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Antibody drugs targeting single inflammatory cytokines have revolutionized the treatment of immune-mediated inflammatory diseases. To investigate whether dual targeting interleukin-17 (IL-17) and IL-36 enhances anti-inflammatory activity, bispecific Ab HB0043 was generated by linking the single chain fragment variables (scFvs) from humanized anti-IL-36R antibody (HB0034) to the C-terminus of the heavy chain of anti-IL-17A IgG1 (HB0017) Fc using a flexible peptide linker. HB0043 largely maintained the binding affinities and biological activities of the two parent monoclonal antibodies (mAbs) in vitro. IL-17 and IL-36 cooperated to amplify the expression of pro-inflammatory and pro-fibrotic genes in normal human dermal fibroblasts (NHDF). However, HB0043 more effectively blocked IL-6 and IL-8 production in NHDF stimulated by IL-17A and IL-36 compared to two monoclonal antibodies. In a mouse model of Oxazolone (OXA)-induced atopic dermatitis and Imiquimod (IMQ)-induced skin inflammation, administration of both anti-IL17A mAb HB0017 and anti-mouse IL-36R surrogate antibody HB0034SA showed improved effectiveness in alleviating skin thickening and inflammation based on histological assessment. Further, in cynomolgus monkeys, HB0043 showed no enhanced target-related toxicity compared with the two parental mAbs in vivo and with a moderate increase in production of anti-drug antibodies. Together, dual blockade of IL-17A and IL-36R in the form of a bispecific antibody may have advantages in blocking the overlapping and non-overlapping functions of these two cytokines in skin inflammation that could not optimally be curtailed with single mAbs. In conclusion, as monotherapy may reach therapeutic celling for certain difficult-to-treat inflammatory and fibrotic diseases, dual targeting could potentially pave a way to combat these diseases.

ObjectivesThis study aimed to assess the effectiveness of iguratimod (IGU) as an alternative treatment for systemic sclerosis (SSc), especially in the prevention of ischemic digital ulcers (DUs).MethodsWe constructed two cohorts from the Renji SSc registry. In the first cohort, SSc patients receiving IGU were observed prospectively with effectiveness and safety. In the second cohort, we picked up all the DU patients with at least a 3-month follow-up to investigate the prevention of IGU on ischemic DU.ResultsFrom 2017 to 2021, 182 SSc patients were enrolled in our SSc registry. A total of 23 patients received IGU. With a median follow-up of 61 weeks (IQR: 15–82 weeks), the drug persistence was 13/23. In total, 91.3% of the patients (21/23) became free of deterioration in the last visit with IGU. Of note, 10 patients withdrew from the study due to the following reasons: two patients withdrew due to deterioration, three due to incompliance, and five due to mild-to-moderate side effects. All the patients with side effects recovered fully after stopping IGU. Of note, 11 patients had ischemic DU, and 8 out of 11 (72.7%) patients had no new occurrence of DU during the follow-up. In the second cohort of 31 DU patients receiving a combination of vasoactive agents with a median follow-up of 47 weeks (IQR, 16–107 weeks), IGU treatment was protective of new DU occurrence (adjusted risk ratio = 0.25; 95% CI, 0.05–0.94; adjusted odds ratio = 0.07; and 95% CI, 0.01–0.49).ConclusionOur study for the first time describes the potential of IGU possibly as an alternative treatment for SSc. To our surprise, this study provides a hint that IGU treatment can be used for the prevention of the occurrence of ischemic DU and merits further investigation.

ObjectivesIGU (IGU), a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective and safe as monotherapy in a small population with refractory lupus nephritis (LN). The aim of this prospective study was to evaluate the efficacy and safety of IGU as an add-on therapy in patients with refractory LN in the context of clinical practice.MethodsThis is a single-arm observational study. We have enrolled LN patients since 2019 at Renji Hospital. All participants should have recurrent or refractory LN with at least one immunosuppressant (IS) and have a baseline urine protein/creatinine ratio (UPCR) >1.0. After enrollment, we added IGU (25 mg twice daily) to one of their previous immunosuppressants (IS) without increasing the dose of steroids. The primary outcome was the complete renal response (CRR) in the 6th month. UPCR decrease of over 50% was defined as partial response (PR). Extended follow-up was performed after the initial 6 months.ResultsWe enrolled 26 eligible participants. 11/26 patients had chronic kidney disease (CKD) stage 2/3 at the baseline. The IS combined with IGU included mycophenolate mofetil, tacrolimus, and cyclosporin A. No IS change was allowed. 80.7% of patients had baseline steroids less than 0.5mg/kg daily and there was no steroids escalation during the IGU treatment. The CRR rate was 42.3% (11/26) at month 6. With a median follow-up of 52 weeks (range: 23-116 weeks), the CRR rate at the last visit was 50% (13/26) and 73.1% (19/26) of patients had UPCR decrease of over 50%. Six patients withdrew, three for no response and three for renal flare after initial CRR. One patient had an estimated glomerular filtration rate worsening of over 20% and was classified as renal flare. Three mild to moderate adverse events were recorded.ConclusionsOur investigation merits further investigation in IGU as a potentially tolerable component of combination therapy for refractory LN.

IntroductionThis study is aimed to map the clinical and immunological features of active lupus patients with different disease duration.MethodsFor clinical phenotype analysis, we enriched eligible medical records with active SLE (SLEDAI-2k≥8) from the Renji Lupus registry, a single-center database of hospitalized SLE patients with standard care, which covered national-wide patients. Patients with repeated hospitalization records in this enrichment were analyzed longitudinally as validation for the cross-sectional study above.ResultsWe enriched a total of 1313 eligible records on active SLE (SLEDAI-2k≥8) for cross-sectional analysis. Stratified into four groups by a 5-year interval of disease duration, these active SLE patients showed a significantly shifting clinical phenotype along with the duration (ascending nephritis, pulmonary hypertension and descending fever, cutaneous symptoms, arthritis, and neuropsychiatric manifestations), especially in stratifications with disease onset age ≤ 45 years old. A longitudinal analysis of 55 patients with repeated hospitalizations for active lupus showed a similar trend. In the cross-sectional study of 222 records with full information on serology and lymphocyte subsets, peripheral B cell proportion, anti-dsDNA antibody, and serum IgG/IgM negatively correlated with duration, while CD8+ T cell proportion was positively correlated (P values, 0.029-4.8×10-17), which were supported by the sensitivity analysis in patient subgroups according to disease onset age and recent treatment. Multivariate linear regression identified duration as the only significant associator with both B cell and CD8+ T cell proportion (P values, 8.9×10-8 and 7.6×10-5, respectively). These duration biased immune phenotypes were highly consistent with the longitudinal observation in 14 patients with repeated hospitalizations.ConclusionsBoth clinical and immunological features of active SLE are significantly duration biased distributed, which merits further investigations in the evolution of SLE pathogenesis.

Objectives: To investigate whether cytomegalovirus (CMV) infection plays a role in the pathogenesis and prognosis of idiopathic inflammatory myopathy (IIM), particularly in anti-MDA5 antibody-positive (anti-MDA5+) dermatomyositis (DM).Methods: A prospective cohort of 204 newly diagnosed IIM patients and 50 healthy individuals were enrolled in the study. CMV-IgM and CMV-IgG antibody concentrations and lymphocyte counts were analyzed. Differences in categorical data were compared using Fisher's exact test and the chi-square test. One-year survival rates were analyzed in MDA5+ DM patients with and without CMV infection.Results: In IIM patients, the median CMV-IgM level was significantly higher than in healthy controls (6 U/mL vs. 0 U/mL, p < 0.05) as was the median CMV-IgG level (114 U/mL vs. 105 U/mL, p < 0.05). The percentage of recent CMV infections in the MDA5+ DM group was much higher than it was in the MDA5− IIM group (19.1% vs. 7.0%, p = 0.009). MDA5+ DM patients with CMV DNA-emia had poorer 1 year survival than the CMV-DNA− group (33.3% vs. 86.3%, p = 0.010). CMV-IgM-positive (CMV-IgM+) MDA5+ DM patients had lower CD4+ T cell counts (245.7 cells/μL vs. 420.5 cells/μL, p < 0.05) and CD19+ B cell counts (97.3 cells/μL vs. 240.6 cells/μL, p < 0.05).Conclusion: The number of CMV infections was significantly higher in IIM patients, particularly in MDA5+ DM patients. Lower CD4+ T cells and CD19+ B cells were observed in CMV-IgM+ MDA5+ DM patients. CMV infection may have an important role in the pathogenesis and prognosis of MDA5+ DM by disrupting immunity.

Enterovirus D68 (EV-D68) is a globally re-emerging respiratory pathogen implicated in outbreaks of severe respiratory illnesses and associated with acute flaccid myelitis. However, effective vaccines or treatments for EV-D68 infections remain scarce. We demonstrated that the active constituent of blueberries, pterostilbene (Pte), and its major metabolite, pinostilbene (Pin), facilitated innate immune responses in EV-D68-infected human respiratory cells. Pte and Pin treatment clearly relieved EV-D68-triggered cytopathic effects. Importantly, both Pte and Pin disrupted viral RNA replication (EC50 rank from 1.336 to 4.997 µM) and infectious virion production in a dose-dependent manner, without cytotoxicity at virucidal concentrations. Pte- or Pin-treated respiratory cells did not show any influences on EV-D68 entry but showed substantially decreased viral RNA replication and protein synthesis. Finally, we showed that Pte and Pin broadly suppressed the replication capacity of circulating EV-D68 strains isolated from recent pandemics. In summary, our results suggest that Pte and its derivative, Pin, enhance host immune recognition of EV-D68 and suppress EV-D68 replication, which represents a promising strategy for antiviral drug development.

Long interspersed element 1 (LINE-1 or L1) is the only active autonomous retrotransposon in the human genome that can serve as an endogenous upstream activator of cytoplasmic nucleic acid sensing pathways to elicit an antiviral immune response. In this study, we investigated the influence of enteroviral infection on L1 mobility. The results showed that infection with different enteroviruses, both EV-D68 and EV-A71, blocked L1 transposition. We screened diverse viral accessory proteins for L1 activity and identified EV-D68 2A, 3A, 3C, and EV-A71 ORF2p proteins as viral L1 inhibitors. EV-D68 2A suppressed L1 mobility by expression suppression of L1 proteins. Viral proteins 3A and 3C restricted ORF2p-mediated L1 reverse transcription in isolated L1 ribonucleoproteins. The newly identified enteroviral protein ORF2p inhibited the expression of L1 ORF1p. Altogether, our findings shed light on the strict modulation of L1 retrotransposons during enterovirus replication.