ACR CONVERGENCE 2021—The ACR Convergence 2021 Late-Breaking Abstracts session highlighted recently published data from abstracts of interest to the general ACR audience. This year, six of our colleagues were selected to share their research.
Breakthrough COVID-19 Infections Post-Vaccination
Jasvinder A. Singh, MD, MPH, professor of medicine and epidemiology, director of rheumatology research, Birmingham Veteran’s Affairs Medical Center, Alabama, shared data on breakthrough COVID-19 infections post-vaccination among immunocompromised patients with autoimmune or inflammatory rheumatic diseases (AIIRDs).1 COVID-19 vaccines are highly effective in the general population, but we know they may be less effective in elderly or immunocompromised patients, especially those taking glucocorticoids or B cell-depleting therapies.2 The risk with other medications and rheumatic diseases is not yet known.
Singh et al. completed a retrospective cohort analysis from the National COVID Cohort Collaborative (N3C), a high-granularity electronic medical record data repository of COVID-19 cases and controls from largely academic U.S. medical centers. Breakthrough COVID-19 infection was defined by incident diagnosis 14 or more days after vaccination. Kaplan-Meier cumulative incidence curves were used to demonstrate the time to breakthrough infection.
Results showed a higher cumulative incidence of breakthrough infection in patients with AIIRD. In particular, the risk for breakthrough infection was higher for patients with inflammatory myositis, rheumatoid arthritis, gout, vasculitis and patients with multiple rheumatic diseases. Risk was also increased for patients taking biologics and more than one AIIRD medication. Timing of medication exposure was also important, with medication use within the past 30 days resulting in a higher risk of breakthrough infection.
Although the study had limitations, Dr. Singh concluded, “Our data indirectly support the use of the third dose of the COVID-19 vaccine for immunocompromised patients with AIIRDs.”
Heterologous vs. Homologous Boosters
Michael Bonelli, MD, associate professor, Division of Rheumatology, Medical University of Vienna, Austria, shared data on homologous vs. heterologous booster vaccination in patients treated with rituximab. Homologous vaccination describes the use of the same vaccine type as a booster (e.g., mRNA vaccine followed by an mRNA booster – either Pfizer-BioNTech or Moderna), whereas heterologous vaccination refers to using a different type of vaccine (e.g., mRNA vaccine followed by AstraZeneca’s vector vaccine) as a booster.
Recent data have shown that patients treated with rituximab have worse COVID-19 clinical outcomes, such as higher rates of hospitalization and mortality.3 Further studies have confirmed a reduced humoral and cellular immune response after COVID-19 vaccination in patients treated with rituximab, with 29% developing neither response.4
Bonelli et al. specifically examined patients treated with rituximab who failed to seroconvert after initial COVID-19 vaccination, randomizing them to receive homologous or heterologous booster vaccines.5
“Ninety-four percent of patients who originally did not seroconvert did develop either humoral or cellular response after the booster shot, which is good news,” said Dr. Bonelli. There was no statistically significant difference between the use of homologous or heterologous boosters, but more patients who received an mRNA booster demonstrated humoral responses than patients who received a vector-based booster.
Humoral & Cellular Immune Responses to the Pfizer-BioNTech Vaccine
Satveer Mahil, PhD, MRCP, consultant dermatologist and senior lecturer, St John’s Institute of Dermatology, Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College, London, shared data on the humoral and cellular immune responses to a second dose of the Pfizer-BioNTech vaccine in people receiving methotrexate or other targeted immunosuppression (e.g., inhibitors of tumor necrosis factor, interleukin [IL] 17 or IL-23).6
To date, we have limited data on COVID-19 vaccine immunogenicity in patients receiving therapeutic immunosuppression because this group was excluded from the COVID-19 vaccine trials. Mahil et al. aimed to better understand vaccine responses in these patients. They used immunogenicity assays to examine humoral immunity (seroconversion and functional capacity of plasma to neutralize wild-type SARS-CoV-2, alpha and delta variants) and cellular immune responses.
Seroconversion rates after the first dose were lower in patients receiving immunosuppressants than in healthy controls. But all patients seroconverted after the second vaccine dose, with similar anti-spike IgG titers to controls. Neutralization activity was also similar between groups for both the alpha and delta variants.
