Comparative effectiveness of biological disease-modifying antirheumatic drugs and Janus kinase inhibitor monotherapy in rheumatoid arthritis.

OBJECTIVES: To examine the effectiveness and drug tolerability of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitor (JAKi) monotherapy in patients with rheumatoid arthritis (RA) in a multicentre cohort study. METHODS: Patients with RA initiated with bDMARD/JAKi monotherapy without conventional synthetic DMARDs were included. Monotherapy regimens were categorised as interleukin-6 receptor inhibitors (IL-6Ri), cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig), JAKi, or tumour necrosis factor inhibitors (TNFi). Multiple propensity score-based inverse probability weighting (IPW) was used to reduce selection bias. Linear mixed-effect models with IPW were used to examine changes in the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) at 24 weeks, and drug retention was compared among monotherapy using IPW Cox proportional hazards models. RESULTS: A total of 849 treatment courses from 635 patients were included (IL-6Ri, 218; CTLA4Ig, 183; JAKi, 92; TNFi, 356). The difference in change in DAS28-ESR at week 24 as the primary outcome was -0.93 (95% CI: -1.20 to -0.66) lower in the IL-6Ri group than TNFi, while that of CTLA4Ig and JAKi was similar with that of TNFi (-0.20 [-0.48 to 0.08], -0.25 [-0.67 to 0.16], respectively). IL-6Ri use was associated with significantly lower overall drug discontinuation than TNFi use (hazard ratio = 0.55 [0.39-0.78], P = 0.001). Similar retention rates were identified among CTLA4Ig and JAKi compared to TNFi. CONCLUSION: In the analysis with IPW to reduce selection bias, IL-6Ri monotherapy was superior to TNFi monotherapy in terms of effectiveness and drug retention. No significant differences were identified between CTLA4Ig, JAKi, and TNFi monotherapy.

Drug retention of biologics and Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVES: This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis. METHODS: The study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation. RESULTS: TNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55). CONCLUSIONS: TNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R.

A mechanistic target of rapamycin inhibitor, everolimus safely ameliorated lupus nephritis in a patient complicated with tuberous sclerosis.

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting oedema in bilateral lower legs for 3 days. The urinalysis showed massive proteinuria with a lot of white blood cell casts. The blood tests revealed hypoalbuminaemia, hypercholesterolaemia, hypocomplementaemia, and elevated anti-double-stranded DNA antibody titre. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis. Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil and tacrolimus, complete remission had not been achieved leading to a steroid-dependent nephrotic syndrome. During the follow-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29 years. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and mycophenolate mofetil and tacrolimus were terminated instead. The activity of lupus nephritis was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for 6 years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.

Persistence of SARS-CoV-2 neutralizing antibodies and anti-Omicron IgG induced by BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic disease: an explanatory study in Japan.

Background: Autoimmune inflammatory rheumatic disease (AIRD) patients are at high risk of the coronavirus disease 2019 (COVID-19), but the medium-term effects of immunosuppressants on vaccine efficacy are unknown. We investigated the duration of humoral responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and Omicron variant in AIRD patients administered with two doses of the BNT162b2 (Pfizer-BioNTech) vaccine. Methods: Serum-neutralizing antibody (NAb) and anti-receptor-binding domain (RBD)/spike antibody levels were measured. Short- and medium-term effects of immunosuppressants were analyzed pre-vaccination (Term 1) and 14-42 days (Term 2) and 100-200 days (Term 3) after the second vaccination. Findings: From Feb 1, 2021, to Feb 28, 2022, 439 AIRD patients and 146 healthy controls were investigated. The seropositivity rate and log10-NAb titers were significantly lower in AIRD patients than in controls at Terms 2 and 3. In rheumatoid arthritis patients, tumor necrosis factor-α inhibitors (TNFis) at Term 3, and older age, glucocorticoids, and abatacept at Terms 2 and 3 were risk factors for reduced responses. Anti-Omicron RBD/spike IgG levels strongly correlated with NAb titers. Interpretation: Glucocorticoids, TNFis, and abatacept treatments negatively affect the longevity of humoral responses to SARS-CoV-2, including Omicron, after two vaccine doses. These findings may inform the timing of additional vaccination for AIRD patients. Funding: Cloud Funding of Peace Winds Japan; Center of Innovation Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science KAKENHI; Japan Agency for Medical Research and Development; Kansai Economic Federation; Mitsubishi Zaidan; and Research Grant from Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology.

Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium.

Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57+ cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury. Single-cell transcriptomics analysis shows that the p57+ cells undergo a dynamic reprogramming process after injury that is characterized by fetal-like conversion and metaplasia-like transformation. Population-level analysis also detects such spatiotemporal reprogramming widely in other differentiated cell types. In intestinal adenoma, p57+ cells manifest homeostatic stem cell activity, in the context of constitutively activated spatiotemporal reprogramming. Our results highlight a pronounced plasticity of the intestinal epithelium that supports maintenance of tissue integrity in normal and neoplastic contexts.

Modulation of TNFR 1-triggered two opposing signals for inflammation and apoptosis via RIPK 1 disruption by geldanamycin in rheumatoid arthritis.

