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OBJECTIVES: Giant cell arteritis (GCA) is a common vasculitis affecting patients aged 50 and older. GCA leads to chronic inflammation of large/medium-sized vessel walls with complications such as permanent vision loss and risk of stroke and aortic aneurysms. Early diagnosis is crucial and relies on temporal artery biopsy (TAB) and ultrasound imaging of temporal and axillary arteries. However, these methods have limitations. Serum biomarkers as autoantibodies have been reported but with inconclusive data for their use in the clinical setting. Additionally, C-reactive protein and erythrocyte sedimentation rate are non-specific and limited in reflecting disease activity, particularly in patients treated with IL-6 inhibitors. This study aimed to identify serum autoantibodies as new diagnostic biomarkers for GCA using a human protein array. METHODS: One commercial and one proprietary human protein array were used for antibody profiling of sera from patients with GCA (n=55), Takayasu (TAK n=7), and Healthy Controls (HC n=28). The identified candidate autoantigens were purified and tested for specific autoantibodies by ELISA. RESULTS: Antibodies against two proteins, VSIG10L (V-Set and Immunoglobulin Domain Containing 10 Like) and DCBLD1 (discoidin), were identified and found to be associated with GCA, with an overall prevalence of 43-57%, respectively, and high specificity as individual antibodies. A control series of TAK sera tested negative. CONCLUSIONS: Detecting GCA-specific autoantibodies may offer a new, non-invasive tool for improving our diagnostic power in GCA. Even though cell-mediated immune responses are crucial for GCA pathogenesis, this finding opens the way for investigating the additional role of humoral immune responses in the disease.
Subject(s)
Autoantibodies , Autoantigens , Biomarkers , Giant Cell Arteritis , Humans , Giant Cell Arteritis/immunology , Giant Cell Arteritis/blood , Giant Cell Arteritis/diagnosis , Autoantibodies/blood , Biomarkers/blood , Autoantigens/immunology , Female , Aged , Male , Middle Aged , Case-Control Studies , Takayasu Arteritis/immunology , Takayasu Arteritis/blood , Takayasu Arteritis/diagnosis , Predictive Value of Tests , Protein Array Analysis , Enzyme-Linked Immunosorbent AssayABSTRACT
OBJECTIVES: MRI is well established for diagnosing GCA. Its role in monitoring disease activity has yet to be determined. We investigated vascular and musculoskeletal inflammation using MRI in the patients of the GUSTO trial to assess the utility of MRI in monitoring disease activity. METHODS: Eighteen patients with newly diagnosed GCA received 500 mg methylprednisolone intravenously for 3 consecutive days followed by tocilizumab monotherapy from day 3 until week 52. Cranial, thoracic and abdominal MRI exams were performed at baseline (active, new-onset disease), and at weeks 24, 52 (remission on-treatment), and 104 (remission off-treatment). MRI findings typical for PMR as well as extent and severity of vasculitic disease were rated. RESULTS: In total, 673 vascular segments and 943 musculoskeletal regions in 55 thoracic/abdominal MRI and 490 vascular segments in 49 cranial MRI scans of 18 patients were analysed. Vasculitic vessels were still detectable in one in four cranial segments at week 24. At weeks 52 and 104, no cranial vascular segment showed a vasculitic manifestation. Large vessels, except for the ascending aorta, and PMR displayed little or no decrease in inflammatory findings over time. CONCLUSION: Vasculitic manifestations in the cranial vessels normalised after 52 weeks of treatment, whereas large vessel and PMR findings persisted despite lasting full remission. The dynamics of cranial vessel signals suggest that MRI of these arteries might qualify as a potential diagnostic tool for monitoring disease activity and for detecting relapse after 52 weeks of treatment.
