Modern Rheumatology

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Biologics in refractory idiopathic inflammatory

myositis (IIM): What experience in juvenile vs
adult myositis tells us about the use of biologics in
pediatric IIM

Anjali Patwardhan & Charles H. Spencer

To cite this article: Anjali Patwardhan & Charles H. Spencer (2021): Biologics in refractory
idiopathic inflammatory myositis (IIM): What experience in juvenile vs adult myositis tells us about
the use of biologics in pediatric IIM, Modern Rheumatology, DOI: 10.1080/14397595.2021.1881027

To link to this article: https://doi.org/10.1080/14397595.2021.1881027

Published online: 06 Apr 2021.

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MODERN RHEUMATOLOGY
https://doi.org/10.1080/14397595.2021.1881027

REVIEW ARTICLE

Biologics in refractory idiopathic inflammatory myositis (IIM): What experience

in juvenile vs adult myositis tells us about the use of biologics in pediatric IIM
Anjali Patwardhana and Charles H. Spencerb
a
School of Medicine, University of Missouri, Columbia, MO, USA; bUniversity of Mississippi Medical Center, Batson Children’s Hospital,
Jackson, MS, USA

ABSTRACT ARTICLE HISTORY

Juvenile dermatomyositis (JDM) is an extremely heterogeneous orphan disease with limited amount of Received 13 November 2020
dedicated research on the subject matter. Recent research suggests that JDM may not just be the clas- Accepted 21 January 2021
sic antibody driven complements mediated microangiopathy as was thought to be in the past. The
etiopathogenesis of JDM also involves inappropriate stimulation of innate immune system followed by KEYWORDS
Anti-TNF agents;
dysregulation of the adaptive immune response through dendritic cells. Many variable immune factors polymyositis; idiopathic
such as genetics, major histocompatibility complex expressions, immunohistochemical variabilities, and inflammatory myopathy;
diversity in specific and associated autoantibodies may make individual IIM and JDM cases unique. juvenile dermatomyo-
The diversity in IIM and JDM also explains individual variability in response to specific therapies. sitis; rituximab
Classifying and matching the right patients to the right treatment is crucial to the successful treatment
of these patients with better outcomes. Sub-type specific biologic therapy may be the best current
treatment that can match the patient to the best treatment options. A PubMed search was performed
to find all the available cases of refractory myositis patients treated with biologics up to July 2020.
Using this search this article reviews all the current biologic treatment options and experiences for
both adults and children in the context of recent basic science to assist pediatric rheumatologists in
choosing the optimal biologic therapy for a child with recalcitrant JDM.

Background been recognized that inappropriate stimulation of the innate

IIM, including JDM, is an extremely heterogeneous group
of muscle disorders with differences in cytokine expression
profiles, genetics, diseases course, response to treatment,
and prognosis. Apart from heterogeneity in the IIM
patients, the diagnostic criteria and criteria for improve-
ment, relapse, and remission selected by different research
groups in North America and Europe have differences and
thereby make the research results harder to compare. There
is limited dedicated research on biologics in adult and espe-
cially pediatric myositis. On most occasions, information
acquired from adult research experience or mixed popula-
tion (adult and pediatric population) is used to treat pediat-
ric myositis populations.
Historically, IIM was recognized as antibody driven-com-
plements mediated microangiopathy that involved skin,
internal organs, and muscles. It was believed that B cells
play a crucial role. Pieces of evidence supported the auto-
immune etiology of IIM, suggesting the role of B cells.
Evidence was found of immune-mediated muscle damage,
presence of myositis-specific and associated autoantibodies
(MAS, MSA), infiltration of muscles with immune cells in
myofibrils, and the overexpression of major histocompatibil-
ity complex (MHC, class I and II) on these myofibrils and
other muscle components [1]. However, since 2005 it has
immune system (interferons and interferon-regulated pro-
teins) followed by dysregulation of the adaptive immune
response through dendritic cells is also crucial to IIM etio-
pathology, especially in DM and JDM [2,3].
There is growing research and published information on
serological and genetic biomarkers to classify IIM into dif-
ferent subgroups better. The specific autoantibodies directed
against some intracellular organelles are becoming an excel-
lent tool for confirming the diagnosis of different IIM dis-
eases and also in identifying the disease subsets, which may
run a similar clinical course. As expected, not all IIM
patients are positive for these autoantibodies, and the role
of these IIM-specific and IIM-associated antibodies
is evolving.
Despite energetic attempts to unravel new treatment
options, the first-line conventional therapy for JDM has not
changed to a great extent over since the 1990s. The initial
treatment still primarily consists of corticosteroids (prednis-
one, intravenous methylprednisolone) as the mainstay of
induction therapy. The disease-modifying anti-rheumatic
drugs (DMARDs) methotrexate (MTX) or azathioprine
(AZA) or mycophenolate (MP) are used with corticosteroids
as the first line steroid-sparing agents with or without IVIg
infusions. Hydroxychloroquine, corticosteroid cream, and
sunblock are adjunctive therapy. The second line of

CONTACT Anjali Patwardhan patwardhana@health.missouri.edu School of Medicine, University of Missouri, 400 Keene Street, Suite 102 H. South Pavilion,
Columbia, MO, 65201, USA
ß 2021 Japan College of Rheumatology
2 A. PATWARDHAN AND C. H. SPENCER
treatment often consists of mycophenolate mofetil (MMF),
cyclosporine (CSA) or tacrolimus as well as MTX or AZA if
not used earlier. The tacrolimus and cyclosporine are con-
sidered better choices if the patient has interstitial lung dis-
ease (ILD). Finally, as third-line agents, intravenous
cyclophosphamide and/or plasma exchange might be
reserved for the critically ill patient [4–7].
Based on the response to the conventional therapy or
frequent relapses on the conventional treatment, diseases
course is called recalcitrant [8]. We will often use the terms,
recalcitrant/resistant-to-treat/refractory based on the individ-
ual study though we prefer recalcitrant. The refractory IIM
is defined by “The Rituximab for the Treatment of
Refractory Adult and Juvenile Dermatomyositis (DM) and
Adult Polymyositis (PM) trial” (ClinicalTrials.gov Identifier:
NCT00106184) as ‘Refractory myositis, defined by intoler-
ance to or inadequate response to corticosteroids plus an
adequate regime of at least one other immunosuppressive
agent. Intolerance is defined as side effects that require dis-
continuation of the medication or an underlying condition
that precludes further use of the medication’ [9]. This
review provides an appraisal of experiences and the treat-
ment options in the context of specific patient types as well
as evolving basic and clinical science to help pediatric
rheumatology clinicians choose biologics in recalcitrant
JDM patients.
Methods
The literature research was conducted on PubMed
(MEDLINE) data source up to July 2020 to look at specific
research question using (PICO) model i.e. people/popula-
tion/problem, intervention, comparisons/placebo, outcomes.
We used (P) patients (adults as well as Juvenile) with
Idiopathic Immune Myositis, (I) Biologic therapies, (C)
compared different studies/experiences, and looked at the
outcomes of individual studies/experiences. A similar search
approach was used to identify reports on individual biologic
use in IIM patients. Only human research was included. In
this review, we are classifying therapies based on their
molecular targets of action. As these diseases are rare, it was
not considered necessary to use other search methods such
as EMBASE, Cochrane Library, or others.
Biologic therapies
B-Cell therapies
Rituximab (RTX, anti-CD20 monoclonal antibody)
The rationale and mechanism for the therapy. B-Cells
appear to play a vital role in the initiation and proliferation
of the B-cell-driven immune reactions and be crucial for the
pathogenesis of IIM, thereby making rituximab a reasonable
therapeutic choice. Rituximab works by depleting CD20 B
cells while sparing memory cells and thus has a latent
period. There are multiple published reports on varied
responses to rituximab therapy in IIM and JDM patients. In
the absence of standardization and control groups, these
published case reports provide limited yet useful informa-
tion about the selection of patients for rituximab, the
response rate, and likely side effects of rituximab therapy in
IIM and JDM [8,10,11].
Experience with rituximab
Currently, rituximab is not yet used as initial therapy but
used in recalcitrant adult and pediatric IIM patients with
reasonable success after corticosteroids, methotrexate and
similar drugs, and IVIg. Before selecting patients for rituxi-
mab therapy, it is optimal to perform due diligence in deter-
mination of the diagnosis and subtyping of the IIM patients
to optimize successful outcomes.
Rituximab is known to have an improvement in muscle
enzymes, muscle strength, and steroid-sparing effect with
good drug tolerability and safety profile in most recalcitrant
adult as well as juvenile IIM patients [8–11]. Though some
patients require repeat treatment cycles [12,13]. The
improvements are mostly reported to continue for a variable
period in different studies ranging from 6 months to 3 years
[14–16]. All the core set measures of myositis responded to
rituximab therapy well. Still, the improvements in muscle
diseases are reported to be greater than the skin diseases in
rituximab-treated patients [8,9,17]. The response in DM
sub-groups of patients appears to be better than JDM and
all other sub-groups of IIMs patients [8,9,17]. Plus, there
appears to be a latent period between the first rituximab
therapy and clinical response, which ranged in different
studies from 2 to 6 months [13,14,18].
Although in the RIM study (RIM: NCT00106184), the
primary and secondary endpoints were not reached, and the
study could not show any significant differences in the
treatment and placebo arm, the overall response in 85% of
patients were considered positive. The failure to reach end-
points in the RIM study was attributed to the study design
in which the rituximab latent period was not taken into
account. However, the researchers could still show that rit-
uximab had a steroid-sparing effect and good tolerability
throughout 44 weeks of the study period as well as improve-
ment in 83% of all randomized patients by 20 weeks [11].
Rituximab did not consistently show improvement in calci-
nosis and lipomatosis in JDM patients [15].
In some un-structured studies, on the re-evaluation of
non-responders to rituximab therapy, new diagnoses (Non-
IIM) were reassigned. These changes in diagnosis re-empha-
size the importance of due diligence in the diagnosis and
subtyping of patients before instituting biologic therapy
[19]. Anecdotal studies in IBM patients have reported a
steroid-sparing effect with improvement in lab abnormalities
after rituximab therapy. These changes included a reduction
in anti-SRP antibodies suggesting the role of B-cell and
anti-SRP in etiology [13,20]. Rapid lab test improvements
but a poor clinical response to rituximab in many patients
with anti-SRP positive myopathy may be due to a lack of
compensatory muscular hypertrophy leading to poor muscle
strength [21].
Table 1. Summary of clinical trials of biologics in immune inflammatory myositis.
Biologic Main mechanism of action
Rituximab Anti-CD20 Myositis is considered an antibody
monoclonal antibody
Belimumab B-cell activating factor The evidence suggests that B- cells
(BAFF) or B-lymphocyte
stimulator (BLyS)
inhibitor human
monoclonal antibody
The rationale of use Clinical trial Status Population Country Sponsor/Collaborator
NCT01862926. A Randomized, Double Rec. Adults with IIM and UK Royal Brampton and Harefield
mediated vasculitis therefore Blind Controlled Trial Comparing connective NHS Foundation Trust
elimination antibody producing Rituximab Against Intravenous tissue diseases
cells should help controlling Cyclophosphamide in Connective Tissue
the disease. Disease Associated Interstitial Lung
Disease. Phase 2 and Phase 3.
Enrollments; 116. Randomized.
Interventional. Treatment. Parallel
Assignment
Quadruple masking. Study Start Date:
November 2014. Completion Date:
November 2019.
NCT00106184. Rituximab Therapy in Com. Adults DM and PM. JDM USA University of Pittsburgh.
Refractory Adult and Juvenile (age ≥5 years)
Idiopathic Inflammatory Myopathy
(IIM). Phase 2. Randomized,
interventional. Parallel Assignment.
Triple masking. Treatment. 200
participants. Study Start Date: March
2006. Study Completion Date:
August 2010.
NCT01632124. Rituximab-induced Com. Adult RA and IIM. CH University Hospital Zurich
pulmonary function changes - an
observational study in patients with
rheumatoid arthritis and inflammatory
myositis. 80 participants. Observational
model. Study start date: January 2012.
Study completion date:
December 2013.
NCT00774462. Rituximab for the Com. Adults with myositis and Paris, France Assistance Publique - Hôpitaux
Treatment of Refractory Inflammatory generalized de Paris and Roche
Myopathies and Refractory Myasthenia myasthenia gravis. Pharma AG
Gravis (FORCE). Phase 2. Enrollment:
200. Interventional. Total 30
participants. Single group assignment.
Open Label. Study Start Date: January
2008. Study Completion Date:
December 2011.
NCT00106184. Rituximab Therapy in Com. Adults and pediatric IIM. Canada, CZ, University of Pittsburgh.
Refractory Adult and Juvenile Sweden, USA Genentech, Inc. Biogen
Idiopathic Inflammatory Myopathy
(IIM). Phase 2.
RIM trial. Study Start Date: March 2006.
Primary Completion Date: February
2010. Randomized.
Interventional for treatment. Parallel
Assignment
Triple masking.
NCT02347891. Belimumab for Maintenance Rec. Adults with DM and PM. USA Northwell Health and
play a significant role in the Therapy in Idiopathic Inflammatory GlaxoSmithKline.
pathogenesis of idiopathic Myositis. Phase 2 and
MODERN RHEUMATOLOGY
inflammatory myositis. High Phase 3. Estimated Enrollment: 60.
levels of the B cell survival Randomized.
(continued)
3

Table 1. Continued.
Biologic Main mechanism of action The rationale of use
cytokine known as B cell
activating factor (BAFF) are
found in the serum and muscle
of the IIM patients therefore
BAFF inhibition is considered as
a therapeutic option for
IIM patients
Alemtuzumab Monoclonal anti- The sensitized, cytotoxic CD8+ T
(Campath) CD52 antibody cells clonally expand in situ and
raid MHC-I-expressing myofibrils
to produce IBM. Alemtuzumab
destroys surface marker CD52
bearing lymphocytes therefore
preventing their clonal
proliferation, activation and
therefore the attack on
muscle fibrils.
TNF Inhibitors
Abatacept Abatacept is a fusion Abatacept is a human soluble
protein that modulates recombinant protein consisting of
CD28-CD80/86 pathway the cytotoxic t cell lymphocyte
mediated T cell co- antigen-4 (CTLA4) fused with Fc
stimulatory signal. region of human IgG1. This is
modified to prevent complement
fixation and therefore antibody-
dependent cytotoxicity. Antigen-
presenting cells (APCs) express
CD80 (B7-1) and CD86 (B7-2)
molecules to which abatacept
binds and leads to inhibition of
signal transduction and T cell
activation when CTLA4 binds with
CD80 or CD86. CTLA4, CD28, CD86,
and CD40 have been found to be
expressed on the inflammatory
cells in the muscle biopsy
specimens and CTLA4 and CD28 on
muscle cells of patients with
myositis and supposed to play the
role in inflammation.
4
Clinical trial Status Population Country Sponsor/Collaborator
Interventional-treatment. Crossover
Assignment
Triple masking.
Study Start Date: January 2015.
Completion Date: December 2019
NCT00079768. Effects of a T cell-depleting Com. IBM United States National Institutes of Health
monoclonal antibody, alemtuzumab, in clinical center,
patients with inclusion body myositis: Bethesda, Maryland
phase 2. A pilot clinicopathological
study. Interventional-treatment.
Enrollment; 20 participants. Study start
A. PATWARDHAN AND C. H. SPENCER
date: march 2004. Actual study
completion date: march 2007
NCT01315938. Abatacept treatment in Study has passed DM, JDM CZ and UK. Karolinska Institute and Institute
polymyositis and dermatomyositis. its completion of Rheumatology, Prague,
Phase 2. Study start date: January date and Czech Republic
2011, enrollment: 20 participants. status has not King’s College Hospital
Estimated study completion date: June been verified NHS Trust
2013. in more than
interventional-treatment. Randomized, 2 years.
single group assignment. Single
masking (outcomes assessor). Delayed-
start trial
NCT03215927. Randomized, controlled Rec. Myositis with interstitial USA Bristol-Myers Squibb and
pilot trial to evaluate the efficacy and lung disease (ILD) University of Pittsburgh
safety of subcutaneous abatacept in
treating interstitial lung disease
associated with the anti-synthetase
syndrome. Phase 2. Study start date:
October 9, 2017. Estimated study
completion date: October 1, 2019.
Enrollment: 20 participants.
Interventional-treatment. Randomized
parallel assignment.1:1 randomization
for abatacept 125 mg vs. Placebo
/weekly SQ injection for 24 weeks.
quadruple masking, only the site
pharmacist is unblinded.
NCT02971683. Randomized, double-blind Rec. active IIM USA Bristol-Myers Squibb
clinical trial to evaluate the efficacy
and safety of abatacept SC with
standard treatment compared to
standard treatment alone in improving
disease activity in adults with active
IIM. Phase 3. Study start date: March
2017. Estimated primary completion
date: June 2020. Enrollment: 150
participants. Randomized.
(continued)
Table 1. Continued.
Biologic Main mechanism of action
Adalimumab Adalimumab a fully human
monoclonal antibody
(Anti-TNF antibody
group of medication)
Etanercept Etanercept a fusion protein
comprising two human p75
TNF-α receptors coupled to
the Fc portion of a
monoclonal human
antibody.
(anti-TNF antibody group
of medication)
The rationale of use
The rationale of use of anti TNF
therapy in resistant to treat IIM
comes from the knowledge that
patients with myositis exhibit
elevated levels of TNF-α both in
the serum as well in the
calcinosis cutis
Clinical trial Status Population Country Sponsor/Collaborator
Interventional-treatment. parallel
assignment. Quadruple masking.
NCT02594735. Abatacept for the treatment Rec. JDM USA George Washington University
of refractory juvenile dermatomyositis.
Phase 4, study start date: November
2015, enrollment: 10 participants.
Estimated study completion date:
December 2017. Interventional-
treatment. Single group assignment.
no masking, open label.
NCT02971683. A ‘Phase 3, Randomized,
Double-Blind Clinical Trial to Evaluate
the Efficacy and Safety of Abatacept SC
With Standard Treatment Compared to
Standard Treatment Alone in Improving
Disease Activity in Adults with Active
Idiopathic Inflammatory Myopathy
(IIM)’. (Study Start Date: 13 March
2017. Estimated Study Completion
Date: 18 June 2021.)
No clinical trials
NCT00282880. NCT00112385. A Pilot Study Com. DM (18–65 years) USA Brigham and Women’s Hospital
of Etanercept in Dermatomyositis. and Amgen
Phase 1. Study Start Date: March 2006.
Enrollment; 16 participants. Actual
Primary Completion Date: June 2010.
Interventional-Treatment. Randomized.
Parallel Assignment. Double masking.
NCT00802815. Double-blind, randomized, Com. IBM USA Washington University School
placebo-controlled trial of etanercept of Medicine and Amgen.
for 12 months in subjects with
inclusion body myositis. Early phase 1.
Interventional-treatment. Study start
date: April 2005. Enrollment: 20
participants. Actual primary completion
date: May 2014.
NCT00035958. Toward improved Term. JDM (age 4 − 16 years) USA Children’s Hospital Medical
understanding of pathogenesis and Center, Cincinnati
treatment of childhood onset Collaborators and
dermatomyositis. Phase 2and National Institute of Arthritis
phase 3study start date: August 2002. and Musculoskeletal and
Enrollment: 75 participants. Actual Skin Diseases (NIAMS)
primary completion date: august 2002.
Interventional-treatment. Randomized.
Parallel assignment. Open label.
Terminated (incorporating the
recommendations of the NIH-formed
MODERN RHEUMATOLOGY
DSMB in the study procedures would
(continued)
5

Table 1. Continued.
Biologic Main mechanism of action The rationale of use
Infliximab Infliximab is a humanized
mouse monoclonal antibody
(Anti-TNF antibody group
of medication)
Interleukin inhibitors
Anakinra Interleukin 1 (IL1) An increased expression of il-1 in
receptor antagonist muscle tissue has been seen in
patients with inflammatory
myopathies. Anakinra might favor
t-cell differentiation into th1 rather
than th17 as indicated by more
interferon gamma (IFNγ) and less
IL-17A secretion
Tocilizumab Anti interlukin-6 antibody IL-6 is involved in the growth and
(anti IL-6Ab) differentiation of inflammatory
cells. Its role in activating B-cell
stimulating factor is recognized.
It is also responsible in growth
and differentiation of ‘T’ cells
therefore playing a crucial role
in adaptive as well in innate
immune responses. T cells, B
cells, monocytes and endothelial
cells all can generate IL-6 which
in turn responsible for release
of inflammatory mediators after
binding to its receptor (IL-6R)
and leading to several
intracellular cytokine networks
6
Clinical trial Status Population Country Sponsor/Collaborator
make the project budget over the limit
for this funding mechanism)
Pilot Study of Etanercept in Patients with Refractory Juvenile Dermatomyositis in USA. (Rouster-Stevens KA. At el.). Not a registered clinical trial.
Interventional-treatment. Enrollment: 9 participants. Open label.
Single center retrospective analysis of 7 patients (Katherine L Green. At el.). USA. Not a registered clinical trial.
NCT00033891. Randomized, double-blind, Com. Adults with DM and PM USA National Institutes of Health
placebo-controlled trial of infliximab in Clinical Center (CC) and
patients with dermatomyositis and National Institute of Arthritis
polymyositis. Phase 2. and Musculoskeletal and
interventional-treatment. randomized. Skin Diseases (NIAMS)
Crossover assignment. Quadruple
masking. Study start date: 10 April
2002.enrollment: 14 participants. actual
A. PATWARDHAN AND C. H. SPENCER
primary completion date: 20 May 2010.
NCT00443222. Phase 2 and Com. adults with DM, PM, IBM Sweden Schering-Plough and
phase 3. An open trial with TNF Karolinska Institute
blockade with infliximab, in patients
with chronic inflammatory myopathies.
First submitted date: 2 March 2007.
Start and completion date not
provided. Interventional-treatment.
non-randomized. Single group
assignment. Open label.
NCT01165008. anakinra in patients with Com. Adult PM, DM and IBM Sweden Karolinska Institute
refractory idiopathic inflammatory
myopathies phase 2-phase 3. Single
group assignment
interventional-treatment. Study start
date: September 2003. Study
completion date: September 2008.
NCT01150526. Phase 1. Enrollment: 41. Com. Adults with PM, DM USA Metabolic Technologies Inc.
Randomized. Interventional. parallel And Iowa State University
assignment. Masking: quadruple
masking. Primary purpose: basic
science. Study start date: October 2010.
Study completion date: July 2012.
NCT02043548. Tocilizumab in the Rec. Adults with DM/PM USA Chester Oddis, University of
treatment of refractory polymyositis Pittsburgh and
and dermatomyositis. Phase 2. Start Genentech, Inc.
date: October 2014. Estimated study
completion date: January, 2019.
Randomized. Interventional-treatment.
parallel assignment. Triple masking.
Recruitment number − 40.
(continued)
 MODERN RHEUMATOLOGY 7

The patients IIM with lower physician’s global assess-

ment of damage and patients treated early (less than 3 years
Sponsor/Collaborator

disease duration) in the disease course are reported to

respond better than others [10,22]. But in the RIM-JDM
patients’ group, this association did not continue beyond 20
weeks post-Rituximab infusion suggesting it may not have
been due to rituximab therapy [22].

The ‘other’ mechanism theory

Country

The response to rituximab therapy in IIM is mostly associ-

ated with adequate B-cell depletion (BCD). Still, relapses are
not necessarily always associated with repopulation/normal-
ization of CD19þ cell count and/or IgG blood levels.
Several researchers have reported unpredictable and variable
correlation between reappearance of CD19þ cells/normal-
Population

ization of IgG and the need for retreatment/relapses, which

may suggest that rituximab may have more than one mech-
anism of actions [16]. The timing of post-rituximab therapy
CD19þ cell repletion and normalization of IgG levels is
considered variable, especially in pediatric patients. The nor-
malization of IgG and B cell numbers at 6 and 12 months
are reported not to be dependent on diseases sub-type or
Status

cycles of RTX therapy received [16,23,24]. Rituximab

induced B cell depletion, and B-cell recovery is not always
associated and proportional to clinical improvement, again
suggesting a possibility of an additional mechanism of
action [17].
The RIM-study results suggested that type-1 IFN-indu-
cible cytokines (IFNCK) and innate cytokine scores at base-
Clinical trial

line can predict the response rate to rituximab therapy in

recalcitrant IIM patients [25].
Most studies including RIM reported good response in
anti-t-RNA synthetase syndrome (ASS) [14,18,23] while
Unger et al. [10] in their series of 19 anti-t-RNA synthetase
syndrome (ASS) patients reported poor response and fre-
quent relapses with rituximab therapy. The autoantibody-
positive patients (MSA/MAA) had better response
correlation between elevated IL-
significantly correlated with the

interferon gene and chemokine

signatures. IL-6 is reported as a
only elevated but the elevation
dermatomyositis (DM) patients,

disease activity. There was also

that both in adult and juvenile

serum levels of IL-6 were not

rate[10,22,25,26].
pathways. There is evidence

inflammation on a mouse
The rationale of use

6 levels and the type I

mediator of muscle

RIM sub-studies
model myositis.

In the RIM sub-study, IFNCK high scores (>30) and posi-

tive autoantibodies were considered the biomarkers for dis-
ease activity [25]. The researchers reported an association
between pretreatment IFN-regulated chemokines levels with
response to rituximab therapy [27]. These biomarkers were
Main mechanism of action

associated with greater clinical responses to rituximab ther-

apy. The clinical response was reported greatest at 16 weeks
of post-rituximab treatment in patients positive for these
biomarkers [25].
Another group of researchers used the RIM study data
retrospectively and reported that at the baseline, the IFNCK
Table 1. Continued.

scores were higher in several MSA positive (anti-synthetase,

TIF1-c, and Mi-2 myositis) patients. They further identified
that after BCD the IFNCK scores improved in anti-synthe-
Biologic

tase, non-myositis associated autoantibodies (MAA), and

Mi-2 positive patients but deteriorated in TIF1-c
8 A. PATWARDHAN AND C. H. SPENCER
autoantibody-positive patients. These results suggested that
anti-synthetase, non-MAA, and Mi-2 autoantibody-positive
patients, as well as those with higher pretreatment IFNCK
scores (>30), may have responded well to rituximab ther-
apy. Researchers reported an association amongst serum lev-
els of autoantibodies, IFNCK scores, correlation with disease
activity, and response to the rituximab treatment. The anti-
SRP antibody levels only correlated with muscle enzyme lev-
els longitudinally and not necessarily with the muscle
strength and clinical response [25].
Summary
Rituximab appears to be a reasonably safe and effective bio-
logic medicine for IIM and JDM. It has shown excellent tol-
erability in single as well as multiple treatment cycles with
only a little additional risk of infections when repeated ther-
apy cycles were needed. It has been reported to induce
medium-term remission in many patients, but long-term
effects on disease outcomes and well as long-term adverse
events are still not known [22–24,26].
Belimumab and similar agents that block B-cell
stimulation
The rationale for therapy and mechanism
The stimulation of B-Cell occurs mostly due to two cytokine
factors: B-cell activating factor (BAFF) and a proliferation-
inducing ligand (APRIL). These two cytokine factors are
also essential for B-cell survival, B-cell proliferation, B-cell
maturation, and B-cell differentiation to plasma cells. The
BAFF is a member of the TNF family and appears to be
crucial for the development of autoimmunity [28–30].
The overexpression of BAFF can lead to prolonged B cell
survival and sometimes B-cell malignancies. BAFF can
increase the expression of a subset of B cells called marginal
zone (MZ) B cells [31]. The MZ cells are known stimulators
for T-cells. An overexpression of MZ cells is seen in several
autoimmune inflammatory conditions.
The BAFF levels are significantly higher in IIMs patients
than normal controls [32,33]. The BAFF serum levels are
reported to be higher in IIM (especially JDM) with positive
autoantibodies but least elevated in anti-SRP positive
patients [32,34]. The Anti-SRP positive patients are reported
to have significantly elevated IL-17 levels when compared to
other IIM subgroups, suggesting a pathogenic role [32].
Elevated BAFF/APRIL serum levels in IIM patients are
also reported to be associated with interstitial lung diseases
(ILD). This appears to be true especially in rapidly progres-
sive interstitial lung disease (RP-ILD) in JDM. JDM patients
with RP-ILD have BAFF/APRIL levels that are significantly
higher than in JDM patients with chronic-ILD. Yet the
BAFF/APRIL serum levels are significantly higher in JDM
patients with chronic-ILD than in normal controls [35].
Interestingly, it is reported that BAFF/APRIL serum levels
in JDM-ILD patients correlated well with blood Krebs von
den Lungen-6 (KL-6) and IL-18 levels, which are the bio-
markers for lung inflammation. The BAFF/APRIL serum
levels also were higher in patients positive for anti-MDA5
autoantibody and their titers were proportionately higher in
patients with high titer anti-MDA5 (>200 U). It is known
that a high anti-MDA5 titer is associated with RP-ILD [35].
The biologics used to block B-cell stimulation through
BAFF/APRIL sites include belimumab as well as tabalumab,
atacicept, and blisibimod [36–39]. Tabalumab is a human
IgG4 monoclonal antibody against both membrane and sol-
uble BAFF. Atacicept is a humanized recombinant fusion
protein that acts as a ‘decoy receptor’ for BAFF/APRIL,
therefore, preventing the attachment of BAFF/APRIL to
their receptors [40].
Experience with belimumab and similar biologics
The only clinical trial currently recruiting to evaluate the
efficacy and safety of belimumab for maintenance therapy
in refractory IIM is in progress. Northwell Health sponsors
it, and GlaxoSmithKline was collaborating. The estimated
study enrollment is 60 subjects. It is a randomized, phase 2
and 3, multicenter (USA) crossover assignment with triple
masking with an estimated completion date was 2020
(NCT02347891).
Summary of B cell stimulators in IIM and JDM
There is not enough current evidence to support the use of
these B-cell stimulation blockers in refractory IIM and espe-
cially JDM, but there may be in the future. More experience
and research with the drug are needed. BAFF/APRIL biolog-
ics are being studied in other autoimmune diseases with
BAFF/APRIL pathways etiologies such as SLE, Sjogren’s,
and multiple arthritis diseases.
Alemtuzumab
The rationale for therapy
Alemtuzumab is a recombinant DNA-derived humanized
monoclonal, IgG1 glycoprotein receptor CD52 antibody that
is specifically targeted against CD52 receptor carrying
immune cells (T-lymphocytes and monocytes).
Alemtuzumab’s immunodepleting action is the rationale
behind its use in IIM and other autoimmune diseases.
Mechanism
Several interesting properties make alemtuzumab different.
This glycoprotein receptor CD52 has a varied and patchy
distribution in the human body. It has a higher distribution
on the B and T lymphocytes, lower on macrophages, and
minimal or none on stem cells, mature NK cells, and neu-
trophils (the innate immune system) [41–43]. A trend of an
increasing number of neutrophils in circulation and lymph-
oid organs is seen with the increase in the alemtuzumab
dose and is believed to be due to demarginalization or
increased recruitment from the bone marrow [41]. In con-
trast, the regulatory phenotypic T cells also show relative
sparing with alemtuzumab therapy [41–44].

Secondly, alemtuzumab’s response is dose-dependent,
and higher doses of the drug are needed to deplete lymph-
oid organs completely. Because of the above two factors,
alemtuzumab therapy is associated with a relatively low
infection rate [41,45–47]. Alemtuzumab infusions are also
associated with non-complement-mediated pulse release of
cytokines (TNF-a, IL-6, and IFN-c) that may lead to severe
infusion reactions, especially with the first infusion [41]. It
can cause side effects in the patient’s even years after it is
stopped. Therefore, more than most biologics, patients
treated with alemtuzumab require ongoing monitoring and
long-term follow-up.
Experience with alemtuzumab
Alemtuzumab has been mostly used in IBM. In a ‘proof-of-
principle study,’ 0.3 mg/kg/day alemtuzumab was used for
four days in 13 sIBM patients (NCT00079768). The primary
endpoint was disease stabilization at a 6-month endpoint
comparative to the natural history of the disease. The study
was powered to capture at least 10% differential gain in
muscle power at six months in therapy. The researchers
reported not only depletion of peripheral blood lympho-
cytes, but endomysial T cells were also depleted after alem-
tuzumab therapy. These changes were believed to be
altering the natural disease course. The total observation
period was 12 months. However, the results showed only a
1.9% overall decline in muscle power, i.e. 13% differential
gain at six months in therapy (p < .002). A 50% mean
reduction in CD3 lymphocytes (p < .008) and reduced stres-
sor molecule mRNA expression was seen in follow-up biop-
sies. The researchers reported a positive outcome of the
treatment suggesting alemtuzumab treatment can slow down
the disease process and change the course of the disease,
reduce muscle inflammation and improve muscle strength
at least for the short term. Long-term outcomes are not
reported (NCT00079768) [43,45]. The mRNA expression
levels of the proinflammatory chemokines did not change
with alemtuzumab treatment [48].
There are a few anecdotal case reports of successful use
of alemtuzumab in adults as well as juvenile recalcitrant PM
patients. Alemtuzumab showed a significant steroid-sparing
effect in these recalcitrant patients. The patients stayed in
moderate to long term remission for few years before one of
them required a successful second therapy cycle of alemtu-
zumab [49–52]. A case of drug-induced IIM was reported in
an adult patient seven months of post-alemtuzumab therapy.
This myositis was later successfully treated with ste-
roids [51,53].
Summary – Alemtuzumab B cell depleting therapy in
IIM and JDM
At this point, alemtuzumab has shown some benefit in IBM.
However, there are not enough prospective research trials or
enough published experience available to recommend its use
of conclusively in any IIM and JDM patients. On the posi-
tive side in the few trials performed, alemtuzumab therapy
MODERN RHEUMATOLOGY 9
has been associated with a short latent period and long
remissions in the treated patients. On the negative side, it
may cause significant infusion reactions and induce other
autoimmune diseases. Despite its use in critically ill patients,
no mortalities have been reported so far. There are two dif-
ferent infectious risks with this drug. Alemtuzumab therapy
carries a relatively lower risk for common infections overall.
Interestingly, the risk of common infection decreases with
subsequent doses of the therapy. It is explained as
‘consistent with preservation of components of protective
immunity’ by Wray S et al. [54]. Though alemtuzumab ther-
apy may be a low risk for common infections, unsurpris-
ingly, it has been explicitly associated with a higher risk of
opportunistic infections and cytomegalovirus reactiva-
tion [55].
Tumor necrosis factor inhibitors
The rationale for therapy
Tumor necrosis factor (TNF), also called cachexin, or
cachectin, is a cytokine mostly produced by activated mac-
rophages but also by several other cells in the process of
systemic inflammation. These include natural killer cells,
CD4þ lymphocytes, mast cells, neutrophils, neurons, and
eosinophils. It is also responsible for producing acute
phase responses.
The rationale of the use of anti-TNF therapy in refractory
IIM patients arises from multiple research studies.
Along with elevated levels of interleukins (IL2, IL1a,
IL1b), TNFb, and interferon (IFN c), myositis patients have
shown elevated titers of TNF-a in their serum as well as in
the calcinosis cutis suggesting a pathogenic role [56–58].
Significantly higher TNF-a levels, soluble TNF-R55 and
TNF-R75 have been demonstrated in serum as well as in
calcium deposits in IIM patients vs. healthy controls [59,60].
The TNFa-308A allele is associated with increased produc-
tion of TNF-a, vascular occlusions, a chronic, polycyclic
JDM disease course, as well as ulcerative skin JDM disease
with calcinosis [61,62].
Mechanisms of action
The TNF-a shows polymorphism at 308 promoter regions
(A-G polymorphism). The osteopontin promoter and TNF-
308A allele polymorphism are found to be associated with
elevated levels of a interferon in the untreated myositis
patients, supporting its etiologic role [63]. TNF-a-308A
allele polymorphism is also associated with a chronic disease
course, increased likelihood of calcinosis cutis, increased
occlusion of capillaries, increased expression of TNF-a in
myofibrils, and increased production of TNF-a by periph-
eral mononuclear cells in JDM patients reinforcing its role
in the etiopathogenesis [56,59]. In an inception cohort of
JDM patients, researchers reported that serum IFN-a was
significantly higher in female JDM patients who carried the
dual (OPN rs28357094G and TNF-a-308 A) alleles than
those who did not, suggesting ‘pathogenic synergy’ and
‘complex gene-gene-sex interaction’ as reported by Niewold
10 A. PATWARDHAN AND C. H. SPENCER
et al. [64]. The OPN rs28357094G gene is identified to be
more prevalent in female JDM patients as well as better
expressed in the female patients [64].
Experience with anti-TNF-a biologics in JDM
The current knowledge is based mostly on open-label stud-
ies and shared experiences from research studies. One
exception is a pilot double-blind placebo-controlled RCT
that concluded that infliximab therapy (5mg/kg) was effect-
ive and safe in a select group of resistant to treatment adult
IIM patients [65,66].
Etanercept and infliximab are the most commonly
researched anti-TNF agents though one study suggested that
etanercept may have no benefit in JDM or even exacerbate
JDM [65,67,68].
Calcinosis is associated with higher initial and prolonged
elevated muscle enzymes (especially CK levels). Efthimiou
et al. [66] reported that the patients who had high initial
serum creatine kinase (CK) levels responded best to anti-
TNF therapy, but others reported the exact opposite [69].
Adalimumab
The rationale for therapy
Adalimumab was the first fully human monoclonal antibody
against TNF-alpha receptor. The name Humira was derived
from ‘human monoclonal antibody in rheumatoid arthritis’.
Adalimumab as a fully humanized IgG1 monoclonal anti-
body to tumor necrosis factor-alpha after multiple studies
and long clinical use is considered easy to give, safe, and as
an effective biologic therapy as any anti-TNF drug. It is not
known to produce the neutralizing autoantibodies or chi-
meric autoantibodies in the recipients; hence it appears to
be better tolerated. Unfortunately, there are no formal RCT
or registered clinical trials on its use in patients with IIM.
Adalimumab historically had an unpredictable effectiveness
and side-effects profile when used in IIM patients, which is
evident from the following examples.
There are several anecdotal reports of patients developing
a myositis reaction after using adalimumab for other unre-
lated rheumatologic diseases within 2 weeks to 3 years of
therapy. Most patients were adults with only a few pediatric
patients who were treated with adalimumab for their pri-
mary diagnosis of [70–72]. The majority of patients who
developed myositis had histologic features of DM, and only
a few had PM features [71]. The myositis in these patients
did not go away after stopping adalimumab and they
needed dedicated therapy for it. Most of the patients who
developed myositis on adalimumab responded to pulse ster-
oid therapy and only a few required additional DMARDs
such as methotrexate and azathioprine. On the other hand,
a flare in myositis is reported in some overlap syndrome
patients after treatment with adalimumab for their arthritis
[73]. Interestingly, anecdotal reports are suggesting success-
ful use of adalimumab in patients who developed orbital
myositis secondary to use of infliximab.
Recently, in a retrospective study in a large cohort of
JDM patients, successful use of adalimumab is
reported [74].
Isolated myositis had been successfully treated with adali-
mumab, such as Crohn’s diseases related to recurrent orbital
myositis, gastrocnemius myositis, and isolated recalcitrant
orbital myositis [75–78].
Adalimumab may have a role as a steroid-sparing treat-
ment for inflammatory-stage thyroid eye disease (TED). The
TED occurs due to the upregulation of proinflammatory
cytokines, mainly tumor necrosis factor-a (TNF-a) [79].
There are also anecdotal reports of efficacy and safety of
adalimumab in the treatment of recalcitrant dermatomyo-
sitis-associated interstitial lung disease [80,81].
Other findings of anti-TNF studies in IIM. Anecdotal expe-
riences, small randomized controlled studies, and open label
studies have shown mixed results ranging from improve-
ments of IIM as well as steroid-sparing effects [82,83] on
the one hand, to worsening of the diseases [84,85], develop-
ing new-onset other autoimmune diseases and malignancy
after the treatment with anti-TNF therapy on the other [63].
Paradoxically, anti-TNF therapy itself can induce auto-
immune myositis in adults as well as juvenile patients. The
patients who have a genetic background and family history
of autoimmunity are more likely to develop autoimmune
myositis after anti-TNF therapy [70,86]. The mechanism of
this paradox is not entirely clear. Still, it is suggested that
after TNF-a blockage, the production of TNY-Y is
increased, which is a known molecule in the etiopathogene-
sis of DM/PM [87]. Anti-TNF therapy has shown promising
results in patients with calcinosis associated myo-
sitis [68,74].
The incidence of developing chronic lung disease, ILD,
and drug-induced secondary PM/DM is increased if the
treated patient is positive for anti-synthetase antibodies plus
has a history of ILD, or RA [63].
Anti-TNF therapy carries a specific benefit and risk in
the treatment of myositis. TNF–a is known to suppress/
downregulate the INF-a system. When anti-TNF treatment
is used, the INF-a system may be upregulated, potentially
leading to flareups of IFN-mediated diseases such as DM,
JDM, or SLE. Fiorentino et al. [88] called this phenomenon
‘the yin and yang of TNF-a inhibition’.
Summary of anti-TNF-a agents in IIM
Infliximab is the most studied anti-TNF agent in IIM
patients and may have a definite benefit in some patients. It
may be the best of the group of anti-TNF biologics for IIM
and JDM in 2020. Other anti-TNF therapy (adalimumab
and etanercept) may be effective for a tiny percentage of
recalcitrant IIM and JDM patients, especially for a short-
term response [74]. Anti-TNF therapy has shown short
term improvement in IIM patients. Repeated cycles of anti-
TNF treatment can lead to the risk of developing anti-chi-
meric antibodies and severe infusion reactions.

The anti-TNF therapy in IIM is ‘Not-For-All’ but is
effective and safe in the very select group of recalcitrant IIM
patients where diligent selection of patients is the key to the
success of the treatment [74]. There are anecdotal reports of
developing myositis after treatment with anti TNF agents
for other rheumatologic conditions such as arthritis and
psoriasis. Some of these patients developed MSA positive
myositis (Anti Jo-1) [89,90].
Biologic therapy with CTLA4 anti-costimulatory
molecules; abatacept
The rationale and mechanism for therapy
Co-stimulatory molecules CD28 and CTLA-4 are known to
be upregulated in the muscle of IIM patients [91,92].
Abatacept (CTLA4-Ig) is a fusion protein engineered to
modulate the CD28-CD80/86 pathway mediated T-cell co-
stimulatory signal. For the activation of the cytotoxic-T cells,
co-stimulation through B7 (CD80/CD86), the binding of the
receptor CD28, is required. The CD28 co-stimulatory mol-
ecule, CTLA-4, CD86, CD40, and receptor CD80, are also
expressed on myofibrils and in inflammatory infiltrates in
JDM as well as in adult (DM, PM) patients identified by
researchers through immunohistochemical staining. This
expression of co-stimulatory molecule CD28 and CTLA-4
appears to be brought about by proinflammatory cyto-
kines [93].
Abatacept is a fusion of immunoglobulin and an extracel-
lular component of cytotoxic T-lymphocyte antigen-4. In
JDM, the plasmacytoid dendritic cells, macrophages, and
CD4þ T and B lymphocytes appear to constitute the main
inflammatory cells scattered in perivascular and perimysium
areas [91]. Macrophages were found sufficiently sensitive to
CTLA4-Ig that on the exposure, they could downregulate
the production of IL1-b, IL-6, TNF-a, and TGF-b at the cel-
lular level through down-regulating the co-stimulatory sig-
nals [92]. By these mechanisms, abatacept is thought to
downregulate the activation of cytotoxic-T cells through co-
stimulatory signals as well as B cell activation [92,94].
There are some anecdotal reports of successful use of
abatacept in recalcitrant IIM patients such as with overlap
features [95], severe calcifications and skin ulcerations
[93,94], anti-signal recognition particle myopathy[96] and
polymyositis [97].
Recently, the interest in abatacept has increased leading
to randomized controlled trials that are underway.
For example:
a. ‘Randomized, Controlled Pilot Trial to Evaluate the
Efficacy and Safety of Subcutaneous Abatacept in
Treating Interstitial Lung Disease Associated with the
Anti-synthetase Syndrome’ is on-going (Study Start
Date: 1 June 2017, Estimated Completion Date: 31
December 2020. NCT03215927);
b. ‘Phase 3, Randomized, Double-Blind Clinical Trial to
Evaluate the Efficacy and Safety of Abatacept SC With
Standard Treatment Compared to Standard Treatment
Alone in Improving Disease Activity in Adults with
MODERN RHEUMATOLOGY 11
Active Idiopathic Inflammatory Myopathy (IIM)’.
(Study Start Date: 13 March 2017. Estimated Study
Completion Date: 18 June 2021. NCT02971683)
c. A phase 4 trial, ‘Abatacept for the Treatment of
Refractory Juvenile Dermatomyositis’. (Study Start
Date: November 2015. Estimated Study Completion
Date: October 2020. NCT02594735)
d. ‘Abatacept in the treatment of adult dermatomyositis
and polymyositis: a randomized, phase IIb treatment
delayed-start trial’ showed significant improvement in
fifty percent of patients with IV Abatacept (10mg/
Kg) [98].
Summary on anti-CTLA4 anti-costimulatory molecule
studies in IIM and JDM
In contrast to some of the anti-TNF biologics, abatacept
appears to be a promising therapy for IIM, including JDM
patients. Several ongoing trials may shed light on abatacept’s
promise. One advantage of using abatacept appears to be its
relatively low renal and hepatic toxicity as compared to
other DMARDs and other biologic therapies.
Further prospective research trials are on the horizon to
evaluate the value of abatacept in IIM.
Interleukin inhibitors in myositis
The rationale for therapy. In IIM patients, an increased
interleukin-1 (IL-1) expression in the muscle fibrils has
been reported suggesting its role in pathogenesis [99].
Anakinra. This biologic is an interleukin 1 (IL1) receptor
antagonist used for rheumatoid arthritis (RA) and systemic
juvenile idiopathic arthritis (sJIA). The experience is limited
and insufficient with IL-1 inhibitors in IIM. Mei Zong et al.
reported in their 12-month prospective use of anakinra on
15 recalcitrant IIM patients. The clinical and molecular
response in muscle biopsy specimens (cellular infiltrates, IL-
1a, IL-1b, IL-1Ra, and major histocompatibility complex-
class I by immunohistochemistry) was assessed in all 15
refractory myositis patients. They were prospectively treated
with Anakinra for 12 months period [100]. The results were
inconclusive. There are few other anecdotal reports of an
inadequate response to anakinra therapy in other recalci-
trant IIM patients [101–103].
Tocilizumab
The rationale for therapy. Tocilizumab is an anti-interleu-
kin-6 antibody (anti-IL-6Ab) used for RA and systemic and
polyarticular JIA. The rationale for the use of interleukin-6
(IL-6) inhibitors in myositis originates from animal studies
and human research that showed the pivotal role of IL-6 in
the pathogenesis of DM, though less so in PM. Several
researchers demonstrated that the serum and the lympho-
cytes infiltrating the muscles in DM had high IL-6 expres-
sion [104–107]. There are a few limited reports available on
the use of tocilizumab in select refractory myositis patients
12 A. PATWARDHAN AND C. H. SPENCER
with anti-synthetase syndrome [108,109], polymyositis [110],
and overlap syndromes [111].
Interestingly, tocilizumab is found to be effective in
Familial Mediterranean Fever (FMF) patients associated
with protracted myalgia, myositis, and fasciitis, and aa amyl-
oidosis despite FMF being a neutrophil-derived autoinflam-
matory disease [112]. Paradoxically, there had been reports
of the development of drug-induced isolated myositis with
the use of tocilizumab also [113].
A multicenter, double-blind placebo-controlled, parallel
assignment, phase two RCT of ‘Tocilizumab in the
Treatment of Refractory Polymyositis and Dermatomyositis
(TIM)’ (NCT02043548) is ongoing and pending results.
Interleukin-17. The role of IL-17A is well recognized in sev-
eral other chronic autoimmune-inflammatory diseases such
as RA. An IIM patient with increased IL-17A producing
cells in the muscle has been reported suggesting a patho-
genic role of IL-17A and the Th17 pathway in IIM
[114,115]. Further research and development are pending to
know the precise value of therapeutic targeting of IL-17A in
IIM patients.
Summary of interleukin therapies in IIM and JDM. Limited
research and experience in interleukin inhibitors prohibit
any recommendations for their routine use in IIM and
JDM. Anti-IL-1 therapy has not been effective in IIM
patients. Theoretically, anti-IL-6 treatment is more likely to
be effective in certain subgroups of DM/PM patients than in
polymyositis patients. The utility of IL-6 inhibitors in DM/
JDM is still being evaluated in RCT’s.
Janus kinase inhibitor: Tofacitinib-(included though not
technically a biologic)
The rationale for therapy. Several cytokines only connect
with Type I and Type II cytokine receptors that employ a
special family of kinases for intracellular signaling and
action, known as janus kinases (JAK). The JAK drugs that
are used to inhibit signaling through JAK receptors are
called janus kinase inhibitors (jakinibs). Cytokines can pro-
duce autoimmune diseases through intracellular signaling
though JAK. There are several types of JAK (JAK1, JAK2,
JAK3 and Tyrosine Kinase 2 or TYK2) and inhibitors (first
generation and second generations).
Tofacitinib is Food and Drug Administration (FDA)
approved for RA (2016), ulcerative colitis (2018) and psori-
atic arthritis (2017). Oral tofacitinib has shown good effi-
cacy, safety and steroid sparing effect in a recalcitrant
classic, and cutaneous dermatomyositis adult patients in the
initial studies [116,117]. In several open label reports on
refractory JDM as well as adult DM patients, tofacitinib
therapy has appeared to lead to improvement in anti–mela-
noma differentiation–associated protein 5 (anti-MDA5)
positive amyopathic dermatomyositis (ADM) associated
interstitial lung disease (ILD) as well as with anti-NXP2 and
anti-TIF1c dermatomyositis-specific autoantibodies positive
patients [118–121]. Interestingly, the muscle expression of
alpha-chemokines (CXCL9, CXCL10) showed reasonable
reduction after 12 weeks of tofacitinib treatment but it did
not reach statistical significance.
There is an open label proof of concept, small (10 sub-
jects) study that is now ongoing titled; Tofacitinib in
Refractory Dermatomyositis (January 2017 – estimated com-
pletion June 2021) (STIR, NCT03002649) [122].
The Jak inhibitors have also been reported to have a
good effect on extensive myositis related calcifications in
JDM [123,124].
Anti-interferon-a monoclonal antibody: Sifalimumab
The rationale for therapy. The type I IFN-alpha is well rec-
ognized in the etiology of immune inflammatory myositis
syndromes. The treatment is still investigational in IIM and
JDM. Sifalimumab is an anti-IFN-a monoclonal antibody.
The treatment with Sifalimumab is recognized to neutralize
and reduce type I IFN gene signature (IFNGS) in the blood
as well as muscles of adult dermatomyositis and polymyosi-
tis patients in several clinical trials (NCT00533091,
NCT00979654; Table 1) [121].
Experiences of pediatric rheumatologists in an
international network
One study has published the recent anecdotal experience of
an international research group of pediatric rheumatologists
in the United States and Canada (Childhood Arthritis and
Rheumatism Research alliance-CARRA) with biologics for
JDM utilizing three surveys from 2011 to 2017. Nominal
group techniques were used for achieving consensus on the
optimal current choices of biologic drugs 2013–2017. The
top four biologics for recalcitrant JDM chosen by these
techniques were in the order of preference rituximab, abata-
cept, tocilizumab, and infliximab [122].
Conclusion
This detailed review of the literature gives a snapshot view
of where we stand today in 2020 in our journey to explore
the best treatment options for patients with difficult to treat
IIM, and for pediatric rheumatologists, JDM.
What does a pediatric rheumatologist do in 2020 in a
recalcitrant JDM patient when conventional corticosteroids,
methotrexate, IVIG, and combinations with other immuno-
suppressive drugs are insufficient, and the patient is doing
poorly? From our literature review, it is clear that the best
alternative biologic therapy remains rituximab that depletes
B cells. Similarly, the B cell-depleting drug alemtuzumab
also may be useful in IIM and JDM but needs more testing.
The other B cell therapies that block B cell stimulation may
be available soon but are further behind in development
and testing (tabalumab, atacicept, blisibimod).
There is enough experience in the literature and anec-
dotally to recommend abatacept as the next biologic alterna-
tive. Rituximab and abatacept have the best literature and
anecdotal support by far. There is modest support for

tocilizumab or infliximab as the next alternatives. There is
insufficient evidence to recommend any of the other com-
mercially available biologics, but no doubt, individual rheu-
matologists may utilize them due to necessity. Good
examples might be the anti-interferon-a monoclonal anti-
body sifalimumab, and the janus kinase inhibitor
tofacitibinib.
There are inherent limitations to these studies that are
the subject of this review as well as the disease category
itself. Most of the published research is found in retrospect-
ive observational studies. The results are mostly in adults in
IIM and not in JDM. Notably, the most significant point is
the type of IIM studied when evaluation the response to
treatment. IIM remains a highly heterogeneous group with
different histopathology and etiopathology mechanisms driv-
ing their clinical outcomes and responses. These differences
may significantly influence the results of these studies. Yet
we must evaluate studies and draw conclusions as best we
can in 2020 for the benefit of IIM and JDM patients who
are not doing well on conventional therapy and may need
biologic treatment to prevent morbidity and mortality.
These drugs will vary in availability in different countries
and in countries with commercial insurance, it may depend
on what is government approved and what the insurances
will pay for.
We believe that future clinical effectiveness trials may be
needed comparing the relative worth of these biologics that
are currently available in most countries. These trials will
help provide better evidence-based recommendations for the
best biologics for recalcitrant JDM. There may be new bio-
logics in the next 5–10 years against other targets that will
be more effective than the biologics available now.
Conflict of interest
None.
ORCID
Anjali Patwardhan http://orcid.org/0000-0002-1467-1011
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