Nama : Andiany Cahyanty Tahir

Nim : 821419003
Kelas : A-S1 FARMASI 2019
Tugas : Farmakoterapi 2

Review Jurnal tentang Obat Adalimumab.

Pada jurnal 1 yang diterbitkan oleh Dovepress dengan judul jurnal “Terapi Adalimumab Pada
Pasien dengan Psoriasis, Down Syndrome, dan Hepatitis Bersamaan Infeksi Virus B” yang ditulis
oleh Abdulaziz Madani dan Qais Almuhaideb pada tahun 2021 menjelaskan bahwa, Adalimumab
merupakan antibodi monoclonal terhadap tumor yang disebabkan oleh faktor nekrosis (TNF)-α, yang
menghalangi adanya interaksi antara TNF dengan reseptor permukaan selnya. Adalimumab adalah obat
yang dikenal dengan untuk mengobati psoriasis plak kronis sedang hingga parah yang terjadi pada orang
dewasa. Akan tetapi data tentang penggunaan adalimumab pada pasien dengan psoriasis dan hepatitis
virus secara bersamaan masih kurang, hanya sedikit yang diketahui tentang keamanan obat yang
sebenarnya terjadi.
Berdasarkan uraian kasus pada jurnal ini , Adalimumab dimulai pada tahun 2020 dengan dosis
80 mg, diikuti dengan dosis 40 mg setiap minggu. Dua bulan setelah perawatan, lesi di batang tubuh
membaik 30% dan lesi di ekstremitas atas dan telinga benar- benar sembuh. Namun, luka pada tungkai
dan kaki tidak kunjung membaik. Pasien tidak mengeluh nyeri atau kaku sendi. Dia telah berhenti
menggunakan obat topikal, jadi salep calcipotriene-betametason topikal diperkenalkan kembali. Tujuh
bulan setelah perawatan, lesi lutut, tungkai, dan kaki menunjukkan perbaikan lebih dari 70 dan tidak ada
nyeri sendi. Pada kasus ini, pasien masih dirawat dengan adalimumab, entecavir, dan calcipotriene salep
betametason.
Hasil yang di dapat disimpulkan pada jurnal ini yaitu, kasus dengan kondisi penyakit
psoriasis berat pada pasien disertai dengan adanya down sindrom dan infeksi virus HBV secara
bersamaan dapat merespons pemberiaan obat adalimumab. Sehingga dokter harus menyadari hubungan
antara Down sindrom dan psoriasis, untuk berhati-hati dengan penggunaan pengobatan biologis pada
pasien dengan Down sindrom. Studi yang lebih luas diperlukan untuk mengevaluasi kemanjuran dan
keamanan adalimumab pada pasien dengan DS dengan psoriasis.
 Pada jurnal 2 yang diterbitkan oleh Oceana Biomedicina Journal pada tahun 2018 dengan judul
“PERKEMBANGAN TERKINI TERAPI RHEUMATOID ARTHRITIS” oleh Hendrata Erry
Andisari menjelaskan bahwa, Terapi pada Rheumatoid Arthritis telah banyak mengalami kemajuan
dewasa ini dan sejalan dengan pengetahuan tentang patogenesis Rheumatoid Arthritis, tujuan terapi saat
ini adalah mengubah perjalanan dan mengontrol aktivitas penyakit Rheumatoid Arthritis. Beberapa
kelompok obat-obatan telah digunakan dalam terapi Rheumatoid Arthritis diantaranya adalah obat
Dengan disease modifying antirheumatic drugs (DMARD) baik yang konvensional (cDMARD) maupun
agen biologi (bDMARD). TNF merupakan suatu sitokin proinflamasi yang dihasilkan oleh monosit yang
teraktivasi yg diupregulasi di sinovium pada RA yang aktif. Penghambatan terhadap TNF telah
dihubungkan dengan perbaikan gejala klinis dan juga mengurangi progresifitas gambaran radiologi.
Sampai saat ini, ada lima agen biologi yang kerjanya menghambat TNF yang telah digunakan dalam
terapi RA salah satunya yaitu adalimumab. Dijelaskan pada jurnal ini bahwa Adalimubab merupakan
fully humanized antibodi monoklonal terhadap TNF yang diberikan secara injeksi subkutan pada dosis
40 mg setiap 2 minggu dengan waktu timbulnya respon yaitu beberapa hari sampai 4 bulan dengan efek
samping yang terjadi pada Reaksi infus, peningkatan risiko infeksi termasuk reaktifasi TB, dan gangguan
demyelinisasi.
Pada Jurnal 3 dengan penerbit Frontiers in Immunology pada tahun 2021 dengan judul “Terapi
Adalimumab Dalam Menyembuhkan Mikrobiota Usus Pada Pasien Dengan Ankylosing
Spondylitis” oleh Zena Chen, Xuqi Zheng, Xinyu Wu, Jialing Wu, Xiaomin Li, Qiujing Wei, Xi Zhang,
Linkai Fang, Ou Jin dan Jieruo Gu menjelaskan bahwa, Ankylosing spondylitis (AS) adalah gangguan
inflamasi kronis yang mempengaruhi kerangka aksial, sehingga menyebabkan nyeri punggung dengan
inflamasi yang khas dan dapat menyebabkan gangguan struktural dan fungsional serta penurunan
kualitas hidup. Sebagai antibodi monoklonal manusiawi yang menargetkan TNF, adalimumab telah
berhasil digunakan untuk mengelola peradangan pada pasien AS di klinik, terutama pada mereka dengan
gejala ekstra-artikular seperti IBD dan uveitis. Dilaporkan untuk memperbaiki gejala dan
mengembalikan mikrobiota usus pada pasien dengan IBD. Selain itu, fitur dasar dari mikrobioma usus
sangat berharga dalam memprediksi respons pengobatan terhadap TNFi pada pasien dengan IBD.
Namun, hubungan antara perubahan mikrobioma usus dan pengobatan adalimumab pada pasien AS
tidak diketahui. Pada penelitian ini terdapat beberapa keterbatasan. Pertama, pasien yang diobati dengan
TNF lain atau pengobatan lain seperti NSAID tidak direkrut, sehingga tidak dapat menyimpulkan bahwa
pemulihan mikrobiota secara khusus terkait dengan pengobatan adalimumab. Kedua, karena informasi
pola diet tidak dikumpulkan, pengaruh diet tidak diperhitungkan. Namun, karena membandingkan
pasien yang sama sebelum dan sesudah perawatan, efek diet apa pun seharusnya agak berkurang.
Sehingga, ukuran cohort yang kecil, dan kekuatan analisis statistik mungkin terbatas. Namun, hampir
30% pasien tidak menunjukkan respons terhadap terapi adalimumab, yang konsisten dengan penelitian
skala besar sebelumnya, sehingga meningkatkan validitas eksternal penelitian kami. Pada Hasil jurnal
ini menunjukkan bahwa mikrobiota usus menjadi alat potensial untuk memprediksi respons pengobatan
terhadap adalimumab pada pasien AS. Studi tambahan diperlukan untuk menyelidiki lebih lanjut spesies
bakteri yang memainkan peran kunci dalam menanggapi pengobatan adalimumab, yang akan membantu
untuk mencapai intervensi medis yang tepat.
Biologics: Targets and Therapy
Open Access Full Text Article
Adalimumab Therapy in a Patient with Psoriasis,
Down Syndrome, and Concomitant Hepatitis
B Virus Infection
