Download Rheumatology Highlights

R.J. Fasenmyer Center for Clinical Immunology
Rheumatology Highlights
VASCULITIS IN TERMS OF PATHOLOGY, DIAGNOSIS,
AND TREATMENT
Leonard H. Calabrese, DO
Abbreviations: ANCA: anti-neutrophil cytoplasmic antibodies; MMF:
mycophenolate mofetil; MPA: microscopic polyangiitis; PML: progressive
multifocal leukoencephalopathy; SLE: systemic lupus erythematosus
Giant cell arteritis
Slavarani C, et al. Risk factors for severe cranial ischemic events in giant cell arteritis. Abstract 622.
Study. Objective: To determine the incidence of cranial ischemic events
(CIEs) in patients with giant cell arteritis. Design: Italian populationbased cohort review of medical records for factors associated with
CIEs in 180 patients with giant cell arteritis (GCA). Results: A total of
38 patients developed CIEs (33 visual loss, 5 strokes). The presence of
GCA significantly increased the risk of CIEs in patients with hypertension, previous ischemic disease, or low inflammatory response based
on the erythrocyte sedimentation rate and C-reactive protein (CRP)
values (defined as absence of CRP levels > 5.38 mg/dL).
Comment: This study was designed to evaluate the impact of traditional cardiovascular risk factors on the occurrence of severe CIEs in a
large population of patients with GCA. Although the investigators had
detailed patient records, their patient selection criteria were not well
defined. Also, this is a rather small study that needs to be replicated in
larger patient cohorts. Not surprisingly, CIEs correlated with older age
and hypertension. But somewhat surprisingly, patients with the lowest
levels of CRP elevation had a significant correlation with these ischemic
events. This might seem counterintuitive, but data have demonstrated
that if one looks at polymyalgia rheumatica and GCA, the polymyalgia
rheumatica has much higher acute-phase reactions than GCA. It is hard
to say what the pathophysiologic implications are of these data.
The logical take-home point is that patients with hypertension, a history of ischemic heart disease, and low inflammatory response should
be approached more rigorously in terms of risk reduction and antiplatelet therapy.
One caveat of this study is that based on the cardiovascular risk factors in this patient population, it is not clear whether the events are
actually related to GCA. This raises the question of whether we are
setting off a hypertensive event by administering high-dose steroids,
especially in older patients. The ischemic events could be unrelated
to the disease itself.
Diseases associated with anti-neutrophil cytoplasmic
antibodies
Mukhtyarl C, et al. Cardiovascular outcomes in ANCA associated vasculitis. Abstract 1856.
Study. Objective: To analyze the effect of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis on the development
of cardiovascular diseases. Design: Evaluated the onset of cardiovascular disease in 554 Swedish patients with new diagnosis of
ANCA-associated vasculitis and at least 5 years of follow-up
data (469 evaluable) from four randomized controlled trials of the
European Vasculitis Consortium. Results: The 5-year prevalence
of coronary artery disease (CAD) and hypertension significantly
increased compared with the rates at disease onset, from 8.6% to 16.7%
(for CAD) and 5.9% to 42.6% (for hypertension).
1
Comment: The results from this study comparing cardiovascular
morbidity at onset and after 5 years are interesting. The rate of CAD
doubled and hypertension increased 8-fold. A diagnosis of microscopic polyangiitis (MPA), older age (> 60 years), and male sex were
strongly associated with CAD in these patients. A higher vasculitisrelated damage index and elevated creatinine at baseline were strong
predictors for hypertension. This seems to indicate that as renal function is affected, hypertension becomes more prevalent. However, it
is not known whether the treatments in the trials — long-term cyclophosphamide versus azathioprine or methotrexate — had an effect on
the outcomes.
Silva F, et al. Mycophenolate mofetil (MMF) for remission induction and maintenance in microscopic polyangiitis (MPA) with mild to moderate renal dysfunction — prospective pilot trial in 17
patients. Abstract 2075.
Study. Objective: To explore the use of oral mycophenolate mofetil
(MMF) as an alternative to cyclophosphamide in patients with MPA.
Design: Researchers from the Mayo Clinic explored the safety and
efficacy of oral MMF as an alternative to cyclophosphamide in 17
patients with MPA, active glomerulonephritis (creatinine ≤ 3 mg/dL),
and no severe extrarenal manifestations. Results: A total of 13 patients
(76%) had remission by month 6 and stable renal function (primary
endpoints); results were sustained at 18 months in 12 patients.
Comment: For MPA, induction with cyclophosphamide is the
standard treatment. However, this drug has long-term alkylating side effects, and it would be desirable to avoid the alkylating agents altogether. These are impressive results. They achieved
remission in 13 of 17 patients at 6 months without alkylating
therapy. At 18 months, there were four relapses and one patient
dropped out because of gastrointestinal side effects, so the stable
remission rate was over 70% using a rather modest dose of MMF
and standard high-dose glucocorticoid therapy, which was tapered
over 6 months. So this study provides some guidance for treating patients without alkylating therapy. Data from trials in peer
review have hinted that MMF is a good drug for remission maintenance, but this study is the first to indicate that it can be used
for induction.
One question to address is whether MMF matches the standard of
care. Other published studies have attempted this type of regimen
in patients who cannot receive alkylating therapy because of factors such as cyclophosphamide intolerance or myelodysplastic syndromes, but these are hard to compare. Data from the European
Vasculitis Study Group using azathioprine as a maintenance agent
[Jayne D, et al. N Engl J Med 2003;349:36-44] showed sustained remission rates of
approximately 70% at 18 months. Those rates are comparable to the
current study, at least on a superficial level. Although they are distinct
investigations, patient entry criteria were similar. In addition, there
are five or six papers in peer review using MMF as a substitute for
alkylating therapy. One trial had a particularly high relapse rate in the
MMF group, so there are still many issues to address regarding treatment doses, regimens, and patient selection criteria.
In the MPA study, the patients’ conditions seem to be a bit different
from what some would label MPA. In actual clinics, many patients
with MPA deteriorate so quickly that it is difficult to get MMF into
them. Furthermore, there is a lack of pathophysiologic differentiation between some types of vasculitis, which raises the question of
whether their label of ANCA-associated vasculitis is accurate. The
point is that we need to look at MPA as a separate clinical entity with
different pathophysiologic features as opposed to just ANCA-associated vasculitis. In addition, the investigators excluded patients with
life-threatening end-organ disease. These points raise the question of
whether the study population was actually a benign subset of MPA
and would have done as well or better without the MMF therapy
intervention.
Davatchi F, et al. Randomized control study (single blinded) of rituximab versus cytotoxic
combination therapy in severe ocular lesions of Behcet’s disease: pilot study. Abstract 2076.
Study. Objective: To evaluate the effect of rituximab versus combination cytotoxic therapy in patients with Behcet’s disease. Design:
This controlled trial randomized 20 Iranian patients with severe
ocular lesions (retinal vasculitis and edema) of Behcet’s disease to
treatment with either rituximab plus methotrexate and prednisolone or to combination cytotoxic therapy with cyclophosphamide
plus azathioprine and prednisolone. Results: Significant 6-month
improvements in Total Adjusted Disease Activity Index were seen
with rituximab; no improvement was noted with cytotoxic therapy.
Edema symptoms had the greatest improvement.
Comment: Behcet’s disease is more severe outside of the United States, and it is not known how to treat it very well. These
investigators from the University of Medical Sciences in Tehran,
Iran, have done substantial research in this area. The treatments
were not pure monotherapy — both groups received methotrexate or azathioprine, and it is not known if the rituximab patients
received methylprednisolone. All patients were listed as having
refractory Behcet’s disease, but it is not known whether they were
infliximab naive.
Patients with truly refractory ocular Behcet’s disease are difficult to
treat. Although this study had a small number of patients, it hints that
the novel B cell-targeting biologics may be able to play a role in treating this patient population. Obviously, a larger and longer-term study is
needed to support the findings.
Although this study suggests efficacy with rituximab, it does not
mean it should be used. The disease-modifying antirheumatic drugs
and tumor necrosis factor (TNF) inhibitors have shown nice remission rates in Behcet’s disease and have a role to play in treatment
protocols, even in this age of biologics. It may be that in the sequencing of drugs, rituximab, given its higher association with progressive multifocal leukoencephalopathy (PML), should be reserved for
patients with ocular Behcet’s disease that is refractory to a TNF
inhibitor rather than be used as first-line therapy.
An alternative view on rituximab is that its association with a
higher incidence of PML is not clear-cut. Recent data on the incidence of PML indicate that it may be more common than thought,
which suggests that it may be time to review the frequency of PML
with rituximab versus its frequency with other diseases and drugs.
Great caution has to be exerted in ascribing causality in the case of
rare events such as PML. The early impression was that rituximab
was the driving force for PML in patients with systemic lupus erythematosus (SLE). A more reflective approach at least raises the
alternative explanation that certain diseases such as SLE may
themselves represent an underlying risk. More epidemiologic work
is clearly needed.
Progressive multifocal leukoencephalopathy in systemic
lupus erythematosus and other rheumatic diseases
Eamonn S, et al. Progressive multifocal leukoencephalopathy — a national estimate of frequency
in SLE and other rheumatic diseases. Abstract 1259.
Study. Objective: To create a national estimate of PML frequency in
patients with SLE and other rheumatic diseases. Design: Reviewed
PML cases in the US Nationwide Inpatient Sample database for the
years 1998 through 2005. Results: A total of 9,675 PML cases were
identified from the nearly 300 million hospital discharges. Nearly
8,000 cases were attributed to human immunodeficiency virus (HIV)
infection (82%). Hematologic cases were associated with 8.4% and
solid cancer with 2.8%. SLE (0.44%), rheumatoid arthritis (0.25%),
and other connective tissue disease (0.26%) combined represented less
than 1%. No cases were reported for systemic vasculitic syndromes.
Comment: PML is a complication recognized in several areas, including natalizumab use in patients with multiple sclerosis and Crohn’s
disease, alefacept use in patients with psoriasis, and rituximab and
MMF use in patients with rheumatic disease, suggesting that there
may be some predisposing factors in these patients. As expected,
most were associated with HIV and cancer, with a small percentage
seen in rheumatic diseases. After eliminating potentially confounding
factors, results show that PML occurs in 4 per 100,000 SLE patients,
0.4 per 100,000 rheumatoid arthritis patients, and 2 per 100,000
patients with other connective tissue disorders.
This adds further strength to the observation that lupus represents the
leading connective tissue disease seen with PML and is likely a risk
factor in itself (regardless of therapy) for this opportunistic infection.
As a clinical caveat, this clearly adds to the admonitions for rheumatologists that in the setting of unexplained neurologic signs and
symptoms with magnetic resonance imaging abnormalities, PML has
to be considered in the differential diagnosis.
