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\begin{document}

\title{Antisynthetase Syndrome after chikungunya infection: a case report}



\author[1]{Raiza Tuão}%
\author[1]{Mariana Macabú}%
\author[1]{Paula Athayde}%
\author[1]{Isac Moulaz}%
\author[1]{Bárbara Dalmaso}%
\author[1]{Valeria Valim}%
\author[1]{Ketty Lysie Machado}%
\affil[1]{Hucam}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Chikungunya is an arboviral disease caused by a virus with wide
geographical distribution in endemic areas. This case report documents a
patient with Antisynthetase Syndrome post-chikungunya infection.
Autoimmune diseases result from breakdown of immune tolerance. Among all
triggers, viruses represent the greatest environmental potential to
precipitate inflammatory myopathy.%
\end{abstract}%



\sloppy


\textbf{Antisynthetase Syndrome after chikungunya infection: a case
report}

\selectlanguage{ngerman}\textbf{Raiza Cansian Tuão¹, Mariana de Oliveira Macabú², Paula dos
Santos Athayde², Isac Ribeiro Moulaz², Barbara Ferraço Dalmaso¹, Valéria
Valim Cristo³, Ketty Lysie Libardi Lira Machado³}

¹Rheumatology Resident at Cassiano Antonio Moraes University Hospital --
HUCAM / UFES

²Medical Student at Cassiano Antonio Moraes University Hospital -- HUCAM
/ UFES

³Rheumatology Attending Physician at Cassiano Antonio Moraes University
Hospital -- HUCAM / UFES

\textbf{ABSTRACT}

Chikungunya is an arboviral disease caused by a virus with wide
geographical distribution in endemic areas. This case report documents a
patient with Antisynthetase Syndrome post-chikungunya infection.
Autoimmune diseases result from breakdown of immune tolerance. Among all
triggers, viruses represent the greatest environmental potential to
precipitate inflammatory myopathy.

\textbf{KEYWORDS:}

Case report, Chikungunya virus, Myositis, Myopathy.

\textbf{INTRODUCTION}

Chikungunya virus (CHIKV) is an alphavirus endemic in Africa, Asia, and
South America and can be found in tropical areas with seasonal
characteristics, with outbreaks reported in several countries worldwide
(1,2). Chikungunya presents a broad symptom spectrum, similar to other
arboviroses, including fever, rash, myalgia, arthralgia, and headache
(3). When duration of symptoms persists beyond three months it reaches
the chronic phase, with persistence of arthritis and joint tenosynovitis
(1).

CHIKV infection can be a trigger for onset of autoimmune diseases in
genetically predisposed individuals (2). In this scenario, inflammatory
myopathy is an extremely rare presentation of CHIKV scarcely described
in the literature. This article aims to report a rare case of an
antisynthetase syndrome (ASS) post-chikungunya infection, characterized
by muscle weakness, interstitial lung disease, and positive anti-Jo-1.

\textbf{CASE PRESENTATION}

We report a 38-year-old female patient, previously healthy, presented
with high fever, adynamia, diffuse myalgia, and polyarthralgia of hands,
wrists, elbows, and knees. She sought medical attention and was
diagnosed with CHIKV infection, confirmed by a positive IgM
Enzyme-Linked Immunosorbent Assay (ELISA) serological study in two
samples. Joint pain and myalgia persisted, and after two months, she
presented progressive complaints of fatigue, difficulty combing her
hair, walking, and getting out of bed. She had frequent falls, dysphagia
for solids, dysphonia, dyspnea on mild exertion, and was bedridden. She
was then admitted to the hospital for investigation.

On physical examination, she presented decreased proximal limb muscle
strength, grade 2 in lower limbs and grade 3 in upper limbs, according
to Medical Research Council (MRC) scale. Pulmonary auscultation
presented fine bilateral basilar crackles. Manual muscle test (MMT) of
64 out of 150 points. Locomotor examination showed arthritis in knees
and ankles bilaterally.

Complementary examinations revealed elevated creatine phosphokinase
(CPK: 25150 U/L {[}VR: 0 A 170 U/L{]}) and increased transaminases (TGO:
377 U/L and TGP: 264 U/L {[}VR: 0 A 31 U/L{]}). Anti-Jo-1 antibody was
reagent (141 U/mL {[}VR: reagent \textgreater{} 10 U/mL{]}). Antinuclear
antibody (ANA) with a mixed pattern of 1/80 fine dotted nuclear type and
1/160 dotted cytoplasmic type. Electroneuromyography of four limbs
confirmed a pattern of myopathy, affecting mostly proximal muscles.
Magnetic resonance imaging (MRI) of thighs showed diffuse edema of
muscles, without areas of liposubstitution, suggesting an acute
inflammatory process (Figures 1 and 2). Chest computed tomography (CT)
scan showed ground-glass opacities in bases up to the middle third of
lungs, compatible with nonspecific interstitial pneumopathy (NSIP).