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OBJECTIVES: We investigated the potential of serum proteins to distinguish clinical and molecular subtypes in patients with giant cell arteritis (GCA). METHODS: Proximity extension assays were used to analyse 1463 proteins in serum samples from patients with new-onset GCA (n = 16) and after achieving remission (n = 13). Unsupervised and supervised cluster analyses were performed. RESULTS: Unsupervised cluster analysis identified three distinct clusters based on the protein signature. Compared with cluster 2, patients of cluster 1 had less polymyalgia rheumatica symptoms, increased levels of macrophage migration inhibitory factor (MIF) and pronounced NF-kB, STAT5 and interleukin-1 signalling. The changes in serum proteins upon remission differed between cluster 1 and 2.Patients with cranial GCA were characterised by altered endothelial and Th17 signalling whereas patients not responding to treatment within the GUSTO-trial showed increased Th1 and diminished B cell signalling. Patients with anterior ischemic optic neuropathy displayed higher levels of CHI3L1 (YKL40), MMP12 and reduced levels of TIMP3. CONCLUSIONS: Protein profiling identifies patient clusters in GCA with distinct proteomic features and therefore likely different pathophysiology. These unique proteomic footprints might lead to more targeted treatments in future.
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OBJECTIVES: To investigate the proportion and distribution of contrast enhancement (CE) of musculoskeletal structures with MRI of the thorax/abdomen/pelvis in giant cell arteritis (GCA). METHODS: CE at 34 musculoskeletal sites was rated with a 4-point ordinal scale. Patients were divided into groups with/without glucocorticoid (GC) treatment and with/without symptoms of polymyalgia rheumatica (PMR). Two composite scores were created: an MRI-score, including seven sites and a Limited-MRI-score, including four sites. RESULTS: Retrospectively, 90 consecutive patients with GCA were included. The population included 54 and 36 patients with and without PMR symptoms, respectively, and 45 (50%) patients were receiving GCs at the time of MRI. CE was found in 90.7% of lumbar spines, 87.5% of the pelvis, 82.2% of shoulder girdles and in 95.6% at any site in patients without GCs. The proportion of patients without and with GCs with at least moderate enhancement was 91.1%/75.6% at ≥ 1-3, 75.6%/51.1% at ≥ 4-6 and 64.4%/28.9% at ≥ 7-9 sites. The mean difference between the proportion of pathological CE in patients with and without GCs was 27.4% for synovial sites and 18.3% for periarticular/musculotendinous sites. Both composite scores captured substantial differences between groups, correlation was very strong between scores. CONCLUSIONS: MRI shows CE of musculoskeletal structures typical of PMR in most patients with GCA, supporting the concept of "GCA-PMR Spectrum Disease". Changes are more frequent at periarticular/musculotendinous sites and in the presence of PMR symptoms. A clear response to GCs is evident, less so for periarticular/musculotendinous sites.
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BACKGROUND: Giant cell arteritis (GCA) is primarily treated with glucocorticoids (GCs), which have substantial toxicity. Tocilizumab, an interleukin-6-receptor inhibitor (IL-6Ri), showed beneficial effects in GCA, leading to its approval. This study investigated the efficacy and safety of sarilumab (another IL-6Ri) in GCA. METHODS: This Phase 3, double-blind study comprised a 52-week treatment period and a 24-week follow-up phase. Eligible GCA patients were randomized to receive sarilumab 200 mg (SAR200 + 26W) or 150 mg (SAR150 + 26W) with a 26-week GC taper, or placebo with a 52-week (PBO + 52W) or 26-week (PBO + 26W) GC taper. The primary efficacy endpoint was sustained remission (SR) at week 52. Additional endpoints were SR at week 24, cumulative GC dose, and safety. The study was discontinued prematurely due to protracted recruitment timelines, because of the impact of COVID-19. Therefore, only descriptive statistics were summarized. RESULTS: Of the planned 360 subjects, only 83 were randomized and 36 were included in the week 52 analysis. At week 52, 46% (n = 6/13) of patients in SAR200 + 26W, 43% (n = 3/7) in SAR150 + 26W, 30% (n = 3/10) in PBO + 52W, and 0 (n = 0/6) in PBO + 26W taper groups achieved SR. Sensitivity analyses, excluding acute-phase reactants from the SR definition, showed similar results for SAR groups, but 60% (n = 6/10) in PBO + 52W and 17% (n = 1/6) in PBO + 26W taper groups achieved SR at week 52. Similar findings were noted at week 24. The proportions of patients who adhered to GC taper from week 12 through week 52 in each group were as follows: 46% (n = 6/13, SAR200 + 26W), 43% (n = 3/7, SAR150 + 26W), 60% (n = 6/10, PBO + 52W), and 33% (n = 2/6, PBO + 26W). The median actual cumulative GC dose received in the SAR200 + 26W group was lower than other groups. Most patients (80-100%) experienced treatment-emergent adverse events, with similar incidences reported across groups. CONCLUSIONS: Owing to the small sample size due to the early termination, it is difficult to draw clear conclusions from this study. There were no unexpected safety findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03600805. Registered on July 26, 2018.
