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\begin{document}

\title{Severe finger necrosis in antisynthetase syndrome with positive anti-OJ
antibodies}



\author[1]{Yugo Horiuchi}%
\author[2]{Kenichi Hashimoto}%
\author[2]{Ryochi Yoshida}%
\author[2]{Yuji Tanaka}%
\affil[1]{National Defense Medical College School of Medicine}%
\affil[2]{National Defense Medical College}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\textbf{INTRODUCTION}

Aminoacyl tRNA synthetases (ARSs) are a group of cytoplasmic enzymes
that bind to transcribed RNA during protein synthesis, esterify amino
acids to transcribed RNA, and function as catalysts for
aminoacyl-transcribed RNA.\textsuperscript{1} Patients who test positive
for anti-ARS antibodies present with various extramuscular symptoms,
such as interstitial pneumonia, mechanic's hands, Raynaud phenomenon,
polyarthritis, fever, and myositis. These symptoms share common clinical
features, which led Targoff in 1992 to term them ''antisynthetase
antibody syndrome.''\textsuperscript{2} Since Jo-1 (histidyl-tRNA
synthetase: HisRS) antibody was discovered in 1980\textsuperscript{3},
eight ARS antibodies have been identified: histidyl-tRNA synthetase-1
(Jo-1), anti-threonyl (PL-7), anti-alanyl (PL-12), anti-glycyl (EJ),
anti-isoleucyl (OJ) anti-asparaginyl (KS), anti-phenylalanyl (Zo) and
anti-tyrosyl (Ha) tRNA synthetase\textsuperscript{4}.\textsuperscript{5,
6} Among these antibodies, anti-OJ is the least prevalent
(3.1\%).\textsuperscript{7} Anti-OJ- positive anti-ARS syndrome is
extremely rare, and is usually accompanied by interstitial
pneumonia.\textsuperscript{8} Anti-OJ and
anti-Sj\selectlanguage{ngerman}ögren's-syndrome-related~antigen A (Ro-52) antibodies are
occasionally detected in patients with dermatomyositis and are a poor
prognostic factor when associated with interstitial
pneumonia.\textsuperscript{9} However, we encountered a patient with
OJ-and Ro-52 positive anti-ARS syndrome without interstitial pneumonia
and with severe phalanx necrosis due to Raynaud phenomenon. The activity
of disease could be suppressed with steroid pulse therapy. We believe
that this is an atypical clinical presentation that deserves
acknowledgement by means of this case report. We also report it here
with a review of the literature.

\textbf{CASE PRESENTATION}

The patient was an 80-year-old Japanese man. During the month before
admission, he experienced progressive dysphagia and muscle weakness in
the lower extremities. Because of difficulty with walking, he sought
medical attention at the hospital. He had a 60-year history of smoking
10 cigarettes per day and infrequent hospital visits and was not
currently on any medication. The patient had no history of Raynaud
phenomenon.

On admission, the patient's temperature was 37.3°C, and no other
abnormalities were detected in his vital signs. Indurated edema was
observed in both lower legs, and a purple color change was observed in
the second to fifth fingers of the left hand (Fig. 1--A). Although
muscle atrophy was not evident because of edematous changes, the patient
experienced generalized muscle pain in the bilateral thighs. The
strength in the upper extremities was assessed as a Muscle Strength
Testing (MMT) score of 4, while the iliopsoas and quadriceps muscles
were graded as an MMT score of 2.

