As the definition of ReA evolved, more and more entities were proposed for inclusion such as Lyme disease, gonococcal arthritis, post-streptococcal reactive arthritis, and rheumatic fever . While it is true that Lyme disease and gonococcal arthritis may not fulfil the classical Koch’s postulates to be defined as an “infection,” both have unique characteristics clinical features. Clubbing them with ReA will neither help in the management nor further research. Similarly, the differences between ReA and post-streptococcal reactive arthritis are elaborated elsewhere .
The most commonly used definition of ReA has been provided by Braun and associates [18, 19]. This definition requires monoarthritis or oligoarthritis preceded by symptomatic diarrhoea or urethritis. For “definite” ReA to be diagnosed by the Braun criteria, an organism with known association with ReA needs to be demonstrated by culture or PCR. Even while these classification criteria were formulated, there was a lack of agreement on various points like the relationship of HLA-B27 with ReA, the existence of ReA without arthritis, or whether it should include only spondyloarthritis presentations or any arthritis . More and more organisms are being added to the list of potential precipitants of ReA . Also, the definition by Braun et al. does not consider the entity of “post-vaccination ReA.”
The American College of Rheumatology (ACR) or the European Alliance of Associations for Rheumatology(EULAR) do not have separate practice guidelines pertaining to ReA as possibly the rheumatologists in Europe or the United States do not see severe cases of ReA[21,22,23]. The incidence is apparently declining in most high-income countries . However, the rest of the world that depend on the ACR and EULAR recommendations may find this gap challenging. For example, Latin America had the largest proportion of patients with “peripheral spondyloarthritis” . ReA from India has arthritis as the predominant feature in 95% of patients  while a report from Finland showed only arthralgia in two and arthritis in none of 17 patients with post-Escherichia coli musculoskeletal conditions . Thus, there seem to be great differences in how clinicians from different parts of the world view ReA.
Only a small percentage of patients who have infections with organisms such as Campylobacter, Salmonella, Shigella, or Yersinia develop ReA . Similarly, amongst millions who have developed SARS-CoV-2 infection, only a minor proportion develops arthritis. Understanding this may help unearth new verities about the immune system and tolerance mechanisms.
Clinical phenotype of post-COVID-19 ReA
Post COVID-19 arthritis more commonly has a rheumatoid like phenotype affecting the wrists, ankles, and small joints of hands and feet. However, a spondyloarthritis-like presentation with axial involvement has also been reported . It can also present as classical ReA with lower limb predominant oligoarthritis . Isolate monoarthritis of a single metacarpophalangeal joint has also been reported . Table 1 summarizes the different phenotypes, treatments given, and outcomes in various case reports of post-COVID-19 reactive arthritis from across the world.
Age and gender
The initial reports of post-COVID-19 ReA were in men past 50 years of age [31,32,33, 35]. This is in contrast to the classical ReA that is most common between 15 and 40 years of age. Again, at least three cases of post-COVID-19 ReA have also been reported in the paediatric age group [41, 45]. Unlike classical ReA, gender distribution appears equal between males and females. However, the total number of reported cases is too small for conclusive comments.
Treatment and outcome
The majority of the patients had responded to non-steroidal anti-inflammatory drugs (NSAIDs) while some received intra-articular steroids or rapidly tapered oral steroids (Table 2). Where outcomes are reported, usually, there was a response within the first week and the steroids /NSAIDs could be tapered down after 4 weeks. Only patients with rheumatoid arthritis-like phenotype with anti-citrullinated peptide antibodies had a chronic course and had to be given methotrexate [48,49,50].
Thus, the phenotype and outcomes of post-COVID-19 ReA appear to be different from those of classical ReA. These differences are summarized in Table 2.
Reactive arthritis after COVID-19 vaccination
Vaccination-induced autoimmunity is a concern since vaccines stimulate the immune system . The first published case of ReA post-COVID-19 vaccination was reported in a 23-year-old woman after the inactivated Sinovac-CoronaVac vaccine . We could identify a total of seven cases of inflammatory arthritis reported post-vaccination (Table 3).
