Journal of Clinical Medicine

Research

13 pages, 1079 KiB

Open AccessArticle

Optimized Treatment of Interleukin (IL-1)-Mediated Autoinflammatory Diseases: Impact of Disease Activity-Based Treatment Adjustments

by Tatjana Welzel, Beate Zapf, Jens Klotsche, Özlem Satirer, Susanne M. Benseler and Jasmin B. Kuemmerle-Deschner

J. Clin. Med. 2024, 13(8), 2319; https://doi.org/10.3390/jcm13082319 - 17 Apr 2024

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Abstract

Background: Effective control of disease activity in Interleukin-1 autoinflammatory diseases (IL-1 AID) is crucial to prevent damage. The aim was to longitudinally analyze the impact of protocolized disease activity-based treatment adjustments in a real-life cohort. Methods: A single-center study of consecutive children with [...] Read more.

Background: Effective control of disease activity in Interleukin-1 autoinflammatory diseases (IL-1 AID) is crucial to prevent damage. The aim was to longitudinally analyze the impact of protocolized disease activity-based treatment adjustments in a real-life cohort. Methods: A single-center study of consecutive children with IL-1 AID followed between January 2016 and December 2019 was performed. Demographics, phenotypes, genotypes, inflammatory markers, physician (PGA), and patient/parent (PPGA) global assessment were captured. Disease activity and treatment changes were assessed. The impact of distinct parameters on disease activity trajectories was analyzed. Results: A total of 56 children were included, median follow-up was 2.1 years reflecting 361 visits. Familial Mediterranean Fever was the most common IL-1 AID. At the first visit, 68% of the patients had moderate/severe disease activity. Disease activity-based treatment adjustments were required in 28/56 children (50%). At last follow-up, 79% had a well-controlled disease. Both PGA and PPGA decreased significantly over time (p < 0.001; p < 0.017, respectively), however, both differed statistically at last visit (p < 0.001). Only PGA showed a significant estimated mean decrease across all IL-1 AID over time. Conclusions: Disease activity-based treatment adjustments can effectively refine treat-to-target strategies, enable personalized precision health approaches, and improve outcomes in children with IL-1 AID. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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19 pages, 5636 KiB

Open AccessArticle

Patient Experiences and Challenges in the Management of Autoinflammatory Diseases—Data from the International FMF & AID Global Association Survey

by Jürgen Rech, Georg Schett, Abdurrahman Tufan, Jasmin B. Kuemmerle-Deschner, Seza Özen, Koray Tascilar, Leonie Geck, Tobias Krickau, Ellen Cohen, Tatjana Welzel, Marcus Kuehn and Malena Vetterli

J. Clin. Med. 2024, 13(5), 1199; https://doi.org/10.3390/jcm13051199 - 20 Feb 2024

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Abstract

Background: Autoinflammatory diseases (AIDs) are rare, mostly genetic diseases that affect the innate immune system and are associated with inflammatory symptoms. Both paediatric and adult patients face daily challenges related to their disease, diagnosis and subsequent treatment. For this reason, a survey was [...] Read more.

Background: Autoinflammatory diseases (AIDs) are rare, mostly genetic diseases that affect the innate immune system and are associated with inflammatory symptoms. Both paediatric and adult patients face daily challenges related to their disease, diagnosis and subsequent treatment. For this reason, a survey was developed in collaboration between the FMF & AID Global Association and the Erlangen Center for Periodic Systemic Autoinflammatory Diseases. Methods: The aim of the survey was to collect the personal assessment of affected patients with regard to their current status in terms of diagnostic timeframes, the interpretation of genetic tests, the number of misdiagnoses, and pain and fatigue despite treatment. Results: In total, data from 1043 AID patients (829 adults and 214 children/adolescents) from 52 countries were collected and analyzed. Familial Mediterranean fever (FMF) (521/50%) and Behçet’s disease (311/30%) were the most frequently reported diseases. The average time to diagnosis was 3 years for children/adolescents and 14 years for adults. Prior to the diagnosis of autoinflammatory disease, patients received several misdiagnoses, including psychosomatic disorders. The vast majority of patients reported that genetic testing was available (92%), but only 69% were tested. A total of 217 patients reported that no increase in acute-phase reactants was detected during their disease episodes. The intensity of pain and fatigue was measured in AID patients and found to be high. A total of 88% of respondents received treatment again, while 8% reported no treatment. Conclusions: AID patients, particularly adults, suffer from significant delays in diagnosis, misdiagnosis, and a variety of symptoms, including pain and fatigue. Based on the results presented, raising awareness of these diseases in the wider medical community is crucial to improving patient care and quality of life. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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10 pages, 8675 KiB