Blood test findings revealed elevated levels of muscle enzymes (creatine
kinase {[}CK{]}, 7,930 U/L and C-reactive protein {[}CRP{]}, 2.0 mg/dL),
an erythrocyte sedimentation rate~(ESR) of 16 mm/h, and an elevated
inflammatory response. Results were negative for antinuclear antibodies,
rheumatoid factor (RF), myeloperoxidase-anti-neutrophil cytoplasmic
antibodies (MPO-ANCA), proteinase-3-anti-neutrophil cytoplasmic
antibodies (PR3-ANCA), anti-Scl-70, U1RNP, centromere, Jo-1, PL-12,
anti-melanoma differentiation-associated gene-5 (MDA5), and
anti-transcriptional intermediary factor 1-\selectlanguage{greek}γ \selectlanguage{english}(TIF1-\selectlanguage{greek}γ\selectlanguage{english}), and for MI-2, Ku,
PM-SCL75, PM-SCL100, SRP, PL-7, EJ, and OJ. However, Ro-52 (EUROLINE
Myositis Profile 3; EUROIMMUN Medizinische~Labordiagnostika AG, Lubeck,
Germany) demonstrated a strong positive result (3+). During the
patient's hospitalization, further testing using immunoprecipitation was
conducted at another institute's laboratory, and the patient was
strongly positive for anti-OJ antibodies.

Contrast-enhanced magnetic resonance imaging (MRI) revealed a contrast
effect in muscle electromyography, and positron emission
tomography-computed tomography also showed extensive soft tissue
accumulation despite normal blood glucose levels (Fig. 2A and B). Muscle
biopsy findings were consistent with myositis, which led to a diagnosis
of anti-ARS antibody syndrome. Chest CT upon admission indicated chronic
obstructive pulmonary disease and mild interstitial pneumonia; however,
no malignancy was detected. MRI of the head showed no abnormality.

After admission, the color of the patient's fingers changed from purple
to black, indicating necrosis (Fig. 1B). Contrast-enhanced CT images
showed no signs of vascular stenosis or obstruction. Intravenous heparin
sodium (10,000 U/day), prostaglandins (limaprost alfadex 30 \selectlanguage{greek}μ\selectlanguage{english}g/day),
tocopherol nicotinate 600 mg/day, and warming agents for a week, the
progression of the finger necrosis did not stop.

On day 10 of hospitalization, the patient's respiratory status
deteriorated, necessitating ventilator management. Worsening
interstitial pneumonia was treated with a methylprednisolone pulse of
1,000 mg for 3 days and post-therapy prednisolone (PSL; 60 mg {[}1
g/kg{]}). Following initiation of treatment, his respiratory condition
rapidly improved, and he was weaned off the ventilator within
approximately 10 days. Close examination revealed no exacerbation of
interstitial pneumonia or changes in Krebs von den Lungen 6 (KL-6; 216
U/mL) or surfactant protein-D (SP-D; 65 ng/mL). This was attributed to
improved carbon dioxide (CO\textsubscript{2}) narcosis. After the first
day of PSL pulse administration, a purple transition zone appeared in
the necrotic area of the fingers, which subsequently ceased expanding
(Fig. 1C).

The patient experienced repeated episodes of aspiration pneumonia owing
to dysphagia; however, over time, both swallowing ability and lower limb
muscle strength gradually improved. On day 40 of hospitalization, the
MMT score of the lower limbs recovered to 3--4, and CK levels were
normal. Additionally, the CRP level and ESR had substantially decreased.
Furthermore, the progression of finger necrosis had ceased. By day 70 of
hospitalization, all MMT scores had improved to 5, indicating complete
recovery of muscle strength. Swallowing function had also improved to
the state before the disease onset, leading to the patient's discharge
from the hospital. Although the necrotic areas of the fingers became
narrower and drier after pulse therapy, necrosis did not progress (Fig.
1D).

\textbf{OUTCOME AND FOLLOWUP}

Following discharge, the patient was transferred to a rehabilitation
hospital for further care. After 2 months of rehabilitation, the patient
was discharged from the rehabilitation hospital and did not experience
any recurrence of symptoms. Furthermore, there was no progression of
necrosis in the fingers following discharge from our hospital. A team
conference was conducted involving nurses, collagen disease physicians,
a plastic surgeon, an orthopedic surgeon, and a family member to discuss
the possibility of amputating the necrotic fingers. Considering that the
patient was receiving PSL and that future use of immunosuppressive drugs
was contemplated, it was decided to not proceed with amputation because
of the associated risk of infection. Instead, the patient's progress
would continue to be monitored.

