UPDATED April 11, 2022
By Jiha Lee, MD, MHS, and Dinesh Khanna, MD, MSc, Department of Internal Medicine, Division of Rheumatology, University of Michigan
Patients with systemic sclerosis (scleroderma) are potentially at higher risk of poor outcomes related to COVID-19 because of an altered immune system, the presence of cardio-pulmonary involvement such as lung fibrosis and pulmonary arterial hypertension, and the use of immunosuppressive drugs. Therefore, vaccination is critical to reduce transmission and severity of COVID-19 infection in the vulnerable scleroderma population. In the US, three vaccines are currently available; two mRNA vaccines made by Pfizer (Cominarty®) and Moderna (Spikevax) both of which are FDA approved, and one viral-vector vaccine made by Janssen (J&J) with Emergency Use Authorization (EUA). None of these vaccines contain the live virus. Approval of a drug by the FDA means that the agency has determined, based on substantial evidence, that the drug is effective for its intended use, and that the benefits of the drug outweigh its risks when used according to the product’s approved labeling.1 In contrast, the FDA can issue EUA during a public health emergency, such as the COVID-19 pandemic, to allow the use of unapproved medical products to diagnose, treat or prevent serious or life-threatening diseases. Prior to issuing EUA, safety and efficacy must be demonstrated, certain FDA criteria must be met; and there also must be evidence that strongly suggests that patients have benefited from a treatment or test, and there are no adequate, approved or available alternatives.2
Scleroderma patients on moderate-to-high doses of steroids (defined as >15 mg of prednisone daily) and/or immunosuppressive medication such as Cellcept (mycophenolate mofetil), methotrexate, or Actemra (tocilizumab) are considered immunocompromised. Plaquenil (hydroxychloroquine) monotherapy is not considered an immunosuppressive therapy. COVID-19 vaccination in immunocompromised patients pose unique challenges as they may not mount adequate immune response after initial vaccination and vaccine effectiveness wanes over time. Studies have shown additional primary dose(s) and booster dose improve protective immune response against COVID-19, and the highly transmissible Omicron variant, leading to fewer emergency room visits, hospitalizations, and death. In addition to efficacy, safety is an important consideration, and some scleroderma patients may be hesitant to receive COVID-19 vaccination. In a recent study focusing on scleroderma patients, localized arm pain, muscle ache, and fatigue were most commonly reported after vaccination, and the proportion experiencing these adverse reactions were similar to the general population.3
In March 2022, the CDC updated vaccination guidelines for immunocompromised patients as shown in the Figure and up to date information can be found on the CDC website.4 Immunocompromised patients who initiated vaccination with either Pfizer or Moderna should receive 3 doses of either mRNA vaccine to complete their primary series. Those who received the J&J vaccine as their first shot, should get a second dose of vaccine with either Pfizer or Moderna at least 28 days after the first J&J dose, to complete the primary vaccination series. For better vaccine efficacy, the American College of Rheumatology (ACR) recommends immunocompromised patients complete primary vaccination series with either Pfizer or Moderna, over the J&J vaccine.5
All immunocompromised patients should receive at least one booster with either Pfizer or Moderna, 3 months after the last dose of their primary series. This means that for immunocompromised scleroderma patients, the first booster will count as their fourth dose if the primary series was completed with either Pfizer or Moderna, and as their third dose if the primary series was started with J&J. In addition, according to the most recently updated CDC guidelines4, immunocompromised adults 18 years of age and older, may choose to receive a second booster of an mRNA vaccine (Pfizer or Moderna) at least 4 months after their first booster.
Additional CDC updates recommend patients on B-cell depleting therapy such as Rituximab who received doses of COVID-19 vaccine prior to or during treatment to be revaccinated. Furthermore, on a case-by-case basis, mRNA COVID-19 vaccines may be administered outside of the FDA and CDC dosing intervals when the benefits of vaccination are deemed to outweigh the potential and unknown risks. Immunocompromised scleroderma patients should discuss with their rheumatologists need for further vaccination and timing of certain immunosuppressive medications, as recommended by the ACR, to improve vaccine effectiveness.
Vaccination is critical to prevent progression to severe COVID-19 infection in the immunocompromised population, however, patients with a history of severe allergy to vaccination or ongoing severe infection should not receive vaccination. For unvaccinated scleroderma patients or those who have not had an appropriate antibody response after vaccination Evusheld may be of benefit. Evusheld (tixagevimab co-packaged with cilgavimab) is a long-acting monoclonal antibody therapy, administered as two intramuscular injections, available under EUA for the prevention of COVID-19 infection in immunocompromised patients. The use of Evusheld does not replace need for vaccination against COVID-19, and Evusheld should be deferred for at least two weeks after vaccination. The comparative effectiveness of additional booster doses versus Evusheld is yet unknown and Dr. Dinesh Khanna at the University of Michigan is co-leading a multi-center NIH clinical trial to address this scientific question. More details are available at https://www.autoimmunecovidbooster.org.
