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ISSN 1439-7595 (print), 1439-7609 (online)
Mod Rheumatol, 2017; 27(5):917–918
ß 2016 Japan College of Rheumatology
DOI: 10.1080/14397595.2016.1253814
LETTER TO THE EDITOR
Successful ledipasvir + sofosbuvir treatment of active synovitis in a
rheumatoid arthritis patient with hepatitis C virus-related mixed
cryoglobulinemia
Sir,
Hepatitis C virus (HCV)-related arthritis is one of the most
common extrahepatic manifestations of HCV infection. Like
rheumatoid arthritis (RA), HCV infection also causes various
immune disorders, such as an autoimmune reaction, deposition of
immune complexes, and lymphoproliferation [1].
The treatment of hepatitis C has dramatically improved since
the development of novel direct-acting antiviral drugs (DAAs).
The combination of the NS5A inhibitor ledipasvir (LDV) and the
NS5B polymerase inhibitor sofosbuvir (SOF) was recently
approved in Japan for the treatment of HCV. Clinical trials have
revealed the safety and efficacy of a once-daily fixed-dose
combination tablet of LDV/SOF without ribavirin in patients
chronically infected with genotype 1 HCV [2]. In addition, a
recent study has shown the efficacy of SOF plus ribavirin for
HCV-related cryoglobulinemic vasculitis [3]. However, the effect
of this treatment on HCV-related arthritis or HCV infection with
RA is not known. In this report, we describe the successful LDV/
SOF-alone treatment of a patient with HCV-related mixed MC
complicated with RA.
A 78-year-old Japanese female was diagnosed with chronic
HCV infection along with MC in 2014. She had suffered morning
stiffness, pain, and swollen joints in her hands for 6 months and
was referred to our hospital for the further evaluation of
polyarthritis. Physical examination revealed symmetric arthritis
with tenderness and swelling of bilateral metacarpophalangeal
(MCP) joints, proximal interphalangeal joints and wrists but no
evidence of cutaneous lesions including palpable purpura. Her
blood and serum chemistry test results were normal except for
aspirate aminotransferase (61 IU/L) and alanine aminotransferase
(59 IU/L). Immunological studies showed the following: rheuma-
toid factor 59 U/ml, anti-citrullinated protein antibody 1.3 U/ml,
antinuclear antibody 51:20, anti-double-stranded DNA antibody
2.8 IU/mL, IgG 3565 mg/dL, and IgA 151 mg/dL. Her C3, C4, and
CH50 levels were all normal. A laboratory investigation confirmed
the type II MC. Quantitative PCR for HCV RNA showed that the
viral load was 5.1 Log IU/mL and the genotype was 1b. An NS5A
sequences analysis found no mutation at L31 or Y93. The X-ray of
the patient’s hands showed typical bone erosions in the second
MCP joint and ulnar styloid processes. The findings of muscu-
loskeletal ultrasound (MSKUS) for her hands revealed active
synovitis and severe tenosynovitis of extensors with high-intensity
power Doppler (PD) signals (Figure 1A, B). Collectively, we
diagnosed HCV-related MC complicated with active RA. There
was no evidence of cryoglobulinemic vasculitis. The Disease
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Activity Score in 28 joints-erythrocyte sedimentation rate (DAS-
ESR) at the diagnosis was 6.60.
Accordingly, we initiated sulfasalazine for the treatment of the
patient’s RA in January 2015 but it did not improve her arthritis.
We then discontinued the sulfasalazine due to liver dysfunction.
We subsequently introduced a course of daily LDV (90 mg)/SOF
(400 mg) treatment from November 2015 to February 2016, and it
rapidly improved her arthritis and resulted in a normalized level of
cryoglobulin. She achieved DAS28-ESR remission as well as a
sustained virological response (SVR) at 12 weeks of LDV/SOF
treatment. Of note, the continuous and substantial improvement of
her PD signals in the hands was observed 3 months after the
treatment (Figure 1C, D).
In the present case, it is important to distinguish three different
clinical conditions: HCV-related arthritis, arthritis complicating a
cryoglobulinemia syndrome (MCS) and HCV infection with RA.
We diagnosed this patient with RA based on the typical erosion in
her hands because HCV-related arthritis is characterized by the
absence of radiological features including bone erosions [4]. In
addition, the high intensity of PD signals in MSKUS also indicated
RA, since power Doppler ultrasonography (PDUS) is a sensitive
and reliable method for the assessment of RA [5]. However,
further studies are needed to assess the utility of MSKUS in
distinguishing HCV-related arthritis from HCV infection with RA.
Although HCV is known to accelerate the production of
autoantibodies [6], this case did not exhibit the clinical manifest-
ation of systemic lupus erythematosus or Sjögren syndrome.
The precise mechanism by which HCV infection accelerates
arthritis in RA has not been determined, but a local inflammatory
response to synovial tissue damage could act directly by viral
invasion or indirectly by the deposition of cryoglobulin-induced
immune complexes in synovial fluid. In addition, the disappear-
ance of HCV following treatment with DAAs may affect the host’s
immune regulation. It has been reported that patients with HCV
infection displayed an increased level of interferon-g-induced
protein 10 (IP-10) [7] and that NS5A activates phosphatidylino-
sitol 3-kinase (PI3K)-protein kinase B (Akt) signaling [8]. As IP-
10 and the PI3K-Akt pathway are implicated in the pathogenesis
of RA [9], it is possible that the treatment with LDV/SOF directly
altered the clinical course of RA in the present case.
The LDV/SOF therapy successfully improved not only the
HCV infection but also the clinical findings of RA along with the
decreased PD signals defined by MSKUS suggesting that
treatment with DAAs has a potential for treating RA. Further
functional studies and case series are required to clarify whether
LDV/SOF therapy might be effective for MCS-induced arthritis in
RA without HCV infection.
918 T. Koga et al. Mod Rheumatol, 2017; 27(5): 917–918

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Figure 1. The findings of musculoskeletal ultrasound in the patient’s hand (A,B: pre-treatment, C,D: post-treatment). The high-intensity power Doppler
signals in (A) the second metacarpophalangeal joint and (B) the tendon of extensor indicis were nearly gone after the LDV/SOF treatment.

Conflict of interest
None.
Tomohiro Koga and Shin-ya Kawashiri
Department of Immunology and Rheumatology,
Unit of Advanced Preventive Medical Sciences, Nagasaki
University Graduate School of Biomedical Sciences,
Nagasaki, Japan
Email: tkoga@nagasaki-u.ac.jp
Kazuhiko Nakao
Department of Gastroenterology and Hepatology,
Nagasaki University Hospital,
Nagasaki, Japan
Atsushi Kawakami
Department of Immunology and
Rheumatology, Unit of Advanced Preventive
Medical Sciences, Nagasaki University
Graduate School of Biomedical Sciences,
Nagasaki, Japan
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