Organ pathology associated with COVID-19 is well-documented, beyond its hallmark pulmonary manifestations of respiratory distress and pneumonia. The liver, kidney, and heart can be affected,1 owing not only to direct viral effects but also to indirect mechanisms, such as cytokine hyperactivation, and its collateral effects distal to the primary infection, hypoxia, and inter-organ interaction.
In light of these widespread complications, the question has been raised whether a causal association exists between COVID-19 and joint pathology.
Cytokine-mediated immune hyperactivation mechanisms overlap between COVID-19 and rheumatoid arthritis (RA),2 which has given rise to concerns that COVID-19 infection could trigger or worsen RA flares.3 However, there has not been a clear indication from empirical studies that COVID-19 infection directly worsens rheumatic disease activity. In part, symptomatic worsening in RA may reflect the effects of fatigue, limitation of physical activity due to constraints of the pandemic, and psychologic factors.4
Less is known about cases of COVID-associated arthralgia without evidence of rheumatic disease or infectious arthritis. Other viral infections, such as hepatitis and herpesviruses, parvovirus B19, and HIV, are associated with nondestructive arthritis.5 Coronaviruses are not known to cause clinically evident joint inflammation or damage. However, joint pain occurs in approximately 15% of patients of COVID-19 infection, regardless of the severity of COVID-19-related respiratory symptoms.6
Mechanisms behind this association are poorly understood, partly because objective tests, such as blood and serology assays, and arthrocentesis, have not been documented systematically. However, clinical testing, when reported, has not yielded evidence of intra-articular sepsis, joint injury, or other overt pathology.
The Clinical Spectrum of COVID-19-Associated Arthralgia
Farisogullari and colleagues conducted a narrative review of case reports of arthralgia co-occurring with COVID-19 infection in patients without preexisting rheumatic disease.7 Individual cases were diagnosed and patients’ joint pain was described as “viral” or “reactive” arthritis. Patients in the study generally presented with peripheral oligoarthritis or symmetrical polyarthritis, with infrequent cases of sacroiliitis. Arthrocentesis was reported in less than one-thirds of cases. A few participants tested positive for human leukocyte antigen (HLA)-B27, HLA-B15, antinuclear antibody, rheumatoid factor, and anticitrullinated protein antibody titer. The researchers did not observe any radiographic evidence of joint erosion or destruction.
Extra-articular rheumatic manifestations typical of reactive arthritis were noted in 2 patients, 1 of whom presented with balanitis and aseptic, noncrystalline arthritis in a knee, during late-stage COVID-19 infection.8 The other patient had profuse extra-articular symptoms, including dactylitis; skin, nail and oral lesions; vulvitis and conjunctivitis; but no joint pain. Titers for HLA-B27 and HLA-B15were positive and bacterial and viral assays were negative, apart from confirmation of COVID-19 infection.9
Joint pain was reported at least 1 week after the diagnosis of COVID-19; but a small number of patients reported painless than a week after onset of COVID-19 symptoms or diagnosis. Concomitant onset of joint pain and COVID-19 symptoms, and joint pain that preceded COVID-19 symptoms, were rare among these patients. The arthralgias generally resolved, either spontaneously or with treatment; total duration of symptoms varied from less than a week to several months. However, in a few patients, residual symptoms were documented after weeks or months of follow-up.7
In clinical case reports, treatment was typically to symptom targets. Drug treatment most often included nonsteroidal anti-inflammatory (NSAID) medications, prednisolone or methylprednisolone, or opioid analgesics. Less frequently used were antibiotics (not prompted by detection of bacterial infection), baricitinib, triamcinolone injection, and physical modalities, such as splinting and occupational therapy. Given the wide variability of presentations, uncertainty regarding the underlying disease processes and lack of data on efficacy of specific treatment regimens, no consensus on optimal treatment of COVID-19-associated arthralgia has emerged.
Gaps in Knowledge
As noted, empirical information on patients with COVID-associated, nonrheumatic arthralgia primarily arises from case reports and narrative reviews of these reports. Clinical presentation, time course of the arthralgic condition, diagnostic workup, and treatment were found to be highly variable among reported cases. Such wide variability and the lack of systematic studies limit understanding of the strength of the association between the arthralgias described and any distinct pathologic process.
