Rheumatology News

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End-stage renal disease risk in lupus
nephritis remains unchanged of late
BY PATRICE WENDLING
Frontline Medical News
From Arthritis & Rheumatology
The world health community has
lost ground in its fight to reduce
end-stage renal disease in patients
with lupus nephritis, a systematic
review and meta-analysis concluded.
The risk of end-stage renal disease
(ESRD) at 5 years of lupus nephri-
tis decreased substantially from the
1970s, when it was 16%, to the mid-
1990s, when it plateaued at 11%.
ESRD risks at 10 years and 15
years declined more sharply in the
1970s and 1980s but also plateaued
in the mid-1990s at 17% and 22%,
respectively.
This plateau was followed by a
notable increase in risk in the late
2000s, particularly in the 10-year
and 15-year estimates, Dr Maria
Tektonidou of the University of
Athens and her coauthors reported.
“Despite extensive use of immu-
nosuppressive medications through
the 2000s, we did not find continued
improvement in ESRD risks, but in-
stead a slight increase in risks in the
late 2000s,” they wrote.
The increase did not appear to be
related to greater representation in
recent studies of ethnic minorities,
who may be more likely to develop
ESRD. In the main analysis involv-
ing 148 of the 187 studies, “trends
suggest this increase may have been
temporary, but further follow-up will
be needed to determine if this is
sustained,” the investigators added.
Notably, patients with class-IV
lupus nephritis had the greatest risk
of ESRD during the 2000s, with a
15-year risk of 44%.
The 15-year risk of ESRD also
was higher by 10 percentage points
in developing countries than in de-
veloped countries during the 2000s.
The trends are worrisome because
ESRD is a costly complication of
lupus nephritis, which affects more
than half of all patients with sys-
temic lupus erythematosus (SLE).
Patients with lupus nephritis have
a 26-fold increased risk of death
and estimated annual health care
costs between US$43,000 and
US$107,000 per patient, the au-
thors noted.
The systematic review and
Bayesian meta-analysis included
187 studies reporting on 18,309
adults with lupus nephritis from
1971 to 2015. The main analysis
of ESRD risk included 102 studies
from developed countries and 46
studies from developing countries.
Across all studies, 86% of patients
were women, 32% had elevated se-
rum creatinine levels at study entry,
and proteinuria averaged 3.6 g daily.
The average age was 31.2 years and
mean duration of lupus nephritis
was 2.7 years.
The proportion of patients treated
with glucocorticoids alone in the
studies declined from 54% in 1966
to 9% in 2010, while use of immu-
nosuppressive therapies increased.
The decrease in ESRD risks early
on coincided with increased use of
immunosuppressives, particularly
cyclophosphamide, and better con-
trol of hypertension and proteinuria.
As for why those gains have stalled,
Dr Tektonidou and her colleagues
said it’s possible that the limits of
effectiveness of current treatments
have been reached and better out-
comes will require new therapies.
“It is also possible that the plateau
primarily reflects lack of progress
in the way currently available and
effective treatments are deployed,”
they added. “This includes health
system factors that result in delays in
treatment initiation, and patient and
health system factors that result in
treatment interruptions and reduced
adherence.”
In an accompanying editorial,
Dr Candace Feldman and Dr Karen
Costenbader, both of Brigham and
Women’s Hospital in Boston, wrote,
“While we have made advances
over the past 50 years in our un-
derstanding of immunosuppressive
medications, there have been few
meaningful improvements in other
domains that contribute to ESRD
and to the persistent and dispropor-
tionate burden among vulnerable
populations”.
Despite the clear importance of
medication adherence to SLE care,
a recent systematic review of ad-
herence interventions in rheumatic
diseases found few SLE-specific
interventions overall and none that
significantly improved adherence
outcomes, Dr Feldman and Dr Cos-
tenbader pointed out.
Dr Tektonidou and her associates
acknowledged that the new system-
atic review and meta-analysis were
limited by the inability to estimate
risks beyond 15 years and because
the findings were similar only when
observational studies were consid-
ered. Factors associated with ESRD,
such as renal flares and uncontrolled
hypertension, were not examined,
and few studies were judged to be
of high-quality.
Still, the results can be used to
counsel patients on risks of ESRD
and also will provide benchmarks
to judge the effectiveness of future
treatments, the authors concluded.
Dr Feldman and Dr Costenbader
disagreed with this conclusion, cit-
ing various study limitations and the
many nuanced factors that play into
a patient’s risk of developing ESRD.
“This study should rather be used
to provide a broad overview of our
understanding of changes in SLE
ESRD over time, rather than data
to counsel an individual patient on
his/her risks,” they wrote.
The study was supported by the
intramural research program of the
National Institute of Arthritis and
Musculoskeletal and Skin Diseases.
The authors reported having no con-
flicts of interest.
DLX105 is a novel treatment strategy
for Behçet’s flares
BY BRUCE JANCIN
Frontline Medical News
At the EADV congress, Copenhagen
An ultrasmall yet highly potent single-chain anti-
body fragment directed against tumour necrosis
factor-alpha showed promise for the treatment
of Behçet’s disease flares in a pilot phase II study
presented at the annual congress of the European
Academy of Dermatology and Venereology.
“We believe that we have something in our hands
that may make a difference to these patients.
Further development with follow-up studies is
planned,” said Dr Thomas Jung, chief medical of-
ficer at Delenex Therapeutics.