Abdulaziz Madani 1
2 with a combination of dysmorphic features, congenital heart disease, and immunological
Qais Almuhaideb
1
Department of Dermatology, College of
Medicine, King Saud University, Riyadh,
Saudi Arabia; 2College of Medicine, King
Saud University, Riyadh, Saudi Arabia
Correspondence: Abdulaziz Madani
King Saud University, Riyadh, 11451, Saudi
Arabia
Tel +966 1-80 66481
Fax +966114671992
Email Amadani1@ksu.edu.sa
Received: 8 June 2021
Accepted: 24 August 2021
Published: 1 September 2021
Dovepress
open access to scientific and medical research
C A S E R E P O RT
Abstract: Down syndrome is the most common chromosomal disorder and may present
deficiency. The association between Down syndrome and psoriasis is unclear. The prevalence
of psoriasis in patients with Down syndrome ranges from 0.5% to 8%. The safety of
biologics in the treatment of Down syndrome-related psoriasis is still debated. Down
syndrome results in mild immunological abnormalities; consequently, the risk of infectious
complications during immunosuppressive therapy might be higher in this group of patients.
We report a case of a 33-year-old male, a case of chronic plaque psoriasis, Down syndrome
(DS), asthma, and hepatitis B. The patient was started on Calcipotriene 0.005%-
betamethasone 0.064% ointment, which failed to control the patient’s psoriasis; thus, adali­
mumab was started. His response to adalimumab was significant, where over 70% improve­
ment of the psoriatic lesions was seen.
Keywords: adalimumab, biologics, trisomy 21, HBV
Introduction
Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by an
additional copy of chromosome 21.1 DS is associated with rare dermatological
conditions and an increased frequency of some common dermatoses.2 Individuals
with DS have a higher prevalence of psoriasis, reaching 8%.3,4 The association
between DS and the development of psoriasis and its severity is unclear.5,6 We
report a case of psoriasis in a patient with DS with concomitant hepatitis B virus
(HBV) infection that successfully responded to adalimumab.
Case Presentation
A 33-year-old male with chronic plaque psoriasis since 2009, DS, and asthma with
atopy, presented to the Dermatology clinic at King Khalid University Hospital in
Riyadh, Saudi Arabia in 2018. At his initial presentation to our clinic, over 10% of
his body surface area (BSA) was covered with hyperkeratotic erythematous scaly
plaques over his lower limbs, knees, and elbows (Figure 1). The patient was started
on topical calcipotriene 0.005%-betamethasone 0.064% ointment daily.
Over the next months, the response to calcipotriene 0.005% betamethasone
0.064% ointment was poor and BSA remained more than 10%. The patient devel­
oped bilateral diffuse erythematous scaly plaques over the upper extremities, trunk,
Biologics: Targets and Therapy 2021:15 375–378 375
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 Madani and Almuhaideb
Figure 1 Extensive bilateral psoriatic lesions over the knee, anterior leg, and
dorsum of the foot.
and left ear in addition to the bilateral hyperkeratotic
plaques over the knees, legs, and foot.
The patient underwent screening to start treatment with
adalimumab. The screening showed a normal complete
blood count and urinalysis; the liver function test was
normal except for low albumin (31.38 g/L). The interferon
gamma release assay (IGRA) test was negative, and hepa­
titis C was not detectable by PCR. Hepatitis B screening
showed positive hepatitis B surface antigen (HBsAg),
hepatitis B e antigen (HBeAg), and hepatitis B core anti­
body (anti-HBc); negative hepatitis B surface antibody
(HBsAb) and hepatitis B e antibody (HBeAb). The patient
was started with entecavir 0.5 mg oral daily by the hepa­
tology team.
Due to the extensive skin involvement and the lack of
improvement with topical treatment, a decision was made
to start the patient on a biologic treatment. Given the lack
of biologic options in our institution, and after discussion
with the hepatology team, a decision was made to start the
patient on adalimumab injections.
Adalimumab was started in 2020 with a dose of 80 mg,
followed by a dose of 40 mg every other week. Two
months after treatment, the lesions in the trunk improved
by 30% and the lesions in the upper extremities and ears
completely cleared up. However, the lesions on the legs
and feet did not improve. The patient did not complain of
376 https://doi.org/10.2147/BTT.S317888
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Figure 2 Significant improvement in psoriatic lesions after treatment with
adalimumab.
joint pain or stiffness. He had stopped using topical med­
ications, so the topical calcipotriene-betamethasone oint­
ment was reintroduced. Seven months into treatment, the
knee, leg, and foot lesions showed an improvement of over
70% (Figure 2), and no joint pain was present. At the time
of this writing, the patient was still being treated with
adalimumab, entecavir, and topical calcipotriene-
betamethasone ointment.
Discussion
Psoriasis affects 2.0% to 3.0% of the world’s population,
while it has been reported to reach 8% in patients with
Down syndrome.3,7 The concomitant presence of the two
diseases has been observed in several studies;3,4,6,8 how­
ever, the association between DS and psoriasis remains not
fully understood.3,5,6
This association can be explained by the dysregulation of
the interferon (IFN) system in DS patients.3,6 In psoriasis,
skin immunocytes produce various cytokines, one of which
is IFN-gamma, a significant culprit of psoriasis formation
and severity.3,5 In DS, the percentage of T cells producing
IFN-gamma and serum levels of IFN-gamma are substan­
tially higher than healthy controls.3 Furthermore, signal
transduction of IFN-gamma requires binding to its receptor
interferon gamma receptor-1 (IFNGR-1) and an accessory
factor, interferon gamma receptor-2 (IFNGR-2), encoded on
Biologics: Targets and Therapy 2021:15
 Dovepress Madani and Almuhaideb