Scleroderma patients who develop mild to moderate COVID-19 that does not require hospitalization or oxygen therapy should contact his/her rheumatologist or primary care provider within 5 days of symptom onset to discuss treatment options. Two antivirals and one monoclonal antibody are available as primary therapeutic agents in the outpatient setting, as summarized in the Table. The antiviral Paxlovid and the monoclonal antibody Sotrovimab are equally efficacious (88% vs 85% risk reduction of hospitalization or death due to COVID-19). Paxlovid is the preferred therapeutic agent and effective against Omicron which is the current dominant variant in the US. However, Paxlovid is contraindicated in patients with severe kidney or liver disease and is a protease inhibitor with a lot of drug-drug interactions. Scleroderma patients who take certain medications, including over the counter and herbal supplements, should discuss with their physicians whether Paxlovid can be safely administered with holding of medications or an alternative COVID-19 therapy such as Sotrovimab would be more appropriate. REGEN-COV (casirivimab/Imdevimab) is another monoclonal antibody authorized for treatment, however, distribution in the US has been paused due to lack of clinical benefit for patients with Omicron infection. Under revised CDC guidelines, there are no recommendations to defer COVID-19 vaccination after monoclonal antibody treatment.
In summary, patients with scleroderma should receive COVID-19 vaccination, including booster dose, preferably with either Pfizer or Moderna, to reduce the risk of developing severe infection that requires a visit to the emergency department and/or hospitalization. Unvaccinated patients and immunocompromised patients with inadequate vaccine response may be able to prevent COVID-19 infection with Evusheld therapy. Following vaccination and/or Evusheld, patients with scleroderma should continue to follow all public health guidelines regarding physical distancing and other preventive measures including masks and good hand hygiene. Should scleroderma patients develop symptomatic COVID, they should contact their physician within 5 days of symptom onset to discuss treatment options. For current guidelines, and data on management and effectiveness of COVID-19 vaccination published on a weekly basis, patients should consider monitoring the CDC website at https://www.cdc.gov/coronavirus/2019-ncov/vaccines.
Figure: Revised CDC recommendations on COVID-19 vaccination for moderately or severely immunocompromised patients4
*See Guidance for COVID-19 vaccination for people who are moderately or severely immunocompromised for schedule for people who are moderately or severely immunocompromised.
†An 8-week interval may be optimal for some people ages 12 years and older, especially for males ages 12–39 years. A shorter interval (3 weeks for Pfizer-BioNTech; 4 weeks for Moderna) between the first and second doses remains the recommended interval for people who are moderately or severely immunocompromised; adults ages 65 years and older; and in situations in which there is increased concern about COVID-19 community levels or an individual’s higher risk for severe disease.
‡ A booster dose is not currently authorized for people ages 5–11 years. For people ages 12–17 years, only Pfizer-BioNTech can be used. An mRNA COVID-19 vaccine is preferred over the Janssen COVID-19 Vaccine for booster vaccination of people ages 18 years and older.
§ People ages 18–49 years who received Janssen COVID-19 Vaccine as both their primary series dose and booster dose may receive an mRNA COVID-19 booster dose at least 4 months after the Janssen booster dose. People ages 50 years and older may choose to receive a second booster dose if it has been at least 4 months after the first booster dose.
**Patients on immunosuppressive therapy are considered immunocompromised, except those on Plaquenil (hydroxychloroquine) monotherapy.
Table: Approved outpatient COVID-19 antivirals and monoclonal antibody treatment options6
References
- U.S Food and Drug Administration (FDA) Drugs Development & Approval Process, https://www.fda.gov/drugs/development-approval-process-drugs
- U.S Food and Drug Administration (FDA) Emergency Use Authorization, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization
- Gordon, et al. Systemic Sclerosis and COVID-19 vaccines: a SPIN Cohort study. The Lancet Rheumatology, Volume 4, Issue 4, e243 – e246
- Centers for Disease Control and Prevention (CDC) COVID-19 Vaccines for Moderately or Severely Immunocompromised People, https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html
- American College of Rheumatology (ACR) COVID-19 Vaccine Clinical Guidance Summary for Patients with Rheumatic and Musculoskeletal Diseases, Version 5 (Revised February 2, 2022), https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-Rheumatic-Diseases-Summary.pdf
- FDA Evusheld Factsheet; https://www.fda.gov/media/154702/download
- Adapted from the National Institute of Health (NIH) COVID-19 Treatment Guidelines, https://www.covid19treatmentguidelines.nih.gov/therapies/
Original Publication Date: March 1, 2022
Revised April 11, 2022