Explore the vast range of titles available.

Adult-onset Still’s disease (AoSD) is a rare but clinically well-known, polygenic, systemic autoinflammatory disease. Owing to its sporadic appearance in all adult age groups with potentially severe inflammatory onset accompanied by a broad spectrum of disease manifestation and complications, AoSD is an unsolved challenge for clinicians with limited therapeutic options. This Review provides a comprehensive insight into the complex and heterogeneous nature of AoSD, describing biomarkers of the disease and its progression and the cytokine signalling pathways that contribute to disease. The efficacy and safety of biologic therapeutic options are also discussed, and guidance for treatment decisions is provided. Improving the approach to AoSD in the future will require much closer cooperation between paediatric and adult rheumatologists to establish common diagnostic strategies, treatment targets and goals.

Adult-onset Still’s disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still’s disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials.

Introduction: The past decade has seen increasingly rapid advances in understanding the pathogenic nature of adult-onset Still’s disease (AOSD) and its shared symptoms with the systemic juvenile idiopathic arthritis (sJIA). Interleukin-1 (IL-1) blocking agents are key elements in the treatment. In this updated systematic review, we focus on studies on efficacy and safety of IL-1 blockers published in the past 5 years and review on latest available therapies. Methods: We conducted searches using Medline, Biosis, Embase, and Cochrane databases between 2016 and 2021 using the terms AOSD, IL1, IL-18, canakinumab, anakinra, tadekinig, and rilonacept and if applicable their trade names. Duplicates, case reports, and manuscripts with incomplete data were excluded. Results: Of the 1013 screened publications, 17 were eligible after careful selection. We only found two published randomized controlled studies in the past 5 years. Review manuscripts of rare diseases, like our work, usually rely on retrospective studies and case series. Anakinra and canakinumab can be successfully used as first- or further-line treatment in patients with AOSD refractory to steroids. A homogeneous outcome is not established yet. Thus, a combination of clinical and laboratory tests can support the experienced clinician in the decision-making process. Conclusion: The approval of IL-1 inhibitors for AOSD brought us into a new era in the treatment of AOSD. The overall efficacy-safety profile of the IL-1 inhibitors is favorable reflecting a targeted approach as standard of care. We can expect that the successful treatment of AOSD with IL-1 inhibition will facilitate further clinical and basic research with impact on other auto-inflammatory and hyper-inflammatory conditions.

Background Upadacitinib (UPA), an oral Janus kinase inhibitor, has shown efficacy with an acceptable safety profile in rheumatoid arthritis (RA) clinical trials. Objective To assess the real-world effectiveness and safety of UPA in adults with moderate-to-severe RA in the UPHOLD observational study. Methods Co-primary endpoints were: (i) proportion of patients achieving disease activity score in 28 joints using C-reactive protein (DAS28[CRP]) remission (< 2.6) at 6 months; and (ii) proportion of those patients maintaining remission at 12 months. Additional analyses included proportions of patients achieving and maintaining DAS28(CRP) low disease activity (LDA; ≤ 3.2), other composite measures of disease activity, and subgroup analyses by therapy strategy and prior treatment. Treatment-emergent adverse events (TEAEs) in the full analysis set (FAS; patients receiving ≥ 1 UPA dose) were reported through August 10, 2023. Co-primary and selected secondary endpoints were analyzed by modified non-responder imputation (mNRI) in modified (m)FAS1 (FAS patients who completed 6 months of treatment and had DAS28[CRP] data available, and those who discontinued before 6 months) and mFAS2 (mFAS1 patients who achieved remission at 6 months, completed 12 months of treatment, and had DAS28[CRP] data available, and those who discontinued between 6 and 12 months); and as observed (AO) in patients with non-missing data. Results Of 1719 participants, 1717 were enrolled; 1701 comprised the FAS. Overall, 400/1719 (23.3%) patients discontinued before 12 months. Of mFAS1 patients, 499 (mNRI: 499/1074 [46.5%]; AO: 499/902 [55.3%]) achieved DAS28(CRP) remission at 6 months; of mFAS2 patients, 269 (mNRI: 269/340 [79.1%]; AO: 269/317 [84.9%]) maintained remission at 12 months. DAS28(CRP) remission or LDA rates were consistent regardless of whether UPA was initiated and maintained as monotherapy or combination therapy. Similar responses were observed across prior treatment subgroups. Among selected TEAEs of special interest, herpes zoster and serious infection occurred at 3.12 and 2.62 events/100 patient-years, respectively. No new safety signals were identified. Conclusions UPA demonstrated real-world effectiveness in moderate-to-severe RA, with approximately half of patients achieving DAS28(CRP) remission at 6 months and most maintaining remission through 12 months. The real-world benefit–risk profile of UPA remains favorable and is consistent with phase 3 clinical trial data. Trial registration NCT04497597