Subject(s)
COVID-19 , Giant Cell Arteritis , Humans , Double-Blind Method , Giant Cell Arteritis/drug therapy , Treatment Outcome , COVID-19 Drug TreatmentABSTRACT
INTRODUCTION: Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. METHODS: In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). RESULTS: AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. DISCUSSION: AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.
Subject(s)
Spondylarthritis , Spondylitis, Ankylosing , Vascular Diseases , Male , Humans , Female , Spondylarthritis/genetics , HLA-B27 Antigen/genetics , Follow-Up Studies , Spondylitis, Ankylosing/geneticsABSTRACT
Objective: Proteome analyses in patients with newly diagnosed, untreated giant cell arteritis (GCA) have not been reported previously, nor are changes of protein expression upon treatment with glucocorticoids (GC) and/or tocilizumab (TCZ) known. The GUSTO trial allows to address these questions, provides the opportunity to learn about the differential effects of GC and TCZ on proteomics and may help to identify serum proteins to monitor disease activity. Methods: Serum samples obtained from 16 patients with new-onset GCA at different time points (day 0, 3, 10, and week 4, 24, 52) during the GUSTO trial (NCT03745586) were examined for 1436 differentially expressed proteins (DEPs) based on proximity extension assay technology. The patients received 500 mg methylprednisolone intravenously for 3 consecutive days followed by TCZ monotherapy. Results: When comparing day 0 (before the first GC infusion) with week 52 (lasting remission), 434 DEPs (213↑, 221↓) were identified. In response to treatment, the majority of changes occurred within 10 days. GC inversely regulated 25 proteins compared to remission. No difference was observed between weeks 24 and 52 during established remission and ongoing TCZ treatment. Expression of CCL7, MMP12, and CXCL9 was not regulated by IL6. Conclusion: Disease-regulated serum proteins improved within 10 days and were normalized within 24 weeks, showing a kinetic corresponding to the gradual achievement of clinical remission. The proteins inversely regulated by GC and TCZ shed light on the differential effects of the two drugs. CCL7, CXCL9, and MMP12 are biomarkers that reflect disease activity despite normalized C-reactive protein levels.
Subject(s)
Giant Cell Arteritis , Giant Cell Arteritis/drug therapy , Giant Cell Arteritis/immunology , Giant Cell Arteritis/metabolism , Humans , Proteomics , Glucocorticoids/therapeutic useABSTRACT
BACKGROUND: Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. METHODS: We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. CONCLUSION: This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.
Subject(s)
Adrenal Insufficiency , Glucocorticoids , Adult , Humans , Adrenal Insufficiency/chemically induced , Adrenocorticotropic Hormone , Glucocorticoids/adverse effects , Glucocorticoids/therapeutic use , Multicenter Studies as Topic , Neoplasm Recurrence, Local/drug therapy , Prednisone/adverse effects , Prednisone/therapeutic use , Prospective Studies , Randomized Controlled Trials as Topic , Withholding TreatmentABSTRACT
AIMS OF THE STUDY: To assess current practices in diagnosing, treating, and following-up giant-cell arteritis by specialists in Switzerland and to identify the main barriers to using diagnostic tools. METHODS: We performed a national survey of specialists potentially caring for patients with giant-cell arteritis. The survey was sent by email to all members of the Swiss Societies of Rheumatology and for Allergy and Immunology. A reminder was sent to nonresponders after 4 and 12 weeks. Its questions covered the following dimensions: respondents' main characteristics, diagnosis, treatment, and imaging's role during follow-up. The main study results were summarized using descriptive statistics. RESULTS: Ninety-one specialists, primarily aged 46-65 years (n = 53/89; 59%), working in academic or nonacademic hospitals or private practice, and treating a median of 7.5 (interquartile range [IQR]: 3-12) patients with giant-cell arteritis per year participated in this survey. Ultrasound of temporal arteries/large vessels (n = 75/90; 83%) and positron-emission-tomography-computed tomography (n = 52/91; 57%) or magnetic resonance imaging (n = 46/90; 51%) of the aorta/extracranial arteries were the most common techniques used to diagnose giant-cell arteritis with cranial or large vessel involvement, respectively. Most participants reported a short time to obtain imaging tests or arterial biopsy. The glucocorticoid tapering scheme, glucocorticoid-sparing agent, and glucocorticoid-sparing treatment duration varied among the participants. Most physicians did not follow a predefined repeat imaging scheme for follow-up and mainly relied on structural changes (vascular thickening, stenosis, or dilatation) to drive treatment choice. CONCLUSIONS: This survey indicates that imaging and temporal biopsy are rapidly accessible for diagnosing giant-cell arteritis in Switzerland but highlights heterogeneous practice in many disease management areas.