Open AccessArticle

VEXAS and Myelodysplastic Syndrome: An Interdisciplinary Challenge

by Virginie Kreutzinger, Anne Pankow, Zhivana Boyadzhieva, Udo Schneider, Katharina Ziegeler, Lars Uwe Stephan, Jan Carl Kübke, Sebastian Schröder, Christian Oberender, Philipp le Coutre, Sebastian Stintzing and Ivan Jelas

J. Clin. Med. 2024, 13(4), 1049; https://doi.org/10.3390/jcm13041049 - 12 Feb 2024

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Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in hematopoietic progenitor cells. This case series of four patients with VEXAS syndrome and comorbid myelodysplastic syndrome (MDS) aims to describe clinical, imaging, and [...] Read more.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in hematopoietic progenitor cells. This case series of four patients with VEXAS syndrome and comorbid myelodysplastic syndrome (MDS) aims to describe clinical, imaging, and hematologic disease presentations as well as response to therapy. Four patients with VEXAS syndrome and MDS are described. A detailed analysis of imaging features, hemato-oncological presentation including bone marrow microscopy and clinical–rheumatological disease features and treatment outcomes is given. All patients were male; ages ranged between 64 and 81 years; all were diagnosed with MDS. CT imaging was available for three patients, all of whom exhibited pulmonary infiltrates of varying severity, resembling COVID-19 or hypersensitivity pneumonitis without traces of scarring. Bone marrow microscopy showed maturation-disordered erythropoiesis and pathognomonic vacuolation. Somatic mutation in the UBA1 codon 41 were found in all patients by next-generation sequencing. Therapy regimes included glucocorticoids, JAK1/2-inhibitors, nucleoside analogues, as well as IL-1 and IL-6 receptor antagonists. No fatalities occurred (observation period from symptom onset: 18–68 months). Given the potential underreporting of VEXAS syndrome, we highly recommend contemporary screening for UBA1 mutations in patients presenting with ambiguous signs of systemic autoinflammatory symptoms which persist over 18 months despite treatment. The emergence of cytopenia, especially macrocytic hyperchromic anemia, should prompt early testing for UBA1 mutations. Notably conspicuous, pulmonary alterations in CT imaging of patients with therapy-resistant systemic autoinflammatory symptoms should be discussed in interdisciplinary medical teams (Rheumatology, Hematology, Radiology and further specialist departments) to facilitate timely diagnosis during the clinical course of the disease. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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11 pages, 1267 KiB

Open AccessArticle

Characteristics of Functional Hyperthermia Detected in an Outpatient Clinic for Fever of Unknown Origin

by Kosuke Oka, Kazuki Tokumasu, Hideharu Hagiya and Fumio Otsuka

J. Clin. Med. 2024, 13(3), 889; https://doi.org/10.3390/jcm13030889 - 03 Feb 2024

Cited by 1 | Viewed by 826

Abstract

Background: Functional hyperthermia (FH) is characterized by hyperthermia resulting from sympathetic hyperactivity rather than inflammation, and it is frequently overlooked by medical practitioners due to the absence of abnormalities in a medical examination. Although FH is an important differential diagnosis for fever of [...] Read more.

