ABSTRACT
OBJECTIVES: COVID-19 vaccine responses in rare autoimmune rheumatic diseases (RAIRD) remain poorly understood, in particular there is little known about whether people develop effective T cell responses. We conducted an observational study to evaluate the short-term humoral and cell-mediated T cell response after the second SARS-CoV-2 vaccination in RAIRD patients compared with healthy controls (HC). METHODS: Blood samples were collected after the second dose and anti-spike, anti-nucleocapsid antibody levels and SARS-CoV-2 specific T cell responses were measured and compared with HC. Activation induced marker and deep phenotyping assays were used to identify differences in T cells between high and low/no antibody groups, followed by multi-dimensional clustering. RESULTS: 50 patients with RAIRD were included (31 with AAV, 4 with other systemic vasculitis, 9 with SLE and 6 with myositis). Median anti-spike levels were significantly lower in RAIRD compared with HC (p< 0.0001). 15 (33%) patients had undetectable and 26 (57%) had lower levels than the lowest HC. Rituximab in the last 12 months (p= 0.003) was associated with reduced immunogenicity compared with a longer pre-vaccination period. There was a significant difference in B cell percentages (p= 0.03) and spike-specific CD4+ T cells (p= 0.02) between no/low antibody vs. high antibody groups. Patients in the no/low antibody group had a higher percentage of terminally differentiated (exhausted) T cells. CONCLUSIONS: Following two doses, most RAIRD patients have lower antibody levels than the lowest HC and lower anti-spike T cells. RAIRD patients with low/no antibodies have diminished numbers and poor quality of memory T cells which lack proliferative and functional capacities.
ABSTRACT
OBJECTIVES: Secondary inefficacy with infusion reactions and anti-drug antibodies (secondary non-depletion nonresponse, 2NDNR) occurs in 14% of SLE patients receiving repeated rituximab courses. We evaluated baseline clinical characteristics, efficacy and safety of obinutuzumab, a next-generation humanized type-2 anti-CD20 antibody licensed for haematological malignancies in SLE patients with 2NDNR to rituximab. METHODS: We collated data from SLE patients receiving obinutuzumab for secondary non-response to rituximab in BILAG centres. Disease activity was assessed using BILAG-2004, SLEDAI-2K and serology before, and 6 months after, obinutuzumab 2× 1000 mg infusions alongside methylprednisolone 100 mg. RESULTS: All nine patients included in the study received obinutuzumab with concomitant oral immunosuppression. At 6 months post-obinutuzumab, there were significant reductions in median SLEDAI-2K from 12 to 6 (P = 0.014) and total BILAG-2004 score from 21 to 2 (P = 0.009). Complement C3 and dsDNA titres improved significantly (both P = 0.04). Numerical, but not statistically significant improvements were seen in C4 levels. Of 8/9 patients receiving concomitant oral prednisolone at baseline (all >10 mg/day), 5/8 had their dose reduced at 6 months. Four of nine patients were on 5 mg/day and were in Lupus Low Disease Activity State following obinutuzumab. After obinutuzumab, 6/9 patients with peripheral B cell data achieved complete depletion, including 4/4 assessed with highly sensitive assays. Of the nine patients, one obinutuzumab non-responder required CYC therapy. One unvaccinated patient died from COVID-19. CONCLUSIONS: Obinutuzumab appears to be effective and steroid-sparing in renal and non-renal SLE patients with secondary non-response to rituximab. These patients have severe disease with few treatment options but given responsiveness to B cell depletion, switching to humanized type-2 anti-CD20 therapy is a logical approach.