\textbf{DISCUSSION}

We diagnosed an older patient with rapidly progressive finger necrosis
and late-onset ARS syndrome who tested positive for anti-OJ and Ro-52
antibodies. The occurrence of ARS syndrome with positive anti-OJ
antibodies is extremely rare, and reports of clinical manifestations of
severe necrosis of the hands without significant interstitial pneumonia
are limited.\textsuperscript{8} Additionally, the commonly used line
immunoassay (LIA) method for measuring anti-OJ antibodies yielded false
negative results in this case, highlighting the effectiveness of
immunoprecipitation.

Ge et al.\textsuperscript{7} reported that only 10 (3.1\%) of 320
patients with anti-ARS antibodies had anti-OJ antibodies. Among them,
90\% had interstitial pneumonia, and 40\% presented with myositis,
mechanic's hands, and arthritis. Most publications describing patients
with anti-OJ antibodies have primarily focused on interstitial
pneumonia\textsuperscript{8}, with only one report mentioning
myositis\textsuperscript{9} and none describing skin changes with
necrosis. Our patient experienced mild interstitial pneumonia, while
muscle weakness and necrosis of the fingers were prominent. Although the
patient remained independent for activities of daily living, he faced
difficulties in swallowing and lost the ability to walk after just 1
month. Finger necrosis was notably absent upon admission but progressed
rapidly and intensely within 3 days.

On admission, anti-Ro-52 was strongly positive. Anti-ARS antibody
syndrome typically involves anti-Ro-52 antibodies, and these are
associated with a poor prognosis when anti-ARS antibody syndrome occurs
along with concomitant interstitial
pneumonia.\textsuperscript{10}Anti-Ro-52 antibodies are found in up to
37\% of patients with myositis, and this often correlates with anti-Jo-1
reactivity.\textsuperscript{1}This, together with the clinical
presentation, indicated myositis involvement. However, anti-Jo-1 and
anti-ARS antibodies were all negative. Few reports have described finger
necrosis due to myositis, and we considered the possibility of a
paraneoplastic acral vascular syndrome.\textsuperscript{12}
Consequently, we requested a test for anti-U5snRNP antibody, which was
negative. Nevertheless, we retested anti-OJ antibody by
immunoprecipitation, which was positive.

We considered initiating PSL at a dose of 1 mg/kg for the patient while
awaiting the examination results. However, because of the sudden
deterioration of the patient's respiratory status, (necessitating the
administration of 10 min of masked oxygen), and the possibility of
exacerbation of the interstitial pneumonia, we opted for
methylprednisolone pulse treatment. Imaging revealed a mildly
exacerbated interstitial shadow, without elevated KL-6 or SP-D. He also
had a history of chronic obstructive pulmonary disease as a cause of
worsening respiratory status, which was thought to be due to
CO\textsubscript{2} narcosis. After administering the methylprednisolone
pulse, the expanding necrotic lesion, which had shown no signs of prior
improvement, exhibited a purple transition zone at the border between
the normal skin and black necrotic area (Fig. 1C). Subsequently, the
expansion of necrosis halted. The pathogenesis of finger necrosis in
anti-ARS syndrome has been documented. For example, Chan et
al.\textsuperscript{13} reported a PL-7(+) case where conventional
angiography revealed occlusion of the second to fourth fingers. Suma et
al.\textsuperscript{14} reported Jo-1(+) anti-ARS antibody (+)
mechanistic hand, with peripheral angiography revealing occlusion of
both the ulnar and radial arteries. Linear hemorrhage of fingernails
accompanied by digital ischemia or digital ulcer in anti-ARS syndrome
has also been reported.\textsuperscript{13--15}In our case, no obvious
stenosis or occlusion was observed on contrast-enhanced CT angiography,
and there was no linear hemorrhage of the nails. However, we observed
extreme necrosis, which was unprecedented in our experience.
Nonetheless, the presence of necrosis would typically suggest ischemia
caused by blood flow obstruction in the vessel, which may be a
limitation of CT angiography. Furthermore, because of the patient's
intubation and poor general condition, angiography was not performed.
Although the patient had no history of Raynaud phenomenon, spasms of the
peripheral arteries in the fingers might have contributed to the
significant necrosis. However, there are \textbackslash{}soutno few
reports of digital necrosis in patients who are positive for anti-OJ
antibodies. Lastly, muscle strength showed significant improvement after
PSL administration, showing the efficacy of PSL pulses in these
patients.

