OUTCOME MEASURES FOR CHILDHOOD-ONSET
SYSTEMIC LUPUS ERYTHEMATOSUS (cSLE).
Hermine Brunner, MD
Childrens Hospital
Medical Center
Cincinnati, Ohio
Nicola Ruperto, MD
Istituto di Ricovero a Cura
a Caraterre Scientifico G. Gaslini
Genoa, Italy
Key-words: Systemic Lupus
Erythematosus, children, cSLE, jSLE, outcome measures, surrogate markers, CRV.
Non-Standard Abbreviations:
BILAG British Isles Lupus Activity Group Index
CRVs Core
response variables
RIFLE Response
Index for Lupus Erythematosus
cSLE
Childhood-onset
Systemic Lupus Erythematosus
ECLAM European Consensus Lupus
Activity Measurement
SELENA Safety of Estrogens in Lupus
Erythematosus – National Assessment
HRQOL Health related quality of life
SLAM Systemic
Lupus Activity Measure
MCID Minimal
clinically important differences
SLEDAI Systemic Lupus Erythematosus
Disease Activity Index
OMERACT Outcome
Measure in Rheumatology Clinical Trials
SDI SLE International
Collaborating Clinics/ American
College of Rheumatology
Damage Index
The study was supported by a Clinical Research
Grant of the Lupus Foundation of America and NIAMS P60 AR47784.
Contact Information:
Hermine Brunner MD. MSc., Cincinnati Children’s Hospital Medical Center,
Division of Rheumatology, E 4010, 3333 Burnet Avenue, Cincinnati, OH
45229-3039, USA; e-mail: hermine.brunner@cchmc.org.
Introduction.
The goal of health care and
medical interventions is to improve patient longevity and health. The classic
outcome measure to verify the effects of medical interventions for chronic
diseases is patient survival. As patient survival increases, this traditional
outcome parameter of medical success is too insensitive to assess the effect of
medical care. This is also true for
children with systemic lupus erythematosus (1, 2). Since the introduction of
steroids, and possibly the off-label use of newer medications for
childhood-onset SLE (cSLE; also juvenile SLE, jSLE), the 5-year survival rate
of children with cSLE has increased from 42%
in the 1950s (3) to over 90% in the 1980s(4). Currently, 5-year survival
is estimated at 97% (5) and, furthermore,
the 10-year survival of children with cSLE is between 85 – 90%
(6-10).
Decreases in patient mortality
with cSLE necessitate the development of other outcome parameters to verify the
response to current therapeutic regimens and test the efficacy of new, less
toxic drugs for cSLE. High quality, easy to measure outcome parameters are
needed to accurately and effectively capture changes in patient health.
This review summarizes the currently available outcome measures for
children with cSLE and provides a brief overview of parameters that should be
considered when assessing cSLE patients in daily practice and clinical
research.
Children with cSLE are not miniature adults with SLE.
Although children
and adults with SLE share many signs and symptoms of disease, they differ in
the degree and frequency of clinical findings of disease activity and damage,
as well as the treatment approaches used by their physicians (11, 12).
Similarly, children remain more often serologically active compared to adults
(13). All disease activity measures incorporate laboratory parameters, and some
also include medication choices.
Because of the
differences in the range of observed disease activity, damage, serologic abnormalities
and treatments between cSLE and adult SLE, one cannot a priori assume that the
disease measures developed for adults are suitable for cSLE. In addition,
pediatric rheumatologists must consider long-term toxicity and the effects of
drugs on growth and development in children with cSLE. Therefore, all outcome
measures developed for adults have to be examined for their usefulness
(measurement properties) in children. Unless specifically mentioned, all
definitions and outcome measures presented in the following have only been
tested for adults with SLE.
Surrogate
& Biological Markers
Recent expert discussions at the National
Institute of Health (NIH) and FDA-supported meetings have stressed the
necessity of developing highly-responsive, easy to measure SLE outcome
parameters to quantify the effects of new and better therapeutic interventions.
