In this research, we reported 10 patients with RA who developed arthritis within a maximum of two months following BNT162b2 vaccination, so we defined these patients as ASIA syndrome. In its current aspect, our study is the first to show the development of RA confirmed by radiological findings after vaccination against SARS-CoV2. Our patients developed inflammatory arthritis for the first time after vaccination, showed a chronic course during their follow-up, and met the 2010 ACR/EULAR RA criteria [7]. Most of the cases (seven of ten) were symptomatic within the first week after vaccination, and the median incubation period was seven days, indicating that the development of RA was related to vaccination. In addition, the presence of typical radiological findings of RA in all patients, both erosion and joint space narrowing, was the strongest evidence of RA.
There were some significant differences between our patients and classical RA. First, our patients developed a rapidly destructive course of arthritis. Although X-Rays were obtained during first visit (in the median of three months after symptom onset of symptoms), erosion was detected in 80% of the patients, and RA-associated X-Ray changes were observed in all cases; this situation is quite different because the patients with classical RA develop erosion with a rate of 25% in three months [9]. Second, we observed an acute exacerbation pattern was more often than the classical insidious onset [10]. Third, classical RA usually starts from small joints of hands and feet [11], but only three of our 10 patients developed arthritis in small joints of hands at the onset of symptoms; the first involved joints were knee in two, temporomandibular in two, shoulder in two cases, and elbow in one case. This is an intriguing feature because preseneting with large joint involvement (especially knee) is a predictive factor for small joint erosions in patients with RA [12].
Shoenfeld first described the ASIA syndrome in 2011 as a syndrome characterized by the body's autoimmune/inflammatory response to adjuvants, and vaccination is a well-known cause of ASIA syndrome [5]. The presence of HLA-DRB1*01 and HLA-DRB4 has been blamed as genetic predisposition factors for the emergence of ASIA syndrome [6], and the same genes have a strong association with the heritability of RA [13], so common genetic risk factors can attribute to the pathogenetic linkage between ASIA syndrome and RA. In the presence of appropriate genetic predisposition, adjuvants can trigger autoimmunity by causing polyclonal B cell activation and inducing cellular immunity. Theoretically, molecular similarity in macromolecular components of vaccines and specific human proteins underlies the development of autoimmunity. The presence of an autoimmune phenomenon developed after previous vaccination, a history of a post-vaccination allergic reaction, the presence of autoimmunity in the family, and previous autoantibody carriage of the patient have been defined as risk factors for the development of ASIA syndrome after vaccination [14].
BNT162b2 vaccine includes SARS-CoV-2 spike protein-encoding mRNA fragment, lipid nano molecules ((4hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyl decanoate), 2 [(polyethylene glycol)-2000] -N, N -di tetradecyl acetamide, 1,2-Distearoyl-sn-glycerol-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate and sucrose [4]. Molecular similarity, an immune response triggered by mRNA fragments, production of some specific pathogenic autoantibodies might have a role in the development of autoimmune events after BNT162b2 vaccination [15]. Type-1 interferon (IFN-1) expression, accumulation of oxidative stress, and DNA damage in mononuclear cells were shown by vaccination in healthy individuals. Some authors have attributed the post-vaccination side effects to the transient burst in interferon-1 (IFN-1) production [16]. Overproduction of IFN-1 triggers a breakdown in immune tolerance and autoimmunity. It is known that the up-regulation of IFN-1 and other immunological pathways causes autoimmune diseases in genetically susceptible individuals [17]. Lipid nano molecules may also act as toll-like receptors (TLR) agonists and affect the type and severity of immune response by activation of IFN-gamma, interleukin-2, tumor necrosis factor (TNF)-alpha, and subsequently CD4 and CD8 T cells [18, 19]. These adjuvants also stimulate age-associated B Cells (ABC Cells), particularly as TLR7/8 and TLR9 agonists. Age-associated B Cells are characterized by the production of immunoglobulin G, presenting high antigen levels to T cells, and forming a germinal center. Another important feature of ABC cells is that when stimulated by TLR 7 signal, they can trigger the production of plasmablasts that provide autoreactive antibodies [20]. All these mechanisms raise serious doubts that mRNA vaccines may trigger the formation of autoimmune rheumatic diseases and exacerbate pre-existing rheumatic diseases. Post-vaccination data revealed that exacerbations might occur in some patients with diagnosed rheumatic diseases.
