Our results demonstrated that the disease activity scores did not differ significantly between IMRD patients during a 6-month follow-up after COVID-19 and those who did not contract the virus. However, clinical worsening was related to fatigue, depression, anxiety, and stress.
Currently, the data regarding the association between SARS-CoV-2 infection and the incidence of IMRD flare are controversial, especially because the published studies have heterogeneous samples and different designs. Consequently, the current uncertainty revolves around whether patient-reported outcomes (PROs) are related to the IMRD flare-up itself after COVID-19, whether it is associated with long COVID-19 or, alternatively, whether a reactive postinfectious immunological response is a potential trigger (1, 12–15).
In rheumatic diseases, a flare is defined as any exacerbation of disease activity that, if persistent, would typically necessitate the initiation or modification of therapy. It signifies a cluster of symptoms of sufficient duration and intensity to warrant the commencement, alteration, or escalation of therapeutic measures (16). In our study, although there was no discernible difference in the mean activity scores among patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or spondyloarthritis (SpA), a subgroup of patients reported a deterioration in immune-mediated rheumatic disease (IMRD). In some of these cases, activity scores increased, aligning with the flare definition employed in this investigation. Given the recognized potential for overestimation of IMRD activity in patients with conditions such as fibromyalgia (17) and other chronic painful disorders, particularly in RA and axial SpA, it is imperative to ascertain the presence of "true" disease activity. This determination holds substantial relevance in decision-making processes related to treatment adjustments. Nevertheless, we observed an association between patients' self-reported worsening after 6 months and the Clinical Disease Activity Index (CDAI) score, along with all its individual components, including swollen joint count (SJC). This association suggests a plausible occurrence of flares in this specific subset of patients.
A cross-sectional study including 32 patients with RA and SpA demonstrated no relevant changes in disease activity after COVID-19 in those who interrupted their treatment (1). According to data from the COVID-19 study, which evaluated 824 patients with IMRD who had at least one SARS-CoV-2 infection between March 2021 and June 18, 2022 (12), 36.9% of patients experienced at least one flare of the underlying IMRD following COVID-19 infection over a 127-day period (IQR = 62–308 days) from the date of infection to the date of the survey. Females and patients with comorbidities had greater odds of flaring of their disease. Patients who reported flares had worse physical health scores, pain VAS scores, fatigue VAS scores, and lower mental health scores than did those who did not report flares. However, as stated by the authors, "this was a self-reported disease flares without verification by a physician which could be impacted by patients' perceptions of flares and their inability to distinguish from ongoing symptoms of long-COVID syndrome or secondary fibromyalgia".
In a study of 92 children with IMRD who had COVID-19 (13), 10% experienced IMRD relapse after infection. Relapse was mild in four patients and moderate in five patients. One patient experienced severe relapse of ARD and required hospitalization, which was not associated with COVID-19 clinical presentation.
Similar to several other viral infections, SARS-CoV-2 infection couldpotentially trigger reactive and autoimmune diseases by inducing type II and type IV hypersensitivity reactions, leading to autoantibody production and autoimmune disease development as long-term complications (18), and in patients with pre-existing IMRD, it may be difficult to identify whether it is a flare of the disease or a postinfection manifestation. A recent study evaluated the effects of COVID-19 on the development and progression of RA using a collagen-induced arthritis (CIA) animal model. The incidence and severity of RA in CIA mice were slightly increased by the SARS-CoV-2 spike protein in vivo. In addition, the levels of autoantibodies and thrombotic factors, such as anti-CXC chemokine ligand 4 (CXCL4, also called PF4) antibodies and anti-phospholipid antibodies, were significantly increased by the SARS-CoV-2 spike protein. Furthermore, tissue destruction and inflammatory cytokine levels in joint tissue were markedly increased in CIA mice by the SARS-CoV-2 spike protein, suggesting that COVID-19 accelerates the development and progression of RA by increasing inflammation, autoantibody production, and thrombosis(19).
In an Italian study, 122 consecutive post-COVID-19 patients were evaluated, with the onset of rheumatic manifestations within 4 weeks of SARS-CoV-2 infection as an inclusion criterion. In this group, most patients had inflammatory joint disease (52.5%); 19.7% of patients were diagnosed with connective tissue diseases, and 6.6% of patients had vasculitis. Interestingly, in this same cohort, patients with inflammatory manifestations post-COVID-19 vaccination were evaluated, and this group had a greater percentage of patients classified as having polymyalgia rheumatica (PMR, 33.1% vs. 21.3%, p = 0.032) (14). Another study evaluated the presence of arthritis associated with COVID-19 by ultrasound in 10 patients with (n = 4) and without previous rheumatic disease (n = 6). In the group without previous disease, 4 of the 6 patients presented with arthritis for 4 to 16 weeks after infection, comparable to reactive arthritis. One patient developed late-onset rheumatoid arthritis. In the group with previous disease, synovitis and tenosynovitis with positive Doppler power were observed, suggesting a possible flare-up of the disease after COVID-19 (20).
A major concern when interpreting musculoskeletal symptoms in these patients is the possibility of developing post-COVID syndrome, also known as long COVID-19. More than 20% of subjects surviving acute COVID-19 may suffer from persistent symptoms and develop new symptoms after one month, and approximately 5% of all infected individuals develop long-term complications after 6 months, possibly due to tissue damage, viral reservoirs, autoimmunity, and persistent inflammation (21, 22). The clinical presentation in these patients, such as fatigue and joint pain, may mimic a disease flare, thereby complicating decision-making regarding treatment changes.
A recent systematic review revealed that the prevalence of arthralgia ranges from 2–65% within a time frame varying from 4 weeks to 12 months after COVID-19. Inflammatory arthritis has been reported to have various clinical phenotypes, including an RA-like pattern similar to that of other prototypical viral arthritis, as well as polymyalgia-like or acute monoarthritis and oligoarthritis of large joints resembling reactive arthritis or SpA (23).
An Iranian study evaluated the prevalence of musculoskeletal symptoms in 239 patients after the acute phase of COVID-19 and its associated factors using an online questionnaire. Almost all of them (98.74%) experienced at least one musculoskeletal symptom after recovering from COVID-19, and the most common symptom was fatigue (91.2%), followed by myalgia, headache, and low back pain. A high BMI, hospitalization, and ICU admission were associated with a greater risk of musculoskeletal symptoms (24).
In addition to musculoskeletal symptoms, patients could develop psychological distress after COVID-19, such as depression, anxiety, and stress, symptoms that could also be present in IMRD. The frequency of these symptoms in IMRD patients post-COVID-19 was significantly greater than that in patients who did not have the infection. Some authors have suggested that the term long COVID-19 is inappropriate and should be replaced by fibromyalgia-like post-COVID-19 syndrome (2).
We acknowledge the limitations of our study, such as the fact that we obtained FACIT and DASS-21 scores only at the last visit and that there was no possibility of comparison with the pre-COVID-19 status. Since the study began in the first months of the pandemic, we do not yet know that these outcomes were important. We decided to include it after the first studies demonstrating the association of these symptoms with SARS-CoV-2 infection were published. However, we know that fatigue, depression, anxiety, and stress are frequent symptoms in patients with IMRD, and we have a group that did not have COVID-19 as a comparator; in the group with COVID-19, these scores were significantly worse. In addition, the greater political and economic instability experienced in our country may have had a direct impact on psychological distress as a bias. On the other hand, we included a representative sample from various regions of Brazil, with a follow-up period of 6 months, compared with a group of patients with IMRD matched by sex and age for the same epidemiological period, which was one of the main strengths of our study.