Certain experts have pointed out that it is important to make a distinction
between so-called surrogate markers of disease, such as disease activity
indices and responder criteria versus true biomarkers of SLE, e.g.
objectively measurable laboratory markers of the disease process and response
to treatment. Currently available
biological markers, including ESR, complement levels, and anti-ds-DNA antibody
titers are all too insensitive to reliably measure a patient’s response to
therapy (14). Because this is more than likely due to the lack of suitable
surrogate and biologic markers, there are only 3 medications
(aspirin, hydroxychloroquine, glucocorticoids) that have ever been fully
approved for adult SLE by the U.S. Food and Drug Administration (FDA), while
there are none for cSLE.
Core
Response Variables for cSLE for use in future definitions of clinical
improvement.
While the search for high-quality biomarkers
for cSLE continues, the development of surrogate
markers has to be pursued. In pediatric rheumatology, surrogate markers of
disease are often based on a set of core
response variables (CRVs). A set of CRVs constitutes a group of disease outcomes that capture all
relevant health aspects of a patient with a certain disease. CRVs have been
developed for juvenile arthritis and myositis (15, 16). In an
international group effort, the Pediatric Rheumatology International Trial
Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group
(PRCSG) have developed CRVs for assessing short-term and long-term changes in
children with cSLE(17) (Table 1).
PRINTO
and PRCSG are currently in the process of developing preliminary criteria for disease improvement or response to therapy for
cSLE based on the set of CRVs described above. The results of a 2nd
International Consensus Conference in September 2003 will be published in the
near future.
Disease
Activity Measures.
Measures of absolute disease
activity.
There are more than 50 disease activity
measures for adult SLE (18). Likely, the most commonly used measure of absolute
disease activity is the SLE Disease Activity Index (SLEDAI) (19). This
is a concise measure of disease activity with excellent test-retest reliability
and high responsiveness to clinically important changes (20, 21). Recently, the
SLEDAI 2K has been introduced in order to increase the usefulness of the SLEDAI
when performing serial assessments of disease activity (22). Another frequently
used and widely validated disease activity instrument is the Systemic Lupus
Activity Measure (SLAM)(18).
Different from the SLEDAI, the SLAM includes not only objective signs
and laboratory parameters but also subjective signs of disease. Thus, the SLAM
is thought to be preferable to the SLEDAI in capturing patient-relevant disease
changes (20). The European Consensus
Lupus Activity Measurement (ECLAM) (23, 24) is a measure of absolute
disease activity for adult SLE that resembles the SLEDAI, but uses a
differential scoring system. The British Isles Lupus Activity Group Index
(BILAG) (25) is yet another disease activity measure that has been
widely validated. This measure is quite comprehensive. Although numeric scores
were not intended by the authors initially, several conversion methods are now
available to transform the alphabetic BILAG score into a numeric disease
activity score (26).
The SLEDAI, SLAM, BILAG and
ECLAM have all been validated for use in cSLE(24, 26, 27). No single
best disease activity measure for cSLE has been identified. In a clinical
setting, the use of the SLEDAI may be preferable because it is concise and easy
to complete. For research purposes, the choice of the disease activity measure
will largely depend on the research question posed.
The American College of
Rheumatology (ACR) organized a consensus building process to determine relevant
changes of the scores of disease activity measures for adult SLE (Table 2)(28).
These criteria have not been
officially adopted by the ACR.
Measures of change in disease activity: flare and response to therapy.
There are several measures that aid the interpretation of changes in disease activity. Generally, these measures of change
in disease activity are less well validated than the SLE measures of absolute
disease activity. The Selena Flare Tool was developed for the SELENA
study (29) to measure flares (Table 3).
A minor flare is present if at least one of the 5 minor/moderate symptoms is
present while a major flare is defined by the presence of at least 1 of the 6
major symptoms in the patient. The SELENA Flare-tool categorizes all patients
without flares as being ‘unchanged or better’.
Similarly, the Response Index
for Lupus Erythematosus (RIFLE) has been developed to capture changes of
disease activity (30, 31). The RIFLE is
a 60–item measure where items are rated on a 5-point Likert scale (not present,
present and unchanged, present and worse, partial response, resolution). This
measure has not been used in children with cSLE.
Especially for observational studies, disease flares have been defined
as the need for significant increases of the doses of corticosteroids and/ or
the need for additional or more intensive immunosuppressive medications (26,
32).
