JAK Inhibitors Research Articles

Disease modification in axial spondyloarthritis - still a controversy?

This review evaluates recent advancements in disease-modifying therapies for axial spondyloarthritis (axSpA). A recent study could not demonstrate an additional effect of NSAID therapy on golimumab [Tumor Necrosis Factor-α inhibitor (TNFi)] on structural progression; however, this might be due to the fact that the study was underpowered. While DMARDs have shown promise in suppressing inflammation, their impact on structural progression remains uncertain. A well powered trial showed no difference in spinal progression between secukinumab [Interleukin17A inhibitor (IL17Ai)] and adalimumab-biosimilar (TNFi). Preliminary data on Janus kinase inhibitors (JAKi) focus on MRI findings but lack evidence on radiographic spinal progression. While some studies suggest promising outcomes, others reveal limitations and inconclusive findings. Recent studies explore the effectiveness of NSAIDs, biological disease-modifying antirheumatic drugs like TNFi and IL-17i, as well as JAK inhibitors in axSpA. Conflicting evidence surrounds these therapies' ability to impede structural progression, with challenges in study design and interpretation. Moreover, changes in demographics and treatment methods underscore the importance of examining trends over time when assessing disease outcomes. Ultimately, ongoing research could benefit from new imaging tools when evaluating therapeutic strategies for modifying disease progression in axSpA.

What is novel in the clinical management of pemphigus vulgaris?

Pemphigus, an uncommon autoimmune blistering disorder affecting the skin and mucous membranes, currently with mortality primarily attributed to adverse reactions resulting from treatment protocols. Additionally, the existing treatments exhibit a notable recurrence rate. The high incidence of relapse and the considerable adverse effects associated with treatment underscore the imperative to explore safer and more effective therapeutic approaches. Numerous potential therapeutic targets have demonstrated promising outcomes in trials or preliminary research stages. These encompass anti-CD-20 agents, anti-CD-25 agents, TNF-α inhibition, FAS Ligand Inhibition, FcRn inhibition, BAFF inhibition, Bruton's tyrosine kinase (BTK) inhibition, CAAR T Cells, JAK inhibition, mTOR inhibition, abatacept, IL-4 inhibition, IL-17 inhibition, IL-6 inhibition, polyclonal Regulatory T Cells, and autologous hematopoietic stem cell transplantation. The most significant studies regarding the impact and efficacy of the mentioned treatments on pemphigus were meticulously curated through a comprehensive search conducted on the PubMed database. Moreover, the investigations of interest cited in these studies were also integrated. The efficacy and safety profiles of the other treatments under discussion do not exhibit the same level of robustness as anti-CD20 therapy, which is anticipated to endure as a critical element in pemphigus treatment well into the foreseeable future.

Evaluating the pharmacokinetics of upadacitinib for the treatment of moderate to severe Crohn's disease.

Janus kinases (JAK) are enzymes involved in signaling pathways that activate the immune system. Upadacitinib, an oral small molecule, is the first JAK inhibitor approved by FDA and EMA for the treatment of moderately to severely active Crohn's disease (CD), following successful phase II and III trials. Compared to other JAK inhibitors, upadacitinib has a high selectivity toward JAK1. This characteristic could improve its efficacy and safety. This review provides an overview of the available knowledge on the pharmacokinetics of upadacitinib as induction and maintenance therapy for CD. The approval of newer targeted small molecules drug, including JAK inhibitors, marked a significant advancement in terms of effectiveness. In fact, the oral administration, the rapid absorption, the excellent bioavailability and the short serum time of maximum concentration are some of the advantages compared to biologics. The selective inhibition of JAK1 by upadacitinib allows for high efficacy while maintaining a reliable safety profile.

Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.

Higher infection risk for JAK inhibitors tofacitinib and baricitinib compared to subcutaneous biological DMARDs.