Background: Functional hyperthermia (FH) is characterized by hyperthermia resulting from sympathetic hyperactivity rather than inflammation, and it is frequently overlooked by medical practitioners due to the absence of abnormalities in a medical examination. Although FH is an important differential diagnosis for fever of unknown origin (FUO), the literature on FUO cases in Japan lacks information on FH. In this study, we aimed to uncover the population of FH patients hidden in FUO cases. Methods: An outpatient clinic for FUO was established at Okayama University Hospital, and 132 patients were examined during the period from May 2019 to February 2022. Results: A diagnosis of FH was made in 31.1% of the FUO cases, and FH predominantly affected individuals in their third and fourth decades of life with a higher incidence in females (68.3%). The frequency of a history of psychiatric illness was higher in patients with FH than in patients with other febrile illnesses. Although the C-reactive protein (CRP) is generally negative in FH cases, some obese patients, with a body mass index ≥ 25 had slightly elevated levels of CRP but were diagnosed with FH. Conclusions: The results showed the importance of identifying FH when encountering patients with FUO without any organic etiology. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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10 pages, 1759 KiB

Open AccessArticle

Autoinflammatory Diseases and COVID-19 Vaccination: Analysis of SARS-CoV-2 Anti-S-RBD IgG Levels in a Cohort of Patients Receiving IL-1 Inhibitors

by Sara Bindoli, Chiara Baggio, Paola Galozzi, Filippo Vesentini, Andrea Doria, Chiara Cosma, Andrea Padoan and Paolo Sfriso

J. Clin. Med. 2023, 12(14), 4741; https://doi.org/10.3390/jcm12144741 - 18 Jul 2023

Cited by 1 | Viewed by 1054

Abstract

The purpose of the study was to evaluate the antibody response after COVID-19 vaccination in patients affected by systemic autoinflammatory diseases (SAID) undertaking IL-1 inhibitors (IL-1i) compared to healthy vaccinated controls (HC). The course of COVID-19 in vaccinated patients on IL-1i was also [...] Read more.

The purpose of the study was to evaluate the antibody response after COVID-19 vaccination in patients affected by systemic autoinflammatory diseases (SAID) undertaking IL-1 inhibitors (IL-1i) compared to healthy vaccinated controls (HC). The course of COVID-19 in vaccinated patients on IL-1i was also assessed. The serological response was evaluated in SAID patients using the CLIA MAGLUMI TM 2000 Plus test after the first vaccination cycle and the booster dose. Fifty-four fully vaccinated healthcare workers were enrolled as HCs. GraphPad Prism 8 software was used for statistical analysis. All patients developed an adequate antibody response. No differences were observed between the antibody titers of patients on IL-1i and those not on IL-1i, either after the first vaccination cycle or the booster dose (p = 0.99), and to HC (p = 0.99). With increasing age, a decrease in antibody production was assessed after the second vaccine in SAID (r = 0.67, p = 0.0003). In general, 11.6% of SAID patients had COVID-19 after receiving vaccination. None of them developed severe disease or experienced flares of their autoinflammatory disease. In conclusion, patients receiving IL-1i develop an antibody response comparable to HC. No side effects after vaccination were observed; IL-1i was continued before and after injections to avoid flare-ups. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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Review

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16 pages, 1391 KiB

Open AccessReview

Targeting Interleukin-17 as a Novel Treatment Option for Fibrotic Diseases

by Margherita Sisto and Sabrina Lisi

J. Clin. Med. 2024, 13(1), 164; https://doi.org/10.3390/jcm13010164 - 27 Dec 2023

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Abstract

Fibrosis is the end result of persistent inflammatory responses induced by a variety of stimuli, including chronic infections, autoimmune reactions, and tissue injury. Fibrotic diseases affect all vital organs and are characterized by a high rate of morbidity and mortality in the developed [...] Read more.

Fibrosis is the end result of persistent inflammatory responses induced by a variety of stimuli, including chronic infections, autoimmune reactions, and tissue injury. Fibrotic diseases affect all vital organs and are characterized by a high rate of morbidity and mortality in the developed world. Until recently, there were no approved antifibrotic therapies. In recent years, high levels of interleukin-17 (IL-17) have been associated with chronic inflammatory diseases with fibrotic complications that culminate in organ failure. In this review, we provide an update on the role of IL-17 in fibrotic diseases, with particular attention to the most recent lines of research in the therapeutic field represented by the epigenetic mechanisms that control IL-17 levels in fibrosis. A better knowledge of the IL-17 signaling pathway implications in fibrosis could design new strategies for therapeutic benefits. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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13 pages, 800 KiB

Open AccessReview

The Role of Sclerostin in Rheumatic Diseases: A Review

by Łukasz Jaśkiewicz, Grzegorz Chmielewski, Jakub Kuna, Tomasz Stompór and Magdalena Krajewska-Włodarczyk

J. Clin. Med. 2023, 12(19), 6248; https://doi.org/10.3390/jcm12196248 - 28 Sep 2023

Cited by 1 | Viewed by 1091

Abstract

Systemic connective tissue disorders constitute a heterogenous group of autoimmune diseases with the potential to affect a range of organs. Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune inflammatory disease affecting the joints. Systemic lupus erythematosus (SLE) may manifest with multiple system involvement [...] Read more.