chromosome 21. With the additional copy of chromosome
21 in DS patients, IFN sensitivity is increased.3 It is thought
that individuals with DS have a greater prevalence of psor­
iasis secondary to both high serum levels of and enhanced
sensitivity to IFN-gamma.3
Immunological alterations present in individuals with DS
can increase susceptibility to infections. Therefore, a higher
risk of infectious complications during immunosuppressive
treatment is expected.6 It is still debated if the use of biologics
in the treatment of DS-related psoriasis is safe.4 Thus, the
decision to initiate systemic immunosuppressive therapy
should be made carefully.6 Few studies have assessed the use
of biologic treatment for psoriasis in patients with DS
(Table 1).
Most of the systemic agents used in the treatment of
psoriasis are immunosuppressive, which poses a therapeutic
challenge in patients with psoriasis and chronic infections
since they are already immunosuppressed. Tumor Necrosis
Factor (TNF)-α plays a fundamental role in the elimination of
the hepatitis virus from infected hepatocytes. Hence, TNF-α
inhibitors may lead to reactivation or exacerbation of hepa­
titis. A study of 257 patients with hepatitis receiving anti–
TNF-α therapy showed that HBV reactivation was 39% in
HbsAg positive patients compared to 5% in anti-Hbc positive
patients. Furthermore, HBV reactivation was more frequent
in patients who did not receive antiviral prophylaxis com­
pared to patients who did.12
Adalimumab is a monoclonal antibody against tumor
necrosis factor (TNF)-alpha, which blocks TNF interaction
with its cell-surface receptors.9 Adalimumab is a known
drug for treating moderate to severe chronic plaque psor­
iasis in adults.10 As data concerning the use of adalimu­
mab in patients with psoriasis and concomitant viral

Table 1 Characteristics of Patients with Down Syndrome and Plaque Psoriasis Treated with Biologic Agents
Demographic The Severity of Previous Systemic Reason for Biologic The Severity
Data Psoriasis Prior to Treatment Stopping Treatment of Psoriasis
Systemic/Biologic After Biologic
Treatment Treatment

A 31-year-old4 After the failure of Anti-TNF Agents Failure of anti-TNF Ustekinumab 45 mg Significant
anti-TNF: agents S.C initially, 4 weeks improvement of
● PASI score: 12 later, then every 12 the PASI score
weeks.

A 12-year-old At the time of Cyclosporine 3.5 mg/kg/d, Massive viral warts Etanercept 0.8 mg/kg, At week 8:
girl6 admission: P.O. for 2 weeks. The dose was and loss of efficacy S.C. every week ● PASI score:
● PASI score: 41 tapered to 1.7 mg/kg/d due to 2.0
● BSA: 78% elevated liver enzymes ● BSA: 5.5%
After: cyclosporine:
● PASI score: 12.7
● BSA: 15.5%

A 12-year-old BSA: 10% Adalimumab 40 mg, S. At week 4:

boy3 C. every other week ● PGA: 1
● BSA: 1%

A 20-year-old BSA: 25% PGA=4 Methotrexate 15 mg weekly and Etanercept was Adalimumab 40 mg Significantly
man3 etanercept 50 mg once a week substituted for every other week and sustained
for 9 months. adalimumab 40 mg methotrexate 15 mg improvement
due to lack of every week for the next 3
efficacy years.

A 30-year-old BSA: 30% Etanercept 25 mg, S. At week 12:

man8 PASI score: 14 C. twice per week PASI score: 4
Abbreviations: DS, Down syndrome; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; Anti-HBc, hepatitis B core antibody; HBsAb,
hepatitis B surface antibody; HBeAb, hepatitis B e antibody; IFN, interferon; IFNGR-1, interferon gamma receptor-1; IFNGR-2, interferon gamma receptor-2; TNF, tumor
necrosis factor; PASI score, Psoriasis area and severity index score; BSA, body surface area; PGA, Physician Global Assessment.

Biologics: Targets and Therapy 2021:15 https://doi.org/10.2147/BTT.S317888

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 Madani and Almuhaideb
hepatitis is lacking, little is known about the drug’s true
safety in this context.11 In this case, we followed the
current expert opinion, suggesting that immunosuppressive
therapies should not be used during the acute stage of
infection. However, biologic treatment can be started in
patients with chronic or resolved hepatitis under close
monitoring and collaboration with a gastroenterologist.12
Conclusion
To our knowledge, this is the first case of severe psoriasis
in a patient with DS with concomitant HBV infection who
successfully responded to adalimumab. Physicians should
be aware of the association between DS and psoriasis. We
encourage physicians to be careful with the use of biologic
treatment in patients with DS. More extensive studies are
needed to evaluate the efficacy and safety of adalimumab
in patients with DS with psoriasis.
Consent Statement
Informed consent to publish this case was obtained from
the patient’s legal guardian. Institutional approval was not
required to publish the case details.
Disclosure
The authors have received honoraria for serving as
a speaker for AbbVie. The authors report no other conflicts
of interest in this work.
References
1. Talamonti M, Galluzzo M, Chiricozzi A, et al. Ustekinumab for treat­
ment of plaque psoriasis in a patient with Down syndrome. J Drugs
Dermatol. 2012;11(8):1000–1002.
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2. Adamczyk M, Michalska-Jakubus M, Krasowska D. A 12-year-old
girl with severe plaque psoriasis and Down syndrome treated suc­
cessfully with etanercept. Acta Dermatovenerol Croat. 2017;25
(2):155–158.
3. Patterson D. Molecular genetic analysis of Down syndrome. Hum
Genet. 2009;126(1):195–214. doi:10.1007/s00439-009-0696-8
4. Madan V, Williams J, Lear JT. Dermatological manifestations of
Down’s syndrome. Clin Exp Dermatol. 2006;31(5):623–629.
doi:10.1111/j.1365-2230.2006.02164.x
5. Marmon S, De Souza A, Strober BE. Psoriasis and Down syndrome:
a report of three cases and a potential pathophysiologic link.
Dermatol Online J. 2012;18(6):13. doi:10.5070/D305M5F4BX
6. Sismour B, D’Acunto K. Down syndrome, severe psoriasis, and
increased risk for cardiovascular events. J Am Acad Physician
Assist. 2019;32(12):31–33. doi:10.1097/01.JAA.0000604860.71819.
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7. Mohd Affandi A, Khan I, Ngah Saaya N. Epidemiology and clinical
features of adult patients with psoriasis in Malaysia: 10-year review
from the Malaysian Psoriasis Registry (2007–2016). Dermatol Res
Pract. 2018;2018:1–8. doi:10.1155/2018/4371471
8. Alcaide AJ, Barrera MV, Habicheyn S, López N, Mendiola MV,
Herrera E. Safety of etanercept therapy in a patient with psoriasis,
Down’s syndrome and concomitant hepatitis C virus infection. J Eur
Acad Dermatol Venereol. 2008;22(12):1514–1516. doi:10.1111/
j.1468-3083.2008.02693.x
9. Wu JJ, Valdecantos WC. Adalimumab in chronic plaque psoriasis:
a Clinical Guide. J Drugs Dermatol. 2017;16(8):779–790.
10. Burness CB, McKeage K. Adalimumab: a Review in Chronic Plaque
Psoriasis. Drugs. 2015;75(18):2119–2130. doi:10.1007/s40265-015-
0503-x
11. Piaserico S, Dapavo P, Conti A, Gisondi P, Russo FP. Adalimumab is
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LITERATURE STUDY Oceana Biomedicina Journal Vol 1 No 2
Jul t Dec 2018

