Discussion
The occurrence of post-infective and para- infectious arthritis following viral infection is not uncommon, but with the current pandemic, the incidence has increased (6). The spectrum of musculoskeletal complaints associated with viral infection can range from mild arthralgia to chronic arthritis (13).
Joint involvement in SARS-CoV-2 infection may occur at any time during the course of infection (14). It may be an initial symptom of the infection, emerge during the acute phase (sometimes during hospitalization), or occur after recovery (14). Coronaviruses generally appear to cause arthralgias and myalgias rather than true inflammatory arthritis (15). Arthralgias are reported in 15% of COVID-19 patients, and myalgias in 44% of patients (13). PCA, which was previously reported in October 2020 during the first wave of the COVID pandemic, has been well established as a clinical entity requiring medical attention (16). Several clinical forms of PCA have been described (17-19). It may present with mono- or oligoarticular involvement, however clinical and epidemiological data of PCA indicate that monoarthritis was the most common form of involvement, with prominent involvement of the lower extremity joints (17). The most frequently affected joints are the knee, ankle, and proximal interphalangeal joint (17) and such was the case in our patients, whose knee joint was affected. PCA is often diagnosed in young adults between the ages of 18 and 40 years (20), such was the case with our 33 year old female patient. The incidence of PCA is high in the male population (17). The lag time between SARSCoV2 infection and arthritis onset varied between cases, usually, starting some days or a few weeks after the resolution of other infection manifestations and usually during the healing period (median: 18 days) (21) similar to that noted in both our patients, whose arhritis onset delay was respectively of 20 and 15 days. The predisposing factors for developping joint involvement following SARS-CoV-2 infection are still unknown, but in reviewing the litterature, it appears that the virus’ prolonged persistence, as evidenced by prolonged positivity of nasopharyngeal swabs for SARS-CoV-2, and its spread from the respiratory tract to other sites, including the gastrointestinal tract, could locally activate immunological and inflammatory pathways and lead to the development of arthritis in some patients (22),
Although different mechanisms have been suggested in the etiopathogenesis of virus-induced arthritis, the exact mechanisms by which COVID-19 could cause joint inflammation are only partially understood (23). For a long time, it was assumed that SARS-CoV-2 infection resulted in macrophage stimulation, which in turn caused the release of high levels of cytokines and chemokines that enhanced the inflammatory process (23). Previous and current studies demonstrate that coronaviruses share molecular epitopes with human proteins (e.g., spike glycoprotein S) that play a key role in host cell invasion and evade immune response attacks, conferring immune invasive capacity to the infectious agent (24). This molecular mimicry appears to be most prominent (25), by triggering humoral and cellular self-reactivity in the host at the end of the process by which the epitope interacts between a viral agent and the host (26), and it is well known to be responsible for eliciting autoimmune responses in susceptible individuals (27). And this mechanism may be involved in the pathogenesis of acute systemic infection and virus-related post-infection immunological consequences (28). Mimetic epitopes may also be present in the synovial membrane and cause acute local inflammation through similar pathways (28). Other suggestive examples of diseases induced by molecular mimicry after COVID-19 come from recent publications reporting cases of Guillain-Barre and Miller Fisher syndrome (29, 30).
Other theories suggest that circulating immune complexes or a possible localization of the virus directly on the joint tissues are involved (31). However, RT-PCR for the detection of SARS-CoV2 nucleic acids did not show that the virus was present in synovial fluid, validating the hypothesis of an immune-mediated process.
Given the worldwide frequency of COVID-19 and the large affected population, the number of reported PCA is small (32). A credible justification for the lower incidence of musculoskeletal inflammation is COVID-19 treatment with corticosteroids, which likely attenuated the musculoskeletal manifestations (32). Although hydroxychloroquine is inefective for treating COVID-19, it has been shown to be effective in the management of systemic rheumatological diseases, especially with inflammatory joint involvement (33). Most reported PCA cases show a prompt and complete response to nonsteroidal anti-inflammatory drugs, and this was also the case in our patients. Treatment duration can be extended for 2-4 weeks, as with other viral arthritis. However, steroid treatment is occasionally needed, and is preferred by intra-articular injection (in case of mono-oligoarticular involvement). In a few cases, systemic steroid is necessary, but generally for short periods (34). Only a few cases of PCA have required immunosuppressive drugs (methotrexate and sulfasalazine) (35). Some patients with joint manifestations and severe lung involvement, as part of a hyperinflammatory syndrome, have been treated with IL-6 inhibitors or Jak inhibitors, with significant improvement in both lung and joint manifestations (36).
In conclusion, As the number of patients recovering from COVID-19 increases, more and more data on post-infectious complications will emerge. Various autoimmune and rheumatic diseases have been reported in COVID-19 survivors. COVID-19 can also cause flare-ups of pre-existing rheumatic diseases. Both of our cases are consistent with what has already been reported in the literature confirming the development of PCA and strengthen the impending necessity of wider studies to identify rheumatologic manifestations in the short- and long-terms after surviving COVID-19. Follow-up in the coming months will help to determine the chronicity of these inflammatory conditions. A better understanding of the immune consequences that accompany SARS-CoV-2 infection is required both to determine the immunopathogenic mechanisms capable of promoting or contrasting the development of rheumatic manifestations, and to adequately deal with such a complication.