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Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges
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Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (1 August 2021) | Viewed by 76932

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Eugen Feist

E-Mail Website
Guest Editor
Department of Rheumatology, Helios Clinic Vogelsang-Gommern, Cooperation Partner of the Otto-von-Guericke University, Sophie-von-Boetticher-Straße 1, 39245 Vogelsang, Germany
Interests: autoinflammation; adult onset Still’s disease; biomarkers; inflammasome; proteasome；rheumatology; rheumatoid arthritis; biologic drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autoinflammation, as a relatively new field in clinical rheumatology, has gained an increasing importance in recent years. The number of identified entities and affected patients has gradually increased, and some of the involved pathways have already been identified. This progress allows a deeper understanding of closely linked diseases, namely, inflammasomopathies, interferonopathies, Relo-pathies, and proteasome associated syndromes. These insights have not only improved their classification but also helped to identify new treatment targets of pro-inflammatory cytokines, including IL-1ß, IL-6, interferon-, and TNF-alpha. Nevertheless, there is still a high medical need, especially in reliable outcome measures, for confirmation of data from controlled clinical trials and, finally, also for long-term experience from registers.

The Special Issue entitled “Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges” of the Journal of Clinical Medicine is now open for submissions. This issue welcomes all types of papers on the broad spectrum of clinical characteristics, prognosis, pathophysiology, and treatment of autoinflammatory diseases. The goal of this Special Issue is to further raise awareness of autoinflammatory processes and to better separate them from well-established autoimmune diseases. It is clear that we have entered a new age in this complex field, linking rheumatology even closer to immunology.

Prof. Dr. Eugen Feist
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • autoinflammation
  • inflammasomopathies
  • interferonopathies
  • Relo-pathies
  • proteasome associated syndromes
  • pro-inflammatory cytokines
  • biomarkers
  • inflammasome

Related Special Issue

Published Papers (20 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 161 KiB  
Editorial
Autoinflammation It Is!
by Eugen Feist
J. Clin. Med. 2021, 10(21), 5157; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10215157 - 03 Nov 2021
Viewed by 1257
Abstract
In recent years, we have entered a new era full of insights into exciting pathways and improved management of a distinct class of inflammatory conditions [...] Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)

Research

Jump to: Editorial, Review, Other

10 pages, 1590 KiB  
Article
Tocilizumab for the Treatment of Familial Mediterranean Fever—A Randomized, Double-Blind, Placebo-Controlled Phase II Study
by Joerg C. Henes, Sebastian Saur, David M. Kofler, Claudia Kedor, Christoph Meisner, Marion Schuett, Martin Krusche, Ina Koetter, Theodoros Xenitidis, Hendrik Schulze-Koops and Eugen Feist
J. Clin. Med. 2022, 11(18), 5360; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11185360 - 13 Sep 2022
Cited by 5 | Viewed by 1843
Abstract
Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active [...] Read more.
Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician’s global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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17 pages, 1209 KiB  
Article
Distinct Effects of Interleukin-1β Inhibition upon Cytokine Profile in Patients with Adult-Onset Still’s Disease and Active Articular Manifestation Responding to Canakinumab
by Khetam Ghannam, Jan Zernicke, Claudia Kedor, Joachim Listing, Gerd-R. Burmester, Dirk Foell and Eugen Feist
J. Clin. Med. 2021, 10(19), 4400; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10194400 - 26 Sep 2021
Cited by 7 | Viewed by 2414
Abstract
Adult-onset Still’s disease (AOSD) is a systemic auto-inflammatory disease characterized by the presence of immunologically mediated inflammation and deficient resolution of inflammation. Canakinumab is an approved IL-1β inhibitor in the treatment of AOSD with a balanced efficacy and safety profile. Since inflammatory cytokines [...] Read more.
