New-onset of rheumatic diseases following COVID-19 vaccination: the report of three cases and a literature review

Abstract

Vaccines against coronavirus disease 2019 (COVID-19) have been distributed in most countries for the prevention of onset and aggravation of COVID-19. Recently, there have been increasing numbers of reports on new-onset autoimmune and autoinflammatory diseases following COVID-19 vaccination, however, only little information is available on the long-term safety of these vaccines. Here, we experienced three cases of new-onset rheumatic diseases following COVID-19 vaccination, one case each of rheumatoid arthritis (RA), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). The symptom onset ranged from one day to a few days following vaccination. The patients of AAV and SLE were treated successfully with glucocorticoid therapy, and the patient of RA died due to COVID-19. In the literature review of new-onset rheumatic diseases following COVID-19 vaccination, which including seven cases of RA, 37 cases of AAV and 18 cases of SLE, the mean time from vaccination to onset was approximately 11 to 12 days. Most cases improved with glucocorticoid, immunosuppressive drugs and biologic agents. Although such adverse effects are rare, and vaccines are useful in prevent onset and severity of infections, continued accumulation of similar cases is important in terms of examining the long-term safety and understanding pathogenic mechanism of rheumatic diseases.

Keywords:

• COVID-19 vaccine
• rheumatoid arthritis
• systemic lupus erythematosus
• ANCA-associated vasculitis
• autoimmune disease

1. Introduction

New onset cases of coronavirus disease 2019 (COVID-19) continue to occur worldwide, and the cumulative number of patients has also been increasing in Japan. COVID-19 vaccines have been distributed widely in most countries to prevent the onset and aggravation of COVID-19 [1]. Vaccine effectiveness against SARS-CoV-2 infection, hospitalization and mortality generally declines over time. Receiving multiple doses of the vaccine improves booster effectiveness and immune recovery and therefore, improves immunity in a population [2]. There is little information regarding rare adverse events or the long-term safety of the COVID-19 vaccines although recently, there have been increasing numbers of case reports on new-onset or relapsed autoimmune or autoinflammatory diseases following COVID-19 vaccination. We have already reported three cases of new-onset adult-onset Still’s disease (AOSD) following COVID-19 vaccination [3]. However, the relationship between development of rare autoimmune or autoinflammatory diseases and COVID-19 vaccination remains controversial. Here we report three additional cases: one case each of rheumatoid arthritis (RA), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and systemic lupus erythematosus (SLE) with the critical literature review on this important topic.

2. Case reports

2.1. Case 1

A 79-year-old woman developed swelling and pain in finger joints and both ankle joints 2–3 days after the second dose of the BNT162b2 mRNA COVID-19 vaccine. She was admitted to our hospital with difficulty walking at 27 days after the vaccination. She had a history of hypertension and nontuberculous mycobacterial (NTM) infection. She and her family had no history of rheumatic diseases. She had no adverse events of note after the first vaccination. Physical examination revealed polyarthritis with swelling in 20/28 joints and tenderness in 23/28 joints, with high disease activity (disease activity score in 28 joints with ESR [DAS-28 ESR]: 8.48 and [DAS-28 CRP]: 7.94). Her health assessment questionnaire disability index (HAQ-DI) score was 1.875. Laboratory test results were as follows: white blood cell count 7680/µL (neutrophils 76.5%, lymphocytes 14.3%), Hb 8.2 g/dL, platelets 47.4 × 10⁴/µL, erythrocite sedimentation rate (ESR) 95 mm/h, albumin 2.3 g/dL, creatine kinase 28 U/L, aspartate aminotransferase (AST) 18 U/L, alanine aminotransferase (ALT) 19 U/L, lactate dehydrogenase (LDH) 158 U/L, creatinine 0.81 mg/dL, C-reactive protein (CRP) 10.69 mg/dL, serum ferritin 621 ng/mL, matrix metalloproteinase-3 (MMP-3) 249.4 ng/mL, antinuclear antibody (ANA) negative, rheumatoid factor (RF) 59 IU/mL and anti-cyclic citrullinated peptide (CCP) antibody 184.6 U/mL. The interferon gamma release assay was negative. polymerase chain reaction (PCR) test for SARS-CoV-2 from nasopharyngeal swabs was negative. Anti-mycobacterium avium complex antibody was positive (1.0 U/mL). Ultrasonography of wrists and finger joints revealed synovitis. X-rays of the joints found no evidence of erosions. RA was diagnosed according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for RA [4]. The patient was treated with subcutaneous abatacept (125 mg, weekly) without methotrexate because of concomitant NTM. Later, her arthritis was refractory to abatacept, followed by etanercept, so she was switched to baricitinib. Baricitinib was effective but was discontinued after she developed a urinary tract infection, and was switched to sarilumab but then discontinued due to herpes zoster. She had been treated with tacrolimus, but then, developed COVID-19 and died (Figure 1).

