8 / 16
Study challenges protein citrullination as a
central cause of RA
BY AMY KARON
Frontline Medical News
At the American College of Rheumatology
annual meeting, San Francisco
A
utoantibodies in patients with
rheumatoid arthritis target both
the native and citrullinated forms
of the RA33 autoantigen, challeng-
ing the idea that protein citrullina-
tion underlies loss of tolerance in
this disease, Dr Maximilian Konig
said at the annual meeting of the
American College of Rheumatology.
“I think the important thing is
that this makes us rethink how RA
actually starts,” Dr Konig said in
an interview. “We identified three
different antibody groups that
clinically behave very differently.
We identified a group of patients
that has cross-reactive antibodies
against RA33, and they seem to
be the ones with the highest and
the most rapid disease progression.
Maybe identifying these patients
early and targeting themmore would
help bring a subset of patients with
the most advanced and aggressive
disease under better control.”
Signs and symptoms are often
inconclusive early in the course of
RA, leading to the search for reliable
biomarkers that can hasten diagno-
sis and treatment. Anti-citrullinated
protein antibodies (ACPAs) are one
hallmark of RA, and protein citrul-
lination has been seen as central to
autoimmunity in its pathogenesis,
said Dr Konig, a postdoctoral fellow
in rheumatology at Johns Hopkins
University, Baltimore. But patients
also have autoantibodies against
native or unmodified proteins,
including calpastatin, Fc-gamma,
peptidylarginine deiminase type 4,
and heterogeneous nuclear ribonu-
cleoprotein A2/B1 (also known as
RA33), which has been correlated
with clinical disease activity, radio-
graphic evidence of bone resorp-
tion, C-reactive protein levels, and
erythrocyte sedimentation rate in
a few previous studies (
Pediatr Int
2009;51:188–92 and
J Immunol Res
2014;2014:516593).
Dr Konig and his coinvestigators
contended that current models of
RA do not adequately account for
autoimmunity against native pro-
teins. To explore that idea, they
tested sera from 196 patients from
the ESCAPE RA (Evaluation of
Subclinical Cardiovascular Disease
and Predictors of Events in Rheu-
matoid Arthritis) cohort study and
from 56 healthy controls. They
used quantitative ELISA to identify
autoantibodies, and performed im-
munoblotting and immunoprecipita-
tion to test antibody specificity. They
also used immunoblotting and mass
spectrometry to study synovial fluid
from the patients.
The assays identified citrullinated
RA33 in the joints of RA patients,
and revealed distinct autoantibodies
that targeted native and citrullinated
RA33. Furthermore, this single anti-
body system seemed to change with
disease duration, Dr Konig said. Au-
toantibody against native RA33 was
almost exclusively found in samples
from patients in early-stage disease,
whereas patients with long-estab-
lished RA had much higher levels of
anti-citrullinated RA33 antibodies.
The switch from a predominance
of anti-RA33 to anti-citrullinated
RA33 autoantibodies seemed to
happen about a decade into the dis-
ease course, Dr Konig added. “These
data suggest that citrullination may
not be required to break tolerance
to RA33, and support a model in
which RA autoantigens are initially
targeted as a native protein, and only
later become targets of a citrulline-
specific response,” he said.
Notably, immunoprecipitation, im-
munoblotting, and competitive assays
all confirmed a third type of autoan-
tibody that cross-reacted against
both RA33 and citrullinated RA33.
The “RA33 [protein] is targeted by
patient sera in three ways: only as a
native protein, both as a native and
as a citrullinated protein, and only
as a citrullinated protein,” Dr Konig
concluded. He and his associates are
exploring the clinical implications
of the finding, particularly because
patients with the cross-reactive anti-
RA33 autoantibodies seem to have
the most rapidly progressive and
severe disease, he added. The pres-
ence of these antibodies might one
day help identify a patient who needs
especially aggressive monitoring and
treatment, he concluded.
Dr Konig had no disclosures.
Don’t stop TNFis during rheumatoid
arthritis pregnancy
BY M. ALEXANDER OTTO
Frontline Medical News
At the American College of Rheumatology
annual meeting, San Francisco
I
t might be best to keep women with rheumatoid
arthritis on their tumour necrosis factor block-
ers during pregnancy, according to German
investigators.
They found that women are likely to flare with-
out them and need more prednisolone, which is
associated with preterm birth and other problems,
while an increasing body of evidence suggests that
tumour necrosis factor inhibitors (TNFis) are rela-
tively safe during pregnancy.
“We should” rethink discontinuing TNFis dur-
ing pregnancy, as recommended in some quarters.
“We do not want women to flare during pregnancy,”
said investigator Dr Rebecca Fischer-Betz of the
department of rheumatology at Heinrich Heine
University in Düsseldorf.
She and her colleagues compared birth out-
comes in 18 rheumatoid arthritis (RA) patients
who discontinued TNFi treatment shortly after
they got pregnant against those of 24 women with
RA who were never exposed to a TNFi because,
in general, they had less severe disease.
Twelve of the women (75%) in the TNFi group
flared, versus four women (17%) in the control
group. Although patients in both groups started
with a mean 28-joint Disease Activity Score us-
ing C-reactive protein (DAS28-CRP) below 3.0,
women in the TNFi group had a rise in activity
to a mean of about 3.5 in the second trimester,
while disease activity in control patients remained
stable.
