Reactive arthritis after vaccination against SARS-CoV-2: A case series and a mini-review

ABSTRACT

The rapid development of COVID-19 vaccines became essential for addressing the global pandemic. Reactive arthritis after vaccination has been a rare phenomenon. Here, we present a case series of three patients with joint inflammation possibly attributed to COVID-19 immunization (mRNA and live adenovirus vectored vaccine). Symptoms were alleviated using non-steroid anti-inflammatory drugs and glucocorticoids. After follow-up, the patients have not been diagnosed with any other rheumatic disease. Reactive arthritis after the COVID-19 vaccine is an unusual adverse effect and poses a negligible risk in comparison to the benefits of immunization, but it should be considered in differential diagnostics by a practicing rheumatologist who cares for patients with new-onset arthritis without apparent cause at the time of pandemic.

KEYWORDS:

• Reactive arthritis
• COVID vaccination
• adverse effect

Introduction

Reactive arthritis (ReA) is considered a subtype of spondyloarthropathy. It may be triggered by an infection that originates at another site, not in the affected joints.¹ Although no universally accepted criteria for ReA have been established,^2,3 it is mostly recognized in patients with monoarthritis or asymmetric oligoarthritis, usually of the lower extremities.¹ Especially in recent years, due to the global COVID-19 pandemic, vaccines have become a highly relevant weapon against the spread of COVID-19. Adverse effects after vaccination include various immune-mediated phenomena that mimic rheumatological conditions.⁴ Examples of septic arthritis, bursitis, and Still’s disease can be found in the literature.⁵ The aim of this article is to present three different cases of patients with post-vaccination arthritis with manifestation similar to ReA after the COVID-19 vaccine from the tertiary rheumatology center in Poland.

Patient 1

The patient was a 39-y-old male who presented to the University Hospital in Cracow with a swollen right knee as well as pain and edema of the metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), and the distal interphalangeal joints (DIP) of both hands that appeared approximately 7 days after being inoculated with a third dose of the COVID-19 vaccine (mRNA vaccine, COVID-19 Vaccine Moderna, currently Spikevax). The first symptoms began the next day after vaccination: fever 38.5°C, headache, and malaise, but they were considered typical after vaccination. On day 5, he developed erythematous skin lesions on the hands and soles of his feet. The patient also had a history of recurring erythematous skin lesions near the urethral orifice that responded to antifungal therapy. There was no history of recent airways, gastrointestinal or urinary tract infection, past symptoms of connective tissue diseases, trauma, or arthrosis. The family history was unremarkable. The patient’s comorbidities were gastroesophageal reflux disease, hypercholesterolemia, and grass pollen allergy but without specific treatment.

On admission, the patient’s vital signs were within the normal range. The test results showed an elevation of inflammatory markers: the C-reactive protein was 90 mg/l (reference<5 mg/l), and the ESR was 69 mm/h (reference<10 mm/h). Furthermore, the liver enzyme levels were above the normal limit, as GGT was 243 U/l (reference 8–61 U/l), ALT was 84 U/l (reference 10–50 U/l), and ALP was 181 U/l (reference 40–129 U/l). The patient also had a low level of vitamin D, 19 ng/ml (reference 30–80 ng/ml). Urinalysis was indicative of leukocyturia and bacteriuria, whereas the urine culture revealed a mixed bacterial flora of Gram-positive and Gram-negative bacteria in titers of 10,000 CFU/ml with no symptoms of urinary tract infection, control urinalysis was normal. The chest radiograph was normal. Serological tests for hepatitis and hepatotropic viruses (HAV, HBV, HCV, CMV, EBV) and HIV were negative. Rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), and HLA-B27 were also negative. Molecular and serological tests for Chlamydia, Mycoplasma, Ureaplasma, and Neisseria gonorrhoeae were negative along with antibodies against Borrelia ssp. There were no signs of psoriatic involvement of the skin and nails. Ultrasound of the right-knee joint showed effusion in the suprapatellar recess without synovial hypertrophy. Joint aspiration of 52 ml of yellow, clear, and sticky synovial fluid was performed. Synovial fluid had modest count of white blood cells with the increase in polymorphonuclears. Synovial fluid culture and examination for crystals were negative. Eventually, the diagnosis of reactive arthritis was made and 4-week celecoxib 400 mg daily treatment was initiated. After the 1 month of follow-up, inflammatory markers and liver enzymes decreased but there was residual swelling of PIP II-IV of hands and right knee. Over the next 6 months, the symptoms resolved completely without therapy.

Patient 2

A 67-y-old woman presented to the outpatient rheumatology clinic with acute onset of arthritis of the right knees that after a few days progressed to symmetric polyarthritis (pain and edema) affecting PIPs, DIPs, wrists, elbows, and ankles. Symptoms occurred 10 days after the second dose of live adenovirus vectored vaccine (COVID-19 Vaccine Astra Zeneca, currently Vaxzevria).

She had no history of arthralgia or joint swelling in the past or any symptoms suggestive of inflammatory arthritis and connective tissue diseases. There was no history of recent infections. She had a history of hypothyroidism, cholelithiasis, and hypercholesterolemia and took levothyroxine. Her sister has been suffering from rheumatoid arthritis. Complete blood count, C-reactive protein, ESR, protein electrophoresis, total calcium level, liver function tests, creatinine, urinalysis, TSH were normal. RF, ACPA, ANA, and HLA-B27 were absent. Serological tests for hepatotropic viruses and Lyme disease, as well as urine molecular tests for Chlamydia, Mycoplasma, Ureaplasma, and Neisseria gonorrhoeae, were all negative. Chest X-ray and hands X-ray were normal. Due to the unsatisfactory effect of non-steroid anti-inflammatory drugs, a short course of methylprednisolone (8 mg per day with gradual dose tapering over 3 weeks) was started that resulted in complete resolution of symptoms. After 1-y follow-up, symptoms did not relapse and the patient remains healthy.

Patient 3

A 33-y-old man with no medical history presented with acute onset of left-knee arthritis. Symptoms began 1 d after receiving the second dose of live adenovirus vectored vaccine (COVID-19 Vaccine Astra Zeneca, currently Vaxzevria). One week before, he had a mild infection of the upper respiratory tract with negative results from the COVID-19 test. He had no other infections in recent months. On admission, he was in good general condition. His left knee was swollen, painful, and warm with erythema on the anterior side of the knee joint. The patient did not have fever. The CRP was 28 mg/l (reference<5 mg/l), and the ESR was 17 mm/h and the level of uric acid was slightly increased − 441 µmol/l (reference 202–416 µmol/l). The urine test detected presence of nitrites, leukocytes − 163.5/µl (reference<13.2/µl) and bacteria 21,989,2/µl (reference<26,4/µl). Urine culture identified E. coli in titers of 10⁶ but there were no symptoms of urinary tract infection. Control urinalysis was normal and antibiotic therapy was not started. The X-ray of the left-knee joint revealed no pathological changes. Immunological tests (RF, ACPA, ANA) were unremarkable. HLA-B27 and HLA-cw6 alleles were absent. Serological tests for HBV, HCV, HIV, and Borrelia were negative. Molecular and serological tests for Chlamydia, Mycoplasma, Ureaplasma, and Neisseria gonorrhoeae were also negative. Treatment with diclofenac allowed resolution of symptoms within 3 days. At one-month and 1 y of follow-up the patient’s condition did not change.

Discussion

Post-vaccination ReA is an emerging phenomenon in recent years. Medline, EMBASE, and Web of Science were searched using the keywords “SARS-CoV-2 immunization,” “COVID immunization,” “SARS-CoV-2 vaccination,” “COVID vaccination,” “post-vaccination arthritis,” “reactive arthritis,” “vaccine-induced arthritis.” To our knowledge, at least 16 cases of ReA have been recorded after COVID-19 vaccination.^6–15 When it comes to sex distribution, the disease presented in 11 women and 5 men. We observed that there were two age groups of patients with ReA, in their 20s or over 60 y old. This is certainly different from the usual age of ‘classical’ ReA (20–40 y old).³ No predilection to a specific vaccine was detected. The disease appeared after inoculation with mRNA vaccines (Moderna, BNT162b2 [Pfizer]), live adenovirus vectored vaccines (Astra Zeneca, Sputnik V) and inactivated vaccines (CoronaVac, Sinovac). A similar number of ReA cases occurred after the first and the second dose of the vaccine regardless of the type of vaccine. Only two patients experienced symptoms after each dose was administered.^6,9 Furthermore, in almost all cases the disease manifested up to a week with one exception, in which it appeared after 3 weeks.⁷ In 11 patients, small joints were affected, whereas in 12 patients, the disease was located in large joints. Of 16 cases, only 4 of them had monoarthritis,^9,11,12,14 1 had oligoarthritis, 1 had sacroilitis, and the rest had polyarthritis. Thirteen patients reported normal condition during follow-up and in two the symptoms reoccurred after the second dose of the vaccine.^6,9 Additionally, one patient had residual pain and swelling at 1-week follow-up,⁷ and the other experienced pain in active range of motion 1 month after the appearance of symptoms.¹¹

The patients presented in this paper had some typical characteristics ReA. First, patients 1 and 3 were both men in their 30s. Although patient 3 had classical signs of asymmetric monoarticular disease affecting the lower extremities, in patient 2 the symptoms started 10 d after vaccination and also began as monoarthritis in the lower extremities, but over time became widespread and symmetrical affecting upper extremities. In all cases, good response to treatment was observed. However, the onset of the disease 1–2 d after inoculation in patients 1 and 3 was unusual for ReA and suggests rather a direct postvaccination reaction. The symptoms of patient 1 started bilaterally in small joints of the hand and then after a few days a swollen left knee was present. Patient 2 was a female in her late 60s and over time the disease also manifested in the small joints of both hands, which is more typical for young women with arthritis caused by viral infection (e.g., parvovirus B19). HLA-B27 was negative in all patients. We may speculate vaccination provides immune stimulus that reveals a transient manifestation of occult susceptibility to arthritis caused by a genetic background (like family history in case 2) or bacterial colonization (asymptomatic bacteriuria in cases 1 and 3) that would otherwise be innocuous.

ReA after immunization was associated with several vaccines including influenza,¹⁶ tetanus,¹⁷ hepatitis B,¹⁸ and the most prominent example BCG immunotherapy.¹⁹ Apart from the latter, ReA after various vaccines was limited to single case reports or case series and was not thoroughly researched. Although the incidence of post-COVID-19 vaccination ReA appears to be relatively low, this is the first time that such a number of cases of self-limiting arthritides temporally related to vaccination were described without any other evident cause. Despite the fact that vaccines have proved to be invaluable against Covid-19, it is important to carefully monitor their adverse events. In particular, patients with ReA after COVID-19 inoculation should be observed to detect and determine the onset of other rheumatic diseases, as not only arthritis but other autoimmune phenomena have been widely described in the literature during COVID-19 period.²⁰

Consent for publication

The authors have obtained the patient’s written informed consent for the print and electronic publication of this case report.

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Additional information

Funding

The author(s) reported that there is no funding associated with the work featured in this article.