Sex: M
Vaccine: COVID19
Symptoms: Anti-cyclic citrullinated peptide antibody, Antinuclear antibody, Blood pressure measurement, Body temperature, Connective tissue disorder
Clinical narrative: This 35-year-old, male, was participating in A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older (mRNA-1273-P301) and experienced medically important event and adverse event of special interest of connective tissue disorder.  The subject's medical history, as provided by the investigator and in medical records, included rosacea, seborrhea, back pain, hyperlipidemia, hypercholesterolemia, family history of psoriatic arthritis (maternal uncle), occasional alcohol use, kidney stones, lithotripsy (extracorporeal shock wave lithotripsy), wisdom teeth removal, family history of asthma (father), family history of heart disease (father), and family history of hypertension (father). Concomitant medications included tamsulosin, ivermectin, phenylephrine hydrochloride, diphenhydramine, brimonidine tartrate, influenza vaccine, hydrocodone bitartrate/paracetamol, ciclopirox, ketoconazole, rosuvastatin, and vitamin D.    The subject previously experienced the serious adverse event of kidney stone (MOD-2021-280546) while participating in this study.   The subject was randomized to receive intramuscular Placebo (dosed on 03 Sep 2020 and 30 Sep 2020) and was unblinded on 08 Jan 2021. The subject consented to receive mRNA-1273 for SARS-CoV-2 vaccination after being unblinded and, prior to event onset, the subject received mRNA-1273 (Dose 2) on 03 Feb 2021, approximately 8 months and 10 days before onset of the event. The subject received mRNA-1273 (Booster, Dose 3) SARS-CoV-2 vaccination on 08 Nov 2021  On 12 Oct 2021, the subject experienced the medically important event of connective tissue disorder. During a site call, the subject noted stiffness in his left hand joints which he had been experiencing for the previous month, starting 'around' 12 Oct 2021.   On 08 Nov 2021, the subject received his mRNA-1273, dose 3 (booster). He reported that stiffness in his left hand joints was a little worse since his booster dose. He had planned to follow up with his primary care physician.   On 29 Nov 2021, the subject reported that his primary care physician (PCP) did labwork and found his rheumatoid factors were elevated. Per the subject, PCP suspected rheumatoid arthritis.  On 03 Dec 2021, the subject visited a rheumatologist with the chief complaint of joint pains (dull pain in both hands); he had been referred for evaluation after he was noted to have a positive antinuclear antibody test. The subject stated that he had been in his usual state of good health until Oct 2021 when he began to experience painful stiffness about the hands; this was about 6 weeks after he received the 'majority' vaccine and he wondered whether there may be a reaction. He went to his primary care provider to obtain blood work and was noted to have a positive antinuclear antibody (ANA) at a titer 1-640. Other serologies, including rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP), were negative. Anti-extractable nuclear antigens (anti-ENA) studies were also obtained and were all negative with the exception of a positive anti-scleroderma (anti-SCL 70). Anti-deoxyribonucleic acid (DNA) was negative. Complement levels were not checked. The subject described painful stiffness about the knuckles and proximal interphalangeal (PIP) joints that occurred when he first woke up in the morning. The stiffness tended to last. He had tried taking naproxen sodium along with topical diclofenac which had not helped much. Rheumatologic review of systems was notable for some mild fatigue and occasional night sweats. He also had a malar rash which he attributed to rosacea. His weight was up about 10 pounds over the past 6 months. He denied fevers, chills, eye inflammation, sinus symptoms, epistaxis, mouth sores, dysphagia, reflux, chest pains, shortness of breath, gastrointestinal symptoms, melena or hematochezia, dysuria, other skin rash, Reynaud's, or photosensitivity. His family history was notable in that a maternal uncle had psoriatic arthritis. His initial blood work was otherwise notable for a normal complete blood count (CBC) and comprehensive metabolic panel (CMP). Vital signs included temperature 98.4 degrees Fahrenheit and blood pressure 122/84 millimeters of mercury. Physical examination revealed restricted range of motion (ROM) in the hands and tender across both sets of metacarpophalangeal joints (MCPs) in the second, third, and fourth