The first case is a 68-year-old woman with rheumatoid arthritis who experienced a flare after she received a BioNTech/Pfi zer vaccination in October 2021. She stopped tofacitinib a week prior to the vaccination and developed pain in the left knee a week after the vaccination. The synovial fluid aspirated through the knee exhibited the pattern of infl ammatory synovial fl uid. Her symptoms were relieved after repeated joint aspiration and intra-articular corticosteroid injections. The second case is a 45-year-old man without underlying diseases who presented with left knee pain on the day after his third dose of the Medigen COVID-19 vaccine in January 2022. The synovial fluid aspirated through the knee exhibited the pattern of infl ammatory synovial fluid. His symptoms were relieved after repeated joint aspiration and oral non-steroidal anti-inflammatory drugs. We discuss the possible mechanism underlying the arthritis fl are and answer the following questions: (1) whether to stop antirheumatic drugs before vaccination; (2) when to resume medication after vaccination.

arthritis, coronavirus disease 2019, JAK inhibitor, Toll-like receptors, vaccination

Since 2019, more than 300 million individuals have been diagnosed as having coronavirus disease 2019 (COVID-19), and more than 5 million individuals have died because of COVID-19. A multicenter, comparative cohort study conducted in the United States in 2020 reported that patients with COVID-19 who had systemic autoimmune rheumatic diseases (ARDs) had higher risks of hospitalization, acute renal failure, intensive care unit admission, and venous thromboembolism than did those without systemic ARDs [1]. Thus, despite the risk of a flare or worsening of rheumatic diseases after COVID-19 vaccination, the current guidance recommends COVID-19 vaccination for patients with stable ARDs because the benefi t outweighs the potential risk of flare [2].

Herein, we report two cases of arthritis fl are after COVID-19 vaccination. In the fi rst case, a patient with rheumatoid arthritis experienced a fl are following her first COVID-19 vaccination. In the second case, a man without a history of arthritis experienced left knee arthritis after his third dose of COVID-19 vaccination. Moreover, we discuss possible mechanisms underlying the fl are and answer the following questions: (1) whether to stop medication for ARDs before vaccination; (2) when to resume medication after vaccination.

The first case is a 68-year-old woman who was diagnosed as having rheumatoid arthritis by a rheumatologist in 2014 after an outpatient department visit because of swelling and pain in multiple joints, including the proximal interphalangeal joints, metacarpophalangeal joints of hands, wrists, elbows, knees, ankles, and feet, for 3 months. She was prescribed several types of medication including non-steroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine, sulfasalazine, prednisolone, and methotrexate. In 2015, she was prescribed adalimumab but exhibited a poor response. Thus, she has been prescribed tofacitinib since 2016, and she had been in clinical remission with the use of tofacitinib (5 mg) twice per day and celecoxib (200 mg) twice per day.

During her last visit in October 2021, no signs of joint effusion or active arthritis were noted. She had no known exposure to COVID-19 cases and presented no symptoms or signs of COVID-19. Because of her plan to receive the fi rst BioNTech/Pfi zer (BNT162b2) vaccine, her rheumatologist suggested stopping tofacitinib a week prior to vaccination. She received the fi rst BNT162b2 vaccine on October 21, 2021, and afterward, the plan was to stop tofacitinib for two additional weeks.

However, 7 days after the vaccination, she developed swelling and pain in the left knee, which woke her up at night, and her numerical rating scale (NRS) score for pain ranged from 7 to 8. Therefore, she visited our outpatient department 20 days after the vaccination. On physical examination, we observed considerable swelling in the left knee (Figure 1A), with pain on fl exion, an empty end feel, and a limited range of motion (ROM) (10°–110°). She, however, had no stiffness, pain, erythema, or swelling in other joints. Her body temperature was 36.5°C. The next day, an ultrasound examination of the left knee revealed moderate compressible hypoechoic effusion in the suprapatellar recess with synovial hypertrophy. Moreover, a mild increase in vascularity was noted on color Doppler.

