Knee Hurt

Category: Knee Arthritis

  • You Don’t Look Sick – Living With Rheumatoid Arthritis: ANOTHER SET OF X-RAYS?

    You Don’t Look Sick – Living With Rheumatoid Arthritis: ANOTHER SET OF X-RAYS?

     

    Today I got up early to go to the foot doctor again. She checked my foot and then sent me down for x-rays. This is my fourth set of x-rays in a month. It turned out that my right foot was not broken a second time. I must have just messed it up. She says my left ligament is still wobbly.

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    So the first thing she did was tell me to exchange my boots. The large boot is now on a break on my right foot and the Birkenstock type boot has been retired. I now wear the night cloth on my left foot all day and at night. She said I can put my left foot with the cuff in a pair of sturdy shoes or sneakers with a hard bottom. Well, it just so happens that my new Inka sneakers have a hard bottom. So when I go outside, I can put my left foot in a sneaker. I also put my left foot with the cloth in my Oofas.

    It’s only been 10 hours and my right foot already feels better. Being protected in the big boot makes such a difference.

    So yesterday I went out and my car battery wouldn’t turn my car on. The battery was not completely empty, but just not strong enough. Today my neighbor came by with a battery starting battery and his trickle battery. After about 20 minutes the car started and I stood outside and let it run for 30 minutes. Luckily a neighbor stopped by to chat with me while I was standing there. I would have sat down, but the trunk doesn’t really fit in the driver’s seat. Now I have to start the car every day this week to charge the battery.

    See you tomorrow..

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  • Anti-TNF-α therapy induced psoriasis in patients with rheumatoid arthritis according to FDA postmarketing surveillance data

    Anti-TNF-α therapy induced psoriasis in patients with rheumatoid arthritis according to FDA postmarketing surveillance data

     

    FDA Adverse Event Reporting System (FAERS)

    The United States Food and Drug Administration Adverse Event Reporting System (FAERS) is a data repository that collects voluntary drug-related reports from healthcare professionals, consumers, and legal representatives. In cases where the adverse reaction (AE) is reported to the manufacturer, the manufacturer is required to forward the report to FAERS. At the time of the survey, FAERS contained 17,392,666 AE reports collected from the first quarter of 2004 (including historical reports since 1982) through the second quarter of 2022. The reports are available online: https://www.fda.gov/ medications/questions-and-answers-fdas-reporting-system-faers-side-effects/fda-reporting-system-faers-last-quarter-data.

    Data preparation

    FAERS reports are added quarterly and stored in a set of text files. Subsets of data are organized by specific report fields (demographics, drug, side effects, outcome, etc.) and their respective case IDs. The data format is not uniform and has changed several times since its inception. Therefore, appropriate changes have been made. Moreover, as the side effect reports are collected from all over the world, the respective brand names of drugs are translated into the generic equivalents19,20,21.

    Study results

    The MedDRA Dictionary version 25.1 was searched to define the measured study outcomes using higher-level terms such as “immune-associated conditions not elsewhere classified (NEC)” and “psoriatic conditions.” All psoriasis-associated preferred terms (PT) were used in the search. To avoid indication-related confounding effects, psoriatic conditions associated with RA, such as psoriatic arthropathy, were excluded from the MedDRA PT list. The following PTs were used for the definition psoriasis in the analysis: erythrodermic psoriasis, guttate psoriasis, nail psoriasis, psoriasiform dermatitis, pustular psoriasis and psoriasis.

    Cohort selection

    Of the total 17,392,666 adverse event reports in FAERS, a total of 881,182 reports included RA indications, and for 663,922 of these, RA was listed as the sole indication. These data were further broken down by monotherapies and only reports from physicians, pharmacists and other healthcare professionals were included to avoid bias and increase clinical relevance. The final monoindication + monotherapy sets were as follows: certolizumab pegol (n = 5168), adalimumab (n = 9221), golimumab (n = 2899), tocilizumab (n = 4819), abatacept (n = 7574), infliximab (n = 5579), rituximab (n = 2519), etanercept (n = 89543), tofacitinib (n = 10686), and methotrexate (n = 6142). Demographic analysis was performed for TNF inhibitors and methotrexate RA AE cohorts (Tables 1 and 2). The following terms for psoriasis are included: erythrodermic psoriasis, guttate psoriasis, nail psoriasis, psoriasiform dermatitis, pustular psoriasis and psoriasis. These psoriasis type terms describe the psoriasis Adverse event rates were calculated for each drug cohort: certolizumab pegol (n = 98), adalimumab (n = 107), golimumab (n = 20), tocilizumab (n = 29), abatacept (n = 40), infliximab (n = 29 ), rituximab (n = 11), etanercept (n = 260), tofacitinib (n = 24), and methotrexate (n = 7). A disproportionality analysis was performed using the reported AE rates to calculate the reporting odds ratios (RORs). These figures were used to calculate psoriasis reported frequencies. Methotrexate was selected as a control cohort because of its unique mechanism of action (MOA) as an immunosuppressant that inhibits the conversion of folic acid to folic acid cofactors, and because of its common use as a monotherapy in RA.

    Demographic analysis

    Gender (Table 1).

    Table 1 The total number of reports of TNF inhibitors and methotrexate in the combined RA cohorts, separated by reported gender.

    Age (Table 2).

    Table 2 The total number of reports of TNF inhibitors and methotrexate in the combined RA cohorts, separated by reported age.

    static analysis

    Descriptive statistics

    The frequencies for each side effect examined (Figs. 1, 3) were calculated using the following equation:

    $$\textFrequency = \left( \textnReports\,\text with \,\textpsoriasis \,\textin \, \texta \,\textcohort \right)/\textnReports\,\text in \,\texta \,\ textcohort*100$$

    (1)

    Frequency error:

    $$\textError = \left( \sqrt \textnReports \,\textwith\, \textpsoriasis\,\text in \,\text a\, \textcohort \right)/\textnReports\,\text in\,\text a \,\textcohort*100$$

    (2)

    Comparative statistics

    The numbers of psoriasis reports were compared via the Reporting Odds Ratio (ROR) analysis for Fig. 2, 4 and 5 and Tables 3, 4 and 5 using the following equations:

    $$\mathrmROR=(\mathrma/\mathrmb)/(\mathrmc/\mathrmd)$$

    (3)

    where Number of cases in exposed group with psoriasis, Number of cases in exposed group without psoriasis, Number of cases in control group with psoriasis, Number of cases in control group without psoriasis.

