Modern Rheumatology

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Which is the best SLE activity index for clinical

trials?

Koichiro Ohmura

To cite this article: Koichiro Ohmura (2021) Which is the best SLE activity index for clinical
trials?, Modern Rheumatology, 31:1, 20-28, DOI: 10.1080/14397595.2020.1775928

To link to this article: https://doi.org/10.1080/14397595.2020.1775928

© 2020 Japan College of Rheumatology.

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Published online: 16 Jun 2020.

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MODERN RHEUMATOLOGY
2021, VOL. 31, NO. 1, 20–28
https://doi.org/10.1080/14397595.2020.1775928

REVIEW ARTICLE

Which is the best SLE activity index for clinical trials?

Koichiro Ohmura
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

ABSTRACT ARTICLE HISTORY

Following the advent of molecular targeted drugs, a paradigm shift in treatment similar to that in Received 30 April 2020
rheumatoid arthritis has been expected in the treatment of systemic lupus erythematosus (SLE), but Accepted 19 May 2020
clinical trials for drugs that many specialists believed to be effective have failed repeatedly. The causes
KEYWORDS
are not simple, but include the heterogeneity of SLE, inclusion criteria, lack of appropriate disease
Activity index; BILAG;
activity measures, and relapse criteria. This review outlines the disease activity indices used in SLE, dis- clinical trial; SLEDAI;
cusses their advantages and disadvantages, and describes the ideal activity index. systemic lupus
erythematosus

Introduction 2. All three representative SLEDAIs have the same weighting

There are many disease activity indices of SLE [1,2], but
most are complicated because they were created based on
clinical trials and clinical studies. In daily clinical practice,
activity is evaluated by comprehensively judging symptoms,
organ damage, and activity markers such as complement
and anti-DNA antibodies.
The disease activity indices are separated into global indi-
ces and organ-specific indices. The former representatives
are SLEDAI (SLE disease activity index) [3–5], SLAM
(Systemic Lupus Activity Measure) [6] and ECLAM
(European Consensus Lupus Activity Measurement) [7], and
the latter representatives are BILAG [8–10], CLASI [11],
and renal activity score [12]. BILAG can also be used as a
comprehensive measure. Each has its own strengths and
weaknesses, and knowledge of their characteristics is neces-
sary. In recent clinical trials, evaluation using SLEDAI and
BILAG and their combinations, such as SRI [13] and
BICLA [14], has been mainstream. Recent SLE clinical trials
and measurement outcomes of primary endpoints are sum-
marized in Table 1. None of the current indices can satisfac-
torily discriminate responders and non-responders. In this
review, I focus mainly on global disease activity indices and
discuss which activity index is best for successful SLE clin-
ical trials.
SLEDAI
In addition to the original SLEDAI [3], there are improved ver-
sions such as SLEDAI-2K [4] and SELENA-SLEDAI [5]. At
present, many clinical trials use SLEDAI-2K or SELENA-
SLEDAI. The basis of the original SLEDAI is shown in Table
for items and organ damage, but have different definitions for
each item. Their comparison is shown in Table 3. In each case,
judgment is made based on symptoms and findings over the
last 10 days. The main differences are proteinuria and skin
rash/stomatitis/hair loss. Proteinuria is scored when it is 0.5 g/
day or more in any SLEDAI system, but the original SLEDAI
and SELENA-SLEDAI can score new-onset proteinuria even
when it is less than 0.5 g/day. In addition, skin rash, stomatitis
(mucosal ulcer), and hair loss are supposed to be scored only
when they are new or relapsed in the original SLEDAI, but
they are scored even when they are not new or relapsed in
SLEDAI-2K and SELENA-SLEDAI.
The biggest advantage of SLEDAI is that it is simple to
score, enabling its use in clinical practice. Another advan-
tage of SLEDAI is that it can be used for retrospective stud-
ies. The disadvantage is that only the presence of each item
is scored and the severity of each item cannot be evaluated.
For example, platelet counts of 1000/ul and 90,000/ul are
both 1 point by SLEDAI. Second, neurological and psychi-
atric symptoms are slightly overemphasized, and neuro-
psychiatric (NP)-SLE is scored highly. On the other hand,
symptoms, such as lupus headache, which is often difficult
to differentiate from normal headache, are scored as 8
points. Pyuria and hematuria (4 points each) need to be
evaluated carefully or the activity score will increase, leading
to unstable activity judgment. Arthritis and myositis are 4
points each, whereas thrombocytopenia and serositis are
only 1 and 2 points, respectively, which is not considered
clinically accurate. There is also a problem that even when
severe conditions, such as hemolytic anemia, lupus enteritis,
transverse myelitis, alveolar hemorrhage, and pulmonary

