Sjorgen's Syndrome and Therapies Flashcards

Question

is anti-TNF useful in SS?

Answer 1

TNFα produced by CD4+ T cells in salivary gland - Anti-TNF blocks salivary epithelial cell apoptosis in vitro and protects those cells - some evidence that anti-TNF may be useful But, Infliximab double-blind RCT (n=103) – no change in: - Objective or subjective measures - Focus score – measure of inflammation in salivary gland Etanercept caused increased IFNα activity and levels of BAFF in the blood, so anti-TNF isn't good for SS

Answer 2

Cytokine networks are crucial - TNF may actually regulate IFN1s - crossregulation - Blocking TNF can drive IFN1s further – not good for SS which is a IFN1-dominant disease

Answer 3

Phase 2a trial of rituximab, small study: - After 1 course of rituximab, improvement in stimulated salivary flow in early phases But, subsequent phase III trials failed

Answer 4

Wrong target? – shouldn’t be true as B cells produce the autoantibody Rituximab is good at depleting B cells from blood but not tissue Pathogenic B cells protected in niche? Patient selection? Primary outcome? Importance of central sensitisation underestimated?

Answer 5

Biopsy of salivary gland - Post-rituximab 12 weeks, B cells are still in salivary gland - not effective at tissue depletion - The B cells that are there in the tissue show a clonal relationship – suggests that the same B cells are there and weren’t depleted (not new B cells coming in) - Showed evidence of somatic hypermutation and BAFF – encouraged B cell survival and proliferation, and BAFF spike can protect B cells from depletion in the pathogenic niche rituximab here is ineffective

Answer 6

ESSPRI: fatigue, limb pain, dryness - 0-10 scale and patients say how they felt Not a great outcome measure for a small study - lots of noise - Limb pain could be from SS or due to something else e.g. these patients are 40s-60s, so may have osteoarthritis in knees and hands – contributes to noise in measures as SS may not be driving the symptoms

Answer 7

it doesn't improve fatigue in the long term compared to placebo - rituximab isn't doing enough, and perhaps outcome measures may not have been good enough to pick up changes

Answer 8

Looked at no. B cells in salivary gland before treatment - Those who clinically responded to rituximab had more B cells in tissue - more likely for treatment to work

Answer 9

no, it may not be the sole cause for fatigue, dryness and pain - Fatigue is common in chronic illness - May not be entirely inflammation-driven (may be triggered by inflammation but not perpetuated by inflammation

Answer 10

suggests a role of centrally-mediated effects in SS: - SS leads to corneal dryness which can disrupt the epithelium of cornea – leading to dryness, erosion and direct cause of pain - Persistent pain input drives C-fibre neurological input, leading to summation and sensitisation - Brain interprets more signals as pain even if pain stimulus is reduced - Even if corneas are treated and epithelium is treated, patients may still feel pain Same reason why it may take a while for fatigue to get better

Answer 11

Symptoms: Dryness, pain, fatigue, anxiety, depression Machine learning clustering – identified 4 disease groups - dryness-dominant with fatigue had more B cell activity in peripheral blood, less pain, anxiety and depression this dryness-dominant fatigue group responded better to rituximab, with improved saliva flow

Answer 12

Anti-BAFF - Open-label study (Beliss) indicates clinical benefit with histological improvement Combination of anti-CD20 and anti-BAFF Anti-BAFF receptor Epratuzumab – binds to CD22 - CD22 gives negative regulatory signal downstream of BCR - drug isn't an agonist, but may help strip the BCR-CD22 off the cell - Open-label study indicates clinical improvement - Phase III study failed in SLE, but SS patients had improved lupus outcomes - SS can be used to stratify SLE, RA Inhibition of BTK

Answer 13

anti-BAFF - blocks BAFF cytokine - used in lupus - Shown to benefit histology and symptoms

Answer 14

Open-label study – give all patients bel – no control or placebo and not blind - This is because SS patients often show lots of response to placebo - shows improved responses to treatment - be cautious though

Answer 15

reduces naive, activated, and plasma B cell subsets increases peripheral memory B cells in circulation – mobilises memory B cells from tissue into blood increases stringency on B cell selection during reconstitution – cells less likely to be autoreactive

