ABSTRACT
Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300mg by monthly iv infusion) following application to the manufacturer's early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI);Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n=5, chilblain LE n=1, subacute cutaneous LE n=1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26;higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved >=75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p<0.001) and EQ5D-VAS (p=0.002) by three months. Lupus-QoL trended toward improvement across all domains but most strongly for fatigue (p=0.01) and pain (p=0.002) by 6 months. One patient discontinued treatment after 4 months due to polydermatomal shingles complicated by sensorineural hearing loss. Infection coincided with background prednisolone dose >15mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG <5g/L). Prolonged aciclovir treatment was required for lesion resolution. Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients.
ABSTRACT
Background: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. Method(s): The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. Finding(s): Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002.7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117.7 (95% CI 98.3-141.0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1.68 [0.60-4.68]) and belimumab groups (1.01 [0.21-4.80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg;2.38 [95%CI 1.47-3.84]), hypogammaglobulinaemia (<6 g/L;2.16 [1.38-3.37]), and multimorbidity (1.45 [1.17-1.80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0.60 [0.41-0.90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. Interpretation(s): In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. Funding(s): None.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
ABSTRACT
Background: As rituximab (RTX) is a B-cell depleting agent, there are concerns regarding its safety during the COVID pandemic. Data from registries during pre-vaccination period reported increased risk of poor outcomes in RTX-treated patients vs TNFi. However, registry data could be limited by reporting bias in determining true incidence. There are also limited data on breakthrough infections following COVID vaccination. Objectives: To assess the incidence of breakthrough infections and predictors of severe COVID outcomes in RTX-treated autoimmune rheumatic diseases (ARDs) with a view to establishing a treatment algorithm for safe RTX administration. Methods: An observational cohort study was undertaken in the frst consecutive 300 ARD patients in a single centre between index date 01/09/2019 (i.e. 6 months prior to pandemic) and 31/01/2022. Only PCR positive cases were included. COVID outcomes were categorised as Mild (i.e. not hospitalised) or Moderate/Severe (i.e. hospitalised and requiring at least oxygenation or death). Predictors of moderate/severe outcomes were analysed using Cox-regression proportional hazard. Results: Mean (SD) at index date was 59 (14) years, 226/300 (75%) patients were female and 254 (85%) were Caucasians. The diagnoses were RA=212 (71%), SLE=33 (11%), AAV=26 (9%), Sjogren=9 (3%), IIM=8 (3%) and others=12 (4%). Therapy included concomitant DMARDs = 205 (68%) and oral prednisolone = 84 (28%). Median (range) no. of previous RTX courses was 4 (0-19). 534 RTX courses were administered. Of 294 patients with available vaccine data, 17 (6%) were unvaccinated, 4 (1%) had a single dose, 47 (16%) were double-vaccinated, 217 (74%) triple-vaccinated and 9 (3%) quadruple-vaccinated. Of those who were vaccinated, for the frst dose, 11% were given within 12 weeks post-RTX, 15% within 26 weeks and 74% were >26 weeks post-RTX. The rate of overall COVID and moderate/severe infections were 11.2/100 PYs and 2.6/100 PYs respectively. Vaccinated patients had lower rate of moderate/severe infection (2.6/100 PYs) vs unvaccinated (18.6/100 PYs) [Table 1]. Over 650.7 PY follow-up, 17/300 patients (5.7%) had moderate/severe COVID including 2 deaths. Factors associated with time-to-infection in imputed multivariable analysis were number of comorbidities [HR 1.46 (95% CI 1.05-2.04)] and low IgG (<6g/L) [6.15 (1.95-19.41)]. A history of COVID vaccination reduced risk [HR 0.13 (0.03-0.51)]. Demographics including concomitant predni-solone, RTX-and vaccine-associated factors (e.g. RTX dose, time from RTX to vaccine, vaccine mode, peripheral B-cell depletion) were not predictive. Conclusion: The rate of moderate/severe COVID infection in this cohort is comparable to the pre-pandemic severe infection rate in rituximab trials in RA. The high vaccination uptake in our cohort was effective in preventing severe infection despite the termination of national shielding programme in March 2021 and the spread of the Delta and Omicron variants. Individualised risk-beneft assessment should be undertaken in those with comorbidities, low IgG and unvacci-nated when scheduling rituximab therapy.
ABSTRACT
Background/Aims Rituximab is a chimeric type-1 anti-CD20 monoclonal antibody approved by NHS England for refractory SLE. Secondary inefficacy with infusion reactions and anti-rituximab-antibodies occurs in 14% of re-treated patients. Obinutuzumab is a next-generation humanised type-2 anti-CD20 antibody licensed for the treatment of haematological malignancies. Methods We collated data from nine SLE patients receiving off-label obinutuzumab for secondary non-response to rituximab with infusion reactions across six centres (Leeds, Bradford, York, UCL, Birmingham and Nottingham). Disease activity was assessed using BILAG-2004 and SLEDAI-2K and serology in local diagnostic laboratories before, and 6 months after, obinutuzumab 2x1000mg infusions 2 weeks apart alongside methylprednisolone 100mg. Results All patients received concomitant oral immunosuppression and prednisolone. 6/9 received hydroxychloroquine. The median number of rituximab cycles before obinutuzumab therapy was 2.5. Before obinutuzumab 6/9 patients had BILAG A/B mucocutaneous, 6/9 had BILAG A/B musculoskeletal and 4/9 had BILAG A/B renal. 6 months after obinutuzumab 1/9 patients had BILAG B mucocutaneous, no patients had BILAG A/B musculoskeletal and 2/9 patients had BILAG A/B renal. Median dsDNA reduced from 118 to 83 IU/mL, C3 increased from 0.53 to 1.02g/L and C4 increased from 0.095 to 0.23g/L. Prednisolone dose was reduced in 5/9 patients;before obinutuzumab all patients received 10mg or more. After obinutuzumab, 4/9 patients received 5mg and were in Lupus Low Disease Activity State (LLDAS). Patient 5 did not respond and required further methylprednisolone and cyclophosphamide at 4 months. Patient 6 had a partial renal response but required renal transplantation, which was successful. Patient 8 responded well to obinutuzumab but died from severe COVID-19 infection (unvaccinated). After obinutuzumab 6 patients with B-cell data all achieved complete depletion including 4/4 assessed with highly sensitive assays. Conclusion These results demonstrate obinutuzumab's efficacy in patients with secondary non-response to rituximab. These patients have severe disease with few treatment options, but previous responsiveness to Bcell depletion. Therefore, switching to another therapy in this class is mechanistically logical. Obinutuzumab appeared effective in renal and non-renal SLE as well as steroid-sparing. Immunological markers also improved. Obinutuzumab was generally well tolerated and will be further investigated for treatment-refractory lupus in the REGENCY and ALLEGORY trials.