key: cord-0972603-6hfmw2i3
authors: Wack, Sarah; Patton, Timothy; Ferris, Laura K.
title: COVID-19 vaccine safety and efficacy in patients with Immune-Mediated Inflammatory Disease: Review of available evidence
date: 2021-08-04
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2021.07.054
sha: 09935949128c25a8dfa041a8c5cc95287d4006f4
doc_id: 972603
cord_uid: 6hfmw2i3

Dermatologists diagnose and treat many immune-mediated inflammatory diseases (IMID). Understanding the inherent immune dysregulation of these diseases as well as the additional disruption that comes as a result of IMID treatments has been important during the COVID-19 pandemic. With vaccines becoming widely available, dermatologists need to be familiar with the risks and benefits of vaccination in these patients, particularly those taking biologics, in order to have informed discussions with their patients. In this review, we present the current evidence related to COVID-19 vaccine safety and efficacy in patients with IMID and review existing recommendations for vaccination against SARS-CoV-2. Given the current evidence, there is minimal concern that these patients are at any greater risk of harm from COVID-19 vaccination compared to healthy controls. For most, the benefit of avoiding severe COVID-19 through vaccination will outweigh the theoretical risk of these vaccines. An outstanding question is whether patients on biologics will generate a sufficient immune response to the vaccine, which may be dependent on the specific biologic therapy and indication being treated. This underscores the importance of following patients with IMID after vaccination to determine vaccine safety, efficacy, and duration in this population.

Biologics have revolutionized therapy for immune-mediated inflammatory diseases (IMIDs), 62 including many dermatologic diseases. While these drugs generally have a more favorable side 63 effect profile than conventional immunosuppressive medications, depending on their 64 mechanism these therapies cause some degree of immune disruption. The implications of this 65 have been important in helping patients navigate their treatment options during the COVID-19 66

pandemic. 67 68

There are two main concerns regarding vaccination against COVID-19 in patients with IMID: the 69 potential that biologics will reduce efficacy of the immune response and concern that 70 vaccination may cause a flare of the underlying inflammatory disease. In addition to presenting antigen as the target of the immune response, vaccines must also 120 contain an adjuvant that activates the innate immune system and provides the necessary 121

second signal for T cell activation and generation of a robust immune response. For mRNA 122 vaccines, the mRNA both encodes the antigen and acts as an adjuvant. Upon entry into a cell, 123 single stranded RNA (ssRNA) activate endosomal toll-like receptors (TLR) including TLR3 and 124 TLR7. 11 Both ssRNA and double stranded RNA (dsRNA) activate the inflammasome in the 125 cytosol. These trigger an inflammatory response and the generation of type I interferons, which 126 are known to flare autoimmune disease. However, vaccine developers have implemented 127 modifications to reduce interferon activation and reduce this risk, including the addition of 128 stabilizing adjuvants and removal of interferon-stimulating double-stranded mRNA from final 129

preparations. 12,13 130 131

Adenoviral vector vaccines also function as adjuvants. The double stranded DNA (dsDNA) inside 132 the viral vector both encodes the spike protein antigen and induces the production of type I 133 interferons via activation through TLR9. 11 In addition to the concerns about potentially flaring 134 inflammatory disease via the production of type I interferons, some inflammatory diseases are 135 associated with an increased risk of thrombosis. Adenoviral vaccines carry a rare but increased 136 risk of thrombosis with thrombocytopenia, potentially due to the production of autoantibodies 137 to platelet factor 4 (anti-PF-4). 14 Thrombosis has occurred 1-2 weeks after vaccination, mostly 138 in women, and primarily in the cerebral venous sinus. The question of vaccine efficacy in patients with IMID has also been addressed by a number of 156 smaller case series (Table 2 ). In a study by Geisen et al comparing vaccine response and side 157 effects in 42 healthy controls and 26 patients with chronic inflammatory disease (of whom 20 158

were taking a biologic drug), antibody titers and neutralization activity were detectable in all 159 patients and controls, though lower in those with inflammatory disease. 17 160 161

By contrast, another study measured responses to BNT162b2 in a larger population (n= 84  162 patients with IMID, 182 controls) over time and found that patients with IMIDs develop 163 antibody responses more slowly than controls, and a greater proportion of the IMID group did 164 not respond at all to the vaccine compared to the control group. These differences were found 165 even when comparing patients with IMID who were not receiving any kind of biologic or 166 DMARD treatment, suggesting that the difference in response may be related to the underlying 167 disease process, rather than the form of treatment. 18 168 169

Association with disease flares or other adverse effects 170

An observational cohort of 325 patients with rheumatic and musculoskeletal disease who 171 received either BNT162b2 or mRNA-1273 were recruited using social media and asked to 172 complete a questionnaire about local and systemic side effects they experienced during the 173 first week following their first vaccine dose. Side effects were similar in severity and frequency 174 to healthy patients in the vaccine trials, with 69% reporting at least one systemic side effect 175 (most commonly fatigue). One patient reported confirmed COVID infection, one reported 176 peripheral neuropathy, and none reported allergic reactions requiring epinepherine. 19 Notably, 177 most participants were female (96%) and white (89%). Data were collected only after the first 178 dose, and since more severe side effects tend to occur after a second dose, the generalizability 179 of these findings is potentially limited. There is also potential for participation bias as those with 180 side effects may have been more likely to participate in the survey than those without side 181 effects. 182 183