Table 1. Symptoms of Reversible Cerebral Vasoconstriction Syndromes
All Cases
N = 120
CC Series
N = 55
MGH Series
N = 65
Headache
113 (94%)
52 (94.5%)
61 (91.3%)
Thunderclap
Headache
63 (53%)
40 (73%)
32 (49%)
Visual sign/
symptoms
51 (43%)
22 (40%)
29 (45%)
Nonthunderclap
15 (13%)
6 (11.0%)
9 (14%)
Weakness/aphasia
42 (35%)
21 (38%)
21 (32%)
Recurrent
thunderclap headache
73 (60%)
34 (62%)
39 (60%)
Seizures
22 (34%)
9 (16.4%)
13 (20%)
Only headaches
47 (39%)
30 (54.5%)
17 (26%)
2
Hajj-Ali R, et al. Reversible cerebral vasoconstriction syndromes. Abstract 2014.
Study. Objective: To determine disease characteristics of reversible
cerebral vasoconstriction syndromes (RCVS). Design: Retrospective
chart review of RCVS cases at the Cleveland Clinic and the Massachusetts General Hospital. Results: Data from 120 cases were analyzed. Mean age was 42.3 years, and 82.5% were females. The most
common symptoms were headache, visual symptoms, weakness/
aphasia, and seizures (see Table 1). Initial computed tomography
scans or magnetic resonance imaging were normal in 53%. Ischemic
strokes developed in 42%, parenchymal hemorrhage in 17%, and subarachnoid hemorrhage in 31%. Cerebrospinal fluid analysis was performed in 80% of patients. Of those, 87% had normal white blood cell
counts and 88% had normal cerebrospinal fluid protein. No vasculitic
changes were seen in brain pathology studies, available in 17.5% of
patients. Vascular abnormalities were reversed in 98% of follow-up
neurovascular imaging, done in 81% of patients.
Comment: During the past 20 years, many different groups have
looked at these diseases in patients presenting to rheumatologists and
at headache clinics. Many names have been used to describe the syndromes including benign angiopathy in the central nervous system,
thunder-clap headache with reversible cerebral vasoconstriction, and
postpartum angiopathy, among others.
This study is the largest collection of patients with RCVS reported
to date. These patients presented with severe headache syndromes,
normal spinal fluid, or a high-probability angiogram consistent with
cerebral vasculitis. Ultimately, angiographic reversibility was used as
the basis of this cohort.
This condition is no longer considered benign. A high rate of stroke
syndromes was noted, including thrombotic and hemorrhagic strokes.
Most initial neuroimaging studies were normal. A high percentage
of patients (81%) had follow-up vascular imaging, which showed
complete reversibility in 98%. Long-term follow-up using the
modified Rankin scale showed that severe neurologic sequelae are
rare and most patients will have good recovery if appropriately
treated.
The important take-home point is that this is a common syndrome
that rheumatologists may confront when asked to consult on a patient
who has “angiographically proven” vasculitis. The angiograms are
indistinguishable between vasospasm and vasculitis. The features
that should alert them to RCVS are female sex, instantaneous onset
with severe thunder-clap headache, and a frequent association with
cofactors such as use of sympathomimetic drugs or abuse of drugs such
as cocaine or cannabis in the postpartum setting.
NONBIOLOGIC THERAPIES INCLUDING DMARDS,
SEQUENCING OF DRUGS, AND GOALS FOR REMISSION
Allan Gibofsky, MD
Abbreviations: ANCA: anti-neutrophil cytoplasmic antibodies; DMARD:
disease-modifying antirheumatic drugs; MTX: methotrexate; RA: rheumatoid
arthritis; SSZ: sulfasalazine
DMARD therapy
van der Woude, D, et al. Prevalence and predictive factors for DMARD-free remission in RA:
lessons from two large early arthritis cohorts. Abstract 1608.
Study. Objective: To determine the prevalence of persistent disease-modifying antirheumatic drugs (DMARDs)-free remission
in patients with rheumatoid arthritis (RA) and identify predictive
factors for remission. Design: Retrospective review of patients
with RA treated with either nonsteroidal anti-inflammatory drugs
or DMARDs in two cohorts from The Netherlands (N = 454; treated during 1993-2003) and Britain (N = 895; treated during 19861996). Persistent DMARD-free remission was defined as at least
1 year with no swollen joints, no current use of DMARDs, and
a classification of remission from the patient’s rheumatologist.
Results: DMARD-free remission was achieved in 15% and 9.4%
of the cohorts, respectively. Five factors were significantly associated with remission in both cohorts: acute onset, shorter symptom
duration at baseline, nonsmoker, and absence of RF IgM and HLA
shared epitope alleles at baseline.
Comment: Remission has become an attainable goal in RA therapy, particularly since the introduction of the biologic agents. As
a result, interest in the nonbiologic DMARDs has waned somewhat. However, there are still lessons to be learned from the use
of DMARDs, especially regarding predictors of remission with
this therapy.
3
This study found that it is possible to obtain DMARD-free remission in a significant number of patients without biologic agents. It
also found that patients more likely to achieve remission are nonsmokers with fewer and more recent symptoms, and no evidence
of auto-antibodies. The results suggest that starting patients on
biologic therapy initially may not be necessary, at least in patients
with specific predictive factors.
Edwards JC, et al. Myocardial infarction in rheumatoid arthritis: the effects of DMARDs and prednisolone. Abstract 688.
Study. Objective: To estimate the incidence of myocardial infarction (MI) in patients diagnosed with RA and to assess the impact
of DMARD and corticosteroid therapy on MI risk. Design: Retrospective review of a United Kingdom database (more than 7
million patient records) to identify the incidence of MI in adults
with RA from 1987 to 2002. Data were compared to a matched
control group. Results: A total of 34,364 patients with RA were
identified. The MI incidence in these patients was 6.49 per 1,000
patient-years, which was significantly increased versus the controls. Overall, the person’s age, gender, and traditional cardiovascular (CV) risk factors were more important predictors of MI
than either DMARD or prednisolone use within 2 months of the
MI. When analyzed individually, the DMARDs hydroxychloroquine, methotrexate (MTX), and sulfasalazine (SSZ) significantly
reduced the MI risk, whereas prednisolone significantly increased
the MI risk.
Comment: Patients with RA have a documented increased risk of
premature death due to CV disease; however, the relative risk and
interplay between the disease activity, therapy, and traditional CV
risk factors is only beginning to be dissected. One area that has not
been well researched is whether the increased risk seen in patients
with RA (and by extension other inflammatory diseases) is solely
due to inflammation or whether other traditional risk factors are
also involved.
In this study, Edwards and colleagues looked at a populationbased cohort that was treated before the introduction of biologics.
Their findings indicate that there may be a positive effect from
lowering inflammation, but the greater contributors to CV disease
and MI risk still appear to be (at least in this prebiologic cohort)
the traditional risk factors of age, gender, body mass index, hypertension, and smoking.
Epidemiology of rheumatoid arthritis
Gabriel S, et al. The rising incidence of rheumatoid arthritis. Abstract 773.
Study. Objective: To analyze trends in incidence and survival
associated with RA based on updated estimates of RA in the United States from 1995 to 2005. Design: Used a population-based
inception cohort of individuals aged 18 years and older who were
diagnosed between 1995 and 2005 and a cohort of patients with
prevalent RA as of January 1, 2005. Results: The overall age- and
sex-adjusted incidence of RA was 41.8/100,000 population and
the prevalence was 0.95%, up from the 1995 estimate of 0.85%.
The incidence rose significantly in females to 54.0/100,000 compared with 36.4/100,000 during 1985 to 1994 (see Fig 1). The
incidence in males was statistically similar, showing a slight
increase to 29.5/100,000 in 2005 compared with 28.6/100,000
from 1985 to 1994.
100
|
80
|
20
|
40
|
60
|
Female
Male
0
|
Age Adjusted incidence per 100,000 pop
Figure 1. Incidence of Rheumatoid Arthritis
|
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1955
|
|
1965 |
1975
|
|
1985
Year
|
|
1995
|
|
2005
Comment: The incidence and prevalence of RA declined from 1955
to 1994, leading to a revision of NHANES estimates, but few data
have been systematically accumulated in the recent decade, particularly since the introduction of the biologic agents. Gabriel and colleagues assembled a cohort of 350 patients with RA diagnosed in
Rochester, NY, between 1995 and 2005, 242 of whom were female,
and compared the results to their 1955 to 1994 Rochester cohort.
Their data analyses suggest that the incidence and prevalence are
actually rising after 40 years of decline, particularly in females.
The reasons for this rise are unknown, but the possibility of
environmental factors on top of a genetic predisposition cannot be
excluded. Another issue that may affect the increased incidence is
the definition of the disease. With the availability of more sensitive
and specific screening and diagnostic tests, especially for auto-antibodies (eg, anti-CCP), it is possible that a specific clinical presentation is being diagnosed as RA earlier, particularly given the trends
for earlier referral. It remains to be seen whether this Rochester
cohort-based observation will be valid in other parts of the country.
Nonbiologic therapy
Schipper LG, et al. Methotrexate therapy in rheumatoid arthritis patients who failed sulfasalazine
therapy: to switch or to add? Abstract 1009.
Study. Objective: To evaluate the clinical efficacy of MTX therapy
in RA patients with an inadequate response to SSZ. Design: Observational study from The Netherlands in 230 patients with RA whose
disease failed to respond to SSZ therapy. Patients were either switched
to MTX monotherapy (n = 124) or had MTX added to their SSZ
regimen (n = 106). The primary endpoint was change in the Disease
Activity Score (DAS28) at 1 year. Results: Mean DAS28 scores
declined significantly in both treatment groups; however, no betweengroup difference was found. The groups also had similar clinical
improvements in European League Against Rheumatism (EULAR)
response. Switching to MTX monotherapy resulted in better drugsurvival rates at 1 year than combination MTX and SSZ.
Comment: One of the controversies with RA therapies is whether to
switch a patient with an inadequate response to one agent to another
agent with the same mechanism of action or to an agent with a different mechanism of action. In this trial of patients with inadequate
response to the DMARD SSZ, the investigators found essentially no
difference between adding MTX to SSZ or switching to MTX monotherapy. This is in contrast to most clinical trials, which have found
greater efficacy for the combination therapy, including two trials that
added MTX to SSZ. What was surprising was that the MTX-SSZ
group had a lower cumulative survival, indicating that adherence to
the 2-drug regimen was lower than adherence to the 1-drug regimen.
This study suggests that even in this era of biologics, conventional
agents such as DMARDs still can play a role in early disease.
This study does raise questions regarding the level of RA burden and
the criteria used to define disease improvement, especially because
no radiologic evidence was presented and the DAS28 scores did not
improve substantially. However, because the Dutch governmentrun schema encourages early treatment of disease, the patients may
not have had radiologic evidence of disease. Plus, the groups were
matched for DAS28 scores at study entry.
The standard for measuring therapeutic efficacy should be a combined
measurement that incorporates three domains: reduction in signs and
symptoms, inhibition of structural progression, and improvement in
the patient’s self-reported quality of life. Many studies show efficacy
in one or two of these domains, but it is rare to see all three.
Verstappen SMM, et al. The beneficial effects of a 3 week course of IM steroid injections in very
early inflammatory polyarthritis: results of the STIVEA trial. Abstract 1645.
