Rheum-CoV-2 Vaccination Case Series

Abstract

Objectives

In this case series, we present 5 cases of autoimmune rheumatic disease onset shortly after receiving mRNA vaccination against coronavirus disease 2019 (COVID-19).

Methods

We identified 5 patients from Brooke Army Medical Center who developed new manifestations of rheumatic disease following the second dose of the Pfizer-BioNTech or Moderna COVID-19 vaccinations. All patients were initially seen in primary care and then referred to rheumatology for further evaluation and management. Clinical data were obtained through review of the electronic medical record.

Results

Three cases involve elderly women with insidious onset of symmetric wrist and hand polyarthritis with seropositivity for rheumatoid factor. One case involves an elderly woman with a subacute onset of lower extremity–predominant, symmetric polyarthritis. One case involves an elderly man with insidious onset of bilateral shoulder and hip stiffness and arthralgias in the setting of elevated erythrocyte sedimentation rate and a rapid response to glucocorticoid therapy.

Conclusion

Whether there exists a causal or contributory relationship between COVID-19 mRNA vaccination and the development of autoimmune rheumatic disease remains to be determined. Ultimately, further research is needed to establish if there is a true connection between the two.

Vaccination is one of the most successful public health interventions. It has saved countless lives and significantly reduced the rates of infectious disease over time. Vaccines are both effective and safe; however, they are not devoid of adverse effects. Among those reported in the literature, one of the most feared is the development of autoimmune disease.¹ There have been thousands of associated case reports classified under the umbrella term of autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) or included in the Vaccine Adverse Event Reporting System. Despite this, a recent meta-analysis by Petráš et al.,¹ evaluating a total of 144 studies spanning from 1968 to 2019, concluded that there was no statistically significant increase in the occurrence of autoimmune disease following administration of common vaccines. However, the novel mRNA vaccinations against coronavirus disease 2019 (COVID-19) were not included in this analysis. Interestingly, a recent study by Connolly et al,² reviewing more than 1000 patients with rheumatic and musculoskeletal disease who received 2-dose mRNA vaccination against COVID-19, found that flares of underlying rheumatic disease were uncommon. More recently, reviews by Chen et al.³ and Jara et al.⁴ identified 276 cases and 36 cases of new-onset autoimmune phenomena, respectively, after COVID vaccination, a small percentage of which involved the development of autoimmune rheumatic disease following mRNA vaccination.

Currently, there are 2 available mRNA vaccinations against COVID-19. These include the Pfizer-BioNTech vaccine and the Moderna-NIAID vaccine. Several case series and case reports citing the potential development of rheumatic disease after mRNA vaccination against COVID-19 have been published. The reported spectrum of rheumatic disease includes rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, reactive arthritis, cutaneous vasculitis, immunoglobulin A (IgA) vasculitis, anti-neutrophil cytoplasmic antibody–associated vasculitis, IgG4 disease, adult-onset Still disease, and autoimmune polyarthritis.^3–13 In this case series, we present 5 cases of newly diagnosed rheumatic disease that developed after receiving either the Pfizer-BioNTech or Moderna-NIAID vaccinations against COVID-19 and discuss the potential pathophysiology.

METHODS

We identified 5 patients from the Brooke Army Medical Center (BAMC) who developed new manifestations of rheumatic disease following the second dose of the Pfizer-BioNTech or Moderna COVID-19 vaccinations (Table). All patients were initially seen in primary care and then referred to rheumatology for further evaluation and management. Clinical data were obtained through review of the electronic medical record, and each patient is being followed up in the BAMC rheumatology clinic.

TABLE.