In the above study by Geisen et al., investigators also measured arthritis activity prior to 184 vaccination and after each vaccine dose; it was not found to be increased in these patients. 185

Systemic side effects also tended to be milder among those patients treated for inflammatory 186 disease than in healthy controls. 17 Results from initial case series and larger studies suggest that TNFi have a less substantial 217 impact on immune response than BCDT, but patients on these therapies may mount less robust 218 immune responses than those in seen healthy controls. 27, 28 In contrast, patients receiving TNFi 219 in the larger cohort from COVaRiPAD were found to have similar antibody titers, but a 220 reduction in neutralization activity, as compared to healthy controls. 16 Based on the available data, the chief concern for patients with IMID appears to be the efficacy 256 of the immune response these patients will be able to generate, depending on the specific 257 biologic therapy and indication being treated. It is important to note that several early studies 258 are small, some lack a healthy control group, and some report antibody titers captured prior to 259 the time point at which maximum immunity would be expected (i.e. prior to two weeks after 260 the final vaccine dose). Also, vaccine induced immunity likely has both a cell-mediated and a 261 humoral response and the studies presented measure only humoral responses which may not 262 correlate directly with protection from infection. Given findings that antibody titers may be 263 slower to reach their peak value in patients with IMID, it is important to remind these patients 264 that they should take seriously the guidance to wait at least 2 weeks after their final vaccine 265 dose to consider themselves fully vaccinated. Current data are not sufficient to offer guidance 266 on masking. 267 268

Although the currently available evidence provides perspective in guiding IMID patients through 269 initial vaccination efforts, it also leaves many unanswered questions. J o u r n a l P r e -p r o o f -3-fold reduction in antibody titers and 2.7-fold decrease in neutralization in patients with IMID vs. immunocompetent controls 1-2 weeks after first dose -Seropositivity rates: 98% in immunocompetent controls; 92% in IMID participants not on prednisone; 65% in IMID participants on prednisone Reduction in antibody and neutralization titers by therapy: -Glucocorticoids: 10-fold reduction; Antimetabolites: 2-3x reduction; BCDT: 36x reduction; -IL-12/23 inhibitors, vedolizumab, TNFi, antimalarials: minimal impact on titers 16 Geisen et al. -Serology 10 or more days after first vaccine dose; 96% had both doses, none with previous COVID infection or baseline antibodies -Patients with IMID, including those without any current treatment, had delayed and reduced immune response relative to healthy controls (lower mean titers at day 28, but equivalent by day 70) -0.5% of the controls failed to develop neutralizing antibody activity (vs. 9.5% of patients with IMID) -lower incidence of side effects in patients than in controls 18 Boyarsk y et al.  Stated that registry data should be collected to inform whether SARS-Cov-2 vaccines either positively or negatively affect psoriasis outcome. 37 International Pemphigus and Pemphigoid Foundation  Patients with autoimmune bullous diseases should be vaccinated when a vaccine is available to them, as these patients are also at high risk for complications of COVID-19.  In most cases, immunosuppressive treatment should not be interrupted to receive a vaccine as this could result in relapse or flare of disease.  In patients treated with rituximab, vaccination should be completed 2 weeks prior to the start of rituximab treatment whenever possible, otherwise it is best to wait 4-6 months after the last rituximab infusion. 38 National Eczema Association  Atopic dermatitis is not a contraindication to vaccination.

 Any patients with history of anaphylaxis or reaction to a vaccine ingredient should consult with their allergist prior to vaccination. 39 Hidradenitis Suppurativa Foundation  People with HS are not at increased risk for severe COVID-19 due to HS or any subsequent treatment and should be able to safely receive the vaccine when it is available to them.  Patients should not stop any biologics in order to receive a vaccine and should speak to their physician regarding any concerns. 40 American College of Rheumatology  Patients with autoimmune and inflammatory rheumatologic disease should be prioritized for vaccination.  For patients with rheumatologic conditions, the theoretical risk of disease flares due to COVID-19 vaccination is outweighed by the definite risk of severe COVID-19 infection.  For those with well-controlled disease: recommend to hold methotrexate and JAK inhibitors for one week after each vaccine dose, to hold subcutaneous abatacept one week prior to and after the first COVID-19 vaccine dose only, and that patients taking cyclophosphamide should time their infusion to be 1 week after each vaccine dose if possible.  In patients treated with rituximab: vaccine series should be initiated four weeks prior to the next scheduled cycle, and the next dose be delayed for 2-4 weeks after the second vaccine dose, if the patient's disease activity allows.  No recommendation for dose or timing modifications for patients taking oral steroids, hydroxychloroquine, IVIG, apremilast, sulfasalazine, leflunamide, oral cyclophosphamide, azathioprine, TNFi, IL-17 inhibitors, IL-12/23 or IL-23 inhibitors, belimumab, or oral calcineurin inhibitors. 41,42 304 J o u r n a l P r e -p r o o f

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 Patients with Immune-Mediated Inflammatory Disease (IMID) may experience disease flares or have diminished immune responses after COVID-19 vaccination, particularly those receiving B cell-depleting therapies

 More research is necessary to determine how biologic therapies impact vaccine responses in patients with IMID and to develop strategies to optimize responses in this population