Study. Objective: To determine whether corticosteroid treatment
in patients who have very early inflammatory polyarthritis (4 to 11
weeks symptom duration) can postpone the need for second-line
therapy and prevent this disease from evolving into RA. Design:
The STIVEA trial randomized 265 patients with early stage arthritis
to receive either intramuscular methylprednisolone or placebo. The
4
primary endpoint was the need for second-line therapy. Results: At 6
months, the percentage of patients needing second-line therapy was
significantly less with the corticosteroid than with placebo. Methylprednisolone therapy also reduced the percentage of patients progressing to RA at 1 year.
Comment: Some patients who present with active inflammatory
polyarthritis may go on to develop RA. Several studies have reported
that early therapy with DMARDs may reduce progression in this population. In this study, the investigators looked at whether a short course
of IM methylprednisolone might postpone the need for DMARD therapy and even prevent this disease from evolving into RA.
measures included health-related quality-of-life and cognitive function tests. Results: Investigators identified 43 patients with rheumatic
fever: 20 with Sydenham’s chorea and 23 without the disease, and a
matched control group of 19 patients. Significantly lower scores were
observed for the group with Sydenham’s chorea in tests involving
attention, memory, and executive functions. No differences were seen
for quality-of-life scores.
The bottom line here is that 3 weeks of IM corticosteroids reduced the
number of patients who went on to RA and postponed the need for
long-term systemic therapy in patients who did go on to RA. Again,
this makes the point that the earlier patients are recognized and treated,
the greater the likelihood of long-term control.
Comment: Rheumatic fever is a clinical entity not usually seen in
children in the developed world, primarily because of better sanitary conditions and the availability of antibiotics for early treatment
of pharyngitis. In underdeveloped countries, however, rheumatic
fever and the development of rheumatic heart disease are significant public health problems. In addition, the increasing reports of
a new entity — post-streptococcal reactive arthritis — suggest that
the relationship between microbial infection and clinical disease is
still significant.
It should be noted, however, that this study may have had a significant
patient-selection bias; it is not clear whether the patients had any clinical features other than acute inflammation, which often responds to
steroid therapy and thus precludes the need for specific DMARD therapy. Finally, it seems somewhat incongruous that the use of short-term
relatively benign therapy produced a rather robust long-lasting effect.
In this study, Cavalcanti and colleagues looked at neuropsychiatric outcomes and quality of life in young adults with rheumatic fever, either
with or without Sydenham’s chorea. They reported that some patients,
even later in life, may have difficulties with tasks related to cognitive
skills, adding more evidence to the pathogenic role that streptococcal
infection may play in altering specific brain circuits.
Rheumatic fever outcomes
So what are the clinical implications? Current evidence suggests that
streptococcal infection early in life may be associated with neurologic dysfunction. In this study, the investigators looked at people
who presented with rheumatic fever and followed them late into life.
They found that many of them still had subtle yet objective signs
of mental acuity dysfunction. This raises the specter that a microbial infection early in life in genetically susceptible people may alter
neurocircuitry resulting in behavioral and neurocognitive deficits
later in life.
Cavalcanti A, et al. Adults who presented Sydenham’s chorea in childhood show poorer scores in
attention and working memory tests. Abstract 1472.
Study. Objective: To evaluate the long-term neuropsychological outcome and health-related quality of life of young adults older than 18
years who had rheumatic fever during their childhood or adolescence,
either with or without Sydenham’s chorea. Design: This observational study from Brazil identified patients with rheumatic fever and
divided them based on whether they had Sydenham’s chorea. Outcome
ADVANCES IN BASIC SCIENCE, INCLUDING IMMUNOLOGIC-ORIENTED
GENETICS OR PROTEASE RESEARCH, PATHOGENETIC RESEARCH
Marc D. Cohen, MD
Abbreviations: ACR: American College of Rheumatology; CV: cardiovascular;
DAS28: Disease Activity Score; DMARD: disease-modifying antirheumatic drug;
EULAR: European League Against Rheumatism; HAQ: Health Assessment
Questionnaire; HAQ-DI: Health Assessment Questionnaire Disability Index; MTX:
methotrexate; RA: rheumatoid arthritis; TCZ: tocilizumab; TNF: tumor necrosis factor
Biologics and rheumatoid arthritis: efficacy studies
van Vollenhoven R, et al. In early RA, patients with a good initial response to MTX monotherapy
continue to have excellent clinical outcomes during the first year of therapy. Abstract 717. van Vollenhoven R, et al. In patients with early RA who fail initial MTX, the addition of anti-TNF yields
better ACR and EULAR responses than the addition of conventional DMARDs: 1-year results of
the SWEFOT Clinical Trial. Abstract 1003.
Study. Objective: To evaluate the efficacy of adding a disease-modifying antirheumatic drug (DMARD) to methotrexate (MTX) in
patients with early rheumatoid arthritis (RA) (< 1 yr) who had not
responded to 3 to 4 months of MTX monotherapy. Design: Of 487
enrolled patients in this clinical trial, 258 had no response to MTX
and were randomized to either triple DMARD therapy (sulfasalazine, hydroxychloroquine, and MTX) or MTX plus an anti-tumor
necrosis factor (TNF) agent (infliximab); 144 had a clinical response
5
(Disease Activity Score [DAS28], < 3.2) and were continued on MTX
monotherapy. Primary endpoint was European League Against Rheumatism (EULAR) good response. Results: At 12 months, the MTX
plus anti-TNF recipients had significantly better EULAR responses
(42% vs 26%; P < 0.01) and American College of Rheumatology
(ACR) 20 and 50 responses (P < 0.05) than the triple DMARD group.
Among the initial responders, 75% continued to maintain low disease
activity at 1 year.
Comment: This is the first well-constructed clinical trial to compare
combination DMARDs versus MTX plus an anti-TNF. All patients
received MTX first. About 30% responded to that initial MTX regimen and were continued on MTX monotherapy. Nonresponders
remained on MTX and were randomized to standard triple DMARD
therapy or an anti-TNF agent. The group that received the anti-TNF
did better with regard to typical clinical endpoints, primarily the
EULAR response. The study actually provided data for two study
outcomes: response to MTX monotherapy and which combination of
DMARDs provides the best response for nonresponders to MTX.
van der Heijde D, et al. Initial combination therapy with adalimumab and methotrexate leads to
better long-term inhibition of radiographic progression in early RA: 5-year results of the PREMIER
trial. Abstract 995.
Breedveld FC, et al. Initial combination therapy with adalimumab and methotrexate sustains clinical
remission and response for early RA patients treated through year 5. Abstract 996.
Study. Objective: To determine long-term efficacy of adalimumab
monotherapy for maintenance therapy in patients with early RA.
Design: In this open-label extension of the PREMIER trial, 799
patients were randomized to adalimumab plus MTX (n = 183), adalimumab alone (n = 159), or MTX alone (n = 155) for 2 years then
continued on open-label adalimumab monotherapy to year 5. Results:
Patients treated initially with combination adalimumab and MTX
continued to show better health assessment questionnaire (HAQ) and
modified total Sharp score (mTSS) at 5 years.
Comment: In this extension of the PREMIER trial, patients who were
initially treated with combination adalimumab and MTX continued to
show better HAQ and clinical scores no matter what they were treated with for maintenance. What this suggests is the ability to possibly
reset early disease with aggressive therapy. However, this trial has
some problems. It was an open-label trial and followed patients who
probably were going to do well. Early aggressive therapy with a TNF
antagonist and MTX may have long-term benefits even in patients in
whom the combination may not be continued.
Emery P, et al. Clinical remission, radiographic non-progression, and normalized function with the
combination of etanercept and methotrexate in the treatment of early active rheumatoid arthritis:
1-year results of the COMET Trial. Abstract 1208.
Study. Objective: To determine the efficacy of combination therapy
with etanercept versus MTX in patients with active, early RA (≤ 2 yrs).
Design: The COMET trial randomized 538 patients to either MTX
alone or MTX plus etanercept. Results: At year 1 of this 2-year trial,
DAS28 remission (< 2.6) was significantly greater in the combination
group than in the MTX monotherapy group (see Fig 2).
Comment: This particular TNF blocker, etanercept, has not been studied before in this patient population. Remission numbers with combination therapy are impressive — twice that of MTX monotherapy. Other
studies have reported similar results with anti-TNFs but never with etanercept. This trial is also unique in that it used DAS28 remission as the
primary clinical endpoint.
Figure 2. DAS28 Remission
|
Patients (%)
|
0.8
*
30
20
|
0.2
|
0
0
*
*
*
40
10
|
0.4
ETN+MTX (n=265)
* 50%
28%
MTX (n=263)
*
|
|
|
|
|
0
12
24
36
52
P<0.01; *P<0.001
Weeks
Solomon DH, et al. TNF blocker use and cardiovascular outcomes. Abstract 1016.
Study. Objective: To determine the risk of cardiovascular (CV) events
associated with DMARD use in patients with RA. Design: Using data
from the US CORRONA registry (10,870 patients; median RA duration, 7 yrs), investigators compiled the number of CV events in patients
receiving TNF blockers (alone or in combination), MTX (alone or in
combination), or other nonbiologic DMARDs. Results: During the
follow-up period (mean, 24 months), 26 new myocardial infarctions
and 45 strokes or transient ischemic attacks occurred. Adjusted models
found TNF blockers significantly reduced the CV risk compared with
nonbiologic DMARDs not including MTX (HR, 0.3; 95% CI, 0.1-0.6).
MTX use was associated with a nonsignificant reduced CV risk versus
nonbiologic DMARDs (HR, 0.6; 95% CI, 0.3-1.2).
Comment: When assessing safety concerns, the large registries provide pretty much all the available data. The investigators looked at
CV events in more than 10,000 patients with RA in this US registry.
Without doing a great deal of statistical manipulation, they determined
that use of TNF blockers may significantly reduce CV events, or at
least change CV outcomes.
Jacobsson LT, et al. Anti-TNF therapy in RA and risk of acute myocardial infarction (AMI), stroke
and any cardiovascular (CVD) events up to 7 years after treatment start. Abstract 1997.
Study. Objective: To assess the long-term risks for CV events associated with TNF blockers in a Swedish registry of 67,208 patients with
RA from 1998 to 2005. Design: This observational study compared
patients on TNF blockers (n = 5,299) against a randomly selected
matched control cohort (n = 21,084) for CV events. The analysis was
adjusted for disease duration, comorbidities, etc. Results: Use of TNF
blockers did not affect the risk for overall CV disease, acute myocardial infarction, or stroke. Women had a significant decrease in overall
CV events. Good EULAR response to TNF blockers also did not have
a significant effect on the risk for CV events.
Comment: In this Swedish cohort study, the investigators tried to
answer the question of whether anti-TNF therapy lowers the risk for
CV events. They used a sophisticated statistical analysis that adjusted
for a number of variables, including comorbidities. Each subject who
received an anti-TNF was matched to 4 control subjects, which was a
slightly different approach than that used by Solomon and colleagues.
The authors had previously conducted a meta-analysis that suggested
anti-TNF therapy significantly lowers the risk of CV events. They now
state that anti-TNF therapy is not a risk factor for or against CV disease, although there is a tendency toward fewer CV events with antiTNF therapy.
Strangfeld A, et al. No increased risk of solid tumours in patients treated with biologics. Abstract 1010.