Answer 16

Depletes CD20-expressing B cells in circulation Less effective in depleting tissue- resident CD20+ B cells

Answer 17

can deplete B cells and reduce BAFF to prevent B cell persistence and survival

Answer 18

Give anti-BAFF first to mobilise B cells from tissue, then give anti-CD20 to deplete B cells

Answer 19

Compared to either alone and double placebo - histology data: - Placebo = little change in tissue B cells - Low B cell tissue change with either alone - Combo = strong reduction in B cell numbers in tissue combo is more effective in tissue B cell depletion

Answer 20

Binds BAFF receptor on B cells and depletes them - Dual mechanism of action: Blocks action of BAFF by blocking the receptor, and is enhanced for B cell depletion (changed glycosylation status of Fc)

Answer 21

ESSDAI measure of systemic disease activity in 190 patients - 3 doses compared to placebo - Highest dose reduces activity - Highest dose increases stimulated salivary flow - No difference in symptom burden between ianalumab and placebo (ESSPRI = mean of dryness, pain, fatigue) - Strong placebo response makes it hard to show action of drug Now in phase 3 trial

Answer 22

BAFF doesn’t just bind BAFF receptor, it also binds TACI and BCMA - BAFF supports early B cell function to mature B cell phase - APRIL is a cytokine supporting plasma cell survival - overlapping function with BAFF in mature B cellsbut some distinction with plasma cells Telitacicept: Took EC domain of TACI which binds both APRIL and BAFF, bound to Fc region of IgG to prolong half life - Mops up both BAFF and APRIL - blocks both cytokines

Answer 23

small phase 2 trial - Dose reduces ESSDAI over time and reduces fatigue - Reduces immunoglobulins IgG, IgA, IgM - But small study

Answer 24

BTK sits below BCR to support signalling, helps signal for B cell proliferation, survival, cytokine production

Answer 25

most inhibitors haven't been successful, in part due to cross reactivity with making other cytokines - off-target effects

Answer 26

Remibrutinib (LOU064) (Novartis) - oral, novel, covalent BTK inhibitor - high selectivity and potency for BTK - binds to an inactive conformation of BTK

Answer 27

improves baseline ESSDAI score over 24 weeks - improves salivary flow - but doesn't improve symptoms

Answer 28

Role of autoantibodies in SS - These may drive pathogenesis - Block Ro52 or Ro60 antigens in mice, leads to autoimmunity - Immune complexes containing Ro can drive IFN1 - maybe they do drive SS disease

Answer 29

Nipo blocks FcRn to prevent IgG recycling Nipo phase 2 trial in SS, 163 patients - Highest dose of nipo can reduce clinical ESSDAI, trends towards improvement of symptoms and ESSSPI - no trend in serious adverse events or infections - Reduces IgG levels, but when drug is removed the IgG levels come back - doesn't cause permanent reduction now in phase 3 trial

Answer 30

TLR antagonists Anti-IFNα monoclonal antibodies - tested in SLE, not SS Anti-IFN1 receptor monoclonal antibodies (anifrolumab) – blocks effects of IFNa and IFNb Induce host immunity against IFN - Bind IFNa to KHL (novel antigen) – give to patient and develops antibody response to IFN - If drug removed, antibodies to IFN reduced - requires continuous administration -Trialed in SLE Block downstream IFN receptor signalling – block JAK1 or TYK2

Answer 31

BDCA2 is an inhibitory receptor expressed exclusively on surface of pDCs

Answer 32

pDCs produce IFN1s in large amounts via TLRs and FcRs - Antibody to BDCA agonistically on surface of pDCs - BDCA is inhibitory receptor - Drug binds and causes receptor internalisation, downregulating TLR-mediated production of IFN1, and blocks activation of FcR

Answer 33

anti-BDCA antibody: blocks pDC activation in vitro through 1) the activation of BDCA2, its subsequent internalization, and prevention of TLR mediated IFN release; 2) the Fc-dependent pathway which blocks pDC activation by immune complex binding to CD32a (Fc gamma RIIa)

Answer 34

Reduces cutaneous skin disease in SLE - not tried in SS yet

Answer 35

IFN1s don’t just come from pDCs, could also be epithelial cells - HCQ reduces IFN1 score, but doesn’t improve symptoms – weak effects