Adult-onset Still’s disease (AOSD) is a systemic auto-inflammatory disease characterized by the presence of immunologically mediated inflammation and deficient resolution of inflammation. Canakinumab is an approved IL-1β inhibitor in the treatment of AOSD with a balanced efficacy and safety profile. Since inflammatory cytokines play a major role in the pathogenesis of AOSD, we investigated the effects of canakinumab on the cytokine profile of AOSD patients from a randomized controlled trial. Multiplex analysis and ELISA were used to test the concentrations of several cytokines at three time points—week 0 (baseline), week 1 and week 4—in two patient groups—placebo and canakinumab. Two-way repeated-measures analysis of variance revealed a significant temporal effect on the concentrations of MRP 8/14, S100A12, IL-6 and IL-18 with a significant decrease at week 4 in the canakinumab group exclusively. Comparing responders with non-responders to canakinumab showed a significant decrease in MRP 8/14, IL-1RA, IL-18 and IL-6 in responders at week 4, while S100A12 levels decreased significantly in responders and non-responders. In summary, canakinumab showed a striking effect on the cytokine profile in patients with AOSD, exhibiting a clear association with clinical response. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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Graphical abstract

9 pages, 239 KiB  
Article
HLA Allele Prevalence in Disease-Modifying Antirheumatic Drugs-Responsive Enthesitis and/or Arthritis Not Fulfilling ASAS Criteria: Comparison with Psoriatic and Undifferentiated Spondyloarthritis
by Elvira Favoino, Livio Urso, Alessandra Serafino, Francesca Misceo, Giacomo Catacchio, Marcella Prete and Federico Perosa
J. Clin. Med. 2021, 10(14), 3006; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10143006 - 06 Jul 2021
Cited by 2 | Viewed by 2110
Abstract
Spondyloarthritis (SpA) is a group of inflammatory rheumatic diseases characterized by common clinical features, such as inflammatory enthesitis, arthritis and/or back pain. SpA is strongly associated with human leukocyte antigen (HLA) class I allotype B27. Ankylosing spondylitis has historically been the SpA subgroup [...] Read more.
Spondyloarthritis (SpA) is a group of inflammatory rheumatic diseases characterized by common clinical features, such as inflammatory enthesitis, arthritis and/or back pain. SpA is strongly associated with human leukocyte antigen (HLA) class I allotype B27. Ankylosing spondylitis has historically been the SpA subgroup with one of the strongest, best-proven associations with HLA-B27. The remaining SpA subgroups, namely psoriatic arthritis (PsA), inflammatory bowel diseases-associated arthritis/spondylitis, reactive arthritis, and undifferentiated SpA (uSpA), have also been associated with HLA allotypes other than HLA-B27. In this retrospective study, we analyzed the association between the HLA class I and II haplotypes and the susceptibility to enthesitis and/or arthritis (E/A). Special attention was paid to E/A responding to disease-modifying antirheumatic drugs (DMARDs) not fulfilling ASAS classification criteria (ASAS−), as compared to ASAS+ forms including PsA and uSpA. The whole E/A group showed significant independent associations with HLA-A28(68), B27, Cw3, Cw12, and DQ1; taken singly, PsA was associated with HLA-B27 and DQ1, uSpA with HLA-B16(38,39) and B27, and E/A ASAS− with HLA-A28(68), Cw8, and Cw12. This study identified novel risk HLA allotypes for different SpA subgroups in an Italian population. HLA typing could aid the diagnosis and treatment of E/A subgroups, including DMARDS-responsive forms not fulfilling ASAS classification criteria. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
19 pages, 4103 KiB  
Article
Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage
by Annika Reddig, Linda Voss, Karina Guttek, Dirk Roggenbuck, Eugen Feist and Dirk Reinhold
J. Clin. Med. 2021, 10(7), 1431; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10071431 - 01 Apr 2021
Cited by 13 | Viewed by 3373
Abstract
Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for [...] Read more.
Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for RA treatment by the European Medicines Agency. Increasing concentrations of JAKi or methotrexate, conventionally used in RA therapy, were either added to freshly mitogen-stimulated or preactivated peripheral blood mononuclear cells (PBMC), isolated from healthy volunteers. A comparable, dose-dependent inhibition of lymphocyte proliferation was observed in samples treated with tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib had to be two orders of magnitude higher. In contrast, antiproliferative effects were strongly attenuated when JAKi were added to preactivated PBMCs. High dosage of upadacitinib and filgotinib also affected cell viability. Further, analyses of DNA double-strand break markers γH2AX and 53BP1 indicated an enhanced level of DNA damage in cells incubated with high concentrations of filgotinib and a dose-dependent reduction in clearance of radiation-induced γH2AX foci in the presence of tofacitinib or baricitinib. Thereby, our study demonstrated a broad comparability of immunomodulatory effects induced by different JAKi and provided first indications, that (pan)JAKi may impair DNA damage repair in irradiated PBMCs. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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13 pages, 1214 KiB  
Article
COVID-19 in Autoinflammatory Diseases with Immunosuppressive Treatment
by Tatjana Welzel, Samuel Dembi Samba, Reinhild Klein, Johannes N. van den Anker and Jasmin B. Kuemmerle-Deschner
J. Clin. Med. 2021, 10(4), 605; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10040605 - 05 Feb 2021
Cited by 13 | Viewed by 5157
Abstract
COVID-19 disease increases interleukin (IL)-1β release. Anti-IL-1-treatment is effective in IL-1-mediated autoinflammatory diseases (AID). This case series presents COVID-19 in patients with IL-1-mediated and unclassified AID with immunosuppressive therapy (IT). Patient 1 is a 34-year-old woman with an unclassified AID and methotrexate. Patients [...] Read more.
COVID-19 disease increases interleukin (IL)-1β release. Anti-IL-1-treatment is effective in IL-1-mediated autoinflammatory diseases (AID). This case series presents COVID-19 in patients with IL-1-mediated and unclassified AID with immunosuppressive therapy (IT). Patient 1 is a 34-year-old woman with an unclassified AID and methotrexate. Patients 2 and 3 (14-year-old girl and 12-year-old boy, respectively) have a Cryopyrin-Associated Periodic Syndrome (NLRP3 p.Q703K heterozygous, CAPS) treated with canakinumab 150 mg/month since three and five years, respectively. Patient 4 is a 15-year-old girl who has had familial Mediterranean fever (MEFV p.M694V homozygous) for 3 years treated with canakinumab 150 mg/month and colchicine. All patients had a mild acute COVID-19 course, particularly the adolescent patients. A few weeks after COVID-19 recovery, both CAPS patients developed increased AID activity, necessitating anti-IL-1-treatment intensification in one patient. At day 100, one out of four patients (25%) showed positive antibody response to SARS-CoV-2. This is one of the first reports providing follow-up data about COVID-19 in AID. The risk for severe acute COVID-19 disease was mild/moderate, but increased AID activity post-COVID-19 was detected. Follow-up data and data combination are needed to expand understanding of COVID-19 and SARS-CoV-2 immunity in AID and the role of IT. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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10 pages, 1025 KiB  
Article
Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) with a New Pathogenic Variant in TNFRSF1A Gene in a Family of the Adult Male with Renal AA Amyloidosis—Diagnostic and Therapeutic Challenge for Clinicians
by Jolanta Zegarska, Ewa Wiesik-Szewczyk, Ewa Hryniewiecka, Beata Wolska-Kusnierz, Dariusz Soldacki, Magdalena Kacprzak, Agnieszka Sobczynska-Tomaszewska, Kamila Czerska, Pawel Siedlecki, Karina Jahnz-Rozyk, Ewa Bernatowska, Radoslaw Zagozdzon and Leszek Paczek
J. Clin. Med. 2021, 10(3), 465; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10030465 - 26 Jan 2021
Cited by 3 | Viewed by 2316
Abstract
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is [...] Read more.
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is AA amyloidosis. We present the diagnostic route of a 33-year-old male with AA amyloidosis and his children, leading to diagnosis of monogenic autoinflammatory syndrome, confirmed by genetic analysis. A novel variant of the in-frame insertion type in one allele of TNFRSF1A gene was found by whole exome sequencing and confirmed by Sanger sequencing, which allowed a diagnosis of TRAPS. Three-dimensional modeling was used to assess the structural changes introduced into TNFR1 molecule by the insertion. The analysis of the 3D model revealed that accommodation of the 4AA insert induces misalignment of three cysteine bridges (especially the C70-C96 bridge) in the extracellular domain, leading to putatively misfolded and improperly functioning TNFR1. Three of the patient’s daughters inherited the same variant of the TNFRSF1A gene and presented TRAPS symptoms. TRAPS is a very rare disease, but in the presence of suggestive symptoms the genetic diagnostic workout should be undertaken. Early diagnosis followed by appropriate clinical management can prevent irreversible complications. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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15 pages, 2874 KiB  
Article
Evaluate the Differences in CT Features and Serum IgG4 Levels between Lymphoma and Immunoglobulin G4-Related Disease of the Orbit
by Wei-Hsin Yuan, Anna Fen-Yau Li, Shu-Yi Yu, Ying-Yuan Chen, Chia-Hung Wu, Hui-Chen Hsu, Jiing-Feng Lirng and Wan-You Guo
J. Clin. Med. 2020, 9(8), 2425; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9082425 - 29 Jul 2020
Cited by 3 | Viewed by 2296
Abstract
Background: Benign immunoglobulin G4 (IgG4)-related orbital disease (IgG4-ROD)—characterized as tumors mimicking malignant orbital lymphoma (OL)—responds well to steroids, instead of chemotherapy, radiotherapy and/or surgery of OL. The objective of this study was to report the differences in computed tomography (CT) features and- serum [...] Read more.