*
*
|
0.6
50
|
1
|
|
1.2
60
Biologics and rheumatoid arthritis: safety trials
Study. Objective: To assess the solid tumor rates in patients with RA
being treated with biologics or conventional DMARDs. Design:
Observational study used the German RABBIT biologics registry of
5,281 patients to determine the relative risk associated with biologic
agents and DMARDs for two outcomes: incidence of solid malignancy, or tumor recurrence of a prior malignancy. Results: No differences were found in incidence of solid tumors or in the risk of recurrent
malignancies in patients regardless of biologic use.
Comment: The investigators concluded that biologic use does not
increase the risk of developing cancer, even in patients with previous
tumors. These are conclusions from another carefully analyzed large
European registry similar to other findings of no increased incidence
of solid malignancies with biologics exposure.
6
Smolen J, et al. Certolizumab pegol with methotrexate improves performance at work in patients
with active rheumatoid arthritis. Abstract 978.
Emory P, et al. Combination therapy with certolizumab pegol plus methotrexate improves household
productivity and daily activities in patients with active rheumatoid arthritis. Abstract 977.
Study. Objective: To evaluate the impact of certolizumab pegol on
work productivity in patients with active RA. Design: Investigators
analyzed RA-related work and household productivity as measured
with the Work Productivity Survey, a validated questionnaire, in the
RAPID 1 (N = 982) and RAPID 2 (N = 619) clinical trials. Results:
Patients who received certolizumab as add-on therapy to MTX had
a cumulative gain of 41.9 fully paid work days per 6 months compared with 35.1 days in the placebo group and a cumulative gain of
29.4 versus 23.0 of productive days. Both findings were statistically
significant. Gains were noted as early as week 4 and continued to
improve over 6 months.
Comment: Certolizumab is a new TNF blocker. These researchers
had previously reported efficacy data; this is their data regarding going
back to work. They included household productivity, so it was not just
going back to the office. This is a different category of efficacy data,
and it will be interesting to see if other groups feel compelled to report
this type of data in the future.
Smolen J, et al. Golimumab, a human anti-TNFα monoclonal antibody, injected every 4 weeks:
efficacy and safety in RA patients previously treated with anti-TNFα agents (GO-AFTER Study).
Abstract 968.
Kay J, et al. Golimumab significantly improves physical function and fatigue in RA patients
previously treated with anti-TNFα agents: results from the GO-AFTER Study. Abstract 1035.
Study. Objective: To evaluate the efficacy and safety of golimumab in
patients with active RA whose disease had not responded to previous anti-TNFα treatment. Design: Clinical trial that randomized
461 patients to golimumab (50 or 100 mg) or placebo. Patients had
been previously treated with 1 (65%), 2 (25%), or 3 (10%) anti-TNF
agents. The primary endpoint was improvement of 20% or more in
ACR 20 at week 14. Results: Golimumab significantly reduced the
signs and symptoms of RA and improved physical function. At 14
weeks, ACR 20 response rates were 35.3% and 37.9% for the golimumab doses compared with 16.9% for placebo (P < 0.001). At 24
weeks, responses were 34.0% and 43.8% versus 16.8% for placebo
(P < 0.001). Golimumab therapy was generally well tolerated.
Comment: This is the first clinical trial to look at this new TNF blocker in patients who had not responded adequately to previous TNF
blocker therapy. Interestingly, the numbers are similar to what has been
reported with rituximab and abatacept in populations of incomplete TNF
responders. These investigators conducted a well-designed trial using two
different golimumab doses in patients who had been unsuccessfully treated with 1 to 3 other TNF blockers.
Emery P, et al. Efficacy and safety of rituximab (RTX) as a first-line biologic therapy in patients with active rheumatoid arthritis: results of a phase III randomized controlled study (SERENE). Abstract 364.
Study. Objective: To determine the efficacy and safety of rituximab
plus MTX in patients with active RA, an inadequate response to MTX,
and no prior biologic treatment. Design: In this phase III clinical trial
(SERENE trial), 512 patients on background MTX were randomized
to rituximab doses of 500 or 1,000 mg or placebo. Patients received a
second course if they had a DAS28 ≥ 2.6 at week 24. The primary endpoint was ACR 20 response at week 24. Results: Both rituximab dose
groups had significantly better ACR responses than the placebo group
(see Fig 3). Rituximab was well tolerated.
Comment: This is an interesting trial of rituximab following an incomplete response to methotrexate. Previously, the Food and Drug Administration approved this drug in patients with incomplete response to TNF
blockers. They used two doses of rituximab and compared results against
patients who received methotrexate plus placebo. The ACR responses
were similar to what has been seen with TNF blockers in this patient
population. The researchers had HAQ data, FACIT data, and SF36 data,
but they did not yet have x-ray data.
There are two main conclusions from this trial: First, rituximab
seems to work similar to other biologics in methotrexate-incomplete
responders even when higher endpoints and patient-reported outcomes
are considered. Second, there is no significant difference in clinical
outcomes between the 500- or 1,000-mg doses.
70
|
60
|
50
40
|
30
|
20
|
51
33
9
|
|
ACR20
ACR20
24
48
Week
Week
n
7
36
26 26
23
5
0
|
0
P < 0.0001 vs Pbo for ACR20/50/70 weeks 24
57 59
|
10
55
|
% ACR Response
Figure 3. Serene: RTX 500 vs 1000 mg x 2
Pbo + MTX
13 14
9 10
0
0
|
|
|
|
ACR50
ACR50
ACR70
ACR70
24
Week
48
24
Week
n RTX 500 + MTX
Week
n
RTX 1000 + MTX
48
Week
Biologic use in nontraditional diseases
Westhovens R, et al. The efficacy and safety of abatacept in methotrexate-naive patients with early
erosive rheumatoid arthritis and poor prognostic factors. Abstract 1213.
Study. Objective: To gauge the efficacy of abatacept in patients with
early RA (≤ 2 years), more than one erosion, and who were MTX
naive. Design: Clinical trial randomized 509 patients to abatacept plus
MTX or placebo plus MTX. Primary endpoints were DAS28 remission
(< 2.6) and joint damage progression (based on Genant-modified
Sharp total score). Results: At 1 year (of 2-year trial), adding abatacept significantly increased the remission rates in MTX recipients
(41.4% vs 23.3%; P < 0.001) and significantly reduced joint damage
progression (mean change from baseline, 0.63 vs 1.06; P < 0.05).
Comment: Abatacept has been used in patients with incomplete
response to MTX or TNF. The DAS28 remission at 12 months as
an endpoint is an interesting choice, and significantly more patients
achieved it with abatacept plus MTX than with placebo plus MTX.
This trial had a radiographic arm, and even though the MTX-placebo
group did not progress very much — only about one sharp unit over a
year —the abatacept plus MTX group had significantly less progression.
Tocilizumab efficacy and safety trials
Jones G, et al. The AMBITION Study: superiority of tociluzumab vs methotrexate monotherapy in
patients with rheumatoid arthritis. Abstract 1210.
Genovese M, et al. Tociluzumab monotherapy improves rheumatoid arthritis outcomes regardless
of disease duration. Abstract 988.
Study. Objective: To evaluate the effect of disease duration on
efficacy and tolerability of tocilizumab (TCZ), an anti-interleukin-6
monoclonal antibody, versus MTX in patients with early active RA
whose disease had not previously failed MTX or biologic therapy.
Design: In this clinical trial (AMBITION trial), 572 patients were
randomized to a 24-week regimen with either TCZ (8 mg/kg IV every
4 weeks) or MTX (7.5 mg titrated up to 20 mg/wk). Primary endpoint
was ACR 20 response. Results: The TCZ recipients had significantly
better results than MTX recipients for both ACR 20 response (70% vs
53%, respectively; P < 0.0001) and DAS28 remission (34% vs 12%;
P < 0.0001). However, TCZ recipients had more serious adverse
events, higher cholesterol levels, and decreased neutrophil counts.
Nevertheless, the authors concluded that TCZ was “safe and well tolerated in these patients.”
Comment: This trial compared TCZ head-to-head with MTX in
patients with early disease and found that the new drug was statistically better at both the ACR and DAS28 endpoints. It also had a
greater statistical improvement in the secondary endpoints of Health
Assessment Questionnaire Disability Index (HAQ-DI), SF-36, and
FACIT. So here is a biologic outperforming MTX head-to-head
using the usual clinical response criteria. The biologic recipients
also had slightly higher infection rates, higher cholesterol levels, and
slightly more neutropenia. Nevertheless, it was a very interesting trial
although its relevance to clinical practitioners is not known because
this was not a superiority trial and looked primarily at the endpoint
of ACR 20 response. It raises the question of whether practitioners
will choose to use this new biologic rather than MTX in patients with
early disease, particularly in the first year the drug is available.
cebo in addition to continuing on MTX. Primary endpoints were
changes from baseline in Genant-modified Sharp score and HAQ-DI.
Results: At year 1 of the 2-year trial, TCZ recipients had significantly
improved Genant-modified Sharp score (mean, 0.29 and 0.34 for 4
and 8 mg/kg doses) and significantly decreased HAQ-DI scores compared with placebo. The ACR 20 scores were also significantly better
in TCZ recipients. Investigators concluded that the side-effect profile
was acceptable although the pooled safety data showed more serious
infections and increases in cholesterol and LDL levels.
Comment: This was the first US trial to present radiographic data
with TCZ. The ACR response is similar to that reported in their previous trial. These scores were significantly improved in the TCZ group,
so again, a biologic demonstrated radiographic suppression. However, these patients’ disease did not progress much, even when given
a placebo.
New molecular therapies
Kremer J, et al. The Oral Jak Inhibitor CP-690,550 (CP) in combination with methotrexate (MTX)
is efficacious, safe and well tolerated in patients with active rheumatoid arthritis (RA) with an
inadequate response to methotrexate alone. Abstract L13.
Study. Objective: To evaluate the efficacy and safety of an oral Jak 3
inhibitor for the treatment of patients with active RA and incomplete
response to MTX. Design: This phase IIB clinical trial randomized
509 patients with RA (disease duration, 7.1 to 11.7 yrs) to 1 of 6
doses of Jak 3 or placebo. The primary efficacy endpoint was ACR 20
response at week 12. Results: The percentage of ACR 20 responders
was significant for the 3-mg to 20-mg doses versus placebo; only the
1-mg dose was not significant. Adverse events were dose-dependent,
with nausea and headache being the most frequent. Serious adverse
events were reported in 1% to 8% of the active-treatment group
versus none in the placebo group. Liver function changes and lipid
increases were not significant.
Comment: In this trial, the Jak 3 inhibitor clearly demonstrated
efficacy, with ACR 20, 50, and 70 scores similar to those reported
with TNF inhibitors. Adverse events do not seem unexpected: a little
nausea, a few headaches, very rare liver function abnormalities, and
a few severe adverse events. The creatinine increases noted in the
phase IIA trial of this agent were not seen in this phase IIB trial.
Based on these initial clinical trial results, this small molecule, formulated as an oral agent, will go forward into phase III trials. There are
some concerning safety data with the Jak 1 and 2 agents, but the Jak 3
inhibitor demonstrated efficacy without any major safety concerns.