Apart from conventional vaccine technology, most mRNA vaccines were used in the vaccination, which is a unique experience for humanity. As has been shown many times with traditional vaccines, autoimmune events can be triggered, albeit in small numbers of RA cases developing after influenza, hepatitis B, and rubella vaccines have been shown [6]. Today, a huge mRNA vaccination campaign at this scale could cause an increase in autoimmune events like conventional vaccines. There is increasing evidence in the literature showing the development of immune thrombotic thrombocytopenia, autoimmune hepatitis, IgA nephropathy, Guillain-Barre syndrome, Graves' disease, and type 1 DM after mRNA-based vaccination [15]. In a report in which 16 centers participated in Italy between January 2021 and August 2021, 66 cases with the onset of rheumatological disease after vaccination were presented; polymyalgia rheumatica-like syndrome was found in 41%, oligoarthritis in 32%, and polyarthritis in 27% of patients. In this case series, the most administered vaccine was BNT162b2, with a ratio of 59%. No patient was defined as RA, the cases had no imaging findings, and RF positivity was detected in only one case. Most of the authors' cases were well-responded to steroids, and no cases of persistent erosive arthritis were found [21]. In another series with ASIA syndrome caused by COVID-19 vaccination from Mexico, only two of 36 patients developed arthritis after the Astra-Zenaca vaccine who did not have detailed anamnesis and imaging findings [20]. Two patients with transient arthritis after inactive SARS-CoV-2 (Sinovac) vaccination was reported from Turkey [22]. Baimukhamedov C et al. reported an early RA patient who had both RF and anti-CCP positivity after Sputnik-V vaccination, but there were no erosive radiological changes [23]. In a study of 1377 rheumatic patients, 11% of patients experienced a worsening after SARS-CoV-2 mRNA-based vaccination, and 48% of them had any diagnosis of inflammatory arthritis such as RA, ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and inflammatory bowel disease–associated arthritis before vaccination [24]. Vaccines are the most powerful weapon in the fight against the COVID-19 pandemic, which started in the world in 2019; to date, over 13 billion vaccine doses have been administered [3]. BNT162b2 and other SARS-CoV-2 vaccines can lead to the development of a newly diagnosed immune-mediated disease or exacerbate the pre-existing immune-mediated disease. Therefore rheumatologists and other physicians should be aware of ASIA syndrome.
The small sample size and lack of detection of the asymptomatic COVID-19 history were the major limitations of our study. Lack of serological (RF and anti-CCP) and radiographic results before vaccination may be another limitation. but it is impossible to obtain in asymptomatic individuals. Rheumatoid arthritis presents in patients who have appropiate genetic predispositon, and environmental exposure [1]. Vaccines can trigger the onset of RA in patients having tendency for the develeopment of RA. We couldn’t test for auto-antibodies or HLA genes in asymptomatic individuals so we couldn’t hypothesize that our patients were preclinical RA or not. Absence of joint ultrasonography (USG) may be an another limitation because USG can detect changes in joints earlier than X-rays but we also observed radiological erosions on X-rays [25]. The strongest point of our series is that all patients had radiological evidence of RA, also they had chronic persistent polyarthritis. In this respect, the definitive exclusion of other arthritis is the strength of our series.
As a result, our cases, which we termed as ASIA syndrome, with erosive radiological features after the administration of the BNT162b2 vaccine, were reported for the first time in the literature, as far as we know. Our cases showed clearly a different onset from the classical RA with an acute exacerbation, a rapidly destructive course on hand articulations, and atypical joint involvement at the onset of disease, raising suspicion that mRNA vaccines may elicit an RA phenotype with an atypical course. To make a definitive comment on this issue, time is needed for studies with larger cases.