Comparative Analysis of Synovial Inflammation After SARS-Cov-2

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Correspondence Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218315 on 6 July 2020. Downloaded from Comparative analysis of synovial inflammation after SARS-CoV-2 infection

Joint and muscle pain is a common symptom seen in many viral infections and we read with interest the report by López- González et al who described four patients with severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) pos who developed monoarthritis or oligoarthritis after hospitalisation related to crystals deposition disease confirmed by synovial fluid assessment.1 However, no data are available on polyarthritis onset after SARS-CoV -2 infection neither on its impact on pre-existing chronic joint diseases, as rheumatoid arthritis (RA), in terms of clinical worsening or remission loss. In our hospital, during the SARS-CoV-2 pandemic, we inves- tigated the synovial tissue (ST) characteristics in a patient (#1) who had joint pain complicated with polyarthritis development as first symptoms of SARS-CoV-2 infection and in a patient (#2) with pre-existing anticitrullinated peptide antibody (ACPA)/ rheumatoid factorpos RA in stable remission who experienced severe pulmonary distress and joint symptoms worsening after SARS-CoV-2 infection. Patient #1 is a 61-year -old man who developed severe asthenia, anorexia and arthromyalgia followed by polyarthritis (Disease Activity Score over 28 joints C-reactive protein (DAS28-CRP):4.5; figure 1A) initially treated with non-steroidal anti-inflammatory drugs (figure 1B). On 14 April 2020, the patient developed cough and mild dyspnoea and chest CT showed mild-interstitial pneumonia (figure 1C) and SARS-Cov-2 nasopharyngeal swab resulted positive. Then, antiviral treatment and hydroxicloroquine were started. Despite a progres- Figure 1 (A–T) Assessment and management of arthritis in patients sive pulmonary function improvement, the articular symptoms with severe acute respiratory syndrome coronavirus-2 (SARS-CoV - worsened (DAS28-CRP:5.8) and the patient was tested for pos 2 ). (A) PaO2/FiO2 and Disease Activity Score over 28 joints C-reactive ACPA and RF which resulted negative. Ultrasound (US) assess- protein (DAS-28-CRP) values across disease course in patient #1. ment showed joint effusion, ST thickness and increased vascu- Dotted green lines indicate reference values for PaO2/FiO2 (200) larity (figure 1D). Arthrocentesis and US-guided ST biopsy of and DAS-28-CRP (2.19) for oxygen support need and joint disease the knee revealed calcium pyrophosphate or monosodium remission, respectively. Timing of SARS-CoV-2 real-time PCR (RT-PCR) http://ard.bmj.com/ urate crystals absence in the synovial fluid and H&E showed and synovial tissue (ST) biopsy performance is indicated on the graph. ST with stromal activation, oedema and moderate inflammatory (B) Timeline of the pharmacological treatment administered to patient features (figure 1E–G),2 3 with perivascular and diffuse infiltrates pos pos pos #1: etoricoxib (200 mg/day); lopinavir-ritonavir (133.3 mg/33.3 mg two composed mostly of CD68 , CD3 and CD138 elements times a day); hydroxicloroquine (800 mg first day followed by 400 mg (figure 1H–J). After multidisciplinary discussion, baricitinib daily afterwards); baricitinib (4 mg/day). (C) Example photograph of 4 mg was started combined with prednisone (10 mg/day) and the chest CT-scan of patient #1. (D) Example photograph of ultrasound (US) patient experienced progressive improvement of joint symptoms assessment of the biopsied joint (knee) of patient #1. (E–G) Example on September 25, 2021 by guest. Protected copyright. (DAS28-CRP:2.8 after 8 days). photographs of H&E staining of US-guided minimally invasive ST biopsy pos Patient #2 is a 50-year-old woman with ACPA/RF RA of patient #1: ST hyperplasia (E–F) and perivascular inflammatory since 2017 in sustained remission under methotrexate (15 mg/ infiltrates (G). (H–J) Example photographs of immunohistochemistry weekly; DAS28-CRP :1.9 in January 2020). On 14 March 2020, (IHC) staining of US-guided ST biopsy of patient #1: (H) CD3, (I) CD138 the patient developed fever (till 39°C), diarrhoea and dyspnoea 3 and (J) CD68 (J). (K) PaO2/FiO2 and DAS-28-CRP values across disease not responsive to cephalosporine. On 23 March 2020, due course in patient #2. (L) Timeline of the pharmacological treatment to sudden worsening of pulmonary function needing oxygen administered to patient #2: lopinavir-ritonavir (133.3 mg/33.3 mg two support (31%) the patient was referred to our emergency depart- times a day), hydroxicloroquine (800 mg first day followed by 400 mg ment where chest X-rays scan showed interstitial pneumonia daily afterwards), ceftriaxone (2 g daily), azithromycin (500 mg daily) and SARS-CoV -2 nasopharyngeal swab was positive (figure 1K). and sarilumab (400 mg) were administered intravenously combining Methotrexate was stopped and antiviral and antibiotic treat- 2 sarilumab 200 mg prefilled syringes mixed in 100 mL 0.9% sodium ment was started (figure 1L). However, the patient developed chloride solution for intravenous use. (M) Example photograph of chest polyarthritis (DAS28-CRP:6.8) and pulmonary function wors- CT-scan of patient #2. (N) Example photograph of US assessment of ening (PaO2/FiO2: 188 at O2 therapy at 40%) and a chest CT the biopsied joint (knee) of patient #2. (O–Q) Example photographs of scan showed bilateral pulmonary consolidation areas with H&E staining of US-guided minimally invasive ST biopsy of patient #2. ground-glass and crazy paving features (figure 1M). Moreover, (R–T) Example photographs of IHC staining of US-guided minimally US showed joint effusion, ST thickness and increased vascu- invasive ST biopsy of patient #2: (R) CD3, (S) CD138 and (T) CD68. CD, larity (figure 1N) and US-guided ST biopsy of the knee showed cluster designation; PaO2/FiO2, ratio of arterial oxygen partial pressure to severe inflammation (Krenn synovitis score: 8) with ST thick- fractional inspired oxygen. ening and fibrin exudates (figure 1O–Q). Moreover, abundant

Ann Rheum Dis Month 2020 Vol 0 No 0 1 Correspondence Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218315 on 6 July 2020. Downloaded from

3Division of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy Correspondence to Dr Stefano Alivernini and Professor Elisa Gremese, Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy; stefano. alivernini@unicatt. it, elisa. gremese@unicatt. it Contributors SA and EG gave substantial contributions to study conception and design. All authors gave substantial contributions to acquisition of data. SA, AC, MG, BT, MF and EG gave substantial contributions to analysis and interpretation of data. SA, AC, BT and EG drafted the article and revised it critically for important intellectual content. All authors gave final approval of the version of the article to be published. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests None declared. Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Patient consent for publication Obtained. Provenance and peer review Not commissioned; internally peer reviewed. This article is made freely available for use in accordance with BMJ’s website Figure 2 Inflammatory cytokines plasma levels in patient with new terms and conditions for the duration of the covid-19 pandemic or until otherwise development of peripheral polyarthritis or in patient with rheumatoid determined by BMJ. You may use, download and print the article for any lawful, arthritis flare after severe acute respiratory syndrome coronavirus-2 non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. infection. Interleukin (IL)-6, IL-8 and tumour necrosis factor α (TNFα) plasma levels (multicytokine test for ELLA-Bio-Techne, Minneapolis) © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. at the time of ultrasound (US)-guided synovial tissue biopsy (patients #1 and #2) and after interleukin 6 receptor inhibitor (IL6R-i) treatment (patient #2). To cite Alivernini S, Cingolani A, Gessi M, et al. Ann Rheum Dis Epub ahead of print: CD3pos, CD138pos and CD20pos cells (figure 1R,S) infiltrates also [please include Day Month Year]. doi:10.1136/annrheumdis-2020-218315 forming aggregates and few follicles were detected. Numerous Received 17 June 2020 ST CD68pos cells were seen (figure 1T). Therefore, sarilumab was Accepted 19 June 2020 started leading to a significant pulmonary function and articular improvement (DAS-CRP :2.3) as shown by the dynamics of cytokines plasma levels (figure 2). At the time of manuscript submis- sion, the patient was in remission (DAS28-CRP:1.9). ►► http://dx. doi. org/ 10. 1136/ annrheumdis- 2020- 218368 Despite rare, arthritis new onset or its worsening after

Ann Rheum Dis 2020;0:1–2. doi:10.1136/annrheumdis-2020-218315 http://ard.bmj.com/ SARS-CoV-2 infection, in patients with pre-existing chronic joint disease, may occur and should be promptly treated within ORCID iDs the pulmonary involvement management. In particular, baric- Stefano Alivernini http://orcid. org/0000- 0002-7383- 4212 itinib which was postulated to have a potential likelihood Elisa Gremese http://orcid. org/0000- 0002-2248- 1058 of impairing SARS-CoV-2 suppression or clearance4 was an effective option for joint symptoms control and interleukin 6 REFERENCES 1 López-González MD, Peral-Garrido ML, Calabuig I, et al. Case series of acute arthritis receptor inhibitor treatment allowed the successful suppression during COVID-19 admission. Ann Rheum Dis 2020;0:1–2. on September 25, 2021 by guest. Protected copyright. 5 6 of both lung and joint inflammation. However, longitudinal 2 Alivernini S, Tolusso B, Petricca L, et al. Synovial predictors of differentiation to definite follow-up of patients with SARS-CoV -2pos who developed new arthritis in patients with seronegative undifferentiated peripheral inflammatory onset of arthritis will reveal its clinical persistency as well as the arthritis: microRNA signature, histological, and ultrasound features. Front Med timing and the need of long-term anti-inflammatory treatments 2018;5:186. 3 Michelutti A, Gremese E, Morassi F, et al. B-Cell subsets in the joint compartments of during the convalescence phase. seropositive and seronegative rheumatoid arthritis (rA) and No-RA arthritides express memory markers and ZAP70 and characterize the aggregate pattern irrespectively of Stefano Alivernini ‍ ‍ ,1 Antonella Cingolani,2 Marco Gessi,3 1 2 1 the autoantibody status. Mol Med 2011;17:901–9. Annamaria Paglionico, Giuliana Pasciuto, Barbara Tolusso, 4 Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV 2 1 Massimo Fantoni, Elisa Gremese ‍ ‍ acute respiratory disease. Lancet 2020;395:e30–1. 1Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS - 5 Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy tocilizumab. Proc Natl Acad Sci U S A 2020;117:10970–5. 2Dipartimento di Scienze di Laboratorio e Infettivologiche - Dipartimento di Sicurezza 6 Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus e Bioetica, Sezione di Malattie Infettive, Fondazione Policlinico Universitario A. adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis Roma, Italy 2017;76:840–7.

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