The Jak inhibitors are an important chapter in the small molecule story
because the primary concern with the small molecules is toxicity. Preclinical animal trials have shown that Jak 1 and 2 are both embryonically lethal, and at least one caused profound leukopenia. Jak 3
has been associated with profound immunodeficiency states. In early
stages of research, one has to be guided by preclinical models, at least
in looking for toxicity. Thus far, Jak 3 has not shown significant side
effects, which may be because it has a short half-life.
Kremer J, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with an
inadequate response to methotrexate: the LITHE study. Abstract L14.
Study. Objective: To investigate the efficacy of TCZ in preventing
structural joint damage in MTX-resistant patients with RA. Design:
Randomized 1,190 patients with moderate-to-severe RA who had
inadequate response to MTX to either TCZ (4 or 8 mg/kg) or pla8
CARDIOVASCULAR DISEASES ASSOCIATED WITH RA
Elaine Husni, MD, MPH
Abbreviations: APO: apolipoprotein; AS: ankylosing spondylitis; CRP: C-reactive
protein; CV: cardiovascular; DMARD: disease-modifying antirheumatic drug; HAQ,
Health Assessment Questionnaire; HDL: high-density lipoprotein; LDL: low-density
lipoprotein; MI: myocardial infarction; MRI: magnetic resonance imaging;
RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; TNF: tumor
necrosis factor
Cardiovascular disease risk in rheumatoid arthritis
Kremers HC, et al. Increased mortality after acute myocardial infarction among patients with
rheumatoid arthritis. Abstract 692.
Study. Objective: To determine mortality and heart failure rates
associated with myocardial infarction (MI) in patients with rheumatoid arthritis (RA). Design: Population-based retrospective review of
patients with RA hospitalized for their first acute MI between 1976
and 2001. Results: Patients with RA had a significantly higher mortality ratio (1.75, 95% CI, 1.20-2.54) than MI patients in the general
population, especially among rheumatoid factor-positive patients with
RA (1.94; 95% CI, 1.24-3.05). The risk of heart failure following an
MI in RA patients was 45% higher but not statistically significant.
There were no differences in the use of acute reperfusion therapy or
medications at hospital discharge.
Comment: This study from the Mayo Clinic provides more evidence
that patients with RA have worse outcomes from an MI than those in the
general population. The increased risks of heart failure and of dying from
heart failure associated with RA highlight the need to institute preventive,
diagnostic, and treatment strategies for MI in patients with RA.
Peters MJ, et al. Rheumatoid arthritis as an important independent risk factor for incident cardiovascular disease. Abstract 691.
Study. Objective: To compare the incidence of cardiovascular (CV)
disease in patients with RA versus that in the general population.
Design: Data from the prospective cohort study (CARRE study) on 335
randomly selected outpatients with RA were used to determine the 3-year
incidence of CV disease. The incidence was compared to the 3-year
incidence of CV disease in 1,852 control patients in a population-based
cohort study. Results: The incidence rate was 9.0% in RA patients (3.30
incidence per 100 patient-years) versus 4.3% in the general population
(1.51 per 100 patient-years), which translated to a significantly elevated
relative risk of CV disease of 2.00. Adjustment for CV risk factors did not
substantially alter the risk. When compared to the general population, the
CV risk in patients with type 2 DM was similar to that for RA patients
without type 2 DM (2.02 vs 2.22, respectively).
Comment: This study from the Netherlands looked at how the
existence of RA compares with that in the general population and with
other chronic diseases as an independent risk factor for CV diseases.
Diabetes is known to be a substantial risk factor for CV diseases, and
this study shows for the first time that RA can be just as intense of a
risk factor for CV disease as DM. It further highlights that RA should
be considered an important risk factor for CV disease.
Another point regarding the importance of documenting the CV risk
in RA patients is the reimbursement issue. Because DM is recognized
as a risk factor, patients can obtain reimbursement for a substantial
amount of ancillary services related to reducing the DM risk. Providing supportive data to have RA placed in that category could have a
tremendous benefit on reimbursement.
9
Lipid profile in inflammatory arthritis
Charles-Schoeman C, et al. Composition and function of pro-inflammatory HDL is different from
anti-inflammatory HDL in patients with rheumatoid arthritis. Abstract 686.
Study. Objective: To identify specific differences in inflammatory
function in high-density lipoprotein (HDL)-associated proteins and
enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL in patients with RA. Design: The anti-inflammatory function of HDL was assessed in 32 patients with RA (16 with
proinflammatory HDL, 16 with anti-inflammatory HDL) and a group
of 16 matched controls. Results: Patients with proinflammatory HDL
had significantly higher levels of haptoglobin, apolipoprotein (APO)
A-1, hemoglobin, and myeloperoxidase compared with patients with
anti-inflammatory HDL (all P < 0.05). Significant correlations of
HDL anti-inflammatory function were observed with HDL-associated haptoglobin, APO A-1, hemoglobin, and myeloperoxidase in
patients with RA (see Table 2).
Comment: Abnormal, proinflammatory HDL has been linked to
coronary artery disease in the general population and to subclinical
atherosclerosis in patients with systemic lupus erythematosus (SLE);
proinflammatory HDL has been associated with increased disease
activity in patients with RA. Because dyslipidemia is recognized as an
independent risk factor for that disease, the need to look more closely
at lipid profiles in patients with RA becomes even more obvious.
This study looked at composition and function of proinflammatory
HDL in patients with RA, specifically subunits of proteins within the
HDL molecule, and found they were very much altered compared
with anti-inflammatory HDL and control patients. This might provide
some clue regarding the mechanism by which active RA increases
the CV risk. It may not be just the HDL level but rather how the HDL
is actually functioning that explains why patients with RA are at this
increased risk of coronary artery disease.
One caveat of this study is that it is very difficult to perform the
proinflammatory assay, so using some surrogate markers that are
a bit easier to perform might be useful as this line of investigation
moves forward.
Garcia-Gomes C, et al. Non-altered conventional cardiovascular lipid risk factors, but high
lipoprotein(a), in rheumatoid arthritis. Abstract 308.
Study. Objective: To evaluate the lipid metabolism in patients with
RA on standard therapy with disease-modifying antirheumatic drugs
(DMARDs) and low-dose glucocorticoids. Design: In this cross-sectional observational study, lipid profiles from 122 patients with RA
(25 men, 19 premenopausal women, 78 postmenopausal women)
were compared against those of a matched control group. Results:
Patients with RA receiving antirheumatic therapy had significantly
lower levels of APO B compared with controls. Levels of APO A1
and triglycerides were not statistically different between the groups.
Pre- and postmenopausal women had significantly higher HDL concentrations than controls; postmenopausal women had lower levels of
low-density lipoprotein (LDL). All patients had lower APO B levels.
Comment: In this study from Spain, the authors compared lipid
profiles as well as lipoprotein profiles between treated patients with
RA and a control group. Their conclusion was that compared with
Table 2. Lipid profiles in pronflammatory and anti-inflammaotry HDL
Group
HSCRP (mg/L)
ESR (mm/h)
DAS28
HII
HDL (mg/dL)
LDL (mg/dL)
TG (mg/dL)
RA-piHDL
*45.7 ± 49.3
*66.4 ± 28.1
7.3 ± 1.3
*1.38 ± 0.30
54 ± 20
99 ± 33
*158 ± 82
RA-aiHDL
4.5 ± 7.3
10.3 ± 6.3
3.3 ± 1.2
*0.32 ± 0.16
61 ± 20
84 ± 27
101 ± 60
Controls
1.3 ± 1.4
12.5 ± 6.8
N/A
0.20 ± 0.11
55 ± 11
105 ± 32
93 ± 42
HII = HDL Inflammatory Index; *p value < 0.05 compared to controls. Correlation of HII with DAS28: r = 0.72; p<0.0001.
HSCRP = High-sensitive C-reactive protein pi = proinflammatory ai = anti-inflammatory
the general population, patients with established RA treated with
DMARD and steroid therapy had a lipid profile that would be considered more protective against CV risk, namely higher HDL concentrations and lower APO B.
Husni ME, et al. The effect of TNF alpha treatment on lipid profiles of patients with systemic
rheumatic disease. Abstract 1045.
Study. Objective: To assess whether anti-tumor necrosis factor (TNF)
therapy modifies the lipid profile in patients with systemic rheumatic
disease. Design: In this observational study using a Cleveland Clinic
database, investigators analyzed lipid profile and C-reactive protein
(CRP) data from 265 patients with systemic rheumatic disease (RA,
SLE, vasculitis, and ankylosing spondylitis [AS]) either treated with
anti-TNF therapy (n = 95) or without anti-TNF therapy (n = 170).
Levels were measured at baseline and at 3-month follow-up. Results:
Anti-TNF therapy was associated with significantly lower triglyceride levels compared with those who did not receive anti-TNF therapy
(119 vs 149, respectively). No statistical differences were noted for
HDL, LDL, or CRP values.
Comment: We found that the lipid profiles were not much different
between those on and not on anti-TNF therapy. Triglyceride levels
were lower in the anti-TNF group, which goes along with the theme
that treatment with anti-TNF or DMARD therapy can improve the
CV risk profile. This may be why some studies show better MI risk
profiles in those treated with anti-TNF agents versus those not treated. Steroid use in the subject population was not able to be accurately
determined.
Although most studies report HDL and LDL, triglycerides are not
regularly reported, which makes it difficult to compare results. And
most rheumatologists do not routinely check baseline lipids. These
results suggest that in most patients with RA, rheumatologists should
run a fasting baseline lipid level.
Genovese MC, et al. Lipid and inflammatory biomarker profiles in patients receiving tocilizumab
for rheumatoid arthritis: analysis of five phase 3 clinical trials. Abstract 987.
Study. Objective: To characterize lipid and inflammatory biomarker
changes during tocilizumab therapy, either alone or in combination
with DMARDs, in patients with RA. Design: Review of data from 5
24-week placebo-controlled clinical trials in patients with moderate
to severe, active RA. Patients with inadequate response to DMARD
or anti-TNF therapy were randomized to receive a DMARD
either with tocilizumab (n = 1,582) or with placebo (n = 1,170).
Patients who had inadequate response to methotrexate or biologic
therapy were randomized to tocilizumab monotherapy (n = 288) or
escalating doses of methotrexate (n = 284). Fasting lipid levels and
inflammatory biomarker levels were evaluated. Results: Groups
receiving tocilizumab had significant elevations in lipid parameters
from baseline, including total cholesterol, LDL, HDL, triglycerides,
and APO A-1 and B. The increases occurred within 6 weeks and persisted for the entire 24 weeks. Substantial reductions were observed
in tocilizumab groups for several inflammatory biomarkers including
CRP, serum amyloid, heptoglobin, and lipoprotein.
Comment: These statistically significant changes in lipids and biomarkers seen with tocilizumab occurred very quickly – within 6
weeks of initiating therapy – and then persisted throughout the rest of
the 24-week trials. The elevations were seen in both the monotherapy
and combination groups. In all these patients, the CRP levels dropped,
so their disease activity acute-phase reactions dropped down.