PIP joints of both hands; normal ROM was observed in the wrists, elbows, shoulder, hips, knees, ankles, and feet. No inflammation of the synovial membrane was present in the upper or lower extremities. Inspection revealed skin abnormalities including malar erythema crossing the bridge of the nose; the nasolabial folds were spared. The subject was diagnosed with connective tissue disease. Assessment: young man presenting with arthralgias of the small joints in a symmetric pattern along with a positive antinuclear antibody test at a titer at 1-640 and positive anti-SCL 70. Physical examination was notable for malar erythema and joint tenderness in the hands. An underlying autoimmune process, such as systemic lupus, was suspected though it did not quite meet definite criteria and would be reevaluated next visit. Plan: trial of hydroxychloroquine in addition to meloxicam daily. The subject was to follow up in 6 weeks, and additional laboratory studies would be obtained at that time.  Treatment for the event included oral meloxicam, oral hydroxychloroquine, and oral prednisone.  The subject received all scheduled doses of study drug prior to the event; therefore, action taken with study drug in response to the event was not applicable.  The event, connective tissue disorder, was reported as resolved with sequelae on 20 Sep 2022. The subject was on stable condition at his final visit on 20 Sep 2022 and was able to discontinue two topical medications.   The investigator assessed the event, connective tissue disorder, as related to study drug and not related to study procedure.  The subject completed the study on 20 Sep 2022.  Follow-up received on 14 Dec 2021 and 16 Dec 2021 included medical records with laboratory/diagnostic test results, medical history, and event details.   Follow-up received on 22 Dec 2021 included no new information.  Follow-up received on 11 Jan 2022 included no new information.  Follow-up received on 20 Sep 2022 included updated event outcome, end date, treatment medication, concomitant medication and subject completion.  Company Comment: This case concerns a 35-year-old, male subject with a medical history of rosacea, seborrhea, back pain, hyperlipidemia, hypercholesterolemia, family history of psoriatic arthritis (maternal uncle), occasional alcohol use, kidney stones, lithotripsy (extracorporeal shock wave lithotripsy), wisdom teeth removal, family history of asthma (father), family history of heart disease (father), and family history of hypertension (father).  who experienced medically important event and adverse event of special interest of connective tissue disorder. The event occurred 8 months and 10 days after second dose of mRNA-1273.  The subject experienced joint stiffness with elevated rheumatoid factor and was diagnosed with connective tissue disorder by a rheumatologist.  The subject received the third dose of mRNA-1273 approximately 26 days after start of symptoms. The subject started treatment and the event was reported as resolved with sequelae. The event was assessed as related to mRNA-1273 in agreement with the Investigator's assessment.  Analysis of similar events: On 14-Dec-2021, the safety database was searched for events similar to Connective Tissue Disorder using the following search criteria:   As of 14-Dec-2021 under IND 019745 for mRNA-1273, 1 case of Connective Tissue Disorder was retrieved which is the current index case. No other cases were retrieved.   The index case concerns a 35-year-old,male subject with a medical history of rosacea, seborrhea, back pain and hyperlipidemia who experienced the medically important event and adverse event of special interest of connective tissue disorder. The subject experienced stiffness in his left hand joints starting 8 months and 8 days after the second dose of mRNA-1273. The subject received the third dose of mRNA-1273 approximately 26 days after the start of symptoms. He was seen by a PCP and by a rheumatologist, he was found to have elevated rheumatoid factor and was diagnosed with connective tissue disorder by the rheumatologist.  The subject started treatment with meloxicam and hydroxychloroquine, and the event was reported as resolving. The Investigator assessed the event as related to mRNA-1273.   Based on review of available data, the Sponsor cannot rule out a possible cause and effect relationship between administration of mRNA-1273 and the occurrence of connective tissue 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.  Follow-up received on 25 Feb 2022 included no new information.