However, T cell response rates differed between groups after the second dose. One hundred percent of healthy controls mounted a T cell response compared with only 71% of immunocompromised patients (P=0.02). Of note, medication doses were not held before or after vaccination during this study, which may have affected the results.
Dr. Mahil said, “The durability of antibody responses in the context of absent T-cell responses is uncertain and warrants further study. Larger and longer-term cohort studies analyzing immunogenicity of further vaccine doses are vital. Real-world clinical effectiveness data will also be critical to interpreting lab assays [because] we don’t know what the clinical thresholds are to interpreting the humoral or cellular responses yet.”
Secukinumab in GCA
Jens Thiel, MD, professor, Division of Rheumatology and Immunology, Medical University of Graz, Graz, Austria, and Clinic for Rheumatology, University Hospital Freiburg, Germany, shared data from TitAIN, a phase 2 randomized controlled trial investigating the efficacy, safety and tolerability of secukinumab in 52 patients with giant cell arteritis (GCA). Biologic naive patients aged 50 years or older with new-onset or relapsing GCA were included in the study. The majority of patients were white and women, with an average age of 73.1 years. 7
The primary end point, the proportion of patients with GCA in sustained remission until week 28, was met. Dr. Thiel said, “Patients treated with secukinumab were 9.3 times more likely to stay in remission compared with patients treated with placebo [median odds ratio 9.3 with 95% credibility interval 3.5–26.3]. The Kaplan-Meier plot of time to first GCA flare after baseline up to week 52 was also quite impressive.”
Further, after the 26-week fixed regimen prednisolone taper, patients treated with secukinumab required less cumulative co-administered prednisolone than patients who received placebo. “Of note, glucocorticoid use in the placebo arm [may] be underestimated when compared with the use in the secukinumab arm because patients who discontinued the study were not taken into account, and more placebo patients discontinued before week 52,” Dr. Thiel said.
The safety profile of secukinumab was consistent with previously reported data, with no unexpected safety signals identified.
“I am very happy to let you know that a phase 3 study just started and recruited its first patients in the U.S., and I’m very honored to be the primary investigator on this study,” Dr. Thiel concluded.
Emapalumab in sJIA/MAS
Fabrizio de Benedetti, MD, PhD, head, Division of Rheumatology, head, Laboratory of ImmunoRheumatology, Ospedale Pediatrico Bambino Gesù, Rome, shared encouraging data on the use of emapalumab, an anti-interferon-gamma (IFNγ) monoclonal antibody, in the treatment of patients with systemic juvenile idiopathic arthritis and macrophage activation syndrome (sJIA/MAS) for whom high-dose glucocorticoids proved ineffective.8
Overproduction of IFNγ is present and pathogenic in several different animal models of hemophagocytic lymphohistiocytosis (HLH) and MAS. Neutralization of IFNγ has been shown to be efficacious in primary HLH and is FDA approved as a treatment.9
De Benedetti et al. studied 14 patients with sJIA/MAS for whom high-dose intravenous glucocorticoids administered for three or more days proved ineffective. Other therapies (e.g., cyclosporine A, anakinra) also proved ineffective for most patients.
Treatment with intravenous emapalumab resulted in rapid IFNγ neutralization and was rapidly efficacious in controlling MAS, with MAS remission achieved after a median time of 25 days. MAS remission was defined as a resolution of clinical signs and symptoms and normalization of laboratory parameters relevant to MAS. Emapalumab also allowed rapid and permanent tapering of glucocorticoids.
Nine adverse events related to emapalumab were reported, most of which were infectious. One patient experienced cytomegalovirus reactivation that resolved with antiviral treatment. All patients were alive at the last visit, and no patient discontinued emapalumab for safety reasons.
“In summary, these results demonstrate the pathogenic role of IFNγ in sJIA/MAS and the therapeutic value of IFNγ neutralization in those who have failed standard therapy,” Dr. De Benedetti said.
Rituximab for Remission Induction in EGPA
Benjamin Terrier, MD, PhD, professor of medicine, Cochin Hospital, Paris, shared results from the French REOVAS trial, a phase 3 randomized controlled trial from the French Vasculitis Study Group that compared rituximab with conventional therapeutic strategy for remission induction in eosinophilic granulomatosis with polyangiitis (EGPA).10 The French guidelines recommend use of cyclophosphamide in combination with glucocorticoids when at least one poor-prognosis factor defined in the 1996 Five-Factor Score (FFS) is present.11 Alternatively, the 2021 ACR/Vasculitis Foundation Guideline recommends either cyclophosphamide or rituximab for remission induction because the comparative effectiveness for EGPA is unknown. Cyclophosphamide is preferred for patients with cardiac, severe neurologic or severe gastrointestinal involvement, or negative anti-neutrophil cytoplasmic antibody (ANCA).12
“The French REOVAS trial aimed to provide high-quality data comparing rituximab with conventional therapy in regard to superiority,” Dr. Terrier said.
