Kenneth Bender, PharmD, MA

A mixed qualitative-quantitative study to characterize frailty in patients with 

 finds that psychosocial factors, including anxiety and depression, could be more important determinants for developing frailty than increasing age.

"We indeed found comparable rates of frailty (across age groups) when using the Groningen Frailty Indicator (GFI), a questionnaire that heavily relies on the psychosocial effects of frailty such as anxiety, loneliness and depressive feelings," the study principle investigator Marloes van Onna, MD, PhD, Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands told 

"It might be possible that the results for frailty measures that more rely on physical effects, such as muscle strength, reduced walking speed and weight loss, do show an age-related effect.We will look into this during future research projects," she added.

van Onna and colleagues explain that while frailty is often defined as an age-associated decline in physiologic reserve and function across multi-organ systems, it can also be measured on a frailty index such as the GFI, and defined as cumulative deficits identified in a comprehensive geriatric assessment.

The investigators undertook two cross-sectional surveys and qualitative follow-up with 90 patients with rheumatoid arthritis in 3 age groups (55-64, 65-74, and ≥75years of age) who regularly visited an outpatient rheumatology clinic, to determine, in the first, whether the occurrence of frailty, measured by the GFI, increased with age; and in the second, to ascertain which of the measured conditions, such as loneliness, contributed to frailty.

In the comparison of frail to non-frail patients, as measured with the GFI, feelings of emptiness were reported in 63.2% vs 3.8%; missing the presence of people around, 65.8% vs 7.7%; feelings of loneliness, 55.3% vs 0%; depression, 73.7% vs 11.5%; and anxiety, 57.9% vs 15.4%.The percentages were similar across age groups.

With the first survey revealing that the distinction between frail and non-frail patients was "almost exclusively" determined by psychosocial factors, the investigators explored the contribution of particular factors by administering several validated questionnaires to the available sub-group (32 [36%]), as well as conducting semi-structured interviews with 10 of the participants.

More frail patients were found to have signs of an anxiety disorder on the Hospital Anxiety and Depression Scale (HADS); and during the interviews, more frail patients reported gloomy feelings, although none confirmed depression or anxiety.

As the investigators noted that rheumatoid arthritis (RA) "might be an extra complicating factor in the interplay between poor psychosocial health and frailty," 

 asked van Onna whether the question could be better ascertained in a population without the condition.

"It is extremely difficult to disentangle the causal conundrum between psychosocial health, multimorbidity and frailty," van Onna responded. "Almost all patients who suffer from frailty also suffer from multimorbidity, including RA.A first step to elucidate the relation between psychosocial factors and frailty might be to investigate psychosocial health in a sample of frail individuals, RA and non-RA, whose frailty was confirmed during a comprehensive geriatric assessment."

To the question of the relative utility of measures focusing on joint pain/function or more comprehensive assessments in managing patients with RA, van Onna responded that the latter is "the gold standard."

"Single-disease oriented care organization is often inefficient in elderly patients with frailty and multicomorbidity, and becomes burdensome for patients when physicians only take one complaint into account," van Onna said. "Elderly patients with rheumatoid arthritis and frailty often have health goals that are not necessarily related to their control of rheumatoid arthritis."

"A more holistic or goal-directed approach might in these cases be preferred," van Onna suggested. "Asking patients about their specific health-related goals, including psychosocial health-related goals, and not only focusing on RA disease control, might ultimately improve the overall outcome of these patients."

Frailty in Relation to Psycho-social Factors in Elderly Patients with Rheumatoid Arthritis: A Cross-Sectional Mixed Qualitiative-Quantitative Study

International Journal of Rheumatic Diseases.

Articles

A study characterizing frailty in patients with rheumatoid arthritis finds psychosocial factors could be more important determinants than aging.

Are Anxiety, Depression Cause or Consequence of Frailty in Elderly with Rheumatoid Arthritis?