Figure 1. Clinical course of case 3, including symptoms, laboratory findings and treatment. ‘Day’ means the number of days after the second vaccination date, set as day 0. ABT, abatacept; ETN, etanercept; BAR, baricitinib; SASP, salazosulfapyridine; SAR, sarilumab; TAC, tacrolimus.

2.2. Case 2

A 71-year-old woman developed a fever and cough the day after her second dose of the BNT162b2 mRNA COVID-19 vaccine. She received medication from her previous physician but did not improve. Seven days after the vaccination, her laboratory data were abnormal with white blood cell count 12,230/µL, CRP 10.9 mg/dL and no computed tomography (CT) findings in the chest and abdomen. Her cough improved with antibiotic treatment, but she then developed pain in her shoulders, lower back and lower legs. She was admitted to our hospital 18 days after her second COVID-19 vaccination. She and her family had no history of rheumatic diseases. She had no adverse events of note after the first vaccination. She developed swelling and pain in the finger joints and grasping pain in the bilateral lower legs. Laboratory test results were as follows: white blood cell count 12,290/µL (neutrophils 75.1%, lymphocytes 14.6%), Hb 10.5 g/dL, platelets 50.2 × 10⁴/µL, ESR 120 mm/h, albumin 2.5 g/dL, creatine kinase 11 U/L, AST 15 U/L, ALT 16 U/L, LDH 128 U/L, creatinine 0.78 mg/dL, CRP 14.53 mg/dL, serum ferritin 248 ng/mL, ANA negative, RF 64 IU/mL and Myeloperoxidase Anti-neutrophil Cytoplasmic Antibody (MPO-ANCA) 12.0 U/mL. PCR test for SARS-CoV-2 from nasopharyngeal swabs was negative. Other infectious diseases were excluded by blood, sputum and urine culture tests. Magnetic resonance imaging demonstrated high signal intensity in the bilateral lower leg muscles on short-tau inversion recovery (STIR) images (Figure 2). A biopsy of the left gastrocnemius muscle revealed fragmented elastic fibers with Elastica van Gieson staining, signifying the presence of blood vessels, and AAV was diagnosed (Figure 3). Oral glucocorticoid therapy (prednisolone 35 mg/day; 0.7 mg/kg/day) was administered initially. Her symptoms improved. The inflammatory findings disappeared, MPO-ANCA decreased to negative and the patient was discharged. During her treatment, she developed pyelonephritis, idiopathic osteonecrosis of the femoral head and urinary tract infection. The dose of prednisolone was gradually reduced to 3 mg, and no relapse was observed (Figure 4).

Figure 2. Magnetic resonance imaging finding in the lower legs. STIR images show heterogeneous high-signal areas in the bilateral tibialis anterior, extensor digitorum longus, peroneus longus, popliteus, soleus, plantaris and gastrocnemius muscles, suggesting myositis or vasculitis spreading to these areas.

Figure 3. Histopathological findings of the left gastrocnemius muscle. Hematoxylin-Eosin staining shows an inflammatory cell infiltrate, including lymphocytes and neutrophils (A, B: arrowheads), and in some cases, neutrophils are clustered. Elastica Van Gieson staining reveals scattered fragmented elastic fibres (C: arrows).

Figure 4. Clinical course of case 4, including symptoms, laboratory findings and treatment. ‘Day’ means the number of days after the second vaccination date, set as day 0. MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody.