Subject(s)
Giant Cell Arteritis , Glucocorticoids , Humans , Glucocorticoids/therapeutic use , Switzerland , Giant Cell Arteritis/diagnostic imaging , Giant Cell Arteritis/drug therapy , Temporal Arteries , Positron Emission Tomography Computed TomographyABSTRACT
BACKGROUND: The Chronic Care Model (CCM) is a longstanding and widely adopted model guiding chronic illness management. Little is known about how CCM elements are implemented in rare disease care or how patients' care experiences relate to health-related quality of life (HRQoL). We engaged patients living with systemic sclerosis (SSc) to assess current care according to the CCM from the patient perspective and their HRQoL. METHODS: We employed an explanatory sequential mixed methods design. First, we conducted a cross-sectional quantitative survey (n = 101) using the Patient Assessment of Chronic Illness Care (PACIC) and Systemic Sclerosis Quality of Life (SScQoL) questionnaires. Next, we used data from individual patient interviews (n = 4) and one patient focus group (n = 4) to further explore care experiences of people living with SSc with a focus on the PACIC dimensions. RESULTS: The mean overall PACIC score was 3.0/5.0 (95% CI 2.8-3.2, n = 100), indicating care was 'never' to 'generally not' aligned with the CCM. Lowest PACIC subscale scores related to 'goal setting/tailoring' (mean = 2.5, 95% CI 2.2-2.7) and 'problem solving/contextual counselling' (mean = 2.9, 95% CI 2.7-3.2). No significant correlations were identified between the mean PACIC and SScQoL scores. Interviews revealed patients frequently encounter major shortcomings in care including 'experiencing organized care with limited participation', 'not knowing which strategies are effective or harmful' and 'feeling left alone with disease and psychosocial consequences'. Patients often responded to challenges by 'dealing with the illness in tailored measure', 'taking over complex coordination of care' and 'relying on an accessible and trustworthy team'. CONCLUSIONS: The low PACIC mean overall score is comparable to findings in patients with common chronic diseases. Key elements of the CCM have yet to be systematically implemented in Swiss SSc management. Identified gaps in care related to lack of shared decision-making, goal-setting and individual counselling-aspects that are essential for supporting patient self-management skills. Furthermore, there appears to be a lack of complex care coordination tailored to individual patient needs.