    Table 3 RORs and 95% CIs were calculated based on comparisons between each TNF inhibitor monotherapy cohort and the methotrexate cohort.
    Table 4 RORs and 95% CIs were calculated based on comparisons between each monotherapy cohort examined and the methotrexate cohort.
    Table 5 RORs and 95% CIs were calculated based on comparisons between the certolizumab pegol monotherapy cohort and each of the other monotherapy cohorts studied.

    $$\mathrmLnROR=\mathrmLn(\mathrmROR)$$

    (4)

    Standard error of odds ratio for log reporting;

    $$\mathrmSE_\mathrmLnROR=\sqrt1/\mathrma+1/\mathrmb+1/\mathrmc+1/\mathrm d$$

    (5)

    95% confidence interval;

    $$95\text\%CI = \left[ {\textexp\left( \textLnROR – 1.96 \times \textSE_\textLnROR \right),\textexp\left( {\textLnROR + 1.96 \times \textSE_{\textLnROR} } \right)} \right]$$

    (6)

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  • Epidemiology and clinical features of interstitial lung disease in patients with rheumatoid arthritis from the JointMan database

    Epidemiology and clinical features of interstitial lung disease in patients with rheumatoid arthritis from the JointMan database

     

    Data source

    Patient demographics and disease characteristics were retrospectively analyzed after data extraction from the Discus Analytics JointMan database, a large US electronic health record-based dataset initiated in March 2009. The JointMan database includes > 17,000 rheumatology patients covered by commercial, Medicare, or Medicaid insurance. plan. Practices in the following eight states are included: Washington, New York, Oregon, Florida, Georgia, California, Wisconsin and Kentucky. Patient data were collected in rheumatology centers and anonymized prior to analysis. In addition to electronic medical record data, the JointMan user interface collects clinical results recorded by physicians at the time of the encounter.

    Patient population

    Patients were included if they were ≥ 18 years old at first visit to a rheumatologist participating in the JointMan network, had a provider-selected diagnosis of RA between January 1, 2009 and September 20, 2019, and had ≥ 1 visit after the first visit. visit date. Patients were excluded if their first encounter occurred after RA diagnosis or if they experienced a drug-induced ILD diagnosis [International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes J70.2 and J70.4] at any time during the study period. Patients were assigned to the RA cohort (patients with confirmed RA but no diagnosis of ILD during the study period) or the RA-ILD cohort (patients with a diagnosis of unmedicated ILD on or after the initial diagnosis date of RA). ). The RA index date was defined as the first RA diagnosis date recorded in the JointMan database (provided by the rheumatologist).

    The total study population consisted of patients followed from the day after the RA index date until the patient’s last encounter date or the end of the study (September 20, 2019), whichever came first. RA was diagnosed according to the ICD, Ninth Revision, CM (ICD-9-CM) code 714.0 and ICD-10-CM codes M05 and M06. ILD was identified by ICD diagnosis codes (ICD-9-CM codes: 516.0, 516.2, 516.3, 516.4, 516.5, 516.8, and 516.9; ICD-10-CM codes: J84.0, J84.1, J84.2, J84 .81, J84.82, J84.83, J84.89 and J84.9) or as indicated by the provider.

    A subanalysis was performed on a series of patients grouped according to ILD diagnosis. For the subanalysis population, the ILD diagnosis index was defined as the first date of ILD diagnosis recorded in the JointMan database (for patients in the RA-ILD cohort), and patient characteristics were described for the 90-day periods before and after the ILD. diagnosis index. For patients without ILD, the index date was based on the distribution of the number of days between RA diagnosis and ILD diagnosis in the RA-ILD cohort; characteristics were described for the 90-day periods before and after the index date (Supplementary Figure S1).

    Primary endpoints

    The primary endpoints, assessed in the total study population, were the prevalence and time to onset of ILD. Prevalence was defined as the proportion of patients with RA and a diagnosis of ILD divided by the total number of patients with RA during the study period. Time to onset of ILD was defined as the time from the initial diagnosis of RA to the first observed non-drug ILD diagnosis.

    Exploratory endpoints

    Exploratory endpoints, assessed in the exploratory analysis population, included baseline demographics, comorbidities, RA characteristics, and overall RA disease activity in the RA cohort compared with the RA-ILD cohort. RA features include joint stiffness, erosions, extra-articular disease, anti-CCP antibodies, joint swelling, ESR, C-reactive protein (CRP), and Clinical Disease Activity Index (CDAI). The CDAI remission score was defined as ≤ 2.8; CDAI low, moderate, and high disease activity scores were defined as >2.8–10, >10–22, and >22, respectively19. The Simplified Disease Activity Index (SDAI) remission score was defined as ≤ 3.3; SDAI low, moderate, and high disease activity scores were defined as > 3.3 to 11, > 11 to 26, and > 26, respectively19. Disease activity score in 28 joints using CRP (DAS28 [CRP]) remission score was defined as ≤ 2.3; DAS28 (CRP) low, moderate and high disease activity scores were defined as > 2.3 to 2.7, > 2.7 to < 4.1 and ≥ 4.1, respectively20. DAS28 (ESR) remission score was defined as <2.6; DAS28 (ESR) low, moderate, and high disease activity scores were defined as 2.6 to 2.6, respectively < 3,2, 3,2–5,1 en > 5.1.19 Routine Assessment of Patient Index Data 3 (RAPID3) remission score was defined as ≤ 3; RAPID3 low, moderate, and high disease activity scores were defined as >3 to 6, >6 to 12, and >12, respectively21. Variables were assessed as potential predictors of RA-ILD.

    Subanalysis endpoints

    For patients included in the subanalysis population, CDAI and RAPID3 scores, number of swollen and swollen28 joints, number of encounters with rheumatologists, and treatment use before and after the ILD diagnosis index were also assessed. The number of swollen and swollen28 joints is part of the DAS/DAS28 score: the number of swollen joints is an assessment of 28 or more (maximum 44) joints, while the number of swollen28 joints is an assessment of only 28 pre-selected joints22.

    static analysis

    The prevalence (95% confidence intervals [CIs]) of the first observed ILD diagnosis during follow-up was calculated. Time to ILD diagnosis was examined using unadjusted Kaplan-Meier survival curves. Descriptive statistics for continuous baseline variables were compared using Student’s Ttest and percentages for categorical and binary basic variables were compared using the Chi-square test.

    Potential predictors of RA-ILD were analyzed with a Cox regression model. Patient demographics and comorbidities were collected at baseline and controlled in the Cox model. RA features were identified during and after initial RA diagnosis and were controlled as time-varying covariates in the Cox model. The final covariate lists were based on clinical rationale and model fit; Hazard Ratios, 95% Confidence Intervals, and P Values ​​were provided for each covariate. Statistical significance for model inclusion was set at P<0.05.

    The number and percentage of patients with visits to a rheumatologist, treatment utilization, and each disease activity score in the pre- and post-index periods were calculated. P-values ​​for the disease activity score category compared pre- and post-index periods and correspond to Fisher’s exact test or Chi-square test with statistical significance set at P<0.05.

