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"Ruderman, Eric"
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Nonradiographic axial spondyloarthritis: clinical and therapeutic relevance
by
Ghosh, Nilasha
,
Ruderman, Eric M.
in
Antiarthritic agents
,
Axial spondyloarthritis
,
Biologic therapy
2017
Current classification criteria for axial spondyloarthritis (axSpA) provide for the inclusion of patients with a wide range of presentations and manifestations. While not considered a formal subclassification, patients are often divided into radiographic or nonradiographic axSpA based on the presence or absence of radiographic sacroiliitis. This review will focus on nonradiographic axSpA and will discuss clinical manifestations of disease that distinguish, or in many cases do not distinguish, this entity from other individuals with axSpA. This review will also cover treatment paradigms for nonradiographic axSpA, particularly the use of biologic therapies, where current data suggest that nonradiographic disease should be managed largely the same as radiographic disease, or classical ankylosing spondylitis.
Journal Article
Bruton’s Tyrosine Kinase Inhibition for the Treatment of Rheumatoid Arthritis
by
Arneson, Laura C
,
Carroll, Kristen J
,
Ruderman, Eric M
in
acalabrutinib
,
Adalimumab
,
Analysis
2021
Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of drugs that inhibit B cell receptor activation, FC-[gamma] receptor signaling, and osteoclast proliferation. Following on approval for treatment of hematologic malignancies, BTK inhibitors are now under investigation to treat a number of different autoimmune diseases, including rheumatoid arthritis (RA). While the results of BTK inhibitors in RA animal models have been promising, the ensuing human clinical trial outcomes have been rather equivocal. This review will outline the mechanisms of BTK inhibition and its potential impact on immune mediated disease, the types of BTK inhibitors being studied for RA, the findings from both preclinical and clinical trials of BTK inhibitors in RA, and directions for future research. Keywords: evobrutinib, spebrutinib, acalabrutinib, fenebrutinib, rheumatoid arthritis, Bruton's tyrosine kinase
Journal Article
Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial
2011
Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide.
In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m
2 intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with
ClinicalTrials.gov, number
NCT00278525.
Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04–∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted.
Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed.
None
Journal Article
Safety of biologic therapy in rheumatoid arthritis
by
Woodrick, Robert S.
,
Ruderman, Eric M.
in
692/699/1670/498
,
692/700/565/1331
,
692/700/565/2194
2011
Biologic therapies, which have transformed the treatment of rheumatoid arthritis (RA) in the 21
st
Century, have the potential to modulate immune responses and thus are associated with a risk of infection, as well as other adverse events. This Review summarizes the available safety data for all such agents approved for the treatment of RA, to assist clinicians in weighing potential risks and therapeutic benefits.
Biologic therapies have revolutionized the treatment of rheumatic diseases in the past decade. As with any drugs, however, a variety of important safety concerns affect the choice and use of these agents. Several issues, such as the risk of infection, malignancy, or administration reactions, apply to all of these compounds, although some conditions that affect patient selection and management within these categories seem to be specific to particular biologic treatments. Other safety concerns with biologic agents, such as congestive heart failure, demyelinating disease, and hyperlipidemia, are associated with individual agents. Despite all these concerns, the therapeutic indices for biologic agents remain fairly high in relation to non-biologic DMARDs. Available safety data for all biologic agents approved for the treatment of rheumatoid arthritis are reviewed in this manuscript. With careful patient selection and appropriate vigilance on the part of treating physicians and other care providers, these compounds can be safely integrated into the therapeutic plan.