Other post-COVID-19 inflammatory arthritis
We have reviewed post-COVID-19 rheumatic diseases at an earlier stage of the pandemic . Post-COVID-19 peripheral nerve entrapment syndromes like carpal tunnel or tarsal tunnel syndromes have been hypothesized to be either due to localized demyelination, microangiopathy involving the vasa nervosum or an immune phenomenon targeting the adjacent synovial sheath . An interesting group is the patients who have clinical phenotype and antibodies suggestive of rheumatoid arthritis developing post-COVID-19. These patients developed anti-cyclic citrullinated peptide antibody-positive arthritis after documented COVID-19 infection [48,49,50].
One concern was whether vaccination would cause a flare in persons with pre-existing autoimmune diseases . Cases with flares of RA temporarily related to vaccination have been reported . However, in a cohort of 724 patients with autoimmune rheumatic disease, only 4 patients had complained of a flare in joint pain. This was managed with NSAIDs and lasted less than a week .
In a cohort of 5493 RA patients from Hong Kong, a propensity-score weighted multivariate analysis did not show any association with COVID-19 vaccination and flare of RA .
Chronic arthritis after other viral infections
Several viruses are associated with acute polyarthritis that lasts less than 6–8 weeks . In a small proportion of cases, such viral arthritis may become chronic such as in the case of HIV (Human Immunodeficiency Virus), Hepatitis B and C viruses [63, 64], parvovirus B19, and Chikungunya . Some authors have argued that it may be better to label “COVID-19 associated arthritis” rather than “COVID-19 ReA” . COVID-19 can also possibly precipitate arthritis in a susceptible individual. There is a case report of a lady with psoriasis and inflammatory bowel disease who developed arthritis post-COVID-19 infection .
Post-chikungunya or Parvovirus B-19 there can be an onset of arthritis indistinguishable from rheumatoid arthritis [68, 69]. A similar phenomenon has been reported post-COVID-19 too [48,49,50]. However, such anti-citrullinated antibody-positive RA has been reported only in 3 cases to date. The possibility of a coincidence cannot be excluded looking at the high incidence of COVID-19 infections and the not uncommon incidence of RA, but the point in support of a “reactive” arthritis is that the arthritis is seen after the acute COVID-19 infection. It is self-limiting. Had it been a direct viral arthritis, the synovitis should have occurred during the seroconversion phase. In acute COVID-19 infection, though arthralgia is common, documented arthritis has been rarely reported.
Possible pathogenic mechanisms
Viruses have been long implicated in the breakdown of immune tolerance and precipitation of autoimmune disease . SARS-CoV-2 activates CD14 + monocytes and PD-L1 + neutrophils via the Osteopontin-mediated inhibition of Interleukin-10. This pathway is involved in rheumatoid arthritis and thus provides a common pathway for the evolution of inflammatory arthritis . In Chikungunya viral infection, a prominent role of monocytes and anti-viral responses such as interferons has been postulated .
Interferon (IFN)-related pathways have been implicated in COVID-19 [73, 74] and these have a role in the initiation of rheumatoid arthritis. The TNF (Tumor Necrosis Factor)-induced animal models of rheumatoid arthritis are dependent on IFN and IFN response elements such as the IRF1 (interferon regulatory factor 1) transcription factor .
Also, various autoantibodies have been reported in COVID-19 . Some of these might have pathological potential and if they persist after the infection, they may lead to rheumatic manifestations like arthritis. At least 15 different autoantibodies have been described in COVID-19 and 34 human peptides have similarities with SARS-CoV-2 proteins . This may have implications for molecular mimicry in COVID-19.
Timelines of classic and post-COVID-19 reactive arthritides
Classical ReA is self-limiting in two-thirds of cases, but can damage the joints even in such a short period. Chronic ReA can have much worse sequelae. In the case of post-COVID-19 ReA, the manifestations appear more transient and self-limiting. This appears more similar to post-streptococcal ReA rather than classical ReA . Also, some cases of post-COVID-19 ReA have different antibodies. There is a possibility that these may evolve into classifiable rheumatic diseases such as rheumatoid arthritis or lupus .
It is not necessary that all arthritis occurring post-COVID-19 should be reactive arthritis. The alternative is that it may be late-onset viral arthritis with actual invasion of the synovial space with the virus . We could identify one study that reported the detection of SARS-CoV-2 RNA in a patient with wrist arthritis that had appeared 15 days after diarrhoea and upper respiratory tract symptoms . However, other cases have not found such evidence . Moreover, a post-mortem study also failed to find any viral RNA in synovial fluid or bone tissue in five patients who had died of COVID-19 .