Clinical Research Directory

Hydrocortisone and Placebo in Patients With Symptoms of Adrenal Insufficiency After Cessation of Glucocorticoid Treatment

Cortisol, a glucocorticoid (GC) hormone secreted from the adrenal glands, is essential for survival. Cortisol also possesses anti-inflammatory actions and GC formulations (prednisolone) are used to treat many inflammatory diseases and conditions. Indeed, three percent of the Danish population (≈ 180.000 individuals) redeems at least one prescription of synthetic GC per year and at least 20,000 patients annually discontinue GC treatment. Pharmacological GC therapy suppresses endogenous cortisol production and thereby induce relative adrenal insufficiency (GIA). The risk of GIA as determined by the adrenal corticotrophic hormone (ACTH) stimulation test has previously been reported to ≈ 25 %, but testing after GC treatment is not routinely performed. Indeed, new evidence suggest that the risk of GIA after planned cessation of prednisolone treatment for polymyalgia rheumatic (PMR) or giant cell arteritis (GCA) is substantially lower, probably 2%. The reason for this discrepancy is undoubtedly selection bias in the previous publications and the use of inaccurate cortisol assays. At the same time, however, it was observed that 25% exhibited pronounced symptoms of adrenal insufficiency based on a questionnaire specific for detecting symptoms of adrenal insufficiency, the so-called AddiQoL-30. Concomitantly, the basal cortisol levels in the same group were significantly lower as compared to the group, who exhibited milder or no symptoms attributable to adrenal insufficiency. This observation aligns with the clinical experience that PMR/GCA patients often complain of fatigue after planned cessation of prednisolone treatment. This often occurs in the absence of objective symptoms or signs of residual PMR/GCA disease activity. The scenario has been designated as "the steroid withdrawal syndrome". This may represent a state of relative adrenal insufficiency prompted by long term, high dose prednisolone treatment. The proper way to tackle this clinical conundrum is to perform a proper randomized trial, which so far has not been conducted. Therefore, investigators of this study will perform the first placebo-controlled randomised controlled trial (RCT) in patients with PMR and GCA after planned cessation of GC treatment. Investigators argue that neither watchful waiting nor routine hydrocortisone replacement are infallible. The study will be the first evidence-based guidance and aid to GIA patients and thus meet an important need for many thousand patients.

Justification And Evaluation of Baricitinib Plus Corticosteroids Versus corticosteroiDs Alone in pOlymyalgia RhEumatica

