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Schmerz (Berlin, Germany) Feb 2024In everyday clinical practice, immunologically mediated systemic vasculitides are among the rare diseases, meaning that basic knowledge of major symptoms and indicative... (Review)
Review
In everyday clinical practice, immunologically mediated systemic vasculitides are among the rare diseases, meaning that basic knowledge of major symptoms and indicative laboratory findings is crucial for the inclusion of these complex clinical entities in differential diagnostic considerations. For many years, systemic vasculitides have been classified according to the primarily affected vessel size, distinguishing large, medium-sized, and small vessels. Pain is very often one of the main complaints of these diseases, be it, for example, the temporally accentuated headache in giant cell arteritis, the early morning myalgias in the shoulder and hip girdle in polymyalgia rheumatica, or the mononeuritis multiplex in eosinophilic granulomatosis with polyangiitis. General symptoms such as fever, weight loss, and night sweats are often accompanied by greatly increased parameters of inflammation. In addition, organ-specific symptoms and/or laboratory abnormalities may provide crucial information. These include ENT symptoms, pulmonary or skin manifestations, as well as signs of renal involvement, such as peripheral edema, rise in blood pressure, hematuria, proteinuria, or a rapid loss of kidney function. If there is reasonable suspicion of disease, patients should be transferred to specialized centers with an interdisciplinary team. In most cases, an immunosuppressive therapy regimen is required, although in recent years the path towards avoiding high glucocorticoid doses with many side effects has been paved by the use of novel therapies.
Topics: Humans; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Headache
PubMed: 37828257
DOI: 10.1007/s00482-023-00760-3 -
Rheumatology (Oxford, England) May 2024Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets...
OBJECTIVE
Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR.
METHODS
We meta-analysed genetic association data from 8,156 cases of PMR (defined using diagnostic codes and self-report) and 416,495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55,792 individuals), using the inverse variance weighted and pleiotropy robust methods.
RESULTS
We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08-1.60; p = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10-1.37; p = 3.10x10-4) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signaling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; p = 1.89x10-32), serum amyloid A2 (OR 1.06, 9.91x10-10) and CXCL6 (OR 1.09, p = 4.85x10-7) retained significance after correction for multiple testing.
CONCLUSION
Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice.
PubMed: 38788669
DOI: 10.1093/rheumatology/keae308 -
Human Vaccines & Immunotherapeutics Dec 2024We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile...
We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2-30) and 7 (range 2-25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.
Topics: Adult; Humans; Middle Aged; Giant Cell Arteritis; Polymyalgia Rheumatica; COVID-19 Vaccines; Ad26COVS1; BNT162 Vaccine; ChAdOx1 nCoV-19; COVID-19; Vaccination
PubMed: 38563792
DOI: 10.1080/21645515.2024.2334084 -
Rheumatic Diseases Clinics of North... May 2024Polymyalgia rheumatica (PMR) immune-related adverse events (ICI-PMRs) represent a novel, distinct entity, despite many clinical, laboratory, and imaging similarities to... (Review)
Review
Polymyalgia rheumatica (PMR) immune-related adverse events (ICI-PMRs) represent a novel, distinct entity, despite many clinical, laboratory, and imaging similarities to classical PMR. Important questions remain in differentiating ICI-PMR from classical PMR, as well as other immune-related adverse events and PMR mimics. Despite this, ICI-PMR currently takes treatment cues from classical PMR, albeit with considerations relevant to cancer immunotherapy. Comparisons between ICI-PMR and classical PMR may provide further bidirectional insights, especially given that important questions remain unanswered about both diseases. The cause of classical PMR remains poorly understood, and ICI-PMR may represent a model of induced PMR, with important therapeutic implications.
Topics: Polymyalgia Rheumatica; Humans; Immune Checkpoint Inhibitors
PubMed: 38670724
DOI: 10.1016/j.rdc.2024.02.001 -
Expert Review of Clinical Immunology 2023Polymyalgia rheumatica is a common inflammatory rheumatic disease in subjects aged 50 years or older and classically presents with shoulder and/or pelvic girdle pain... (Review)
Review
INTRODUCTION
Polymyalgia rheumatica is a common inflammatory rheumatic disease in subjects aged 50 years or older and classically presents with shoulder and/or pelvic girdle pain and prolonged morning stiffness. Glucocorticoids represent the standard of treatment; glucocorticoid therapy is usually required for 1-2 years and often results in significant glucocorticoid-related side effects, especially in the elderly.
AREAS COVERED
In this review, we aimed to provide a comprehensive overview of the management of polymyalgia rheumatica, with a particular focus on adjunctive therapies to the standard glucocorticoid treatment.
EXPERT OPINION
Given the high frequency of disease relapses (one-third of patients) and the adverse events related to prolonged glucocorticoid use, the need for glucocorticoid-sparing agents remains an important issue in the management of polymyalgia rheumatica. In selected patients, who are at risk for glucocorticoid-related side effects or in those with glucocorticoid-refractory disease, the addition of a glucocorticoid-sparing agent, either a synthetic or biologic disease-modifying anti-rheumatic drug, may represent a reasonable and effective therapeutic approach.
Topics: Aged; Humans; Polymyalgia Rheumatica; Glucocorticoids; Giant Cell Arteritis; Antirheumatic Agents; Steroids
PubMed: 37480289
DOI: 10.1080/1744666X.2023.2240519 -
The Lancet. Rheumatology Dec 2023Medium-dose glucocorticoids can improve symptoms in nearly all patients with polymyalgia rheumatica. According to its good safety profile, abatacept could be used... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Medium-dose glucocorticoids can improve symptoms in nearly all patients with polymyalgia rheumatica. According to its good safety profile, abatacept could be used instead of glucocorticoids in early polymyalgia rheumatica. We aimed to determine whether the efficacy of abatacept is sufficient to justify larger studies in early polymyalgia rheumatica.
METHODS
To evaluate whether abatacept allows low disease activity without glucocorticoids in early polymyalgia rheumatica, we conducted a proof-of-concept, randomised, double-blind, placebo-controlled, parallel-group trial. Participants were recruited from five centres in France (in Brest, Le Mans, Morlaix, Dinan and Saint Malo, and Strasbourg) and were included if they had recent-onset (<6 months) polymyalgia rheumatica with a C-reactive protein (CRP) polymyalgia rheumatica activity score (PMR-AS) of more than 17 without any signs or symptoms of giant cell arteritis (clinical and [F]fluorodeoxyglucose PET-CT evaluation). Participants were randomly assigned (1:1) to receive weekly subcutaneous abatacept (125 mg) or matching placebo, with glucocorticoid rescue therapy allowed in cases of high disease activity, for 12 weeks, and then glucocorticoid treatment based on disease activity, until week 36. Investigators, patients, outcome assessors, and sponsor personnel were masked to group assignments. The primary endpoint was low disease activity (CRP PMR-AS ≤10) at week 12 without glucocorticoids and without rescue treatment. The study was powered to demonstrate a 60% difference in response rates between groups. Open-ended adverse events were collected at each visit by clinicians and were categorised following system organ class classification after study completion. The ALORS trial is registered with ClinicalTrials.gov, NCT03632187.
FINDINGS
34 patients (22 women and 12 men) were randomly assigned between Dec 13, 2018, and Oct 21, 2021. All patients who had been randomly assigned were included in the analysis. The primary endpoint was reached by eight (50%) of 16 patients in the abatacept group and four (22%) of 18 patients in the placebo group (relative risk 2·2 [0·9-5·5]); crude p=0·15; adjusted p=0·070). Eight (50%) patients in the abatacept and 15 (83%) in the placebo group had adverse events. Four patients (one [6%] in the abatacept group and three [17%] in the placebo group) had serious adverse events. There were no deaths or new safety concerns.
INTERPRETATION
This study suggests that the effect of abatacept alone is not strong enough to justify larger studies in early polymyalgia rheumatica. This is only a first step in deciding whether a larger study should be conducted in early polymyalgia rheumatica and does not exclude a potential effect of abatacept in glucocorticoid-dependent polymyalgia rheumatica.
FUNDING
BMS Pharma France.
Topics: Female; Humans; Male; Abatacept; C-Reactive Protein; Giant Cell Arteritis; Glucocorticoids; Polymyalgia Rheumatica; Positron Emission Tomography Computed Tomography; Proof of Concept Study
PubMed: 38251563
DOI: 10.1016/S2665-9913(23)00246-1 -
RMD Open Mar 2024The C reactive protein polymyalgia rheumatica activity score (CRP-PMR-AS) is a composite index that includes CRP levels and was developed specifically for PMR. As... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The C reactive protein polymyalgia rheumatica activity score (CRP-PMR-AS) is a composite index that includes CRP levels and was developed specifically for PMR. As treatments such as interleukin-6 antagonists can normalise CRP levels, the erythrocyte sedimentation rate (ESR) of PMR-AS, the clinical (clin)-PMR-AS and the imputed-CRP (imp-CRP)-PMR-AS have been developed to avoid such bias. Our primary objective was to measure the correlation of these activity scores. Our secondary objective was to evaluate the concordance between different cutoffs of the PMR-ASs.
METHOD
Data from the Safety and Efficacy of tocilizumab versus Placebo in Polymyalgia rHeumatica With glucocORticoid dEpendence (SEMAPHORE) trial, a superiority randomised double-blind placebo-controlled trial, were subjected to post hoc analysis to compare the efficacy of tocilizumab versus placebo in patients with active PMR. The CRP-PMR-AS, ESR-PMR-AS, clin-PMR-AS and imp-CRP-PMR-AS were measured at every visit. The concordance and correlation between these scores were evaluated using kappa correlation coefficients, Bland-Altman correlations, intraclass correlation coefficients (ICCs) and scatter plots.
RESULTS
A total of 101 patients were included in the SEMAPHORE trial, and 100 were analysed in this study. The correlation between the PMR-ASs was excellent, as the ICC and kappa were >0.85 from week 4 until week 24 (CRP-PMR-AS ≤10 or >10). Bland-Altman plots revealed that the differences between the CRP-PMR-AS and the other threescores were low. The cut-off values for the clin-PMR-AS were similar to those for the CRP-PMR-AS 86% of the time.
CONCLUSION
The correlation between all the PMR-ASs was excellent, reflecting the low weight of CRP. In clinical trials using drugs that have an impact on CRP, the derived activity scores can be used.
TRIAL REGISTRATION NUMBER
NTC02908217.
Topics: Humans; Polymyalgia Rheumatica; Giant Cell Arteritis; Glucocorticoids; C-Reactive Protein; Blood Sedimentation
PubMed: 38490696
DOI: 10.1136/rmdopen-2023-003741 -
Rheumatology (Oxford, England) Aug 2023The efficacy of anti-IL6 receptors such as Tocilizumab (TCZ) was demonstrated in patients with Polymyalgia Rheumatica (PMR) in two recent randomized controlled trials....
OBJECTIVES
The efficacy of anti-IL6 receptors such as Tocilizumab (TCZ) was demonstrated in patients with Polymyalgia Rheumatica (PMR) in two recent randomized controlled trials. The objective of this multicentre retrospective study was to assess the efficacy of TCZ in PMR patients requiring GC-sparing treatment, as well as different strategies for TCZ withdrawal.
METHODS
We conducted a multicentre study in French tertiary health care departments for patients with PMR. PMR patients receiving off-label TCZ between 2015 and 2022 were included. The primary end point was the proportion of patients tapering to glucocorticoids (GCs) ≤5mg/day 6 months after the first TCZ infusion. The secondary endpoints were the proportion in whom GC was discontinued during follow-up, and the proportion of patients in whom TCZ was discontinued.
RESULTS
Fifty-three PMR patients were included. Thirty-one (31) patients suffered from active PMR despite csDMARDs. GCs were ≤5mg/day in 77% of the patients (95% confidence interval [CI95%]: 36-89) at 6 months, and in 97% of the patients at 12 months. Six and 12 months after the first TCZ infusion, the proportions of GC-free patients were 22.5% (CI95%: 12.7-37.8) and 58.3% (CI95%: 43.2-74.1), respectively. Among TCZ withdrawal strategies, TCZ infusion spacing and TCZ dose reduction were more successful (success in 87% and 79% of attempts, respectively) than TCZ discontinuation (success in 52% of attempts; p= 0.012 and p= 0.039, respectively).
CONCLUSION
In GC-dependent PMR patients, treatment with TCZ led to a drastic decrease in GC dose and remission of PMR. TCZ dose reduction or TCZ infusion spacing are good options to consider in TCZ withdrawal.
PubMed: 37603729
DOI: 10.1093/rheumatology/kead426 -
Best Practice & Research. Clinical... Apr 2024Giant cell arteritis (GCA) is a prototypic autoimmune disease with a highly selective tissue tropism for medium and large arteries. Extravascular GCA manifests with... (Review)
Review
Giant cell arteritis (GCA) is a prototypic autoimmune disease with a highly selective tissue tropism for medium and large arteries. Extravascular GCA manifests with intense systemic inflammation and polymyalgia rheumatica; vascular GCA results in vessel wall damage and stenosis, causing tissue ischemia. Typical granulomatous infiltrates in affected arteries are composed of CD4 T cells and hyperactivated macrophages, signifying the involvement of the innate and adaptive immune system. Lesional CD4 T cells undergo antigen-dependent clonal expansion, but antigen-nonspecific pathways ultimately control the intensity and duration of pathogenic immunity. Patient-derived CD4 T cells receive strong co-stimulatory signals through the NOTCH1 receptor and the CD28/CD80-CD86 pathway. In parallel, co-inhibitory signals, designed to dampen overshooting T cell immunity, are defective, leaving CD4 T cells unopposed and capable of supporting long-lasting and inappropriate immune responses. Based on recent data, two inhibitory checkpoints are defective in GCA: the Programmed death-1 (PD-1)/Programmed cell death ligand 1 (PD-L1) checkpoint and the CD96/CD155 checkpoint, giving rise to the "lost inhibition concept". Subcellular and molecular analysis has demonstrated trapping of the checkpoint ligands in the endoplasmic reticulum, creating PD-L1 CD155 antigen-presenting cells. Uninhibited CD4 T cells expand, release copious amounts of the cytokine Interleukin (IL)-9, and differentiate into long-lived effector memory cells. These data place GCA and cancer on opposite ends of the co-inhibition spectrum, with cancer patients developing immune paralysis due to excessive inhibitory checkpoints and GCA patients developing autoimmunity due to nonfunctional inhibitory checkpoints.
PubMed: 38599937
DOI: 10.1016/j.berh.2024.101943