    Ethical approval

    This study was conducted in accordance with the International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices and applicable regulatory requirements23. The study protocol was reviewed by the internal BMS Observational Protocol Review Committee (OPRC). No identifiable protected health information was retrieved from or accessed from the database during the study. Therefore, the BMS OPRC confirmed that this analysis did not require ethical oversight. In addition, the study did not involve the collection, use, or transmission of individually identifiable data, and the data was collected in the setting for the patient’s usual care. Informed consent from the study participants was not required because the dataset used in this observational study consisted of anonymized secondary data released for research purposes.

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  • Fibroblast multiplicity in RA: a synovial state of the art

    Fibroblast multiplicity in RA: a synovial state of the art

     

    • Zhang, F. et al. Defining inflammatory cell states in rheumatoid arthritis synovial tissues by integrating single-cell transcriptomics and mass cytometry. Wet. Immunol. 20928–942 (2019).

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    • Smith, MH et al. Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis. Wet. Immunol. https://doi.org/10.1038/s41590-023-01527-9 (2023).

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    • Nygaard, G. & Firestein, G.S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Wet. Rev. Rheumatoid. 16316–333 (2020).

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    • Müller-Ladner, U. et al. Synovial fibroblasts from patients with rheumatoid arthritis adhere to and invade normal human cartilage when grafted into SCID mice. Ben. J. Pathol. 1491607–1615 (1996).

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    • Ainsworth, RI et al. Systems biology analysis of fibroblast-like synoviocytes in rheumatoid arthritis implicates cell lineage-specific transcription factor function. Wet. Just. 136221 (2022).

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    • Yan, M. et al. ETS1 regulates pathological tissue remodeling programs in disease-associated fibroblasts. Wet. Immunol. 231330–1341 (2022).

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    • Wei, K. et al. Notch signaling drives synovial fibroblast identity and arthritis pathology. Nature 582259–264 (2020).

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    • Boyle, DL et al. Enhancement of transcriptome fidelity after synovial tissue disaggregation. Front side. Of. 9919748 (2022).

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    • Firestein, GS Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheumatism. 391781–1790 (1996).

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  • Relevance of circulating semaphorin 4A to rheumatoid arthritis response to treatment

    Relevance of circulating semaphorin 4A to rheumatoid arthritis response to treatment

     

    Analysis of cohort 1 from Cochin Hospital, Paris

    Study population

    Between May 2016 and February 2018, a total of 101 patients (85 women, 84%) with established RA were included. These patients had a mean age of 58 ± 13 years, a mean disease duration of 14 ± 11 years, and a mean follow-up age. -from 41 ± 15 months. Positive rheumatoid factors and anti-CCP antibodies were detected in 80 (79%) and 83 (82%) patients, respectively. Erosions were present in 63 (62%) patients; 70 patients (69%) received corticosteroids (including 9 at a dose > 10 mg/day), 78 received conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), including 61 (60%) with MTX, and 59 (58%) received targeted biological DMARDs (bDMARDs). During the inclusion visit, 13 patients initiated a first-line bDMARD or switched to another bDMARD due to inadequate disease control. Detailed characteristics of our study sample are shown in Table 1.

    Table 1 Characteristics of patients from the two cohorts at baseline.

    Results

    The number of annual consecutive visits ranged from 2 to 5 (88 patients with 3 visits, 72 with 4 visits, and 65 with 5 visits). Disease flares occurred in 38 patients during the mean follow-up period of 41 ± 15 months. Of these 38 patients, targeted therapy was added or modified in 26 patients due to inadequate disease control: 10 started on a bDMARD or a targeted synthetic (ts)-DMARD and 16 switched from a bDMARD to a new b- or tsDMARD (Table S1) . The mean time to treatment adaptation was 35 ± 13 months.

    Primary endpoint: evaluation of the predictive value of SEMA4A for the occurrence of treatment failure

    Baseline SEMA4A levels > 94 ng/ml were predictive of treatment failure, defined by the occurrence of flares AND treatment escalation (n = 26 patients), with an HR of 2.73 (95% CI 1.24 –5.96) (Fig. 1A). Results were unchanged after excluding the 13 patients with active disease at baseline who requested addition or change to a bDMARD (HR: 2.83, 95% CI 1.14–7.52).

    Figure 1
    Figure 1

    Predictive value of SEMA4A for the progression of rheumatoid arthritis in Paris cohort 1. (a) Time to treatment failure (defined as flares AND treatment escalation) according to circulating SEMA4A concentrations (≤ or > 94 ng/ml). (b) Survival without disease flare according to circulating SEMA4A concentrations (≤ or > 94 ng/ml).

    Secondary endpoints

    Elevated SEMA4A levels (>94 ng/ml) at baseline were predictive of flare occurrence (n = 34 patients) during the follow-up period (Fig. 1B) with a hazard ratio (HR) of 2.43 (95% confidence interval ). , CI 1.27–4.68). Results were unchanged after excluding the 13 patients with active disease at baseline (HR 2.36, 95% CI 1.15–4.89).

    Baseline SEMA4A concentrations were significantly increased in patients who experienced flares during the follow-up period (78 ± 30 ng/ml vs. 60 ± 24 ng/ml, p < 0.001) (Fig. 2A). SEMA4A levels were also significantly higher in the 13 patients with active disease at baseline who requested the addition or modification of a bDMARD, compared with the 88 patients on stable treatment (84 ± 33 ng/ml vs. 63 ± 26, p = 0.011). Although baseline SEMA4A concentrations were higher in patients experiencing flares AND treatment escalation compared to those on stable treatment (75 ± 31 ng/ml vs. 63 ± 26 ng/ml, p = 0.060), this did not reach significance (Fig. 2B). Patients with elevated SEMA4A levels at baseline maintained higher DAS28 levels throughout the follow-up period, with significant differences at visits 1, 2, and 5 (Fig. 2C).

    Figure 2
    Figure 2

    Baseline circulating SEMA4A levels according to the occurrence of (a) disease flare or (b) treatment failure (defined as flares AND treatment escalation) during the prospective follow-up period in Paris cohort 1. (c) Course of the DAS28 during the follow-up period according to baseline SEMA4A concentrations (≤ or > 94 ng/ml). All data are presented as the mean ± SEM. *p < 0.05, **p < 0.01 and ***p < 0.001, determined by Student’s t-test.

    Integration of SEMA4A with other predictors of treatment failure

    A baseline DAS28 > 3.2 (HR 2.17, 95% CI 1.01–4.72) and the presence of active synovitis, defined by at least grade 2 Doppler activity8, detected at at least one joint on power Doppler ultrasound (PDUS) (HR 3.60, 95% CI 1.07–12.15) were predictive of further treatment failure. These results were not changed after excluding the 13 patients with active disease at baseline.

    Baseline age, disease duration, ACPA or RF positivity, smoking status, presence of erosions, series of targeted DMARDs, corticosteroid treatment, and CRP levels were not predictive of treatment failure (Table 2). Multivariate Cox analyzes adjusted for these covariates confirmed that SEMA4A was the only independent predictor of treatment failure (HR 2.71, 95% CI 1.14–6.43).

    Table 2 Univariate and multivariate Cox analyzes to identify independent predictors of treatment failure (primary endpoint) and RA flares (secondary endpoint) in Paris cohort 1.

    SEM4A was also confirmed as an independent predictor of flares, along with DAS28 and synovial hyperhemia (Table 2).

    We then assessed the possible combination of DAS28, PDUS and SEMA4A concentrations to predict the occurrence of treatment failure and flares (Table 3). The combination that provided the best predictive value was a DAS28 > 3.2 and/or presence of active synovitis on PDUS and/or SEMA4A concentrations > 94 ng/ml (HR 10.42, 95% CI 1.41–76 .94 for treatment failure and 4.88, 95% CI 1.50–15.89 for flares) (Fig. 3A,B). Matrix models also highlighted the ability of the combination of these 3 parameters to predict the occurrence of treatment failure and flares (Fig. S1): Treatment failure and flares of RA occurred in 53% and 73% of patients with DAS28 > 3.2 at baseline and the presence of active synovitis at PDUS and SEMA4A concentrations > 94 ng/ml, respectively. Furthermore, only one patient with a DAS28 ≤ 3.2, no active synovitis and SEMA4A ≤ 94 ng/ml experienced treatment failure and RA attacks.

    Table 3 Predictive value of circulating SEMA4A alone or in combination DAS28-CRP and/or active synovitis on power Doppler ultrasound for the occurrence of treatment failure (primary endpoint) and RA attacks (secondary endpoint) in Paris cohort 1.
    figure 3
    figure 3

    Predictive value of SEMA4A, alone or in combination with a Disease Activity Score (DAS) 28 > 3.2 and/or the presence of active synovitis on power Doppler ultrasound (PDUS) in cohort 1 from Paris. (a) Time to treatment failure (defined as flares AND escalation of treatment) according to circulating SEMA4A concentrations (> 94 ng/ml) and/or a DAS28 > 3.2 and/or the presence of active synovitis on PDUS. (b) Survival without disease flare according to circulating SEMA4A concentrations (> 94 ng/ml) and/or a DAS28 > 3.2 and/or the presence of active synovitis on PDUS.

    Predictive value of SEMA4A in the subgroup of patients with low disease activity or remission

    Among the 58 patients with a DAS28 < 3.2 at baseline, treatment failed in 11 (19%) patients during the observation period. In this population, increased SEMA4A concentration was the only variable predicting the occurrence of treatment failure (HR 3.50, 95% CI 1.02–12.01). The presence of active synovitis detected on at least one joint on PDUS and other clinical or biological variables did not predict treatment failure (Table S2).

    In the 37 patients with a DAS28 < 2.6, treatment failure occurred in 4 patients (11%) and elevated SEMA 4A showed a trend for predicting treatment failure (HR 3.30, 95% CI 0.82–152.11, p = 0.069).

    Elevated SEMA4A concentration was also identified as the only predictor of flares (n = 16, 28%) in this subgroup of 58 patients with DAS28 < 3.2 (HR 3.68, 95% CI 1.33–10.17 ).

    Analysis of cohort 2 from Pelegrin Hospital, Bordeaux

    Study population

    A total of 40 patients (29 women, 73%) were included. These patients had a mean age of 57 ± 14 years, a mean disease duration of 5 ± 6 years, and active disease with a mean DAS28 of 5.12 ± 1.40. Positive rheumatoid factors and anti-CCP antibodies were detected in 27 (79%) and 28 (82%) patients, respectively. Erosions were present in 16 (40%) patients; 26 patients (65%) received corticosteroids. During the inclusion visit, 15 patients started MTX as first-line treatment and 25 started tocilizumab. Tocilizumab initiators were older, had longer disease duration and disease activity, and received corticosteroids more often than MTX initiators. Detailed characteristics of our study sample are given in Tables 1 and S3.

    Analysis of the course of SEMA4A serum levels according to response to treatment

    Of the 40 patients included, 4 experienced no response to treatment, 10 had a moderate response and 26 had a good response. As previously observed, baseline SEMA4A levels correlated with the DAS28 (r = 0.29, p = 0.038) and a trend was observed with CRP (r = 0.26, p = 0.10). At month 3, SEMA4A concentrations correlated with DAS28 and CRP (r = 0.31, p = 0.029 and r = 0.38, p = 0.017, respectively). Furthermore, baseline SEMA4A concentrations were significantly increased in active patients at inclusion, defined by a DAS28 > 3.2 (Fig. S2A). Interestingly, baseline SEMA4A levels were significantly higher in patients who otherwise experienced no or moderate response (198 ± 30 ng/ml) compared to patients with a good response (176 ± 24 ng/ml, p = 0.035) (Fig. S2B ). It was found that serum SEMA4A levels decreased significantly between m0 and m3, especially in the group of patients with good clinical response (Fig. S2C). This result was observed in the subgroups of patients starting MTX or tocilizumab (Fig. S2D,E).

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  • Novel nanoparticle-based system developed for the comprehensive treatment of rheumatoid arthritis

    Novel nanoparticle-based system developed for the comprehensive treatment of rheumatoid arthritis

    shutterstock 390538711 6b3c40fdd32742caa54307db3553cab1

    A team of scientists led by KOO Sagang of Seoul National University and the Center for Nanoparticle Research within the Institue for Basic Science Center (IBS), in collaboration with researchers from the Korea Institute of Science and Technology (KIST) and the Seoul National University, developed a new solution for the treatment of rheumatoid arthritis (RA).

    RA is a chronic disease that unfortunately cannot be cured. The disease causes a mix of troublesome symptoms, such as inflamed joints, harmful cytokines, and immune system imbalances, which work together to create a relentless cycle of worsening symptoms. While addressing some of these factors can provide short-term relief, others remain unresolved, leading to a frustrating cycle of remission and flare-ups.

    One of the biggest hurdles in treating RA is the inability to restore the immune system to a healthy state. This leaves the body unable to control the continued production of harmful substances such as reactive oxygen species (ROS) and inflammatory cytokines, leading to persistent inflammation and discomfort.

    Essentially, the ideal treatment for RA should not only provide immediate relief from inflammation and symptoms, but also address the cause by restoring the immune system to its normal, balanced state.

    New nanoparticle-based system as a solution

    The novel platform involves immobilizing ceria nanoparticles (Ce NPs) on mesenchymal stem cell-derived nanovesicles (MSCNVs). Both components can hinder various pathogenic factors, allowing them to work individually and together to achieve comprehensive treatment.

    Ce NPs – can scavenge the overproduction of ROS in RA-induced knee joints. They also cause polarization of M1 macrophages into M2, immediately relieving inflammation and symptoms.

    MSCNVs – deliver immunomodulatory cytokines, which convert dendritic cells (DC) into tolerogenic dendritic cells (tDCs). This consequently generates regulatory T cells for long-term immune tolerance.

    In short, this approach aims to bridge both innate and adaptive immunity to achieve short-term pain relief, and to convert the tissue environment into an immune-tolerant state to prevent recurrence of symptoms.

    Researchers confirmed the efficacy of this approach using a collagen-induced arthritis mouse model. The Ce-MSCNV system was able to comprehensively treat and prevent RA by simultaneously easing and restoring immediate T cell immunity. Supporting data suggests that improvement in conditions can be achieved after only a single dose treatment.

    The mice treated with the Ce-MSCNV combination did much better compared to the mice treated with the Ce NP or MSCNV group alone. This clearly demonstrates the synergy between anti-inflammatory agents and immunomodulation and underlines the importance of the combined therapy for effective treatment of RA. Furthermore, administration of Ce-MSCNV prior to booster injection significantly reduced the incidence and severity of symptoms, supporting the prophylactic potential of these nanoparticles.

     

    One of the most difficult decisions in the treatment of intractable diseases is determining how long to continue treatment. For RA, it would not be appropriate to stop treatment just because the target marker has stabilized. A safer indicator should be that the innate and adaptive components of the collapsed immune system are normalized to protect the body.”

     

    Koo Sagang, first author

     

    Koo believes that Ce-MSCNVs’ strategy of working together with different treatment mechanisms offers a unique advantage in this regard. Furthermore, she predicts that a similar approach for this purpose would also be applicable to other refractory, inflammatory and autoimmune diseases. The components within the system can also be changed. For example, depending on the type of disease, other catalysts can be used to generate ROS or other cell-derived nanovesicles. Overall, this study proves the potential of a hybrid nanoparticle system for the comprehensive treatment of autoimmune diseases and modulation of the immune system.

    Source:

    Institute for Basic Sciences

    Magazine reference:

    Koo, S., et al. (2023). Ceria-vesicle nanohybrid therapeutic agent for modulation of innate and adaptive immunity in a collagen-induced arthritis model. Nature Nanotechnology. doi.org/10.1038/s41565-023-01523-y.

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  • Carriers of HLA-DRB1*04:05 have a better clinical response to abatacept in rheumatoid arthritis

    Carriers of HLA-DRB1*04:05 have a better clinical response to abatacept in rheumatoid arthritis

     

    In this study, we showed that among the SE alleles, HLA-DRB1*04:05 in particular was strongly associated with the prognosis of ABT treatment. The allele frequency of HLA-DRB1*04:05 in Japanese patients with ACPA-positive RA is reported to be approximately 28%. Because each individual carries two HLA-DRB1 alleles, approximately half of ACPA-positive RA patients have at least one copy of HLA-DRB1*04:05. And HLA-DRB1*04:05 is strongly associated with the development of ACPA-positive RA, with an odds ratio of 5.023. HLA, which is innate and unchangeable throughout a person’s life, suggests that the association between HLA and treatment prognosis is not merely coincidental. In other words, the HLA genotype is the cause, which leads to favorable treatment results. Although several associations between the efficacy of SE and ABT have been reported9,10,11details at the allele level are limited, even though the significance of the specific alleles as potential biomarkers is promising.

    In this study, it was found that only HLA-DRB1*04:05 showed an association with response to ABT treatment, while HLA-DRB1*01:01 and 04:10, which share similar SE, showed no significant association. with treatment responsiveness. In addition to the effect of small sample size, the following reasons can be considered. Amino acids at positions 11, 13 and 67 of HLA-DRB1, which are different amino acid sequences than SE, are also involved in the risk of developing RA. Specifically, it was found that in DRB1*04:05 and 04:10, the valine at position 11 is the amino acid most strongly associated with RA sensitivity, while DRB1*01:01 has another amino acid, leucine, at position 11.25. Furthermore, in a study on the risk of developing RA in the Japanese population, it was shown that the risk of RA differs based on the variant of HLA-DRB1, even sharing the same HLA SE allele. It is suggested that HLA-DRB1*01:01, 04:05 and 04:10 are not bioequivalent23. Furthermore, HLA risk alleles for autoimmune diseases have been reported to significantly influence the pattern of CDR3 sequences in T cell receptors. Furthermore, CDR3 sequences modified by HLA risk alleles have been associated with the recognition of citrullinated antigens. Therefore, sequences other than SE are also believed to be associated with the development and progression of RA and other diseases26.

    SE and ACPA-positive RA are strongly associated, and ACPA is also associated with the prognosis of ABT treatment27,28. Previous reports have also shown that SE is associated with ABT outcomes, even after adjusting for the effect of ACPA9,10. In this study, both multiple regression analysis and mediation analysis suggested that the effect of the HLA-DRB1*04:05 allele was not an indirect effect mediated by ACPA (Table 4, Figure 2). The impact of SE has been reported to be stronger in ACPA-positive RA than in ACPA-positive non-RA controls29.30. In other words, SE may be involved in the pathogenesis of RA through mechanisms other than direct effects on ACPA positivity. RA risk HLA is robustly associated with CD4 T cell receptor repertoire+ T cells26.31. RA-sensitive HLA alleles, such as HLA-DRB1*04:05, are associated with autoreactive CD4+ T cells, which may be therapeutic targets for ABT.

    In this study, methotrexate use was low in the abatacept group. Because in general it has been reported that concurrent use of MTX may not increase the effectiveness of ABT. For example, in a phase III study, ABT did not induce immunogenicity associated with loss of safety or efficacy either with or without MTX32. Also in a retrospective cohort study of RA patients with similar background characteristics who underwent treatment with abatacept, concurrent MTX did not appear to influence clinical outcomes.33. Based on these findings, we believe that ABT would be a suitable treatment option in daily clinical practice in patients with contraindications to MTX.

    In this study, the association between the HLA-DRB1*04:05 allele, an SE allele, and favorable treatment outcomes was significant only in ABT-treated patients, but not in those treated with the IL-6 receptor inhibitor TCZ or a TNF drug. inhibitors. This is consistent with the association between the better prognosis with ABT and SE reported in the Early-AMPLE trial comparing ABT with the TNF inhibitor adalimumab.11. SE was also not strongly associated with the efficacy of the JAK inhibitor tofacitinib10. These findings may reflect the difference in mechanism of action between ABT, which inhibits costimulation of antigen-presenting cells, and CD4.+ T cells and IL-6 receptor inhibitors, TNF inhibitors and JAK inhibitors, which are drugs that block inflammatory cytokine signaling.