CONTACT Koichiro Ohmura ohmurako@kuhp.kyoto-u.ac.jp Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of
Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
ß 2020 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in
any way.
 MODERN RHEUMATOLOGY 21

Table 1. Recent clinical trials of molecular targeted drugs for SLE (non-organ specific).
Drug Target Outcome for primary endpoint Primary endpoint satisfied? References (author, year) Phase/study name
Rituximab CD20 BILAG Failure Merrill, 2010 [15] II/III/EXPLORER
Abatacept CD80/86 BILAG Failure Merrill, 2010 [16] IIb
Atacicept BAFF/APRIL BILAG Failure Isenberg, 2015 [17] IIb/APRIL-SLE
Belimumab BAFF SELENA-SLEDAI, SFI Failure Wallace, 2009 [18] II
SRI-4 Success Navarra, 2011 [19] III/BLISS-52
SRI-4 Success Furie, 2011 [20] III/BLISS-76
Tabalumab BAFF SRI-5 Failure Isenberg, 2016 [21] III/ILLUMINATE1
SRI-5 Success Merrill, 2016 [22] III/ILLUMINATE2
Epratuzumab CD22 BICLA Failure Wallace, 2014 [14] IIb/EMBLEM
BICLA Failure Clowse, 2016 [23] III/EMBODY1&2
PF-04236921 IL-6 SRI-4 Failure Wallace, 2014 [24] II
Rontalizumab IFN-a BILAG-2004 Failure Kalunian, 2016 [25] II/ROSE
Sifalimumab IFN-a SRI-4 Success Khamashta, 2016 [26] IIb
Anifrolumab type I IFN-R SRI-4 Failure Furie, 2019 [27] III/TULIP 1
BICLA Success Furie, 2020 [28] III/TULIP 2

Table 2. Items and their weight in SLEDAI (original).
Weight Descriptor
8 Seizure
8 Psychosis
8 Organic brain syndrome
8 Visual disturbance
8 Cranial nerve disorder
8 Lupus headache
8 Cerebrovascular accidents
8 Vasculitis
4 Arthritis (>2 joints)
4 Myositis
4 Urinary casts
4 Hematuria (>5 RBC/HPF)
4 Proteinuria
4 Pyuria (>5 WBC/HPF)
2 New rash
2 Alopecia
2 Mucosal ulcers
2 Pleurisy
2 Pericarditis
2 Low complement
2 Increased DNA binding
1 Fever (>38.5 C)
1 Thrombocytopenia (<100,000/ul)
1 Leukopenia (<3000/ul)
Sum of all positive scores is the SLEDAI score.
hypertension are present, they are evaluated as having no
activity because there are no items for them.
Flare using SELENA-SLEDAI is finely defined [5]. Severe
flare is defined as fulfilling either of the following six items.
1. Change in SELENA-SLEDAI score to greater than 12; 2.
Development or deterioration of the following conditions:
CNS, vasculitis, nephritis, myositis, Plt <60,000/ul or hemo-
lytic anemia (Hb < 7 g/dL or decrease in Hb > 3 g/dL),
requiring doubled prednisolone (PSL), PSL increase to
>0.5 mg/kg/day, or hospitalization; 3. Increase in PSL to
>0.5 mg/kg/day; 4. New administration of cyclophospha-
mide, azathioprine, or methotrexate for SLE activity; 5.
Hospitalization for SLE activity; or 6. Increase in physician’s
global assessment (PGA) score to >2.5. The definition of
mild or moderate flare is defined separately [5].
BILAG (British Isles Lupus Assessment Group)
BILAG differs from SLEDAI in that it can evaluate activity for
each organ, whereas SLEDAI expresses overall disease activity
by the total score. The classic BILAG index [8] has been revised
several times, and BILAG-2004, which was also revised in 2009,
is currently used [9,10]. In the revised BILAG-2004, there are a
total of 97 items in 9 domains, i.e. constitutional, mucocutane-
ous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastro-
intestinal, ophthalmic, renal, and hematological domains. For
each of the 97 items, 0 (not present), 1 (improving), 2 (same),
3 (worse), or 4 (new) is scored by evaluating the activity in the
last 4 weeks compared with that in the previous 4 weeks
(Figure 1), and using the evaluation algorithm in each of the 9
domains, A (severe), B (moderate), C (mild), D (no activity),
or E (no history) is determined for each organ (domain). This
determination algorithm is complicated and requires a com-
puter, making it unsuitable for practical clinical use. An algo-
rithm for judging mucocutaneous symptoms as an example is
shown in Table 4. The 5-level evaluation of each item is set
based on whether the physician wants to strengthen treatment
considering the change in symptoms between the last visit and
the current visit. Therefore, the BILAG system does not always
evaluate the lupus activity at the current visit. The differences
between the classic BILAG and BILAG 2004 are summarized
in Table 5. In general, BILAG-2004 reflects disease activity
change more sensitively and reports less false-positive disease
activity than the classic BILAG index. Past clinical trials used
the classic BILAG [16,17] for the endpoint and recent clinical
trials used BILAG-2004 [25], which may have affected the out-
come to some extent.
As the basic concept of using BILAG is to examine the
activity of each organ, the lupus activity of a patient is
described as, for example, having two BILAG As and 3
BILAG Bs (out of 9 domains). However, it is possible to use
BILAG for overall disease activity. The BILAG-2004 index
can be calculated by adding the scores of each domain as
A ¼ 12 points, B ¼ 8 points, C ¼ 1 point, D ¼ 0 points, E ¼ 0
points [29], but such usage is not recommended.
PGA (physician’s global assessment)
Although the PGA is not an activity index per se, it is one
of the disease activity markers comprehensively evaluated by
an attending physician, and it may be the most comprehen-
sive disease activity index in a sense. Indeed, the PGA can
be evaluated by taking fatigue into account, which cannot
be evaluated by SLEDAI or BILAG. A 3-point scale (as
22 K. OHMURA

Table 3. Comparison of the three different SLEDAI.

Descriptor
Seizure
Visual disturbance
Cranial nerve disorder
Cerebrovascular accident
Arthritis
Proteinuria
Rash, alopecia, mucosal ulcers
Pleurisy Pericarditis
SLEDAI
>2 joints
>0.5 g/day. New onset or recent
increase of >0.5 g/day.
Only new onset or recurrence
Subjective AND objective findings
SELENA-SLEDAI SLEDAI-2K
Added the exclusion of seizure due
to irreversible CNS change
Included scleritis or episcleritis
Included vertigo due to lupus
Added the exclusion of
hypertensive causes
>2 joints 2 joints
New onset or recent increase of >0.5 g/day
>0.5 g/day
Included ongoing symptoms Included ongoing symptoms
Subjective OR objective findings Subjective AND objective findings

described in the supplementary appendix of [5]) is currently
used, which was introduced in the flare index of SELENA-
SLEDAI [5] and the PGA is one of the items of many activ-
ity indices such as SRI(19), BICLA(14), and LLDAS [30]. As
the PGA is a visual analogue scale (VAS), it should be con-
tinuous; however, there are calibrations at 0, 1, 2, and 3,
and the distribution of the data is biased around them,
which may be a disadvantage of this scale.
[2] no deterioration of disease activity (no new BILAG-2004
A scores and 1 new B score); [3] no worsening of the total
SLEDAI-2K score from baseline; [4] no significant deterior-
ation (<10% worsening) on 100-mm visual analogue PGA,
and [5] no treatment failure (defined as non-protocol treat-
ment, i.e. new or increased immunosuppressives or antima-
larials; increased parenteral corticosteroids; or premature
discontinuation of study treatment).

