Real-World Effectiveness and Metabolic Effects of Upadacitinib in Rheumatoid Arthritis after Tumor Necrosis Factor Inhibitor Failure

Abstract

Objectives: To evaluate the real-world effectiveness and laboratory impact of upadacitinib in patients with rheumatoid arthritis (RA) who had an inadequate response to at least one tumor necrosis factor inhibitor (TNFi), with a specific focus on clinical disease activity, inflammatory biomarkers, and metabolic indices. Methods: This single-center, retrospective, real-world study included 82 patients with RA who initiated upadacitinib (15 mg/day) following TNFi failure. Demographic data, disease characteristics, Disease Activity Score in 28 joints (DAS28-CRP), inflammatory markers (CRP and ESR), hematological indices, liver enzymes, and a comprehensive lipid profile were analyzed. In addition, the triglyceride–glucose (TyG) index and the HDL-to-monocyte ratio were calculated as markers of metabolic and cardiovascular risk. Clinical and laboratory parameters were compared between baseline and Week 12 using paired-sample statistical tests. Results: At Week 12, the DAS28-CRP score significantly decreased from 5.4 to 2.9 (p < 0.001), with 80.5% of patients achieving low disease activity or remission. While total cholesterol, LDL-C, and HDL-C levels increased (all p < 0.001), the HDL/monocyte ratio improved significantly by 7.7% (p = 0.012). A moderate negative correlation was observed between the change in DAS28-CRP and the change in HDL/monocyte ratio (rho = -0.42, p = 0.001). Creatine kinase (CK) levels showed a modest but statistically significant increase (+8.1%, p = 0.025); however, values remained within normal reference ranges and were not associated with muscular symptoms or treatment discontinuation. Clinical efficacy was consistent across rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) subgroups. No serious adverse events or treatment discontinuations due to adverse events were observed during the 12-week follow-up period. Conclusions: In this difficult-to-treat, real-world cohort of TNFi-refractory RA patients, upadacitinib demonstrated rapid and robust clinical effectiveness. Despite the anticipated elevations in lipid parameters, the concomitant increase in HDL cholesterol, the stable TyG index, and the marked suppression of systemic inflammation suggest no evident short-term deterioration in metabolic parameters. However, given the 12-week follow-up duration, these metabolic findings should be considered exploratory and hypothesis-generating rather than definitive regarding cardiovascular or metabolic safety. These results support upadacitinib as an effective therapeutic option for anti-TNF–resistant RA in routine clinical practice.

Keywords

• Upadacitinib; Rheumatoid arthritis
• Janus kinase inhibitors; Real-world evidence
• Lipid paradox; Triglyceride–glucose index

TNF İnhibitörü Başarısızlığı Sonrası Romatoid Artritte Upadasitinibin Gerçek Yaşam Etkinliği ve Metabolik Etkileri

Abstract

Amaç: En az bir tümör nekroz faktörü inhibitörüne (TNFi) yetersiz yanıt veren romatoid artrit (RA) hastalarında upadasitinibin gerçek yaşam koşullarındaki etkinliğini ve laboratuvar etkilerini; özellikle klinik hastalık aktivitesi, inflamatuvar biyobelirteçler ve metabolik göstergeler üzerindeki etkilerini değerlendirmek. Yöntemler: Bu tek merkezli, retrospektif, gerçek yaşam çalışmasına TNFi başarısızlığı sonrası upadasitinib (15 mg/gün) başlanan 82 RA hastası dahil edildi. Demografik veriler, hastalık özellikleri, 28 eklemde Hastalık Aktivite Skoru (DAS28-CRP), inflamatuvar belirteçler (CRP ve ESR), hematolojik indeksler, karaciğer enzimleri ve kapsamlı lipid profili analiz edildi. Ayrıca metabolik ve kardiyovasküler risk belirteçleri olarak trigliserid–glukoz (TyG) indeksi ve HDL kolesterolün mutlak monosit sayısına oranı olarak tanımlanan HDL/monosit oranı hesaplandı. Klinik ve laboratuvar parametreleri başlangıç ile 12. hafta arasında eşleştirilmiş örneklem istatistiksel testleri kullanılarak karşılaştırıldı. Bulgular: 12. haftada DAS28-CRP skoru 5,4’ten 2,9’a anlamlı olarak azaldı (p < 0,001) ve hastaların %80,5’inde düşük hastalık aktivitesi veya remisyon sağlandı. Toplam kolesterol, LDL-K ve HDL-K düzeylerinde artış gözlenmesine rağmen (tümü p < 0,001), HDL/monosit oranı %7,7 oranında anlamlı bir iyileşme gösterdi (p = 0,012). DAS28-CRP’deki değişim ile HDL/monosit oranındaki değişim arasında orta düzeyde negatif bir korelasyon saptandı (rho = -0,42; p = 0,001). Kreatin kinaz (CK) düzeylerinde %8,1 oranında istatistiksel olarak anlamlı bir artış izlenmiş (p = 0,025) olmakla birlikte, bu artış klinik referans aralıkları içinde kalmış ve tedavi kesilmesini gerektirmemiştir. Klinik etkinlik romatoid faktör (RF) ve anti-CCP alt gruplarında tutarlıydı. On iki haftalık takip süresince ciddi advers olay gözlenmemiş ve tedavi kesilmesine yol açan yan etki bildirilmemiştir. Sonuç: TNFi’ye dirençli, tedavisi zor bu gerçek yaşam RA kohortunda upadasitinib hızlı ve güçlü bir klinik etkinlik göstermiştir. Beklenen lipid parametre artışlarına rağmen, HDL kolesteroldeki eş zamanlı yükselme, TyG indeksinin stabil kalması ve sistemik inflamasyonun belirgin baskılanması kısa dönemde metabolik parametrelerde belirgin bir bozulma olmadığını düşündürmektedir. Bununla birlikte, 12 haftalık takip süresi kardiyovasküler veya metabolik güvenlik açısından kesin çıkarımlar yapmak için yeterli değildir ve bu bulgular keşifsel nitelikte değerlendirilmelidir. Bu sonuçlar, anti-TNF’ye dirençli RA hastalarında upadasitinibin etkili bir tedavi seçeneği olduğunu desteklemektedir.

Keywords

• Upadasitinib; Romatoid artrit
• Janus kinaz inhibitörleri;
• Gerçek yaşam verileri; Lipid paradoksu; Trigliserid– glukoz indeksi.

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