CURRENT THERAPY OF RHEUMATOID ARTHRITIS (part 2)

PERKEMBANGAN TERKINI TERAPI RHEUMATOID ARTHRITIS (bagian 2)
Hendrata Erry Andisari
Divisi Rematologi Departemen Penyakit Dalam FK UHT/Rumkital Dr Ramelan
Surabaya

Abstrak
Terapi pada RA telah banyak mengalami kemajuan dewasa ini dan sejalan
dengan pengetahuan tentang patogenesis RA, tujuan terapi saat ini adalah mengubah
perjalanan dan mengontrol aktivitas penyakit RA. Beberapa kelompok obat-obatan
telah digunakan dalam terapi RA diantaranya adalah obat antiinflamasi nonsteroid
(OAINS), disease modifying antirheumatic drugs (DMARD) baik yang konvensional
(cDMARD) maupun agen biologi (bDMARD), golongan glukokortikoid dan obat-
obatan anti nyeri. Dalam beberapa tahun terakhir, perkembangan agen biologi yang
memiliki target spesifik terhadap mediator-mediator inflamasi seperti interleukin
(IL)-1, IL-6 dan Tumor Necrosis Factor (TNF) menunjukkan efek terapi yang poten
terhadap RA. Pada artikel ini akan dipaparkan agen biologi terbaru sebagai terapi
terkini pada RA.

Kata Kunci: konvensional DMARD, agen biologi

Abstract
Therapy in RA has undergone many advances today and in line with
knowledge of the pathogenesis of RA, the current therapeutic goal is to alter the
journey and control the activity of RA disease. Several groups of drugs have been
used in RA therapy including non-steroidal anti-inflammatory drugs (NSAIDs),
conventional disease-modifying antirheumatic drugs (DMARDs) as well as
biological agents (bDMARD), glucocorticoids and anti-pain medicines. In recent
years, the development of biological agents that have specific targets for
inflammatory mediators such as interleukin (IL) -1, IL-6 and Tumor Necrosis Factor
(TNF) suggests a potent therapeutic effect on RA. In this article will be presented the
latest biological agents as the latest therapy on RA.

Keywords : conventional DMARDs, biological agents

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LITERATURE STUDY Oceana Biomedicina Journal Vol 1 No 2
Jul t Dec 2018

Tabel 1. Jenis-jenis cDMARD yang dipakai sebagai terapi RA (1).

Waktu
Mekanisme
DMARD Dosis timbulnya Efek Samping
Kerja
respon

Methotrexate Inhibitor 7.5-25 mg 1-2 bulan Mual, diare,

(MTX) dihidrofolat p.o, i.m atau kelemahan, ulkus
reduktase, s.c per mulut, ruam,
menghambat minggu alopesia,
kemotaksis, gangguan fungsi
efek hati, penurunan
antiinflamasi leukosit dan
melalui induksi trombosit,
pelepasan pneumonitis,
adenosine sepsis, penyakit
hati, limfoma
yang
berhubungan
EBV, nodulosis
Sulfasalazine Menghambat: 2-3 gr p.o 1-3 bulan Mual, diare, sakit
respon sel B, per hari kepala, ulkus
angiogenesis mulut, ruam,
alopesia,
mewarnai lensa
kontak,
oligospermia
reversible,
gangguan fungsi
hati, leukopenia
Hidroksiklorokuin Menghambat: 200 ± 400 2-6 bulan Mual, sakit
(Plaquenil), sekresi sitokin, mg p.o. kepala, sakit
Klorokuin fosfat enzim perhari, perut, miopati,
lisosomal dan toksisitas pada
fungsi 250 mg p.o retina
makrofag per hari

Leflunomide Menghambat 100 mg p.o 4-12 Mual, diare,

(Arava) sintesis per hari minggu ruam, alopesia,
pirimidin selama 3 sangat teratogenik
hari meskipun obat
kemudian telah dihentikan,

91
LITERATURE STUDY Oceana Biomedicina Journal Vol 1 No 2
Jul t Dec 2018

10-20 mg leukopenia,
p.o per hari hepatitis,
trombositopenia
Cyclosporine Menghambat 2.5-5 2-4 bulan Mual, paresthesia,
sintesis IL-2 mg/KgBB tremor, sakit
dan sitokin sel p.o per hari kepala, hipertrofi
T lainnya gusi
D-Penicilamine Menghambat 250-750 mg 3-6 bulan Mual, hilangnya
(Cuprimine) fungsi sel Th p.o per hari rasa kecap,
dan penurunan
angiogenesis trombosit yang
reversible

Agen Biologi (bDMARD)

Pengobatan yang terbaru dan paling efektif untuk rheumatoid arthritis adalah
agen-agen biologi. Terapi biologi secara genetik direkayasa proteinnya. Mereka
dirancang untuk menghambat komponen spesifik sistem kekebalan tubuh yang
memainkan peran penting dalam peradangan dan merupakan komponen kunci dalam
RA (2).