The limited number of reports may be attributed to the rarity of this
condition and challenges in testing. Anti-OJ antibodies are difficult to
detect among all myositis-specific antibodies. Unlike other tRNA
synthetase targets of autoantibodies, including Jo-1, PL-7, PL-12, KS,
EJ, and Zo, OJ antibodies are complex high-molecular-weight proteins
with several subunits, posing challenges for antigen
selection.\textsuperscript{16} The LIA method has lower sensitivity in
detecting anti-OJ antibodies.\textsuperscript{17--19} However, it is
still widely applied in clinical practice owing to the lack of
alternative methods and its ease of use, despite the superior diagnostic
performance of advanced immunoprecipitation methods.\textsuperscript{20,
21} In this case, although the patient initially tested negative for
anti-OJ antibodies using the LIA method, he tested positive based on the
immunoprecipitation method. The single enzyme-linked immunosorbent assay
kit commonly used for the anti-ARS antibody assay no longer detects
anti-Zo and anti-Ha antibodies, as they have only been reported in
isolated cases.

If clinicians suspect the presence of anti-OJ antibodies and myositis
and finger necrosis are more prominent than symptoms of interstitial
pneumonia, a diagnosis should be confirmed through immunoprecipitation.

\textbf{CONCLUSION}

We described the case of an older patient with late-onset ARS syndrome
who tested positive for anti-OJ and anti-Ro-52 antibodies. Interstitial
pneumonia is an established complication of anti-ARS antibody syndrome,
particularly when accompanied by positive anti-OJ antibodies. However,
it can also result in rapid necrosis of the fingers without interstitial
pneumonia. Prednisolone pulse therapy was remarkably effective, leading
to the rapid cessation of disease progression. Detecting anti-OJ
antibodies by immunoprecipitation is potentially more reliable than the
LIA method. Information on the clinical course of this atypical ARS
syndrome and treatment could contribute to the daily practice of
rheumatology for clinicians.

\textbf{AUTHOR CONTRIBUTIONS}

\textbf{Yugo Horiuchi} : Conceptualization; data curation; project
administration; writing-original draft.

\textbf{Kenichi Hashimoto} : Conceptualization; data curation; project
administration; supervision; writing-review and editing.

\textbf{Ryochi Yoshida:} Supervision; writing-review and editing.

\textbf{Yuji Tanaka:} Supervision; writing-review and editing.

\textbf{ACKNOWLEDGMENTS}

We thank Editage\textsuperscript{} for providing professional English
editing of the manuscript.

\textbf{PATIENT CONSENT}

Written informed consent was obtained from the patient.

ORCID\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}ID

Kenichi Hashimoto \emph{https://orcid.org}. 0000-0001-6838-1215

Ryochi Yoshida \emph{https://orcid.org}. 0000-0001-5215-2266



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\textbf{FIGURE LEGENDS}

\textbf{Figure 1} . Imaging findings of affected fingers

Hospitalization days 1 (A), 3 (B), 10 (C) after first prednisolone pulse
and 70 (D) at discharge. Red arrow (D) shows purple transition zone
between black necrotic area and normal skin.

\textbf{Figure 2} . PET-CT imaging findings on day 1 of hospitalization

Widespread accumulation centered on (A) soft shoulder tissues and on (B)
quadriceps muscle.

Blood glucose levels are normal.

PET-CT, positron emission tomography-computed tomography\selectlanguage{english}
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