Background: Benign immunoglobulin G4 (IgG4)-related orbital disease (IgG4-ROD)—characterized as tumors mimicking malignant orbital lymphoma (OL)—responds well to steroids, instead of chemotherapy, radiotherapy and/or surgery of OL. The objective of this study was to report the differences in computed tomography (CT) features and- serum IgG4 levels of IgG4-ROD and OL. Methods: This study retrieved records for patients with OL and IgG4-ROD from a pathology database during an eight-year-and-five-month period. We assessed the differences between 16 OL patients with 27 lesions and nine IgG4-ROD patients with 20 lesions according to prebiopsy CT features of lesions and prebiopsy serum IgG4 levels and immunoglobulin G (IgG) levels This study also established the receiver-operating curves (ROC) of precontrast and postcontrast CT Hounsfield unit scales (CTHU), serum IgG4 levels, serum IgG levels and their ratios. Results: Significantly related to IgG4-ROD (all p < 0.05) were the presence of lesions with regular borders, presence of multiple lesions—involving both lacrimal glands on CT scans—higher median values of postcontrast CTHU, postcontrast CTHU/precontrast CTHU ratios, serum IgG4 levels and serum IgG4/IgG level ratios. Compared to postcontrast CTHU, serum IgG4 levels had a larger area under the ROC curve (0.847 [95% confidence interval (CI): 0.674–1.000, p = 0.005] vs. 0.766 [95% CI: 0.615–0.917, p = 0.002]), higher sensitivity (0.889 [95% CI: 0.518–0.997] vs. 0.75 [95% CI: 0.509–0.913]), higher specificity (0.813 [95% CI: 0.544–0.960] vs. 0.778 [95% CI: 0.578–0.914]) and a higher cutoff value (≥132.5 mg/dL [milligrams per deciliter] vs. ≥89.5). Conclusions: IgG4-ROD showed distinct CT features and elevated serum IgG4 (≥132.5 mg/dL), which could help distinguish IgG4-ROD from OL. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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9 pages, 630 KiB  
Article
Combined Use of Febuxostat and Colchicine Does Not Increase Acute Hepatotoxicity in Patients with Gout: A Retrospective Study
by Yoon-Jeong Oh and Ki Won Moon
J. Clin. Med. 2020, 9(5), 1488; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9051488 - 15 May 2020
Cited by 5 | Viewed by 2842
Abstract
Colchicine has been effectively used to prevent acute flares in patients with gout, but drug-related adverse events have frequently occurred. We investigated whether colchicine therapy with febuxostat is associated with hepatotoxicity in gout patients. Gout patients treated with (n = 121) or [...] Read more.