Complete Response to Therapy and
Remission. The OMERACT group and others have proposed various
definitions to describe patients with
quiescent disease. Often complete clinical response or remission is defined as
the absence of signs or symptoms of active disease (SLEDAI score =’0’)(33) for
at least 3 months(34). It is unclear whether patients of with complete clinical
response or in remission can be treated with drugs including immunosuppressives,
or whether they should be off all medications.
Assessments for renal disease of adult SLE. Definitions
of renal flare have been proposed for SLE trials by the OMERACT group
and others. The most commonly used definition has been proposed by Moroni et
al.(35) (Table 4).
Similarly, renal improvement
is often defined as, 1) the stabilization of renal function; 2)
absence of casts; 3) decrease of hematuria by > 50% (max < 10 RBC/
hpf);and, 4) a decrease of proteinuria
by > 50% with a maximum absolute daily proteinuria of 3 gram or 1
gram in patients who presented with or without nephrotic syndrome, respectively
(36).
There are several published definitions of renal remission. Often renal remission is defined as: 1) the stabilization
or improvement in renal function; 2) the resolution of urine sediment
abnormalities; 3) the absence of red blood cells and casts in the urinary
sediment, and, 4) proteinuria < 1 gram/ day for at least 6 months, but
preferably up to 3 years (36). Clarification
is still required as to whether patients in renal remission can be maintained
on immunosuppressives, ACE inhibitors or related drugs. Another issue to be clarified is whether
concomitant complement levels should be within normal limits.
Health-related
Quality of Life.
The Medical Outcomes Survey Short-form 36
(SF36)(37) or the SF20 are often used for adults with SLE(38). These
questionnaires can be used for patients ages 16 years and older. HRQOL of
children younger than 16 years of age has been measured by the PedsQL Inventory
(39, 40) and the Child Health Questionnaire (17, 41, 42). It remains to be
determined whether these tools adequately capture all of the relevant health
domains of children with cSLE.
Disease
Damage.
The Systemic Lupus Erythematosus SLE International Collaborating Clinics/ American College of Rheumatology Damage Index
(SDI) is currently the only available measure of disease damage for both adults
and children with SLE (43, 44). The SDI includes disease-specific and
non-disease-specific damage occurring after the diagnosis with SLE. To be
considered in the SDI, an SDI item has to be present for at least 6 continuous
months since the diagnosis with SLE or cSLE. Damage scored by the SDI is
grouped into 12 different domains (ocular, neuropsychiatric, renal, pulmonary,
cardiovascular, peripheral vascular, gastrointestinal, musculoskeletal, skin,
premature gonadal failure, diabetes mellitus, and malignancy). SDI scores
correlate survival with disease activity over time (31, 45, 46). However,
the use of SDI domain scores, rather than the overall SDI summary score, may be
preferable in statistical analyses (47).
Summary.
Important advantages have been made to
measure the level of health and the degree of disease activity and damage of
children with cSLE. The development of the cSLE CRVs constitutes an important
step towards the standardized assessment and reporting of cSLE. Nonetheless,
many of the surrogate markers developed for adult SLE have yet to be assessed
in cSLE. Additionally, there exists a
lack of high-quality measures to evaluate neuropsychiatric involvement with
cSLE in clinical practice and research. There is, however, ongoing intensive
research in sensitive, specific and responsive SLE biomarkers. In the future,
such superior disease markers may make the use of surrogate markers including
global assessment, neuropsychiatric testing batteries, and disease indices
unnecessary. Nevertheless, in the interim,
standardized surrogate markers that capture clinically relevant changes in the
patient are essential for improving the medical care of children with cSLE.
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APPENDIX.
App 1. SLEDAI
App 2. SLAM
App 3. ECLAM
App 4. BILAG
App 5. SELENA Flare Tool
App 6. RIFLE
App 7. SDI
App. 1: SYSTEMIC LUPUS
ERYTHEMATOSUS DISEASE ACTIVITY INDEX
ITEMS PRESENT DURING THE
PRECEEDING 10 DAYS TO THE VISIT
ARE:
Weight SLEDAI Descriptor Definition
Score
8
______ Seizures Recent onset, exclude
metabolic, infectious, or other drug causes.