Penghambat TNF
TNF merupakan suatu sitokin proinflamasi yang dihasilkan oleh monosit
yang teraktivasi yg diupregulasi di sinovium pada RA yang aktif. Penghambatan
terhadap TNF telah dihubungkan dengan perbaikan gejala klinis dan juga
mengurangi progresifitas gambaran radiologi. Sampai saat ini, ada lima agen biologi
yang kerjanya menghambat TNF yang telah digunakan dalam terapi RA yaitu:
Infliximab (INF), Etarnecept (ETN), Adalimumab (ADA), Golimumab (GLM) dan
Certolizumab (CMZ) (10,11,12).
INF merupakan obat golongan TNF inhibitor yang pertama kali tersedia. INF
merupakan chimeric antibodi monoklonal terhadap TNF dan diberikan secara infus
intravena dengan dosis 3-10 mg/KgBB, kemudian selanjutnya pada minggu keenam
setelah pemberian pertama dan dilanjutkan minggu kedelapan. Pemberian MTX
secara bersama-sama mungkin akan mengurangi immunogenicity dari INF (13,14).

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ETN yang merupakan soluble dimer dari reseptor p75 TNF berikatan dengan
komponen Fc IgG1, yang fungsinya adalah mencegah TNF berikatan dengan sel.
ETN juga mempunyai kemampuan menetralkan lymphotoxin (sebuah sitokin
proinflamasi yang berikatan dengan reseptor TNF p55 dan p75). Hal inilah yang
membedakan ETN dari TNF inhibitor lainnya. ETN diberikan melalui injeksi
subkutan (25 mg 2x per minggu atau 50 mg 1x per minggu) (15,16).
ADA merupakan fully humanized antibodi monoklonal terhadap TNF yang
diberikan secara injeksi subkutan pada dosis 40 mg setiap 2 minggu (17,18). GLM
juga merupakan fully humanized antibody monoklonal terhadap TNF yang digunakan
dalam terapi RA pada tahun 2009. GLM diberikan secara injeksi subkutan dengan
dosis 100 mg setiap 4 minggu. (19,20).
CMZ merupakan fully humanized antibodi monoklonal terhadap TNF, yang
berikatan dengan 2 molekul Polyethylene Glycol (PEG). Molekul PEG ini berfungsi
untuk meningkatkan waktu paruh CMZ dan meningkatkan distribusi dari CMZ ke
dalam jaringan inflamasi. Walaupun berbeda dengan penghambat TNF lainnya
karena tidak mempunyai komponen Fc, yang akibatnya pada ketidakmampuan untuk
membentuk kompleks imun dengan TNF, oleh karena itu CMZ tidak mengaktivasi
proses lisis sel melalui prose complement-dependent cell atau antibody-dependent
toxicity. CMZ juga tidak dapat membunuh sel dengan cara berikatan pada TNF.
CMZ diberikan secara injeksi subkutan pada dosis pemeliharaan 200 mg setiap 2
minggu atau 400 mg setiap 4 minggu setelah loading dose (21,22).
Meskipun efikasi dari penghambat TNF telah terbukti, namun beberapa
pasien gagal mencapai remisi atau aktifitas penyakit yang rendah dengan obat-obatan
tersebut. Apakah mengganti dengan penghambat TNF lainnya atau memakai obat
dengan mekanisme kerja yang berbeda adalah paling tepat dalam respon inkomplit
masih belum jelas. Mengganti dari bentuk chimeric ke fully humanized antibodi
monoklonal telah menunjukkan efektifitas terhadap peningkatan kontrol aktifitas
penyakit pada banyak pasien, sama seperti mengganti dari antibodi monoklonal
dengan fusion protein (10).
Penghambat TNF sebagian besar dapat ditoleransi dengan baik, walaupun
golongan ini juga dihubungkan dengan gambaran efek samping yang berbeda-beda.

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Pada beberapa penelitian terdapat kecenderungan periode peningkatan kerentanan

terhadap infeksi dalam 3-6 bulan terapi anti-TNF. Risiko reaktivasi dari tuberkulosis
(TB) laten telah dilaporkan berhubungan dengan penggunaan obat-obat penghambat
TNF sehingga skrining TB laten sebelum dimulai pengobatan golongan penghambat
TNF ini harus dilakukan (10,11).
Hal yang penting lainnya adalah kemungkinan terjadinya keganasan pada
pasien-pasien yang mendapat terapi penghambat TNF inhibitor, khususnya limfoma.
Laporan post-marketing oleh US FDA telah melaporkan 26 kasus limfoma yang
telah terjadi pada pasien yang mendapat terapi penghambat TNF. Sebuah penelitian
observational telah melaporkan peningkatan insiden penyakit limphoproliferative
(terutama limfoma Non-Hodgkin dan Hodgkin Limfoma) pada pasien-pasien RA dan
risiko terjadinya limfoma kelihatannya berhubungan dengan aktifitas penyakit.
Penghambat TNF telah terbukti mempunyai efektifitas yang baik dalam
pengobatan RA. Saat ini, tidak ada data yang menyatakan adanya efikasi yang
berbeda-beda diantara obat-obatan golongan penghambat TNF. Namun demikian,
salah satu penghambat TNF mungkin lebih menguntungkan daripada penghambat
TNF lainnya pada pasien-pasien tertentu. Misalnya, pada pasien-pasien dengan risiko
tinggi terhadap TB, ETN lebih cocok untuk diberikan karena rendahnya insiden TB
yang dilaporkan. Sebaliknya, golongan antibodi monoklonal mungkin merupakan
pilihan yang tepat pada pasien-pasien yang menderita skleritis. Disamping tiu,
pilihan pasien tentang cara pemberian obat-obatan juga memegang peranan penting
pada pemilihan obat-obatan golongan penghambat TNF. Obat-obatan golongan
penghambat TNF tidak menunjukkan efek teratogenik pada penelitian di binatang
dan kategori B untuk kehamilan. Saat ini, peningkatan prevalensi anomali
kongenital, terutama pada mereka dengan sindrom VACTERL (Vertebral, Anal
Atresia, Cardiac defects, Tracheoesophageal, Renal dan Limb abnormalities) telah
dilaporkan pada wanita-wanita yang mendapat terapi obat-obatan golongan
penghambat TNF (ETN dan INF) selama kehamilan. Kontraindikasi terapi obat-
obatan golongan penghambat TNF adalah pada penderita yang mengalami hepatitis
B akut dan gagal jantung kongestif NYHA klas III dan IV (10).