Key Points
Although randomized, controlled trials provide important initial information about the safety of new therapeutic agents, post-marketing data are often necessary to understand the true risk of specific adverse events
Infections remain the greatest safety concern with biologic therapies; no single agent carries a clearly reduced overall risk of infection in comparison with the others
The risk of specific infections, such as tuberculosis, seems to be higher with some biologic agents than with others
Screening for latent tuberculosis in all patients can reduce the risk of reactivation of this infection with TNF inhibitor therapy
Whereas the overall risk of solid malignancies does not seem to increase with biologic therapy, the risk of non-melanoma skin cancer is increased with TNF inhibitor therapy
TNF inhibitors may be used during pregnancy if clinically indicated; insufficient data guide the potential use of other biologic agents during pregnancy
Journal Article
Low-dose Methotrexate Therapy Does Not Affect Semen Parameters and Sperm DNA
by
Stein, Adam
,
Christensen, Lisbet Ambrosius
,
Kelsen, Jens
in
Inflammatory diseases
,
Morphology
,
Motility
2022
Background Methotrexate is widely used in inflammatory diseases during the patients’ reproductive years. The effect on male fertility and sperm DNA integrity is largely unknown. We evaluated sperm DNA integrity and basic semen parameters according to the World Health Organization (WHO) in male patients with inflammatory diseases treated with methotrexate. Methods Semen samples from 14 patients on low-dose maintenance methotrexate were compared with samples from 40 healthy volunteers. Further, 5 patients delivered samples on and off methotrexate therapy for paired comparison. Sperm DNA fragmentation index (DFI), concentration, motility, and morphology were evaluated. Blood sex hormones and methotrexate levels were measured in blood and semen. Results DNA fragmentation index in methotrexate-treated patients was comparable with that in healthy volunteers (DFI, 11.5 vs 15.0; P = .06), and DFI did not change significantly on and off methotrexate in the paired samples (DFI, 12.0 vs 14.0; P = 0.35). Sperm concentration, motility, and morphology did not differ between men treated with methotrexate and healthy volunteers. Sperm progressive motility increased off therapy compared with on therapy (65.0% vs 45.0%, P = .04), but all fluctuations in progressive motility were within the WHO reference interval. All methotrexate polyglutamates1-5 were detected in blood, but only methotrexate polyglutamate1 in semen. Serum testosterone was unaffected by methotrexate therapy. Conclusions Patients treated with low-dose methotrexate have a sperm quality comparable with that of healthy volunteers, and methotrexate treatment does not increase sperm DNA fragmentation. This study does not support cryopreservation of semen before treatment initiation nor a 3-month methotrexate-free interval prior to conception.
Journal Article
IL-6 inhibition in RA—déjà vu all over again?
2015
In a phase II–III trial, a novel antibody targeting IL-6 receptor α (IL-6Rα), sarilumab, conferred clinical, functional and structural benefits in rheumatoid arthritis. These results, though, seem quite similar to those for tocilizumab, the existing anti-IL-6Rα antibody, as well as for other agents currently in development that target this same pathway.
Journal Article
Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis
2013
Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group.
We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m2) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5–6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests.
Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05).
Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated.
None.
Journal Article
Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials
by
Rubbert-Roth, Andrea
,
Lippe, Ralph
,
Lertratanakul, Apinya
in
Infections
,
Kinases
,
Monoclonal antibodies
2022
IntroductionThis integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug.MethodsSafety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020.ResultsA total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon.ConclusionsUpadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib.Trial Registration NumbersSELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.Plain Language SummaryPsoriatic arthritis is a disease that causes inflammation of the skin and joints. Upadacitinib and adalimumab are medicines that can be used to treat this condition. This analysis combined safety data from two studies of adults with psoriatic arthritis who took upadacitinib, adalimumab, or placebo (no medicine) for up to 3 years. The most common side effects of treatment with upadacitinib were infection and inflammation of the nose and throat and higher amounts of a protein in the blood called creatinine phosphokinase. The total number of cancer cases, heart (cardiovascular) problems, blood clots (embolisms), and deaths were similar across treatment groups, including the placebo (no medicine) group. However, more patients who took upadacitinib than adalimumab or placebo (no medicine) had a painful rash that causes blisters known as herpes zoster (shingles) and infections usually seen in people with a weakened immune system. Most patients had normal blood test results and continued their treatment. Overall, upadacitinib was well tolerated for up to 3 years in patients with psoriatic arthritis. These results agree with what has been found in studies of upadacitinib in patients with rheumatoid arthritis. Safety data of upadacitinib use over a longer time will be reported later.
Journal Article