Compared with controls, women who stopped
TNFis were also far more likely to flare (odds
ratio, 10.0; 95% confidence interval, 2.3–42.8;
P = 0.002), even after adjusting for age, DAS28-
CRP at conception, rheumatoid factor and cyclic
citrullinated peptide status, and other potential
confounders. They also relied more heavily on
prednisolone, taking, for example, a mean dose
of 13 mg in the second trimester versus 8 mg in
the control group. Perhaps not surprisingly, the
mean duration of pregnancy was 37 weeks in the
TNFi group, with six women (33%) delivering at
or before 37 weeks; women in the control group
delivered, on average, at 39 weeks, with four
(17%) delivering at or before week 37.
The investigators found that the risk of preterm
birth increased with every cumulative milligram
of prednisolone (OR, 1.08; 95% CI, 1.02–1.15;
P < 0.01).
“Women with RA who discontinue TNFis at
conception face a high risk for flares during preg-
nancy, independently of known risk factors like
seropositivity. Flares are usually treated with pred-
nisolone. We found a dose-dependent, significant
increased risk for preterm birth associated with
prednisolone. In this era of treat-to-target man-
agement of RA, our paradigm for RA pregnancy
management may need adjusting. By controlling
RA activity with medications considered relatively
safe in pregnancy, we may be able to improve
both the pregnancy experience and pregnancy
outcomes,” the investigators concluded.
The women were 33 years old on average, and
all had live births; four early miscarriages were
excluded from analysis. All the pregnancies were
planned, with methotrexate discontinued at
least 3 months before conception. There was no
statistical difference in the rate of seropositivity
between the groups, “which is interesting because
we know seropositivity is a risk factor for staying
active during pregnancy,” Dr Fischer-Betz said.
Two boys born to women who took TNFis had
minor malformations, one with nasal bone aplasia,
retrognathia, and hydronephrosis, and the other
with hypospadias. Both of their mothers had taken
etanercept in the first trimester. There was one
malformation in the control group, a girl born with
hydronephrosis.
There was no outside funding for the work, and the
investigators have no disclosures.
These data suggest that citrullination may not be required to
break tolerance to RA33, and support a model in which RA
autoantigens are initially targeted as a native protein, and only
later become targets of a citrulline-specific response.
Rheumatologists aren’t giving
methotrexate a fair shot
BY M. ALEXANDER OTTO
Frontline Medical News
At the American College of Rheumatology annual meeting, San Francisco
O
ral methotrexate is frequently underdosed, given for an inadequate length of time,
and rarely switched to subcutaneous formulations before rheumatologists move
on to biologics, according to an analysis of claims data from 35,640 rheumatoid
arthritis patients.
“There’re some major concerns here. Methotrexate is the anchor drug for rheumatoid
arthritis, the best drug we have. More appropriate [use] could lead to better control”
and “produce significant cost savings,” said investigator Dr James O’Dell, chief of
the division of rheumatology at the University of Nebraska Medical Centre, Omaha.
When patients don’t fully respond to lower doses, the ground rules for oral metho-
trexate include escalation up to 25 mg or a switch to subcutaneous formulations,
which have better bioavailability. Those moves should be considered before turning
to biologics, Dr O’Dell explained at the American College of Rheumatology annual
meeting.
Rheumatologists, by and large, aren’t playing by those rules, according to the analysis.
“We need to own these data because the majority of patients, over three-quarters, were
treated by rheumatologists. We are not doing a great job,” Dr ODell said.
The claims data came from Symphony Health Solutions, which captures about
92% of prescriptions written in the US. The 35,640 rheumatoid arthritis patients in
the study were started on methotrexate in 2009 and followed through 2014; 15,599
(43.8%) didn’t need anything else and stayed on oral methotrexate alone throughout
the study period.
Prescribers, however, gave up on oral methotrexate at a mean dose of 15.3 mg
and moved 17,528 patients (49%) straight to a biologic without giving subcutaneous
methotrexate a shot. They did that after a median of less than 6 months, and within
3 months in more than 40% of patients.
Just 2513 patients (7%) moved on to subcutaneous methotrexate when their oral
formulation wasn’t enough. That’s all most of them needed; 1802 (72%) remained
on subcutaneous methotrexate alone for the remainder of the study period. The rest
moved on to a biologic, but after a median of almost a year, not a few months. When
their time on oral and subcutaneous methotrexate was included, their median time
to a biologic was more than 2 years.
The investigators checked to see if things improved for patients who started on
oral methotrexate in 2012. “The answer was no. We didn’t do better,” Dr O’Dell said.
He didn’t speculate on why methotrexate is underused in the US.
Claims data can’t address why patients were switched from methotrexate and other
issues, but such nuances “don’t even begin to explain the doses and the timing of
switch that we saw here,” he said.
Dr O’Dell is an adviser for AbbVie, Lilly, Coherus, Bristol-Myers Squibb, Antares, and
Medac. Other investigators disclosed relationships with those or other companies.
R
heumatology
N
ews
• Vol. 4 • No. 1 • 2016
8
RHEUMATOID ARTHRITIS