Discussion

The patient presented 7 days after resolution of SARS-CoV-2 infection with typical, although mild, symptoms of COVID-19 with severe swelling and pain in the left ankle joint and forefoot. Based on the overall picture, ReA appears to be the most likely cause of the patient’s symptoms. The most common differential diagnoses for oligoarthritis are ReA, spondyloarthritis, psoriatic arthritis, sarcoidosis, Lyme arthritis, gouty arthritis and arthritis associated with IBD, as well as soft connective tissue disease or vasculitis. No symptoms suggestive of pathologies other than ReA—such as lymphadenopathy, back pain, skin lesions, a history of tick bites or Borrelia antibodies, IBD, psoriasis or symptoms consistent with soft connective tissue disease or vasculitis—were found on history, clinical presentation and comprehensive diagnostic examination.

ReA is a sterile joint inflammation complicating an extra-articular infection. There are no universally accepted diagnostic criteria, and the diagnosis is based mainly on clinical aspects such as oligoarthritis of the lower limbs that develops within 1–6 weeks of the previous infection, especially in young, HLA-B27-positive individuals. The suspected diagnosis of ReA was supported by the typical case constellation: the patient was young, HLA-B27-positive, had asymmetric oligoarthritis involving the lower extremity, the synovial fluid was sterile and symptoms began several days after resolution of infection. Complete response to NSAIDs and glucocorticoids was also consistent with typical features for ReA. The HLA-B27 allele is the genetic hallmark of SpA, including ReA; the phenotype is found in 50%–80% of cases with ReA,12 however, in many of the reports describing arthritis following infection with SARS-CoV2 published to date, patients were HLA-B27 negative or were not tested for HLA-B27. The mechanism by which HLA-B27 contributes to ReA is not yet fully understood. However, HLA-B27 correlates with more severe and prolonged arthritis and sacroiliitis and a higher incidence of extra-articular manifestations. Screening our patient for underlying respiratory and gastrointestinal coinfections, common in ReA, was negative, leading us to assume an association with SARS-CoV-2 infection.

However, there is no formal evidence of a causal relationship with COVID-19, as the arthritis in our patient may have been caused by a subclinical infection that was not detected during the comprehensive diagnostic workup. A limitation in this case is that although a comprehensive diagnostic workup was initiated, urinalysis was not performed for genitourinary tract infections, which are commonly associated with ReA. In at least 25% of patients with ReA, the previous infection is asymptomatic.13 It is also possible that the pathogen of a possible subclinical coinfection could no longer be detected at the time of serological diagnosis.

On the other hand, viral arthritides have been described after COVID-19.3 4 Viral arthritis is frequently described in association with acute infection with parvoviruses, hepatitis B, hepatitis C, HIV and alphaviruses.14 In our patient, viral arthritis cannot be completely excluded. Nevertheless, the features of viral arthritis are typically different from the manifestation of ReA, as viral arthritis presents as acute polyarthritis in combination with other symptoms such as fever, rash or lymphadenopathy, mimicking rheumatoid arthritis, and is usually self-limiting.14 All of these features were not present in our patient. Therefore, testing for SARS-CoV-2 in the aspirated synovial fluid was not performed because a positive finding was considered highly unlikely.

The pathogenesis of ReA is only partially understood, and many proposed mechanisms are still under debate.15 16 In well-studied pathogens such as C. trachomatis, it is known that the vital organism is transported to the joint in infected monocytes/macrophages and settles in the synovial tissue, leading to infection of the synovium.17 Other pathogens do not reach the joint in a vital and intact state, but in parts—including so-called ‘arthritogenic peptides’.15 18 A local inflammatory reaction is then triggered in the synovium. Common hypotheses suggest that the inflammation is caused either by direct cross-reactivity of HLA-B27 with these arthritogenic antigens or, at least in part, by molecular mimicry.15 18 Although molecular mimicry has been shown to trigger autoimmunity and has been discussed in acute SARS-CoV-2 infection as well as in the postinfectious immunological phenomena reported to date,19 20 molecular mimicry between SARS-CoV-2 and HLA-B27 has not yet been demonstrated or described.

The causal relationship between SARS-CoV-2 infection and new-onset arthritis has not been proven, and further studies are needed to understand the immunopathogenic mechanisms. However, as more cases are reported and clinical manifestations are heterogeneous, physicians should be sensitive to this phenomenon. Overall, we believe it is likely that SARS-CoV-2 infection can cause ReA.