI95% 0.745-0.907) in patients. However, reoptimization of the model weights in the patient cohort allowed to increase the model's performance to AUC = 0.912 ± 0.058. Conclusion: Radiomic signatures of experimental ILD derived from microCT scans translated to HRCT of humans with SSc-ILD. We showed that the experimental model of BLM-induced ILD is a promising system to test radiomic models for later application and validation in human cohorts.
RESUMEN
OBJECTIVES: As a rare and heterogeneous disease, mixed connective tissue disease (MCTD) represents a challenge. Herein, we aimed to unravel potential pitfalls including correct referral diagnosis, distinction from other connective tissue diseases (CTD) and treatment modalities. METHODS: We characterised the MCTD cohort at our tertiary referral centre. All patients were evaluated for fulfilment of classification criteria of various CTDs. SLEDAI-2 K and EUSTAR-AI were used in accordance with previous research to evaluate disease activity and treatment response. RESULTS: Out of 85 patients initially referred as MCTD, only one-third (33/85, 39%) fulfilled the diagnostic MCTD criteria and the other patients had undifferentiated CTD (16/85, 19%), non-MCTD overlap syndromes (11/85, 13%) and other rheumatic diseases. In our final cohort of 33 MCTD patients, 16 (48%) also met the diagnostic criteria of systemic sclerosis, 13 (39%) these of systemic lupus erythematosus, 6 (18%) these of rheumatoid arthritis and 3 (9%) these of primary myositis. Management of MCTD required immunomodulating combination therapy in most cases (15/28, 54%), whereas monotherapy was less frequent (10/28, 36%), and only a few (3/28, 11%) remained without immune modulators until the end of the follow-up period. Treatment led to a significant decline in disease activity. CONCLUSIONS: Our study showed a high risk for misdiagnosis for patients with MCTD. As a multi-organ disease, MCTD required prolonged immunomodulating therapy to achieve remission. The establishment of an international registry with longitudinal data from observational multi-centre cohorts might represent a first step to address the many unmet needs of MCTD.