Polymyalgia rheumatic (PMR) is an inflammatory rheumatic disease affecting the elderly. The diagnosis is based on established ACR/EULAR classification criteria. The activity of the disease is evaluated using the PMR-AS, a disease activity score based on morning stiffness, ability to elevate the upper limbs, physician's global disease assessment and pain assessment measured by the patient using VAS, and the C-reactive protein (CRP) level. The PMR-AS-CRP (PMR-AS) is considered as relevant to define disease activity (low activity \<7; moderate activity 7 to 17; high activity \>17), flare (\>10), remission (\<1.5), but also to decide if treatment has to be decreased, unchanged or increased (PMR-AS \<10: decrease, PMR-AS \>20 increase, 10≤ PMR-AS ≤20: stable dose) \[10-12\]. Long term low-dose glucocorticoid (GCs) (prednisone or prednisolone started at 12.5 to 25 mg/day progressively tapered) is the mainstay of the treatment. But comorbidities in PMR are due to GCs and 30% of the patients underwent a relapse when tapering GCs. Today, the physicians do not know what is the best duration and the best dosage of GCs. The international recommendation suggests to start prednisone at a dose between 12.5 to 25 mg, to be at 10 mg at 1 or 2 months, and then to decrease slowly. The treatment is generally ordered for 6-18 months but it is possible to try a shorter treatment duration when patients have been previously treated with GCs or in case of comorbidities. The TENOR study, a phase 2 study, demonstrated efficacy of tocilizumab as first line treatment in PMR and its ability to spare GCs. The Semaphore study confirmed the usefulness of tocilizumab in corticodependent forms and demonstrated its efficacy. Another IL-6 inhibitor, sarilumab was authorized for the treatment for polymyalgia rheumatic in adult patients with inadequate response to corticosteroid or relapsing disease but is not reimbursed in France. Baricitinib is an oral selective JAK inhibitor of JAK1 and JAK2 with a short half-life. There are two dosages available (i.e., 2-mg and 4-mg) which can help conduct a simple dose tapering. Administration of baricitinib resulted in a rapid dose dependent inhibition of IL-6 induced STAT3 phosphorylation. An evaluation could be made using the PMR-AS with and without imputation to minimize the effect of baricitinib on CRP by anti-IL-6 effect. Preliminary results of the BACHELOR study (34 patients treated with baricitinib or placebo) suggested a great efficacy of baricitinib in early PMR without steroids. It could be a treatment of PMR, with low dose or no steroids only during the first month, to minimize the adverse events of steroids. JAK inhibitors have been reevaluated by EMA, the Oral Surveillance study suggesting that tofacitinib (Xeljanz®) increases the risk of major cardiovascular problems, cancer, VTE, serious infections and death due to any cause when compared with medicines belonging to the class of TNF-alpha inhibitors. EMA has concluded that these safety findings apply to all approved uses of JAK inhibitors in chronic inflammatory disorders. Nevertheless, the risk was not increased during the first months of treatment in all studies and a short treatment could have lower risks than steroids. As no suitable treatment alternatives are available, excepted GCs which increase the vascular risk and osteoporosis, short treatment by jak inhibitor could be a relevant alternative treatment of PMR. Indeed, the physicians do not have any disease modifying drug (excepted anti IL6 off-label) in treatment of PMR. So, GCs are used for more than one year in the treatment of PMR. Baricitinib, used only 6 months demonstrated its ability to cure early PMR without steroids. It could be an alternative to steroid when physicians consider that ratio benefit/risk is better with a 6 months treatment by baricitininib than \>one year by steroids. Our goal is now to demonstrate in a large cohort the ability of a 6-month treatment with baricitinib in comparison to placebo to decrease glucocorticoids and then to maintain low disease activity without corticosteroids in PMR and a good safety profile. Due to the possible lower risk of 2 mg than 4 mg of baricitinib, but probably a lower efficacy, the investigators plan to compare both baricitinib (4 mg and 2 mg) to placebo. The study will be conducted in France.

Using Novel Imaging to Rethink Diagnostic and Treatment Strategies for Polymyalgia Rheumatica

Polymyalgia rheumatica (PMR) is the most common chronic inflammatory rheumatic disease among the elderly and is characterized by proximal extremity pain and fatigue. Treatment with prednisolone carries several significant adverse effects, and it is therefore essential to avoid unnecessary treatment. However, clinical diagnosis and even imaging such as positron emission tomography and computed tomography (PET/CT) has low diagnostic accuracy, which decrease after start of prednisolone. The purpose is to evaluate a new method to diagnose PMR with PET/CT using magnetic resonance imaging (MRI) for informing the interpretation of PET in 111 patients suspected of PMR at baseline and after 8 weeks prednisolone treatment. In addition, a treatment initiation strategy guided by clinical diagnosis combined with PET will be evaluated in 100 patients with newly diagnosed PMR.

Pilot Study to evaluateThrombomodulin to Rule Out Giant Cell Arteritis (GCA) in Polymyalgia Rheumatica (PMR) Patients. (THROPIQ)

