Axial spondyloarthritis in patients with recurrent fever attacks: data from the AIDA network registry for undifferentiated autoInflammatory diseases (USAIDs)

Antonio Vitale^{1

2}, Valeria Caggiano^{1

2}, Isabel Silva³, Daniel G Oliveira^{4

5}, Piero Ruscitti⁶, Francesco Ciccia⁷, Ibrahim Vasi⁸, Abdurrahman Tufan⁸, Giuseppe Lopalco⁹, Ibrahim A AlMaghlouth¹⁰, Jurgen Sota^{1

2}, Ewa Wiesik-Szewczyk¹¹, Carla Gaggiano^{1

2}, Henrique Ayres Mayrink Giardini¹², Veronica Spedicato⁹, Gaafar Ragab^{13

14}, Florenzo Iannone⁹, Alberto Balistreri¹⁵, Micol Frassi¹⁶, José Hernández-Rodríguez¹⁷, Claudia Fabiani^{2

18}, Paolo Falsetti^{1

2}, Nunzia Di Meglio^{2

19}, Bruno Frediani^{1

2}, Maria Antonietta Mazzei^{2

19}, Donato Rigante^{20

21}, Raquel Faria²², Luca Cantarini^{1

2}

Affiliations

¹ Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, University of Siena, Siena, Italy.
² Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center] Siena, Siena, Italy.
³ Medicine Department, Centro Hospitalar Universitário de Santo António, Porto, Portugal.
⁴ UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
⁵ Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
⁶ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
⁷ Department of Precision Medicine, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy.
⁸ Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Türkiye.
⁹ Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
¹⁰ Rheumatology Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹¹ Department of Internal Medicine, Pneumonology, Allergology and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Military Institute of Medicine, National Research Institute, Warsaw, Poland.
¹² Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Universidade de São Paulo, São Paulo, Brazil.
¹³ Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
¹⁴ Faculty of Medicine, Newgiza University, Giza, Egypt.
¹⁵ Bioengineering and Biomedical Data Science Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
¹⁶ Rheumatology and Clinical Immunology, Spedali Civili and Department of Clinical and Experimental Sciences, University of Brescia [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Brescia, Italy.
¹⁷ Vasculitis Research Unit and Autoinflammatory Diseases Clinical Unit, Department of Autoimmune Diseases, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Barcelona, Spain.
¹⁸ Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
¹⁹ Unit of Diagnostic Imaging, Department of Medical, Surgical and Neuro Sciences and of Radiological Sciences, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
²⁰ Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
²¹ Rare Diseases and Periodic Fevers Research Centre, Università Cattolica Sacro Cuore, Rome, Italy.
²² Unidade de Imunologia ClínicaCentro Hospitalar Universitário de Santo António Porto [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Porto, Portugal.

PMID: 37324154
PMCID: PMC10263060
DOI: 10.3389/fmed.2023.1195995

Axial spondyloarthritis in patients with recurrent fever attacks: data from the AIDA network registry for undifferentiated autoInflammatory diseases (USAIDs)

Antonio Vitale et al. Front Med (Lausanne). 2023.

. 2023 May 30:10:1195995.

doi: 10.3389/fmed.2023.1195995. eCollection 2023.

Authors

Affiliations

¹ Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease Clinic, University of Siena, Siena, Italy.
² Azienda Ospedaliero-Universitaria Senese [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center] Siena, Siena, Italy.
³ Medicine Department, Centro Hospitalar Universitário de Santo António, Porto, Portugal.
⁴ UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
⁵ Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
⁶ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
⁷ Department of Precision Medicine, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy.
⁸ Division of Rheumatology, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Türkiye.
⁹ Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
¹⁰ Rheumatology Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
¹¹ Department of Internal Medicine, Pneumonology, Allergology and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Military Institute of Medicine, National Research Institute, Warsaw, Poland.
¹² Rheumatology Division, Faculdade de Medicina, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Universidade de São Paulo, São Paulo, Brazil.
¹³ Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
¹⁴ Faculty of Medicine, Newgiza University, Giza, Egypt.
¹⁵ Bioengineering and Biomedical Data Science Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
¹⁶ Rheumatology and Clinical Immunology, Spedali Civili and Department of Clinical and Experimental Sciences, University of Brescia [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Brescia, Italy.
¹⁷ Vasculitis Research Unit and Autoinflammatory Diseases Clinical Unit, Department of Autoimmune Diseases, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Barcelona, Spain.
¹⁸ Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
¹⁹ Unit of Diagnostic Imaging, Department of Medical, Surgical and Neuro Sciences and of Radiological Sciences, University of Siena, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
²⁰ Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
²¹ Rare Diseases and Periodic Fevers Research Centre, Università Cattolica Sacro Cuore, Rome, Italy.
²² Unidade de Imunologia ClínicaCentro Hospitalar Universitário de Santo António Porto [European Reference Network (ERN) for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (RITA) Center], Porto, Portugal.

PMID: 37324154
PMCID: PMC10263060
DOI: 10.3389/fmed.2023.1195995

Abstract

Beckground: Despite the recent advances in the field of autoinflammatory diseases, most patients with recurrent fever episodes do not have any defined diagnosis. The present study aims at describing a cohort of patients suffering from apparently unexplained recurrent fever, in whom non-radiographic axial spondylarthritis (SpA) represented the unique diagnosis identified after a complete clinical and radiologic assessment.