Description of Patients With New Rheumatic Disease Following mRNA Vaccination Against COVID-19

Patient	Sex	Age, y	COVID-19 mRNA Vaccination	Time From the 2nd Dose of Vaccination to Symptom Onset	Clinical Evaluation	Initial Laboratory Evaluationa	Diagnosis
1	Female	36	Moderna	1 d	Symmetric polyarthritis involving the MCP joints, PIP joints, wrists, and elbows	RF >130 IU/mL (0–13.9) ACPA >250 U/mL (0–19) ESR 40 mm/h (0–20) CRP 7.0 mg/dL (0–0.5)	Rheumatoid arthritis overlap syndrome
2	Female	61	Pfizer	7 d	Symmetric polyarthritis involving the MCP joints and wrists	RF 16 IU/mL ACPA 5 U/mL ESR 41 mm/h CRP 3.7 mg/dL	Rheumatoid arthritis
3	Female	72	Pfizer	1 d	Symmetric polyarthritis involving the MCP joints, PIP joints, and MTP joints	RF >130 IU/mL ACPA >250 U/mL Normal ESR and CRP	Rheumatoid arthritis
4	Female	66	Pfizer	1 d	Symmetric polyarthritis involving the knees, ankles, and MTP joints	Negative RF and CCP Negative ANA cascade ESR >120 mm/h CRP 22.7 mg/dL	Undifferentiated polyarthritis
5	Male	69	Pfizer	7 d	Symmetric arthralgias and stiffness involving the shoulders, hips, wrists, and knees	Negative RF and CCP Normal CK and aldolase ESR 79 mm/h CK 5.07 mg/dL (26.0–192.0)	Polymyalgia rheumatica

^aReference laboratory values are noted in the parentheses.

ANA, antinuclear antibody; CK, creatine kinase.

RESULTS

Patient 1

A 36-year-old African American woman presented to BAMC rheumatology with 2 months of symmetric polyarthritis involving the shoulders, elbows, wrists, hands, knees, and toes with prolonged morning stiffness. Symptom onset occurred 1 day after completing the Moderna-NIAID vaccination series. The patient had a primary relative with systemic lupus erythematosus, but no personal history of autoimmune disease or COVID infection. The patient never received immunosuppression in the past, and no medication changes were made at the time of vaccination. On initial examination, synovitis was noted at the bilateral second to fourth metacarpophalangeal (MCP) joints, second and third proximal interphalangeal (PIP) joints, wrists, and elbows. Laboratory evaluation was remarkable for an elevated rheumatoid factor (RF) (>130 IU/mL; reference range, 0–13.9 IU/mL), anticitrullinated peptide antibody (ACPA) (>250 U/mL; reference range, 0–19 U/mL), erythrocyte sedimentation rate (ESR) (40 mm/h; reference range, 0–20 mm/h), and C-reactive protein (CRP) (7.0 mg/dL; reference range, 0–0.5 mg/dL). Evaluation was also notable for a fluorescent antinuclear antibody with a 1:1280 titer (centromere pattern) and positive anticentromere antibodies (>8.0 IU/mL; reference, <1 IU/mL). She had no clinical signs or symptoms of limited cutaneous systemic sclerosis. Serologic testing for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and COVID-19 (polymerase chain reaction [PCR]) were negative. Bilateral hand and foot radiographs were negative for erosive changes. Chest x-ray was negative for an acute cardiopulmonary process. Although the patient met the 2010 American College of Rheumatology (ACR) classification criteria for rheumatoid arthritis, her symmetric polyarthritis may represent the initial manifestation of an overlap syndrome between rheumatoid arthritis and systemic sclerosis, which is yet to manifest. After intolerance to treatment with both methotrexate and leflunomide, the patient achieved clinical remission with adalimumab. Close observation for the development of signs or symptoms of systemic sclerosis is ongoing.

Patient 2

A 61-year-old White woman presented to BAMC rheumatology with 4 months of symmetric polyarthritis involving the wrists and MCP joints in the setting of prolonged morning stiffness. Symptom onset occurred 1 week after completing the Pfizer-BioNTech vaccination series. The patient had a history of Hashimoto thyroiditis, no history COVID infection, and no family history of autoimmune disease. The patient never received immunosuppression in the past, and no medication changes were made at the time of vaccination. Examination was remarkable for synovitis at the bilateral wrists and second to fourth MCP joints. Laboratory evaluation was notable for elevated RF (16 IU/mL; reference range, 0–13.9 IU/mL), CRP (3.7 mg/dL), and ESR (41 mm/h). Anticitrullinated peptide antibody, fluorescent antinuclear antibody (FANA) test, HBV, HCV, HIV, and COVID-19 testing (PCR) were negative. Bilateral hand and foot radiographs were negative for erosive changes. The patient met the 2010 ACR classification criteria for rheumatoid arthritis. She was treated initially with a prednisone taper and achieved clinical remission on oral methotrexate.