As noted in the study conclusion, the clinical relevance of these lipid
changes is unclear. There seems to be a great deal of evidence in support of a relationship between tocilizumab and substantial elevations
in cholesterol levels. This is a real issue with this drug. Clearly, these
are not favorable lipid patterns. On the other hand, there is a profound
turning off of the acute disease phase with this drug. What it means
will require reviews of long-term safety databases with well-defined
CV endpoints to determine. The Food and Drug Administration
recently declined approval of tocilizumab, and the changes in lipids
are probably part of their issue with this drug.
In some ways, these lipid elevations are counterintuitive because
interleukin 6 is thought to be the player in atherogenesis, so suppressing it should be beneficial. The other question is whether these are
just short-term changes occurring because interleukin 6 is synthesized in the liver or whether it reflects a surge of lipoproteins that will
eventually change.
Some well-constructed TNF lipid studies have shown that there is a
time element. Lipids tend to go up but then fall back to the mean 12
months later. In tocilizumab studies with at least 12 months of data,
the lipid changes do not progress but they do not go away either.
Some have suggested that these may be negative acute-phase reactions and that when the phase is turned off, the lipids gravitate up. It
remains to be determined whether that will have the same meaning as
it does in the huge population-based study for interpreting CRP and
inflammation. Obviously, rheumatologists need to be a bit skeptical
until more data are presented regarding the clinical implications.
10
Cardiovascular risk management
Khasnis A, et al. Comparison of coronary atherosclerosis progression in patients with and
without systemic inflammation: an IVUS study. Abstract 298.
Study. Objective: To determine coronary atherosclerotic disease
progression in patients with and without systemic inflammation.
Design: This was a retrospective analysis of five trials that used
intravascular ultrasound (IVUS) to measure plaque progression
in 3,282 patients with systemic inflammatory disease, mostly
RA, who were receiving immunosuppressive therapy, defined as
chronic prednisone and/or DMARDs (n = 265), versus those not
receiving the medications. Results: At 18 months, plaque progression, as measured by the percent atheroma volume inside the external elastic lamina, was 2.3 times greater in the systemic inflammatory therapy group, a statistically significant difference.
Comment: The IVUS technology provides a direct and detailed
imaging of coronary plaque progression and vascular remodeling
in atherosclerosis. It is a well-standardized technology used by
cardiologists to measure plaque. The results showed that in these
patients with systemic inflammatory disease, the rate of progression for coronary atherosclerosis was much greater than the rate
for patients without this disease. This highlights a technology that
is available to rheumatologists to evaluate the level of coronary
artery plaque rather than waiting for a clinical event. This invasive
IVUS technology has not been compared in head-to-head trials
to noninvasive technologies that measure surrogates for carotid
atherosclerosis such as intimal media thickness.
del Rincon I, et al. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Abstract 278.
Study. Objective: To estimate the rate and progression of atherosclerosis over time in patients with RA and to identify factors predictive of rapid progression. Design: Investigators used a high-resolution ultrasound scan of the common carotid arteries to measure
the intima-media thickness (IMT) at baseline and 3 years later.
Results: In the 566 patients with RA who completed the study, the
carotid IMT significantly increased (mean, 0.05 mm). Factors that
predicted rapid progression included the number of established
CV risk factors and the erythrocyte sedimentation rate.
Comment: This technology is basically a computed tomography
scan that uses high-resolution ultrasound to detect plaque burden.
One objective of this study was to determine the factors that predict which patients are at risk for rapid progression. So they looked
at the patients with the greatest IMT progression and determined
which baseline factors were associated with this rapid progression.
They found that a higher number of CV risk factors and a more
intensive sedimentation rate are more likely to predict worsening
atherosclerosis.
Syndesmophyte development in rheumatoid disease
Maksymowych WP, et al. Inflammatory lesions of the spine on MRI predict the development
of new syndesmophytes in ankylosing spondylitis: evidence for coupling between inflammation and new bone formation. Abstract 2009.
Study. Objective: To determine whether inflammation at the
vertebral corner in AS that shows an active inflammatory lesion
visible on magnetic resonance imaging (MRI) is more likely to
evolve into a syndesmophyte lesion visible on plain x-ray than
a vertebral corner that shows no inflammation on MRI. Design:
MRI scans and radiographs were performed in 29 patients recruited into clinical trials of anti-TNF therapy. Results: New syndes11
mophytes developed significantly more frequently in AS patients
with inflammation at vertebral corners visible on MRI at baseline
compared with those without visible inflammation. This occurred
regardless of whether the lesion persisted or resolved after antiTNF treatment.
Comment: Patients with AS who have syndesmophyte lesions
lose a great deal of mobility in their spine. This study showed
that a syndesmophyte is more likely to develop at an area with
prior inflammatory lesions. It also appears to couple inflammation with exuberant syndesmophyte growth. What is interesting is
that if you treat these patients with a TNF blocker, they can still
get syndesmophyte formation. So there might be something other
than this coupling.
van der Heijde D, et al. MRI-inflammation of the vertebral unit (VU) only marginally contributes to new syndesmophyte formation in that unit: a multi-level analysis. Abstract 2011.
Study. Objective: To investigate the relationship between MRI
inflammation at a vertebral unit and the initiation and growth of
syndesmophytes at the same vertebral unit in patients with AS.
Design: A random sample of 182 patients from a clinical trial
comparing infliximab monotherapy versus placebo in patients
with active AS. MRIs were taken at baseline, week 24, and week
102. Results: More than 75% of new syndesmophytes occurred
in areas without MRI activity at baseline. New syndesmophyte
lesion development was not associated with treatment. Growth
of existing lesions at the vertebral unit level was not associated
with MRI activity.
Comment: This study found that most new syndesmophytes
occurred at MRI sites without previous inflammation, which seems
to contradict the previous study.
Baraliakos X, et al. The relationship between inflammation and new bone formation in patients
with ankylosing spondylitis. Abstract 2117.
Study. Objective: To determine whether spinal inflammation at
baseline is associated with radiographic progression after 2 years in
patients with AS treated with anti-TNF agents. Design: Spinal
MRIs and conventional x-rays were reviewed in 39 patients with
AS treated with infliximab or etanercept to quantify the degree of
structural damage at baseline and at 2 years. Results: New syndesmophytes occurred significantly more often in vertebral edges
with inflammation. Even in patients treated with anti-TNF therapy, syndesmophyte formation occurred almost 3-fold more often
in regions with MRI-proven spinal inflammation at baseline.
Comment: This group from Germany looked at the relationship
between inflammation and new bone formation in AS. This
study was one of the first that was longer than the previous
two studies. This study’s conclusion that the syndesmophyte
formation occurred more often in regions of spinal inflammation, even in patients treated with anti-TNF, concurs with the
first abstract by Maksymowych. This study suggests both a link
and some dissociation between inflammation and new bone
formation, but presents no evidence of a major uncoupling
of the characteristic features in AS. More effective suppression of spinal inflammation may lead to a better inhibition of
radiographic progression in AS.
These studies raise questions regarding how these syndesmophytes
form and whether we have more insight into the mechanism of AS.
These studies differ from radiographic progression previously reported
with TNF inhibitors in clinical trials in that they were relatively short,
24 weeks. Syndesmophyte formation often takes 18 months to be visible, so 24 weeks may not really predict how much ankylosing will
occur, regardless of TNF inhibitor therapy. In addition, some
researchers report that the thoracic spine may differ in syndesmophyte formation compared with the cervical or lumbar spine area.
This raises the question in research studies of whether they are
adequately comparing the same portion of spine before and after
treatment rather than using a composite score for the entire spine.
Novel outcome measurement tools
Fries JF, et al. Progress in assessing disability in arthritis patients: computerized adaptive testing (CAT). Abstract 2035.
Study. Objective: To determine the degree of accuracy of Item
Response Theory (IRT) and Computerized Adaptive Testing
(CAT) in assessing physical function/disability outcomes. Design:
More than 21,000 subjects, including 1,475 patients with arthritis,
were studied to determine the accuracy of items used to measure
physical function/disability. IRT was used to identify 124 items
for a final item bank. Results: The CAT-based assessment provided superior performance over traditional measurement forms
of the same or greater length.
Comment: This abstract deals with measuring the signs and symptoms of RA beyond disease activity scores. The investigators evaluated CAT, which uses a selective computerized algorithm that follows a pathway and skips question that are not pertinent. Basically,
this study looked at CAT as a superior outcome tool that uses shorter
and more precise instruments to measure for patient outcomes, and
one that could replace more traditional measures such as the Health
Assessment Questionnaire (HAQ). They concluded that a 10-item
CAT outperformed all of the traditional measures, including HAQ
and SF 36. Refined CAT approaches using larger item pools may
yield greater gains.
Amjadi S, et al. Validating and assessing the sensitivity of the Health Assessment Questionnaire-disability index derived SF-6D in patients with early aggressive rheumatoid arthritis.
Abstract 2036.
Study. Objective: To evaluate the construct validity of the HAQ disability index-derived Short Form 6D (SF-6D) score and assess its
responsiveness to change over 6- and 12-month follow-up periods
in patients with early aggressive RA. Design: Observational study
of 277 patients with RA who completed self-reported measures of
symptoms and HAQ disability index at baseline, 6, and 12 months.
Results: The SF-6D scores had moderate to high correlations with
patient-reported measures and negligible to low correlations with
clinical measures. The SF-6D scores were able to discriminate
between mild, moderate, and severe patient global assessments of
pain, fatigue, arthritis, severity, and physician global assessments
of disease. Overall, the data support the validity and responsiveness to change of SF-6D scores in patients with early RA.
Comment: This abstract looks at validity of the SF-6D instrument, which uses a small number of questions, to assess quality of life in patients with early aggressive RA and to evaluate
its responsiveness to change. Their results support the use of
the SF-6D in RA cohorts and clinical trials in which no preference-based measure has been collected. One would think
that sensitivity might go down because it has fewer questions,
but this group found that even going down to the SF-6D form,
they are able to keep enough responsiveness to change. One
of the problems with SF36 and HAQ instruments is that they
require a large population base to statistically sense change, so the
SF-6D method might allow researchers to look at some smaller
cohorts. Another problem is getting patients to complete the
forms. Patients might be more prone to complete a shorter form.
It ultimately may be a matter of weighing what is easier to do in
practice against sacrificing a little sensitivity.
IMPLICATIONS OF REGULATORY T CELLS AND
TH - 17 CELLS
Daniel Furst, MD
Abbreviations: IL: interleukin; SLE: systemic lupus erythematosus; Th: T helper;
T-reg cells: regulatory T cells
Regulatory T cells in autoimmune disease
Bonelli M, et al. Analysis of regulatory and effector T cell populations from patients with
autoimmune disease. Abstract FR10080 EULAR 2007.
Study. Objective: To determine if regulatory T cells (T-reg cells) are
decreased in patients with active lupus. Design: This cross-sectional
study used phenotypic analysis of CD4+ and CD25+ cells as markers
for T-reg cells in patients with systemic lupus erythematosus (SLE)
(n = 22). Results: Patients with active SLE had consistently lower
levels of CD4 and CD25 activity. Further analyses indicated that
the CD regulatory cells prevented the activation of autoreactive T
cells. Investigators observed a population of CD4+ cells that lacked
expression of CD25.