    There are several limitations to this study. First, due to the retrospective nature of this analysis, we cannot exclude the possibility of selection bias. Second, the number in each treatment group is small, so the effect of HLA alleles with small frequency or small effect size may not have been fully realized. Third, since this study was conducted in a single Japanese cohort and there are ethnic differences in the frequencies of the HLA-DRB1 allele, it is necessary to verify whether the results can be generalized to other cohorts, including other ethnic groups.

    In conclusion, we analyzed the association between HLA-DRB1 alleles and prognosis in Japanese patients with RA who initiated treatment with ABT, TCZ, and TNF inhibitors, and we showed that among SE alleles, the HLA-DRB1*04 :05 allele was associated with better outcomes with ABT. This study demonstrates the feasibility of stratifying RA patients based on disease risk HLA alleles and supports the need for a larger prospective study.

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  • Ginger shows promise as a natural defense against autoimmune diseases

    Ginger shows promise as a natural defense against autoimmune diseases

     

    This is evident from a recent study published in the journal JCI Insight, the authors built on their previous work examining the anti-autoimmune disease effects of 6-gingerol, the most abundant phytochemical produced by the roots of the ginger herb. Because their previous work showed that this plant extract could reverse the effects of neutrophil hyperactivity in mouse model systems, the researchers herein evaluated whether oral consumption of whole ginger extracts could have similar effects both in mouse models and in human pilot trials. Their results show that ginger consumption for just seven days neutralizes hyperactivity in neutrophils in both in vivo systems. When taken by healthy individuals, it increases their resistance to developing conditions, including lupus and antiphospholipid syndrome (APS).

    Study: Ginger intake suppresses the formation of extracellular neutrophils in autoimmune mice and healthy humans. Image credits: Nataly Studio / ShutterstockStudy: Ginger intake suppresses extracellular neutrophil formation in autoimmune mice and healthy humans. Image credits: Nataly Studio / Shutterstock

    Neutrophilic autoimmune diseases and the untapped potential of herbs

    Antiphospholipid antibody syndrome (APS) is an autoimmune disease that mainly affects women between the ages of 30 and 40. APS results in the formation of abnormal proteins that promote clot formation in veins and arteries and is especially harmful to both mother and her fetus during pregnancy. APS and lupus, a frequent comorbidity characterized by circulating immune complexes that damage organs after their deposition, are lifelong, incurable conditions resulting from genetics, environmental exposure, or a combination of these. Both diseases result in significant mortality, morbidity and healthcare costs.

    Previous research has shown that, despite having very different clinical profiles, both APS and lupus are pathologically caused by the exaggerated and abnormal formation of extracellular neutrophils, medically termed ‘NETosis’. During NETosis, neutrophils overexpress and secrete their nuclear chromatin in the form of web-like structures with pro-inflammatory properties and potentially harmful granule-derived proteins that, despite being localized in organs and the circulatory system, have serious consequences on the health.

    Recent studies have shown that excessive NETosis, in addition to its own negative consequences, can result in sustained formation of autoantibodies, resulting in other autoimmune diseases that would otherwise have been suppressed by the body’s adaptive immune tolerance. Considering that most of these autoimmune diseases are incurable, require constant and usually expensive medical interventions, and carry significant mortality costs, finding a low-cost therapy for NETosis is imperative.

    In recent years, scientific attention has shifted to the potential of herb-derived phytochemicals with anti-inflammatory properties as a wealth of safe and natural remedies against autoimmune diseases in general, and NETosis in particular. In a previous study, the authors of the current work showed that a purified ginger extract, 6-gingerol, shows promise in stimulating intracellular cyclic adenosine monophosphate (cAMP) and attenuating neutrophil phosphodiesterase (PDE) activity, both of which are important mechanistic results are from NETose.

    In particular, their research found that NETs and neutrophils in manifestations of thromboinflammatory diseases not only influence APS, lupus and similar autoimmune diseases, but also promote adverse outcomes in communicable diseases such as coronavirus disease 2019 (COVID-19).

    About the study

    The current study aimed to determine whether whole ginger extracts have similar NETosis-reversing effects as 6-gingerol and have beneficial effects on consumption even for healthy individuals who do not exhibit autoimmune symptoms. This study represents a pilot study that may form the basis for future clinical testing of ginger’s beneficial proteins in the treatment of a spectrum of NETosis-related autoimmune diseases, including APS, lupus, vasculitis, rheumatoid arthritis, and even COVID-19.

    Researchers began testing the efficacy of powdered whole ginger obtained from Aurea Biolabs (Kerala, India) in in vitro testing. Immunoglobulin G (IgG) was obtained from both APS and lupus patients (cases) and healthy controls and purified using the Protein G Agarose Kit (Pierce). The purity and concentration of IgG were estimated using Coomassie staining and BCA protein assay, respectively. For NETosis assays in human neutrophils, blood was collected from healthy human volunteers, purified via density gradient centrifugation, and neutrophils were isolated using dextran sedimentation and red blood cell (RBC) lysis. Flow cytometry and nuclear morphology microscopy were used to verify purity.

    For NETosis assays, the above purified neutrophils were mixed with neutrophils derived from APS and lupus patients (three volunteers, respectively). In vitro assays consisting of immunofluorescence microscopy, measurements of phosphodiesterase (PDE) activity, and calculations of intracellular cAMP levels.

    In vivo APS models included venous thrombosis experiments performed on male C57BL/6 mice (10-13 weeks). Female BALB/c mice (9 weeks old) were used for lupus testing. The venous thrombosis testing was performed using an electrolytic inferior vena cava (IVC) model. Circulating myeloperoxidase (MPO)-DNA complexes were then quantified and isolated thrombi were processed via thrombus section and immunohistochemistry.

    Finally, the pilot study was conducted in humans. Participants older than 18 years and without NETosis-associated autoimmune diseases were recruited. Female participants had to be fertile to allow the evaluation of ginger consumption in combination with contraception. Women who were pregnant, lactating, or suffering from cardiovascular disease, diabetes, or cancer were excluded to avoid confusion due to their illness or the medications they were taking. All statistics performed in this study were 1-way analysis of variance (ANOVA) corrections based on multiple corrections.

    Findings of the study

    The main findings of this study were that ginger consumption significantly inhibited NETosis in healthy study participants, even after stimulation (mixing) of neutrophils from APS or lupus patients. This was expected given that their previous research reported the same findings on the use of purified 6-gingerol supplementation, and whole ginger extracts contained approximately 20% 6-gingerol. Similarly, this study presents that consumption of whole ginger inhibited cAMP-specific PDE activity, confirming previous findings.