8 ______ Psychosis Altered ability to function
in normal activity due to severe disturbance in
the
associations, impoverished thought content, marked illogical thinking,
bizarre,
disorganized, or catatonic behavior. Exclude uremia, and drug causes.
8 ______ Organic Brain Syndrome Altered mental function with
impaired orientation, memory, or other intellectual function, with
rapid
onset and fluctuation clinical features. Include clouding of consciousness with reduced
capacity
to focus, and inability to sustain attention
to environment, plus at least 2 of the following:
perceptual
disturbance, incoherent speech, insomnia or daytime drowsiness, or increased or
decreased
psychomotor activity. Exclude metabolic, infectious, or drug causes.
8
______ Visual disturbances Retinal changes of SLE. Include Cytoid bodies, retinal
hemorrhages, serous
exudates
or hemorrhages in the choroid, or optic neuritis. Exclude hypertension,
infection,
or drug causes.
8
______ Cranial nerve disorder New onset of sensory or motor neuropathy involving
cranial nerves.
8 ______ Lupus headaches Severe,
persistent headaches; may be migrainous, but must be non-responsive to narcotics.
8 ______ CVA New onset of cerebrovascular
accident(s). Exclude arteriosclerosis.
8 ______ Vasculitis Ulceration, gangrene, tender finger
nodules, periungual infarction, splinter
hemorrhages,
or biopsy or angiogram proof of vasculitis.
4 ______ Arthritis >2 joints with pain and signs
of inflammation (i.e. tenderness, swelling, or
effusion).
4 ______ Myositis Proximal muscle aching/ weakness,
associated with elevated creatine, phospho kinase/aldolase
or
electromyogram changes or a biopsy showing myositis.
4 ______ Urinary casts Heme-granular casts or red cell casts.
4 ______ Hematuria > 5 red blood cells/ high power
field. Exclude stone, infection, or other cause.
4 ______ Proteinuria > 0.5 gram/24 hours (children: >
30mg/kg/24 hours). New onset or recent increase
by
> 0.5 gram/24 hours.
4 ______ Pyuria > 5 white blood cells/ high
power field. Exclude infection.
2 ______ New rash New onset or recurrence of
inflammatory type rash.
2 ______ Alopecia New onset or recurrence of
abnormal, patchy, or diffuse loss of hair.
2 ______ Mucosal ulcers New onset or recurrence of oral or nasal
ulcerations.
2 ______ Pleurisy Pleuritic chest pain with pleural rub or effusion, or pleural
thickening.
2 ______ Pericarditis Pericardial pain with at least 1 of the
following: rub, effusion, EKG or ECHO.
2 ______ Low complement Decrease in CH50, C3, C4, below the lower limit of normal for
testing laboratory.
2 ______ Increased DNA
binding > 25% binding by Farr assay or above normal range for testing
laboratory.
1 ______ Fever > 38°C.
Exclude infectious cause.
1 ______ Thrombocytopenia < 100.000 platelets/ mm3.
1 ______ Leukopenia < 3000 white blood cells/ mm3
APP 4: BILAG
ASSESSMENT FORM (version 3)
(All events refer to the
previous month unless noted otherwise.)
Patient:
Maximum dose in last month or
since last visit
GENERAL
Answer: 1) Improving
2) Same 3) Worse 4) New
|
1.
Pyrexia (documented)
2.
Weight loss –
unintentional > 5%
3.
Lymphadenopathy/splenomegaly
4.
Fatigue/malaise/lethargy
5.
Anorexia/nausea/vomiting
|
( )
( )
( )
( )
( )
|
MUCOCUTANEOUS
Answer: 1) Improving
2) Same 3) Worse 4) New
|
6.
Maculopapular rash
– severe, active (discoid/bullous)
7.
Maculopapular
eruption – mild
8.
Active discoid
lesions – generalized, extensive
9.
Active discoid
lesions – local, inc. lupus profundus
10.
Alopecia –
severe, active
11.
Alopecia – mild
12.
Severe
panniculitis
13.
Angioedema
14.
Extensive mucosal
ulceration
15.
Small mucosal
ulcers
16.
Malar erythema
17.
Subcutaneous
nodules
18.