Subject(s)
Quality of Life , Scleroderma, Systemic , Humans , Cross-Sectional Studies , Switzerland , Chronic Disease , Scleroderma, Systemic/therapy , Surveys and QuestionnairesABSTRACT
Autoimmune rheumatic diseases (ARD) can affect women and men during fertile age, therefore reproductive health is a priority issue in rheumatology. Many topics need to be considered during preconception counselling: fertility, the impact of disease-related factors on pregnancy outcomes, the influence of pregnancy on disease activity, the compatibility of medications with pregnancy and breastfeeding. Risk stratification and individualized treatment approach elaborated by a multidisciplinary team minimize the risk of adverse pregnancy outcomes (APO). Research has been focused on identifying biomarkers that can be predictive of APO. Specifically, preeclampsia and hypertensive disorders of pregnancy tend to develop more frequently in women with ARD. Placental insufficiency can lead to intrauterine growth restriction and small-for-gestational age newborns. Such APO have been shown to be associated with maternal disease activity in different ARD. Therefore, a key message to be addressed to the woman wishing for a pregnancy and to her family is that treatment with compatible drugs is the best way to ensure maternal and fetal wellbeing. An increasing number of medications have entered the management of ARD, but data about their use in pregnancy and lactation are scarce. More information is needed for most biologic drugs and their biosimilars, and for the so-called small molecules, while there is sufficient evidence to recommend the use of TNF inhibitors if needed for keeping maternal disease under control. Other issues related to the reproductive journey have emerged as "unmet needs", such as sexual dysfunction, contraception, medically assisted reproduction techniques, long-term outcome of children, and they will be addressed in this review paper. Collaborative research has been instrumental to reach current knowledge and the future will bring novel insights thanks to pregnancy registries and prospective studies that have been established in several Countries and to their joint efforts in merging data.
Subject(s)
Autoimmune Diseases , Biosimilar Pharmaceuticals , Rheumatic Diseases , Male , Child , Pregnancy , Female , Infant, Newborn , Humans , Prospective Studies , Reproductive Health , Placenta , Pregnancy Outcome , Autoimmune Diseases/complications , Autoimmune Diseases/therapy , Rheumatic Diseases/complications , Rheumatic Diseases/drug therapyABSTRACT
Introduction: The inflammatory milieu after acute retinal necrosis (ARN) may lead to a breakdown of the inner and outer blood-retinal barrier and consequently to a cystoid macular edema (CME) with accumulation of intra- and subretinal fluid. Up to now, there is no established therapeutic approach for CME in ARN patients.Case report: We report a case of an immunocompetent 14-year-old female with chronic ARN-related CME, which was unresponsive to valacyclovir, prednisone and intravitreal ranibizumab injections. A combination treatment of tocilizumab, an interleukin-6 receptor inhibitor, and intravitreal aflibercept was successful to control the CME.Conclusion: In selected patients with treatment-refractory CME following ARN a therapy with tocilizumab and intravitreal aflibercept might be considered.
Subject(s)
Macular Edema , Retinal Necrosis Syndrome, Acute , Female , Humans , Adolescent , Macular Edema/diagnosis , Macular Edema/drug therapy , Macular Edema/etiology , Angiogenesis Inhibitors/therapeutic use , Retinal Necrosis Syndrome, Acute/diagnosis , Retinal Necrosis Syndrome, Acute/drug therapy , Ranibizumab , Recombinant Fusion Proteins/therapeutic use , Intravitreal Injections , Tomography, Optical CoherenceABSTRACT
OBJECTIVE: The lifetime recurrence rate (RR) of axial spondyloarthritis (axSpA) among first-degree relatives (FDR) and the effect of proband's gender, HLA-B27 and radiographic status is unclear. Our 35-year-follow-up family study has enabled these issues to be addressed. METHODS: In 1985, 363 ankylosing spondylitis (AS) probands (members of the Swiss AS Patient Society) and 806 FDR recruited into the study, completed questionnaires regarding axSpA manifestations, underwent a physical examination and most also underwent pelvic radiography and HLA-B27 typing. At follow-up in 2018-2019, of the former participants whose current addresses could be retrieved, 162 had died and 485 (125 patients with AS plus 360 FDR) completed a postal questionnaire. RESULTS: At follow-up, 48 of 177 HLA-B27(+) FDR had developed axSpA, an RR of 27.1% (95% CI 20.6% to 33.7%). 27/148 (18.2%) children of AS probands (modified New York (mNY) criteria) were affected versus 2/50 (4.0%) children of non-radiographic axSpA probands (p=0.0138, OR=5.36; 95% CI 1.23 to 23.40). Children of female probands were more often affected (12/22; 54.5%) than of male probands (15/78; 19.2%) (p=0.0003; OR=4.89; 95% CI 1.96 to 12.23). This increased risk applies equally to sons and daughters. CONCLUSION: The lifetime RR of axSpA for HLA-B27(+) FDR is substantial (27.1%), and disease severity (as defined by radiographic sacroiliitis by the mNY criteria) is an additional risk factor. Affected mothers pass on the disease significantly more often to their offspring than do affected fathers. These findings may lead to better assessment of lifetime risk for axSpA in the offspring. Moreover, investigation of this gender effect may uncover additional putative disease susceptibility factors.
