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Comparative analysis of synovial inflammation after SARS-CoV-2 infection
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  1. Stefano Alivernini1,
  2. Antonella Cingolani2,
  3. Marco Gessi3,
  4. Annamaria Paglionico1,
  5. Giuliana Pasciuto2,
  6. Barbara Tolusso1,
  7. Massimo Fantoni2,
  8. Elisa Gremese1
  1. 1 Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy
  2. 2 Dipartimento di Scienze di Laboratorio e Infettivologiche - Dipartimento di Sicurezza e Bioetica, Sezione di Malattie Infettive, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy
  3. 3 Division of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy
  1. Correspondence to Dr Stefano Alivernini, Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy; stefano.alivernini{at}unicatt.it; Professor Elisa Gremese, Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy; elisa.gremese{at}unicatt.it

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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 investigated 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 progressive pulmonary function improvement, the articular symptoms worsened (DAS28-CRP:5.8) and the patient was tested for ACPA and RF which resulted negative. Ultrasound (US) assessment showed joint effusion, ST thickness and increased vascularity (figure 1D). Arthrocentesis and US-guided ST biopsy of the knee revealed calcium pyrophosphate or monosodium urate crystals absence in the synovial fluid and H&E showed ST with stromal activation, oedema and moderate inflammatory features (figure 1E–G),2 3 with perivascular and diffuse infiltrates composed mostly of CD68pos, CD3pos and CD138pos elements (figure 1H–J). After multidisciplinary discussion, baricitinib 4 mg was started combined with prednisone (10 mg/day) and the patient experienced progressive improvement of joint symptoms (DAS28-CRP:2.8 after 8 days).

Figure 1

(A–T) Assessment and management of arthritis in patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2pos). (A) PaO2/FiO2 and Disease Activity Score over 28 joints C-reactive protein (DAS-28-CRP) values across disease course in patient #1. Dotted green lines indicate reference values for PaO2/FiO2 (200) and DAS-28-CRP (2.19) for oxygen support need and joint disease remission, respectively. Timing of SARS-CoV-2 real-time PCR (RT-PCR) and synovial tissue (ST) biopsy performance is indicated on the graph. (B) Timeline of the pharmacological treatment administered to patient #1: etoricoxib (200 mg/day); lopinavir-ritonavir (133.3 mg/33.3 mg two times a day); hydroxicloroquine (800 mg first day followed by 400 mg daily afterwards); baricitinib (4 mg/day). (C) Example photograph of chest CT-scan of patient #1. (D) Example photograph of ultrasound (US) assessment of the biopsied joint (knee) of patient #1. (E–G) Example photographs of H&E staining of US-guided minimally invasive ST biopsy of patient #1: ST hyperplasia (E–F) and perivascular inflammatory infiltrates (G). (H–J) Example photographs of immunohistochemistry (IHC) staining of US-guided ST biopsy of patient #1: (H) CD3, (I) CD138 and (J) CD68 (J).3 (K) PaO2/FiO2 and DAS-28-CRP values across disease course in patient #2. (L) Timeline of the pharmacological treatment administered to patient #2: lopinavir-ritonavir (133.3 mg/33.3 mg two times a day), hydroxicloroquine (800 mg first day followed by 400 mg daily afterwards), ceftriaxone (2 g daily), azithromycin (500 mg daily) and sarilumab (400 mg) were administered intravenously combining 2 sarilumab 200 mg prefilled syringes mixed in 100 mL 0.9% sodium chloride solution for intravenous use. (M) Example photograph of chest CT-scan of patient #2. (N) Example photograph of US assessment of the biopsied joint (knee) of patient #2. (O–Q) Example photographs of H&E staining of US-guided minimally invasive ST biopsy of patient #2. (R–T) Example photographs of IHC staining of US-guided minimally invasive ST biopsy of patient #2: (R) CD3, (S) CD138 and (T) CD68. CD, cluster designation; PaO2/FiO2, ratio of arterial oxygen partial pressure to fractional inspired oxygen.

Patient #2 is a 50-year-old woman with ACPA/RFpos RA since 2017 in sustained remission under methotrexate (15 mg/weekly; DAS28-CRP:1.9 in January 2020). On 14 March 2020, the patient developed fever (till 39°C), diarrhoea and dyspnoea not responsive to cephalosporine. On 23 March 2020, due to sudden worsening of pulmonary function needing oxygen support (31%) the patient was referred to our emergency department where chest X-rays scan showed interstitial pneumonia and SARS-CoV-2 nasopharyngeal swab was positive (figure 1K). Methotrexate was stopped and antiviral and antibiotic treatment was started (figure 1L). However, the patient developed polyarthritis (DAS28-CRP:6.8) and pulmonary function worsening (PaO2/FiO2: 188 at O2 therapy at 40%) and a chest CT scan showed bilateral pulmonary consolidation areas with ground-glass and crazy paving features (figure 1M). Moreover, US showed joint effusion, ST thickness and increased vascularity (figure 1N) and US-guided ST biopsy of the knee showed severe inflammation (Krenn synovitis score: 8) with ST thickening and fibrin exudates (figure 1O–Q). Moreover, abundant CD3pos, CD138pos and CD20pos cells (figure 1R,S) infiltrates also forming aggregates and few follicles were detected. Numerous ST CD68pos cells were seen (figure 1T). Therefore, sarilumab was 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 submission, the patient was in remission (DAS28-CRP:1.9).

Figure 2

Inflammatory cytokines plasma levels in patient with new development of peripheral polyarthritis or in patient with rheumatoid arthritis flare after severe acute respiratory syndrome coronavirus-2 infection. Interleukin (IL)-6, IL-8 and tumour necrosis factor α (TNFα) plasma levels (multicytokine test for ELLA-Bio-Techne, Minneapolis) 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).

Despite rare, arthritis new onset or its worsening after SARS-CoV-2 infection, in patients with pre-existing chronic joint disease, may occur and should be promptly treated within the pulmonary involvement management. In particular, baricitinib which was postulated to have a potential likelihood of impairing SARS-CoV-2 suppression or clearance4 was an effective option for joint symptoms control and interleukin 6 receptor inhibitor treatment allowed the successful suppression of both lung and joint inflammation.5 6 However, longitudinal follow-up of patients with SARS-CoV-2pos who developed new onset of arthritis will reveal its clinical persistency as well as the timing and the need of long-term anti-inflammatory treatments during the convalescence phase.

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Footnotes

  • 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.

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