and multiple studies report the development of autoantibodies in patients with COVID-19.
However, progression into clinical autoimmunity in adults has only been described in case reports.
141 patients had a diagnosis code for systemic rheumatic disease according to the International Classification of Diseases
after the date of SARS-CoV-2 PCR positivity (appendix p 2). Of the patients who were PCR-negative for SARS-CoV-2, 420 had a diagnosis code for systemic rheumatic disease after the date of SARS-CoV-2 PCR negativity. A flow diagram illustrating case identification for both groups is included in the appendix (p 4).
For patients with a diagnosis code for systemic rheumatic disease after PCR testing, we screened medical records to identify possible incident systemic rheumatic disease diagnosed after COVID-19 onset. We defined systemic rheumatic disease as incident when both symptom onset and clinical diagnosis occurred after initial COVID-19 symptoms or after a positive PCR test if asymptomatic. Two rheumatologists independently reviewed each case to verify incident systemic rheumatic disease and its onset after SARS-CoV-2 testing and extracted data about COVID-19 disease course and rheumatic disease diagnoses. Incident systemic rheumatic disease cases had to be diagnosed by a rheumatologist or other qualified clinician. In addition, two independent abstractors independently agreed with the diagnosis and its temporal relationship with SARS-CoV-2 testing or COVID-19 symptoms. Information supporting the diagnosis, including laboratory and imaging results, signs and symptoms, and classification criteria were also collected.
He was treated with pulse-dose intravenous glucocorticoids and intravenous immunoglobulin. His disease is most consistent with dermatomyositis characterised by anti-Mi2 and anti-TIF1g autoantibodies. At the time of writing, he remained on glucocorticoids and monthly intravenous immunoglobulin due to persistent muscle weakness.
The remaining three patients developed systemic rheumatic disease more than two months after PCR positivity. One patient with a history of pulmonary embolism and deep vein thrombosis (DVT) two months before COVID-19 symptom onset, in the setting of prolonged immobility due to air travel (with negative antiphospholipid antibodies and normal partial thromboplastin time at that time), was diagnosed with antiphospholipid syndrome 74 days after COVID-19 symptom onset (ie, fever, chills, and rhinorrhea). The patient developed an unprovoked DVT while on rivaroxaban for five months and had a newly positive lupus anticoagulant test, which persisted on repeat testing at three months; at the time of writing, she was being treated with warfarin. Another patient with hand arthralgias without synovitis on previous rheumatology evaluation developed seronegative inflammatory arthritis 89 days after PCR positivity. COVID-19 symptoms included fever, chills, and cough. The patient developed bilateral hand and wrist swelling and laboratory tests were negative for rheumatoid factor and anti-citrullinated protein antibodies. She was initially treated with low-dose prednisone and hydroxychloroquine but had persistent signs and symptoms after stopping prednisone, so methotrexate and infliximab were subsequently added to hydroxychloroquine. The remaining patient was diagnosed with primary Sjögren's syndrome 104 days after PCR positivity. COVID-19 in this patient was characterised by fever, fatigue, and non-productive cough lingering for nearly two months. She was diagnosed with primary Sjögren's syndrome on the basis of new onset of sicca symptoms, bilateral parotid sialadenitis on MRI, positive anti-nuclear antibodies (1:1280, speckled pattern), high-titre anti-Ro52, anti-Ro60, and anti-ribonucleoprotein, and mildly elevated anti-Smith antibodies with no dsDNA antibodies. Clinically, she was thought to have primary Sjögren's syndrome but with some serological features of systemic lupus erythematosus or mixed connective tissue disease (no evidence of Raynaud's phenomenon) and was treated with hydroxychloroquine.
Among the matched comparators, we identified five cases of incident systemic rheumatic disease after negative PCR results for SARS-CoV-2. This number provides an estimate of the background rate of systemic rheumatic disease development in a contemporaneous population who also presented for testing for SARS-CoV-2. Interestingly, four of the five patients were diagnosed with polymyalgia rheumatica between 30 and 129 days after SARS-CoV-2 testing.
The remaining patient developed seronegative rheumatoid arthritis 100 days after SARS-CoV-2 testing. This case series and comparative study of patients with PCR-confirmed COVID-19 and incident systemic rheumatic disease shows that some patients developed systemic rheumatic diseases following COVID-19. Although COVID-19 could trigger de novo rheumatic disease by inducing type I interferonopathy, it might also accelerate the progression of pre-existing subclinical autoimmunity into clinical disease. Similarly, the COVID-19 hypercoagulable state might have increased the propensity of thrombosis in the patient with antiphospholipid syndrome. These data contribute to the evidence on the possible relationship between SARS-CoV-2 and autoimmunity, although the similar rate of incident systemic rheumatic disease among the comparators suggests that these cases of incident systemic rheumatic diseases could have been due to chance. It is also possible that individuals might have been tested for SARS-CoV-2 due to symptoms of an undiagnosed systemic rheumatic disease. We did our study at a large health-care system using a sensitive screen to maximise the ability to systematically detect all incident cases of systemic rheumatic disease after PCR testing, and we confirmed their presence and timing by medical record review. However, it is possible that some individuals might have been diagnosed with systemic rheumatic diseases outside of our health-care system and would not have generated the relevant diagnosis codes to be identified in our study. It is also possible that some patients developed incident systemic rheumatic disease but did not seek or could not access care during the pandemic, and our study would not have identified these patients. Therefore, we used a contemporary comparator group that was also navigating these health-care access difficulties. The number of incident systemic rheumatic diseases confirmed by medical record review among those that screened positive were relatively low. This result is probably because we used a sensitive screen that only required a single diagnosis code after a PCR date, and many actually had prevalent systemic rheumatic disease at the time of PCR testing. Finally, although the raw numbers of incident systemic rheumatic disease among cases and comparators were similar, nearly all of the comparators were diagnosed with polymyalgia rheumatica. It is possible that some patients with non-specific early polymyalgia rheumatica symptoms were tested for SARS-CoV-2, therefore biasing our results towards the null. The differing distributions of age, sex, and type of incident polymyalgia rheumatica in the PCR-positive group and PCR-negative group are unlikely to be explained by an imbalance of demographic factors at baseline since age and sex were matching factors. Despite these limitations, ours is the first study to our knowledge to systematically identify incident systemic rheumatic diseases within a large health-care system that included a comparator group. Further research is needed to delineate potential links between COVID-19 and autoimmunity.
We thank Michael DiIorio, Claire Cook, Lauren Prisco, Lily Martin, Alessandra Zaccardelli, and Kathleen Vanni for their assistance. ZSW receives research support from Bristol-Myers Squibb and Principia and consulting fees from Viela Bio and MedPace. JAS receives research support from Amgen and Bristol-Myers Squibb and consultancy fees from Bristol-Myers Squibb, Gilead, Inova, Janssen, Optum, and Pfizer. All other authors declare no competing interests. KMD and NJP are supported by the NIH Ruth L Kirschstein Institutional National Research Service Award ( T32-AR-007258 ). KMD is supported by the Rheumatology Research Foundation Scientist Development Award . ZSW is funded by NIH/NIAMS ( K23AR073334 and L30 AR070520 ). JAS is funded by NIH/NIAMS ( K23 AR069688 , R03 AR075886 , L30 AR066953 , P30 AR070253 , and P30 AR072577 ), the Rheumatology Research Foundation R Bridge Award, the Brigham Research Institute, and the R Bruce and Joan M Mickey Research Scholar Fund.
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Published: April 06, 2021
© 2021 Elsevier Ltd. All rights reserved.
- COVID-19: consider cytokine storm syndromes and immunosuppression
As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%,1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality.