Sex: M
Vaccine: COVID19
Symptoms: Red blood cell sedimentation rate, Rheumatoid arthritis, Rheumatoid factor, Spinal X-ray
Clinical narrative: RHEUMATOID ARTHRITIS; This 57-year-old, male subject was participating in Study.  The subject's medical history, as provided by the investigator, included gastroesophageal reflux disease, hypothyroidism, hypertension, asthma, environmental allergies and left outer thigh pain (8-10 inches below the hip joint secondary to use of surgical boot worn in Jan 2020). The subject had no medical history of joint pain/swelling. Concomitant medications included rabeprazole, levothyroxine, enalapril, fluticasone furoate/vilanterol trifenatate, salbutamol, levocetirizine, and montelukast.  Additional information regarding the subject's medical history of hypothyroidism was provided in response to queries. Hypothyroidism was diagnosed around the early 1990's and the subject reported that a possible cause considered was exposure to iodine radioisotopes (I-125); however, a definitive cause was not identified. He did not recall whether an autoimmune work-up was pursued at that time.  The subject received their first, and only, dose of blinded study drug on 31 Aug 2020.  On 31 Aug 2020, the subject experienced rheumatoid arthritis. Later that same day, through 06 Sep 2020, the subject reported muscle and joint aches/pain (Vaccine Toxicity Scale Grades 1 to 2 in severity) in the diary. The subject also experienced tinnitus, insomnia and constipation post-vaccination.  During the time period starting around 10 Sep 2020 through the last week of Sep 2020, the subject experienced recurrent muscle joint aches/pain. The quality of the pain was different than the joint aches/pain previously reported, with the left knee and right shoulder bothering him the most. It was constant regardless of rest or activity and was not worse at any particular time of the day. The subject also experienced joint stiffness in the mornings, which improved with a shower and movement. He denied joint swelling. Additionally, he had intermittent pain at base of his neck. The subject treated his symptoms with oral paracetamol and diclofenac, which reduced his pain. Diclofenac use lasted only a few days, at the peak of pain.  On 25 Sep 2020, relevant laboratory results included complement component 3 of 194 (high), rheumatoid factor (RF) 62.5 IU/mL (0-13), cyclic citrullinated peptide (CCP) antibody >250 units (<20), complement component 4 of 32, antinuclear antibody test was negative, erythrocyte sedimentation rate 4 mm/hr, and C-reactive protein <0.1.  On 29 Sep 2020, the Rheumatology provider noted that the subject reported ongoing mild pain in the left elbow with lifting objects, in the right shoulder, and in the right knee. He reported feeling a little weak at the peak of his pain and denied shortness of breath, chest pain, rash, and fevers during his arthralgias. The subject also felt his heart rate was higher than usual; in the 80s, when it was typically in the 50s-60s. Vital signs during the visit included blood pressure 124/71 mmHg, heart rate 70 per minute, body mass index 29.78, and pain score of 6.5. The subject's review of systems was positive for weight gain, weakness, hearing loss, tinnitus, wheezing, constipation, nausea, headache, insomnia, joint pain, and muscle weakness. Physical examination findings included 5/5 strength in bilateral upper and lower extremities, mild left elbow discomfort with extreme flexion and with lifting a box of surgical gloves, tenderness to bilateral elbows at the lateral epicondyles, and no other findings of musculoskeletal tenderness, swelling, effusion, or limitations to range of motion. The Rheumatology provider's initial assessment was that the subject had reactive arthritis based on mild symptoms and tenderness over lateral epicondyles. However, after reviewing the laboratory results, the provider was concerned about the possibility of rheumatoid arthritis due to the high level of CCP antibody and RF. Diagnoses included rheumatoid arthritis and lateral epicondylitis, and no new medications or treatment was prescribed. The provider noted that he was suspicious of a positive causal relationship to study drug due to the subject's lack of symptoms prior to study drug administration. The plan was to follow-up with rheumatology in two weeks for re-evaluation.   On 20 Oct 2020, the subject had a follow-up visit with Rheumatology, where he reported recurrence of pain in both elbows and arms starting about six days prior and also had right knee pain. The pain was worse on the left side and with activities, such as lifting weights. The back of his hand hurt with fist clenching and he had forearm pain with lifting his laptop. The subject noted that the base of his neck was painful at times and he felt this caused his right arm to feel weak, but he denied numbness, tingling, or burning pain in the right arm. The right hip was still bothering him, though not as bad as before. He had noticed twitching in the left index finger when at rest in the past week and denied joint stiffness or swelling. The subject had taken paracetamol for a couple of days preceding the follow-up visit and noted that his pain was much improved. Vital signs included blood pressure 119/77 mmHg, pulse 70 beats per minute, body mass index 30.55 and pain scale 2/10. Review of systems was positive for weight gain, joint pain, joint swelling, muscle cramping, myalgia, neck pain and neck stiffness. Physical exam findings included right lateral neck tenderness with cervical spine range of motion and on palpation, assessed as possibly muscular. Hand grip caused lateral and medial elbow pain bilaterally and the subject felt nauseated and had to lay down. He had lateral and medial epicondyle tenderness of both elbows. Laboratory results included c-reactive protein 0.88 (1-3) and sedimentation rate 13 (0-20). Joint exam did not reveal active inflammatory arthritis, though he still had arthralgias to varying degrees by history. The rheumatologist noted that early rheumatoid arthritis can manifest in a palindromic pattern, consistent with subject's presentation. The subject began treatment with oral meloxicam and was instructed to use elbow straps during activities. A cervical spine x-ray was ordered, and he was instructed to follow-up in four weeks.  On 20 Nov 2020, magnetic resonance imaging (MRI) of the right elbow revealed mild distal triceps tendinosis and no findings to suggest rheumatoid arthritis. MRI of the left elbow revealed medial and lateral epicondylitis, low grade insertional tearing of the common extensor tendon, and distal long head biceps tendinosis without evidence of tear. A cervical spine x-ray with flexion/extension views revealed overall mild multilevel, multifactorial degenerative changes, normal alignment, and no listhesis with flexion or extension.  On 04 Dec 2020, the subject had a follow-up visit with Rheumatology, where he reported ongoing elbow pain that was exacerbated with movement and interfered with his sleep.  Use of forearm straps, meloxicam, and ice helped to relieve his elbow pain during the day but woke up with elbow pain at night despite use of elbow straps at night. He felt that meloxicam was helping with all of his other pains, but he also reported that he was taking. Vital signs included blood pressure 127/75 mmHg, pulse 59 beats per minute, BMI 30.4, and pain scale 7/10. During the review of systems, the subject reported weight gain, dyspnea, constipation, bowel changes, polydipsia, headache, sleep disturbances, joint pain, joint tenderness, morning stiffness, neck pain and neck stiffness. During the physical exam, hand grip caused lateral and medial elbow pain bilaterally, which led to the subject to feeling nauseated, without dizziness, and he had to lay down. Physical exam revealed right shoulder joint tenderness; right elbow moderate medial epicondyle tenderness; and left elbow severe medial and moderate lateral epicondyle tenderness. No other joint swelling, tenderness, effusion, or decreased range of motion was noted.  The subject's Clinical Disease Activity Index (CDAI) score was 8 out of 76. Laboratory results included CCP 103.0 (0.0-6.9), RF Immunoglobulin A 118 (0-35), RF Immunoglobulin G 42 (0-20), RF Immunoglobulin M 64 (0-25), CRP 1.74 (1-3) and sedimentation rate 12 (0-20). Meloxicam was discontinued due to incomplete pain relief and treatment with oral celecoxib 200 mg twice daily was prescribed.  On 17 Dec 2020, the subject had a follow-up visit with Rheumatology, where he reported he felt better in general after taking celecoxib, however, the past few days he had recurrent left elbow and mild right elbow pain. He reported that the left elbow pain was both laterally and medially and hurt when he used his arm, straightening his elbow, it hurt overnight when he was still for a while and when he moved it to turn over or pull covers. He was having significant morning stiffness, though it improved when he moved around. His neck felt much better with celecoxib and his right ankle felt like it was "giving out" on him intermittently. He reported that he does not lift much and that his profession was in information technology. Pain assessment was 6/10. There was no change from the prior visit to the subject's review of systems or physical. Triamcinolone acetonide 40 mg injection was given in left elbow medial and lateral epicondyles. Additional treatment of oral hydroxychloroquine 200 mg twice daily was started.  On 1-Apr-2021 the subject received the second dose of mRNA-1273  and 28 OCT 2021 the subject received the booster dose.  On 30 Jul 2022, the subject was started on oral tramadol.  Study drug was withdrawn in response to the event.   The event, rheumatoid arthritis, was reported as resolved with sequelae, on 11 Oct 2022. The sequela was specified as "new baseline".  The investigator assessed the event, rheumatoid arthritis, as related to study drug and not related to study procedure.    Follow-up information received on 14 Oct 2020, 15 Oct 2020, 16 Oct 2020 included updated medical history, concomitant and treatment medications, and onset of the event. A consultation note was also received which included assessment, vitals, and laboratory results.   Follow-up received on 28 Oct 2020 included no new information.   Follow-up received on 09 Nov 2020 included information regarding outcome and treatment medications.   Follow-up received on 18 Nov 2020 included updated medical history and treatment medications. Rheumatology visit notes were also received which included laboratory results, assessment and treatment.   Follow-up received on 30 Nov 2020 included updated medical history details and event outcome.   Follow-up received on 29 Dec 2020 included rheumatology consult notes which included assessment, vitals and laboratory results.  Follow-up received on 12 Oct 2022 included updated event end date and outcome, treatment,  concomitant medication details and administration of second and booster dose.   Company comment: This case concerns a 57-year-old, male subject with medical history of left outer thigh pain, hypertension, hypothyroidism, asthma, and environmental allergies, who experienced an unexpected event of rheumatoid arthritis. The event occurred the day of the first, and only, study vaccine administration. The study vaccine was withdrawn at the time of the event. The event, rheumatoid arthritis, was reported as resolved with sequelae, which was specified as "new baseline". The event was considered related to the study vaccine in agreement with the Investigator's assessment based on close temporal association and immune-mediated etiopathogenesis of the event. The subject received the second dose of mRNA-1273 7 months after the event, and the booster dose almost 1 year 2 months after the event.   Analysis of Similar Events: On 23-Oct-2020, the safety database was searched for events similar to rheumatoid arthritis and immune-mediated/autoimmune disorders using the following search criteria: PT: Rheumatoid arthritis, HLGT: Immune disorders NEC, HLGT: Autoimmune disorders, HLGT: Connective tissue disorders (excl congenital) and SMQ: Arthritis.  As of 23-Oct-2020 under study, safety report of similar adverse events had been previously submitted. The case reporting the following event was submitted as IND Safety Report: possible polymyalgia rheumatica: MOD-2020-000211.  There were five events that were non-IND Safety Reports (unexpected and unrelated to the IMP) reporting the following events: worsening right knee pain MOD-2020-000443, left hip osteoarthritis MOD-2020-000509, left total shoulder arthroplasty related to osteoarthritis MOD-2020-000412, gout exacerbation in right knee MOD-2020-000288 and left hip arthroplasty MOD-2020-000337.   Based on review of available data, the Sponsor cannot rule out a possible cause and effect relationship between administration of mRNA-1273 / blinded IMP and the occurrence of rheumatoid arthritis. All previously reported non-IND cases involved patients with preexisting arthritic conditions.  The causal association for the index case is confounded by prior medical history of left outer thigh pain, and hypertension and hypothyroidism which may suggest pre-existing autoimmune disorder.  After review of the clinical details and investigator comments pertaining to this adverse event, and based upon experience to date, the Sponsor does not believe that changes to the conduct of this clinical trial are warranted. The Company will continue to monitor these and other serious adverse events reported in association with the IMP and will communicate any relevant changes to the protocol, Informed Consent Form, Investigator's Brochure, and/or Core Safety Information.