SRI (SLE responder index)
SRI is not an indicator of disease activity, but it is currently
one of the most frequently used primary endpoints in clin-
ical trials. For example, achieving SRI4 is defined as
SLEDAI improvement of 4 points or more, PGA not wor-
sening by 0.3 points or more (10% or more), and BILAG
having no new As and not having two or more new Bs.
This index was designed by post-hoc analysis of a failed
belimumab phase II clinical trial [18], and belimumab was
later approved by the FDA after phase III clinical trials
[19,20] due to the development of this index. After the suc-
cess of belimumab clinical trials using SRI, many lupus clin-
ical trials adopted SRI for their primary endpoints
thereafter. It was considered successful until anifrolumab
(anti-type I interferon receptor antibody) failed in one of
the phase III clinical trials using SRI4 (23) as a primary
endpoint even though a phase II clinical trial using SRI4
[31] and another phase III clinical trial using BICLA [28]
were successful. Depending on clinical trials, SRI3, SRI5, or
SRI6 is used in addition to SRI4.
BICLA (BILAG-based composite lupus assessment)
BICLA was first used in the clinical trial of the anti-CD22
antibody epratuzumab [14], but it was unable to demon-
strate effectiveness in the epratuzumab arm. However,
BICLA was suddenly highlighted when one of the phase III
clinical trials of anifrolumab [27] failed using SRI4 as a pri-
mary endpoint, but the following phase III clinical trial of
anifrolumab [28] succeeded using BICLA as a primary end-
point. SRI and BICLA are similar activity indices, but SRI
weighs more on SLEDAI and BICLA weighs more on
BILAG. Requirements for BICLA response were: [1]
BILAG-2004 improvement (all A scores at baseline
improved to B/C/D, and all B scores improved to C or D);
LLDAS (lupus low disease activity state)
LLDAS [30] is not an activity index as is, but it can be used
as one of the endpoints in clinical trials [32,33]. LLDAS is
defined as satisfying all of the following 5 items, which con-
sist of disease activity and immunosuppressive medications:
1. SLEDAI-2K 4, with no activity in major organ systems
(renal, CNS, cardiopulmonary, vasculitis, or fever) and no
hemolytic anemia or gastrointestinal activity; 2. No new fea-
tures of lupus disease activity compared with the previous
assessment; 3. SELENA-SLEDAI PGA 1; 4. Current pred-
nisolone (or equivalent) dose 7.5 mg daily; and 5. Well-tol-
erated standard maintenance doses of immunosuppressive
drugs and approved biological agents, excluding investiga-
tional drugs. LLDAS may be a target for SLE treat-to-target
(T2T) [34], and LLDAS achievement is associated with sig-
nificant protection against flare and damage accrual [35].
Why rituximab failed to demonstrate efficacy?
Many experts believed that rituximab, an anti-CD20 antibody,
would be effective in clinical trials because it was used for
many refractory SLE patients with successful results [36]. The
EXPLORER trial [15] was a double-blind placebo-controlled
trial in patients with moderate to severe SLE, excluding central
nervous system (CNS) disorders and renal disorders.
The EXPLORER trial included patients with a history of
meeting the American College of Rheumatology (ACR)
revised classification criteria, BILAG A  1 organ system or
BILAG B  2 organ systems, stable use of one immunosup-
pressant at entry, and excluded severe CNS or organ-threat-
ening lupus or any other active conditions requiring
significant use of steroids or recent treatment by cyclophos-
phamide or calcineurin inhibitors. The study design was as
follows: Patients were randomized at a 2:1 ratio to receive
i.v. rituximab (two 1,000 mg doses given 14 days apart) or
 MODERN RHEUMATOLOGY 23

BILAG2004 INDEX Centre: Date: Initials/Hosp No:

Only record items due to SLE Disease Activity & assessment refers to manifestations occurring in the last 4
weeks (compared with the previous 4 weeks). ♦♦ TO BE USED WITH THE GLOSSARY ♦♦
Scoring: ND Not Done CARDIORESPIRATORY
1 Improving 44. Myocarditis - mild ( )
2 Same 45. Myocarditis/Endocarditis + Cardiac failure ( )
3 Worse 46. Arrhythmia ( )
4 New 47. New valvular dysfunction ( )
Yes/No OR Value (where indicated) 48. Pleurisy/Pericarditis ( )
‰ indicate if not due to SLE activity 49. Cardiac tamponade ( )
(default is 0 = not present) 50. Pleural effusion with dyspnoea ( )
51. Pulmonary haemorrhage/vasculitis ( )
CONSTITUTIONAL 52. Interstitial alveolitis/pneumonitis ( )
1. Pyrexia - documented > 37.5ºC ( ) 53. Shrinking lung syndrome ( )
2. Weight loss - unintentional > 5% ( ) 54. Aortitis ( )
3. Lymphadenopathy/splenomegaly ( ) 55. Coronary vasculitis ( )
4. Anorexia ( )
GASTROINTESTINAL
MUCOCUTANEOUS 56. Lupus peritonitis ( )
5. Skin eruption - severe ( ) 57. Abdominal serositis or ascites ( )
6. Skin eruption - mild ( ) 58. Lupus enteritis/colitis ( )
7. Angio-oedema - severe ( ) 59. Malabsorption ( )
8. Angio-oedema - mild ( ) 60. Protein losing enteropathy ( )
9. Mucosal ulceration - severe ( ) 61. Intestinal pseudo-obstruction ( )
10. Mucosal ulceration - mild ( ) 62. Lupus hepatitis ( )
11. Panniculitis/Bullous lupus - severe ( ) 63. Acute lupus cholecystitis ( )
12. Panniculitis/Bullous lupus - mild ( ) 64. Acute lupus pancreatitis ( )
13. Major cutaneous vasculitis/thrombosis ( )
14. Digital infarcts or nodular vasculitis ( ) OPHTHALMIC
15. Alopecia - severe ( ) 65. Orbital inflammation/myositis/proptosis ( )
16. Alopecia - mild ( ) 66. Keratitis - severe ( )
17. Peri-ungual erythema/chilblains ( ) 67. Keratitis - mild ( )
18. Splinter haemorrhages ( ) 68. Anterior uveitis ( )
69. Posterior uveitis/retinal vasculitis - severe ( )
NEUROPSYCHIATRIC 70. Posterior uveitis/retinal vasculitis - mild ( )
19. Aseptic meningitis ( ) 71. Episcleritis ( )
20. Cerebral vasculitis ( ) 72. Scleritis - severe ( )
21. Demyelinating syndrome ( ) 73. Scleritis - mild ( )
22. Myelopathy ( ) 74. Retinal/choroidal vaso-occlusive disease ( )
23. Acute confusional state ( ) 75. Isolated cotton-wool spots (cytoid bodies) ( )
24. Psychosis ( ) 76. Optic neuritis ( )
25. Acute inflammatory demyelinating ( ) 77. Anterior ischaemic optic neuropathy ( )
polyradiculoneuropathy
26. Mononeuropathy (single/multiplex) ( ) RENAL
27. Cranial neuropathy ( ) 78. Systolic blood pressure (mm Hg) value ( ) ‰
28. Plexopathy ( ) 79. Diastolic blood pressure (mm Hg) value ( ) ‰
29. Polyneuropathy ( ) 80. Accelerated hypertension Yes/No ( )
30. Seizure disorder ( ) 81. Urine dipstick protein (+=1, ++=2, +++=3) ( ) ‰
31. Status epilepticus ( ) 82. Urine albumin-creatinine ratio mg/mmol ( ) ‰
32. Cerebrovascular disease (not due to vasculitis) ( ) 83. Urine protein-creatinine ratio mg/mmol ( ) ‰
33. Cognitive dysfunction ( ) 84. 24 hour urine protein (g) value ( ) ‰
34. Movement disorder ( ) 85. Nephrotic syndrome Yes/No ( )
35. Autonomic disorder ( ) 86. Creatinine (plasma/serum) μmol/l ( ) ‰
36. Cerebellar ataxia (isolated) ( ) 87. GFR (calculated) ml/min/1.73 m2 ( ) ‰
37. Lupus headache - severe unremitting ( ) 88. Active urinary sediment Yes/No ( )
38. Headache from IC hypertension ( ) 89. Active nephritis Yes/No ( )

MUSCULOSKELETAL HAEMATOLOGICAL
39. Myositis - severe ( ) 90. Haemoglobin (g/dl) value ( ) ‰
40. Myositis - mild ( ) 91. Total white cell count (x 109/l) value ( ) ‰
9
41. Arthritis ( severe) ( ) 92. Neutrophils (x 10 /l) value ( ) ‰
42. Arthritis (moderate)/Tendonitis/Tenosynovitis ( ) 93. Lymphocytes (x 109/l) value ( ) ‰
43. Arthritis (mild)/Arthralgia/Myalgia ( ) 94. Platelets (x 109/l) value ( ) ‰
95. TTP ( )
Weight (kg): Serum urea (mmol/l): 96. Evidence of active haemolysis Yes/No ( )
African ancestry: Yes/No Serum albumin (g/l): 97. Coombs’ test positive (isolated) Yes/No ( )

Figure 1. The BILAG-2004 index score sheet [10].

placebo on days 1, 15, 168, and 182. Immunosuppressants
(azathioprine, mycophenolate mofetil or methotrexate) were
continued as a background treatment. Additional daily oral
prednisone (0.5, 0.75, or 1.0 mg/kg), based on the BILAG
score at entry and the amount of steroids already being
taken at the time of entry, was administered and tapered
beginning on day 16, with the goal of reaching a dosage of
10 mg/day over 10 weeks and 5 mg/day by week 52.
The primary endpoint was the percentage of patients
who achieved and maintained a major clinical response or a
24 K. OHMURA

partial clinical response at week 52 using 8 BILAG index The patient background was not significantly different
organ system scores. Of note, the classic BILAG-index [8] between the rituximab and placebo groups, the disease dur-
was used in this trial, not BILAG-2004. A major clinical ation was approximately 8 years, and 50% of patients had
response was defined as achieving BILAG C scores or better BILAG A, 30% had 3 BILAG Bs, and 20% had only 2
in all organs at week 24 without a severe flare (1 new BILAG Bs. The affected organs were mainly mucocutaneous,
domain with a BILAG A score or 2 new domains with a musculoskeletal, and general domains, and renal and neuro-
BILAG B score) from day 1 to week 24, and maintaining logical domains were negligible. The distribution of assigned
this response without a moderate or severe flare (1 new prednisolone doses was 60%, 30%, and 10% for 0.5, 0.75,
domains with a BILAG A or B score) to week 52. The def- and 1 mg/kg/day, respectively.
inition of partial clinical response was complicated and is The achievement rates of major clinical response and
described in the original paper. partial clinical response were all in the 10% range in both
rituximab and placebo groups, demonstrating no significant
differences between rituximab and placebo in the pri-
Table 4. The algorithm to score the BILAG-2004 index for the mucocutane-
ous domain. mary endpoint.
Category A Assuming that rituximab is an effective treatment for
Any of the following recorded as 2 (same), 3 (worse), or 4 (new): SLE, possible explanations for the failure are as follows:
Skin eruption – severe
Angio-oedema – severe
Mucosal ulceration – severe 1. Flare criteria were overly strict (only one BILAG B dur-
Panniculitis/Bullous lupus – severe ing the last 6 months of the study becomes ‘no
Major cutaneous vasculitis/thrombosis
Category B response’). There were 17 patients (14.2%) who were
Any Category A features recorded as 1 (improving) OR judged as ‘no response’ with only one BILAG B in the
Any of the following recorded as 2 (same), 3 (worse), or 4 (new): rituximab group and there were 4 patients (6.3%) in
Skin eruption – mild
Panniculitis/Bullous lupus – mild the placebo group.
Digital infarcts or nodular vasculitis 2. The activity was not sufficiently controlled by the first
Alopecia – severe
Category C
steroid treatment. Indeed, more than 70% of the
Any Category B features recorded as 1 (improving) OR patients did not reach BILAG C or better at week 24.
Any of the following recorded as > 0: This suggested that BILAG remission was overly strict.
Angio-oedema – mild
Mucosal ulceration – mild 3. Conversely, steroids and immunosuppressants may have
Alopecia – mild been overly effective. The placebo group did not relapse
Periungual erythema/chilblains to the baseline level. If the observation period was lon-
Splinter hemorrhage
Category D ger, the placebo group may have relapsed and a differ-
Previous involvement ence may have been noted. This was supported by the
Category E
No previous involvement
sub-analysis focusing on treatment-resistant blacks and
Hispanics yielding a difference. There was also a

Table 5. The main differing points between the classic BILAG index and BILAG-2004.
1. In general, the vasculitis domain was removed (moved to other domains), and gastrointestinal and ophthalmic domains
were added.
2. When the features that contributed to the A score were improving, they contributed to the C score in the classic BILAG
index, but they contribute to the B score in the BILAG-2004.
Constitutional or General  Fatigue/malaise/weakness were removed in the BILAG-2004
Mucocutaneous  Swollen fingers, sclerodactyly, calcinosis, and telangiectasia were removed
in the BILAG-2004.
Neuropsychiatric  Stroke, organic depressive illness, and episodic migrainous headaches
were removed in the BILAG-2004.
Musculoskeletal  Any myositis was classified as category A in the classic BILAG index, but
only severe myositis was classified as category A and mild myositis was
classified as category B in the BILAG-2004.
Cardiorespiratory  Symptoms, such as pleuropericardial pain, dyspnea, or mild or remittent
chest pain were removed.
 Cardiac failure or symptomatic effusion plus two other criteria, or four of
the criteria were necessary for category A in the classic BILAG index, but
only one criterion was sufficient for category A criteria in the BILAG-2004.
Gastrointestinal  Peritonitis, enteritis, protein losing enteropathy, intestinal pseudo-
obstruction, hepatitis, acute cholecystitis, and acute pancreatitis were
newly included in the BILAG-2004.
Ophthalmic  Orbital inflammation, keratitis, uveitis, episcleritis, and scleritis were newly
included in the BILAG-2004.
Renal  No major change
Hematological  Circulating anticoagulant was removed and TTP was added in the
BILAG-2004.
 Criteria in category B were changed as follows: White cell count <2500
¼ > 1000-1900, hemoglobin <11 ¼ > 8-8.9, and platelet count <150
¼ > 25-49.