Background/Objectives: Whole-body cryotherapy (WBC) is increasingly utilized as a physical modality for managing chronic pain, although its mechanism of action remains incompletely understood. This study evaluated whether WBC influences serum levels of substance P, calprotectin, β-nerve growth factor (β-NGF), and calcitonin gene-related peptide (CGRP), which are implicated in pain modulation. Methods: Serum samples from 61 participants—37 undergoing WBC and 24 not receiving WBC—were collected at the start and end of a multimodal inpatient pain treatment program. Pain intensity was assessed using a numerical rating scale (NRS). Biomarker concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results: Both groups reported an average significant pain reduction of more than 1.39 points on the NRS. Of the biomarkers analyzed, only calprotectin showed a statistically significant reduction in the overall cohort (p = 0.007) and in the WBC subgroup (p = 0.032). Among patients who did not experience significant pain reduction, those in the WBC group exhibited a greater decline in calprotectin compared to controls (p = 0.042), especially among those without medication changes (p = 0.016). No significant differences were detected for the other serum parameters. Conclusions: The analgesic effects of WBC could not be attributed to changes in the neuromodulatory peptides measured. However, the significant reduction in calprotectin suggests a potential anti-inflammatory effect of WBC on the innate immune response.

Rheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients’ profiles and comorbidities is essential for optimal outcomes. A ‘treat-to-profile’ approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars – lower-cost alternatives to biologics – further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities. Plain language summary What have we learnt from the inhibition of IL-6 in RA and identifying the clinical opportunities for patient outcomes? Rheumatoid arthritis (RA) is a condition where joints become swollen and painful due to long-term (chronic) inflammation. If left untreated, it can cause severe joint damage, disability and even increase the risk of death. The disease is driven by cytokines, which are proteins in the body that help control the immune system and can cause inflammation. One important cytokine is interleukin-6 (IL-6), and scientists are studying ways to block its effects to help people with RA. This review looks at how IL-6 works in RA and how blocking it might help. Despite new treatments, it is still hard to fully control RA. Researchers are trying to find better ways to personalise treatments based on the symptoms of individual patients. One drug called tocilizumab stops IL-6 from working by attaching to its receptor. A receptor is a part of a cell that receives signals from substances like cytokines. When IL-6 attaches to its receptor, it triggers inflammation. Tocilizumab stops IL-6 from attaching to its receptor, reducing pain and inflammation in people with RA. This drug not only helps the joints but may also improve other problems like anaemia, heart disease and even depression that often come with RA. The review suggests that treating RA should involve looking at the person’s overall health, not just the joints. IL-6 blockers might be particularly useful for patients with other health issues or for those who have not responded well to other treatments. Biosimilars, which are similar to the original IL-6 blocking drug but less expensive, have expanded the treatment options. Combining personalised treatments with more affordable options could help improve the lives of people with RA. Overall, IL-6 blockers seem to be a promising way to help people with RA, especially when used in a personalised approach that considers the whole person and their overall health.

Background Patients with rheumatoid arthritis (RA) have an increased prevalence of comorbidities, which is associated with higher RA disease activity and worse disease outcomes. The aim of this analysis was to evaluate the impact of the comorbidity burden on the efficacy of the IL-6 inhibitor olokizumab (OKZ) and the tumour necrosis factor (TNF) inhibitor adalimumab (ADA) in the CREDO-2 randomized controlled clinical trial cohort of patients with active RA. Methods A total of 1402 patients with RA were included in the analysis and divided into two groups on the basis of the modified Charlson Comorbidity Index (mCCI) at baseline: those having no comorbid conditions, NCC (mCCI = 1; RA only) vs. those having comorbid conditions, CC (mCCI ≥ 2; RA and ≥ 1 comorbidity). The key outcomes at Week (W) 24 were the proportions of patients with CDAI ≤ 10 and CDAI ≤ 2.8, other outcomes were ACR50 (W12, W24), proportions of patients with SDAI ≤ 3.3 (W24). Results All groups had similar proportions of approximately 25% of patients with mCCI ≥ 2. There was no significant difference in efficacy between the OKZ q4w or q2w-treated NCC and CC groups at 3 and 6 months of treatment. The same was observed for the placebo group. In contrast, comorbidities reduced CDAI ≤ 10 and ACR50 outcomes upon ADA treatment at 6 months. Conclusion This post hoc analysis of the phase III CREDO-2 study suggests that the presence of at least one CCI comorbidity, including common disorders such as chronic pulmonary diseases and cardiovascular diseases, does not affect the OKZ treatment results in RA patients. In contrast, comorbidities reduce several efficacy outcomes upon ADA treatment at 6 months. The CCI was not associated with placebo group results and had no influence on safety outcomes. Trial registration NCT02760407 submitted 2016-05-02.