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Deplesi sel B
Peranan yang tepat dari sel B dalam patogenesis RA masih belum dimengerti
dengan jelas, walaupun terdapat bukti yang menunjukkan sel B berperan dalam
manifestasi gejala RA. Baik sel B matur dan sel pre-B mengekspresikan antigen
permukaan pada sel CD-20. Rituximab (RTX) telah dipakai secara efektif dalam
pengobataan limfoma Non-Hodgkin sejak akhir tahun 1990. Keuntungan pemakaian
RTX dalam terapi RA pada tahun 2006 adalah RTX mengurangi gejala klinik secara
efektif (23).
RTX diberikan secara dua infus terpisah dengan dosis 500-1000 mg setiap 2
minggu. Berdasarkan konsensus ketika ingin mengobati kembali pasien yang
sebelumnya tidak datang pada pengobatan kedua, RTX sebaiknya diberikan kurang
dari 6 bulan setelah pemberian infus pertama. Pendekatan yang tepat untuk
pengobatan kembali masih belum dimengerti dengan jelas. Apakah RTX sebaiknya
diberikan sesuai jadwal (setiap 6-12 bulan) walaupun tanpa gejala atau apakah
sebaiknya RTX diberikan kembali ketika aktifitas penyakit bertambah berat (23).
RTX telah menunjukkan tingkat keamanan yang baik ketika digunakan
sebagai terapi terhadap RA. Namun demikian, pemanjangan deplesi sel B dan
immunoglobulin dapat mengakibatkan risiko terjadinya infeksi (24).
Adverse event yang biasanya terjadi pada saat pemberian pertama, risiko
terjadinya infeksi, hampir sama pada kelompok plasebo dan yang mendapat terapi
RTX yaitu pada minggu ke 24 dan 28. Komplikasi lain dari terapi RTX adalah
Progressive Multifocal Leukoencephalopathy (PML) walaupun sangat jarang tetapi
dapat merupakan komplikasi yang fatal. Kontraindikasi terapi RTX adalah acute
viral hepatitis, hepatitis B atau C kronik (Child Pugh B atau C), atau dalam kondisi
infeksi yang aktif (24).

Penghambat aktifitas sel T (T-cell costimulatory blocking)

Abatacept (ABT) merupakan obat penghambat aktifitas sel T yang baru.
Fungsinya adalah melalui penghambatan dari sinyal kedua yang dibutuhkan untuk
aktifasi sel T. ABT merupakan fully humanized soluble fusion protein yang bekerja
langsung melawan sel cytotoxic T-lymphocite associated antigen-4 (CTLA4). ABT

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telah disetujui untuk digunakan sebagai terapi RA dan diberikan secara infus dengan
dosis 100-100 mg (berdasarkan berat badan) setelah dosis loading pada minggu ke 0,
2 dan 4 (25,26).
ABT mempunyai efek daya tahan yang baik dengan efikasi bisa
dipertahankan sampai 5 tahun pada open-label extension clinical trials. Pada pasien-
pasien RA yang gagal dengan salah satu terapi TNF inhibitor, kemudian mendapat
terapi ABT ternyata ABT dapat memperbaiki kualitas hidup pasien-pasien ini (25).
Walaupun tidak ada kontraindikasi khusus pada penggunaan ABT , namun
ABT harus digunakan dengan hati-hati pada pasien penyakit paru obstruktif kronik
karena dapat memperburuk kondisi penyakit PPOK. Terapi awal ABT tidak
direkomendasikan pada pasien dengan akut hepatitis B atau C, kronik hepatitis B
atau C (Child-Pugh B atau C) atau pada pasien dengan tanda infeksi yang aktif.
Skrining TB laten direkomendasikan sebelum memulai terapi ABT, walaupun belum
ada kasus reaktifasi hepatitis B pada pasien yang mendapat terapi ABT (26).

Penghambat Sitokin
Tocilizumab (TCZ) merupakan fully humanized antibodi monoklonal yang
bekerja langsung pada resptor IL-6. IL-6 merupakan sitokin pleiotropik yang
dihasilkan oleh beberapa sel dan telah menunjukkan peranannya pada proses
inflamasi yang terjadi pada RA. IL-6 terlibat dalam proses differensiasi sel B
menjadi sel plasma dan sel T menjadi sel T sitotoksik, induksi differensiasi
osteoklast, aktivasi osteoklast, produksi reaktan fase akut khususnya C-reactive
protein (CRP). Semua proses ini berperan dalam terjadinya sinovitis dan destruksi
tulang pada RA. Proses inflamasi kronik pada RA dihubungkan dengan peningkatan
produksi IL-6 dan reseptor IL-6. TCZ saat ini disetujui untuk digunakan pada pasien
RA dengan respon yang inkomplet terhadap TNF inhibitor dan diberikan setiap bulan
melalui infus dengan dosis 8 mg/KgBB (27,28,29).
TCZ mempunyai efek samping yang berbeda dengan agen biologi lainnya
yaitu terjadinya neutropenia. Neutropenia terjadi dalam beberapa hari setelah
mendapat terapi TCZ dan dipostulasikan sebagai akibat dari penghambatan IL-6
terhadap neutrofil. Data dari penelitian jangka panjang, menemukan bahwa terjadi

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infeksi yang serius pada 17.5% pasien RA yang mendapat terapi TCZ dengan angka
insiden 5.7 per 100 pasien-tahun. Pneumonia merupakan yang paling sering
ditemukan, diikuti oleh herpes zoster, bronkitis dan pielonefritis. Efek samping
lainnya adalah peningkatan tes fungsi liver (transaminase dan bilirubin) dan
peningkatan total kolesterol, trigliserida dan HDL (28).