Systemic connective tissue disorders constitute a heterogenous group of autoimmune diseases with the potential to affect a range of organs. Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune inflammatory disease affecting the joints. Systemic lupus erythematosus (SLE) may manifest with multiple system involvement as a result of inflammatory response to autoantibodies. Spondyloarthropathies (SpAs) such as ankylosing spondylitis (AS) or psoriatic arthritis (PsA) are diseases characterised by the inflammation of spinal joints, paraspinal tissues, peripheral joints and enthesitis as well as inflammatory changes in many other systems and organs. Physiologically, sclerostin helps to maintain balance in bone tissue metabolism through the Wnt/β-catenin pathway, which represents a major intracellular signalling pathway. This review article aims to present the current knowledge on the role of sclerostin in the Wnt/β-catenin pathway and its correlation with clinical data from RA, SLE, AS and PsA patients. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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16 pages, 1869 KiB

Open AccessFeature PaperReview

Interleukin-23 Involved in Fibrotic Autoimmune Diseases: New Discoveries

by Margherita Sisto and Sabrina Lisi

J. Clin. Med. 2023, 12(17), 5699; https://doi.org/10.3390/jcm12175699 - 01 Sep 2023

Cited by 1 | Viewed by 1108

Abstract

Interleukin (IL)-23 is a central pro-inflammatory cytokine with a broad range of effects on immune responses. IL-23 is pathologically linked to the induction of the production of the pro-inflammatory cytokines IL-17 and IL-22, which stimulate the differentiation and proliferation of T helper type [...] Read more.

Interleukin (IL)-23 is a central pro-inflammatory cytokine with a broad range of effects on immune responses. IL-23 is pathologically linked to the induction of the production of the pro-inflammatory cytokines IL-17 and IL-22, which stimulate the differentiation and proliferation of T helper type 17 (Th17) cells. Recent discoveries suggest a potential pro-fibrotic role for IL-23 in the development of chronic inflammatory autoimmune diseases characterized by intense fibrosis. In this review, we summarized the biological features of IL-23 and gathered recent research on the role of IL-23 in fibrotic autoimmune conditions, which could provide a theoretical basis for clinical targeting and drug development. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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17 pages, 2206 KiB

Open AccessReview

Immune and Non-Immune Inflammatory Cells Involved in Autoimmune Fibrosis: New Discoveries

by Margherita Sisto and Sabrina Lisi

J. Clin. Med. 2023, 12(11), 3801; https://doi.org/10.3390/jcm12113801 - 31 May 2023

Cited by 2 | Viewed by 1245

Abstract

Fibrosis is an important health problem and its pathogenetic activation is still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases, such as chronic inflammatory autoimmune diseases. Fibrotic tissue is always characterized by mononuclear immune [...] Read more.

Fibrosis is an important health problem and its pathogenetic activation is still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases, such as chronic inflammatory autoimmune diseases. Fibrotic tissue is always characterized by mononuclear immune cells infiltration. The cytokine profile of these cells shows clear proinflammatory and profibrotic characteristics. Furthermore, the production of inflammatory mediators by non-immune cells, in response to several stimuli, can be involved in the fibrotic process. It is now established that defects in the abilities of non-immune cells to mediate immune regulation may be involved in the pathogenicity of a series of inflammatory diseases. The convergence of several, not yet well identified, factors results in the aberrant activation of non-immune cells, such as epithelial cells, endothelial cells, and fibroblasts, that, by producing pro-inflammatory molecules, exacerbate the inflammatory condition leading to the excessive and chaotic secretion of extracellular matrix proteins. However, the precise cellular mechanisms involved in this process have not yet been fully elucidated. In this review, we explore the latest discoveries on the mechanisms that initiate and perpetuate the vicious circle of abnormal communications between immune and non-immune cells, responsible for fibrotic evolution of inflammatory autoimmune diseases. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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Other