Rheumatoid arthritis (RA) is usually treated with disease modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs) and more recently, Janus kinase inhibitors (JAKi). Randomized trials suggest similar infection risks for JAKi and bDMARDs, but real-world data are scarce. From a nationally representative prescription database, adult RA patients starting a new JAKi or bDMARD between August 1st, 2018, and January 31st, 2021, were included. Prescriptions of antibiotic, antiviral or antifungal medication were used as proxy for infections. Infection incidence rates (IR) were compared between JAKi and bDMARDs and infection risks were estimated using multilevel Poisson regression adjusted for follow-up time and potential confounders and stratified for age < 65 and ≥ 65 years. In 14,989 patients, we identified 20,050 treatment episodes with either JAKi or bDMARDs. The infection IR was significantly higher in JAKi (48/100 patient years) compared bDMARDs (35/100 patient years, adjusted incidence rate ratio (IRR) 1.22, 95% CI 1.12-1.33). More herpes zoster infections were seen in JAKi compared to bDMARDs (adjusted IRR 2.65, 95% CI 1.94-3.60). No significant differences in infection IRs were found comparing JAKi baricitinib and tofacitinib. In older patients, infection IRs were higher, but IRRs were similar between age groups. In comparison to bDMARDs, JAKi are associated with a slightly higher infection risk and a higher risk of herpes zoster specifically. In older patients, infection IRs are higher but similar infection risks for JAKi and bDMARDs are observed. No differences in infection risk between tofacitinib and baricitinib were found. Key Points • Compared to bDMARDs, JAKi are associated with a slightly higher infection risk for all ages • An increased risk of herpes zoster in patients who use JAK inhibitors was confirmed • No significant differences in infection incidence were found between tofacitinib and baricitinib.

Efficacy of JAK inhibitors in the treatment of psoriasiform atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease with multiple clinical manifestations. Among AD phenotypes, psoriasiform AD shows the coexisting of eczematous itching lesions in flexural areas with psoriasiform plaques. The use of anti-IL-4 and anti-IL-13 in psoriasiform AD may lead to therapeutic failure or worsening of manifestations. A recent Delphi consensus proposed JAK inhibitors (JAKi) as a viable alternative, even in the first line, in patients with different clinical phenotypes of AD, including psoriasiform AD. A retrospective analysis of patients in our dermatology clinic with moderate-severe AD and treated with JAKi was performed. Among the 192 overall patients, 21 had psoriasiform AD. EASI, p-NRS and DLQI were the severity scores considered and their reduction was observed in all 21 patients at weeks 4, 16 and 24 of treatment. At week 16 the percentage of patients achieving EASI-75 and EASI-90 was 80.95% and 66.67%, respectively. While at week 24 95.23% of patients achieved EASI-75 and 85.71% obtained EASI-90. No adverse event lead to treatment interruption. This study confirmed the clinical effectiveness of JAKi treatment in adult patients with moderate-to-severe psoriasiform AD, with a good safety profile. These drugs are proposed as the first choice for the treatment of this form of AD, although further studies with larger cohorts are required.

Refractory moderate-to-severe paediatric-onset alopecia areata with elevated serum IgE treated by JAK inhibitors

Refractory moderate-to-severe paediatric-onset alopecia areata with elevated serum IgE treated by JAK inhibitors

RuBi-Ruxolitinib: A Photoreleasable Antitumor JAK Inhibitor.

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.

JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation.

JAK inhibitors are well known for the treatment of rheumatoid arthritis (RA), but whether they can be used to treat pulmonary fibrosis, a common extra-articular disease of RA, remains to be clarified. A jak2 inhibitor, CEP33779 (CEP), was administered to a rat model of RA-associated interstitial lung disease to observe the degree of improvement in both joint swelling and pulmonary fibrosis. HFL1 cells were stimulated with TGF-β1 to observe the expression of p-JAK2. Then, different concentrations of related gene inhibitors (JAK2, TGFβ-R1/2, and p-STAT3) or silencers (STAT3, JAK2) were administered to HFL1 cells, and the expression levels of related proteins were detected to explore the underlying mechanisms of action. CEP not only reduced the degree of joint swelling and inflammation in rats but also improved lung function, inhibited the pro-inflammatory factors IL-1β and IL-6, reduced lung inflammation and collagen deposition, and alleviated lung fibrosis. CEP decreased the expression levels of TGFβ-R2, p-SMAD, p-STAT3, and ECM proteins in rat lung tissues. TGF-β1 induced HFL1 cells to highly express p-JAK2, with the most pronounced expression at 48 h. The levels of p-STAT3, p-SMAD3, and ECM-related proteins were significantly reduced after inhibition of either JAK2 or STAT3. JAK2 inhibitors may be an important and novel immunotherapeutic drug that can improve RA symptoms while also delaying or blocking the development of associated pulmonary fibrotic disease. The mechanism may be related to the downregulation of p-STAT3 protein via inhibition of the JAK2/STAT signaling pathway, which affects the phosphorylation of SMAD3.