We collected 4 mL of red turbid fluid (Figure 1B) through ultrasound-guided aspiration (transverse scan, in-the-plane, lateral to medial) from the left knee with an 18-gauge needle and subsequently administered an intra-articular injection of triamcinolone (20 mg). Analysis of the synovial fl uid revealed a red blood cell (RBC) count of 15,930 per mm3 and a white blood cell (WBC) count of 17,235 per mm3 , of which 17% were lymphocytes and 83% were neutrophils. The string test resulted in 3.5-cm strings. No crystals were noted in the synovial fl uid, and no growth was observed in a bacterial culture. The results suggested infl ammatory synovial fl uid, compatible with the fl are of rheumatoid arthritis. Her blood tests revealed elevation of C-reactive protein (CRP) (1.090 mg/dL; normal range, < 0.3 mg/dL) and erythrocyte sedimentation rate (23 mm/hr; normal range, < 20.0 mm/hr).

Because of continuous pain in the left knee, she visited our outpatient department a week later. During her visit, we aspirated 30 mL of turbid brownish synovial fluid under ultrasound guidance on the 28th day after vaccination (Figure 1C). A week later, an additional 12 mL of turbid reddish brownish synovial fluid was aspirated from her left knee (Figure 1D). Subsequently, an intra-articular injection of triamcinolone (20 mg) was administered to her. Her pain subsided after treatment, and her NRS score was 2.

The second case is a 45-year-old man who visited our outpatient department for severe left knee pain on February 10, 2022, after his third dose of Medigen COVID-19 (MVC-COV1901) vaccination on January 27, 2022. He did not have a history of arthritis and denied doing exercises or experiencing trauma. According to himself, the left knee pain developed on the day after vaccination, and the swelling and pain progressed to the extent that he could barely walk or go upstairs on the 5th day.

The physical examination on February 10, 2022, revealed moderate swelling in the left knee (Figure 2A), with a positive ballottement test, empty end feel, and limited ROM (0°–90°). Ultrasound examination of the left knee on the same day showed a massive hypoechoic fl uid collection in the suprapatellar pouch. Ultrasound-guided aspiration got 63 mL of yellowish turbid fluid (blood-tinged at the end of aspiration, Figure 2B). The synovial fluid analysis revealed a cell count of RBC of 350 cells per mm3 , and WBC of 2,565 per mm³ , of which 45% were lymphocytes and 55% were neutrophils. The string test was 4 cm. There were no crystals, and no organisms were found on bacterial cultures. The results favored an inflammatory synovial fl uid. His blood tests revealed mild elevation of CRP (0.420 mg/dL) and no elevation of urid acid and rheumatoid factor. Oral NSAIDs was prescribed for him.

A week later, the patient’s knee pain improved a little. Repeated ultrasound-guided aspiration of the left knee joint fl uid got 45 mL yellowish turbid fl uid (Figure 2C), of which the synovial fl uid examination revealed results similar to those of the last exam, but with an improved string test (9 cm). Afterward, the knee pain was relieved, and further treatment was not required.

The fi rst case presented with infl ammatory synovial fl uid after BNT vaccination without evidence of infection, and the infl ammation was possibly related to the fl are of rheumatoid arthritis. The volume of the fi rst aspiration was only 4 mL, which may have been due to obstruction caused by a blood clot or synovial debris.

Many studies have reported cases of new-onset arthritis or arthritis fl are following COVID-19 vaccination [3-7]. An observational study including more than 6 million individuals from three countries who received COVID-19 vaccinations reported 27 cases of immune-mediated disease fl ares or new-onset disease, of whom 23 received BNT vaccination [8].

A propensity-weighted cohort study that included 5,493 patients with rheumatoid arthritis revealed no signifi cant association between COVID-19 vaccination and arthritis flares [9].