Polymyalgia rheumatica (PMR) is a rheumatologic condition occurring in patients \> 50 years old, characterized by inflammatory pain of the scapular (shoulder) and pelvic (hip) girdles. PMR is most often isolated but can be associated with giant cell arteritis (GCA), a large vessels vasculitis, in 16 to 21% of case. The main features of GCA are headaches, jaw claudication, visual disturbances, abnormal temporal artery, scalp tenderness associated to elevated CRP and/or ESR. However, GCA could be asymptomatic in particular in case of isolated involvement of large vessels (subclinical GCA). GCA requires high doses of glucocorticoids, compared to isolated PMR, to avoid complications resulting from vascular remodeling (stroke, blindness). Ruling out GCA in PMR patients relies on the performance of some complementary exams that explore cranial vessels as color doppler ultrasound and/or temporal artery biopsy and large vessels that relies on PET/FDG or angio CT scan. The aim of this study is to identifie serum biomarkers that could rule out or identifies GCA in patients with PMR features. Ultimately, if biomarkers are identified, this could allow to select PMR patients in whom complementary exams are needed or not. For this study, investigators chose to explore thrombomodulin. Thrombomodulin is a protein that is increased in the circulating blood during vascular inflammation, and therefore seems to be a good candidate for distinguish isolated PMR from PMR associated with GCA.

Clinical Assessment for Rheumatologic Disease - Research and Advancement in Safety and Efficacy

The CARe RAiSE project represents a pioneering translational initiative aimed at advancing precision medicine in the treatment of autoimmune rheumatic diseases. The primary objective is the development and implementation of an innovative cell-based ex vivo assay that enables individualized prediction of therapeutic response to disease-modifying antirheumatic drugs (DMARDs). By identifying the most effective treatment option for each patient, this approach seeks to enhance therapeutic efficacy, reduce time to clinical response, and minimize healthcare costs. Despite the availability of numerous DMARDs, clinical decision-making remains largely empirical due to considerable interindividual variability in treatment response. This frequently results in a prolonged trial-and-error process, placing a significant burden on patients and the healthcare system. CARe RAiSE aims to overcome this limitation by providing a functional diagnostic tool that can predict a patient's immunological response to specific DMARDs prior to treatment initiation. The assay is based on peripheral blood mononuclear cells (PBMCs) obtained from individual patients, enabling a physiologically relevant assessment of immune responsiveness to targeted therapies. Combining high-content imaging with homogeneous well-based cytokine and inflammasome activity assays, the platform allows for a detailed single-cell analysis of inflammatory pathways. These data are used to generate predictive signatures of treatment response, thereby facilitating a mechanistically informed and personalized therapeutic strategy. Through this approach, CARe RAiSE introduces a scientifically grounded, efficient, and patient-specific method for DMARD selection, with the potential to substantially improve patient outcomes and reduce the socioeconomic impact of autoimmune rheumatic diseases.

AYLo - AutoimmunitY and Loss of y

The AYLo study (AutoimmunitY and Loss of y - Investigating the Role of Hematopoietic Mutations and Mosaic Mutation in the Y Chromosome in Autoimmune Rheumatologic Diseases) aims to systematically investigate hematopoietic mutations, such as hematopoietic (mosaic) loss of the Y chromosome (mLOY), focusing on their underlying causes, pathophysiological significance, patterns of manifestation, and impact on disease progression in autoimmune, rheumatologic disorders. This research seeks to bridge existing knowledge gaps by exploring how such mutations influence immune homeostasis, cellular function, and susceptibility to inflammation-driven pathologies. Through the integration of advanced immunological profiling, the study aspires to uncover key mechanisms that drive the initiation, progression, and complications of autoimmune rheumatic diseases. These analyses will combine single nucleotide polymorphisms (SNP) arrays, multiplex assays, transcriptomics, and flow cytometry staining of peripheral blood mononuclear cells to delineate the interplay between hematopoietic mutations and immune dysregulation. A further objective is the development of a multimodal framework for disease-specific characterization, enabling precise mapping of mutation-driven phenotypes across diverse autoimmune conditions. This framework will incorporate clinical, molecular, and imaging data. Additionally, the AYLo study aims to explore the potential role of mLOY and other hematopoietic mutations as biomarkers for disease stratification, prognosis, and therapeutic response. The findings may open avenues for personalized treatment approaches, leveraging the molecular insights to inform targeted interventions and improve patient outcomes in autoimmune rheumatic disorders. By integrating translational and basic science approaches, this study has the potential to redefine current paradigms in autoimmune disease research and therapy.