Spinal lipocalin 2 as a factor in the development of central post-stroke pain.

Central poststroke pain (CPSP) is a type of central neuropathic pain whose mechanisms remain unknown. Recently, we showed that activated astrocytes and microglial cells are present in the spinal cord of CPSP model mice. Activated glial cells exacerbate cerebral ischemic pathology by increasing the expression of inflammatory factors. However, the involvement of spinal glial cells in CPSP remains unknown. We hypothesized that spinal glial cell-derived molecules cause hyperexcitability or promoted the development of CPSP. In this study, we identified glial cell-derived factors involved in the development of CPSP using a bilateral common carotid occlusion (BCAO)-induced CPSP mouse model. Male ddY mice were subjected to BCAO for 30 min. The von Frey test assessed mechanical hypersensitivity in the right hind paw of mice. BCAO mice showed hypersensitivity to mechanical stimuli and astrocyte activation in the spinal cord 3 days after treatment. DNA microarray analysis revealed a significant increase in lipocalin 2 (LCN2), is known as neutrophil gelatinase-associated lipocalin, in the superficial dorsal horns of BCAO-induced CPSP model mice. LCN2 colocalized with GFAP, an astrocyte marker. Spinal GFAP-positive cells in BCAO mice co-expressed signal transducer and activator of transcription 3 (STAT3). The increase in the fluorescence intensity of LCN2 and GFAP in BCAO mice was suppressed by intrathecal injection of AG490, an inhibitor of JAK2 and downstream STAT3 activation, or anti-LCN2 antibody. Our findings indicated that LCN2 in spinal astrocytes may be a key molecule and may be partly involved in the development of CPSP.

Comparison of Old and New Systemic Treatments for Moderate to Severe Atopic Dermatitis.

Historically, systemic treatments for atopic dermatitis (AD) primarily consisted of immunosuppressive agents such as corticosteroids and Disease Modifying Antirheumatic Drugs (DMARDS), which provided symptomatic relief but often had long-term adverse effects. Newer treatments have shown significant efficacy with less side effects in clinical trials. This review discusses and compares conventional and newer systemic treatments for AD. Newer medications for AD including dupilumab, tralokinumab, lebrikizumab, and oral JAK inhibitors have been shown to be safe and efficacious. High dose cyclosporine and dupilumab were more effective than methotrexate and azathioprine in improving clinical signs of AD. High-dose upadacitinib was shown in another meta-analysis to be most effective in the measured outcomes but had the highest frequency of adverse events. Targeted biologic treatments are increasingly favored over traditional immunosuppressive treatments of AD. Treatment can be individualized based on potency, adverse side effects, mechanism of action, and administration preference. Ongoing research continues to expand treatment options for AD.