The agent, known for now as DLX105, utilises the
company’s proprietary PentraBody platform. DLX105
inhibits soluble as well as membrane-bound TNF-
alpha. Because the protein antibody is so small, it
has the capacity to penetrate into inflamed tissue,
be it skin or cartilage. DLX105 is also being explored
as a potential therapy for other flaring inflammatory
skin and autoimmune disorders, he added.
“The antibody also leaves the tissue very rapidly.
It doesn’t stick around as long as an IgG antibody.
The typical half-life of this molecule is about 1
day. We believe this is actually an advantage when
we talk about treating a flaring disease such as
Behçet’s, where we want exposure for a certain
time frame, but we don’t want to overexpose the
patient over weeks and months when it is not really
necessary,” Dr Jung explained.
Behçet’s disease is a chronic autoimmune vas-
culitic disease which presents most often as oral
ulcers, papulopustular skin lesions, genital ulcers,
uveitis, and/or arthritis. Cardiac, gastrointestinal,
and CNS involvement occurs less frequently. The
pathogenesis of the disease is unknown; no specific
cause or triggers have been identified. Behçet’s
disease affects an estimated 20,000 people in the
US, but is far more common in Turkey, the Middle
East, and Asia. All treatment is off-label; there is
no approved therapy for Behçet’s disease. The most
widely used agents are corticosteroids, colchicine,
and cyclosporine, with the biologic TNF inhibitors
often being utilised in an effort to prevent blindness
when uveitis occurs.
Dr Jung presented results of the small phase II
open-label study, which involved six patients with
Behçet’s disease for a mean of 10 years. All pre-
sented with a disease flare. All six had oral aphthous
ulcers, four had skin lesions, three had joint pain,
two had erythema nodosum, and one had genital
ulcers. All participants received a single intrave-
nous infusion of DLX105 at 10 mg/kg.
All of the oral ulcers healed within 1 week follow-
ing the single dose of DLX105. Patients with joint
pain reported it was substantially improved within
1–2 days after treatment. Genital lesions healed
completely within 2 weeks. The skin lesions were
also markedly improved. The clinical improvement
was maintained up to 4 weeks post treatment.
The improvement in joint symptoms was not
unexpected. DLX105 has been shown to inhibit
human TNF-alpha-induced joint swelling in rats
with an efficacy comparable to infliximab, accord-
ing to Dr Jung.
Perhaps most impressively, Dr Jung observed,
erythema nodosum healed completely in both af-
fected patients. Erythema nodosum can be notori-
ously difficult to treat. Indeed, one of the patients
had erythema nodosum for 5 years during which
multiple systemic therapies were employed without
benefit.
Axis I psychiatric disorders high in
skin-restricted lupus patients
BY NICOLA GARRETT
Frontline Medical News
From British Journal of Dermatology
The prevalence of psychiatric disor-
ders is high among people with skin-
restricted lupus (SRL), compared
with the general population, yet most do
not receive specialist mental health care
or appropriate psychotropic treatment,
researchers report.
Investigators led by psychiatrist Isa-
belle Jalenques of the Clermont-Ferrand
(France) University Hospital noted that
psychiatric disorders had been extensively
reported in patients with systemic lupus
erythematosus (SLE), but no data existed
on patients with skin-restricted disease.
A previous exploratory study by the
research group had shown that 60% of
the 20 patients with subacute cutaneous
lupus erythematosus and discoid lupus
erythematosus studied had at least one
psychiatric disorder. However the study
was limited by its size and lack of a control
group.
In the current multicentre study, the
researchers compared 75 outpatients with
SRL with 150 controls. Mean age of pa-
tients was 46 years and mean duration
of disease was 10 years. They discovered
that almost 49% of the patients with SRL
fulfilled criteria for at least one current
Axis I psychiatric disorder, compared with
13% of controls (OR, 5.0; P < 0.001).
Furthermore, 73% of patients fulfilled
criteria for at least one lifetime Axis I
psychiatric disorder, compared with 43%
of controls (OR, 4.4; P < 0.001).
The rates were close to that of patients
with SLE for both current (42.2 and
46.7%) and lifetime psychiatric disorders
(72%), Dr Jalenques and her associates
noted.
Patients with SRL were at a particularly
high risk of the following psychiatric dis-
orders, compared with controls:
• Major depressive disorder: current
(9% vs 0%; P = 0.0007) and lifetime
(44% vs 26%; P = 0.01).
• Generalised anxiety disorder: current
(23% vs 3%; P < 0.001) and lifetime
(35% vs 19%; P = 0.03).
• Panic disorder: current (7% vs 0%;
P = 0.004) and lifetime (21 % vs 3 %;
P < 0.001).
• Suicide risk: current (24% vs 7%;
P = 0.003).
• Alcohol dependence: current (7% vs
0%; P = 0.004).
• Lifetime agoraphobia: (20% vs 9%;
P = 0.01).
Many patients were not receiving spe-
cialist mental health care or appropriate
psychotropic treatment despite psychi-
atric disorders being a well-known cause
of psychological distress, excess mortal-
ity, impaired global functioning, and poor
compliance with medical treatment,
Dr Jalenques and her associates noted.
“Clinicians should be aware of the high
prevalence of these disorders among SRL
patients and not hesitate to refer such
patients for psychiatric evaluation,” they
concluded.
This study was supported by a grant from
the French Ministry of Health and from
Société Française de Dermatologie. The
authors declared they have no conflicts of
interest.
We believe that we have something in our
hands that may make a difference to these
patients. Further development with follow-
up studies is planned.
Vol. 4 • No. 1 • 2016 • Rheumatology News 11
LUPUS/CONNECTIVE TISSUE DISEASES