Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study.

OBJECTIVES: To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS). METHODS: A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug. RESULTS: At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was -2.5% (95% CI -21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups. CONCLUSIONS: Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS. TRIAL REGISTRATION NUMBER: NCT02047110; Pre-results.

Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial.

BACKGROUND: IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit. OBJECTIVE: This first-in-human proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. METHODS: We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. RESULTS: Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066-treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066-treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed (r = 0.73, P = 2 × 10(-6)). CONCLUSIONS: BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.

Risks of mortality associated with common laboratory tests: a novel, simple and meaningful way to set decision limits from data available in the Electronic Medical Record.

BACKGROUND: Laboratory tests provide objective measurements of physiologic functions, but are usually evaluated by demographic reference-intervals (RI), instead of risk-based decision-limits (DL). We show that hospital electronic medical record (EMR) data can be utilized to associate all-cause mortality risks with analyte test values, thereby providing more information than RIs and defining new DLs. METHODS: Our cohort was 39,964 patients admitted for any reason and discharged alive, during two 1-year periods, at Sarasota Memorial Hospital, Florida, USA. We studied five routinely-performed in-hospital laboratory tests: serum creatinine, blood urea nitrogen, serum sodium, serum potassium, and serum chloride. By associating a mortality odds ratio with small intervals of values for each analyte, we calculated relative risk of all-cause mortality as a function of test values. RESULTS: We found mortality risks below the population average within these proposed DLs: potassium 3.4-4.3 mmol/L; sodium 136-142 mmol/L; chloride 100-108 mmol/L; creatinine 0.6-1.1 mg/dL; blood urea nitrogen (BUN) 5-20 mg/dL. The DLs correspond roughly to the usually-quoted RIs, with a notable narrowing for electrolytes. Potassium and sodium have reduced upper limits, avoiding a "high-normal" area where the odds ratio rises 2 to 3 times the population average. CONCLUSIONS: Any clinical laboratory test can be transformed into a mortality odds ratio function, associating mortality risk with each value of the analyte. This provides a DL determined by mortality risk, instead of RI assumptions about distribution in a "healthy" population. The odds ratio function also provides important risk information for analyte values outside the interval.

Interleukin-1ß-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study.

OBJECTIVE: Uveitis and retinal vasculitis are sight-threatening manifestations of Behçet's disease with limited treatment options. This pilot study aimed to evaluate the safety, pharmacokinetics and clinical activity of XOMA 052 (gevokizumab), a recombinant humanised anti-interleukin 1ß antibody, in Behçet's disease patients with uveitis. METHODS: Patients with acute posterior or panuveitis, and/or retinal vasculitis, resistant to azathioprine and/or ciclosporin, and receiving 10 mg/day or less of prednisolone, were enrolled into the 98-day study. Immunosuppressive agents were discontinued at baseline. Patients received a single infusion of XOMA 052 (0.3 mg/kg). The safety and uveitis status and pharmacokinetics of XOMA 052 were evaluated. RESULTS: Seven patients enrolled and completed the study. No treatment-related adverse event was observed. XOMA 052 treatment was associated with rapid and durable clinical response in all patients. Complete resolution of intraocular inflammation was achieved in 4-21 days (median 14 days), with a median duration of response of 49 days (range 21-97 days); one patient remained exacerbation free throughout the study. CONCLUSIONS: Well tolerated, XOMA 052 resulted in a rapid onset and sustained reduction in intraocular inflammation in patients with resistant uveitis and retinal vasculitis. Moreover, the effect was observed despite discontinuation of immunosuppressive agents and without the need to increase corticosteroid dosages.

Manipulation under anesthesia: a report of four cases.

OBJECTIVE: To report the results of manipulation under anesthesia (MUA) for 4 patients with chronic spinal, sacroiliac, and/or pelvic and low back pain. METHODS: The treatment group was arbitrarily selected from the chiropractor's patient base who received the MUA protocol along with a follow-up in-office articular and myofascial release program that mimics the MUA procedures. The chiropractic adjustments and articular and myofascial release procedures were performed in a chiropractic office. The MUA procedures were performed in an outpatient ambulatory surgical center. Patients with chronic pain who had not adequately responded to conservative medical and/or a reasonable trial (4 months minimum) of chiropractic adjustments, and had no contraindications to anesthesia or adjustments, were selected. The 4 patients went through 3 consecutive days of MUA followed by an 8-week protocol of the same procedures plus physiotherapy in-office without anesthesia. Data included pre- and post-MUA passive ranges of motion, changes in the visual analog scale, and neurologic and orthopedic examination findings. The patients had follow-up varying from 9 to 18 months. RESULTS: Increases in passive ranges of motion, decreases in the visual analog scale rating, and diminishment of subsequent visit frequency were seen in each of the patients. CONCLUSION: Manipulation under anesthesia was an effective approach to restoring articular and myofascial movements for these 4 patients who did not adequately respond to either medical and/or in-office conservative chiropractic adjustments and adjunctive techniques.

Shared decision-making at end-of-life is aided by graphical trending of illness severity.

The Rothman Index (RI) gives a visual picture of patient's condition and progress for the physician and family to view together. This case demonstrates how the RI graph facilitates physician-family communication. An 85-year-old man with normal pressure hydrocephalus and ventriculoperitoneal shunt presented with a subdural haematoma. He required a temporoparietal craniotomy and evacuation of left subdural haematoma, followed by care in an intensive inpatient rehabilitation unit. His course was complicated by aspiration pneumonia, dehydration, renal failure and phenytoin toxicity. During hospitalisation, the patient's RI graph was reviewed daily with his family. The RI provided an unambiguous visualisation of the trend of patient acuity, which depicted the patient's persistent decline in health, and made clear to the family the situation of the patient. This clarity was instrumental in prompting frank discussions of prognosis and consideration of comfort measures, resulting in timely transfer to hospice.

Placing clinical variables on a common linear scale of empirically based risk as a step towards construction of a general patient acuity score from the electronic health record: a modelling study.

OBJECTIVE: To explore the hypothesis that placing clinical variables of differing metrics on a common linear scale of all-cause postdischarge mortality provides risk functions that are directly correlated with in-hospital mortality risk. DESIGN: Modelling study. SETTING: An 805-bed community hospital in the southeastern USA. PARTICIPANTS: 42302 inpatients admitted for any reason, excluding obstetrics, paediatric and psychiatric patients. OUTCOME MEASURES: All-cause in-hospital and postdischarge mortalities, and associated correlations. RESULTS: Pearson correlation coefficients comparing in-hospital risks with postdischarge risks for creatinine, heart rate and a set of 12 nursing assessments are 0.920, 0.922 and 0.892, respectively. Correlation between postdischarge risk heart rate and the Modified Early Warning System (MEWS) component for heart rate is 0.855. The minimal excess risk values for creatinine and heart rate roughly correspond to the normal reference ranges. We also provide the risks for values outside that range, independent of expert opinion or a regression model. By summing risk functions, a first-approximation patient risk score is created, which correctly ranks 6 discharge categories by average mortality with p<0.001 for differences in category means, and Tukey's Honestly Significant Difference Test confirmed that the means were all different at the 95% confidence level. CONCLUSIONS: Quantitative or categorical clinical variables can be transformed into risk functions that correlate well with in-hospital risk. This methodology provides an empirical way to assess inpatient risk from data available in the Electronic Health Record. With just the variables in this paper, we achieve a risk score that correlates with discharge disposition. This is the first step towards creation of a universal measure of patient condition that reflects a generally applicable set of health-related risks. More importantly, we believe that our approach opens the door to a way of exploring and resolving many issues in patient assessment.

Clinical implications and validity of nursing assessments: a longitudinal measure of patient condition from analysis of the Electronic Medical Record.

OBJECTIVES: This study investigates risk of mortality associated with nurses' assessments of patients by physiological system. We hypothesise that nursing assessments of in-patients performed at entry correlate with in-hospital mortality, and those performed just before discharge correlate with postdischarge mortality. DESIGN: Cohort study of in-hospital and postdischarge mortality of patients over two 1-year periods. SETTING: An 805-bed community hospital in Sarasota, Florida, USA. SUBJECTS: 42 302 inpatients admitted for any reason, excluding obstetrics, paediatric and psychiatric patients. OUTCOME MEASURES: All-cause mortalities and mortality OR. RESULTS: Patients whose entry nursing assessments, other than pain, did not meet minimum standards had significantly higher in-hospital mortality than patients meeting minimums; and final nursing assessments before discharge had large OR for postdischarge mortality. In-hospital mortality OR were found to be: food, 7.0; neurological, 9.4; musculoskeletal, 6.9; safety, 5.6; psychosocial, 6.7; respiratory, 8.1; skin, 5.2; genitourinary, 3.0; gastrointestinal, 2.3; peripheral-vascular, 3.9; cardiac, 2.8; and pain, 1.1. CI at 95% are within ±20% of these values, with p<0.001 (except for pain). Similar results applied to postdischarge mortality. All results were comparable across the two 1-year periods, with 0.85 intraclass correlation coefficient. CONCLUSIONS: Nursing assessments are strongly correlated with in-hospital and postdischarge mortality. No multivariate analysis has yet been performed, and will be the subject of a future study, thus there may be confounding factors. Nonetheless, we conclude that these assessments are clinically meaningful and valid. Nursing assessment data, which are currently unused, may allow physicians to improve patient care. The mortality OR and the dynamic nature of nursing assessments suggest that nursing assessments are sensitive indicators of a patient's condition. While these conclusions must remain qualified, pending future multivariate analyses, nursing assessment data ought to be incorporated in risk-related health research, and changes in record-keeping software are needed to make this information more accessible.

Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes.

OBJECTIVE: Metabolic activation of the innate immune system governed by interleukin (IL)-1ß contributes to ß-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1ß antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. RESULTS: The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG(2), with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. CONCLUSIONS: This novel IL-1ß-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.

Etanercept in adult patients with early onset ankylosing spondylitis.

OBJECTIVE: To determine whether twice-weekly subcutaneous etanercept improves the signs and symptoms of adult patients with early onset ankylosing spondylitis (AS). METHODS: A retrospective analysis was performed on a subgroup of patients with AS with onset < 18 years of age from a multicenter, double-blind, placebo-controlled, randomized study of etanercept in the treatment of patients with AS. Twenty patients met criteria and are presented. RESULTS: As early as week four, 5/9 (56%) patients who received etanercept achieved an Assessments in Ankylosing Spondylitis 20% response (ASAS 20) versus only 1/11 (9%) of those who received placebo (p = 0.032). The observed ASAS 20 response continued through week 24, with 6/9 (66%) patients receiving etanercept responding, versus 2/11 of patients receiving placebo (p = 0.025). CONCLUSION: Etanercept improves signs and symptoms of early onset AS in adult patients for at least 24 weeks.

Interleukin-1 blockade by anakinra improves clinical symptoms in patients with neonatal-onset multisystem inflammatory disease.

Neonatal-onset multisystem inflammatory disease (NOMID) is a rare, childhood-onset disease that is characterized by chronic, systemic inflammation. The purpose of this report is to describe the effects of interleukin-1 (IL-1) blockade on the clinical symptoms of 2 patients with NOMID. At the time of this report, the patients had been treated with anakinra (Kineret), a recombinant human IL-1 receptor antagonist, for 1.5 and 2 years, respectively. Both patients demonstrated rapid improvement in clinical symptoms and laboratory markers of inflammation. The use of anakinra in these patients seemed to be effective, without any safety concerns. These observations suggest that IL-1 plays a critical role in the pathogenesis of this inflammatory disease, and that blockade with anakinra should be further studied as a treatment for patients with NOMID and related disorders.

A phase 2 dose-finding study of PEGylated recombinant methionyl human soluble tumor necrosis factor type I in patients with rheumatoid arthritis.

OBJECTIVE: In a phase 2 study, to assess the efficacy and safety of pegsunercept, a soluble tumor necrosis factor receptor type I, for the treatment of rheumatoid arthritis (RA). METHODS: Patients were randomized to receive weekly subcutaneous injections of placebo (n = 61) or active drug [400 microg/kg (n = 67) or 800 microg/kg (n = 66)] for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. Secondary efficacy measures included ACR50 and ACR70 responses, and changes in individual ACR components at Week 12. Safety assessments included summaries of adverse events including infectious episodes. RESULTS: Treatment with pegsunercept resulted in a significantly higher ACR20 response at Week 12 in the 800 microg/kg group (45%) compared with the placebo group (26%; p = 0.020). The treatment effect of pegsunercept (both doses) over the study period showed statistically significant improvement for most ACR components and health related quality of life, with the 800 microg/kg group showing greater clinical improvements in efficacy measures. The overall incidence of adverse events and infectious episodes was similar among the treatment and placebo groups. CONCLUSION: In this 12 week dose-finding study of 194 patients, weekly subcutaneous dosing with pegsunercept showed beneficial effects in improving the signs and symptoms of RA. It appeared to be safe and well tolerated in this small number of patients. Significant clinical improvements were seen in patients in the 800 microg/kg group; however, this dose may be suboptimal, and further evaluation of this product with higher doses or a more frequent dosing regimen is warranted.

Rheumatic manifestations of human immunodeficiency virus.

Since July 1983, various rheumatic, musculoskeletal, or other immune disorders characterized by dysregulation have been associated with HIV and AIDS. Infections occur, but with a lower frequency than expected in a patient population with a disorder primarily characterized by significant cellular immune deficiencies. Reactive arthritis, psoriatic arthritis, acute nonspecific arthritis, Sjögren syndrome, and inflammatory myositis have been reported. The initial reports of "acute painful joints," however, have not maintained prominence in the literature. A review of the literature over the past several years has reinforced the perception that the initial excitement over a possible association between HIV and AIDS and rheumatic or definable autoimmune disorders remains limited to a small segment of illnesses dominated by the reactive arthritidies.

A reassessment of normal cervical range of motion.

STUDY DESIGN: Intraexaminer and interexaminer/procedure reliability and error analysis using a repeated-measures design. OBJECTIVE: To quantify sources of discrepancies in cervical range of motion values between two procedures that use the same potentiometric technology. SUMMARY OF BACKGROUND DATA: Studies using an early version of an electrogoniometer system, which was connected between a helmet worn by the study participant and a chair on which they sat, reported unusually high values for active and passive cervical range of motion, although measurements were reliable. To understand the sources of the discrepancies between that study and later studies (using upgraded software), the current study was designed to quantify possible sources of error contributed by various components of the procedures: helmet, thoracic reference, chair, and software. METHODS: A total of 22 asymptomatic study participants were evaluated in two separate sessions, 1-3 days apart. Components of two procedures were changed systematically in a series of repeated measurements to provide concurrent reliability and to assess sources of error between the two procedures. RESULTS: The reliabilities of both procedures were generally high with no systematic trends, except for lower values for flexion-extension studies with Procedure 2. Procedure 2 also provided systematically greater range of motion values (2-8 degrees ) than Procedure 1, except for flexion (half-cycle). The source of the greatest discrepancy between the two procedures was the software, when comparing the original with the updated versions. With regard to the instrumentation, the greatest source of variability was in the thoracic reference post; next was the helmet, and least significant was the type of seat used. A comparison of overall procedure discrepancies and summation of individual elements of the procedures accounted for virtually all of the observed error. CONCLUSION: The potentiometer-based electrogoniometer is a reliable instrument for determining cervical range of motion. Measurements appear to be more valid when the thoracic reference point is physically attached to the study participant's body. The original software provided with the system appears to have contributed to systematic overestimation of ranges of motion, but current units provide measurements that are both reliable and valid.

The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions.

OBJECTIVE: To determine in a placebo-controlled, double-blind trial the safety profile of daily anakinra (Kineret) use in patients with active rheumatoid arthritis (RA) and concurrent comorbid conditions. METHODS: In 169 centers in 9 countries, 1,414 patients with active RA were randomly assigned to receive either anakinra (100 mg) or placebo treatment (4:1 anakinra-to-placebo allocation ratio), with study drug administered by daily subcutaneous injection for 6 months. The current post hoc analysis assessed baseline comorbid conditions, and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following: cardiovascular event, pulmonary event, central nervous system-related event, infection, diabetes, malignancy, or renal impairment. Within each treatment group (anakinra or placebo), incidence rates were summarized for serious adverse events, infectious events, and serious infectious events in high-risk patients and compared with these incidence rates in patients without comorbid conditions. RESULTS: The majority of patients in the trial had one or more comorbid conditions. In these high-risk patients, there were no differences in the incidence of serious adverse events or infectious events between treatment groups. The incidence of serious infectious events with anakinra use was similar between high-risk patients (2.5%) and the entire study population (2.1%) and was not attributable to any single comorbidity. CONCLUSION: Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high-risk patient population.

Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis.

OBJECTIVE: To examine the safety of anakinra when added to a background of standard rheumatoid arthritis (RA) medications in patients with RA with active disease. METHODS: This analysis further evaluates data from the first 6 months of a blinded, placebo controlled safety trial that had a subsequent 30 month, open label portion (not reported here). Patients with RA with a wide range of comorbid conditions, disease activity, and background medications were randomly assigned in a 4:1 allocation ratio to treatment with anakinra 100 mg or placebo administered daily by injection. Safety was assessed by comparing adverse event profiles between anakinra and placebo patients according to concomitant medications received. RESULTS: Anakinra patients (n = 1116) showed no difference in the incidence of upper respiratory infections or overall serious adverse events compared with placebo patients (n = 283). The anakinra group had more injection site reactions (72.6% vs 32.9% in placebo) and a small increase in serious infections (2.1% vs 0.4% in placebo). Anakinra's safety profile did not differ in patients receiving antihypertensive, antidiabetic, or statin drugs. CONCLUSION: This study indicates that anakinra has a good safety profile in patients typically seen in a rheumatology practice who are considered candidates for therapy with agents that are immunomodulatory and disease modifying. Except for injection site reactions and a nonstatistically although potentially clinically significant increase in serious infections in the anakinra versus the placebo groups, the addition of anakinra to a stable background regimen of RA medications introduced no other important safety risk in patients with RA.