Total eosinophil count as a biomarker for therapeutic effects of upadacitinib in atopic dermatitis over 48 weeks

BackgroundAtopic dermatitis (AD) is a chronic skin disease characterized by type 2-skewed immune responses, and significantly influenced by cytokines dependent on Janus kinases (JAKs). Upadacitinib, a JAK1 inhibitor, is effective for moderate-to-severe AD. This study aims to identify biomarkers that reflect long-term therapeutic effects of upadacitinib 15 mg or 30 mg.MethodsA retrospective study from August 2021 to July 2023 included 213 AD patients treated with upadacitinib 15 mg and 70 AD patients with 30 mg. We analyzed eczema area and severity index (EASI), peak pruritus-numerical rating scale (PP-NRS), serum immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), and total eosinophil count (TEC) at weeks 0, 4, 12, 24, 36, and 48 of treatment.ResultsBoth treatments with upadacitinib 15 mg and 30 mg significantly reduced EASI and PP-NRS scores over week 4 to 48 compared to baseline. Upadacitinib 15 mg or 30 mg treatment significantly decreased TEC compared to baseline through week 4 to 36 or week 4 to 48, respectively. The percent reduction of TEC correlated with those of EASI and PP-NRS through week 4 to 48 of treatment with upadacitinib 15 mg, or through week 12 to 48 with 30 mg, respectively. After adjusting for % reductions of other laboratory markers, the significance of correlations was preserved at weeks 36 and 48 of 15 mg treatment, while at weeks 4 and 36 of 30 mg treatment.ConclusionThe % reduction of TEC correlated with those of EASI and PP-NRS during upadacitinib treatment, indicating its potential as a biomarker reflecting treatment responses to upadacitinib in AD patients. However, the variability of significant correlation during treatment indicates that further inspection is needed for its usefulness in monitoring responses to upadacitinib treatment for AD.

Real-world experience with filgotinib for rheumatoid arthritis in Germany : Aretrospective chart review.

Real-world data for filgotinib, aJanus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA). To explore real-world filgotinib use in patients with RA in Germany. This retrospective chart review included patients aged ≥ 18years with confirmed moderate to severe RA who initiated filgotinib before December1, 2021, with ≥ 6months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded. In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6‑months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity. In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

Gram-negative anaerobes elicit a robust keratinocytes immune response with potential insights into HS pathogenesis.

Hidradenitis Suppurativa (HS) is a chronic autoinflammatory skin disease with activated keratinocytes, tunnel formation and a complex immune infiltrate in tissue. The HS microbiome is polymicrobial with an abundance of commensal gram-positive facultative (GPs) Staphylococcus species and gram-negative anaerobic (GNA) bacteria like Prevotella, Fusobacterium and Porphyromonas with increasing predominance of GNAs with disease severity. We sought to define the keratinocyte response to bacteria commonly isolated from HS lesions to probe pathogenic relationships between HS and the microbiome. Type strains of Prevotella nigrescens, Prevotella melaninogenica, Prevotella intermedia, Prevotella asaccharolytica, Fusobacterium nucleatum, as well as Staphylococcus aureus and the normal skin commensal Staphylococcus epidermidis were heat-killed and co-incubated with normal human keratinocytes. RNA was collected and analysed using RNAseq and RT-qPCR. The supernatant was collected from cell culture for protein quantification. Transcriptomic profiles between HS clinical samples and stimulated keratinocytes were compared. Co-staining of patient HS frozen sections was used to localize bacteria in lesions. A mouse intradermal injection model was used to investigate early immune recruitment. TLR4 and JAK inhibitors were used to investigate mechanistic avenues of bacterial response inhibition. GNAs, especially F. nucleatum, stimulated vastly higher CXCL8, IL17C, CCL20, IL6, TNF and IL36γ transcription in normal skin keratinocytes than the GPs S. epidermidis and S. aureus. Using RNAseq, we found that F. nucleatum (and Prevotella) strongly induced the IL-17 pathway in keratinocytes and overlapped with transcriptome profiles of HS patient clinical samples. Bacteria were juxtaposed to activated keratinocytes invivo, and F. nucleatum strongly recruited murine neutrophil and macrophage migration. Both the TLR4 and pan-JAK inhibitors reduced cytokine production. Detailed transcriptomic profiling of healthy skin keratinocytes exposed to GNAs prevalent in HS revealed a potent, extensive inflammatory response vastly stronger than GPs. GNAs stimulated HS-relevant genes, including many genes in the IL-17 response pathway, and were significantly associated with HS tissue transcriptomes. The close association of activated keratinocytes with bacteria in HS lesions and innate infiltration in murine skin cemented GNA pathogenic potential. These novel mechanistic insights could drive future targeted therapies.