Subject(s)
Axial Spondyloarthritis , Spondylarthritis , Spondylitis, Ankylosing , Child , Female , Follow-Up Studies , HLA-B27 Antigen/genetics , Humans , Male , Prospective Studies , Spondylarthritis/diagnosis , Spondylarthritis/epidemiology , Spondylarthritis/genetics , Spondylitis, Ankylosing/diagnosisABSTRACT
Many vaccines demonstrate high effectiveness for years. This prospective multicentre study was conducted in Switzerland to assess the long-term persistence of antibodies to the diphtheria/tetanus (dT)-vaccine in adult patients with rheumatic diseases (PRDs). 163 PRDs and 169 controls were included in the study. The median age of all participants was 50 years (range: 18-83 years) and 56% were female. After a median time interval of 16 years after vaccination, the median anti-vaccine antibody concentrations were lower in PRDs than in controls for tetanus (1.68 vs 2.01; p = 0.049) and diphtheria (0.05 vs 0.22; p = 0.002). Based on the currently accepted seroprotection threshold (antibody concentration ≥ 0.1 IU/ml), PRDs had lower proportions of short-term tetanus and diphtheria protection as demonstrated by crude odds ratios (OR) of 0.30 (p = 0.017) and OR: 0.52 (p = 0.004), respectively. After adjusting for 'age' and 'time since last dT vaccination', the strength of associations became weaker; for tetanus, borderline evidence remained for a true difference between PRDs and controls (OR: 0.36 [p = 0.098]), however, not for diphtheria (OR: 0.86 [p = 0.58]). We hypothesize that in the presence of rheumatic diseases and its immunosuppressive treatment, vaccine-specific long-lived plasma cells (LLPCs) may be diminished or competitively displaced by rheumatism-specific LLPCs, a process which may decrease the persistence of vaccine-specific antibodies. Novel studies should be designed by incorporating methodologies allowing to determine the attributable fraction of immunosuppressive/immunomodulatory medications and rheumatic disease itself on long-lasting vaccine-specific antibody persistence, as well as, further study the role of LLPCs.
Subject(s)
Diphtheria , Rheumatic Diseases , Tetanus , Whooping Cough , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Bacterial , Diphtheria/prevention & control , Diphtheria-Tetanus Vaccine , Diphtheria-Tetanus-Pertussis Vaccine , Female , Humans , Immunization, Secondary/methods , Male , Middle Aged , Prospective Studies , Tetanus/prevention & control , Vaccination/methods , Whooping Cough/prevention & control , Young AdultABSTRACT
BACKGROUND: Subcutaneous tocilizumab (TCZ SC) is approved globally for giant cell arteritis (GCA). This phase Ib study investigated the pharmacokinetics, pharmacodynamics, safety, and exploratory efficacy of intravenous (IV) TCZ 6 and 7 mg/kg in patients with GCA. This study explored an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA). METHODS: Patients with GCA who had received ≥ 5 doses of TCZ IV 8 mg/kg Q4W and achieved remission were enrolled. Patients received 5 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, 5 doses of 6 mg/kg Q4W in period 2. Pharmacokinetic endpoints were maximum concentration (Cmax), minimum concentration (Ctrough), area under the curve over a dosing interval (AUCτ), and mean concentration (Cmean) of TCZ after the last dose of each period. Other endpoints included pharmacodynamic markers, safety, and exploratory efficacy. RESULTS: In 24 patients, the median (range) age was 65.5 (57-90) years, and 62.5% were female. TCZ exposures (Cmax and AUCτ) were 11.2% and 20.0% lower at the 6- than 7-mg/kg dose. The mean interleukin 6 (IL-6) serum concentrations were elevated at baseline and remained elevated, with slightly higher concentrations in period 1 than in period 2. The mean serum soluble IL-6 receptor concentrations were elevated at baseline and comparable between the 2 doses at steady state. C-reactive protein levels and most erythrocyte sedimentation rates were within normal ranges throughout the study. Overall, 22 patients (91.7%) had ≥ 1 adverse event, and 4 (16.7%) had a serious adverse event. No patients experienced a GCA flare, and all remained in remission throughout the study. CONCLUSIONS: Both doses of TCZ IV Q4W were generally well tolerated in patients with GCA. The Cmax and Cmean achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those in patients with RA treated with 8 mg/kg IV Q4W, and Ctrough was within the range observed in patients with GCA treated with SC dosing every week or every 2 weeks. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03923738.