2.3. Case 3

A 32-year-old woman developed chest pain, left axillary lymphadenopathy and erythema on her cheeks 2–3 days after her third dose of the COVID-19 vaccine (first and second vaccines, BNT162b2; third vaccine, mRNA-1273). The erythema spread and lip swelling appeared. She developed a low-grade fever around 37 °C. Despite treatment by a dermatologist, the erythema on her cheeks spread and appeared also on her upper extremities and body. After treatment with methylprednisolone (drug dosage unknown) by her previous physician, the fever and lip swelling improved. The patient was admitted to our hospital with suspected collagen disease approximately four months after the vaccination. She had no history of rheumatic diseases and her grandmother had Takayasu arteritis. She had no adverse events of note after the first and second vaccinations. On physical examination, there was discoid lupus around her nasal wings, erythema chilblains with desquamation of her auricle, erythema chilblains on her fingers and left axillary lymphadenopathy. Laboratory test results were as follows: white blood cell count 2500/µL (neutrophils 56.4%, lymphocytes 30.8%), Hb 12.8 g/dL, platelets 16.2 × 10⁴/µL, ESR 64 mm/h, albumin 3.8 g/dL, creatine kinase 24 U/L, AST 40 U/L, ALT 39 U/L, LDH 346 U/L, creatinine 0.46 mg/dL, CRP 0.19 mg/dL, 50% hemolytic complement (CH 50) activity 19.9 U/mL (normal range: 31.6–57.6), the third component of complement (C3) 36 mg/dL (normal range: 73–138), the fourth component of complement (C4) 7 mg/dL (normal range: 11–31), serum ferritin 87 ng/mL, IgG 1735 mg/dL, IgA 299 mg/dL, IgM 92 mg/dL and activated partial thromboplastin time 33.4 s. ANA was positive (1:160, speckled patterns). Anti-ribonucleoprotein antibody (119.0 U/mL), anti-Sm antibody (481.0 U/mL) and anti-SS-A antibody (1200.0 U/mL) were positive. Anti-dsDNA antibody, lupus anticoagulant test and anticardiolipin IgG were negative. PCR test for SARS-CoV-2 from nasopharyngeal swabs was negative. Real-time PCR test for Epstein-Barr virus was negative. Other infectious diseases were excluded by blood, sputum and urine culture tests. CT of the neck, chest, abdomen and pelvis revealed multiple lymphadenopathy at the bilateral axillas and splenomegaly. SLE was diagnosed according to the 2019 European League Against Rheumatism/ACR criteria for SLE [5], based on discoid lupus, leukopenia, low complement, ANA-positivity and anti-Sm antibody–positivity. Oral glucocorticoid therapy (prednisolone 30 mg/day; 0.6 mg/kg/day) was administered initially. Hydroxychloroquine was then used concomitantly. Her symptoms improved and the inflammatory findings disappeared, and the patient was discharged. The dose of prednisolone was then gradually reduced to 5 mg, and no relapse was observed (Figure 5).

Figure 5. Clinical course of case 5, including symptoms, laboratory findings and treatment. ‘Day’ means the number of days after the third vaccination date, set as day 0. HCQ, Hydroxychlorquine; CH50, 50% hemolytic complement activity; dsDNA, double-stranded deoxyribonucleic acid; WBC, white blood cell.

3. Discussion

We have previously reported three cases of AOSD following COVID-19 vaccination [3]. We herein report additional three cases, including one case each of RA, AAV and SLE that developed following vaccination with an mRNA COVID-19 vaccine. The symptom onset ranged from one day to a few days following vaccination. The patients of AAV and SLE were treated successfully with glucocorticoid therapy, and the patients of RA, experienced with several infections under disease-modifying antirheumatic drugs, died due to COVID-19.

Tables 1–3 summarize the details of the previously reported and present cases of new-onset autoimmune diseases following COVID-19 vaccination.

Table 1. Previous and present cases of rheumatoid arthritis following COVID-19 vaccination.

	Study	Age (years)/sex	Vaccine		Days from vaccination to onset	Symptoms and clinical findings	Laboratory findings	Treatment	Response	References
			Type	Dose number
1	Baimukhamedov et al.	38/F	Vector	1st	20	Pain and stiffness in both shoulders and knee joints	RF 170 IU/mL, ACPA 157 U/mL	MTX 25 mg/week, mPSL 100 mg/day, iv, for 3 days	Improved	[6]
2	Yonezawa et al.	54/M	mRNA	2nd	1	Polyarthritis	RF 1712 IU/mL, ACPA 162 U/mL	mPSL 8 mg/day, iguratimod 25 mg/day	Improved	[7]
3	Watanabe et al.	53/M	mRNA	2nd	4 Weeks	Swelling and pain in left knee	RF 51 IU/mL, ACPA 1200 U/mL	MTX 3 mg/day, PSL 5 mg/day, etanercept, tocilizumab	Improved	[8]
4	Emran et al.	81/F	mRNA	2nd	3 Weeks	Diffuse joint pains and swelling	RF negative, ACPA negative	MTX 10 mg/week	Improved	[9]
5	Singh et al.	50s/F	inactivated	1st	7	Acute onset facial puffiness, polyarthritis	RF 68 IU/mL, ACPA 279 U/mL	PSL 10 mg/day, MTX 7.5 mg/week	Improved	[10]
6	Nahra et al.	74/M	mRNA	1st	10	Polyarthritis and rash	RF 24 IU/mL, ACPA negative	PSL 30 mg/day, leflunomide	Improved	[11]
7	Our case 1	79/F	mRNA	2nd	A few days	Potyarthritis	RF 59 IU/mL, ACPA 184.6 U/mL	PSL 10 mg/day, abatacept, etanercept, baricitinib, sarilumab, tacrolimus	Died of COVID-19

iv, intravenous; mPSL, methylprednisolone; mRNA, messenger ribonucleic acid; MTX, methotrexate; PSL, prednisolone; ACPA, anti-CCP antibody.