OBJECTIVES: To evaluate the ability of geldanamycin to modulate two opposing TNFα/TNFR1-triggered signals for inflammation and cell death. METHODS: The effects of geldanamycin on TNFα-induced proinflammatory cytokine production, apoptosis, NF-κB activation, caspase activation, and necroptosis in a human rheumatoid synovial cell line (MH7A) were evaluated via ELISA/qPCR, flow cytometry, dual-luciferase reporter assay, and western blotting assay, respectively. In addition, therapeutic effects on murine collagen-induced arthritis (CIA) were also evaluated. RESULTS: Geldanamycin disrupted RIPK1 in MH7A, thereby inhibiting TNFα-induced proinflammatory cytokine production and enhancing apoptosis. TNFα-induced NF-κB and MLKL activation was inhibited, whereas caspase 8 activation was enhanced. Recombinant RIPK1 restored the geldanamycin-mediated inhibition of TNFα-induced NF-κB activation. In addition, GM showed more clinical effectiveness than a conventional biologic TNF inhibitor, etanercept, in murine CIA and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA. CONCLUSIONS: GM disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway, while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line. Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF inhibitor. Key Points • Geldanamycin (GM) disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line, MH7A. • GM showed more clinical effectiveness than a conventional biologic TNF-inhibitor, etanercept, in murine collagen-induced arthritis (CIA), and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA. • Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF-inhibitor.

Diffusion-weighted Whole-body Imaging with Background Body Signal Suppression (DWIBS) as a Novel Imaging Modality for Disease Activity Assessment in Takayasu's Arteritis.

A 26-year-old woman with Takayasu's arteritis (TAK) experienced back and neck pain during tocilizumab (TCZ) treatment. The levels of C-reactive protein were normal, and ultrasonography revealed no significant changes. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement in the walls of several arteries. Contrast computed tomography showed arterial inflammation in the same lesion. After increasing the dose of prednisolone and TCZ, all signal enhancements decreased and continued to decrease, as observed on days 76 and 132. Thus, DWIBS may be a novel imaging modality for assessing the disease activity of TAK, particularly during follow-up.

Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor -kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking.

OBJECTIVES: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. METHODS: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. RESULTS: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1ß and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. CONCLUSIONS: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Sporotrichal Tenosynovitis Diagnosed Helpfully by Musculoskeletal Ultrasonography.

A 72-year-old man presented with persistent oligoarthritis and positive results for rheumatoid factor and was suspected of having rheumatoid arthritis (RA). However, the musculoskeletal ultrasonography (MSUS) findings were not consistent with those of typical RA. He had undergone surgery for carpal tunnel syndrome, which allowed both histopathological and microbiological examinations to be performed. A synovial tissue culture was positive for Sporothrix schenckii, and he was diagnosed with sporotrichal tenosynovitis. He received anti-fungal therapy, and the sporotrichal tenosynovitis resolved. This case suggests that MSUS is a useful modality, and sporotrichal tenosynovitis, though rare, should be considered in the differential diagnosis of RA.

Increased efficiency in the generation of induced pluripotent stem cells by Fbxw7 ablation.

Induced pluripotent stem cells (iPSCs) share many biological properties with embryonic stem cells (ESCs), and are generated from somatic cells by expression of some transcription factors such as Oct3/4, Sox2, Klf4 and c-Myc. Among these factors, the abundance of c-Myc is strictly regulated by Fbxw7, a subunit of Skp1-Cul1-F-box protein-type ubiquitin ligase. We have now shown that the expression of Fbxw7 was increased as ESCs differentiated. To investigate the role of Fbxw7 in the ESCs/iPSCs, we examined the impact of Fbxw7 ablation in the efficiency in iPSC generation. The frequency of iPSC generation from mouse embryonic fibroblasts (MEFs) lacking Fbxw7 was markedly greater than that from control MEFs. Depletion of Fbxw7 also resulted in promotion of iPSC generation. Morphology of iPSC clonies from Fbxw7-depleted MEFs appeared more undifferentiated than that from MEFs overexpressing c-Myc. Additional depletion of c-Myc did not abrogate the effect of Fbxw7 depletion, suggesting that c-Myc accumulation is not necessarily required for the increased efficiency in iPSC generation by Fbxw7 ablation. Substrates of Fbxw7 other than c-Myc might therefore play a key role in iPSC generation. These results suggest that transient inhibition of Fbxw7 would be a more promising approach to efficient generation of iPSCs than c-Myc over-expression.

Fbxw7ß resides in the endoplasmic reticulum membrane and protects cells from oxidative stress.

Oxidative stress has been implicated in cancer initiation and progression. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of oncoproteins such as c-Myc, c-Jun, Notch, and cyclin E. Fbxw7 is therefore thought to function as a tumor suppressor, and indeed the Fbxw7 gene is frequently mutated in many human malignancies. The Fbxw7 gene locus encodes three protein isoforms: Fbxw7α, Fbxw7ß, and Fbxw7γ. Whereas Fbxw7α and Fbxw7γ are resident in the nucleus, Fbxw7ß shows a cytoplasmic distribution suggestive of localization to the endoplasmic reticulum (ER). The specific function of Fbxw7ß has remained unknown, however. We now show that Fbxw7ß contains a putative transmembrane domain near its NH(2) -terminus, and topological analysis revealed that Fbxw7ß is inserted in the ER membrane. Fbxw7ß assembled with Skp1, Cul1, and Rbx1 to form an SCF complex, although the efficiency of this process appeared lower than that for Fbxw7α or Fbxw7γ. To explore the physiological role of Fbxw7ß, we generated mice specifically lacking this isoform of Fbxw7. Although these animals did not exhibit any apparent abnormalities in development, primary cultures of neurons prepared from the mutant mice were more vulnerable to oxidative stress than were those prepared from wild-type mice. Conversely, overexpression of Fbxw7ß rendered cells resistant to oxidative stress, without affecting sensitivity to ER stress or other apoptosis-inducing agents. Our results thus suggest that Fbxw7ß contributes to the protection of cells from oxidative stress.