Colchicine has been effectively used to prevent acute flares in patients with gout, but drug-related adverse events have frequently occurred. We investigated whether colchicine therapy with febuxostat is associated with hepatotoxicity in gout patients. Gout patients treated with (n = 121) or without (n = 57) colchicine were enrolled upon initiating febuxostat as a urate-lowering treatment, and clinical and laboratory data at diagnosis were compared. Logistic regression analysis was performed to evaluate the risk factors related to hepatotoxicity. Median age of the with-colchicine and without-colchicine groups was 51.0 (37.0–62.0) and 56.0 (43.5–68.5) years, respectively. During the three months of febuxostat prescription, the prevalence of hepatotoxicity was 13/121 (10.9%) in the with-colchicine group and 4/57 (7.0%) in the without-colchicine group, without statistical significance. The rate of colchicine use was not different between the study subjects with or without hepatotoxicity (76.5% vs. 67.1%, p = 0.587). Pre-existing liver disease was significantly associated with increased risk of hepatotoxicity after febuxostat treatment (odds ratio, 4.083; 95% confidence interval, 1.326–12.577; p = 0.014). Colchicine may be safely used as a prophylactic agent for gout patients with febuxostat. However, upon initiating febuxostat, it is recommended to monitor the development of acute liver injury in gout patients with underlying liver disease. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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Review

Jump to: Editorial, Research, Other

14 pages, 2016 KiB  
Review
Syndrome of Undifferentiated Recurrent Fever (SURF): An Emerging Group of Autoinflammatory Recurrent Fevers
by Riccardo Papa, Federica Penco, Stefano Volpi, Diana Sutera, Roberta Caorsi and Marco Gattorno
J. Clin. Med. 2021, 10(9), 1963; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10091963 - 03 May 2021
Cited by 21 | Viewed by 4213
Abstract
Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, [...] Read more.
Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, we focused on the studies enrolling patients suspected of AID and genotyped them with next generation sequencing technologies in order to describe the clinical manifestations and treatment response of published cohorts of patients with SURF. We also propose a preliminary set of indications for the clinical suspicion of SURF that could help in everyday clinical practice. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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15 pages, 11349 KiB  
Review
Autoinflammatory Features in Gouty Arthritis
by Paola Galozzi, Sara Bindoli, Andrea Doria, Francesca Oliviero and Paolo Sfriso
J. Clin. Med. 2021, 10(9), 1880; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10091880 - 26 Apr 2021
Cited by 47 | Viewed by 6929
Abstract
In the panorama of inflammatory arthritis, gout is the most common and studied disease. It is known that hyperuricemia and monosodium urate (MSU) crystal-induced inflammation provoke crystal deposits in joints. However, since hyperuricemia alone is not sufficient to develop gout, molecular-genetic contributions are [...] Read more.
In the panorama of inflammatory arthritis, gout is the most common and studied disease. It is known that hyperuricemia and monosodium urate (MSU) crystal-induced inflammation provoke crystal deposits in joints. However, since hyperuricemia alone is not sufficient to develop gout, molecular-genetic contributions are necessary to better clinically frame the disease. Herein, we review the autoinflammatory features of gout, from clinical challenges and differential diagnosis, to the autoinflammatory mechanisms, providing also emerging therapeutic options available for targeting the main inflammatory pathways involved in gout pathogenesis. This has important implication as treating the autoinflammatory aspects and not only the dysmetabolic side of gout may provide an effective and safer alternative for patients even in the prevention of possible gouty attacks. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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19 pages, 1943 KiB  
Review
Role of Proteasomes in Inflammation
by Carl Christoph Goetzke, Frédéric Ebstein and Tilmann Kallinich
J. Clin. Med. 2021, 10(8), 1783; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10081783 - 20 Apr 2021
Cited by 44 | Viewed by 5013
Abstract
The ubiquitin–proteasome system (UPS) is involved in multiple cellular functions including the regulation of protein homeostasis, major histocompatibility (MHC) class I antigen processing, cell cycle proliferation and signaling. In humans, proteasome loss-of-function mutations result in autoinflammation dominated by a prominent type I interferon [...] Read more.
The ubiquitin–proteasome system (UPS) is involved in multiple cellular functions including the regulation of protein homeostasis, major histocompatibility (MHC) class I antigen processing, cell cycle proliferation and signaling. In humans, proteasome loss-of-function mutations result in autoinflammation dominated by a prominent type I interferon (IFN) gene signature. These genomic alterations typically cause the development of proteasome-associated autoinflammatory syndromes (PRAAS) by impairing proteasome activity and perturbing protein homeostasis. However, an abnormal increased proteasomal activity can also be found in other human inflammatory diseases. In this review, we cast a light on the different clinical aspects of proteasomal activity in human disease and summarize the currently studied therapeutic approaches. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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12 pages, 1071 KiB  
Review
The Pathogenic Role of Interferons in the Hyperinflammatory Response on Adult-Onset Still’s Disease and Macrophage Activation Syndrome: Paving the Way towards New Therapeutic Targets
by Ilenia Di Cola, Piero Ruscitti, Roberto Giacomelli and Paola Cipriani
J. Clin. Med. 2021, 10(6), 1164; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10061164 - 10 Mar 2021
Cited by 16 | Viewed by 2220
Abstract
Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology affecting young adults, which is burdened by life-threatening complications, mostly macrophage activation syndrome (MAS). Interferons (IFNs) are signalling molecules that mediate a variety of biological functions from defence against viral infections, [...] Read more.
Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology affecting young adults, which is burdened by life-threatening complications, mostly macrophage activation syndrome (MAS). Interferons (IFNs) are signalling molecules that mediate a variety of biological functions from defence against viral infections, to antitumor and immunomodulatory effects. These molecules have been classified into three major types: IFN I, IFN II, IFN III, presenting specific characteristics and functions. In this work, we reviewed the role of IFNs on AOSD and MAS, focusing on their pathogenic role in promoting the hyperinflammatory response and as new possible therapeutic targets. In fact, both preclinical and clinical observations suggested that these molecules could promote the hyperinflammatory response in MAS during AOSD. Furthermore, the positive results of inhibiting IFN-γ in primary hemophagocytic lymphohistiocytosis may provide a solid rationale to arrange further clinical studies, paving the way for reducing the high mortality rate in MAS during AOSD. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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21 pages, 1717 KiB  
Review
Adult-Onset Still’s Disease: Clinical Aspects and Therapeutic Approach
by Stylianos Tomaras, Carl Christoph Goetzke, Tilmann Kallinich and Eugen Feist
J. Clin. Med. 2021, 10(4), 733; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10040733 - 12 Feb 2021
Cited by 36 | Viewed by 10474
Abstract
Adult-onset Still’s disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still’s disease in children, currently named systemic-onset [...] Read more.
Adult-onset Still’s disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still’s disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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17 pages, 691 KiB  
Review
Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?
by Tatjana Welzel and Jasmin B. Kuemmerle-Deschner
J. Clin. Med. 2021, 10(1), 128; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10010128 - 01 Jan 2021
Cited by 43 | Viewed by 7405
Abstract
The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), [...] Read more.
The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), the moderate phenotype is also known as Muckle–Wells syndrome (MWS), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) describes the severe phenotype. The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic. Nevertheless, making the CAPS diagnosis is challenging as several patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. Somatic mosaicisms and low-penetrance variants lead to atypical clinical symptoms and disease courses. To avoid morbidity and to reduce mortality, early diagnosis is crucial, and a targeted anti-IL-1 therapy should be started as soon as possible. Furthermore, continuous and precise monitoring of disease activity, organ damage, and health-related quality of life is important. This review summarizes the current evidence in diagnosis and management of patients with CAPS. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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11 pages, 5256 KiB  
Review
Imaging of Joints and Bones in Autoinflammation
by Katharina Ziegeler, Iris Eshed, Torsten Diekhoff and Kay Geert Hermann
J. Clin. Med. 2020, 9(12), 4074; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9124074 - 17 Dec 2020
Cited by 8 | Viewed by 3712
Abstract
Autoinflammatory disorders are commonly characterized by seemingly unprovoked systemic inflammation mainly driven by cells and cytokines of the innate immune system. In many disorders on this spectrum, joint and bone involvement may be observed and imaging of these manifestations can provide essential diagnostic [...] Read more.
Autoinflammatory disorders are commonly characterized by seemingly unprovoked systemic inflammation mainly driven by cells and cytokines of the innate immune system. In many disorders on this spectrum, joint and bone involvement may be observed and imaging of these manifestations can provide essential diagnostic information. This review aimed to provide a comprehensive overview of the imaging characteristics for major diseases and disease groups on the autoinflammatory spectrum, including familial Mediterranean fever (FMF), Behçet disease (BD), crystal deposition diseases (including gout), adult-onset Still’s disease (AoSD), and syndromatic synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO)/chronic recurrent multifocal osteomyelitis (CRMO). Herein, we discuss common and distinguishing imaging characteristics, phenotypical overlaps with related diseases, and promising fields of future research. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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22 pages, 2069 KiB  
Review
The Impact of Dysphagia in Myositis: A Systematic Review and Meta-Analysis
by Bendix Labeit, Marc Pawlitzki, Tobias Ruck, Paul Muhle, Inga Claus, Sonja Suntrup-Krueger, Tobias Warnecke, Sven G. Meuth, Heinz Wiendl and Rainer Dziewas
J. Clin. Med. 2020, 9(7), 2150; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9072150 - 08 Jul 2020
Cited by 36 | Viewed by 5638
Abstract
(1) Background: Dysphagia is a clinical hallmark and part of the current American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) diagnostic criteria for idiopathic inflammatory myopathy (IIM). However, the data on dysphagia in IIM are heterogenous and partly conflicting. The aim of this [...] Read more.
