Viral Arthropathy and Myalgia Following COVID-19

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A study led by researchers from Southern Illinois University Edwardsville-USA and Hospital Sisters Health System-Illinois-USA has found that a high proportion of the population that has been exposed to the SARS-CoV-2 virus will eventually develop viral arthropathy beside myalgia.

The study findings were published in the peer reviewed Journal of Pain Research.
https://www.dovepress.com/patterns-of-viral-arthropathy-and-myalgia-following-covid-19-a-cross-s-peer-reviewed-fulltext-article-JPR

This study found that patients with a self-reported previous infection of COVID-19 experienced new onset symptoms of joint or muscle pain during after their COVID-19 experience. Arthralgia has been an increasingly cited component of long-covid syndrome, with an estimated prevalence of 19% (95% CI 7–34).17

We believe ours is the largest study to date to specifically describe the characteristics and timing of arthralgia and myalgia associated with COVID-19. A growing body of literature describing these COVID-19 sequelae exits.

In a retrospective, observational case series, Pal et al report their experiences with 23 patients presenting to a specialty rheumatology clinic in India with a history of documented confirmed COVID-19.18 Patients with positive acute phase reactants, rheumatoid factor, or anti-cyclic citrullinated peptide were excluded from the report.

The mean age of patients was 42.8 (± 14.1) years and 19 (82.6%) reported symptoms consistent with COVID-19. Patients reported an average duration of 25.9 (± 12.8) days from the time of onset of fever and subsequent arthritis symptoms. Most frequently reported joint involvement was knees (16 of 23), ankles (15 of 23), and low back (7 of 23). Additionally, 9 of 23 patients experienced pain suggestive of enthesitis.

Numerous case reports of confirmed COVID-19 patients experiencing arthropathy have been reviewed in a recent case series.19 Here, Kocyigit and Akyol present an aggregated view of the joints involved, with the knee and ankle being the most frequently reported sites. Our results outlining affected joints was largely congruent with Kocyigit and Akyol, although our respondents reported a higher prevalence of axial spine involvement. Given problems with recall bias in a survey of this nature, symptom onset and proximity to active COVID-19 infection could certainly be suspect.

Timing of new onset arthropathy following COVID-19 symptom resolution has also been described. Gracia-Ramos et al report a mean (SD) onset of arthropathy following COVID-19 symptom resolution of 20.2 (11.5) days.20 This onset of arthropathy symptoms is substantially delayed in comparison to our results of 6.5 (24.3) days. However, some of the patients reported by Gracia-Ramos may have represented undiagnosed autoimmune arthritides versus a true viral arthropathy.

Several unanswered questions regarding COVID-19 arthropathy and myalgia exist. Potentially the most pertinent is the underlying etiopathogenesis and the likelihood of arthropathy following resolution of COVID-19 symptoms representing an uncovered autoimmune disease versus a true component of long-covid syndrome.

The pathogenesis of the more common viral arthritides has been well described previously.1 Molecular mimicry, a phenomenon in which immune cells react with epitopes both derived from the virus and from self, is one proposed mechanism for an autoimmune etiology of new-onset arthritis. This is opposed to actual synovial intrusion by the virus. Similar pathogenesis has been described relating to the receipt of COVID-19 vaccination as well.21,22

Gracia-Ramos et al published a systematic review of 99 cases outlining new-onset autoimmune disease following resolution of COVID-19.20 These authors propose three distinct patterns of new-onset COVID-19 related arthropathy based on symptom timing (ie, prior to COVID-19 symptoms, during the active infection, or following recovery/symptom resolution).

Of the 99 cases reviewed, 46 patients demonstrated some type of vasculitis. Six patients met criteria for Rheumatoid arthritis, nine met criteria for Ankylosing Spondylitis, six met criteria for systemic lupus erythematosus, and nine were considered to have an inflammatory myopathy.