The diagnosis of Antisynthetase Syndrome, an immune-mediated
inflammatory myopathy, post-Chikungunya infection, was then established.
The patient presented with a compatible clinical, with proximal muscle
weakness in all four limbs, MRI of thighs showing a muscular
inflammatory process, electroneuromyography with a myopathic pattern,
interstitial pneumopathy, and a positive Anti-Jo1 antibody, in addition
to joint involvement.

Other etiological causes were investigated and ruled out, such as viral
infections by hepatitis virus, cytomegalovirus, HIV, syphilis, and
COVID-19, metabolic disorders, use of previous medications, and
screening for neoplasms, confirming chikungunya as the trigger for
myopathy.

Pulse therapy was started with methylprednisolone for 3 days and human
immunoglobulin for 6 monthly cycles. The patient had clinical recovery
and a gradual decrease in muscle enzymes, reaching 257 U/L (VR: 0 to 170
U/L) after 6 months. She was also given monthly intravenous
cyclophosphamide for a period of 6 months due to pulmonary involvement.
The patient maintained motor and respiratory physical therapy, evolving
with grade V muscle strength in the four limbs, with no complaints of
fatigue, dysphagia, or dysphonia.

\textbf{Figure 1:} A) Coronal T1 (hip and thigh images): absence of
muscle liposubstitution. B) Coronal T2 with fat saturation (SPAIR
technique): Diffuse muscular edema affecting the pelvic girdles and
thighs.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 2:} C) Axial T1: mild muscle volume reduction, with no
evidence of liposubstitution. D) Axial T2 with fat saturation (SPAIR
technique): diffuse edema of musculature of the anterior, posterior and
medial compartments.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{DISCUSSION}

Chikungunya is an arboviral disease caused by an RNA virus with wide
geographical distribution in endemic areas, and other tropical areas
with seasonal characteristics that are favorable to development of
disease vectors (Aedes aegypti and Aedes albopictus) (4). The chance of
large outbreaks of CHIKV worldwide is high, especially in developing
countries due to abundance of vectors (5). In 2007, an infected tourist
from India introduced chikungunya to northern Italy, resulting in the
identification of 292 suspected cases (6).

Chikungunya is self-limited and has a broad clinical spectrum, being
characterized by a characteristic triad consisting of fever, arthralgia,
and rash (5). The clinical course of the disease can be divided into
acute and chronic phases. In acute phase, there may be fever,
symmetrical polyarthralgia, headache, nausea, vomiting, fatigue, and
myalgia. Arthralgia affects large and small joints and preferentially
involves more distal regions such as ankles, wrists, and phalanges (4).
Joint pain may persist, characterizing onset of chronic phase, which
lasts for 12 weeks to years (4). The prevalence of chronic phase is
highly variable and may affect more than half of the patients (1).
Complications of cardiovascular, renal, respiratory, hepatic,
gastrointestinal and adrenal systems are associated with the infection
and are referred to as atypical features (3).

In addition, CHIKV, like other viruses, can act as a trigger for
autoimmune diseases, among them, autoimmune inflammatory myopathies, a
group of diseases characterized by presence of inflammation of skeletal
muscle and subdivided into Dermatomyositis (DM), Polymyositis (PM),
Necrotizing Autoimmune Myopathy (MAN), Inclusion Corpuscle Myopathy
(ICM) and Anti-synthetase Syndrome (SAS), according to clinical,
histological, immunopathological and autoantibody characteristics (7).

Autoimmune diseases are the result of hyperstimulation of immunity,
caused by breakdown of immune tolerance, which has a multifactorial
etiology. Among all potential triggers for development of autoimmune
diseases, viruses represent the greatest environmental potential to
trigger inflammatory myopathy (IM) in genetically susceptible
individuals. Inflammatory myopathy has been observed during or after
viral infection, but attempts to amplify viruses from muscles, including
coxsackievirus, influenza, paramyxovirus, mumps, cytomegalovirus, and
Epstein-Barr virus have failed. The best studied viral relationship so
far has been with retrovirus (7). However, there are fewer case reports
in the literature highlighting association of CHIKV with the development
of autoimmune diseases, especially inflammatory myopathies (5,8).

Dev, et al (2019), reported a case of inflammatory myositis following
Chikungunya infection in 2019 in India (8). Martins, et al (2016),
reported a case of a patient presenting with myositis and encephalitis
post-CHIKV infection in Brazil (5). However, this is the first case of
antisynthetase syndrome post-chikungunya infection characterized in
literature.

There are possible hypothesized mechanisms for development of
post-infection-induced autoimmune disease. Autoreactive T cells can be
activated by cross-linking with a viral antigen that bears similarity to
autoantigen, and become pathogenic. Stimulation of Toll-like receptors
and other pattern-recognition receptors on antigen-presenting cells
leads to production of pro-inflammatory mediators, which can trigger
tissue damage. Tissue destruction by T-cells and inflammatory mediators
further increase release of autoantigens, potentiating the immune
response (2).

Another possible mechanism is the evasion of host's innate and adaptive
immune responses by the virus, as seen in mice showing a chronic
inflammatory process in ankles after inoculation with CHIKV RNA and
persistence of the virus in the local tissue. Furthermore, several
alphaviruses, including CHIKV, have been shown to antagonize STAT
activation by type I and type II interferon (9).

ASS is a rare disease with unknown incidence and a prevalence twice
higher in females. It presents a broad clinical picture, with proximal
muscle weakness, arthritis, arthralgia, Raynaud's phenomenon, fever,
''mechanic's hands'' and interstitial lung disease. It is related to
presence of anti-synthetase autoantibodies, especially anti-Jo-1, and to
histological presentation of perimysial and perifascicular muscle fiber
necrosis. Pulmonary involvement is related to high morbidity and
mortality rates, especially interstitial lung disease (ILD), which can
present with dyspnea, cough, and chest pain (7).

In this case, the patient presented with proximal muscle weakness in all
four limbs, MRI of thighs showing a muscular inflammatory process,
electroneuromyography with a myopathic pattern, interstitial
pneumopathy, and a reagent Anti-Jo1 antibody, in addition to joint
involvement. The case report presented some limitations, such as the
fact that the patient did not perform a muscle biopsy, due to lack of
availability of the procedure at the service. The patient also did not
present mechanic's hands, a classic but not specific sign (10).

\textbf{CONCLUSION}

More studies are needed to highlight and detail the pathophysiology of
CHIKV in development of autoimmune diseases in genetically susceptible
individuals, as well as its diverse clinical presentations. It is known
that viral infections can be triggers for inflammatory myopathies and
therefore attention should be given to patients who persist with muscle
weakness and myalgia after a Chikungunya infection.

\textbf{ACKNOWLEDGMENT}

No acknowledgments to be made.

\textbf{CONFLICT OF INTEREST}

No conflict of interest.

\textbf{AUTHOR CONTRIBUTIONS}

Raiza Cansian Tu\selectlanguage{ngerman}ão and Ketty Lysie Libardi Lira Machado: conceptualized
the study, wrote, revised and edited the manuscript, analyzed and
interpreted the muscle magnetic resonance images. Mariana de Oliveira
Macabú, Paula dos Santos Athayde, Isac Ribeiro Moulaz and Barbara
Ferraço Dalmaso: wrote, revised and edited the manuscript. Valéria Valim
Cristo conceptualized and revised the manuscript. All authors were
involved in editing and approving the manuscript.

\textbf{ETHICAL APPROVAL}

This case report was carried out following the recommendations of the
ethics committee of the Cassiano Antonio Moraes University Hospital -
HUCAM, Brazil.

\textbf{CONSENT}

Written informed consent was obtained from the patient for the
publication of this case report.

\textbf{DATA AVAILABILITY STATEMENT}

All data included in this report are accurate to the best of our
knowledge. We will make available data (images and reports) upon
request.

\textbf{ORCID}

Raiza Cansian Tuão https://orcid.org/0000-0003-3002-3185

\textbf{REFERENCES}

1 -- Ministério da Saúde, Brazil: Chikungunya clinical management.
Brasília: 2017; 1: 1-67.
https://bvsms.saude.gov.br/bvs/publicacoes/chikungunya\_manejo\_clinico.pdf.
Accessed October 10, 2021.

2 - Getts MT, Miller SD: 99th Dahlem conference on infection,
inflammation and chronic inflammatory disorders: triggering of
autoimmune diseases by infections. Clin. exp. immunol. 2010; 160: 15-21.

3- Vairo F, Haider N, Kock R, Ntoumi F, Ippolito G, Zumla A:
Chikungunya: Epidemiology, Pathogenesis, Clinical Features, Management,
and Prevention. Infect Dis Clin North Am. 2019; 33: 1003-25.

4- Castro APCR, Lima RAN, Santos J: Chikungunya: vision of the pain
clinician. Revista Dor (online) 2016; 17: 299-302.

5- Martins HA, Bernardino SN, Santos CC, Ribas VR: Chikungunya and
Myositis: A Case Report in Brazil. J Clin Diagn Res 2016; 10: OD05-06.

6- Choudhary N, Makhija P, Puri V, Khwaja GA, Duggal A: An Unusual Case
of Myelitis with Myositis. J Clin Diagn Res 2016; 10: OD19-20.

7- Dalakas MC: Inflammatory myopathies: update on diagnosis,
pathogenesis and therapies, and COVID-19-related implications. Acta myol
2020; 39: 289-301.

8- Dev N, Kumar R, Gogna A, Sharma S: Chikungunya-induced inflammatory
myositis: a case report in India. Trop Doct 2019; 49: 241-3.

9 - Morrison TE, Oko L, Montgomery SA, et al.: A mouse model of
chikungunya virus-induced musculoskeletal inflammatory disease: evidence
of arthritis, tenosynovitis, myositis, and persistence. Am J Pathol
2011; 178: 32-40.

10. Carboni RCS, Pinto GLB, Shinjo SK. High YKL-40 serum levels and its
expression in the muscle tissues of patients with antisynthetase
syndrome. Adv. Rheumal 2021; 61:44.

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