Table 6. Comparison of the characteristics of each outcome measure.
Comprehensive Organ severity
Outcome measure organ evaluation assessment
SLEDAI 䉭 
BILAG  䉭
SRI  䉭
BICLA  
PGA  䉭
LLDAS  
SLE-DAS  䉭
LuMOS 䉭 䉭
n.a.: not applicable.
difference in the sub-analysis of patients who were tak-
ing MTX, but not in those who were taking MMF.
4. The classic BILAG index may be insufficient to discrim-
inate responders vs non-responders. As shown in Table
5, BILAG-2004 can better discriminate the disease activ-
ity by increasing the chance of medium response to cat-
egory A to B rather than A to C compared with the
classic BILAG index.
Next are some specific examples of disease activity of
BILAG B in the BILAG-2004. First, the definition of BILAG
B of the mucocutaneous domain is shown in Table 3. For
example, if face erythema remained, it became Category B
and the major response was unable to be achieved, whereas
if face erythema disappeared and re-appeared, it changed
from Category C to B and was judged as relapse. In the
musculoskeletal domain, if arthritis/tenosynovitis was
observed in one or more joints and restricted range of
motion was present and lasted for several days (more than 4
weeks), it became Category B. These examples demonstrate
how easily category B can be satisfied by chance.
Why belimumab was demonstrated as effective?
After the EXPLORER trial of rituximab, a clinical trial of
belimumab, a biologic targeting the same B cells, was con-
ducted and the drug was finally approved by the FDA.
What was different from the EXPLORER trial is discussed
below. Belimumab failed to meet the primary endpoint in
the phase II trial [18]; however, post hoc analysis revealed it
to be significantly more effective in serologically active
patients (71% of the total) in the belimumab group. In add-
ition, a new treatment response index SRI was devised, and
post-analysis of the phase II trial using SRI4 at 52 weeks as
an endpoint yielded good results. Therefore, phase III trials
(BLISS-52 (19) and BLISS-76 (22)) included patients who
were positive for ANA or anti-DNA antibody at the time of
screening, and adopted SRI4 at 52 weeks as a primary end-
point. The study was successful and the many of the follow-
ing clinical trials used SRI as a primary endpoint. Thus,
strict entry criteria and appropriate outcome measurement
are essential for the success of clinical trials. SRI was consid-
ered to be the best activity index of clinical trials until the
failure of anifrolumab in a phase III clinical trial [27].
However, this is understandable after examining the BLISS-
MODERN RHEUMATOLOGY 25
Quantitative Immunological Incorporation of
measure variables treatment measure
  
 
n.a.  
n.a. 䉭 
 䉭 䉭
n.a. 䉭 
 䉭 

76 trial in detail. In the BLISS-76 trial, there was no signifi-
cant difference in efficacy (satisfying SRI4) at week 76,
although it was satisfied at week 52 and the primary end-
point was met. Therefore, the trial was barely successful. Of
note, in the BLISS-76 trial, the mean percent change from
baseline in the SELENA-SLEDAI score was significantly dif-
ferent and the differences were larger according to the treat-
ment period. Such outcomes using % change may be better
endpoints than SRI.
Best SLE activity index for clinical trials?
Now, the readers can understand how difficult it is to dem-
onstrate efficacy in a clinical trial for SLE patients. There
are several important points to consider in SLE trial proto-
cols. Of importance are the inclusion criteria, background
steroid and immunosuppressant treatment, and evalu-
ation criteria.
First, it should be discussed whether the inclusion criteria
should be the entire SLE or a part of SLE such as lupus
nephritis. Narrowing down to antinuclear antibody-positive
cases or anti-DNA antibody-positive cases at screening has
been adopted in many recent trials.
Background steroid and immunosuppressive treatments
are important. It is not ethically permissible to insufficiently
treat active SLE that may cause organ damage; therefore,
many trials use a sufficient amount of steroids (± immuno-
suppressive drugs) as remission induction therapy and
evaluate relapse rates. Setting an appropriate treatment
protocol to reach an appropriate remission and relapse rate
is difficult. Targeting relatively mild SLE or SLE in remis-
sion with stable doses of PSL (as in the MIRRA trial [37] in
eosinophilic granulomatosis with polyangiitis) may be one
method to demonstrate efficacy.
The most important thing for successful clinical trials is
the endpoint. Next, a comprehensive disease activity index
is discussed. Recently, SRI has been used most frequently
due to the success of belimumab clinical trials. However, as
SRI is mainly based on SLEDAI, it easily reveals the weak-
nesses of SLEDAI. The biggest weak point of SLEDAI is
that there is only binary evaluation of each symptom or
item, and it cannot evaluate improvement. As described
above, the rate of SRI4 responders between the belimumab
group and placebo group was not significantly different at
week 76 of the BLISS76 trial, but the SELENA-SLEDAI
26 K. OHMURA
mean % change from baseline was significant at most
points. Therefore, continuous evaluation may be better than
binary evaluation. SRI4 is required to improve SLEDAI by 4
points or more, making it unsuitable for such patients with
cytopenia, which gives only low points, whereas patients
with a high SLEDAI can easily improve SLEDAI by
4 points.
On the other hand, BILAG classifies the severity of each
organ system as A (severe), B (moderate), C (mild), or D
(inactive) semi-quantitatively. The BILAG system is compre-
hensive but complicated, and simple is sometimes better
than perfect. The weakness of BILAG is that does not con-
tain serological evaluation.
SLAM [6] and ECLAM [7] are indices created to score
the severity of each organ disorder. The concept is good,
and the symptoms and items are more comprehensive than
SLEDAI, but the weighting may not be appropriate (e.g. 0.5
points for renal injury in ECLAM, equivalent to fatigue),
and some items may not be an SLE activity such as general
malaise, blood pressure, abdominal pain, and Raynaud’s
phenomenon (SLAM). There are many points to be
improved in SLAM and ECLAM.
Considering the overall disease activity, it is not always
more severe for many organs to be involved, and a single
severe organ disorder is often more severe than many minor
organ disorders. Physicians usually decide treatment
strength depending on the most severely affected organ (s).
As such, addition does not always represent the disease
activity well. Evaluating only the most severely affected
organs may be a better activity assessment than summing all
categories. Moreover, as the activity index differs for each
patient (i.e. some patients have no increase in anti-DNA
antibody), the activity index of the patient should be appro-
priately reflected. It may be better to evaluate the degree of
improvement by continuous values, such as 50% improve-
ment, rather than numerical values, such as SLEDAI 4-point
improvement, especially for patients with low disease activ-
ity. If disease activity was evaluated using the most severely
affected organ (± serological index), disease activity may be
evaluable like DAS [38] for rheumatoid arthritis, and disease
activity can be categorized as high, medium, or low and can
be simplified.
Many studies have tried to find the best activity measure-
ment for SLE clinical trials. Abrahamowicz et al. used the
raw data of the belimumab BLISS-76 trial, and found the
best combination of measurement outcomes and coefficients
to discriminate the outcome of the 10-mg/kg belimumab
arm from the placebo arm and validated it using the BLISS-
52 trial (LuMOS formula). The LuMOS model incorporated
the following response criteria: a  4-point reduction on the
SELENA-SLEDAI (yes/no), increase in complement C4 level
(mg/dL), a decrease in anti-double-strand DNA titers (IU/
dL), and changes in BILAG scores for organ system mani-
festations (no deterioration of renal components and
improvement in mucocutaneous components) (yes/no). The
LuMOS score discriminated placebo vs belimumab groups
better than SRI4.
As a continuous activity measure, SLE-DAS was recently
published [39]. SLE-DAS is calculated using 21 clinical and
laboratory items, most of which are evaluated by presence,
but some are continuous measures (swollen joint count,
proteinuria, platelet count, and leukocyte count). SLE-DAS
discriminated clinically meaningful (PGA  0.3) deterior-
ation or improvement better than SLEDAI-2K, but the com-
plement and anti-DNA antibody titers were treated as
binary measures.
Lastly, the definition of flare is important. The flare index
of SELENA-SLEDAI [5] has been well demonstrated to
judge mild/moderate flare or severe flare, but some revisions
are desired in order to not misjudge the transient worsening
of symptoms or lab tests, i.e. rash by UV exposure, protein-
uria by exercise, and/or excess protein-rich food. By chang-
ing the definition of flare to ‘increasing steroid or adding
immunosuppressants is necessary’, such misjudgment may
be avoided. Another flare index often used is BILAG. In the
EXPLORER trial of rituximab, a single BILAG B score after
achieving a BILAG C score or better in all organ systems
was judged as flare, which was slightly strict. Therefore, the
clinical trials thereafter adopted a single new BILAG B score
as acceptable for no flare (as in SRI).
Table 6 summarized the characteristics of each outcome
measure. Those who use these indices should understand
the advantages and disadvantages of each index and apply
to clinical trials.
Conclusion
Clinical trials of SLE and facing difficulties in judging a
treatment as effective by one gold-standard outcome index
taught us many new things. SRI is not the best, BICLA is a
good candidate at present, and LLDAS may be a good prac-
tical goal but it needs to be tested in clinical trials. All meas-
urements used SLEDAI and/or BILAG, but SLEDAI is
overly simple and BILAG is overly complicated. As indices
using continuous values are expected, a novel SLE activity
index should be created.
Conflict of interest
KO has received research grants and/or speaker’s fee from
Abbvie, Actelion, Asahikasei Pharma, Astellas, AYUMI,
Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli
Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku,
Nippon Shinyaku, Novartis, Sanofi and Takeda.
ORCID
Koichiro Ohmura http://orcid.org/0000-0003-2927-9159
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