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9 pages, 2669 KiB

Open AccessBrief Report

Anti-Interleukin-1 Therapy Does Not Affect the Response to SARS-CoV-2 Vaccination and Infection in Patients with Systemic Autoinflammatory Diseases

by Leonie Geck, Koray Tascilar, David Simon, Arnd Kleyer, Georg Schett and Jürgen Rech

J. Clin. Med. 2023, 12(24), 7587; https://doi.org/10.3390/jcm12247587 - 08 Dec 2023

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Abstract

Patients with systemic autoinflammatory diseases (sAIDs) are a section of the population at high risk of severe COVID-19 outcomes, but evidence on the efficacy of SARS-CoV-2 vaccination in this group of patients is scarce. To investigate the efficacy of SARS-CoV-2 vaccination in patients [...] Read more.

Patients with systemic autoinflammatory diseases (sAIDs) are a section of the population at high risk of severe COVID-19 outcomes, but evidence on the efficacy of SARS-CoV-2 vaccination in this group of patients is scarce. To investigate the efficacy of SARS-CoV-2 vaccination in patients with sAIDs receiving interleukin-1 (IL-1) inhibition is important. Vaccination and infection responses from 100 sAID patients and 100 healthy controls (HCs) were analyzed. In total, 98% of patients were treated with IL-1 inhibitors at the time of vaccination (n = 98). After the second SARS-CoV-2 vaccination, sAID patients showed similar anti-SARS-CoV-2 antibody responses (mean (standard deviation (SD)): 6.7 (2.7)) compared to HCs (5.7 (2.4)) as well as similar neutralizing antibodies (85.1 ± 22.9% vs. 82.5 ± 19.7%). Anti-SARS-CoV-2 antibody responses and neutralizing antibodies were similar in sAID patients after SARS-CoV-2 infection and double vaccination. Furthermore, while antibodies increased after the first and second vaccination in sAID patients, they did not further increase after the third and fourth vaccination. No difference was found in antibody responses between anakinra and anti-IL-1 antibody treatment and the additional use of colchicine or other drugs did not impair vaccination responses. Primary and booster SARS-CoV-2 vaccinations led to protective antibody responses in sAID patients, which were at the same level of vaccination responses in HCs and in sAID patients after SARS-CoV-2 infection. Immunomodulatory treatments used in sAID do not seem to affect antibody responses to the SARS-CoV-2 vaccine. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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7 pages, 1465 KiB

Open AccessCase Report

Intracardiac Thrombi in Morbus Adamantiades–Behçet in Two Swedish Patients

by Raffaele Da Mutten, Alexander Borg, Katerina Chatzidionysiou and Ioannis Parodis

J. Clin. Med. 2023, 12(16), 5377; https://doi.org/10.3390/jcm12165377 - 18 Aug 2023

Viewed by 736

Abstract

Morbus Adamantiades–Behçet (MAB) is an inflammatory disease typically manifesting with oral and genital aphthosis, erythema nodosum, and vasculopathy, and in only around 2%, cardiac involvement. Its prevalence is usually higher along the historic Silk Road, but rarer in Scandinavia where 0.64–4.9 in 100,000 [...] Read more.

Morbus Adamantiades–Behçet (MAB) is an inflammatory disease typically manifesting with oral and genital aphthosis, erythema nodosum, and vasculopathy, and in only around 2%, cardiac involvement. Its prevalence is usually higher along the historic Silk Road, but rarer in Scandinavia where 0.64–4.9 in 100,000 people are affected. We herein present two Swedish patients with cardiac manifestations of Morbus Adamantiades–Behçet. Along with the intracardial thrombi, which both patients presented with, one patient also had cerebrovascular insults leading to visual field deficits as well as involvement of peripheral nerves. Being of Scandinavian origin and showing uncommon symptoms as their initial manifestations of MAB, the 62- and 35-year-old patients presenting herein constitute rare cases. Full article

(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges Series 2)

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