Subject(s)
Arthritis, Rheumatoid , Giant Cell Arteritis , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Arthritis, Rheumatoid/drug therapy , Blood Sedimentation , Female , Giant Cell Arteritis/drug therapy , Humans , Male , Treatment OutcomeABSTRACT
OBJECTIVES: JAK Inhibitors (JAKi) are recommended DMARDs for patients with moderate-to-severe RA who failed first-line therapy with methotrexate. There is a lack of data allowing an evidence-based choice of subsequent DMARD therapy for patients who had discontinued JAKi treatment. We aimed to compare the effectiveness of TNF inhibitor (TNFi) therapy vs JAKi vs other mode of action (OMA) biologic DMARD (bDMARD) in RA patients who were previously treated with a JAKi. METHODS: RA patients who discontinued JAKi treatment within the Swiss RA registry SCQM were included for this observational prospective cohort study. The primary outcome was drug retention for either TNFi, OMA bDMARD or JAKi. The hazard ratio for treatment discontinuation was calculated adjusting for potential confounders. A descriptive analysis of the reasons for discontinuation was performed. RESULTS: Four hundred treatment courses of JAKi were included, with a subsequent switch to either JAKi, TNFi or OMA bDMARD. The crude overall drug retention was higher in patients switching to another JAKi as compared with TNFi and comparable to OMA. A significant difference of JAKi vs TNFi persisted after adjusting for potential confounders. CONCLUSION: In a real-world population of RA patients who discontinued treatment with a JAKi, switching to another JAKi resulted in a higher drug retention than switching to a TNFi. A switch to a second JAKi seems an effective therapeutic option.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Biological Products , Janus Kinase Inhibitors , Humans , Janus Kinase Inhibitors/therapeutic use , Tumor Necrosis Factor Inhibitors/therapeutic use , Biological Products/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/chemically induced , Prospective Studies , Treatment Outcome , Tumor Necrosis Factor-alpha , Antirheumatic Agents/therapeutic use , Biological Factors/therapeutic useABSTRACT
OBJECTIVE: Axial spondyloarthritis (axSpA) comprises both radiographic and non-radiographic disease. However, the paucity of specific objective measures for the disease and current classification criteria showing suboptimal specificity contribute to disease heterogeneity observed in clinical practice and research. We used a historical cohort of patients with axSpA to assess sources of heterogeneity. METHODS: The study involved 363 axSpA probands recruited from membership of the Swiss Ankylosing Spondylitis Patient Society. Participants underwent examination by a rheumatologist, completed questionnaires and provided blood samples for HLA typing. Patients underwent radiography of sacroiliac joints and were categorised according to the New York (NY) criteria (ankylosing spondylitis (AS) or non-radiographic axSpA (nr-axSpA)) and HLA-B27 status. Genetic characterisation by single nucleotide polymorphism microarray was performed and AS polygenic risk scores (PRS) were calculated. RESULTS: Considerable heterogeneity was observed. The male to female ratio for AS (NY+) was 3:1, but 1:1 for nr-axSpA. For HLA-27(+) AS, the ratio was 2.5:1, but nearly 1:1 for HLA-B27(-) disease. Women with nr-axSpA had strikingly lower mean PRS and lower HLA-B27 prevalence than men with nr-axSpA or NY(+) male and female patients with AS. PRS was able to distinguish male but not female patients with nr-axSpA from related healthy first-degree relatives. Radiographic sacroiliitis was strongly associated with HLA-B27, especially in men. CONCLUSION: Women clinically diagnosed with axSpA but without radiographic sacroiliitis as a group have a disease that is distinct from AS by the modified New York criteria overall and from nr-axSpA in men. Given the high degree of heterogeneity, stratified or adjusted analysis of effectiveness studies is indicated, taking genetics, sex and radiographic damage (sacroiliitis) into account.