In some cases, patients have often received diagnoses of viral or reactive arthritis. Taken together, however, these diagnostic labels overlapped with regard to patients’ clinical presentations and laboratory workups, leaving it unclear whether the arthralgias represented either disorder, as typically defined.
Viral arthritis is not commonly associated with coronaviruses. Joint pathology may result from direct viral invasion or secondarily from immune responses; however, these mechanisms have not yet been confirmed in the presence of SARS-CoV-2. Meanwhile, reactive arthritis is generally understood to be an aseptic arthropathy arising from immune dysregulation following distant bacterial infection (typically of the gastrointestinal or genitourinary tract).
Given this unclear correspondence between clinical variables and diagnostic label, Farisogullari and colleagues7 proposed the more agnostic term “COVID-19-associated arthritis.”
COVID-19 infection may cause objectively verifiable joint pathology through a mechanism that is yet to be elucidated. For example, synovial tissue could mimic antigen-presenting elements of SARS-CoV-2; this would lead to the aseptic inflammatory response observed in some patients. In addition to identifying candidate molecular and cellular mechanisms, population-level research should investigate whether rheumatic diseases have become more prevalent during the COVID-19 epidemic.7 Confirming such patterns could help assign COVID-associated arthritis to better-recognized diagnostic categories.
Also uncertain is the degree to which COVID-associated arthritis affects patients’ daily living, in physical, psychologic, or socioeconomic dimensions. Standard measures of intensity of COVID-associated arthralgia have not yet been reported. However, in most cases, symptoms were either self-limiting or resolved with treatment; therefore any arthritis-related disability or adverse lifestyle consequences may be temporary.
Finally, joint pain and myalgia can form part of acute, recovery-stage, and post-acute sequelae of SARS-CoV-2 (“long COVID”) presentations10; but it remains unclear whether arthritis in each stage reflects distinct pathologic and immunologic processes. Confirming such distinctions, in turn, may help clarify the physiologic underpinnings of organ dysfunction in COVID-19.
- Anka AU, Tahir MI, Abubakar SD, et al. Coronavirus disease 2019 (COVID-19): An overview of the immunopathology, serological diagnosis and management. Scand J Immunol. 2021;93(4):e12998. doi:10.1111/sji.12998
- Dewanjee S, Kandimalla R, Kalra RS, et al. COVID-19 and rheumatoid arthritis crosstalk: emerging association, therapeutic options and challenges. Cells. 2021;10(12):3291. doi:10.3390/cells10123291
- Silva Andrade B, Siqueira S, de Assis Soares WR, et al. Long-COVID and post-COVID Health complications: an up-to-date review on clinical conditions and their possible molecular mechanisms. Viruses. 2021;13(4):700. doi:10.3390/v13040700
- Mancuso CA, Duculan R, Jannat-Khah D, Barbhaiya M, Bass AR, Mehta B. Rheumatic disease-related symptoms during the height of the COVID-19 pandemic. HSS Journal®. 2020;16(1):36-44. doi:10.1007/s11420-020-09798-w
- Calabrese LH, Vassilopoulos D. Virally associated arthritis 2008: clinical, epidemiologic, and pathophysiologic considerations. Arthritis Res Ther. 2008;10:215. doi:10.1186/ar2480
- Guan W jie, Ni Z yi, Hu Y, et al. Clinical characteristics of coronavirus isease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032
- Farisogullari B, Pinto AS, Machado PM. COVID-19-associated arthritis: an emerging new entity? RMD Open. 2022;8(2):e002026. doi:10.1136/rmdopen-2021-002026
- Liew IY, Mak TM, Cui L, Vasoo S, Lim XR. A case of reactive arthritis secondary to coronavirus disease 2019 infection. J Clin Rheumatol. 2020;26(6):233. doi:10.1097/RHU.0000000000001560
- Santacruz JC, Londoño J, Santos AM, Arzuaga A, Mantilla MJ. Extra-articular manifestations in reactive arthritis due to COVID-19. Cureus. 2021;13(10). doi:10.7759/cureus.18620
- Cascella M, Del Gaudio A, Vittori A, et al. COVID-Pain: acute and late-onset painful clinical manifestations in COVID-19 – molecular mechanisms and research perspectives. J Pain Res. 2021;14:2403-2412. doi:10.2147/JPR.S313978