Table 2. Previous and present cases of ANCA-associated vasculitis following COVID-19 vaccination.

	Study	Age (years)/sex	Vaccine		Days from vaccination to onset	Symptoms and clinical findings	Antineutrophil cytoplasmic antibody	Affected organs	Treatment	Response	References
			Type	Dose number
1	Villa et al.	63/M	Vector	1st	7	Hemoptysis	MPO-ANCA	Kidney: a focal class of ANCA-associated pauchi-immune glomerulonephritis	High-dose GCs, iv, PSL 60 mg/day	Improved	[12]
2	Shakoor et al.	78/F	mRNA	2nd	6	Nausea, vomiting, diarrhea	MPO-ANCA	Kidney: crescentic necrotizing glomerulonephritis	mPSL pulse, PSL 1 mg/kg/day, RTX	Improved	[13]
3	Okuda et al.	36/F	mRNA	1st	12	Erythema on the forearm precordium	MPO-ANCA, PR3-ANCA	Auricular cartilage	PSL 30 mg/day	Improved	[14]
4	Hakroush et al.	79/F	mRNA	2nd	14	Weakness upper thigh pain	MPO-ANCA	Rhabdomyolysis, kidney: pauci-immune crescentic glomerulonephritis	mPSL pulse, PSL 60 mg/day, cyclophosphamide 10 mg/kg, iv	Improved	[15]
5	Chen et al.	70/F	mRNA	1st	7	Hematuria, proteinuria, acute renal failure	MPO-ANCA	Pulmonary hemorrhage, kidney: pauci-immune crescentic glomerulonephritis	plasma exchange, mPSL pulse, anti-CD20 therapy	Improved	[16]
6	Prabhahar et al.	51/M	Vector	1st	15	Fever, polyarthritis	PR3-ANCA	Kidney: pauci-immune crescentic glomerulonephritis	PSL 60 mg/day, RTX	Improved	[17]
7	Al-Yafeai et al.	62/F	mRNA	1st	One month	Polyarthralgia, hematemesis	PR3-ANCA	Pulmonary hemorrhage, brain hemorrhage	mPSL pulse, IVIG, plasmapheresis, RTX, cyclophosphamide	Partially Improved	[18]
8	Baier et al.	57/F	mRNA	3rd	5	Pulmonary hemorrhage	MPO-ANCA, PR3-ANCA	Pulmonary hemorrhage	mPSL pulse, PSL 1 mg/kg/day, plasma exchange	Improved	[19]
9	Nappi et al.	63/M	mRNA	3rd	1	Diplopia, left temporo-parietal headache, disturbance of vision	negative	Asthma, pulmonary consolidations, eosinophilia, myopericarditis, III cranial nerve palsy	mPSL pulse, cyclophosphamide, iv	Improved	[20]
10	So et al.	42/M	mRNA	2nd	NA	Shortness of breath, edema, gross, hematuria, weight loss	MPO-ANCA	Kidney: necrotizing and crescentic glomerulonephritis	mPSL pulse, RTX, PSL 1 mg/kg/day, plasma exchange	Improved	[21]
11	Kim et al.	72/F	mRNA	3rd	18	Tinnitus, nasal congestion, bloody rhinorrhea	MPO-ANCA	Kidney: pauci-immune crescentic glomerulonephritis	Plasmapheresis, mPSL pulse, cyclophosphamide, iv	Improved	[22]
12	Hasbani et al.	47/F	mRNA	1st	3	Bilateral flank pain, bilateral lower extremity swelling	MPO-ANCA	Kidney: pauci-immune crescentic glomerulonephritis	mPSL pulse, PSL 50 mg/day, azathioprine	Improved	[23]
13	Noel et al.	62/F	mRNA	2nd	4 Weeks	Lower-extremity edema	MPO-ANCA	Kidney: pauci-immune crescentic glomerulonephritis	mPSL pulse, cyclophosphamide, iv, MMF	Improved	[24]
14	Christodoulou et al.	72/F	mRNA	2nd	15	Alveolar hemorrhage, rapidly progressive glomerulonephritis	MPO-ANCA	Kidney: focal necrotizing glomerulonephritis	mPSL pulse, PSL 1 mg/kg/day, cyclophosphamide, iv, plasma exchange	Improved	[25]
15	Yadav et al.	52/F	Vector	1st	12	Fever, joint pain, weakness of all limbs	p-ANCA, c-ANCA	Kidney: necrotizing and crescentic glomerulonephritis with insignificant glomerular immune complex deposit	mPSL, cyclophosphamide	Improved	[26]
16	Suzuki et al.	72/M	mRNA	2nd	Half a day	Fever, fatigue, loss of appetite	MPO-ANCA	Pulmonary nodules, kidney: pauci-immune crescentic glomerulonephritis	mPSL pulse, PSL 0.8 mg/kg/day, Hemodialysis, RTX	Improved	[27]