    In in vivo mouse models, consumption of whole ginger APS was shown to attenuate IgG-mediated venous thrombosis and NETosis. Remarkably, consumption of whole ginger attenuates lupus-relevant disease activity even in lupus-positive female BALB/c mice.

    Pilot human experiments confirm that ginger is an important focus in future clinical trials, as it was found to stimulate neutrophil cAMP and reduce NETosis in healthy human volunteers, even after just seven days of ginger diet supplementation. To verify these results and confirm that the findings were not a byproduct of the small sample size (N = 9; 3 men, 6 women), the study was repeated with an unrelated volunteer cohort (N = 8). findings consistent across replications. Furthermore, the second cohort study revealed a reduction in plasma NET levels (measured by the MPO-DNA complexes).

    Conclusion

    The current study highlights the potential of whole ginger consumption as a safe and natural intervention, both to treat existing cases of APS, lupus and other NETosis-associated diseases and to prevent the development of these conditions in previously healthy people . They combined in vitro testing with in vivo mouse and human models and found that consumption of whole ginger attenuates venous thrombosis (APS) and significantly reduces the clinical features of lupus in mouse models.

    In healthy human volunteers, ginger consumption for just seven days was associated with a notable reduction in NETosis and cAMP, confirming its potential against autoimmune diseases in future clinical trials.

    “…we found that the dissolved ginger extract counteracted the PDE activity of neutrophils. The result was increased neutrophil intracellular cAMP levels, which were associated with blunted NETosis by human neutrophils in vitro. Such data complement recent studies that have reported a role for ginger extracts, and in particular 6-gingerol, as inhibitors of cAMP-specific PDE activity. Importantly, the suppressive effects of ginger on NETosis can be attenuated by blocking PKA activity, a key downstream cAMP-dependent kinase. The fact that increasing neutrophil cAMP and activating PKA would be beneficial for disease activity in mice is in good agreement with our previous work demonstrating the potential therapeutic target of this pathway in APS and lupus models with synthetic PDE4 inhibitors. ”

    Magazine reference:

    • Ramadan A. Ali, Valerie C. Minarchick, Miela Zahavi, Christine E. Rysenga, Kristin A. Sturm, Claire K. Hoy, Cyrus Sarosh, Jason S. Knight, M. Kristen Demoruelle. Ginger intake suppresses extracellular neutrophil formation in autoimmune mice and healthy humans. JCI Insight. 2023;8(18):e172011, DOI – https://doi.org/10.1172/jci.insight.172011, https://insight.jci.org/articles/view/172011

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  • Patient-centered assessment of rheumatoid arthritis using a smartwatch and customized mobile app in a clinical setting

     

    Study design

    This was a prospective study among participants with moderate to severe RA and 28 controls, matched for age (± 3 years), gender, and race. A sample size of 60 was chosen to facilitate one-on-one follow-ups. RA and control participants were recruited from the rheumatology clinic and general medical clinic of the Reliant Medical Group (Worcester, Massachusetts). All participants were provided with an Apple Watch Series 4 and an iPhone 7 with a pre-loaded, customized, study-specific mobile application. Personal training was provided by an on-site study coordinator on how to use the devices and application, perform the guided testing, and complete the PRO measures. Participants were required to complete PRO measurements weekly, daily, or twice daily, and guided testing twice daily for 14 days (Fig. 2; Supplementary Table S3). The data was transmitted in near real time to monitor compliance and to allow study coordinators to contact participants to encourage task completion if necessary.

    Figure 2
    Figure 2

    Study design. JMAP joint pain card, BALL patient reported outcome measure, RA Rheumatoid arthritis, VAS visual analogue scale.

    Prior to the start of the study, an advisory board of patients with RA (who did not participate in the study) provided input on the study design and mobile app; This was followed by a beta test over a period of five days, involving five participants with RA, to gather feedback on the usability of the app, the clarity of the instructions and the feasibility of the assessment scheme. Feedback from the beta test included issues remembering how to charge the devices, inconsistent syncing of data with the backend server, and limitations of the iPhone leg strap. In response to this feedback, the training was updated with more specific instructions on when to charge the devices, the software was updated to improve data synchronization, and the leg strap was redesigned, along with a detailed pictorial guide on how to attach it.

    Study objectives

    The following research objectives were investigated:

    1. 1.Construct validity: correlations between guided test performance and PRO measure severity.
    2. 2.Clinical utility: differences in guided test performance and PRO measure scores between RA and control cohorts.
    3. 3.Feasibility: Survey assessment completion rates and Apple Watch wear rates in RA and control cohorts.
    4. 4.Repeatability and reproducibility: Changes in guided test performance and PRO measures over time in RA and control cohorts.

    Ethics

    All documentation, including the study protocol, any amendments, and informed consent procedures, was reviewed and approved by the Reliant Medical Group Institutional Review Board. All participants provided written informed consent before any research procedures were undertaken. The study was conducted in accordance with the principles of Good Clinical Practice of the International Committee for Harmonization and the Declaration of Helsinki.

    Selection of participants

    The full list of inclusion and exclusion criteria for participants is included in Supplementary Table S4. Briefly, participants with RA were recruited by physicians from the Reliant Medical Group during a clinical visit if they had a clinically verified diagnosis of moderate to severe RA, with severity assessed using Routine Assessment of Patient Index Data 3 (RAPID- 3; score ≤ 12). : moderate RA; score > 12: severe RA). Controls were outpatients of the Reliant Medical Group and were excluded if they had a previous or current diagnosis of a rheumatologic disease, inflammatory disease, malignancy, or other relevant diseases.

    Study assessments

    The rating scheme and example screenshots of the custom mobile application used to collect the statistics of these ratings are provided in Supplementary Table S3 and Supplementary Figure S3, respectively.

    For the guided tests, the iPhone was used to collect accelerometer and gyroscope data while participants performed predefined guided tests of physical function. The guided exercises are designed using clinical and patient feedback to test aspects of participants’ functionality that are likely to be affected by the symptoms most important to patients with RA (i.e. joint pain, stiffness, fatigue and sleep ).2. Participants were instructed to perform each guided test daily, once in the morning (immediately after waking) and once in the afternoon, to assess change in stiffness throughout the day. The wrist ROM test is described in detail in the PARADE study5. Briefly, while holding the iPhone pointed upward over the edge of a table, participants flexed and extended their wrist joint to the maximum angle (without going outside the comfort zone), repeating the movement for 10 seconds. The test was performed once with both hands. For the sit-to-stand test, participants sat on a chair with the iPhone strapped to their right thigh and their arms crossed over their chest. Then they stood up and sat down five times at their own pace. The average time taken to go from sitting to standing and from standing to sitting was extracted from accelerometer and gyroscope data. For the lie-to-stand test, participants lay on a bed with their legs extended and the iPhone strapped to their right thigh, then stood up on the floor twice at their own pace. The average time taken to transition from lying down to standing and from standing to lying down was extracted from accelerometer and gyroscope data. Other guided tests included the walking test and the 9-hole peg test (ResearchKit; Apple Inc., CA, USA)5. In the walking test, participants were asked to attach the iPhone to their right thigh and walk in a straight line for 30 seconds. In the 9-hole peg test, which measures manual dexterity, participants are asked to use two fingers of their left hand to drag a circular “peg” on the iPhone screen to a “hole” elsewhere on the screen and then two Use fingers of their right hand to remove the pin from the hole. The Apple Watch was also used to continuously collect background accelerometer data to passively measure daily and nightly activity counts, the data of which are not reported in this article.

    PROs were assessed on days 1, 7, and 14 and included the following: Functional Assessment of Chronic Disease Therapy – Fatigue (FACIT Fatigue) to assess fatigue28; HAQ-DI and SF-3629 questionnaires to indicate the impact on the participant’s quality of life24,30,31; Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference to assess how pain disrupts participants’ daily well-being, and PROMIS Sleep Disturbance to assess sleep quality32; RASIQ to quantify the severity of symptoms and their impact on the participant4. RA-specific assessments (RASIQ, PGA, stiffness) were not performed in controls.

    Short questionnaires were administered every day, except for morning stiffness, which was administered on days 2–6 and 8–13. Morning stiffness and stiffness severity were assessed based on responses to questions 11, 12, and 13 of RASIQ4. The JMAP recorded the number and severity of painful joints experienced at a given time, from 55 pre-specified joints, displayed on a body map; pain was scored as no pain, mild pain, moderate pain, or severe pain11. Pain VAS assessed the severity of pain on a scale ranging from 0 mm (no pain) to 100 mm (worst pain)33. PGA generally measures how RA affects participants and/or disease activity, using a single-item question and the VAS score34. A global assessment of fatigue over the past 24 hours was measured on a 10-point scale ranging from ‘no fatigue’ (0) to ‘as bad as you can imagine’ (10).

    Guided testing algorithms

    Details of the algorithms for the wrist ROM test, sit-to-stand test, and lie-to-stand test are given in Supplementary Methods S1. An illustrative flowchart of the algorithm for the lie-to-stand test is shown in Supplementary Figure S4 and has been previously reported for the wrist ROM test11.

    Data quality assessment

    Automated and manual data quality assessments were performed throughout the study to ensure that the data analyzed came only from properly conducted tests. The quality control of the wrist test was performed manually, and both manual and algorithmic quality controls were performed for the walking test, the sit-to-stand test, and the lie-to-stand test. Tests that were clearly performed incorrectly were removed from the sample.

    static analysis

    Descriptive statistics were used for demographic and clinical characteristics, PRO measures, and guided testing. Wilcoxon signed-rank tests were used for matched (i.e., participants with RA vs. controls and morning vs. afternoon) and rank-sum tests for unmatched (i.e., participants with moderate vs. severe RA) comparisons. Nonparametric tests were used because a normal distribution could not be assumed due to the small sample size. Trends over time were assessed using univariate mixed effects models, with study day as fixed effect and individual differences as random effects. ICCs were calculated to measure the consistency of guided testing over time for each participant using a two-way mixed effect, single rater, consistency convention; a higher ICC indicated more regular test performance over the study period than a lower ICC. Correlations between PROs and supervised tests were assessed using Pearson correlation coefficients, and one-way ANOVA was performed using the Kruskal-Wallis test by rank, with Mann-Whitney U tests for post-hoc pairwise comparisons. There was no adjustment for multiplicity in this study, and the study was not suitable for hypothesis testing; therefore, Pvalues ​​were used for quantification/descriptive purposes only.

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  • Scientists achieve breakthrough in the treatment of ‘neglected’ polymyalgia rheumatica

    Scientists achieve breakthrough in the treatment of ‘neglected’ polymyalgia rheumatica

    shutterstock 390538711 6b3c40fdd32742caa54307db3553cab1

    Scientists have had success treating a ‘neglected’ inflammatory disease, polymyalgia rheumatica, with a drug that could offer patients an alternative to steroids.

    The study, conducted by Anglia Ruskin University (ARU) and published in the New England Journal of Medicine, describes a successful trial of sarilumab. The drug, approved in Britain to treat rheumatoid arthritis, blocked the protein interleukin-6, which can cause inflammation.

    Polymyalgia rheumatica (PMR) is characterized by pain and morning stiffness in the shoulder and hips and affects people over the age of 50. It can significantly affect quality of life and is currently mainly treated with the steroids glucocorticoids.

    Although glucocorticoids can control the condition, more than half of PMR patients experience a relapse of their condition when they reduce their steroid medication. Interleukin-6 has been implicated in the pathophysiology of PMR because circulating elevated levels and increased tissue expression of interleukin-6 have been found in PMR patients.

    During the year-long clinical trial conducted by researchers, 118 patients received either twice-monthly injections of sarilumab or a placebo. The sarilumab group received a tapering dose of glucocorticoid for 14 weeks in combination with bimonthly injections of sarilumab, while the placebo group received a tapering dose of glucocorticoid for 52 weeks.

    The primary outcome at the end of the study was sustained remission of the condition. This happened in 28% of people taking sarilumab, compared to 10% of people taking the placebo. After achieving remission at 12 weeks, there were more disease flares in the placebo group (57%) compared to those who received sarilumab (24%).

    Lead PMR expert and senior author of the study, Professor Bhaskar Dasgupta, from the Medical Technology Research Center at Anglia Ruskin University (ARU), said: “Polymyalgia rheumatica is a poorly managed and neglected condition for which current treatment is unsatisfactory and can have long-term side effects. Patients can relapse while tapering their medications, and these relapses currently have very limited treatment options.

    “Our findings show promise that sarilumab can be used to treat PMR and improve outcomes for people coming off steroid medications.

    “This is an exciting development that has the potential to improve treatment options for a condition common in older people. PMR is the most common reason for long-term steroid prescriptions. Any effective drug that can spare the use of steroids would be a should have a major impact.” on reducing the serious side effects of such steroids, including diabetes, osteoporotic fractures and infections.”

    The research was funded by Sanofi and Regeneron Pharmaceuticals.

    Earlier this year, a review paper was published in the journal Nature reviews by Professor Dasgupta and colleagues highlighted the emerging view that relapsed PMR patients also have underlying giant cell arteritis, in which the main blood vessel aorta and its branches become inflamed. Researchers suggested that the two should be treated as linked conditions under the term GCA-PMR Spectrum Disease (GPSD).

    Source:

    Magazine reference:

    Tomelleri, A., et al. (2023). Disease stratification in GCA and PMR: state of the art and future perspectives. Nature Reviews Rheumatology. doi.org/10.1038/s41584-023-00976-8.

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