The failure of many new, mostly biologic, drugs to meet their primary end points in double-blind clinical trials in patients with systemic lupus erythematosus (SLE) has caused a profound sense of ...disappointment among both physicians and patients. Arguably, the success of B cell depletion with rituximab in open-label clinical trials, the approval of belimumab (which blocks B cell-activating factor (BAFF)) for use in patients with lupus nephritis in the USA and in difficult-to-treat patients with SLE in the UK and the recognition that clinical trial design can be improved have given some cause for hope. However, changes to therapies in current use and the development of new approaches are urgently needed. The results of the latest studies investigating the use of several new approaches to treating SLE are discussed in this Review, including: fully humanized anti-CD20 and anti-CD19 monoclonal antibodies; inhibition of tyrosine-protein kinase BTK; CD40 ligand blockade; interfering with the presentation of antigen to autoreactive T cells using a peptide approach; a receptor decoy approach using an analogue of Fcγ receptor IIB; dual blockade of IL-12 and IL-23; and inhibition of Janus kinases.
Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. ...In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.
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•pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner•Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism•pDCs are hyperactivated in SLE and fail to induce Breg cells•Patients responding to rituximab display a normalized pDC-Breg cell interaction
The signals required for Breg cell differentiation in humans are currently unknown. Mauri and colleagues show that plasmacytoid dendritic cells, via the provision of IFN-α, govern the differentiation of immature B cells into regulatory B cells that restrain inflammation.
Summary Systemic lupus erythematosus is a remarkable and challenging disorder. Its diversity of clinical features is matched by the complexity of the factors (genetic, hormonal, and environmental) ...that cause it, and the array of autoantibodies with which it is associated. In this Seminar we reflect on changes in its classification criteria; consider aspects of its more serious clinical expression; and provide a brief review of its aetiopathogenesis, major complications, coping strategies, and conventional treatment. Increased understanding of the cells and molecules involved in the development of the diseases has encouraged the identification of new, better targeted biological approaches to its treatment. The precise role of these newer therapies remains to be established.
Therapeutic antibodies targeting disease-associated antigens are key tools in the treatment of cancer and autoimmunity. So far, therapeutic antibodies have targeted antigens that are, or are presumed ...to be, extracellular. A largely overlooked property of antibodies is their functional activity inside cells. The diverse literature dealing with intracellular antibodies emerged historically from studies of the properties of some autoantibodies. The identification of tripartite motif (TRIM) 21 as an intracellular Fc receptor linking cytosolic antibody recognition to the ubiquitin proteasome system brings this research into sharper focus. We review critically the research related to intracellular antibodies, link this to the TRIM21 effector mechanism, and highlight how this work is exposing the previously restricted intracellular space to the potential of therapeutic antibodies.
Monoclonal antibodies targeting extracellular antigens are well established as key therapeutic tools in cancer and autoimmunity. However, most disease-associated protein variants are arguably found inside cells.
Both the delivery and the function of antibodies inside cells are being investigated to target intracellular components. Some autoantibodies, and antibodies bound to some infectious organisms, can penetrate inside cells and may offer clues to optimise intracellular delivery.
The cytosolic Fc receptor tripartite motif 21 (TRIM21) links Fc-mediated antibody recognition to the ubiquitin proteasome system, a general mechanism of immune surveillance coupled to innate immune signalling and antigen degradation. TRIM21 has also been linked to initiation of autophagy.
Antibodies to some intracellular proteins delivered systemically in vivo are reported to be therapeutically effective.
B cells perform many immunological functions, including presenting lipid antigen to CD1d-restricted invariant natural killer T (iNKT) cells, known to contribute to maintaining tolerance in ...autoimmunity. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remain elusive. We report that B cells are essential for iNKT cell expansion and activation in healthy donors but fail to exert a similar effect in SLE patients. Defective B cell-mediated stimulation of iNKT cells in SLE patients was associated with altered CD1d recycling, a defect recapitulated in B cells from healthy donors after stimulation with interferon-α (IFN-α) and anti-immunoglobulin (Ig). iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d expression exclusively in repopulated immature B cells. We propose that healthy B cells are pivotal for iNKT cell homeostasis.