17	Ma et al.	70/F	Inactivated	1st	0	Poor appetite, nausea	MPO-ANCA	Kidney: pauci-immune crescentic glomerulonephritis	mPSL pulse, cyclophosphamide	Improved	[28]
18	Obata et al.	84/M	mRNA	2nd	1	Spike fever, malaise, cough	MPO-ANCA	Kidney: focal necrotizing glomerulonephritis with cellular crescents	mPSL pulse, PSL 40 mg/day	Improved	[29]
19	Zamoner et al.	58/F	Vector	1st	5	Fatigue, paleness, polyarthralgia, foamy urine, elevated blood pressure	MPO-ANCA	Kidney: crescentic glomerulonephritis with glomerular sclerosis	mPSL pulse, cyclophosphamide, iv, azathioprine	Improved	[30]
20	Uddin et al.	59/M	mRNA	2nd	12	Fever, malaise, polyarthralgia	MPO-ANCA, PR3-ANCA	Kidney: pauci-immune crescentic glomerulonephritis	mPSL pulse, RTX, PSL 1 mg/kg/day	Improved	[31]
21	Anderegg et al.	81/M	mRNA	1st and 2nd	NA	Flu-like symptoms, AKI	PR3-ANCA	Kidney: crescentic glomerulonephritis Lung: necrotic masses, pleural effusion	Cyclophosphamide, high-dose GCs, plasma exchange	Improved	[32]
22	Dube et al.	29/F	mRNA	2nd	16	AKI	MPO-ANCA	Kidney: crescentic glomerulonephritis	RTX, cyclophosphamide, GCs	Improved	[33]
23	Takenaka et al.	75/F	mRNA	1st	4	Blurred vision in the right eye	MPO-ANCA	Relative afferent pupillary defect in the right eye	mPSL pulse	Improved	[34]
24	Gupta et al.	23/M	mRNA	2nd	14	AKI, weakness, fatigue and weight loss	MPO-ANCA, anti-GBM, ANA	Kidney: crescentic glomerulonephritis	NA	NA	[35]
25	Klomjit et al.	82/F	mRNA	2nd	28	AKI, haematuria, proteinuria	MPO-ANCA	NA	RTX, GCs	Improved	[36]
26	Prema et al.	58/M	inactivated	2nd	14	Hemoptysis, breathlessness	PR3-ANCA, anti-GBM	Kidney: crescentic glomerulonephritis	Cyclophosphamide, plasma exchange, Pulse GCs	Improved	[37]
27	Prema et al.	45/M	inactivated	1st	12	Generalized edema, oliguria, hemoptysis, breathlessness	MPO-ANCA	Kidney: crescentic glomerulonephritis	Cyclophosphamide, plasma exchange, Pulse GCs	Improved	[37]
28	Caza et al.	76/M	mRNA	2nd	11	AKI, haematuria, proteinuria	ANCA, ANA	Kidney: crescentic glomerulonephritis	RTX, GCs	Dialysis dependent	[38]
29	Caza et al.	81/F	mRNA	2nd	2	AKI, haematuria, proteinuria	ANCA, ANA	Kidney: crescentic glomerulonephritis	RTX	Partial response	[38]
30	Caza et al.	76/F	mRNA	1st	5	AKI, haematuria, proteinuria	ANCA, ANA	Kidney: crescentic glomerulonephritis	RTX, GCs	Partial response	[38]
31	Caza et al.	71/F	mRNA	2nd	14	Haematuria, proteinuria	ANCA, ANA	Kidney: crescentic glomerulonephritis	RTX, GCs	Did not improved	[38]
32	Caza et al.	65/F	mRNA	2nd	14	AKI, haematuria, proteinuria	ANCA	Kidney: crescentic glomerulonephritis	Cyclophosphamide, GCs	dialysis dependent	[38]
33	Davidovic et al.	54/F	mRNA	1st/2nd	35/14	AKI, haematuria, proteinuria	MPO-ANCA	Kidney: Pauci-immune glomerulonephritis	RTX, GCs	Improved	[39]
34	Seif et al.	66/M	mRNA	2nd	3 Weeks	Fevers and intermittent headaches	MPO-ANCA	Kidney: crescentic glomerulonephritis	RTX, GCs	Improved	[40]
35	Feghali et al.	58/M	mRNA	2nd	4	Evaluation of nausea, vomiting	MPO-ANCA, PR3-ANCA	Kidney: crescentic glomerulonephritis	RTX, Cyclophosphamide, GCs, plasma exchange	Improved	[41]
36	Gen et al.	82/F	mRNA	3rd	One month	Pyrexia and general malaise	MPO-ANCA	Kidney: pauci-immune glomerulonephritis	PSL 40 mg/day	Improved	[42]
37	Our case 2	71/F	mRNA	2nd	1	Pain in shoulders, lower back and lower legs, polyarthritis	MPO-ANCA	Gastrocnemius muscle biopsy: blood vessels	PSL 35 mg/day	Improved