Despite recent promising developments in the treatment of rheumatoid arthritis (RA), a substantial proportion of patients still cannot achieve the treatment targets: low disease activity and remission. Janus kinase (JAK) inhibitors have the potential to fill this important gap with their high efficiency, rapid onset of action, and acceptable safety profile. The fact that the previously approved two JAK inhibitors, tofacitinib and baricitinib, inhibit more than one JAK molecule raised the question whether a safer profile can be possible by inhibiting fewer JAK molecules. Upadacitinib, a JAK 1 selective molecule developed in this context has been evaluated in the SELECT phase-III study program and demonstrated a high and rapid efficacy in monotherapy as well as in combination with csDMARDs both in csDMARD-naive RA patients and in patients refractory to csDMARD and bDMARD treatments. Upadacitinib 15 mg once daily displayed a similar safety profile except for increased creatine phosphokinase (CPK) levels and herpes zoster (HZ) risk compared to its active comparators methotrexate (MTX) and adalimumab. Most of the CPK elevations were asymptomatic, and most of the HZ cases were not serious. Along with the randomized-controlled studies and meta-analysis results, upadacitinib 15 mg once daily has a favorable efficacy/safety profile. Long-term extensions of current studies and real-world data will be important to fully appreciate its potential in the treatment of RA.

Background/Objectives: This study aims to report and compare data from the PRO-AOSD (patient-reported outcomes adult-onset Still’s disease) survey in patients with AOSD from the perspective of patients and their treating physicians. Methods: PRO-AOSD comprised blinded patient and physician surveys. The surveys were designed to assess perceived symptoms and physical impairment. Outcomes reported here include patient demographics; physicians’ assessment of the patient’s health state; physician-reported laboratory findings; pain; disease activity; symptoms; physicians’ treatment goals; and the impact of lifestyle factors on disease improvement. Results: Adult patients with AOSD were recruited from 19 centers in Germany. A total of 124 patients were included, with 74 (59.7%) females; the mean age was 45.5 years. The mean time from first symptom to diagnosis was 2 years, and the mean time was 7 years from diagnosis to survey completion (N = 123). Of 107 patients, most (81.3%) had inactive disease defined by CRP levels. At the time of the survey, around two-thirds of patients were receiving biologic therapy, with 84.1% (69/82) reporting an improvement in symptoms. Many patients had previously received antibiotics (47.6% [n = 58] and 30.4% [n = 37], per patient and physician reports, respectively). Persistent symptoms were reported more frequently by patients than by physicians, including back pain (39.5%), fatigue and weakness (38.7%), and joint inflammation (27.4%). Physicians classified 35.5% of patients as symptom-free. Patients reported exercise as having a positive impact on symptoms (52.4%), while stress (74.2%) and sleep deprivation (62.9%) were reported to worsen symptoms. Targeting systemic manifestations, such as the absence of fever (58.1%, n = 72), was considered the most important treatment goal by physicians. Conclusions: Data from PRO-AOSD highlight distinct differences between patients’ and physicians’ interpretations of the same cases of AOSD. Prior Presentation: These data were presented at the German Congress of Rheumatology (DGRh; 30 August–2 September 2023; Leipzig, Germany).

Background/Objectives: To report patients’ perspectives on the impact of adult-onset Still’s disease (AOSD) on their health-related quality of life (HRQoL), work productivity and the effect of coronavirus (COVID)-19, using data from the PRO-AOSD (patient-reported outcomes adult-onset Still’s disease) survey in Germany. Methods: The PRO-AOSD survey comprised blinded patient and physician surveys. An additional post-hoc analysis was performed to determine the relationship between HRQoL and disease activity (defined per C-reactive protein and Physician’s Global Assessment data). The following outcomes were reported: patients’ perspectives on the impact of AOSD on their physical and mental HRQoL and work productivity, outcomes for patients with active versus inactive disease, and the effect of COVID-19 on their general health and work productivity. Results: Adult patients with AOSD were recruited from 19 centers in Germany. A total of 124 patients were included: 59.7% (74/124) were female, and the mean age of diagnosis was 38.2 years. Reported HRQoL was impaired in almost all domains, especially physical health. For the 58 patients whose data enabled categorization into active (31.0%, 18/58) versus inactive disease (69.0%, 40/58), patients with active disease reported significantly worse outcomes in the following (p < 0.001): likelihood of perceiving their health as excellent or similar to other people’s health, severity of pain in the past month, and the ability to complete strenuous activities. Although all patients were of working age, not all were employed (60.5%, 75/124). Many patients felt that compared to their peers, they were more burdened by the COVID-19 pandemic (33.9%) and were more afraid of contracting COVID-19 (49.2%). Conclusions: Patients with AOSD suffered from impaired HRQoL, which was worsened by active disease and the COVID-19 pandemic.