Answer 36

SS lags behind other illnesses for finding genetic risks - Found 22 risk genes only with GWAS study (over 100 in RA) - Polymorphism in TYK2 (downstream of IFN1 receptor signal) - IL-12 polymorphism (downstream of TYK2) informs use of TYK2 inhibitor

Answer 37

Inhibits TYK2 - TYK2 has enzymatic and regulatory domains - This drug binds regulatory domain and locks it in inactive state – advantage as there is no cross reactivity with other kinases, its specific for TYK2, as it doesn’t target catalytic domain - avoids off-target effects - Blocks IFN1, IL-23, IL-12 In SLE: - dose met primary endpoint to reduce systemic disease activity - Also reduced pain and fatigue – secondary endpoints SS shares TYK2 polymorphisms with SLE - anti-Ro antibodies can drive IFN signature in peripheral blood

Answer 38

CD40: B cells, DCs, macrophages, epithelial cells, haematopoietic precursors - broad expression CD40L: activated T cells, activated B cells, activated platelets - during inflammation: PBMC, endothelial cells, smooth muscle cells, mononuclear phagocytes - more restricted to activated cells

Answer 39

- T-cell activation requires two signals: Peptide-MHC/TCR + CD80/86/CD28 (+cytokines from APC) - Licensing/maturation of APC is crucial to activate CD40 - CD40 activation leads to upregulation of CD80/86 to enable T cell co-stim - CD40 with CD40L is important for B cell-Tfh GC response and activation

Answer 40

- DC uptake of necrotic cells → DC maturation → immunity - DC uptake of apoptotic cells = T cell anergy/deletion and induce regulatory cells - Persistent presentation of self-Ag by immature DCs maintains peripheral tolerance If DC takes up apoptotic cell without danger signal, CD80 isn’t upregulated, so DC induces tolerance in T cell - mechanism for preserving peripheral immune tolerance If DC takes up necrotic cell with DAMPs, DC is matured with CD80, so activates T cell

Answer 41

CD40 pathway is crucial in immune system: - Important in B cell/T cell interactions - Co-stimulation for multiple cells types - Licences dendritic cells - Important for B cell function including proliferation, antibody class switching, germinal centre formation

Answer 42

In salivary glands of SS patients, there are ectopic lymphoid structures, organisation/segregation and GC formation - CD40 is crucial for this

Answer 43

SNPs in CD40 and its signaling pathway (TNFAIP3 and TRAF1-C5) associated with RA - CD40 expressed on RA synoviocytes/fibroblasts in synovium: Fibroblast proliferation, adhesion molecules increased, IL-6, GM-CSF and MIP-1α – increases cytokine production - Synovial macrophages secrete TNF in response to CD40 binding - Subset of RA patients have increased frequency of CD40L +ve CD4 T cells and no. of these cells associated with higher disease activity

Answer 44

Giving anti-CD40L before model induction prevents CIA induction Anti-CD40L can inhibit arthritis induction in KBxN if given at onset But if its given when arthritis is already induced, its not great at reducing arthritis ability of blocking CD40 pathway to control inflammation depends on path of inflammation, context and timing

Answer 45

CD40L overexpressed on T and B cells in LSE patients - CD40L+ B cells produce antibody which is CD40L-dependent - B cell CD40L transgenic mice develop SLE-like features – overexpression of CD40L - Soluble CD40L in serum correlates with disease activity CD40 SNPs associated with SLE

Answer 46

Simultaneous blockade of CD40-CD40L and CD28 leads to prolonged benefit in preventing murine lupus: - Block CD40 improves survival while control dies quickly - CTLA-4-Ig combined with anti-CD40L improves survival Anti-CD40L in established lupus nephritis model - ↑ survival - ↓ severity of renal lesion - But, later in disease process required more aggressive treatment to see effects

Answer 47

Different mechanisms in early versus late disease - Early treatment prevents AAb production and immune complex deposition in kidney - Late treatment limits tissue damage in established disease – doesn't block initial Aab production

Answer 48

3 drugs for SLE in small trials Ruplizumab (BG9588) - Partial clinical responses - reduced anti-dsDNA, increased C3, lower immune complex activity - signs that drug does something - 2/18 had 50% reduction in 5/5 with haematuria resolved (improved blood in urine, better kidney function) - but trial stopped early because several patients developed thromboembolic events Toralizumab - No efficacy

Answer 49

CD40L is on activated platelets, which also express FcRs - FcγRIIa on human but not mouse platelets - Binding to CD40L on activated platelets and FcγRIIa on adjacent platelets could lead to aggregation - Or Immune complexes of soluble CD40L and antibody could crosslink FcγRIIa on platelets and form thrombus CD40L intact IgG1 mAb, hu5c8 (Antova), has been associated with thromboembolic events

Answer 50

Four agents and control saline in Rhesus macaques - Replaced Fc with PEG to increase halflife - Created mAbs with different glycosylation of Fc region so it can no longer bind FcRs - two PEGylated antibody fragments (the monovalent Fab' PEG CDP7657 and a bivalent di-Fab' PEG format using the same variable region) - two intact mAbs (hu5c8, and the Fc function-deficient aglycosyl hu5c8) - Only hu5c8 also produced pulmonary intravascular thrombosis or intimal hyperplasia (5/8 animals) Fab bound to PEG or Fc silent antibody didn’t cause thromboembolism - Fc component is what drives thrombus formation

Answer 51

Engineer to reduce complement or FcR binding e.g. aglycosyl ruplizumab - change Fc status by inducing amino acid mutations to block its binding to the FcR or complement e.g. altered glycosylation status - Does not prevent graft rejection in models (does not allow complement-dependent T cell elimination) - Prolongs survival and decreases AAb in murine model Replace Fc region with PEG Block CD40 Soluble ligands that block CD40/CD40L

Answer 52

- Evidence of B cell hyperactivity - T cells in foci enable this and contribute to glandular destruction - Increased expression of CD40 and CD40L in T and B cell infiltrates - Increased soluble CD40L in blood of subset of patients - Epithelial cell lines derived from Sjogren’s inflamed microenvironment have constitutively upregulated CD40

Answer 53

Early-life CD40 signalling required for TLS neogenesis - NOD mice develop inflammation of salivary gland - CD40 K/O NOD mouse have no T cell foci/TLS in salivary gland unlike normal NOD - Gave dose of anti-CD40L to NOD mice in early life (4-5 weeks old) before salivary gland infiltration – these mice didn’t get inflammation of salivary gland at 24 weeks later - anti-CD40L in early life can prevent SS-like disease

Answer 54

Anti-CD40L given once NOD mice had inflammation in salivary glands - Clears CD3 T cells and B cells from tissue in established disease

Answer 55

CXCL13 is a plasma biomarker of germinal centre formation and activity - CXCL13 attracts B cell to sites of inflammation - TFh in GCs positively associated with CXCL13 in blood

Answer 56

Anti-CD40 Fc silent – no agonist function, just blocking - Used ESSDAI to measure systemic disease in phase II PoC - Distinction between placebo and active disease in trial - clear improvement (mean delta = 5.6 by week 12) in CFZ533 group vs placebo Symptoms measured by ESSPRI Fatigue by MFI - All favour active intervention compared to placebo Drug reduces CXCL13 levels in blood

Answer 57

Study of Safety and Efficacy of Multiple Doses of CFZ533 in Two Distinct Populations of Patients With Sjögren's Syndrome (TWINSS) - recruited patients with high systemic disease - ESSDAI as primary outcome - also looked at second cohort of patients with low ESSDAI but high symptom burden, can the drug work here too?

Answer 58

Drug had clear effect - dose-response plateau – small dose, medium dose, and high dose to test and select besqt dose for a late-phase study - All the doses reduced ESSDAI

Answer 59

Trend toward symptom burden improvement e.g. dryness, fatigue (ESSPRI) - Statistically significant in high and low systemic disease patients (all improved) - Improved (un)stimulated whole saliva flow - Also studied in transplantation – but led to opportunistic infections, so may not go ahead for SS because of this

Answer 60

Tenacin molecules have Ig folds which can be mutated to have high antigen specificity - Took 2 modified tenacin molecules and bound to albumin to increase half life - Reduced ESSDAI compared to placebo in high systemic disease - Reduced symptom burden (ESSPRI) compared to placebo in low systemic disease high symptom burden cohort - now in phase 3 trial