c-ANCA, cytoplasmic-anti-neutrophil cytoplasmic antibody; GCs, glucocorticoids; iv, intravenous; IVIG: intravenous immunoglobulin; MMF, mycophenolate mofetil; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibody; mPSL, methylprednisolone; mRNA, messenger ribonucleic acid; p-ANCA, perinuclear-anti-neutrophil cytoplasmic antibody; PR3-ANCA, proteinase3-anti-neutrophil cytoplasmic antibody; PSL, prednisolone; RTX, rituximab; AKI, acute renal failure; ANA, antinuclear antibody, GBM, glomerular basement membrane.

Table 3. Previous and present cases of SLE following COVID-19 vaccination.

	Study	Age (years)/sex	Vaccine		Days from vaccination to onset	Inicial symptoms	Autoantibodies	Clinical findings, affected organs	Treatment	Response	References
			Type	Dose number
1	Hidaka et al.	53/F	mRNA	2nd	7	Shortness of breath	ANA 1/160 (speckled, nucleolar), lupus coagulant	Evans syndrome	PSL 60 mg/day	Improved	[43]
2	Nune et al.	24/M	mRNA	2nd	14	Polyarthralgia, joint stiffness, fever, fatigue, oral ulcers	ANA 1/2560, anti-dsDNA	Leukopenia, lymphopenia	PSL 60 mg/day, MTX 15 mg/week	Improved	[44]
3	Báez-Negrón et al.	27/F	mRNA	2nd	14	Tiredness, weight loss, polyarthralgia, morning stiffness	ANA 1/160(speckled), anti-Ro, anti-La, anti-dsDNA	Urinary protein	HCQ 300 mg/day, PSL 20 mg/day, MMF 2 g/day	Improved	[45]
4	Zevala-Miranda et al.	23/F	Vector	1st	7	Nephrotic syndrome	ANA 1/1280 (homogeneous), anti-dsDNA	Lymphopenia, lupus nephritis	High-dose PSL, MMF, HCQ	Improved	[46]
5	Patil and Patil	22/F	Vector	2nd	10	Fever, polyarthralgia, bipedal edema, cutaneous rash over fingertips, petechiae over lower limb	ANA 1/320, anti-dsDNA	Bilateral cervical lymphadenopathy, mild hepatomegaly, anemia	PSL 50 mg/day, HCQ 400 mg/day, MMF 2 g/day	Inproved	[47]
6	Kaur et al.	54/M	mRNA	2nd	14	Flu-like symptoms	ANA 1/1280 (nuclear, speckled), anti-DNA, anti-Sm, anti-chromatin, anti-histone	Pancytopenia, diffuse lymphadenopathy, erythematous maculopapular palpable purpuric lesions on bilateral feet, nephritis	mPSL pulse, MMF 3 g/day	Improved	[48]
7	Molina-Rios et al.	42/F	mRNA	1st	14	Polyarthralgia	ANA 1/1280, anti-dsDNA, Beta-2 glycoprotein IgG, Beta-2 glycoprotein IgM, Lupus anticoagulant	APS, pulmonary embolism	mPSL pulse, PSL 0.5 mg/kg/day, azathioprine, HCQ 200 mg/day, sulfasalazine, Anticoagulation, colchicine, azathioprine	With APS Improved	[49]
8	Sogbe et al.	72/F	mRNA	3rd	7	Pleuritic chest pain	ANA 1/160, anti-dsDNA, anti-histone antibody	Myocarditis	PSL 1 mg/kg/day	Improved	[50]
9	Sagy et al.	24/M	mRNA	1st	7	Rash on the head, morning’s stiffness	ANA 1/160, ribosomal P, chromatin	Psoriasiform papulosquamous rash, a non-scarring alopecia, arthritis	HCQ 200 mg BID, etoricoxib	Imoroved	[51]
10	Sagy et al.	23/M	mRNA	2nd	One month	Fever, malar rash, oral ulcers, non-resolving headache	ANA 1/160, Ro/SSA, beta-2 glycoprotein IgG	Pancytopenia, lymphadenopathy	HCQ 200 mg BID, PSL 1 mg/kg/day, azathioprine 2 mg/day, G-CSF, eltrombopag	Improved	[51]
11	Sagy et al.	56/M	mRNA	2nd	One month	Arthritis	ANA 1/160, anti-dsDNA, Smith	Lymphadenopathy	HCQ 200 mg BID, etoricoxib	Partially improved	[51]
12	Mousa et al.	22/F	mRNA	1st	7	Epigastric abdominal pain, nausea, vomiting, erythematous non-blanching maculopapular rashes over extremities	ANA 1/1200 (homogeneous), anti-dsDNA	Leukopenia, lymphopenia, autoimmune hemolytic anemia, thrombocytopenia, autoimmune pancreatitis	mPSL pulse, PSL 40 mg/day, HCQ 200 mg, azathioprine	Improved	[52]
13	Lemoine et al.	68/F	mRNA	1st	2	Bilateral proximal upper and lower extremity muscle weakness, stiffness, and pain	ANA 1/640 (cytoplasmic), p-ANCA, c-ANCA, anti-MPO, ds-DNA	Arthritis, pyuria	PSL 20 mg/day, azathioprine, MTX 20 mg/week	Improved	[53]
14	Khanna et al.	18/F	mRNA	1st	7	Facial rash	ANA 1/2560 (nuclear), anti-RNP antibody, anti-Smith antibody	Neutrophilic urticarial dermatosis	PSL 50 mg/day, HCQ	Improved	[54]
15	Raviv et al.	24/M	mRNA	1st	2	Facial rash, arthralgia	ANA 1/160 (speckled), anti-nucleosome, ribosomal P	Cutaneous lupus erythematosus	HCQ, topical steroids	Improved	[55]
16	Zengarinin et al.	30/F	mRNA	2nd	10	Papules and plaques on her face and upper back	ANA, anti-dsDNA, SSA, Smith, RNP, nucleosome histone	Cutaneous lupus erythematosus	PSL 0.4 mg/kg/day	Improved	[56]
17	Kim et al.	60/F	Vector	2nd	One month	Asthenic, malaise, fever, bilateral pitting edema	ANA 1/1280, anti-dsDNA, Smith	Pancytopenia, lupus nephritis, patchy, nodular consolidations on chest CT	mPSL pulse, cyclophosphamide, HCQ 200 mg/day	Improved	[57]
18	Our case 3	32/F	mRNA	3rd	A few days	Chest pain, erythema in cheeks	ANA 1/160(speckled), anti-RNP, anti-Sm, anti-SS-A	Multiple lymphadenopathy, splenomegaly	PSL 30 mg/day, HCQ	Improved

