Dear Editor
Although the effect of COVID-19 on patients with rheumatic disorders has been extensively assessed [1–3], the influence of SARS-CoV2 infection on the clinical course of these diseases is not fully elucidated. Diffuse lymphadenopathy and cerebritis have been reported as short-term flare-up manifestations of systemic lupus erythematosus (SLE) after COVID-19 [4, 5]. To the best of our knowledge, however, no data on longer periods are available, neither for SLE nor for other connective tissue diseases. By considering the shared expertise on antisynthetase syndrome (ASSD) [6, 7], our centres evaluated the 6-month clinical evolution of ASSD after COVID-19, looking for disease flares or the de novo occurrence of clinical findings. We have identified 12 patients, mainly females (n = 9, 75%), with a median age of 51 years (interquartile range — IQR 48–63.5) and a median ASSD disease duration of 60.5 months (IQR 21–77) at COVID-19 onset. The complete form of ASSD (arthritis, myositis and interstitial lung disease — ILD) was observed in 7 cases (58%), and 11 patients (92%) had ILD. At the time of SARS-CoV2 infection, all patients had a well-controlled ASSD for at least 6 months and did not receive the SARS-CoV2 vaccine, because it was not available at the time of their infection. As previously reported [8], immunosuppression was managed, by maintaining cyclosporine, and stopping azathioprine and methotrexate, whereas COVID-19 was treated according to the guidelines available at that time. Corticosteroids were maintained at the same or increased dosages according to COVID-19-related needs. Six patients (50%) were admitted to the hospital, mostly for COVID-19-related pneumonia (5 patients, 41.6%). Healing was achieved when patients were asymptomatic for acute COVID-19 manifestations and displayed at least one negative polymerase chain reaction (PCR) for SARS-Cov2 on a nasal swab. The median time to COVID-19 healing was 20 days (IQR 13.5–31). Two weeks after the healing, patients resumed previously stopped immunosuppressants. Among the patients, 2 (17%) experienced significant changes in the clinical status of ASSD.
Patient 1 developed Raynaud’s phenomenon after 1 month, and severe dyspnoea, which led to oxygen supplementation after 2 months. High-resolution computed tomography (HRCT) showed ILD worsening, with the appearance of ground-glass opacities (GGOs) and extension of reticulations. We transiently increased prednisone to 50 mg/day and started an anti-fibrosing drug (nintedanib) with benefit. After 4 months, the patient had an articular flare. At month 5, after prednisone tapering, dyspnoea worsened. Chest CT scans showed a reduction of GGOs and no signs of pulmonary thromboembolism. Pulmonary function tests (PFTs) were repeated, confirming a restrictive pattern with stable forced vital capacity (FVC), but showing a severe reduction of diffusing capacity for carbon monoxide (DLCO) compared to pre-COVID PFTs. At month 6, precapillary pulmonary hypertension was diagnosed at the right heart catheterization. Furthermore, magnetic resonance imaging showed signs of chronic myocarditis. The patient started sildenafil and rituximab. Patient 11 had a worsening of the dyspnoea starting from month 4 and was reassessed at month 6. Chest HRCT was stable, but a significant impairment (ultrasound assessment) and superelevation (chest X-rays) of the diaphragm were observed, leading to high doses of corticosteroid treatment. In Table 1, we report the main clinical variables collected and the results of PFTs before (no more than 3 months) and after (6 months) COVID-19. For both FVC and DLCO, no statistically significant differences were observed at the 2 established timepoints.
Table 1.
“Patients’ and disease’s characteristics and outcomes”: characteristics of enclosed patients for both disease and COVID-19 and results of pulmonary function tests before SARS-CoV2 infection (no more than 3 months) and 6 months after the healing from COVID-19
| Patients’ disease characteristics at COVID-19 infection | COVID-19 characteristics | |||||||||||
| Patient | Sex | ARS | Anti-Ro52 | Age (years) | Disease duration (months) | ASSD triad | Lung pattern | Ongoing treatment | COVID-19 length (days) | Hospital admission | Dyspnoea | Pneumonia |
| 1 | m | Jo1 | Negative | 68 | 22 | AMI | NSIP | Cys + MTX + PDN (5 mg/day) + O2 (intermittent) | 16 | yes | yes | yes |
| 2 | f | Jo1 | Negative | 26 | 103 | AMI | UIP | Cys | 24 | No | No | No |
| 3 | f | Jo1 | Negative | 50 | 141 | MI | NSIP + OP | Aza + HCQ + PDN (6.25 mg/day) | 42 | No | No | No |
| 4 | f | Jo1 | Positive | 38 | 91 | AMI | NSIP | Cys | 10 | No | No | No |
| 5 | f | Jo1 | Negative | 49 | 41 | AMI | NSIP | Cys + MTX + HCQ + PDN (5 mg/day) | 6 | Yes | Yes | Yes |
| 6 | f | PL7 | Positive | 51 | 19 | MI | NSIP | Cys + PDN (7.5 mg/day) + O2 (intermittent) | 46 | No | No | No |
| 7 | m | Jo1 | Negative | 44 | 72 | AMI | OP | Cys + Aza + PDN (7.5 mg/day) | 16 | No | No | No |
| 8 | f | PL12 | Negative | 65 | 68 | AM | – | MTX | 28 | No | No | No |
| 9 | m | Jo1 | Negative | 60 | 58 | AMI | NSIP | MTX | 50 | Yes | Yes | Yes |
| 10 | f | PL7 | Negative | 51 | 12 | MI | NSIP | MTX + PDN (5 mg/day) + O2 therapy (intermittent) | 14 | Yes | Yes | Yes |
| 11 | f | Jo1 | Negative | 85 | 63 | AMI | NSIP | Cys + PDN (7.5 mg/day) + O2 (intermittent) | 24 | Yes | Yes | Yes |
| 12 | f | PL7 | Positive | 63 | 16 | I | NSIP | – | 9 | Yes | Yes | No |
| COVID-19 characteristics | ASSD manifestations outcome | |||||||||||
| Minimum SaO2 | T max (°C) | Other symptoms | Covid-19 treatment | Disease flares (months after COVID-19) | New clinical findings (months after COVID-19) | Basal FVC | 6 months FVC | Basal DLCO | 6 months DLCO | |||
| 90 | 38.5 | - | Desa + Rem + LWMH + O2 | Lung (2), joints (4) | Raynaud's phenomenon (1), pulmonary hypertension (6), myocarditis (6) | 87 | 84 | p=0.128* | 59 | 40 | p=0.684* | |
| 97 | 37.5 | Anosmia, diarrhea, headache | – | No | No | 62 | 58 | 54 | 44 | |||
| 98 | 36.4 | Anosmia | – | No | No | 106 | 99 | 57 | 78 | |||
| 97 | 37.9 | Anosmia, headache | – | No | No | 80 | 84 | 76 | 75 | |||
| 92 | 38.5 | Diarrhea | Desa + LWMH | No | No | 83 | 94 | 59 | 66 | |||
| 97 | 37.7 | Anosmia, ageusia | – | No | No | 38 | 46 | 32 | 33 | |||
| 98 | 36.5 | Anosmia | – | No | No | 78 | 77 | 45 | 47 | |||
| 98 | 37.5 | Anosmia, ageusia, headache | – | No | No | 136 | 102 | 95 | 101 | |||
| 93 | 38 | Headache | – | No | No | 94 | 85 | 95.6 | 128 | |||
| 89 | 38 | Diarrhea, Headache | PDN | No | No | 82 | 82 | 45 | 42 | |||
| 90 | 38 | Anosmia | Desa + LWMH + O2 | No | Diaphragm impairment (6) | 69 | 42 | 42 | 35 | |||
| 95 | 38 | Anosmia, ageusia | – | No | no | 114 | 100 | 51 | 45 | |||
ASSD antisynthetase syndrome, ARS anti-aminoacyl tRNA synthetase antibodies, T max (°C) maximum body temperature in Celsius degree, m male, f female, PL7 anti-threonyl-tRNA synthetase antibodies, PL12 anti-alanyl-tRNA synthetase antibodies, Jo1 anti-histidyl-tRNA synthetase antibodies, AMI arthritis, myositis, interstitial lung disease, MI myositis, interstitial lung disease, AM arthritis, myositis, I interstitial lung disease, NSIP non-specific interstitial pneumonia, UIP usual interstitial pneumonia, OP organizing pneumonia, Cys Cyclosporine, MTX methotrexate, Aza Azathioprine, PDN prednisone, HCQ hydroxychloroquine, FVC forced vital capacity, DLCO diffusing capacity for carbon monoxide, SaO2 peripheral oxygen saturation, O2 oxygen, Desa dexamethasone, Rem remdesivir, LWMH low weight molecular heparin
*Statistical analysis by paired sample t-test
Our results confirm that, after healing, COVID-19 may trigger ASSD flares and induce previously lacking clinical findings. To the best of our knowledge, this is the first paper evaluating, in a prolonged period, the outcome of a rheumatic disease after SARS-CoV2 infection. A strict clinical-instrumental follow-up is necessary for ASSD patients after healing from COVID-19 because of the risk of possible worsening of the disease. In conclusion, our results support the SARS-CoV2 vaccination strategy for autoimmune diseases.
Author contribution
Conceptualization, L.C., V.V., G.Z. and F.M.; methodology, L.C. and F.M.; formal analysis: V.V. and L.C.; investigation: all authors; resources: all authors; data curation, V.V., G.Z., L.C.; writing-original draft preparation, L.C., V.V. and G.Z.; writing-review and editing, L.C., V.V. and G.Z.; visualisation, all authors; supervision, all authors; project administration, L.C. All the authors have read and agreed to the published version of the manuscript.
Data availability
The data that support the findings of this study are available on request from the corresponding author, VV. The data are not publicly available due to their containing information that could compromise the privacy of research participants. Data are stored in a secured pc with limited access.
Declarations
Ethics approval
This study was approved by Ethics Committee Area Pavia (protocol code 20200046007, date 05/06/2020).
Disclosures
None.
Footnotes
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Valentina Vertui and Giovanni Zanframundo contributed equally to this work.
Contributor Information
Valentina Vertui, Email: valentina.vertui@gmail.com.
Giovanni Zanframundo, Email: gio.zanframundo@gmail.com.
Santos Castañeda, Email: scastas@gmail.com.
Alessandro Biglia, Email: alejpage@hotmail.it.
Bianca Lucia Palermo, Email: biancalucia.palermo01@universitadipavia.it.
Ilaria Cavazzana, Email: ilariacava@virgilio.it.
Federica Meloni, Email: f.meloni@smatteo.pv.it.
Lorenzo Cavagna, Email: lorenzo.cavagna@unipv.it.
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Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author, VV. The data are not publicly available due to their containing information that could compromise the privacy of research participants. Data are stored in a secured pc with limited access.