In the French REOVAS trial, the primary end point was complete remission at day 180, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and prednisone dose of less than 7.5 mg daily. The study randomized 105 patients—70% with newly diagnosed disease, 60% with an FFS of 0 and 56% with no anti-neutrophil cytoplasmic antibodies (ANCA). No statistically significant difference was found between groups in complete remission at day 180 or day 360. Subgroup analyses showed no difference in relapse-free survival according to ANCA status, disease severity assessed by the FFS or naive vs. relapsing disease. Also, no significant difference was found in average daily glucocorticoid dose or quality of life between the two arms. Serious adverse events were comparable between groups.
In summary, rituximab was not superior to conventional induction therapy in EGPA, and remission rates and relapse-free survival during the first year were comparable between the two arms.
“[Because] this was a negative superiority trial, I still think [cyclophosphamide] should be preferentially used in sicker patients. We don’t have enough data to propose rituximab as a new agent with high quality evidence. However, in young females in whom there is a fertility concern, I think it’s good to know that rituximab can be an effective therapeutic option,” Dr. Terrier concluded.
Samantha C. Shapiro, MD, is an academic rheumatologist and an affiliate faculty member of the Dell Medical School at the University of Texas at Austin. She received her training in internal medicine and rheumatology at Johns Hopkins University, Baltimore. She is also a member of the ACR Insurance Subcommittee.
References
- Singh J, Singh N, Anzalone A, et al. Breakthrough COVID-19 infections post-vaccination among immunocompromised patients with autoimmune or inflammatory rheumatic diseases: A retrospective cohort analysis from a U.S. nationally sampled electronic medical record data repository [abstract L16]. Arthritis Rheumatol. 2021 Oct;73(suppl 10).
- Deepak P, Kim W, Paley MA, et al. Effect of immunosuppression on the immunogenicity of mRNA vaccines to SARS-CoV-2. Ann Intern Med. 2021 Nov;174(11):1572–1585.
- Sparks JA, Wallace ZS, Seet AM, et al. Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry. Ann Rheum Dis. 2021 Sep;80(9):1137–1146.
- Mrak D, Tobudic S, Koblischke M, et al. SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity. Ann Rheum Dis. 2021 Oct;80(10):1345–1350.
- Bonelli M, Mrak D, Tobudic S, et al. Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: A randomized controlled trial [abstract L17]. Arthritis Rheumatol. 2021 Oct;73(suppl 10).
- Mahil SK, Bechman K, Raharja A, et al. Humoral and cellular immune responses to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: A cohort study [abstract L18]. Arthritis Rheumatol. 2021 Oct;73(suppl 10).
- Venhoff N, Schmidt W, Bergner R, et al. Secukinumab in giant cell arteritis: A randomized, parallel-group, double-blind, placebo-controlled, multicenter phase 2 trial [abstract L19]. Arthritis Rheumatol. 2021 Oct;73(suppl 10).
- de Benedetti F, Grom A, Brogan P, et al. Efficacy of emapalumab, an anti-IFNγ antibody in patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) who had failed high-dose glucocorticoids (GCs) [abstract L20]. Arthritis Rheumatol. 2021 Oct;73(suppl 10).
- Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020 May 7;382(19):1811–1822.
- Terrier B, Pugnet G, de Moreuil C, et al. Rituximab versus conventional therapeutic strategy for remission induction in eosinophilic granulomatosis with polyangiitis: A double-blind, randomized, controlled trial [abstract L21]. Arthritis Rheumatol. 2021 Oct;73(suppl 10).
- Terrier B, Darbon R, Durel CA, et al. French recommendations for the management of systemic necrotizing vasculitides (polyarteritis nodosa and ANCA-associated vasculitides). Orphanet J Rare Dis. 2020 Dec 29;15(suppl 2):351.
- Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis Rheumatol. 2021 Aug;73(8):1366–1383.