Subject(s)
Axial Spondyloarthritis , Sacroiliitis , Spondylarthritis , Spondylitis, Ankylosing , Female , HLA-B27 Antigen/genetics , Humans , Male , Spondylarthritis/diagnosis , Spondylarthritis/epidemiology , Spondylarthritis/genetics , Spondylitis, Ankylosing/diagnosis , Spondylitis, Ankylosing/epidemiology , Spondylitis, Ankylosing/geneticsABSTRACT
OBJECTIVE: Factors predicting axial spondyloarthritis (axSpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) patients need to be defined. We investigated the predictive value of the probands' HLA-B27 and radiographic sacroiliitis status on disease occurrence among their FDR. We also assessed the predictive value of features of the clinical history, including chronic inflammatory back pain (CIBP) and acute anterior uveitis (AAU), among the FDR and how they can be used to improve classification and diagnosis of axSpA. METHODS: In 1985, we studied 363 AS probands and 806 FDR who underwent rheumatologic examination, completed questionnaires, provided blood samples for HLA-typing and underwent radiography of sacroiliac joints. At follow-up in 2018-2019, 125 patients and 360 FDR were available for study, and completed a postal questionnaire about axSpA features. FDRs were asked to report whether after 1985 they had been diagnosed by Swiss rheumatologists as having axSpA. RESULTS: Among HLA-B27(+) FDR, axSpA occurred in 25.4%-26.3%, independent of the radiographic sacroiliitis status of the proband. AAU occurred in 13/34 (38.2%) FDR with axSpA vs 29/251 (11.6%) FDR without axSpA (p=0.00004, OR=4.74 95% CI 2.15 to 10.47). The presence of CIBP at baseline did not predict later occurrence of axSpA but combining CIBP and pain/discomfort at the thoracic spine and at anterior (ventral) chest wall ever, assessed at follow-up in 2018-2019, provided 83.1% sensitivity and 87.2% specificity for current axSpA. CONCLUSION: Occurrence of AAU among FDR of axSpA probands should prompt screening for axSpA. Moreover, co-occurrence of CIBP and pain/discomfort in the thoracic spine and at anterior chest wall as a three-question tool may further enhance clinical suspicion of axSpA among these FDR.
Subject(s)
Axial Spondyloarthritis , Sacroiliitis , Spondylarthritis , Spondylitis, Ankylosing , Uveitis, Anterior , Back Pain/genetics , HLA-B27 Antigen/genetics , Humans , Sacroiliitis/diagnostic imaging , Sacroiliitis/epidemiology , Sacroiliitis/genetics , Spondylarthritis/diagnosis , Spondylitis, Ankylosing/diagnostic imaging , Spondylitis, Ankylosing/epidemiologyABSTRACT
BACKGROUND/OBJECTIVE: Constant pain causes suffering and affects performance of activities of daily living (ADL). In clients with chronic musculoskeletal pain, we wanted to determine (i) the relationship between the perceived burden of suffering (measured with the Pictorial Representation of Illness and Self Measure (PRISM)) and the observed quality of ADL task performance (measured with the Assessment of Motor and Process Skills (AMPS)); and (ii) the change in these assessments before and after a 12-week pain programme. METHODS: In this cross-sectional cohort study, we retrospectively collected data from participants in a Swiss pain management programme. We calculated the relationship, correlations and effect sizes for the PRISM and AMPS using non-parametric tests. We set the level of significance at α = 0.05. RESULTS: Out of 138 clients, 74 participated. We found no significant correlations between the PRISM and AMPS (p = 0.55-0.36), except for the PRISM and AMPS process ability measure after the pain management programme (p = 0.023). Pre-post-correlations of the AMPS and PRISM were significant, with medium to strong effect sizes (-0.48-0.66). CONCLUSION: Participation in this pain programme improved both, the PRISM and AMPS scores. The lack of correlation between these assessments in clients with chronic musculoskeletal pain, however, strongly argues for a thorough clinical assessment.