Moderna (mRNA-1273) and BNT162b2 are mRNA vaccines against COVID-19. Their mechanism of action involves innate immune system activation through the binding of Toll-like receptors (TLRs; TLR3 and TLR7) to single-stranded RNA [10]. MVCCOV1901 is a protein-based subunit vaccine which comprises S-2P protein and TLR 9 agonist CpG 1018 [11]. Similarly, autoreactive immune responses are driven by TLR7 and TLR9 in systemic autoimmune diseases [12]. Therefore, this mechanism of action may be responsible for flares or worsening of rheumatic diseases after COVID-19 vaccination.

According to the American College of Rheumatology Guidance established in 2021, the timing of COVID-19 vaccination should not be delayed or adjusted in patients with rheumatic and musculoskeletal diseases receiving immunomodulatory therapies, except for rituximab. Regarding when to resume immunomodulatory therapies after COVID-19 vaccination, no modifi cations are required except for patients taking methotrexate, mycophenolate, Janus kinase (JAK) inhibitors, abatacept, cyclophosphamide, or rituximab [2]. Our fi rst patient regularly used tofacitinib, a type of JAK inhibitor; withholding tofacitinib for a week after each vaccination is recommended. In a previous study, decreased infl uenza and pneumococcal vaccine responses were observed in tofacitinib-treated patients with rheumatoid arthritis; the decrease in response may be attributable to the inhibition of certain signaling pathways [13].

A prospective observational study in 2019 enrolled 100 rheumatoid arthritis patients achieving remission or low disease activity after tofacitinib treatment for a year [14]. Afterward, they were assigned to a dose-reduction, withdrawal, or continuation group. In the subsequent years, the incidence rate for disease flare was significantly higher following immediate withdrawal of tofacitinib (0.73 per patient-year) than following dose reduction (0.44 per patient-year). The median time to flare was lesser in the withdrawal group (7 months) than in the dose-reduction group (21 months). Therefore, though stopping tofacitinib for a week seems short, there is a possibility that it causes a flare of rheumatoid arthritis.

The flare of arthritis in the first case may have been caused by BNT vaccination or stopping tofacitinib. Stopping tofacitinib before vaccination is not required. Regarding the treatment of the arthritis flare, the patient effectively responded to intra-articular steroids, similar to previous cases [7,8]. The flare of arthritis in the second case may have been caused by Medigen COVID-19 vaccination, which involved the similar pathway as autoreactive immune responses. The arthritis was treated effectively by joint fluid aspiration and oral NSAIDs.

Vaccines against COVID-19 were newly developed more than a year ago. Thus, guidance has mostly been based on recent experience and the evidence of studies on other vaccines, as studies providing direct evidence regarding the safe timing of immunomodulatory therapies in relation to COVID-19 vaccination are lacking. Furthermore, whether to receive COVID-19 vaccination depends on the condition of each individual, and it should not be completely based on the guidance.

In conclusion, we present two cases of arthritis flare receiving BNT162b2 and MVC-COV1901 vaccination respectively. We reviewed the current studies, and noted that there is no need of stopping tofacitinib before vaccination, but resuming it a week after vaccination is suggested. The flares responded well to joint fluid aspiration, intra-articular steroids treatment, and oral NSAIDs.

Figure 1. Examination for the First Case
(A) Physical examination showing considerable swelling in the left knee (white arrow). (B) Ultrasound-guided aspiration (transverse scan, in-the-plane, lateral to medial) through the left knee with an 18-gauge needle (white arrows). (C) Part of the synovial fluid aspirated from the left knee
on day 28. (D) Synovial fluid aspirated from the left knee on day 35.
Abbreviations: ANT, anterior; F, femur; Lat, lateral; Med, medial; TR, transverse scan.

Figure 2. Examination for the Second Case
(A) Physical examination of the second case showing moderate swelling in the left knee (white arrow). (B) Synovial fluid drawn from the left
knee on the day after vaccination. (C) Synovial fluid drawn from the left knee three weeks after vaccination.