Molekul-molekul kecil
Protein kinase merupakan enzim intraselular yang menghantar sinyal melalui
fosforilasi substrat. Sekali teraktivasi, protein kinase menghasilkan gen yang
menyebakan proses transkripsi dari sitokin proinflamasi seperti TNF, IL-6 dan IL-1.
Dengan demikian, protein kinase telah diteliti sebagai target potensial untuk
menggangu kaskade inflamasi pada RA melalui penekanan terhadapa produksi
sitokin proinflamasi. Obat-obatan golongan penghambat protein kinase dapat
diberikan secara oral sehingga memberikan kemudahan dibanding dengan agen-agen
biologi lainnya.
Penghambatan terhadap 3 jenis protein kinase (p38 mitogen-activated protein
kinase, MAPK; spleen tyrosine kinase, SyK; dan janus kinase, JAK) telah diteliti
sebagai terapi untuk pasien RA (30,31,32). p38 MAPK merupakan regulator utama
terhadap produksi sitokin proinflamasi dan penghambatan terhadap enzim
merupakan mekanisme untuk mengganggu kaskade inflamasi yang terjadi pada RA.
Walaupun data dari penelitian pada binatang, penelitian klinik dari penghambatan
MAPK dalam manajemen RA tidak menunjukkan hasil yang menjanjikan (30).
Ketika terktivasi, SyK menghasilkan peningkatan produksi IL-6 dan MMPs.
Pada sebuah penelitian klinik, pemberian penghambat SyK oral telah menunjukkan
perbaikan dalam pencapaian ACR respon pada pasien-pasien RA dengan respon
suboptimal terhadap MTX. Namun demikian, penghambat SyK tidak efektif dalam
mengurangi aktifitas penyakit RA pada penyakit-penyakit yang aktif dibandingkan
dengan TNF inhibitor (31).
JAK memainkan peran yang menonjol dalam aktivasi, fungsi dan proliferasi
dari limfosit. Pemberian secara oral penghambat JAK (CP690 550) telah diteliti
untuk digunakan sebagai terapi RA. Dibandingkan dengan plasebo, CP690 550
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dihubungkan dengan perbaikan aktifitas penyakit secara klinis yang diukur

menggunakan ACR respon 20 dalam 6 minggu (32).

Tabel 2. Jenis-jenis bDMARD yang dipakai sebagai terapi RA (1).

Waktu
Mekanisme
DMARD Dosis timbulnya Efek Samping
Kerja
respon

Adalimumab Antibody TNF 40 mg s.c Beberapa hari Reaksi infus,

(Humira) (human) setiap 2 ± 4 bulan peningkatan
minggu risiko infeksi
termasuk
reaktifasi TB,
gangguan
demyelinisasi
Etanercept Reseptor TNF 25 mg s.c Beberapa hari Reaksi ringan
(Enbrel) terlarut dua kali per ± 12 minggu pada tempat
(soluble) minggu atau suntikan,
50 mg s.c per kontraindikasi
minggu pada infeksi,
demyelinisasi
Infliximab Antibody TNF 3 mg/KgBB Beberapa Reaksi infus,
(Remicade) (chimeric) i.v infus hari-4 bulan peningkatan
pelan pada risiko infeksi
minggu ke-0, termasuk
2 dan 6 reaktivasi TB,
kemudian gangguan
setiap 8 demyelinisasi
minggu
Certolizumab Human anti- 1 mg; 5 mg 4 minggu * Uji klinis fase II
Pegol TNF-a atau 20
(CDP870) antibody mg/KgBB
infus tunggal
Golimumab Fully human 50 mg atau 16 minggu* Uji klinis fase II
protein 100 mg s.c (Uji Klinis fase
antibody yang setiap 2 atau III mulai Februari
mengikat 4 minggu 2006-Juli 2012)
TNF-a
Rituximab Antibody anti- 1000 mg 3 bulan * Reaksi infus,
(Mabthera) sel B (CD20) setiap 2 aritmia jantung,
minggu x 2 hipertensi,
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dosis infeksi, reaktivasi

hepatitis B,
sitopenia, reaksi
hipersensitifitas
Ocrelizumab Humanized 10 mg, 50 4 minggu * Uji klinis fase II
ant-CD 20 mg, 200 mg,
antibody 500 mg dan
1000 mg
infus pada
hari 1 dan 15
Ofatumumab Human 300 mg, 700 24 minggu * Uji Klinis Fase II
(Humax- monoclonal mg atau 100
CD20) anti-CD20 mg infus
IgG1 antibody pada hari-0
dan 14
Denosumab Human 60 mg atau 6 bulan * Uji Klinis Fase II
monoclonal 180 mg s.c
IgG2 antibody setiap 6
terhadap bulan selama
RANKL 1 tahun