Comment. The researchers looked at the CD4+ and CD25+ cells to
determine if they prevent the activation of autoreactive T cells. They
collected data from mice before moving to human study. The patients
have a large range of CD4+ and CD25+ cells. In inactive lupus, the
number of those cells is approximately the same. In active lupus,
there are decreased numbers of CD4+ and CD25+ cells indicating
decreased T-reg cells. In populations of patients with high levels of Treg cells, few patients have active lupus, which supports the concept
that T-regs are decreased in patients with SLE.
Likuni N, et al. Anti-SNA IG peptides promote the activity of T-reg cells in SLE patients. Abstract
OP0080 EULAR 2008.
Singh RP, et al. pConsensus peptide induces tolerogenic CD8+ T cells in lupus-prone (NZB x
NZW) F1 mice by differentially regulating Foxp3 and PD1 molecules. J Immunol 2008;180:2069-80.
Study. Objective: To evaluate whether tolerogenic peptides
derived from anti–double-stranded DNA antibodies induce T-reg cells.
Design: Used in vitro cultures to determine numbers of peripheral
blood mononuclear cells (PBMC) in 36 patients with SLE and 23
controls. Results: T-reg cells were decreased in patients with SLE
compared with controls. Treatment of PBMC with pConsensus peptides restored the number of T-reg cells by increasing proliferation of
T-reg cells and FoxP3 activity.
12
Comment. The research by Singh and colleagues (previous study)
provided the background for this study. They examined the pConsensus peptide of the anti–double-stranded DNA antibodies and
found it decreased the double-stranded DNA, improved survival,
and induced T-reg cells in lupus-prone mice. Likuni designed a trial
to evaluate the results in a human population. Although this study
has design problems, it supports the idea that increasing T-regs with
pConsensus peptides might be a therapeutic approach to SLE.
Scherer H, et al. CD4+ CD25+ regulatory T cells inhibit inflammation by shedding soluble
TNFRII. Abstract OP0237 EULAR 2008.
Study. Objective: To determine whether T-reg cells inhibit inflammation by secreting soluble tumor necrosis factor (TNF) receptors.
Design: Subjected murine and human T-reg cells to TCR/CD28
stimulation and measured for soluble TNF receptors as compared
with a control population that was TNFRII-negative. Results: T-reg
cells shed soluble TNFRII in biologically relevant amounts when
activated whereas effector T cells did not shed TNFRII. T-reg-derived soluble TNFRII was able to control inflammation in a murine
adoptive transfer system (see Fig 4).
6
|
5
|
4
|
3
|
2
|
1
|
0
|
IL-6 levels (pg/m)
Figure 4. T-reg cells etanercept suppress inflammation in mice
Control
TREG Cells
ETN
Comment. In this study, the researchers found that in mice, T-reg
cells that produce interleukin (IL)-6 are increased. In the presence of
T-reg cells, the production of IL-6 was decreased. They also found that
T-reg cells express TNFRII, and TNFRII increases with activation. Isolated activated T-reg cells inhibited TNF-alpha by shedding
TNFRII. Although the results from this mice model are nonspecific, they do support some of the concepts presented in the previous
abstracts.
Mus A, et al. Vitamin D and IL27, but not IL10, are strong inhibitors of TH17 polarization of
splenic T cells from naive and CII immunized DBA-1 mice using different mechanisms. Abstract
OP0005 EULAR 2008.
Study. Objective: To identify the effect of vitamin D on T helper cell
(Th1 and Th17) production and to evaluate the mechanism of action
of vitamin D on IL-27 and IL-10 production. Design: Isolated CD4+
T cells from the spleen of DBA-1 mice with collagen-induced arthritis were stimulated with transforming growth factor-beta IL-23
and IL-6 to produce Th17 cells. Vitamin D was added to determine
13
its regulatory effect. Results: Vitamin D and IL-27 but not IL-17 significantly inhibited Th17 polarization. In contrast, neither high nor
low levels of IL-10 inhibited Th17 differentiation. Vitamin D was
increased in IL-4+ and IL-10+ cells under Th17 polarizing conditions accompanied by an increase in IL-4 levels but not IL-27 levels.
Comment: In this model, the investigators showed that vitamin D
significantly increased IL-4 production and decreased IL-17 production by peripheral blood mononuclear cells in early arthritis
conditions via an unknown mechanism of action. What was new
is the finding that physiologic doses of vitamin D (10-7 to 10-9 M)
were therapeutically effective in normalizing the abnormal Th17. It
indicates that vitamin D has homeostatic properties in the integrated
immune response, which suggests that supplements could have a
role in patients with autoimmune disorders because many of them
are vitamin D deficient.
Haque UJ, et al. Does vitamin D level influence RA disease activity and function? Abstract 981
ACR 2007.
Toloza S, et al. Vitamin D insufficiency is prevalent in SLE patients. Abstract 1117 ACR 2007.
Haque study. Objective: To evaluate vitamin D deficiency and its
association with disability. Design: Longitudinal study of disease
progression in 62 patients with rheumatoid arthritis (RA) (82% white
females) in whom vitamin D levels were available. Approximately
60% had low vitamin D levels, defined as 25-hydroxyvitamin D
serum levels  30 ng/mL. Results: Vitamin D levels were
significantly associated with Health Assessment Questionnaire
(HAQ) scores; patients deficient in Vitamin D had an odds ratio of
3.2, for a HAQ score ≥ 1.25. No significant associations were evident
between vitamin D levels and markers of RA disease activity.
Toloza study. Objective: To determine the vitamin D status in a large
cohort of patients with SLE and assess its relationship with bone
mineral density (BMD). Design: Retrospective study of 274
patients with SLE in whom T scores and vitamin D levels were
available. Results: A total of 84.5% of subjects had vitamin D levels
considered suboptimal (< 75 nmol/L) or deficient (< 40 nmol/L).
No significant associations were found between vitamin D levels
and BMD results. No correlations with vitamin D levels were found
for clinical covariates including disease duration, disease activity,
or bone damage, indicating that vitamin D levels are a poor indicator of long-term bone loss in patients with SLE.
Comment: These two studies looked for an association between
vitamin D levels and disease severity in patient populations with
either RA or SLE. In the RA patients, those with low vitamin D
levels, but which were not necessarily deficient, had a significantly
increased chance of having decreased disease-specific activities
of daily living. The SLE patients had low vitamin D levels that
correlated with increased disease activity scores on the Systemic
Lupus Erythematosus Disease Activity Index (SLEDAI) and
European Consensus Lupus Activity Measurement (ECLAM)
scales. Those on hydroxychloroquine tended to have high vitamin
D levels.
T-reg and IL-17 regulation of mouse lupus
IIkuni N, et al. Natural TREG cells protect murine lupus by directly suppressing autoantibodyproducing B cells. Abstract OP0079 EULAR 2008.
Study. Objective: To determine whether T-reg cells can suppress
B cell production of autoantibodies in lupus-prone mice. Design:
Assessed the results of adoptive transfer of purified T-reg cells in
lupus-prone mice characterized by double-stranded DNA autoantibodies, glomerulonephritis, proteinuria, and low levels of T-reg cells.
Results: The adoptive transfer of T-reg cells increased T-reg cells,
decreased double-stranded DNA antibody production, decreased
immunoglobulin levels, delayed renal disease, improved proteinuria, and increased survival. Treatment with anti-CD25 led to depletion of T-reg cells, with decreased outcomes in those measures. In
vivo and in vitro tests showed T-regs directly suppress B cell autoantibody production without CD4+ T cells.
Comment: The lupus-prone mice in this study had immune-mediated glomerulonephritis, proteinuria, and low levels of T-reg cells.
When their T-reg cells were increased, outcomes improved. When
the T-reg cells were decreased using anti-CD25, outcomes worsened.
One caveat is that in this type of mouse, almost any treatment affects
its survival, so we will have to await clinical trials to see how this
change affects humans. However, the data confirm the beneficial role
of T-regs in murine SLE models. In active SLE, T-reg cells may be
decreased, potentially leaving Th17 cells relatively increased. Thus,
SLE activity may be (at least in some part) due to T-reg dysregulation.
Lee J, et al. Synovial RANKL/OPG mRNA expression ratio and IL-17 in collagen-induced arthritis. Abstract OP0078 EULAR 2006.
Study. Objective: To investigate the synovial messenger RNA
expression of receptor activity. Design: Randomized mice with
collagen-induced arthritis to treatment with IL-17, anti–IL-17
monoclonal antibodies, or placebo. Results: Treatment with IL-17
aggravated synovial inflammation and bone erosion while anti–IL17 reduced the synovial inflammation and bone erosions.
Comment: Blocking IL-17 reduced the disease effects, indicating
that IL-17 blockage might be an approach to therapy. However, this
study was reported several years ago, and we are still waiting for
follow-up studies evaluating their approach.
SYSTEMATIC LUPUS ERYTHEMASTOSUS AND
ASSOCIATED CONDITIONS
Susan Manzi, MD, MPH
Abbreviations: CHB: congenital heart block; CV: cardiovascular; SLE:
systemic lupus erythematosus
Cardiovascular disease in systemic lupus
erythematosus
McMahon MA, et al. PiHDL is a stronger predictor of atherosclerosis than other high-risk
inflammatory lipids, and is associated with a 17-fold increased risk of subclinical atherosclerosis
in SLE. Abstract 664.
Study. Objective: To determine whether proinflammatory highdensity lipoprotein (HDL) is associated with the presence of carotid
artery plaque in patients with systemic lupus erythematosus (SLE)
and whether apolipoprotein (APO) A-1 or paraoxonase could be
surrogate markers for proinflammatory HDL. Design: Measured
existence of plaque in the carotid arteries using B-mode ultrasound
as well as the existence of proinflammatory HDL, paraoxonase activity, and APO A-1 levels in 171 females with SLE and 85 controls.
Results: Significantly more women with SLE had proinflammatory
HDL than controls (50.3% vs 7.1%). In the SLE population, significantly more women with plaque had proinflammatory HDL than
did those without plaque (83.3% vs 43.3%). The only significant
risk factor independently associated with plaque was proinflammatory HDL (OR, 16.6). No associations were found linking proinflammatory HDL with paraoxonase or APO A-1.
Comment: As expected, this group found that significantly more
women with SLE had proinflammatory HDL, which agrees with
their previous research findings that about 45% of the patients with
SLE had this dysfunctional or proinflammatory HDL versus 5% of
healthy controls.
This study had two primary objectives: to determine (1) whether
dysfunctional proinflammatory HDL is a risk factor for atherosclerosis and (2) whether paraoxonase and APO A-1 could be surrogate
markers for proinflammatory HDL. Their results showed that having proinflammatory HDL is a very potent independent risk factor
for atherosclerosis. Unfortunately, paraoxonase and APO A-1 levels
did not correlate with the existence of proinflammatory HDL, which
means that these blood tests cannot be used as surrogate measures
of proinflammatory HDL.
Hak AE, et al. Systemic lupus erythematosus and risk of cardiovascular disease. Results from the
Nurses’ Health Study. Abstract 667.