Perniotic skin
lesions
19.
Periungual
erythema
20.
Swollen fingers
21.
Sclerodactyly
22.
Calcinosis
23.
Telangiectasia
|
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
Y/N
Y/N
Y/N
Y/N
|
NEUROLOGICAL
Answer: 1) Improving
2) Same 3) Worse 4) New
|
24.
Deteriorating
level of consciousness
25.
Acute psychosis
or delirium or confusional state
26.
Seizures
27.
Stroke or
stroke syndrome
28.
Aseptic
meningitis
29.
Mononeuritis multiplex
30.
Ascending or
transverse myelitis
31.
Peripheral or
cranial neuropathy
32.
Disc
swelling/cytoid bodies
33.
Chorea
34.
Cerebellar
ataxia
35.
Headaches –
severe unremitting
36.
Organic
depressive illness
37.
Organic brain
syndrome inc. pseudotumor cerebri
38.
Episodic migrainous
headaches
|
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
( )
|
MUSCULOSKELETAL
Answer: 1) Improving
2) Same 3) Worse 4) New
|
39.
Definite
myositis (Bohan and Peter)
40.
Severe polyarthritis
– with loss of function
41.
Arthritis
42.
Tendonitis
43.
Mild chronic
myositis
44.
Arthralgia
45.
Myalgia
46.
Tendon
contractures and fixed deformity
47.
Aseptic
necrosis
|
( )
( )
( )
( )
( )
( )
( )
( )
( )
|
CARDIOVASCULAR AND RESPIRATORY
Answer: 1) Improving
2) Same 3) Worse 4) New
|
48.
Pleuropericardial
pain
49.
Dyspnea
50.
Cardiac failure
51.
Friction rub
52.
Effusion
(pericardial or pleural)
53.
Mild or
intermittent chest pain
54.
Progressive CXR
changes – lungs
55.
Progressive CSR
changes – heart
56.
ECG evidence of
pericarditis or myocarditis
57.
Cardiac
arrhythmias including tachycardia > 100 in absence of fever
58.
Pulmonary
function fall by > 20%
59.
Cyto-histological
evidence of inflammatory lung disease
|
( )
( )
( )
( )
( )
Y/N
Y/N
Y/N
( )
Y/N
( )
|
VASCULITIS
Answer: 1) Improving
2) Same 3) Worse 4) New
|
60.
Major cutaneous
vasculitis including ulcers
61.
Major abdominal
crisis due to vasculitis
62.
Recurrent
thromboembolism (excluding stroke)
63.
Raynaud’s
64.
Livedo
reticularis
65.
Superficial phlebitis
66.
Minor cutaneous
vasculitis (nailfold, digital, purpura, ulcers)
67.
Thromboembolism
(excluding stroke) 1st
episode
|
( )
( )
( )
( )
( )
( )
( )
( )
( )
|
RENAL
Answer with number (value) or
Y/N
|
68.
Systolic BP
mmHg
69.
Diastolic BP (5th
phase)
70.
Accelerated
hypertension
71.
Dipstick (- =
1, ++ = 2, +++ = 3)
72.
24 h urine
protein (g)
73.
Newly
documented proteinuria of > 1 g/24 h
74.
Nephrotic
syndrome
75.
Creatinine
(plasma/serum)
76.
Creatinine
clearance/GFR (ml/min)
77.
Active urinary
sediment
78.
Histological
evidence of active nephritis (within 3 months)
|
( )
( )
Y/N
( )
( )
( )
( )
Y/N
( )
( )
Y/N
( )
|
HEMATOLOGY
Answer with number (value) or
Y/N
|
79.
Hemoglobin
(g/dl)
80.
Total white
cell count x 109/1
81.
Neutrophils x
109/1
82.
Lymphocytes x
109/1
83.
Platelets x 109/1
84.
Evidence of
active hemolysis
85.
Coombs test
positive
86.