(1) Background: Dysphagia is a clinical hallmark and part of the current American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) diagnostic criteria for idiopathic inflammatory myopathy (IIM). However, the data on dysphagia in IIM are heterogenous and partly conflicting. The aim of this study was to conduct a systematic review on epidemiology, pathophysiology, outcome and therapy and a meta-analysis on the prevalence of dysphagia in IIM. (2) Methods: Medline was systematically searched for all relevant articles. A random effect model was chosen to estimate the pooled prevalence of dysphagia in the overall cohort of patients with IIM and in different subgroups. (3) Results: 234 studies were included in the review and 116 (10,382 subjects) in the meta-analysis. Dysphagia can occur as initial or sole symptom. The overall pooled prevalence estimate in IIM was 36% and with 56% particularly high in inclusion body myositis. The prevalence estimate was significantly higher in patients with cancer-associated myositis and with NXP2 autoantibodies. Dysphagia is caused by inflammatory involvement of the swallowing muscles, which can lead to reduced pharyngeal contractility, cricopharyngeal dysfunction, reduced laryngeal elevation and hypomotility of the esophagus. Swallowing disorders not only impair the quality of life but can lead to serious complications such as aspiration pneumonia, thus increasing mortality. Beneficial treatment approaches reported include immunomodulatory therapy, the treatment of associated malignant diseases or interventional procedures targeting the cricopharyngeal muscle such as myotomy, dilatation or botulinum toxin injections. (4) Conclusion: Dysphagia should be included as a therapeutic target, especially in the outlined high-risk groups. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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Other

14 pages, 925 KiB  
Brief Report
Variant in the PLCG2 Gene May Cause a Phenotypic Overlap of APLAID/PLAID: Case Series and Literature Review
by Tatjana Welzel, Lea Oefelein, Ursula Holzer, Amelie Müller, Benita Menden, Tobias B. Haack, Miriam Groβ and Jasmin B. Kuemmerle-Deschner
J. Clin. Med. 2022, 11(15), 4369; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11154369 - 27 Jul 2022
Cited by 7 | Viewed by 2108
Abstract
Background: Variants in the phospholipase C gamma 2 (PLCG2) gene can cause PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. Linking the clinical phenotype with the genotype is relevant in making [...] Read more.
Background: Variants in the phospholipase C gamma 2 (PLCG2) gene can cause PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. Linking the clinical phenotype with the genotype is relevant in making the final diagnosis. Methods: This is a single center case series of five related patients (4–44 years), with a history of autoinflammation and immune dysregulation. Clinical and laboratory characteristics were recorded and a literature review of APLAID/PLAID was performed. Results: All patients had recurrent fevers, conjunctivitis, lymphadenopathy, headaches, myalgia, abdominal pain, cold-induced urticaria and recurrent airway infections. Hearing loss was detected in two patients. Inflammatory parameters were slightly elevated during flares. Unswitched B-cells were decreased. Naïve IgD+CD27− B-cells and unswitched IgD+CD27+ B-cells were decreased; switched IgD-CD27+ B-cells were slightly increased. T-cell function was normal. Genetic testing revealed a heterozygous missense variant (c.77C>T, p.Thr26Met) in the PLCG2 gene in all patients. Genotype and phenotype characteristics were similar to previously published PLAID (cold-induced urticaria) and APLAID (eye inflammation, musculoskeletal complaints, no circulating antibodies) patients. Furthermore, they displayed characteristics for both PLAID and APLAID (recurrent infections, abdominal pain/diarrhea) with normal T-cell function. Conclusion: The heterozygous missense PLCG2 gene variant (c.77C>T, p.Thr26Met) might cause phenotypical overlap of PLAID and APLAID patterns. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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15 pages, 430 KiB  
Registered Report
Comparing the Clinical and Laboratory Features of Remitting Seronegative Symmetrical Synovitis with Pitting Edema and Seronegative Rheumatoid Arthritis
by Misako Higashida-Konishi, Keisuke Izumi, Satoshi Hama, Hiroshi Takei, Hisaji Oshima and Yutaka Okano
J. Clin. Med. 2021, 10(5), 1116; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10051116 - 07 Mar 2021
Viewed by 2603
Abstract
In seronegative arthritis with extremity edema, it is difficult to differentiate between remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) and seronegative rheumatoid arthritis (SNRA). We compared the clinical characteristics of RS3PE and SNRA in patients with and without malignancies. We retrospectively [...] Read more.
