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Do B-cell targeted therapies still have a place for the treatment of Sjogren’s?

B-cells play a major role in the pathogenesis of primary Sjogren’s syndrome (pSS) through antibody-dependent and antibody-independent functions, as well as evident by progression to B-cell malignancies/lymphoma. Hence, targeting B-cell is an attractive option.

Despite efficacy of B-cell depleting therapy with rituximab (RTX) in Phase II trials and case series, it failed to meet its primary endpoint when investigated in two Phase III trials, the French TEARS and the British TRACTISS. It is worth noting that the primary endpoint used in both trials was a subjective measure (i.e., improvement in patient visual analogue scale (VAS)). Post-hoc analyses however showed greater improvement in objective measures such as salivary flow rate and salivary gland ultrasound score in RTX-treated group vs placebo.

Therefore, do B-cell targeted therapies still have a place for the treatment of pSS?

Dr Pontarini (OP0136) performed transcriptomic and histological analyses of salivary gland (SG) biopsy from N=26 patients randomised to either RTX or placebo at 3 time-points: 0, 16 and 48 weeks using samples from the TRACTISS trial. They reported that RTX therapy showed beneficial effects on labial SG inflammatory infiltration by i) downregulating genes involved in immune cell recruitment and inflammatory aggregate organisation (e.g. CCR7, CCL19, CD52, and PDCD1); ii) blocking class-switched- and memory-B-cells infiltration in SG; and iii) downregulating leukocyte migration, MHC class II antigen presentation, and T-cell co-stimulation immunological pathways. In contrast, Placebo-treated labial SGs showed worsening inflammation highlighted by the increment of B-cell density, development of new follicular dendritic cell networks, and a higher germinal ectopic prevalence at week 48 vs RTX-treated patients.

Can we enhance efficacy of RTX through combination therapy? Prof Mariette (OP0135) presented safety and efficacy data from a phase II trial of subcutaneous or intravenous belimumab (BEL) and RTX combination. 86 patients were randomised to 4 treatment arms stratified for baseline EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores 5-12 or >12: placebo (PBO; N=13), BEL/RTX (N=24), BEL monotherapy (N=24) or RTX monotherapy (N=25). Primary endpoint was safety. 60/86 patients completed the study. At Week 68, no unexpected safety issues were identified with BEL/RTX relative to BEL or RTX. Greater reduction numerically in ESSDAI over time than PBO was evident with the greatest difference at Week 68, but were not differentiated from BEL or RTX monotherapy. There was a trend to improvement in stimulated salivary flow favouring BEL/RTX vs PBO over later time points. Importantly, in comparison with PBO, BEL, and RTX, salivary gland biopsies from BEL/RTX showed almost complete B-cell depletion at Week 24.

How about dual blockade? Prof Dorner (POS0692) presented data from longer-term blinded treatment period (TP2; 52 weeks) of ianalumab, a B-cell depleting, BAFF receptor-blocking mAb in pSS. As you may recall, the primary endpoint (changes in ESSDAI from baseline) was met at 24 weeks in the ianalumab group when the results were presented at the 2020 EULAR congress. N=190 patients were randomised equally to receive subcutaneous ianalumab (5, 50, 300 mg) or PBO every 4 weeks. At Week 24, PBO-treated pts were switched to ianalumab 150 mg, and those on 300 mg were re-randomised to either continue 300 mg or PBO for 28 Wks. Due to small sample size for placebo in TP2, only descriptive analyses were reported. At Week 52, efficacy was sustained for patients who continued 300 mg in TP2 (ESSDAI, ESSPRI, PaGA, PhGA CHB). Efficacy was partially lost for those switched to PBO at Week 24 and conversely, improvement was noted for PBO patients switched to 150 mg. No major safety concern was reported. Tracheobronchitis and pneumonia were mild to moderate severity and not associated with treatment-associated late-onset neutropaenia.

So what do these results imply?

Treatment with B-cell targeted therapies should not be discounted in people with pSS. It is unlikely that rituximab be further investigated formally in clinical trials. However, newer type 2 anti-CD20 mAb such as obinutuzumab, with enhanced ADCC and depletion is a promising therapeutic option. Moreover, combination therapy (BEL/RTX) should be evaluated in larger trial and results from ongoing Phase III trial of ianalumab would be eagerly anticipated in the next few years. Since there is still no licensed bDMARDs in pSS, perhaps we can learn from progress in SLE. Further works should focus on establishing clinically meaningful endpoints and improving patient selection into trials. 

 

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