► B cells sustain iNKT cell homeostasis and activation in healthy individuals ► SLE B cells fail to sustain iNKT cell homeostasis and activation ► SLE B cells were characterized by a profound decrease in surface CD1d expression ► Correct trafficking of CD1d is important for the maintenance of iNKT cell homeostasis
Since its development in the 1950s, the vitamin K (VKA) antagonist warfarin has been a standard anticoagulant, which for 40 years has utilised the International Normalisation Ratio (INR) to regulate ...the required dose. Although effective in the treatment of blood clots and reducing the risk of stroke in atrial fibrillation, its use necessitates significant food restrictions and the avoidance of many types of drugs. In contrast, direct oral anticoagulants (DOACs) are fixed-dose, more predictable, require no routine monitoring, have no interactions with food or alcohol and many fewer drug interactions than warfarin.The RAPS study demonstrated that rivaroxaban is not inferior to warfarin in the treatment of patients with venous thromboembolism with a target INR of 2–3.1 Quality of life consideration favoured rivaroxaban in that study. Notably, 27% of the patients in this trial were triple positive for anti-phospholipid antibodies (APAbs).In contrast, in the TRAPS trial, patients with high risk triple-positive antiphospholipid syndrome (APS) on rivaoxaban were shown to be at increased risk of developing thromboembolic events2 – a concern mirrored by a report from Ordi-Ross et al, although the numbers of arterial events comparing rivaroxaban and warfarin was not in fact statistically significantly different.3 In addition, there are several early studies reporting approximately 3% of patients per year develop recurrent thrombosis while on warfarin.4Currently, the Medicine and Healthcare Products Regulatory Agencies (MHRA) in the UK advise that DOACs are not recommended for patients with a history of thrombosis who are diagnosed with APS and particularly for those who are triple positive. DOACs may, however, be considered in patients who have difficulty achieving a target INR despite compliance with warfarin. EULAR recommendations indicate that rivaroxaban should not be used in APS patients with triple APAbs positivity. However, there is an ongoing need for a prospective evaluation of DOACs versus VKA inhibitors in patients with provoked venous thromboembolism, particularly in those without triple positive disease. The ongoing RISAPS study (NCT03684564) is comparing patients with APS with single/double positivity only for APAbs, who have a history of ischaemic stroke or other brain ischaemic injury. The endpoint is the rate of change in brain white matter hyperintensity volume between baseline and 24 months follow-up assessed on magnetic resonance imaging as a surrogate marker of ischaemic damage.In summary DOACS are not dead…… but their ‘existence’ in APS/systemic lupus erythematosus is threatened!ReferencesCohen H, et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016 Sep;3(9):e426–36.Pengo V, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018 Sep 27;132(13):1365–1371.Ordi-Ros J, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med 2019 Nov 19;171(10):685–694.Cohen H, et al. 16th international congress on antiphospholipid antibodies task force report on antiphospholipid syndrome treatment trends. Lupus 2020 Oct;29(12):1571–1593.Learning ObjectivesExplain that while widely used VKAs, notably warfarin, while often effective, have major drawbacks in terms of requirement for regular blood tests, and the avoidance of many types of food and drugsDescribe how the RAPS study demonstrated the comparative effectiveness of rivaroxaban compared to warfarin in treatment with venous thromboembolic disease with a target INR of 2–3Describe how the TRAPS and later studies identified a risk of thromboembolic disease in patients on DOACs compared to warfarin in triple APAb positive patients, although earlier studies demonstrated that there is an increased risk (about 3% per annum) of recurrent thromboembolic risks on warfarinExplain, whilst the current advice from the MHRA and EULAR is to avoid DOACs in the treatment of triple positive APS patients, there remains a desperate need for clinical trials to compare the effectiveness of DOACs with VKAs in single and double positive antiphospholipid antibody APS
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