In seronegative arthritis with extremity edema, it is difficult to differentiate between remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) and seronegative rheumatoid arthritis (SNRA). We compared the clinical characteristics of RS3PE and SNRA in patients with and without malignancies. We retrospectively examined patients diagnosed with RS3PE (McCarty criteria) and SNRA at our hospital in 2007–2020. Malignancy was diagnosed within 2 years before or after RS3PE or SNRA diagnosis. Overall, 24 RS3PE and 124 SNRA patients were enrolled. The median ages were 79.5 and 68.5 years, and men comprised 54.2% and 37.1% of RS3PE and SNRA patients, respectively. RS3PE patients had higher inflammation levels (p = 0.004) and more incidences of malignancy (p = 0.034). Matching for age and sex, RS3PE patients had higher inflammation levels (p = 0.021) and more incidences of malignancy (p = 0.005). Overall, odds ratios (ORs) for malignancy were higher for older age (OR 1.06, p = 0.037), male sex (OR 4.34, p = 0.007), RS3PE patients (OR 4.83, p = 0.034), and patients with extremity edema (OR 4.83, p = 0.034). Inflammation levels and associated factors of malignancy were higher in RS3PE patients than in SNRA patients. Patients who are older, male, with extremity edema, or had RS3PE should be screened for malignancies. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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4 pages, 195 KiB  
Registered Report
Comparing the Clinical and Laboratory Features of Remitting Seronegative Symmetrical Synovitis with Pitting Edema and Seronegative Rheumatoid Arthritis: Stage 1
by Misako Higashida-Konishi, Keisuke Izumi, Satoshi Hama, Hiroshi Takei, Hisaji Oshima and Yutaka Okano
J. Clin. Med. 2021, 10(2), 340; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10020340 - 18 Jan 2021
Cited by 2 | Viewed by 1252
Abstract
In seronegative arthritis with extremity edema, the differential diagnosis between remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) and seronegative rheumatoid arthritis (SNRA) is difficult. We compared the clinical characteristics of RS3PE and SNRA and those of such patients with and without [...] Read more.
In seronegative arthritis with extremity edema, the differential diagnosis between remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) and seronegative rheumatoid arthritis (SNRA) is difficult. We compared the clinical characteristics of RS3PE and SNRA and those of such patients with and without malignancies. We retrospectively examined patients diagnosed with RS3PE (McCarty criteria) and SNRA at our hospital in 2007–2020. Malignancy was diagnosed within 2 years before or after RS3PE or SNRA diagnosis. Overall, 24 RS3PE and 124 SNRA patients were enrolled. The mean ages were 79.0 and 66.5 years, and men comprised 54.2% and 37.1% of RS3PE and SNRA patients, respectively. RS3PE patients had higher inflammation levels (p < 0.01) and more incidences of malignancy (p < 0.01). Matching for age and sex, RS3PE patients had higher inflammation levels (p < 0.01) and more incidences of malignancy (p = 0.02). Overall, odds ratios (ORs) for malignancy were higher for older age (OR 1.06, p = 0.04), male sex (OR 4.34, p = 0.02), RS3PE patients (OR 4.83, p = 0.01), and patients with extremity edema (OR 4.83, p = 0.01). RS3PE patients had higher inflammation levels and associated factors of malignancy than SNRA patients. Patients who are older, male, with extremity edema, or with RS3PE should be screened for malignancies. Full article
(This article belongs to the Special Issue Systemic Autoinflammatory Diseases—Clinical Rheumatic Challenges)
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