BID, bis in die; CT, computed tomography; G-CSF, granulocyte-colony stimulating factor; HCQ, hydroxychlorquine; MMF, mycophenolate mofetil; mPSL, methylprednisolone; mRNA, messenger ribonucleic acid; MTX, methotrexate; NPSLE, neuropsychiatric SLE; PSL, prednisolone.

The previously reported cases of RA were only six cases and the mean time from vaccination to onset of RA was 12.8 days (Table 1 [6–11]:), in contrast, our case had a short time, 2-3 days, between onset and vaccination. RF and ACPA were strongly positive in five cases including our case. The previously reported cases improved with methotrexate, iguratimod, leflunomide or biologics concomitant with glucocorticoid. Although the disease activity of our patient also improved with biologics and JAK inhibitors, she died from COVID-19 since our case was an advanced age, as a risk factor.

The previously reported cases of AAV are summarized in Table 2 [12–42]. The mean time from vaccination to onset was 11.8 days, and most cases occurred within 7 days. Of the 37cases, 22 were MPO-ANCA positive, 4 PR3-ANCA positive, 4 both positive and 1 both negative. One was positive for both p-ANCA and C-ANCA. Thirty patients were diagnosed with glomerulonephritis on renal biopsy. The organ lesions of other cases included auricular cartilage, pulmonary hemorrhage or brain hemorrhage. All previously reported cases improved with glucocorticoid, immunosuppressive drugs, biologic agents, and plasma exchange. Our case diagnosed vasculitis on muscle biopsy with MPO positive and responded well to glucocorticoid therapy.

The previously reported cases of SLE are summarized in Table 3 [43–57]. The mean time from vaccination to onset was 12.8 days, and most cases occurred within 14 days. ANA was positive in all 18 cases, anti-dsDNA antibody was positive in 12 cases, and anti-Sm antibody was positive in six cases. Lupus anticoagulant test was positive in two cases and beta-2 glycoprotein IgG was positive in two cases. Affected organs included Evans syndrome in one patient, leukopenia in three patients, pancytopenia in three patients, lupus nephritis in three patients, myocarditis in one patient, autoimmune pancreatitis in one patient and one patient had complication of antiphospholipid syndrome. There was no specific trend in the clinical features of patients. All cases improved or partially improved with glucocorticoid and immunosuppressive drugs.