Patient 3

A 72-year-old White woman presented to BAMC rheumatology with 2 months of symmetric polyarthritis involving the MCP joints, PIP joints, and metatarsophalangeal (MTP) joints with prolonged morning stiffness. Symptom onset occurred 1 day after completing the Pfizer-BioNTech vaccination series. The patient had a history of type I diabetes mellitus, no history COVID infection, and no family history of autoimmune disease. The patient never received immunosuppression in the past, and no medication changes were made at the time of vaccination. Examination was remarkable for synovitis at the bilateral second to fourth MCP joints, second to fourth PIP joints, and first to fifth MTP joints. Laboratory evaluation was notable for elevated RF (>130 IU/mL) and ACPA (>250 U/mL). FANA test, HBV, HCV, HIV, and COVID-19 testing (PCR) were negative. Hand and foot radiographs demonstrated no erosive changes. The patient met the 2010 ACR classification criteria for rheumatoid arthritis. She was initially treated with prednisone and achieved clinical remission with leflunomide and golimumab.

Patient 4

A 66-year-old White woman presented to BAMC rheumatology with 2 months of symmetric polyarthritis involving her knees, ankles, and MTP joints in the setting of low-grade fever and chills. Symptom onset occurred 1 day after completing the Pfizer-BioNTech vaccination series. The patient had no personal or family history of autoimmune disease and no history of COVID infection. The patient never received immunosuppression in the past, and no medication changes were made at the time of vaccination. Examination was remarkable for synovitis of the bilateral knees and ankles, which improved after a 2-week course of indomethacin. Laboratory evaluation was remarkable for a leukocytosis (16,310/μL), normocytic anemia (9.9 g/dL), and thrombocytosis (548 × 10³), as well as an elevated ESR (>120 mm/h), CRP (22.7 mg/dL), and ferritin (1820 ng/mL; reference range, 15–150 ng/mL). FANA test, RF, ACPA, HBV, HCV, HIV, rapid plasma reagin test, and COVID-19 testing (PCR) were negative. Radiographic survey was negative for chondrocalcinosis, and the patient did not meet the criteria for adult-onset Still disease. A contrasted computed tomography scan of the chest, abdomen, and pelvis was negative for occult malignancy. Subsequent positron emission tomography/computed tomography was remarkable for uptake in the left second and right second and third MTP joints. The patient was diagnosed as having undifferentiated polyarthritis and continued on indomethacin for another 4 weeks before transitioning to ibuprofen as needed. At the 4-month interval, her synovitis had improved, but her inflammatory markers took 2 more months to resolve.

Patient 5

A 69-year-old White man presented to BAMC rheumatology with 2 months of bilateral arthralgias and stiffness in the shoulders, hips, wrists, and knees. Symptom onset was 1 week after completing the Pfizer-BioNTech vaccination series. The patient had a primary relative with rheumatoid arthritis, but no personal history of autoimmune disease or COVID infection. The patient never received immunosuppression in the past, and no medication changes were made at the time of vaccination. Examination was notable for tenderness in the bilateral shoulders, wrists, hips, and knees, which resolved with a 3-week course of prednisone. He had no clinical evidence of temporal arteritis. Laboratory evaluation was remarkable for an elevated ESR (79 mm/h) and CRP (5.07 mg/dL). Rheumatoid factor, ACPA, creatine kinase, and aldolase testing were normal. COVID-19 testing (PCR) was negative. Repeat ESR and CRP normalized in 3 weeks on prednisone. The patient met the 2012 ACR criteria for polymyalgia rheumatica and was treated with a slow steroid taper over a period of 13 months.

DISCUSSION

We cannot determine if these rheumatic diseases were clearly caused by or correlated with either Moderna-NIAID or Pfizer-BioNTech vaccinations but feel that the temporal association was compelling and reportable. At this point in the pandemic, new-onset autoimmune disease following COVID-19 vaccination has become a well-described phenomenon. Although the pathogenesis is incompletely understood, molecular mimicry is among the proposed mechanisms leading to the development of autoimmune disease³ and provides a relevant basis for our discussion of possible adverse events related to vaccination.

Both the Moderna-NIAID and Pfizer-BioNTech are novel mRNA vaccinations, which stimulate robust immune responses involving both cell-mediated and humoral immunity without the risk of exposing the recipient to an intact virus. Each features an mRNA transcript that encodes the SARS-CoV-2 full-length spike protein modified by 2 proline substitutions.¹⁴ Once isolated, the mRNA transcript is encapsulated into a lipid nanoparticle, which facilitates cellular uptake, and acts as an adjuvant, inducing both B-cell and T follicular helper cell immune responses.¹⁴ Once within the cell, the COVID spike protein is manufactured by host cellular machinery and then expressed on the cell surface for antigen presentation, recognition by various immune cells, and further amplification of the immune response. Interestingly, the response of the antibody to the receptor-binding domain (RBD) in both vaccines demonstrated a higher titer of antibodies than in patients recovering from an actual infection with COVID-19.¹⁴

One of the proposed mechanisms of autoimmunity developing from mRNA vaccination is molecular mimicry, in which an immune response against epitopes shared by microbial and host proteins leads to the formation of cross-reacting antibodies that damage host cells.¹⁵ In turn, the significant degree of sequence similarity between the COVID spike protein and human proteins is worth considering. Kanduc and Shoenfeld¹⁶ reported a significant peptide similarity between the COVID spike protein and human proteins with sharing of more than 25 heptapeptides and more than 300 hexapeptides, which was a surprising result based on probability calculations. Importantly, these shared peptide sequences are equal to or larger than the usual minimal antigenic determinants for T cells, which usually contain a core of 5 to 6 amino acids. As a result, this sequence homology could provide opportunities for immune responses raised against the COVID spike protein to cross-react with host tissues.

Another important consideration is the timing of development of autoimmune adverse events following mRNA vaccination against COVID-19. Research by Wheeler et al.¹⁷ demonstrated that the first dose of either vaccine induced the production of specific antibodies within 2 weeks to the RBD, S1 subunit, and S2 subunit of the COVID spike protein. The second vaccine dose caused a significant increase in tested antibodies of up to 100-fold in all participants, even in those who responded suboptimally to the first dose. In prior studies, the Pfizer-BioNTech and Moderna-NIAID vaccinations were found to have detectable levels of RBD-binding IgG by the day of the second dose, with the peaks ranging from 1 to 2 weeks after, respectively.^18,19 This described effect coinciding with the second dose of mRNA vaccine could explain disease development and chronologically agrees with our cases. Although symptom onset for previously reported cases of “ASIA” can overlap with this timeline, these syndromes were typically short-lived, which contrasts the robust and enduring inflammatory syndromes that we observed. Even in patient 4, for which clinical remission was achieved soonest, clinical synovitis was ongoing for 4 months postvaccination, and her inflammatory markers took several months to resolve.

CONCLUSION

Each of the 5 patients reported involved the development of new rheumatic disease that was temporally associated with mRNA vaccination against COVID-19. In each case, symptoms developed within 1 week after the second dose of vaccination, which is a reasonable interval for antibody formation and autoimmune-mediated damage to occur. Of the possible autoimmune mechanisms, molecular mimicry seems plausible based on the significant sequence homology between the COVID spike protein and human proteins. Although the absolute risk for development of autoimmune disease following mRNA vaccination against COVID-19 seems to be low, further research is warranted to delineate if there is a true causal relationship.