ObjectiveLittle is known regarding the reactogenicity and related SARS–CoV‐2 vaccine response in patients with chronic inflammatory disease (CID). Our objective was to characterize the adverse event profile of CID patients following SARS–CoV‐2 vaccination and understand the relationship between reactogenicity and immunogenicity of SARS–CoV‐2 vaccines.MethodsCID patients and healthy controls eligible to receive messenger RNA (mRNA) SARS–CoV‐2 vaccines participated in 3 study visits (pre‐vaccine, after dose 1, and after dose 2) in which blood and clinical data were collected. Assessment of adverse events were solicited within 7 days of receiving each dose. Serum anti–SARS–CoV‐2 spike IgG ± antibody titers were quantified following vaccination. Statistical analysis was performed utilizing mixed models and tobit regressions, with adjustment for covariates.ResultsThe present study included 441 participants (322 CID patients and 119 control subjects). Compared to controls, CID patients reported greater symptom severity after dose 1 (P = 0.0001), including more myalgia and fatigue (P < 0.05). For immunogenicity, a higher symptom severity after dose 1 and a higher number of symptoms after dose 2 was associated with higher antibody titers (P ≤ 0.05). Each increase of 1 symptom was associated with a 15.1% increase in antibody titer. Symptom association was strongest with site pain after dose 1 (105%; P = 0.03) and fatigue after dose 2 (113%; P = 0.004).ConclusionPatients with CID have a distinct reactogenicity profile following SARS–CoV‐2 vaccination compared to controls. Furthermore, there is an association between increased reactogenicity and increased vaccine response. This finding may speak to the more variable immunogenicity in CID patients and may be an important indicator of vaccine response to the novel SARS–CoV‐2 vaccines.