Previous studies have reported autoimmune diseases that developed after vaccines other than COVID-19 vaccine, such as vaccines for influenza virus, human papilloma virus and hepatitis B virus [58–60]. These vaccines have been suspected to trigger autoimmunity through molecular mimicry and immune crossreactivity. The possibility that adjuvants in vaccines may cause autoimmune diseases has also been considered.

There are two main types of COVID-19 vaccine formulations; mRNA encoding the SARS-CoV-2 spike protein (S) encapsulated in lipid nanoparticles and adenovirus (AdV) vectors encoding the S protein [61]. COVID-19 vaccine mRNA and AdV particles invade dendritic cells, resulting in the production of S-proteins. The adjuvant activity of the vaccine activates innate immune sensors, resulting in the production of type I interferon and multiple pro-inflammatory mediators, which activate T cells and induce immunity against SARS-CoV-2 [62]. Increased production of type I interferon and multiple pro-inflammatory mediators following vaccination may trigger the onset or exacerbation of existing pre-autoimmune conditions and develop autoimmune diseases such as RA, AAV or SLE. In most of reported cases in Tables 1–3, the duration of vaccination and onset of the diseases is relatively short, that is, within a month, suggesting that the stimulation of existing pre-autoimmune conditions considered to be the main pathogenic factor. Padjen et al. [63] analyzed the onset of arthralgia and arthritis following COVID-19 vaccination and reported that the mean time from vaccination to arthralgia onset ranged from 1.54 to 5.31 days and the mean time to arthritis onset ranged from 7.74 to 13.60 days. These results were similar to those of the cases we summarized here.

The clinical features of autoimmune disease following COVID-19 vaccination are reported to be short-lived and responsive to glucocorticoid and other immunosuppressive drugs, with a good prognosis [64, 65]. Kim et al. investigated autoimmune disorders reported following COVID-19 vaccination using the World Health Organization (WHO) database [66]. They identified 25,219 adverse events following immunizations (AEFIs) associated with autoimmune disorders following COVID-19 vaccination, including mRNA (n = 21,470) and viral vector (n = 3366) platforms in the WHO database. The number of AEFIs appeared to be two times higher in females than in males. The tendency for AEFI related to autoimmune disorders to be more prevalent in females was consistently observed in all other vaccine groups as well. They also reported that the age of patients who developed autoimmune disorders following COVID-19 vaccination was predominantly between 45 and 64 years old, while the age of patients who developed them after other vaccinations was mostly under 18 years old. Approximately half of the cases of autoimmune disorders following COVID-19 vaccination occurred within 7 days, whereas after other vaccinations, occurrences within 7 days and beyond 28 days were approximately 30% each. Among autoimmune diseases, ankylosing spondylitis or psoriatic arthritis, inflammatory bowel disease, polymyalgia rheumatica and thyroiditis were significantly more frequently reported to occur following COVID-19 vaccines than following all other vaccines. Meanwhile, the reported rates of RA, vasculitis and SLE were similar or lower after COVID-19 vaccines than after all other vaccines.

With regard to the number of vaccinations, in our cases and in the previously reported cases summarized in the Tables, RA and AAV tended to develop more after the second dose of mRNA vaccine and more after the first dose of Vector vaccine. In contrast, the incidence of SLE was similar after the first and second doses of mRNA vaccine. The most common type of vaccine was mRNA: 71.4% of RA cases, 79.5% of AAV cases and 84.2% of SLE cases. Further case accumulation is considered necessary to analyze trends according to the number of vaccinations and types of vaccine.

Risk factors for developing autoimmune disease after vaccination include a history of symptoms after vaccination in the past, history of allergy to vaccines, immunosuppressed state, family history of autoimmune disease or known autoantibodies, and genetic predisposition are presumed [67, 68]. Therefore, individuals who develop symptoms of autoimmune disease after receiving the vaccine should consider the possibility that similar symptoms may occur when they receive the vaccine again.

We report three cases of new-onset rheumatic disease following COVID-19 vaccination. Although such adverse effects are rare, and vaccines are useful in prevent onset and severity of infections, continued accumulation of similar cases is important in terms of examining long-term safety. It may provide an opportunity to elucidate the pathogenic mechanism of autoimmune diseases and to clarify the risk factors and effective treatments in the future.

Ethical approval statement

Ethics approval for this study was obtained from the Institutional Review Board of Saitama Medical University Hospital (Approval Number: 2021-142).

Acknowledgment

We are grateful to Mei Hamada and Atsushi Sasaki (Pathology, Saitama Medical University, Saitama, Japan) for providing technical assistance.

Disclosure statement

The authors have no conflicts of interest.