Evidence of
circulating anticoagulant
|
( )
( )
( )
( )
( )
( )
( )
( )
|
SCORE
|
Gen
|
Muc
|
NS
|
Msk
|
Car
|
Vas
|
Ren
|
Hae
|
Scoring system for the BILAG index
(version 3)
It is implicit in this scoring system that all
features scored are thought to be due to active lupus. The questionnaire asks whether features are
improving, the same, worse, or new. If a
new feature has developed in the last month (or since the last assessment if
less than a month ago) it should be scored as new (i.e. 4), even if it has
subsequently improved or resolved. For
the first assessment any response will register the feature as a
criterion. For subsequent assessments,
features will only contribute to the score if they are the same, worse, or
new. These different grades have been
used so that BILAG can be used to identify all patients who have developed a
particular feature for the first time and also to document the response of
particular features to treatment. In the
renal and hematological assessments (which include laboratory tests) they must
confirm that abnormal results are due to active lupus (rather than drug
side-effects for example).
When assessing a patient for the first time there may
be no data to enter for a particular system.
In this circumstance the patient should be assigned to either category D
or E for that particular system. “D”
should be entered if the patient has ever had any involvement of that system
and “E” if there has never been previous involvement. Once a patient has scored an A, B, C, or D in
a particular system they will always score at least a D in the future. The score E implies no involvement of the
system ever.
1. General
non-specific manifestations
1.
Pyrexia
2.
Weight loss –
unintentional > 5% in 1 month
3.
Lymphadenopathy
4.
Fatigue/malaise/weakness
5.
Anorexia/nausea/vomiting
Category A
Pyrexia
plus 2 other
Category B
Pyrexia
or 2 other
Category C
Any
other criterion
Category D
Previous
involvement
Category E
No
involvement
2. Mucocutaneous
Category A
Any
one of:
1.
Severe
maculopapular, discoid, or bullous eruption; i.e. active facial and/or
extensive (> 2/9 body surface), scaring or causing disability.
2.
Angioedema
3.
Extensive mucosal
ulceration
Category B
Any
one of:
1.
Malar erythema
2.
Mild
maculopapular eruption
3.
Panniculitis
4.
Localized active
discoid lesions including lupus profundus
5.
Severe active
alopecia
6.
Subcutaneous
nodules
7.
Pernotic skin
lesions
Category C
Any
one of:
1.
Periungual
erythema
2.
Swollen fingers
3.
Sclerodactyly
4.
Calcinosis
5.
Telangiectasia
6.
Mild alopecia
7.
Small mucosal
ulceration
Category D
Previous
involvement
Category E
No
previous involvement
3. Nervous
system (first assessment)
Category A
Any
one of:
1.
Impaired level of
consciousness
2.
Psychosis or
delirium or confusional state
3.
Grand mal seizure
4.
Stroke or stroke
syndrome
5.
Aseptic
meningitis
6.
Mononeuritis
multiplex
7.
Ascending or
transverse myelitis
8.
Peripheral or
cranial neuropathy
9.
Chorea
10. Cerebellar ataxia
Category B
Any
one of:
1.
Headache (severe
unremitting)
2.
Organic
depressive illness
3.
Chronic brain
syndrome including pseudotumor cerebri
4.
Disc swelling or
cytoid bodies
Category C
Episodic
migrainous headaches
Category D
Previous
involvement
Category E
No
previous involvement
NS disease
(subsequent assessments)
Category A
Any
one of the following scored “worse” or “new”:
1.
Impaired level of
consciousness
2.
Psychosis or
delirium or confusional state
3.
Grand mal seizure
4.
Stroke or stroke
syndrome
5.
Aseptic meningitis
6.
Mononeuritis
multiplex
7.
Ascending or
transverse myelitis
8.
Peripheral or
cranial neuropathy
9.
Chorea
10.
Cerebellar ataxia
Category B
Any
one of the following scored “new” or worse”:
1.
Headache (severe
unremitting)
2.
Organic
depressive illness
3.
Chronic brain syndrome
including pseudotumor cerebri
4.
Disc swelling or
cytoid bodies
Or any one of the following scored “new” or “worse”:
5.
Impaired level of
consciousness
6.
Psychosis,
delirium, or confusional state
7.
Grand mal seizure
Category C
1.
Episodic
migrainous headaches, or “A” 4-10 or “B” 1-4 scored “same” or “improving”
Category D
Previous
involvement
Category E
No
previous involvement
4. Musculoskeletal
Category A
One
or more of: