Autoimmunity Reviews 11 (2012) 739–745

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Autoimmunity Reviews
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Review

Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive

patients with antisynthetase syndrome
I. Marie a,⁎, S. Josse a, O. Decaux b, S. Dominique c, E. Diot d, C. Landron e, P. Roblot e, S. Jouneau b,
P.Y. Hatron f, K.P. Tiev g, O. Vittecoq h, D. Noel a, L. Mouthon i, J.-F. Menard j, F. Jouen k
a
Department of Internal Medicine, CHU Rouen, and INSERM U 905, University of Rouen IFRMP, Institute for Biochemical Research, Rouen, France
b
Department of Internal Medicine, CHU Rennes, Rennes, France
c
Department of Pneumology, CHU Rouen, Rouen, France
d
Department of Internal Medicine, CHU Tours, Tours, France
e
Department of Internal Medicine, CHU Poitiers, Poitiers, France
f
Department of Internal Medicine, CHU Lille, Lille, France
g
Department of Internal Medicine, Hôpital Saint-Antoine, Paris, France
h
Department of Rheumatology, CHU Rouen, Rouen, France
i
Université Paris Descartes, Pôle de Médecine Interne, Hôpital Cochin, Paris, France
j
Department of Biostatistics, CHU Rouen, Rouen, France
k
Laboratory of Immunology, CHU Rouen, and INSERM U 905, University of Rouen IFRMP, Institute for Biochemical Research, Rouen, France

a r t i c l e i n f o a b s t r a c t

Article history: The aims of the present study were to: compare the characteristics between antisynthetase syndrome (ASS)
Received 2 January 2012 patients with anti-Jo1 antibody and those with anti-PL7/PL12 antibody. The medical records of 95 consecu-
Accepted 21 January 2012 tive patients with ASS were reviewed. Seventy-five of these patients had anti-Jo1 antibody; the other patients
Available online 3 February 2012
had anti-PL7 (n = 15) or anti-PL12 (n = 5) antibody. At ASS diagnosis, the prevalence of myalgia (p = 0.007)
and muscle weakness (p = 0.02) was significantly lower in the group of anti-PL7/PL12-positive patients than
Keywords:
Antisynthetase syndrome
in those with anti-Jo1 antibody; median value of CK (p = 0.00003) was also lower in anti-PL7/PL12 patients.
Anti-Jo1 antibody Anti-Jo1 positive patients developed more rarely myositis resolution (21.3% vs. 46.2%); in addition, the over-
Anti-PL7 antibody all recurrence rate of myositis was higher in anti-Jo1 positive patients than in patients with anti-PL7/PL12 an-
Anti-PL12 antibody tibody (65.9% vs. 19.4%). Anti-Jo1-positive patients, compared with those with anti-PL7/PL12 antibody, more
Outcome often experienced: joint involvement (63.3%vs. 40%) and cancer (13.3% vs. 5%). By contrast, anti-PL7/PL12
Cancer positive patients, compared with those with anti-Jo1 antibody, more commonly exhibited: ILD (90% vs.
Interstitial lung disease 68%); in anti-PL7/PL12 positive patients, ILD was more often symptomatic at diagnosis, and led more rarely
Prognostic factors
to resolution of lung manifestations (5.6% vs. 29.4%). Finally, the group of anti-PL7/PL12 positive patients
more commonly experienced gastrointestinal manifestations related to ASS (p = 0.02). Taken together, al-
though anti-Jo1 positive patients with ASS share some features with those with anti-PL7/PL12 antibody,
they exhibit many differences regarding clinical phenotype and long-term outcome. Our study underscores
that the presence of anti-Jo1 antibody results in more severe myositis, joint impairment and increased risk of
cancer. On the other hand, the presence of anti-PL7/PL12 antibody is markedly associated with: early and severe
ILD, and gastrointestinal complications. Thus, our study interestingly indicates that the finding for anti-Jo1 and
anti-PL7/PL12 antibodies impacts both the long-term outcome and prognosis of patients with ASS.
© 2012 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
2. Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
2.1. Initial evaluation of ASS patients with anti-Jo1 and anti-PL7/PL12 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
2.2. Outcome of ASS patients with anti-Jo1 and anti-PL7/PL12 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
2.2.1. Outcome of myositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
2.2.2. Outcome of ILD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741

⁎ Corresponding author at: Département de Médecine Interne, CHU de Rouen, 76031 Rouen Cedex, France. Tel.: + 33 02 32 88 90 03; fax: + 33 02 32 88 90 26.
E-mail address: isabelle.marie@chu-rouen.fr (I. Marie).

1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2012.01.006
740 I. Marie et al. / Autoimmunity Reviews 11 (2012) 739–745

2.2.3. Survival status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741

2.3. Statistical analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
3.1. General characteristics of anti-PL7 and anti-PL12 positive patients with ASS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
3.2. Comparison of features between anti-Jo1 positive patients and patients with anti-PL7/PL12 antibodies . . . . . . . . . . . . . . . . . . 741
3.2.1. Myositis and joint manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
3.2.2. Extra-muscular manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
3.2.3. ILD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
3.2.4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
3.2.5. Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744

1. Introduction
Antisynthetase syndrome (ASS) is characterized by polymyositis/
dermatomyositis (PM/DM) associated with antisynthetase antibodies,
fever, arthritis, Raynaud's phenomenon, mechanic's hands and intersti-
tial lung disease (ILD) [1–11]. To date, 8 antisynthetase antibodies have
been identified in patients with ASS, i.e.: anti-histidyl (anti-Jo1), anti-
threonyl (anti-PL7), anti-alanyl (anti-PL12), anti-isoleucyl (anti-OJ),
anti-glycyl (anti-EJ), anti-asparaginyl (anti-KS), anti-phenylalanyl
(anti-Zo) and anti-tyrosyl-tRNA (anti-YRS) synthetase [12]. Anti-Jo1
antibody is the more common of antisynthetase antibodies, being en-
countered in 60 to 80% of patients with ASS; on the other hand, anti-
PL7 and anti-PL12 antibodies are less frequent, being reported in
10–15% and 5–10%, respectively, of patients with ASS [12,13]. Among
the clinical manifestations, ILD is the most frequent complication of
ASS, occurring in 70 to 89% of patients; in patients with ASS, ILD has
been found to result in increased morbidity and mortality [12–20].
However, to date, no series has previously compared the long-
term outcome of ASS between anti-Jo1- and anti-PL7/PL12-positive
patients. Therefore, the aims of the current study were to compare
both the characteristics and long-term outcome between ASS patients
with anti-Jo1 antibody and those with anti-PL7/PL12 antibody.
2. Patients and methods
This retrospective study began with a search of the institutional cen-
ters' medical record index, which provides access to the diagnoses of the
centers' patients. The first electronic search involved use of the codes PM
and DM to identify patients with a diagnosis of PM/DM seen from January
1995 to January 2011 in 6 academic centers (Lille, Paris, Poitiers, Rennes,
Rouen, Tours). The diagnosis of PM/DM was based on Bohan and Peter
criteria [21,22]: 1) symmetric muscle weakness, 2) increased serum
muscle enzymes, 3) myopathic changes on electromyography, 4) typical
histologic findings on muscle biopsy; and 5) characteristic dermatologic
manifestations. All these PM/DM patients were tested for the presence
of: 1) anti-Jo1 antibody, using immmunodiffusion with subsequent con-
firmation by ELISA; and 2) anti-PL7 and anti-PL12 antibodies, by immu-
nodot and Western blot using protein extracts from Hep 2 cells.
A second search was used to isolate the subset of ASS patients
with: 1) anti-Jo1 antibody; and 2) anti-PL7 and anti-PL12 antibodies.
Thus, 95 consecutive ASS patients with anti-Jo1 (n = 75) and anti-
PL7/PL12 antibodies (n = 20) were included in the study; none of
these patients had other connective tissue disorders or myopathy. Fi-
nally, two physicians (IM and SJ) used a standard form to record the
characteristics of these patients from medical files.
2.1. Initial evaluation of ASS patients with anti-Jo1 and anti-PL7/PL12
antibodies
was gauged for proximal muscles (i.e.: neck, flexors, trapezius, del-
toid, biceps, psoas, maximus and medius gluteus and quadriceps) by
a modification of the British Medical Research council grading system,
resulting in scores ranging from 0 to 11 [theoretical maximum score:
88 points] [23]. All patients had an initial evaluation of organ involve-
ment, which resulted in the detection of systemic complications, in-
cluding: 1) Raynaud's phenomenon; 2) mechanic's hands; 3) joint
impairment: arthralgia/arthritis (using the count of painful and/or
swollen joints); and 4) esophageal dysfunction. The diagnosis of
PM/DM-related esophageal involvement was based on the presence
of clinical manifestations, i.e.: dysphagia, gastro-esophageal reflux
into pharynx and/or mouth, coughing while eating, aphagia for solids
and liquids; 5) respiratory muscle involvement resulting from venti-
latory insufficiency related to striated muscle weakness, when pa-
tients had ventilatory failure with decreased vital capacity; 6)
aspiration pneumonia; and 7) cardiac dysfunction (using electrocar-
diogram and echocardiography). In addition, patients were also ex-
amined for underlying malignancy.
ILD was systematically investigated initially by pulmonary function
tests (PFT) and high resolution computed tomography (HRCT)-scan of
the lungs. The following PFT parameters were assessed: vital capacity
(VC), forced vital capacity (FVC) and diffusing capacity of carbon monox-
ide (DLCO). VC and FVC were measured by spirometry (using a water-
sealed spirometer); the DLCO was obtained by the single-breath method.
Data are expressed as percentages of predicted values. The predicted
values for each subject, based on sex, age, height, and weight, were
obtained from standard tables [24]. Lung function was considered abnor-
mal when volumes were less than 80% of predicted values and when
DLCO was less than 70% of the predicted value. HRCT of the lungs was per-
formed to evaluate radiographic abnormalities consistent with ILD: pa-
renchymal micronodules and nodules, irregular linear opacities,
irregularity of the interfaces between peripheral pleura and aerated
lung parenchyma, ground-glass opacities, honeycombing, and traction
bronchiectases or bronchiolectases. [12,14,25–28]. HRCT-scan pattern
has been correlated with pulmonary histological findings, i.e.: 1) crypto-
genic organizing pneumonia (COP), characterized by consolidation and
linear opacities; 2) nonspecific interstitial pneumonia (NSIP), determined
by ground-glass opacities and irregular linear opacities; 3) usual intersti-
tial pneumonia (UIP), characterized by honeycombing and traction bron-
chiectases; and 4) diffuse alveolar damage, defined by bilateral and
extensive consolidation with airspace and ground-glass opacities
[12,14,27,29–31]. The severity of ILD on HRCT was scored according to
Warrick et al. [32]. Additionally, according to HRCT-scan pattern, patients
were, in fact, divided into 4 groups: COP, NSIP, UIP and DAD [20,22–24].
Finally, patients also underwent biochemical assessment, i.e.: cre-
atine kinase (CK).
2.2. Outcome of ASS patients with anti-Jo1 and anti-PL7/PL12 antibodies

At diagnosis, muscle weakness involving both upper and lower Patients had a minimal follow-up of 18 months, although patients
limbs and neck extensors and flexors was assessed; muscle power who died before 18 month follow-up were also included.
 I. Marie et al. / Autoimmunity Reviews 11 (2012) 739–745 741

2.2.1. Outcome of myositis
The outcome of ASS patients was defined as: 1) remission: disap-
pearance of skin manifestations, stable increase of muscle strength
and normalization of serum muscle enzyme levels (CK) persisting
after therapy discontinuation; 2) improvement: when muscle and
skin signs improved and CK levels decreased with therapy; and 3) dete-
rioration when muscle and skin signs worsened, and CK levels increased
despite therapy. Recurrences of myositis were diagnosed on the basis of
clinical relapses. Recurrences were divided into short term and long
term recurrences: 1) short term recurrences occurred during tapering
of therapy; and 2) long term recurrences occurred after termination of
therapy.
2.2.2. Outcome of ILD
The outcome was categorized as resolution, improvement/stabili-
zation or deterioration. Resolution was defined as complete remission
of pulmonary symptoms associated with disappearance of radio-
graphic signs of ILD and normalization of standard PFT values. Im-
provement was defined as when any of the former pulmonary
alterations improved without returning to normal value; according
to an international consensus statement of the American Thoracic So-
ciety on idiopathic pulmonary fibrosis [33], changes of ≥10% in FVC
and/or ≥15% in DLCO were considered to be significant, and were
used as determinant of improvement. Deterioration was defined as
when any of the former pulmonary condition worsened despite insti-
tution of therapy; changes of ≥10% in FVC and/or ≥15% in DLCO were
considered to be significant, and were used as determinant of deteri-
oration [33].
2.2.3. Survival status
Finally, survival status was based on hospital records (i.e.: data
obtained during routine follow-up visit) or by contacting patients'
family physicians. The cause of death was determined through hospi-
tal or physician records.
2.3. Statistical analyses
3.2. Comparison of features between anti-Jo1 positive patients and patients
with anti-PL7/PL12 antibodies
We compared the characteristics between ASS patients with anti-
Jo1 antibody and those with anti-PL7/PL12 antibodies. The median
duration of patients' follow-up did not differ between the two groups
of patients (37 vs. 34 months; p = 0.985).
We found no statistical difference between ASS patients with anti-
Jo1 antibody and those with anti-PL7/PL12 antibodies regarding: age
(p = 0.5) and sex (p = 1) (Table 1).
3.2.1. Myositis and joint manifestations
At ASS diagnosis, the prevalence of myalgia (p= 0.007) and muscle
weakness (p= 0.02) was significantly lower in the group of anti-PL7/
PL12-positive patients than in those with anti-Jo1 antibody (Table 1).
Furthermore, median value of CK (91 vs. 658 IU/L; p = 0.00003) was
also lower in anti-PL7/PL12-positive patients (Table 1). Interestingly,
anti-PL7/PL12-positive patients less frequently experienced DM than
patients with anti-Jo1 antibody (11.1% vs. 38.7%) (Table 1).
In addition, anti-PL7/PL12-positive patients less frequently exhib-
ited joint involvement (p = 0.02) (Table 1). We failed to find differ-
ences between anti-PL7/PL12- and anti-Jo1 positive patients
regarding the prevalence of: non-erosive arthritis (p = 1) and synovi-
tis (p = 1); however, erosive arthritis tended to be more common in
patients with anti-Jo1 (12% vs. 5%), although not significantly so.
Therapy for ASS was different between anti-Jo1- and anti-PL7/
PL12 positive patients for the use of: cytotoxic drugs (76% vs. 50%;
p = 0.03) and intravenous immunoglobulins (44.4% vs. 15%;
p = 0.02). Overall outcome of myositis tended to be poorer in anti-
Jo1 positive patients (p = 0.12); these patients developed more rarely
myositis resolution (p = 0.08) (Table 2). At last follow-up, the median
score of muscle power was also lower in the group of patients with
anti-Jo1 antibody (p = 0.007). Additionally, the overall recurrence
rate of myositis was higher in the group of anti-Jo1 positive patients
(65.9% vs. 19.4%) (Table 2); finally, short term (p = 0.0009) and
long-term (p = 0.04) recurrence rates were also higher in the group
of ASS patients with anti-Jo1 antibody.

We compared both the features and long-term outcome of ASS be-

tween anti-Jo1 positive patients and those with anti-PL7/PL12 anti- Table 1
bodies. For group comparison involving binary data, we used either Comparison of clinical characteristics between anti-Jo1 positive ASS⁎ patients and
the chi-square test or Fisher's exact test, depending on the cells' those with anti-PL7/PL12 antibody.
expected count (more or less than 5, respectively). Comparisons in-
Presence of Presence of p
volving continuous data were performed using the Mann–Whitney anti-Jo anti-PL7/PL12
U test. The results were regarded as significant when the p value antibody antibody
was b0.05. (n = 75) (n = 20)

General characteristics
Age (years) 53 [range: 18–75] 59 [range: 18–79] 0.10
3. Results Sex: male/female 37.3%/62.7% 40%/60% 1
DM subset⁎ 38.7% DM 11.1% DM 0.01
Clinical characteristics
3.1. General characteristics of anti-PL7 and anti-PL12 positive patients
Myalgia 81.3% 50% 0.007
with ASS Muscle weakness 69.3% 40% 0.02
Raynaud's phenomenon 46.7% 40% 0.62
The 20 anti-PL7- (n = 15) and anti-PL12- (n = 5) positive patients Mechanic's hands 29.3% 30% 1
comprised 8 men and 12 women with a median age of 59 years Esophageal involvement 22.7% 20% 1
Gastrointestinal signs 1.3% 17.6% 0.02
[range: 31–79] at ASS diagnosis; only 2 of these 20 patients had DM Joint manifestations 63.3% 40% 0.02
(10% of cases). ILD⁎ 68% 90% 0.05
Ten patients had myalgia (50%), and 8 exhibited muscle weakness Ventilatory insufficiency 13.3% 0% 0.11
(40%). The patients experienced ASS-related complications: fever related to striated muscle
weakness
(n = 6), Raynaud's phenomenon (n = 8), mechanic's hands (n = 6),
Aspiration pneumonia 13.3% 15% 1
joint impairment (n = 8), esophageal dysfunction (n = 4), gastroin- Cardiac impairment 4.1% 0% 0.59
testinal manifestations (n = 3), ILD (n = 18), aspiration pneumonia Malignancy 13.3% 5% 0.44
(n = 3) and cardiac dysfunction (n = 3). One patient (5%) had cancer. ⁎ ASS: antisynthetase syndrome; ILD: interstitial lung disease; DM: dermatomyositis.
Finally, 3 patients died (15%). Death was due to pyogenic pneumo- Except where indicated, values are median; p values were obtained with chi-square or
nia (n = 2) and cancer (n = 1). Fisher's exact tests.
742 I. Marie et al. / Autoimmunity Reviews 11 (2012) 739–745

Table 2 Table 3
Comparison of musculoskeletal outcome between anti-Jo1 positive patients and those Comparison of ILD⁎ characteristics between anti-Jo1 positive patients and those with
with anti-PL7/PL12 antibody. anti-PL7/PL12 antibody.

Presence of anti-Jo Presence of anti-PL7/PL12 p Presence of anti-Jo Presence of anti-PL7/PL12 p

antibody (n = 75) antibody (n = 20) antibody (n = 75) antibody (n = 20)

Outcome of myositis Presenting pulmonary

Median score of 76 85 0.007 symptoms
muscle power at last Fever 18.7% 30% 0.36
follow-up Dyspnea 37.3% 83.3% 0.009
Remission 21.3% 46.2% 0.08 Cough 30.4% 63.2% 0.01
Improvement 66.7% 38.4% 0.19 Asymptomatic 56.8% 22.2% 0.01
Deterioration 12% 5.7% 0.66 Time onset
Recurrence 65.9% 19.4% 0.0003 Before PM/DM⁎ 17.6% 27.8% 0.49
Mortality 15% 10.7% 0.43 Concomitant with 62.7% 66.7% 1
PM/DM ⁎
Except where indicated, values are median; p values were obtained with chi-square or ⁎
After PM/DM 19.6% 5.6% 0.27
Fisher's exact tests.
PFT⁎ findings at
ILD⁎ diagnosis
FVC⁎ 82% 72% 0.26
VC⁎ 84% 75% 0.15
DLCO⁎ 60% 57% 0.41
3.2.2. Extra-muscular manifestations ⁎
HRCT -scan pattern
We found no statistical difference between ASS patients with anti- COP ⁎ 19.6% 16.7% 1
Jo1 antibody and those with anti-PL7/PL12 antibodies for: fever NSIP⁎ 62.8% 50% 0.41
UIP⁎ 17.6% 33.3% 0.19
(p = 0.35), Raynaud's phenomenon (p = 0.62), mechanic's hands
Outcome of ILD⁎
(p = 1), esophageal impairment (p = 1), aspiration pneumonia Remission 29.4% 5.6% 0.05
(p = 1) and cardiac impairment (p = 1) (Table 1). Improvement/ 56.9% 61.1% 0.79
Ventilatory insufficiency related to striated muscle weakness stabilization
Deterioration 13.7% 33.3% 0.08
tended to be more frequent in the group of anti-Jo1 positive patients
(13.3% vs. 0%; p = 0.11). ⁎ ILD: interstitial lung disease; PM/DM: polymyositis/dermatomyositis; PFT: pulmo-
Finally, we found that anti-PL7/PL12-positive patients more com- nary function tests; FVC: forced vital capacity; VC: vital capacity; DLCO: diffusing ca-
pacity of carbon monoxide; HRCT: high resolution computed tomography; COP:
monly experienced gastrointestinal manifestations related to ASS cryptogenic organizing pneumonia; NSIP: non-specific interstitial pneumonia; UIP:
(p= 0.02) (Table 1). Interestingly, intestinal pseudo-obstruction usual interstitial pneumonia.
tended to be more commonly encountered in patients with anti-PL7/
PL12 antibody, although not significantly so (10% vs. 1.3%; p = 0.11).

3.2.3. ILD However, death tended to me more frequently due to ILD-associated

The prevalence of ILD was higher in anti-PL7/PL12-positive pa-
tients (90% vs. 68%; p = 0.05). ILD occurred more rarely during the
course of ASS in the group of anti-PL7/PL12-positive patients (5.6%
vs. 19.6%). Moreover, the presence of cough (p = 0.01) and dyspnea
(p = 0.0009) at ILD diagnosis could be considered predictive factors
of the presence of anti-PL7/PL12 antibody. We found no significant
difference between anti-PL7/PL12- and anti-Jo1 positive patients for
PFT findings at initial diagnosis of ILD; median FVC (p = 0.26), VC
(p = 0.15) and DLCO (p = 0.40) values were similar between both
groups of patients (Table 3). Furthermore, the median score of fibro-
sis on HRCT-scan did not differ in patients with anti-PL7/PL12 and
anti-Jo1 antibody (p = 0.66) at ILD diagnosis. HRCT-pattern did not
differ between both groups of patients regarding: COP (p = 1), NSIP
(p = 0.41); by contrast, UIP tended to be more frequent in anti-PL7/
PL12 patients (33.3% vs. 17.6%) (Table 3).
Overall outcome of ILD was poorer in the group of anti-PL7/PL12
positive patients (p = 0.05) (Table 3). Resolution of lung status was,
in fact, less frequent in the group of patients with anti-PL7/PL12 anti-
body (6% vs. 29.4%) (Table 3). The median FVC (83% vs. 89%;
p = 0.267), VC (85% vs. 90.5%; p = 0.155) and DLCO (63.5% vs. 72%;
p = 0.406) values did not significantly differ between both anti-PL7/
PL12 and anti-Jo1 positive patients at last follow-up; however, the
median score of fibrosis on HRCT was higher (16.7 vs. 11.2;
p = 0.008) in anti-PL7/PL12 positive patients at last follow-up.
3.2.4. Cancer
Anti-Jo1 positive patients tended to exhibit more commonly can-
cer (13.3% vs. 5%), although not significantly so (p = 0.44) (Table 1).
3.2.5. Mortality
Finally, mortality rate was similar between anti-PL7/PL12 positive
patients and those with anti-Jo1 antibody (15% vs. 10.7%; p = 0.434).
lung complications in the group of anti-PL7/PL12 positive patients
(66.7% vs. 37%).
4. Discussion
Patients with ASS auto-antibodies exhibit characteristic features.
However, in our review of the Medline database, we found no series
comparing both the features and long-term outcome between ASS
patients with anti-Jo1 antibody and those with anti-PL7/PL12 anti-
body. Thus, the current study is, to the best of our knowledge, the
first to compare the characteristics between anti-Jo1 and anti-PL7/
PL12-positive patients. Our series considered 95 consecutive anti-
Jo1 (n = 75) and anti-PL7/PL12- (n = 20) positive patients without
prior selection based on clinical presentation, which tends to be rep-
resentative of ASS patients' population. From a practical point of view,
the accurate significance of anti-Jo1 and anti-PL7/PL12 antibodies ap-
pears of utmost importance in ASS patients to improve these patients'
management.
Muscle involvement in ASS can postdate other manifestations, es-
pecially ILD by up to several years and may lack in some patients
[7,13,17,34–40]. Myositis is common in anti-Jo1 positive patients
with ASS, being encountered in 78 to 91% of cases [7,13,17,34–40].
Our findings are in accordance with previous series' data, as we
found that 81.3% of anti-Jo1 positive patients had myositis. On the
other hand, few authors have reported that myositis less commonly
occurs in anti-PL7/PL12 positive patients (51 to 67% of cases)
[7,16,35,38,40–47]. In a recent series of 12 anti-PL7 positive patients,
Hervier et al. [16] mentioned that up to 50% of patients did not devel-
op muscle involvement. Anti-PL7/PL12-associated ASS has indeed
been found previously to be associated with isolated ILD or arthritis
[7,16,35,38,40–47]. Finally, in our literature review, we have found
 I. Marie et al. / Autoimmunity Reviews 11 (2012) 739–745
that the presence of anti-PL7/PL12 antibodies was associated with a
good prognosis of myositis, resulting in resolution/improvement of
muscle symptoms in up to 90% of patients [46,48].
Our large cohort of 95 patients also underscores that anti-Jo1 pos-
itive patients more commonly experience myositis (i.e.: myalgia and
muscle weakness) than patients with anti-PL7/PL12 antibodies. Inter-
estingly, we have further shown that the group of anti-Jo1 positive
patients: 1) more rarely achieved remission of myositis; and 2)
more frequently presented short term and long-term recurrences of
myositis. Additionally, our series demonstrates that the presence of
anti-Jo1 antibody leads to decreased functional status at long-term
follow-up, as shown by lower muscle power score. Taken together,
our findings show that the presence of anti-Jo1 antibody confers a
poorer prognosis of myositis in ASS patients, compared with anti-
PL7/PL12 antibodies. Moreover, we have also interestingly observed
that anti-Jo1 positive patients more often experienced ventilatory in-
sufficiency related to striated muscle weakness than patients with
anti-PL7/PL12 antibodies; thus, these latter findings further suggest
that the presence of anti-Jo1 antibody is associated with more severe
and diffuse myositis in ASS patients. Regarding therapy responsive-
ness, previous authors have reported that two-thirds of anti-Jo1 pa-
tients had refractory myositis [48]. Our findings confirm these
previous data; in our experience, anti-Jo1 positive patients more
often exhibit steroid-resistant myositis than patients with anti-PL7/
PL12 antibodies, as shown by more common use of intravenous im-
munoglobulins and cytotoxic drugs.
Another main finding in the present series was that some extra-
muscular manifestations differ between of anti-Jo1 positive patients
and those with anti-PL7/PL12 antibody.
Joint impairment is more frequent in PM/DM patients with ASS, com-
pared with those without [7,17]. Previous series have indeed described
joint manifestations in 75 to 90% of anti-Jo1 positive patients with ASS
[39,49]. In anti-Jo1 positive patients, joint manifestations usually range
from arthralgia to non-erosive and distal polyarthritis involving the
hands, wrists, elbows and knees [7,19,23,49]. Few cases of deforming ar-
thropathy have also been reported, i.e.: subluxation of interphalangeal
joints of the thumbs, periarticular hydroxyapatite calcifications and ero-
sions of metacarpophalangeal and interphalangeal joints and wrists [49].
In our literature review, joint impairment occurred in 12 to 60% of anti-
PL7/PL12 positive patients [7,16,35,38,40–47]. In the current study, the
prevalence of joint involvement was, in fact, higher in the group of
anti-Jo1 positive patients compared with those with anti-PL7/PL12 anti-
bodies. Moreover, we have interestingly shown that patients with anti-
Jo1 antibody more frequently experienced severe joint involvement (as
shown by higher count of painful and/or swollen joints). Nevertheless,
we failed to find significant differences between anti-Jo1 and anti-PL7/
PL12 positive patients regarding joint features, i.e.: prevalence of non-
erosive arthritis, synovitis; on the other hand, we have found that anti-
Jo1 positive patients more often exhibited: 1) erosive arthritis. None of
these anti-Jo1 positive patients had coexistent anti-CCP antibody; and
2) periarticular and intra-articular calcifications of both hands and wrists
and erosions of interphalangeal joints (2.7% vs. 0%). Our latter findings
suggest that the presence of anti-Jo1 antibody seems to be associated
with more severe joint manifestations in ASS; nevertheless, further in-
vestigations are required to confirm our latter data.
Gastrointestinal manifestations are uncommon in PM/DM patients;
in PM/DM patients, gastrointestinal involvement may lead to life-
threatening complications, including: intestinal pseudo-obstruction,
hemorrhage and perforation related to vasculitis, spontaneous abdom-
inal hematoma and pneumatosis cystoides intestinalis [50,51]. In our
literature review, we found only one case of anti-Jo1 positive patient
exhibiting intestinal pseudo-obstruction. In this instance, we have in-
terestingly shown that anti-Jo1 positive patients more rarely developed
PM/DM-related gastrointestinal complications than patients with anti-
PL7/PL12 antibody, especially intestinal pseudo-obstruction. Our find-
ings suggest that the evaluation of anti-PL7/PL12 positive patients
743
should include routinely digestive physical examination in order to de-
tect such gastrointestinal complications at an early stage.
The prevalence of ILD in PM/DM patients is 23 to 65% [12,14,19].
Patients with ASS more often experience ILD than patients without;
indeed, ASS antibodies are the strongest predictive factors for devel-
oping ILD in the setting of PM/DM [12,14,19,52]. Previous authors
have reported the high frequency of ILD in anti-Jo1 positive patients
(76 to 90% of cases) [12,14,19,52]. Based on previous series, anti-
PL7 and anti-PL12 antibodies have been described to be more strong-
ly associated with ILD than anti-Jo1 antibody [7,16,35,38,40–47]. In 7
anti-PL7 positive patients, Sato et al. [46] observed ILD in all cases. In
31 anti-PL12 positive patients, Kalluri et al. [44] further found a high
frequency of ILD (90% of cases). In our literature review, we have also
observed that 85 to 100% of anti-PL7/PL12 positive patients experi-
enced ILD [7,16,35,38,40–47]. Our series also underscores the marked
association between ILD and the presence of anti-PL7/PL12 antibody.
Thus, we have shown that up to 90% of anti-PL7/PL12 positive pa-
tients exhibited ILD, whereas only two-thirds of anti-Jo1 positive pa-
tients had ILD. Taken together, our findings reinforce that the
detection of anti-PL7/PL12 and anti-Jo1 antibodies is useful in pa-
tients with ILD for predicting underlying ASS. Our series also confirms
that screening for subclinical ILD should be made (through PFTs and
HRCT-scan) in all anti-PL7/PL12 and anti-Jo1 positive patients, result-
ing in diagnosis of ILD at an earlier stage.
In this instance, we have also found that the presence of anti-PL7/
PL12 antibody was associated with a particular phenotype of ILD in
ASS. Thus, we have interestingly observed that ILD more commonly
preceded the onset of myositis in the group of anti-PL7/PL12 positive
patients. Regarding lung presenting manifestations, we have further
shown that anti-PL7/PL12 positive patients less commonly exhibited
asymptomatic form of ILD; such patients experienced either acute
onset or progressive onset of ILD; our data underline that PL7/
PL12-associated ILD should be viewed as a clinical spectrum ranging
from an acute presentation to a slowly progressive ILD. Previous au-
thors have reported that the presence of anti-PL7/PL12 antibody is
associated with a poor prognosis in patients with ILD [7,16,42]. Our
series further underlines that anti-PL7/PL12 positive patients exhib-
ited a more coarse and severe ILD, as shown by: 1) more frequent
lung symptoms (cough and dyspnea) at ILD diagnosis; 2) higher
score of fibrosis on HRCT-scan of the lungs at patients' last-follow-
up. Furthermore, we have also shown that anti-PL7/PL12 positive pa-
tients more rarely achieved resolution of ILD despite therapy (5.6%
vs. 29.4%). Finally, ILD complications were more often responsible di-
rectly for 66.7% of overall causes in the group of anti-PL7/PL12 posi-
tive patients.
In addition, malignancy has been described in patients with auto-
immune neuromuscular diseases, including myasthenia gravis
[53,54] and polymyositis/dermatomyositis [55]. Thus, previous au-
thors [55] found an increase in risk of cancer for DM [OR: 6.2; 95%
CI: 3.9–10.0] and PM [OR: 2.0; 95% CI: 1.4–2.7]; although the risk of
cancer was highest around the time of PM/DM diagnosis, the in-
creased risk persisted beyond 5 years [OR: 1.6; 95% CI: 1.0–2.6] [55].
Other investigators postulated that the presence of anti-Jo1 antibody
was a protective factor of malignancy in PM/DM patients [56]; in this
latter series, ASS was negatively associated with cancer. However,
cancer-associated myositis in the presence of antisynthetase anti-
bodies has been reported [57–59]. The last main finding in the current
study was that anti-Jo1 positive patients more commonly exhibited
cancer than those with anti-PL7/PL12 antibody. Taken together, our
findings underline that anti-Jo1 positive patients with ASS, especially
those aged over 50 years, are at higher risk of developing cancer than
patients with anti-PL7/PL12 antibody. Because the presence of anti-
Jo1 antibody does not appear to be a protective factor of cancer in
ASS patients in the present study, we suggest that these patients re-
quire evaluation for cancer, especially digestive and gynecologic can-
cers; in our experience, 50% and 40% of our patients, in fact,
744 I. Marie et al. / Autoimmunity Reviews 11 (2012) 739–745
developed digestive (mainly colon cancer) and gynecologic (ovarian,
uterus and breast cancers) malignancies, respectively.
Taken together, anti-Jo1 positive patients with ASS share some fea-
tures with anti-PL7/PL12 antibody with some differences regarding
clinical phenotype and long-term outcome. Thus, our study demon-
strates that anti-Jo1 positive patients more often developed: 1) severe
myositis and joint manifestations, including erosive arthritis; and 2)
cancer. On the other hand, anti-PL7/PL12 positive patients more com-
monly exhibited: 1) early and severe ILD; and 2) gastrointestinal com-
plications. Taken together, our study underscores that the finding for
anti-Jo1 and anti-PL7/PL12 antibodies appears to impact the long-
term outcome of patients with ASS.
Take-home messages
• Our study underscores that anti-Jo1 positive patients with ASS
share some features with anti-PL7/PL12 antibody with some differ-
ences regarding clinical phenotype and long-term outcome.
• Anti-Jo1 positive patients more often developed severe myositis
and joint manifestations, including erosive arthritis.
• Anti-Jo1 positive patients more often exhibited cancer. Our findings
suggest that these patients require evaluation for cancer, especially
digestive and gynecologic cancers which were responsible for 90%
of overall cancers in our anti-Jo1 positive patients.
• Anti-PL7/PL12 positive patients more commonly experienced early
and severe ILD. Our findings indicate that the detection of anti-
PL7/PL12 antibodies is useful in patients with ILD for predicting un-
derlying ASS.
• Anti-PL7/PL12 positive patients more frequently had gastrointesti-
nal complications, especially intestinal pseudo-obstruction.
• We suggest that the finding for anti-Jo1 and anti-PL7/PL12 anti-
bodies appears to impact both the long-term outcome and progno-
sis of patients with ASS.
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Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions

Transforming growth factor-β is considered to play a key role in the process of fibrosis in systemic sclerosis (SSc) and in the development of
regulatory T cells (Treg) and pro-inflammatory Th17 T cells producing interleukin 17 (IL-17) and IL-22. Mathian A. et al. (Ann Rheum Dis
2012; 71(7): 1227-34) therefore postulated that SSc could be characterised by a marked Treg/Th17 imbalance. Previous works did not dis-
tinguish between the different subsets of Treg and the non-regulatory FoxP3(+) cells leading to inconsistent results. Combined phenotypic
and functional analysis of Th17 cells and FoxP3(+)CD4 T cells, discriminating activated Tregs and resting Tregs from non-regulatory
FoxP3(+) T cells, in blood and skin of SSc patients. In early disease stages, there is a decreased proportion of activated Tregs. A concomitant
resting Treg deficit becomes more apparent with disease progression. Active and diffuse forms of the disease are characterised by a relatively
higher proportion of all FoxP3(+) subsets, including non-regulatory T cells. No peripheral or local IL-17 amplification was observed. How-
ever, the authors found significantly increased IL-22 transcription levels in SSc lesional skin, as compared with healthy skin. Cytofluorometry
confirmed the existence in SSc patients and controls of a distinct subset of T cells producing IL-22 in the absence of IL-17. SSc pathogenesis
does not appear to be linked to IL-17-, but rather to IL-22-producing cells with skin-homing potential and a concomitant quantitative Treg
defect. Active and diffuse forms of the disease are associated with a FoxP3 signature. Altogether, their data depict a status of regulatory/
pro-inflammatory T cell imbalance in SSc.