Total knee and hip replacement in rheumatoid arthritis: А current trend

Total joint replacement (TJR) is a surgical procedure widely used in severe destructive joint damage. TJR of the knee and hip joint (TKR and THR respectively) occupies an important place in the complex treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), and can significantly reduce pain and improve function in patients with severe structural joint damage due to an ineffectiveness of conservative therapy. In recent years, due to the development of the modern concept of active treatment of RA (treat-to-target) and the introduction of new classes of anti-inflammatory drugs, such as biologic disease modifying antirheumatic drugs and JAK inhibitors, the need for TJR in RA has begun to decrease. At the same time, the aging of the population, the increase in the number of patients with OA and the lack of generally approved pathogenetic therapy determine the increase of TKR/THR incidence in this disease. This review presents the long-term dynamics of the incidence of TKR and THR according to the national registers of different countries. The issues of the complication risks in patients with RA and OA, current recommendations for anti-rheumatic therapy in RA in the perioperative period are also considered.

JAK/STAT Inhibition Normalizes Lipid Composition in 3D Human Epidermal Equivalents Challenged with Th2 Cytokines

Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.

Efficacy of upadacitinib in the achievement of clinical and endoscopic remission in hospitalized patients with ulcerative colitis.

Janus kinase (JAK) inhibitors have been developed and are clinically available for management of active UC patients although most studies have been conducted for the outpatients and few studies have demonstrated its efficacy in endoscopic and histological remission of hospitalized patients with UC. The aim of the present study was to investigate the efficacy of upadacitinib, which is a novel selective JAK1 inhibitor, in the treatment of ulcerative colitis. We present the cases of three hospitalized patients with ulcerative colitis who achieved clinical remission after significant and rapid improvement with upadacitinib. While upadacitinib was used as the second-line treatment for patients with insufficient treatment effects for corticosteroids or ustekinumab, a patient received it just after admission because they were steroid dependent and previously used advanced therapy before hospitalization. All patients demonstrated rapid clinical responses within 7days and the partial Mayo scores were 0 at week 8. All patients achieved confirmed endoscopic and histological remissions. We conclude that upadacitinib is a potential treatment option for hospitalized patients with an inadequate response to other biologics and JAK inhibitors.

P117 Efficacy of filgotinib in patients with rheumatoid arthritis: Week 156 results from a long-term extension study

Abstract Background/Aims In the treatment of RA, JAK inhibitors are a valuable option to meet remission or low disease activity (LDA) treatment targets following an inadequate response (IR) or intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (DMARD). FIL is a JAK1 preferential inhibitor available in two doses for the treatment of moderate to severe RA. Objectives: To evaluate long-term efficacy of two doses of FIL in clinically relevant pt populations. Methods In this interim analysis, efficacy (non-responder imputation) of FIL 200 mg (FIL200) and 100 mg (FIL100) was assessed from LTE baseline (BL) to W156 in pts with an IR to methotrexate (MTX-IR) and biologics (bDMARD-IR), enrolled from FINCH 1 (NCT02889796) and 2 (NCT02873936) parent studies (PS), respectively, receiving ≥1 FIL dose in FINCH 4 (NCT03025308). Results Study design, BL characteristics and W48 outcomes for MTX-IR1 and bDMARD-IR2 pts were reported previously. For MTX-IR and bDMARD-IR pts who received FIL200 or FIL100 in the PS, W156 remission rates using Boolean 1.0 criteria were 20.5% and 15.8%, and 18.2% and 8.9%, respectively. Adopting the Boolean 2.0 criteria slightly increased remission rates for FIL200 and FIL100 at W156: +4.2% and +4.9% for MTX-IR pts, and +1.5% and +2.4% for bDMARD-IR pts, respectively. For pts rerandomized to FIL on entering the LTE, Boolean 2.0 criteria also increased remission rates vs Boolean 1.0. Both MTX-IR and bDMARD-IR pts maintained long-term Boolean remission through W156 with FIL200 and FIL100, irrespective of prior FIL. Results for Disease Activity Score 28 with C-reactive protein (DAS28-CRP) &amp;lt;2.6, Clinical Disease Activity Index (CDAI) ≤2.8, and Simplified Disease Activity Index (SDAI) ≤3.3, and mean change from PS BL in Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain are shown (Table). Similar trends in efficacy were seen for LDA and ACR response criteria. Conclusion In FINCH 4, both FIL200 and FIL100 showed sustained efficacy up to W156 in clinically relevant pt populations. Boolean 2.0 criteria classified more pts in remission, in line with the range reported in the validation study. Disclosure M.H. Buch: Consultancies; AbbVie, CESAS Medical, Galapagos, Gilead, and Pfizer (all paid to host institution). Member of speakers’ bureau; AbbVie (paid to host institution). Grants/research support; Gilead (paid to host institution). D. Aletaha: Consultancies; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Member of speakers’ bureau; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. Grants/research support; AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi. R. Caporali: Consultancies; AbbVie, Fresenius, Galapagos, Lilly, Novartis, Pfizer, and UCB. Member of speakers’ bureau; AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB. B. Combe: Consultancies; AbbVie, Galapagos, Gilead, Janssen, Lilly, Novartis, and Roche-Chugai. Member of speakers’ bureau; AbbVie, Celltrion, Galapagos, Janssen, Lilly, Pfizer, and Roche-Chugai. H. Schulze-Koops: Consultancies; AbbVie, Galapagos, Lilly, and Pfizer. Member of speakers’ bureau; AbbVie, Galapagos, Lilly, and Pfizer. J. Gottenberg: Consultancies; AbbVie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis, and Pfizer. Grants/research support; BMS and Pfizer. Y. Tanaka: Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Mitsubishi-Tanabe, and Pfizer. Grants/research support; AbbVie, Asahi-Kasei Pharma, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Takeda. R. Blanco: Consultancies; AstraZeneca, Galapagos, Janssen, Novartis, and Pfizer. Member of speakers’ bureau; AbbVie, Amgen, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Sanofi. Grants/research support; AbbVie and Roche. T. Takeuchi: Consultancies; AbbVie GK, Astellas, Chugai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, and Pfizer Japan Inc. Member of speakers’ bureau; AbbVie GK, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, Pfizer Japan Inc., and Sanofi K.K. Grants/research support; AbbVie GK, Asahi-Kasei Pharma, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Mitsubishi-Tanabe, Nippon Kayaku, and UCB Japan. E. V. Ekoka Omoruyi: Consultancies; Galapagos and Janssen. Shareholder/stock ownership; UCB. K. Van Beneden: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. V. Rajendran: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. C. Watson: Shareholder/stock ownership; Galapagos. Other; Employee of Galapagos. F. De Leonardis: Other; Employee of Galapagos. P. Emery: Consultancies; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung.

P039 A systematic review and meta analysis of anti rheumatic drugs and pneumococcal vaccine immunogenicity in inflammatory arthritis

Abstract Background/Aims Pneumococcal pneumonia is an important cause of morbidity and mortality amongst patients with inflammatory arthritis. Vaccination is recommended by the National Institute of Clinical Excellence (NICE) but it remains unclear how vaccine efficacy is impacted by different immunosuppressive agents. Our objective was to compare the chance of a seroconversion following vaccination against pneumococcus in patients with inflammatory arthritis to the general population as well as to compare the chance of seroconversion across different targeted therapies. Methods We searched MEDLINE, Embase and the Cochrane library databases from inception until 20th June 2023. We included randomised controlled trials and observational studies. Aggregate data were used to undertake pairwise meta-analysis. Our primary outcome of interest was vaccine seroconversion. We accepted the definition of serological response reported by the authors of each study. Results 20 studies identified in the systematic review (2,807 patients) with 10 reporting sufficient data to be included in the meta-analysis (1,443 patients). The odds of seroconversion in patients receiving targeted therapies, relative to the general population, was 0.61 (95% CI 0.35 to 1.08). The reduced odds of response was skewed strongly by the effects of abatacept and rituximab with no difference between patients on TNF inhibitors or IL6 inhibition and healthy controls. In the analysis comparing within inflammatory arthritis populations the findings remained consistent with rituximab having the strongest negative impact on vaccine response. TNF inhibition monotherapy associated with a greater odds of vaccine response compared with methotrexate (2.25 (95% CI 1.28 to 3.96)). JAK inhibitor studies were few in number and did not present comparable vaccine response endpoints to include in meta-analysis. The information available does not suggest a significant detrimental effects of JAK inhibitor on vaccine response. Conclusion This updated meta-analysis confirms that for the majority of patients with inflammatory arthritis, pneumococcal vaccine can be administered with confidence that it will achieve comparable seroconversion rates to the healthy population. Patients on rituximab were the group least likely to achieve a response and further research is needed to explore the value of multiple course pneumococcal vaccination schedules in this population. Disclosure D. Nagra: Honoraria; Abbvie, Galapagos, UCB. K. Bechman: None. M. Adas: None. Z. yang: None. E. Alveyn: None. S. Patel: None. M. Russell: None. S. Norton: None. C. Wincup: None. C. Baldwin: None. J. Galloway: None.

OA05 Potential impact of European Medicines Agency measures to minimise risk of serious side effects on those using JAK inhibitors in the UK

Abstract Background/Aims Janus kinase inhibitors (JAKi) are effective therapies for rheumatoid arthritis (RA). However, concerns about their safety in certain 'at-risk' populations have resulted in risk minimisation measures introduced by European Medicines Agency (EMA) in January 2023, which limits JAKi prescription to certain patient subgroups unless no suitable alternative is available. The potential impact on current and future JAKi use in the UK is unknown. Using a national cohort study of patients who have already started their first JAKi, this analysis aimed to describe the proportion meeting ≥1 of these criteria and therefore may be impacted by these changes. Methods RA patients starting their first-ever JAK inhibitor (tofacitinib, baricitinib, upadacitinib, or filgotinib) therapy in the British Society for Rheumatology RA Biologics Register (BSRBR-RA) before 31st May 2022 (pre-EMA warning) were included. Patients with missing data in any EMA criteria related variables were excluded. Descriptive statistics were used to present patients' characteristics at the start of JAKi. This analysis defined four at-risk criteria assessed at the treatment start: 1) aged ≥65; 2) increased risk of major cardiovascular issues (history of hypertension, hyperlipidaemia, diabetes, ischaemic heart disease, or stroke); 3) current or past smokers; 4) increased risk of cancer (defined as prior cancer). The previous number of distinct biological disease-modifying antirheumatic drugs (bDMARDs) classes was described among those who met the criteria. Results A total of 1,362 patients starting their first JAKi were included, most commonly baricitinib (76%), followed by tofacitinib (16%; see Table). The cohort was 78% female, with an average age of 60. Among them, 28% of patients had received ≥3 prior bDMARDs classes. 80% percent of patients (1,090) met ≥1 EMA risk criterion, with the most common individual criterion current/past smoker (54%). Of those who met ≥1 risk criteria, 645 (59%) met ≥1 EMA risk criterion and 29% had already received ≥3 prior bDMARDs classes. Conclusion A very high proportion of patients, four-in-five, initiating JAKi in UK before the EMA advisory would have fallen into the ‘high-risk' category for whom prescribing would only be advised if no suitable alternatives were available. Whilst almost a third of them had previously received ≥3 different bDMARDs classes, it’s likely that many of them would have suitable alternatives. These data highlight the enormous impact of the recent licensing updates for JAKi class. Disclosure Z. Tian: None. L. Kearsley-fleet: None. J. Galloway: Honoraria; Abbvie, Galapagos, Janssen, Lilly, Novartis, Pfizer, UCB, Vifor. Grants/research support; Abbvie, Galapagos, GSK, Janssen, Pfizer. K. Watson: None. M. Lunt: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; Pfizer, BMS.