The remaining 17 patients were determined to have reactive arthritis, although the authors correctly comment that traditional diagnostic criteria for reactive arthritis involves bacterial versus viral etiologies and variability of onset.

Yokogawa et al additionally describe their experiences with 306 patients admitted to their institution for COVID-19. While approximately one-fourth of these patients reported joint and muscle pain, four patients developed joint aspiration confirmed crystal-associated arthritis (eg, gout) with variable timing of onset, ranging from eight to 27 days from COVID-19 symptom presentation.23

One difficulty in reviewing the literature for this particular topic is the potentially problematic use of the term, reactive arthritis (ReA), to describe COVID-19 related arthropathy. Traditionally, ReA is considered to be clinically similar to axial or peripheral spondyloarthropathies arising from bacterial gasteroentero- or genitourinary infections.8,24 More generally, this disorder is characterized by sterile synovitis in one or more large joints distant to the primary site of infection.

There were several limitations of this study. Recall bias was a major limitation considering the survey responses were based on subjective feedback from the participants and depending on the time frame from which they experienced the infection, accuracy in their responses may be diminished. Additionally, the study population was limited to the Amazon MTurk community, those with computer literacy, and those with the financial means to access the internet.

The financial incentive offered to complete the questionnaire may also present a limitation. Another major drawback is the study’s lack of objective laboratory values to determine extent of inflammatory response during their COVID experience as well as self-report of COVID-19.

While the invitation to participate specifically requested only those persons with documented COVID-19 positive histories complete the questionnaire (via laboratory or point of care testing), there does exist the possibility of persons completing the survey that did not have confirmed COVID-19. Lack of information regarding variability in treatment used during their COVID experience, especially with respect to glucocorticoids, also confounds the generalizability of the results.

There may additionally be confusion among lay persons when asking about “joint pain” and “muscle pain.” While this was not identified as problematic during our questionnaire review, anecdotally we have noted these terms used interchangeably by patients. Also of concern is the increasing reports of post-COVID, new-onset autoimmune conditions (eg, rheumatoid arthritis).

Unfortunately, the investigators did not stipulate in the questionnaire if potentially confounding conditions were diagnosed before or after the respondents’ COVID-19 experience. This could potentially have skewed results given respondents indicating the presence of these conditions were excluded from data analysis.

The findings of myalgia and arthralgia prevalence and timing based on vaccination status, while interesting, cannot be interpreted as having a causal relationship, especially given the timing of vaccination in relation to the onset of COVID-19 was not captured. This may represent a significant bias in interpreting this data considering COVID-19 vaccination has been reportedly associated with both new onset and flare of several autoimmune disorders which might present with myalgia and/or arthralgia.

Future prospective studies of new-onset, post-COVID-19 arthropathy and myalgia are certainly required to more clearly elucidate this disorder. Consideration of a consensus-driven terminology to describe these two symptoms is certainly warranted in the context of viral illness (versus bacterial pathogens).

Measurement of acute phase reactants, as well as specific proteins associated with autoimmune inflammatory disorders, would aid in the diagnosis, especially in those patients with no previous history of autoimmune conditions. Owing to the lack of testing capacity for the various strains of SARS-CoV-2, limitations in generalizing these results to all strains exist. Additionally, comparing incidence or prevalence in arthralgia or myalgia in those with or without vaccination, type of vaccination, and booster status should all be considered.

Conclusions

Arthropathy and myalgia are common symptoms experienced during and following COVID-19. After controlling for self-reported, pre-existing conditions, we found approximately one-fifth to one-quarter of patients reported experiencing arthralgia or myalgia, respectively. More noteworthy was new onset joint pain or myalgia following resolution of COVID-19 symptoms.

Additionally, COVID-19 vaccination may also contribute to the onset of these symptoms making causal inferences difficult. Viral arthropathy due to COVID-19 infection should be considered in a differential diagnosis when encountering patients with new onset polyarthropathy or myalgia.

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