Study. Objective: To confirm the increased risk of cardiovascular
(CV) disease events in women with SLE. Design: Prospective, population-based study of 119,329 women participating in the Nurses’
Health Study followed over 28 years; subjects were free of CV disease at baseline. Results: A total of 157 women developed incident
SLE, confirmed by medical record review, at a mean age of 53 years.
Of those, 24 suffered a subsequent CV event. After adjusting for
potential confounding factors, the relative risk of CV events in
women with SLE versus those without SLE was 2.34 (95% CI,
1.57-3.51), a significant difference. Risks for CV disease and stroke
were also significantly greater (see Table 3).
Comment: A large database, such as in the Nurses’ Health Study,
can provide the statistical power to evaluate specific factors, and it
confirmed the increased risk of CV events in women with SLE. This
risk was not as high as previous reports, but this may be due to the
relatively older age at onset in this lupus population. The highest relative risk for CV disease in lupus was in premenopausal women.
Elliott JR, et al. Carotid intima-media thickness and plaque predict future cardiovascular events
in women with systemic lupus erythematosus. Abstract 669.
Study. Objective: To determine whether carotid plaque or intimamedia thickness (IMT) are independent predictors of future CV
events in women with SLE. Design: Longitudinal study of 289
women with SLE enrolled in 1995; incident CV events were identified. Results: Over a median of 10 years, 13.4% had a CV event. In
a multivariate analysis, carotid IMT was significantly predictive of
any CV event, with an increased hazard ratio (HR) of 1.24 (95%
CI, 1.04-1.48). In a second multivariate model, presence of plaque
at baseline independently predicted time to CV event, with an HR
of 5.97 (95% CI, 1.52-23.38).
14
Comment: This is the first study in patients with SLE to show
that both carotid plaque and IMT measures can accurately predict
future CV events, independent of other risk factors. SLE patients
with plaque in their carotid artery had an extremely high risk of
having a CV event within 10 years, either a myocardial infarction or
stroke (HR, 5.97). The study had a relatively small number of participants, and larger clinical trials are needed to confirm the results;
however, it does provide data to begin considering carotid IMT and
plaque as surrogate endpoints in future intervention trials.
Table 3. Data from the Nurses’ Health Study on coronary heart disease
and stroke risks associated with SLE
Person-years of
follow up
SLE
No SLE
2,575
3,074,250
738
222
P value
CHD
• Incidence/
100,000
person-years
• No. CHD cases 19
6,835
• Age-adjusted
RR (95% CI)
2.81 (1.79-4.41)
1.0 (ref)
<0.001
• Multivariable
RR* (95% CI)
2.31 (1.47-3.64)
1.0 (ref)
<0.001
Stroke
Kamen DL, et al. Influence of vitamin D deficiency on disease activity among African Americans
with systemic lupus erythematosus. Abstract 450.
Study. Objective: To evaluate correlations between vitamin D levels and disease activity, including double-stranded DNA autoantibody levels, at baseline and following repletion with oral vitamin D.
Design: Data were obtained from 28 African American patients with
SLE as part of a vitamin D replacement study screening visit. Threemonth follow-up data were available on 12 patients who took oral
vitamin D replacement daily. Results: The mean 25 (OH) D level was
low at 23.6 ng/mL, with 11% being severely deficient (< 10 ng/mL).
Patients in the lowest quartile of serum vitamin D levels had significantly higher SLE disease activity scores and higher double-stranded
DNA autoantibody levels after adjusting for potential confounders. In
the 12 patients with follow-up data who received vitamin D therapy,
there was no change in SLE disease activity or DNA levels.
Comment: The prevalence of vitamin D deficiency in patients with
SLE is particularly high in African Americans. This study shows
the association between vitamin D and disease activity in African
Americans with SLE. Their findings associating low vitamin D with
higher SLE disease and DNA scores are similar to those from earlier studies. Replacing vitamin D in these 12 patients substantially
increased vitamin D levels. Unfortunately, it did not change disease
activity or the double-stranded DNA levels. The numbers are small,
and larger studies to evaluate the benefit of vitamin D replacement
on disease activity in lupus are needed.
Pregnancy and congenital heart block
• Incidence/
100,000 person- 194
years
65
No. stroke cases 5
2,000
• Age-adjusted
RR (95% CI)
2.67 (1.11-6.43)
1.0 (ref)
<0.05
• Multivariable
RR* (95% CI)
2.45 (1.01-5.92)
1.0 (ref)
<0.05
Llanos C, et al. Pregnancy outcomes subsequent to a child with autoimmune associated congenital heart block (CHB) and associated fetal/maternal risk factors. Abstract 1928.
*Adjusted for age, race, CVD risk factors, and medication
Vitamin D
Aranow C, et al. The effect of vitamin D supplementation on the interferon signature in patients
with SLE. Abstract 448.
Study. Objective: To determine whether vitamin D repletion affects
the interferon (IFN) signature in patients with SLE. Design: In this
pilot study, 9 patients with mild SLE and a vitamin D deficiency
received vitamin D supplements. The IFN signature was determined
by measuring the relative expression of the 3 IFN-inducible genes.
Results: Treatment with vitamin D diminished the expression of
IFN-inducible genes in 6 patients. Despite repletion of vitamin D, 3
patients did not show a decrease in expression.
15
Comment: In addition to its role in calcium metabolism, vitamin
D regulates the immune response with inhibitory effects on T cells,
B cells, and dendritic cells. Vitamin D deficiency is common in
patients with SLE. The potential ability of vitamin D to diminish the
upregulation of IFN-inducible genes represents a new and relatively
nontoxic intervention for treating SLE. This is a very preliminary,
hypothesis-generating study and confirmation in a larger cohort of
patients is needed.
Study. Objective: To determine the recurrence rates of congenital
heart block (CHB) and associated risk factors in the United States.
Design: A retrospective study of data from a large US-based cohort
examined 120 pregnancies immediately following the birth of a child
with CHB. Results: The recurrence rate for cardiac disease (including heart block and cardiomyopathy) in a child subsequent to birth
of a child with CHB was 20%. Maternal health status including presence of SLE, severity of first affected child, fetal gender, and use of
steroids during pregnancy were not predictive of CHB in a subsequent pregnancy.
Comment: Determining the frequency of giving birth to another
child with CHB is important both for counseling women with Ro
antibodies and in understanding the pathogenesis of Ro-mediated injury. It also provides data on risk rates for prevention trials.
Among those giving birth to a child with CHB, the majority were
Ro-positive. Prophylactic steroid use did not affect the rates. Aside
from careful monitoring of the infants with weekly fetal echocardiograms, no standard of care model has been developed due to the
lack of randomized, controlled intervention studies. Prophylactic
steroids are not recommended, even for high-risk mothers. An intervention trial of dexamethasone with plasmapheresis is being studied
to determine efficacy in reducing Ro antibodies in the mother.
Izmirly P, et al. Decreased risk of anti-Ro/La associated congenital heart block (CHB) in fetuses
exposed to hydroxychloroquine (HCQ). Abstract 1743.
Merrill JT, et al. The efficacy and safety of abatacept in SLE: results of a 12-month exploratory
study. Abstract L15.
Study. Objective: To evaluate whether pregnant mothers with autoantibodies to SSA/Ro and/or SSB/La who took hydroxychloroquine
(HCQ) during pregnancy would have a reduced risk of giving birth
to a child affected with CHB. Design: An observational retrospective analysis was conducted of 771 pregnancies in 436 mothers with
antibodies to Ro/La. HCQ exposure was defined as dose of at least
200 mg/d through the time of delivery. Results: Use of HCQ by
mothers during pregnancy was associated with a decreased rate of
CHB, with an odds ratio of 0.23 (95% CI, 0.11-0.49).
Study. Objective: To assess the safety and efficacy of abatacept
in patients with SLE and flare of polyarthritis, serositis, or discoid
lesions. Design: In this 1-year, phase II trial, patients with SLE and
active disease were randomized to abatacept or placebo. Primary
and secondary endpoints were based on new disease flares. Results:
In 175 patients, occurrence of new flares was similar in both groups:
79.7% for abatacept and 82.5% for placebo. In post-hoc analyses,
the percentage of new flares as rated by the treating physician was
63% versus 82%, respectively. In patients with polyarthritis, the
results were 57% versus 84%. Abatacept-treated patients had more
significant adverse events: 19% versus 6%. These events were primarily related to disease.
Comment. This was an observational study that looked at how HCQ
use affected the chances of having a child with CHB. It was not a
controlled clinical trial. From the results, it appears that HCQ therapy
is safe during pregnancy and may be considered to prevent CHB;
however, prospective studies are needed to confirm the results.
Epidemiology and outcomes in systemic lupus
erythematosus
Costenbader KH, et al. Incidence of end-stage renal disease due to lupus nephritis in the U.S.,
1995-2004. Abstract 1927.
Comment: Basically, this was a 12-month exploratory trial in
patients with active disease. It was a negative trial based on the
primary endpoint of new disease flare. When they looked at physician-blinded analysis they found a significant difference in flares,
particularly in the polyarthritis group. The clinical measures and
several of the biomarker responses support further evaluation of
this therapy in patients with SLE.
Study. Objective: To determine the incidence rates of end-stage
renal disease (ESRD) associated with lupus nephritis. Design:
Assessed the rates of lupus nephritis in the United States, stratified according to age, sex, race, and ethnicity from 1995 to 2004
using the US Renal Data System. Results: A total of 10,035 cases
of ESRD caused by lupus nephritis occurred in the United States
during the time period. The incidence rate rose from 3.0 to 3.9 cases
per million person-years. Rates were highest in the 20 to 39 age
group. Most cases occurred in women (82%). The incidence among
African Americans increased 37%, the highest in all racial and
ethnic groups.
Comment: The US Renal Data System is estimated to capture 94% of
patients with ESRD. Overall, the ESRD rates rose in the United States,
which was disproportionately high among women and African Americans. More cases now occur annually among African Americans than
among Whites. The data do not provide enough details to speculate on
the causes for the changes, but theories include decreased access to care
and/or less effective therapies for lupus nephritis in African Americans.
Treatments for systemic lupus erythematosus
Merrill JT, et al. Efficacy and safety of rituximab in patients with moderately to severely
active systemic lupus erythematosus (SLE): results from the randomized, double-blind phase II/
III study EXPLORER. Abstract L12.
Study. Objective: To assess the efficacy and safety of rituximab in
patients with moderately to severely active extrarenal SLE. Design:
This randomized, double-blind, placebo-controlled EXPLORER
clinical trial compared the effects of a 52-week rituximab regimen
versus placebo in 257 patients with active disease. Results: Endpoints showed no statistically significant differences between rituximab and placebo. No differences were seen when analyzing disease activity over 12 months on primary or secondary endpoints.
The safety profile was similar to placebo. [potential table]
Comment. This trial evaluated rituximab in patients with very
active disease but no significant renal disease. The investigators used
some complicated measures of clinical response, but the bottom line
is there was no difference in response. In a breakout analysis, African Americans and Hispanics on rituximab appeared to have a better
response than those not on the drug.
16
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