Oral upadacitinib was superior to placebo and appeared non-inferior to subcutaneous adalimumab in treating symptoms of psoriatic arthritis.

The Janus kinase inhibitor upadacitinib improved symptoms of 

 in a 24-week, phase 3 placebo-controlled trial with active comparator adalimumab, a tumor necrosis factor α inhibitor approved for the indication.

Both 15 and 30mg oral daily doses of upadacitinib provided significantly greater relief than placebo, and the higher dose was superior to adalimumab 40mg subcutaneously every other week on the American College of Rheumatology 20 (ACR20) measure.

"Psoriatric arthritis is a chronic, painful autoimmune disease," said Iain McInnes, MD, PhD, Professor of Medicine and Versus Arthritis Professor of Rheumatology at University of Glasgow, UK and the lead study author, in an 

"I am encouraged by these results showing that upadacitinib can improve outcomes for people living with psoriatic arthritis who are facing the potentially debilitating impact of joint and skin symptoms, along with other debilitating challenges like fatigue," he stated.

McInnes and colleagues randomized 1,705 adult patients at 281 sites in 45 countries on a 1:1:1:1 ratio to receive either 15 or 30mg daily upadacitinib, placebo or adalimumab.Eachpatient had received a diagnosis of psoriatic arthritis, fulfilled the Classification Criteria for Psoriatic Arthritis, and had history of, or current plaque psoriasis.Demographic and clinical characteristics were similar across groups.

A total of 1704 patients received at least one dose of active drug or placebo, and so were included in the modified intention-to-treat analysis; and 548 patients completed the full 24-week study period.The primary end point was at least 20% improvement from baseline on the ACR20 measure of tender and swollen joints with upadacitinib as compared with placebo at week 12.

An additional primary target for the agent was improvement of at least 20% in at least 3 of 5 other domains, including assessment of disease activity on a numerical scale rated by both patient and physician, assessment of disability level based on a patient questionnaire, the patient's assessment of pain on a numerical rating scale, and high-sensitivity C-reactive protein level.

Although the trial design had included 14 multiplicity-controlled secondary end points, changes were made to the protocol and statistical analysis during the conduct of the trial to address regulatory-agency feedback on the method for testing noninferiority against adalimumab and for ordering of multiplicity-controlled end points on the basis of data from other trials.

Planned end points which could not be analyzed due to failure of the hierarchy at the point of ACR20 response with upadacitinib 15mg dose compared with adalimumab include resolution of dactylitis comparing upadacitinib with placebo, and comparing the change from baseline in the patient's assessment of pain with the adalimumab and upadacitinib.

"ACR50 and ACR70 responses are of special interest to the field of rheumatology, and comparisons of the 15mg and 30mg doses of upadacitinib with placebo and with adalimumab for these end points were prespecified," McInnes and colleagues indicated, "however, confidence intervals were not adjusted for multiple comparisons, and no conclusions can be drawn from the results."

The investigators were able to determine that the percentage of patients with psoriatic arthritis who had an ACR 20 response at week 12 was significantly higher with 15mg (70.6%) or 30mg (78.5%) upadacitinib than with placebo (36.2%).The 30mg dose, but not the 15mg dose was superior to adalimumab (13.5 percentage point difference between 30mg upadacitinib and adalimumab, and 5.6 point difference between the 15mg dose and the comparator).

In safety measures, serious infections were more frequent with the 30mg dose of upadacitinib than with placebo or adalimumab; but incidences of herpes zoster were similar (approximately 1%) for both doses of upadacitinib and placebo.Dose-dependent elevations in creatine kinase and adverse events involving hepatic disorders were reported with upadacitinib.

"There are limited data on which to base assumptions for comparisons of upadacitinib with adalimumab," McInnes and colleagues acknowledged.

"Longer and larger trials are required to determine the effect and risks of upadacitinib and its effects as compared with other drugs used to treat psoriatic arthritis," they concluded.

The study, "Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis," was published online in 

Upadacitinib Improved Psoriatic Arthritis Symptoms in Trial with Adalimumab

Abrocitinib appeared superior to dupilumab in reducing itch of 

, while the agents were comparable and superior to placebo in other treatment outcomes, in the phase 3 JADE COMPARE trial sponsored by the abrocitinib manufacturer, Pfizer.

The orally-administered investigational Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces both interleukin-4 and interleukin-13 signaling, was compared to placebo and to the subcutaneously administered anti-interleukin-4-receptor α monoclonal antibody, dupilumab, which is currently approved for treatment of atopic dermatitis.

Thomas Bieber, MD, PhD, Chair, Department of Dermatology and Allergy, Christine Kühne-Center for Allergy Research and Education, University of Bonn, Germany and colleagues described the rationale for these agents in atopic dermatitis.

"When topical therapies are insufficient, treatment with systemic agents, including dupilumab and immunospressants, are recommended.JAK inhibitors, such as baricitinib, abrocitinib, and upadacitinib, are being investigated as systemic treatments for atopic dermatitis," the investigators explained.

Bieber and colleagues screened over 1,200 patients at multiple sites, and randomized 838 adult patients who had at least a 1-year history of atopic dermatitis that was moderate to severe at baseline and who had inadequate response to at least 4 weeks of topical medications; or who were deemed to require systemic therapy to control their disease.

Participants were eligible for the study with disease severity at baseline marked by the following measures:

Score of 3 or higher on the Investigator's Global Assessment (IGA) 5-point scale where 0 is clear skin and 1 is almost clear to 4 severe

Score of at least 16 on the Eczema Area and Severity Index (EASI) that measures from 0 to the greatest severity at 72 

Score or at least 4 on the Peak Pruritus Numerical Rating Scale (PP-NRS), in which 10 is most severe

Participants were randomly assigned in a 2:2:2:1 ratio to receive a 16-week regimen of either 200mg or 100mg of abrocitinib orally once daily; 300mg of dupilumab subcutaneously every other week, after a loading dose of 600mg; or placebo. Non-systemic treatments at baseline were continued throughout the study. Patients, investigators and representatives of the sponsor were blinded to the trial group assignments.

The primary endpoints were an IGA response (with score of 0 or 1) and an EASI-75 response (>75% improvement from baseline) at week 12. Key secondary endpoints were itch response (≥4-point improvement from baseline PP-NRS) at week 2; and IGA and EASI-75 responses at week 15.

Bieber and colleagues reported an IGA response at week 12 in 48.4% of patients in the 200mg abrocitinib group; 36.6% in the 100mg abrocitinib group, 36.5% in the dupilumab group; and 14% of those receiving placebo.The EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1% and 27.1%, respectively.

The investigators indicated that the 200mg dose, but not the 100mg dose of abrocitnib was superior to dupilumab with respect to itch response at week 2; but that neither abrocitinib dose differed statistically significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16.

 article on atopic dermatitis, Sonja Ständer, MD, Department of Dermatology and Center for Chronic Pruritus (KCP), University Hospital Münster, Münster, Germany concurred that the study had associated both agents with reductions in signs and symptoms relative to placebo, and that abrocitinib appeared superior to dupilumab in reduction of itch at 2 weeks. "...otherwise," she indicated, "the two drugs had similar outcomes."

While acknowledging the benefits of the treatments, particularly when symptoms have not responded to topical treatments,Ständer warned that the adverse effects can be significant.She noted, for example, that dupilumab therapy has been associated with long-term, functionally impairing conjunctivitis; and that JAK inhibitors carry a risk of thromboembolism and cancer, and have been associated with decreased white-cell counts and with respiratory tract infections and herpes zoster infection.

"Adverse effects such as skin infections or worsening of asthma necessitate careful evaluation of the future use of these new therapies in sensitive populations (children) and in patients with typical complications of atopic dermatitis," Ständer cautioned.

Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis

The oral Janus kinase 1 inhibitor abrocitinib produced similar outcomes to dupilumab in a placebo-controlled comparison for atopic dermatitis.



Trial Finds Abrocitinib, Dupilumab Comparable for Atopic Dermatitis

Approximately two-thirds of patients with 

 responded to a change in immunosuppression treatment while a significant minority showed no response, in a large prospective study of treatment outcomes.

Liza Rajasekhar, MD, Associate Professor, Nizam’s Institute of Medical Sciences, Hyderabad, India and colleagues point out that lupus nephritis is present in approximately one-third of patients at diagnosis of systemic lupus erythematosus (SLE).

“Progression to end-stage renal disease is a dreaded outcome,” Rajasekhar and colleagues emphasized.

The investigators undertook what they describe as among the largestprospective observational studies of response to changing treatment regimens in patients with lupus nephritis who do not respond to initial, first-line therapy.

They enrolled 48 patients consecutively admitted between August 2018 to January 2019 for lupus nephritis who had either not improved within 3 months of diagnosis, had not achieved partial renal response at 6 months, or had not achieved complete renal response after 2 years of treatment.The median duration of SLE was 3 years (range, 2-6 years).

“Since it is not easy to conduct a randomized controlled trial in this group of patients, we believe that this study presenting such data in 48 patients, followed prospectively with well documented details of therapy and outcome, will contribute to evidence which will guide therapy in initial non-responders,” Rajasekhar and colleagues explained.

Lupus nephritis was defined per American College of Rheumatology (ACR) criteria, with complete renal response marked by single “spot” urine protein:creatinine ratio (UPCR) <50mg/mmol (equivalent to proteinuria <0.5g/24h) and normal or near-normal (within 10%) glomerular filtration rate (GFR). 

Partial renal response corresponded to ≥50% reduction in proteinuria to sub-nephrotic levels and normal or near-normal GFR.Lack of improvement, categorized as no renal response, was marked by no reduction in proteinuria or a deterioration of GFR.

Initial treatment strategies for RLN involved switching to another first-line drug, such as mycophenolic acid (MPA) from cyclophosphamide (CYC), and vice versa. Alternative approaches used at the discretion of the treating physicians included switching to tacrolimus, rituximab, or combination therapy such as MPA and tacrolimus. All patients received maintenance doses of oral corticosteroids, hydroxychloroquine, calcium/vitamin D, and ACE inhibitors. Steroid dose was not increased during switching of treatment.

Follow-up occurred during a flare and every 3 months, with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and notations on response to treatment and adverse events. The median follow-up period was 15 months (range, 12-27 months).

Rajasekhar and colleagues reported that 28 had complete renal response, 9 had partial response and 8 showed no response to a switch in an immunosuppressive agent. There were 3 deaths, all related to infection.There was no significant difference in treatment outcome and time to attain response associated with a particular immunosuppressive agent or sequence of agents. 

None of the measured variables, including duration of SLE or nephritis, baseline SLEDAI score, leukopenia, hypertension, predicted renal response.

The investigators noted that the combination of tacrolimus and MPA produced a relatively high global response rate, consistent with previous reports of complete and partial response in 57-95%.There were no responders to tacrolimus as monotherapy, however. Approximately half of patients responded to MPA as a single agent, as did half of those receiving cyclophosphamide per NIH protocol and half on regimens which included rituximab.

“Numerically, best responses were seen using MPA and tacrolimus combination while switching immunosuppressive agents in any sequence proved effective in almost half the patients,” Rajasekhar and colleagues reported.

Treatment Outcomes in Refractory Lupus Nephritis: Data from an Observational Study

Investigators conducted what's believed to be the largest prospective observational studies of response to changing treatment regimens in patients with lupus nephritis who do not respond to initial, first-line therapy.