Materials and methods: Patients' data were obtained from the international registry on Undifferentiated Systemic AutoInflammatory Diseases (USAIDs) developed by the AutoInflammatory Disease Alliance (AIDA) network.

Results: A total of 54 patients with recurrent fever episodes were also affected by non-radiographic axial SpA according to the international classification criteria. SpA was diagnosed after the start of fever episodes in all cases; the mean age at the diagnosis of axial SpA was 39.9 ± 14.8 years with a diagnostic delay of 9.3 years. The highest body temperature reached during flares was 42°C, with a mean temperature of 38.8 ± 1.1°C. The most frequent manifestations associated to fever were: arthralgia in 33 (61.1%) cases, myalgia in 24 (44.4%) cases, arthritis in 22 (40.7%) cases, headache in 15 (27.8%) cases, diarrhea in 14 (25.9%) cases, abdominal pain in 13 (24.1%) cases, and skin rash in 12 (22.1%) cases. Twenty-four (44.4%) patients have taken daily or on-demand non-steroidal anti-inflammatory drugs (NSAIDs) and 31 (57.4%) patients have been treated with daily or on demand oral glucocorticoids. Colchicine was used in 28 (51.8%) patients, while other conventional disease modifying anti-rheumatic drugs (cDMARDs) were employed in 28 (51.8%) patients. Forty (74.1%) patients underwent anti-tumor necrosis factor (TNF) agents and 11 (20.4%) were treated with interleukin (IL)-1 inhibitors. The response to TNF inhibitors on recurrent fever episodes appeared more effective than that observed with anti-IL-1 agents; colchicine and other cDMARDs were more useful when combined with biotechnological agents.

Conclusion: Signs and symptoms referring to axial SpA should be inquired in patients with apparently unexplained recurrent fever episodes. The specific treatment for axial SpA may lead to a remarkable improvement in the severity and/or frequency of fever episodes in patients with unexplained fevers and concomitant axial SpA.

Keywords: SpA; arthritis; autoinflammatory diseases; diagnosis; outcome; treatment.

Copyright © 2023 Vitale, Caggiano, Silva, Oliveira, Ruscitti, Ciccia, Vasi, Tufan, Lopalco, AlMaghlouth, Sota, Wiesik-Szewczyk, Gaggiano, Giardini, Spedicato, Ragab, Iannone, Balistreri, Frassi, Hernández-Rodríguez, Fabiani, Falsetti, Di Meglio, Frediani, Mazzei, Rigante, Faria and Cantarini.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**Figure 1**
Bar charts describe the highest temperature observed during flares **(A)** and the mean duration of fever episodes **(B)** among the 54 patients enrolled.

**Figure 2**
Response to different treatments performed by patients included in the study; monotherapy and combination treatment with conventional or biotechnological disease modifying anti-rheumatic drugs (cDMARDs and bDMARDs, respectively) or colchicine were pointed out. The figure specifically describes treatment with colchicine **(A)**, cDMARDs **(B)**, anti-tumor necrosis factor (TNF) **(C)**, and anti-interleukin (IL)-1 **(D)**.

**Figure 3**
Bar charts describe the frequency of the main clinical manifestations observed during inflammatory attacks at the start and at the last assessment while on treatment with anti-tumor necrosis factor (TNF) agents **(A)** and interleukin (IL)-1 inhibitors **(B)**. Skin manifestations observed among patients treated with TNF inhibitors consisted of urticarial skin rash in 2 patients, pustular rash in one patient, erythematous skin rash in one patient; the latter one persisted at the last assessment. Skin manifestations observed among patients treated with IL-1 inhibitors consisted of erythematous skin rash in one patient and maculo-papular skin rash in a second patient. None of them resolved during IL-1 inhibition.

See this image and copyright information in PMC

References

1. Rigante D, Lopalco G, Vitale A, Lucherini OM, Caso F, de Clemente C, et al. . Untangling the web of systemic autoinflammatory diseases. Mediat Inflamm. (2014) 2014:948154: 1–15. doi: 10.1155/2014/948154 - DOI - PMC - PubMed
1. Statler VA, Marshall GS. Evaluation of prolonged and recurrent unexplained fevers. Pediatr Ann. (2018) 47:e347–53. doi: 10.3928/19382359-20180806-01, PMID: - DOI - PubMed
1. Cantarini L, Vitale A, Lucherini O, Muscari I, Magnotti F, Brizi G, et al. . Childhood versus adulthood-onset autoinflammatory disorders: myths and truths intertwined. Reumatismo. (2013) 65:55–62. doi: 10.4081/reumatismo.2013.55 - DOI - PubMed
1. Muscari I, Iacoponi F, Cantarini L, Lucherini OM, Simonini G, Brizi MG, et al. . The diagnostic evaluation of patients with potential adult-onset autoinflammatory disorders: our experience and review of the literature. Autoimmun Rev. (2012) 12:10–3. doi: 10.1016/j.autrev.2012.07.015, PMID: - DOI - PubMed
1. Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol. (1998) 27:S18–24. doi: 10.1016/S0720-048X(98)00038-2 - DOI - PubMed

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Axial spondyloarthritis in patients with recurrent fever attacks: data from the AIDA network registry for undifferentiated autoInflammatory diseases (USAIDs)

Affiliations

Axial spondyloarthritis in patients with recurrent fever attacks: data from the AIDA network registry for undifferentiated autoInflammatory diseases (USAIDs)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources