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 Table of Contents  
Year : 2022  |  Volume : 17  |  Issue : 2  |  Page : 107-109

Coronavirus disease 2019 infection and autoimmunity: We see only a tip of the iceberg

Department of Clinical Immunology and Rheumatology, Sanjay Gandhi postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission02-Jun-2022
Date of Acceptance02-Jun-2022
Date of Web Publication13-Jun-2022

Correspondence Address:
Dr. R Naveen
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_113_22

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How to cite this article:
Naveen R. Coronavirus disease 2019 infection and autoimmunity: We see only a tip of the iceberg. Indian J Rheumatol 2022;17:107-9

How to cite this URL:
Naveen R. Coronavirus disease 2019 infection and autoimmunity: We see only a tip of the iceberg. Indian J Rheumatol [serial online] 2022 [cited 2022 Aug 18];17:107-9. Available from:

The long-drawn coronavirus disease 2019 (COVID-19) pandemic caused by novel severe acute respiratory syndrome coronavirus 2 (nSARS-CoV-2) has brought the role of immunology and immunologist to the forefront. The implications of the virus observed on rheumatic disease (RD) patients include flare of the RD, uncovering of preexisting autoimmunity, or new-onset COVID-19-triggered autoimmunity.[1] There is growing body of evidence for new-onset vasculitis,[2] inflammatory myositis,[3] inflammatory arthritis,[4] Guillain–Barre syndrome (GBS), autoimmune cytopenia, and lupus following COVID-19 infection.[5] Similarly, does vaccination against the virus trigger autoimmunity? There is increasing evidence for safety of the vaccines in RD patients with reports of flares being 4.4% overall and 0.6% being major flare following vaccination.[6] Large prospective studies have shown that breakthrough infection rates are similar among RDs on immunosuppressants and healthy controls.[7] It has been noted that except for B-cell-depleting therapy, RD patients on all other immunosuppressive agents behaved similarly with regard to breakthrough infection severity and hospitalizations.[8]

The case series on vasculitis (n = 15) following COVID-19 infection showed reports of cutaneous leukocytoclastic vasculitis (IgA vasculitis), necrotizing vasculitis, immune complex-mediated vasculitis, and rarely large-vessel vasculitis. Except for two who were aged >80 years and had comorbidities, all others had survived and had a full recovery with treatment with steroids and/or other immunosuppression.[2] The series on inflammatory myositis (n = 22) report cases ranging from dermatomyositis, acute viral myositis, rhabdomyolysis, paraspinal myositis, and asymptomatic myositis.[3] Similarly, the reported cases and series of new-onset autoimmune RD following COVID-19 infection are largely small numbers considering the proportion of infected population.

In this issue, the observation study by Sinha et al.[9] on COVID-19-associated arthritis has piqued our interest. They have reported a series of 14 patients who have developed arthritis and/or enthesitis following COVID-19 infection from a tertiary care center. Even though an observation study stays low in the level of evidence, it is the predecessor of a randomized controlled study. With this regard any study, even case reports are an effort toward improvement of science. There are some perspectives that we want to highlight regarding this data.

First, the denominator is very important to understand the proportion of patients who developed these musculoskeletal manifestations following COVID-19 infection. 14 number is too small a number of reported new-onset arthritis/arthralgia for a tertiary center with a large routine outpatient clinic. We might be looking at the tip of the iceberg, as only a small proportion of patients could have availed the clinic services due to the ongoing pandemic due to logistic reasons. It could also be due to the survivorship bias, as patients who developed more severe autoimmune disease (AID) or those who died in peripheral centers could not make it to the investigation center. Such biases can be avoided by prospective studies or by registry-based international/regional surveillance systems or tele-consultation-based surveys. International efforts like COVID-19 global rheumatology alliance and national registries like TriNetX have answered multiple such research questions in this regard.

Second, in the midst of multiple waves of the pandemic, when almost every individual had either got nSARS-CoV-2 infection either in recent past, present, or in forthcoming future, how can we tell these 14 patients who developed arthritis have not developed de novo rheumatoid arthritis, spondyloarthritis, or reactive arthritis triggered by any other etiological agent? The argument that many would put forth to this point will be these patients had polymerase chain reaction-proven COVID-19 infection in the recent past. This brings us to the important question, does temporality alone be sufficient to establish causation or etiology. Causation can be proved in infectious agents using either Koch's postulates,[10] wherein the suspected microbe must be found in abundance in all organisms suffering the disease; it should be isolated and grown in culture from the diseased animal; when the cultured microbe is reinoculated into a healthy animal, it should cause the disease. Finally, it should be isolable from the inoculated host. In epidemiological studies, often this is not possible. In epidemiological studies, the evidence for causation can be proved if these rules are proved: (1) the etiological agent and the disease are associated; (2) the etiological agent precedes the disease onset (temporality); (3) all other possible etiologies are accounted for and ruled out; and (4) treating the etiological agent prevents/alleviates the development of disease. In this regard, the recent article proving Epstein–Barr virus as the etiological agent for multiple sclerosis in US veterans from stored serum samples is a very good example to establish causation. In the present study, the 14 patients who developed arthritis (mostly reactive arthritis), whether all possible alternatives considered and ruled out? This would include work-up for all etiological agents for reactive arthritis, prior seropositivity for rheumatoid factor, anti-CCP, and HLA-B27 in the relevant patients.

Does a person who gets COVID-19 infection develop arthritis or autoimmune features most of the time? The answer is no. As the authors have rightly pointed out, “the statements by Conway et al. on “Inflammatory arthritis in patients with COVID-19,” it has been pointed out that despite about 44 million cases of nSARS-CoV-2 infection worldwide during the first wave, only 9 discrete cases of acute arthritis have been reported in the literature”. This is a very small proportion. Does the incidence for new-onset AIDs during the pandemic year much more than prepandemic year? This might suggest the virus as a possible trigger for autoimmunity in the population. This again needs large registry-based data or surveillance to record any and all autoimmunity in general population.

Another point to consider is, did these patients have any other autoimmune features such as myositis, Raynaud's, sicca, vasculitis, lupus, or autoimmune cytopenia? There is growing body of evidence of COVID-19-triggered autoimmunities such as arthritis,[4] inflammatory myositis,[3] vasculitis,[2] GBS, and antiphospholipid syndrome. However, these case reports and series need to be interpreted with utmost caution. The same fallacies have been noted here-assuming causality just by temporality alone, not considering all the possible alternate etiologies, not differentiating de novo autoimmunity from viral triggered autoimmunity, and most importantly not considering the denominator/proportions. Many a times, it is impossible to rule out all other established etiologies for a disease like reactive arthritis. Autoimmunity triggered by COVID-19 infection is treated similar to other de novo AIDs. Similar observation is noted in these 14 patients who were treated with nonsteroidal anti-inflammatory drugs and/or low-dose steroids. Most had resolution of symptoms in 2 months and only 2 had symptoms beyond 2 months. While viral-triggered AIDs have been known to extend for as long as 1–2 years as in alpha viral infections like chikungunya arthritis, it comes as no surprise if SARS-CoV-2 infection can produce similar long-term arthritis.

When the human body fails to eliminate the virus infecting the cell (either due to innate defects in interferon pathways or due to viral escape mechanisms), then second- and third-line defenses of the body are brought in.[11] When these defenses fail, then there is cytokine storm which is equivalent to a napalm in a war zone, it would destroy anything in the area. The resulting damages to lungs and other organs are at times irreparable, leading in mortality in short-term and long-term morbidity and possible autoimmunity. MIS-C or Kawa-COVID-19 is an autoimmunity triggered by COVID-19 infection, caused possibly by the nonneutralizing antibody response and cytokine storm.[12],[13] Long COVID syndrome or post-COVID syndrome identifies those patients who have prolonged symptoms (mostly fatigue) 12 weeks after the last COVID-19 infection. This might be due to the damage caused by COVID-19 infection, secondary adrenal failure/hypothalamic–pituitary axis suppression, or persistent immune dysregulation and autoimmunity,[14] while autoimmunity can be due to molecular mimicry, bystander activation, epitope spreading, and/or unmasking of underlying autoimmunity.[15]

Better study designs can answer these vital research questions appropriately. While simple observations in the clinic give rise to research hypothesis, they need to be tested in prospective studies preferably in randomized control trials. The tsunami of data and research on COVID-19 needs to be interpreted with caution and utmost precision. The denominator, the population studied, and the study design are the most important factors in interpretation and generalizability of the results. The evidence so far suggests low frequency of flares following COVID-19 infection, and rarer proportion of patients developing new-onset RD following COVID-19 considering the population infected.

  References Top

Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, et al. Covid-19 and autoimmunity. Autoimmun Rev 2020;19:102597.  Back to cited text no. 1
Hočevar A, Simonović Z, Rotar Ž, Tomšič M. Vasculitis as temporally associated with COVID-19 infection or vaccination: A single-center experience. J Rheumatol 2022;49:232-3.  Back to cited text no. 2
Saud A, Naveen R, Aggarwal R, Gupta L. COVID-19 and myositis: What we know so far. Curr Rheumatol Rep 2021;23:63.  Back to cited text no. 3
Conway R, Konig MF, Graef ER, Webb K, Yazdany J, Kim AH. Inflammatory arthritis in patients with COVID-19. Transl Res 2021;232:49-59.  Back to cited text no. 4
Tang KT, Hsu BC, Chen DY. Autoimmune and rheumatic manifestations associated with COVID-19 in adults: An updated systematic review. Front Immunol 2021;12:645013.  Back to cited text no. 5
Machado PM, Lawson-Tovey S, Strangfeld A, Mateus EF, Hyrich KL, Gossec L, et al. Safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: Results from the EULAR coronavirus vaccine (COVAX) physician-reported registry. Ann Rheum Dis 2022;81:695-709.  Back to cited text no. 6
Boekel L, Stalman EW, Wieske L, Hooijberg F, van Dam KP, Besten YR, et al. Breakthrough SARS-CoV-2 infections with the delta (B.1.617.2) variant in vaccinated patients with immune-mediated inflammatory diseases using immunosuppressants: A substudy of two prospective cohort studies. Lancet Rheumatol 2022;4:e417-29.  Back to cited text no. 7
Liew J, Gianfrancesco M, Harrison C, Izadi Z, Rush S, Lawson-Tovey S, et al. SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease: Results from the COVID-19 Global Rheumatology Alliance provider registry. RMD Open 2022;8:e002187.  Back to cited text no. 8
Sinha D, Mondal S, Ghosh A. Coronavirus disease-19 associated arthritis – An observational study. Indian J Rheumatol 2022. Available from:;type=0. [Last accessed on 2022 May 31].  Back to cited text no. 9
Segre JA. What does it take to satisfy Koch's postulates two centuries later?: Microbial genomics and propionibacteria acnes. Invest Dermatol 2013;133:2141-2.  Back to cited text no. 10
Shah VK, Firmal P, Alam A, Ganguly D, Chattopadhyay S. Overview of immune response during SARS-CoV-2 infection: Lessons from the past. Front Immunol 2020;11:1949.  Back to cited text no. 11
Pouletty M, Borocco C, Ouldali N, Caseris M, Basmaci R, Lachaume N, et al. Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): A multicentre cohort. Ann Rheum Dis 2020;79:999-1006.  Back to cited text no. 12
Rowley AH, Shulman ST, Arditi M. Immune pathogenesis of COVID-19-related multisystem inflammatory syndrome in children. Clin Invest 2020;130:5619-21.  Back to cited text no. 13
Nabavi N. Long covid: How to define it and how to manage it. BMJ 2020;370:m3489.  Back to cited text no. 14
Knight JS, Caricchio R, Casanova JL, Combes AJ, Diamond B, Fox SE, et al. The intersection of COVID-19 and autoimmunity. Clin Invest 2021;131:e154886.  Back to cited text no. 15


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