Predictive Factors for Treatment Response in Patients With Newly-diagnosed Polymyalgia Rheumatica and Giant Cell Arteritis

This prospective study is to explore different predictive factors for response to steroid treatment in patients with PMR and/or GCA. It evaluates the association of endogenous GC suppression (plasma and urinary cortisol and cortisone) to the responsiveness of PMR/GCA to GCs.

Vaccination Against Herpes Zoster in Patients With Inflammatory Rheumatic Diseases

The purpose of HZ-REUMA study is explore vaccine response and protection against shingles (herpes zoster, HZ) after vaccination with two doses of Shingrix in immunosuppressed patients with inflammatory rheumatic diseases (IRD) compared to immunocompetent patients with IRD (controls). Hypothesis: The immunological disturbance as part of the rheumatic disease in combination with different immunomodulating treatments may impair vaccine response to non-live HZ vaccine (Shingrix) and thereby lead to an insufficient protection against infection. Primary objective (outcome) 1. The impact of modern anti-rheumatic treatments including synthetic disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate and different biological treatments (anti-TNF, anti IL6r, anti-IL12/23/17, anti-CD20, anti-BlyS, anti-INFERON treatment, or targeted DMARDs (JAK-inhibitors) on antibody response elicited by two doses of subunit vaccine against herpes zoster (HZ) administrated 1-2 months apart in patients with IRD. Secondary outcomes 2. The numbers and frequency of antigen specific CD4 2+ T cells expressing ≥2 or more activation markers (TNFalpha, INF-gama, interleukin-2 or CD40ligand) 3. Long-term immunogenicity of two doses of Shingrix in immunosuppressed patients with IRD measured 3 and 5 after vaccination 4. the tolerability of the vaccine, the impact on existing rheumatic disease, and possible association with onset of new autoimmune diseases 5. if vaccination against herpes zoster protects against infections in patients with inflammatory rheumatic diseases Study Population Adult patients (18 years and older) with a clinically diagnosed inflammatory rheumatic disease and regularly followed at Skåne University Hospital, section for rheumatology in Lund/Malmö, Sweden are eligible for the study and will be offered vaccination free of charge. Control group comprises adult individuals with known inflammatory rheumatic disease without immunosuppressive treatment except for low dose prednisone (max 5 mg daily) . Inclusion criteria: * age ≥18 years (patients) * regular follow up at Skåne University Hospital, section for rheumatology Lund/Malmö due to an inflammatory rheumatic disease (patients) * receive active treatment with disease modifying anti-rheumatic drugs (DMARDs) such conventional synthetic (cs), biologic (b) or targeted synthetic (ts) DMARDs or patients without active immunosuppressive treatment (controls) Exclusions criteria * age \<18 years (patients) * pregnancy (women of childbearing potential, WOCBP, are not excluded since all patients using DMARDs are advised to use a safe and effective contraceptive method) * allergy/intolerability of any component in the vaccine * active infection inclusive herpes zoster (shingles) * received Shingrix vaccine previously * ongoing treatment with any immunosuppressive drug for the other diseases Target enrolment/sample size: 240. Study start date: December, 17 2024- June 30, 2029

A Registry Study Assessing PRO, Dosing Patterns, and Safety of Vunakizumab in Patients With General Rheumatic Diseases.

Ankylosing spondylitis, radiographically negative axial spondyloarthritis, psoriatic arthritis, polymyalgia rheumatica, Takayasu arteritis, giant cell arteritis, non-ocular Behcet's disease, and enthesitis-related arthritis are common diseases in rheumatology. Traditional anti-rheumatic drugs are less effective and have greater side effects than biological agents. At present, there has been no large-scale registration study on rheumatic autoimmune diseases such as spondyloarthritis in China. However, data such as patient characteristics, medication patterns, and patient outcome reports of different rheumatology diseases can often serve as a reference for rheumatology clinicians to reasonably select treatment methods for different patients. Therefore, a large-scale registration study is needed to fill the gap in multi-disease registration studies in rheumatology departments in China.