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102

Edited by:
Maria I. Bokarewa,
University of Gothenburg, Sweden
Reviewed by:
Daniella Schwartz,
National Institute of Allergy and
Infectious Diseases (NIH),
United States
Wenru Su,
Sun Yat-sen University, China
*Correspondence:
Ou Jin
jinou@mail.sysu.edu.cn
Jieruo Gu
gujieruo@mail.sysu.edu.cn
Specialty section:
This article was submitted to
Autoimmune and
Autoinflammatory Disorders,
a section of the journal
Frontiers in Immunology
Received: 26 April 2021
Accepted: 17 August 2021
Published: 01 September 2021
Citation:
Chen Z, Zheng X, Wu X, Wu J, Li X,
Wei Q, Zhang X, Fang L, Jin O and
Gu J (2021) Adalimumab Therapy
Restores the Gut Microbiota in
Patients With Ankylosing Spondylitis.
Front. Immunol. 12:700570.
doi: 10.3389/fimmu.2021.700570
Frontiers in Immunology | www.frontiersin.org
ORIGINAL RESEARCH
published: 01 September 2021
doi: 10.3389/fimmu.2021.700570
Adalimumab Therapy Restores the
Gut Microbiota in Patients With
Ankylosing Spondylitis
Zena Chen , Xuqi Zheng , Xinyu Wu , Jialing Wu , Xiaomin Li , Qiujing Wei , Xi Zhang ,
Linkai Fang , Ou Jin * and Jieruo Gu *
Rheumatology and Immunology Department, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Growing evidence suggests that the gut microbiota is involved in the initiation and
progression of ankylosing spondylitis (AS). In this study, we aimed to explore the gut
microbiome alterations during adalimumab therapy and verify microbiome biomarkers
predicting treatment response. By evaluating the gut microbial features of 30 AS patients
before and after adalimumab therapy for 6 months and 24 healthy controls, we confirmed
that the microbiome was restored remarkably after 6 months of adalimumab therapy in AS
patients. We then compared the baseline gut microbiome of 22 adalimumab responders
with 8 non-responders, a higher abundance of Comamonas was revealed in the latter,
although no statistical difference was found after adjusting for the false discovery rate.
These results suggested that adalimumab therapy restored the gut microbiome in AS
patients and indicated the utility of gut microbiome to be potential biomarkers for
therapeutic evaluation. These findings provided an insight into the development of
predictive tools and the establishment of precise medical interventions for clinical practice.
Keywords: adalimumab, TNF, gut microbiome, ankylosing spondylitis, biomarker
INTRODUCTION
Ankylosing spondylitis (AS) is a chronic inflammatory disorder that affects the axial skeleton,
causing characteristic inflammatory back pain that can lead to structural and functional
impairments and a decreased quality of life (1). Among patients with AS, 40–60% present with
subclinical intestinal inflammation, and 5–10% progress to clinical inflammatory bowel disease
(IBD) (2). In recent years, substantial evidence has indicated the vital role of the gut microbiota in
the initiation and progression of IBD (3). Similarly, a growing number of studies revealed perturbed
gut microbiota in AS or spondyloarthritis (SpA) patients (4), and also in AS animal model typically
HLA-B27 transgenic rats (5). Moreover, some altered species like Dialister, was related to AS disease
activity (6). Recently, HLA- B27- positive healthy individuals were identified with a significantly
different microbiome (7), indicating that the gut microbiota may in fact be a driver of AS.
The development of tumor necrosis factor inhibitor (TNFi) and its introduction into clinics was
a milestone in the treatments for autoimmune diseases, including AS, IBD, psoriasis, and
rheumatoid arthritis. It is well known that TNFi improves symptoms and inflammatory cytokine
levels in patients with AS. However, it is unknown whether TNFi affects the gut microbiome due to a
lack of evidence. A previous study analyzed the gut microbiome of SpA patients before and after
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Chen et al.
3 months of TNFi treatment, using stool samples (8). Only a
modest difference in the alpha diversity of the gut microbiome
was found, while no specific bacterial taxa were observed. But
this study did not include healthy controls, so it is uncertain
whether TNFi treatment was responsible for restoring the gut
microbiome to a healthier status. Recently, restoration of gut
microbiota composition was revealed in proteoglycan-induced
AS mice after TNFi treatment (9), indicating that TNFi
treatment might affect the gut microbiota.
As humanized monoclonal antibody targeting TNF,
adalimumab has been successfully used to manage
inflammation in AS patients in clinic, especially in those with
extra-articular symptoms such as IBD and uveitis (10). It was
also reported to improve symptoms and restore gut microbiota
in patients with IBD (11). In addition, baseline features of the gut
microbiome were valuable in predicting the treatment response
to TNFi in patients with IBD (12). However, the association
between the gut microbiome alteration and adalimumab
treatment in AS patients is unknown.
In this study, we recruited AS patients prescribed
adalimumab and healthy controls to evaluate the effect of
adalimumab treatment on the gut microbiome. Further, we
explored whether the gut microbiome can be used to predict
the response to adalimumab treatment in AS patients.
MATERIALS AND METHODS
Populations and Sample Size
We conducted a prospective observational study between January
2017 and July 2018. Patients with AS who were initiated
adalimumab therapy were consecutively recruited at the
outpatient clinic of Rheumatology at the Third Affiliated Hospital
of Sun Yat-sen University. The inclusion criteria were as follows: (1)
age of 18 years or older, (2) fulfillment of the 1984 modified New
York Criteria for AS (13), (3) inadequate improvement despite
taking at least two non-steroidal anti-inflammatory drugs (NSAIDs)
for 4 weeks, (4) Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI) > 4 at baseline, and (5) no TNFi treatment in the 6
months prior to recruitment. The exclusion criteria were as follows:
(1) antibiotic or probiotic treatment within 2 months of fecal
collection, and (2) chronic infectious disease such as tuberculosis
or hepatitis B. Fecal samples and clinical data, including
demographic information, disease-related characteristics, and
measurements of disease activity or functional status, were
collected by trained investigators at baseline (M0) and after 6
months of adalimumab treatment (M6). Disease activity of AS
was assessed using the Ankylosing Spondylitis Disease Activity
Score (ASDAS) according to its cutoff points, while therapeutic
response was defined using the change in ASDAS (△ASDAS) as
reported previously (14, 15). Clinical response was defined
as ASDAS change > 1.1, and no clinical response was defined as
ASDAS change ≤ 1.1. In order to determine the suitable sample size,
we hypothesized that, after treatment with adalimumab, 50-60% of
patients would experience an alteration in the abundance of
potentially disease-related components of gut microbiota (16).
Frontiers in Immunology | www.frontiersin.org
Adalimumab Therapy Restores Gut Microbiota
A total sample size of at least 13 pairs of AS patients (pre- and
post-treatment) was required to achieve a power of 90% and a two-
sided significance of 5%. The sample size was estimated by PASS 15
software (https://www.ncss.com).
Healthy controls were recruited from volunteers, at the same
hospital, who had not been diagnosed with AS, other rheumatic
diseases, or chronic infectious diseases, and who had not received
antibiotic or probiotic treatment within 2 months of fecal collection.
This study was conducted in compliance with the Declaration
of Helsinki and was approved by the ethics committee of the
Third Affiliated Hospital of Sun Yat-sen University. Before
enrollment, written informed consent was obtained from all
subjects for research and publication of their data.
Fecal Sample Collection
Fresh fecal samples were collected from the patients at baseline
and at 6 months, and from healthy controls at baseline. After
defecation fecal samples were collected and immediately placed
on dry ice, and then transferred to the laboratory within 2 hours,
followed by the storage at -80°C until DNA extraction.
DNA Extraction and 16S rRNA
Gene Sequencing
Microbial genomic DNA was extracted from fecal samples using
a DNA isolation kit (Tiangen Biotech Co., Ltd., Beijing, China)
according to the manufacturer’s instructions. The V4 region of
the 16S rRNA gene from each sample was amplified by
polymerase chain reaction (PCR) using specific primers (515F,
5’ - G T G C C A G C M G C C G C G G T A A - 3 ’ , a n d 8 0 6 R , 5’ -
GGACTACHVGGGTWTCTAAT-3’) with barcodes (17). After
purification, the DNA library was obtained and sequenced using
the Illumina Hiseq2500 platform to generate 250 bp paired-
end reads.
The reads were purified and merged and then processed using
a QIIME-based bioinformatics pipeline (v1.9.1) (18). Briefly, we
curated the sequences to reduce sequencing and PCR errors,
aligned the resulting sequences to the SILVA 16S rRNA sequence
database, and used UCHIME to remove any chimeric sequences
as per to the GOLD database. Sequences were clustered into
operational taxonomic units (OTUs) with a 97% similarity cutoff
using the average neighbor algorithm. All sequences were
classified using a naïve Bayesian classifier trained on the RDP
training set, and the OTUs were assigned a classification based
on the taxonomy with the majority consensus of sequences
within a given OTU at a threshold of 80%. We obtained the
OTU table and taxonomy tree, and further analysis of the a- and
b-diversity indices was conducted using Microbiomeanalyst (19).
It is a web-based tool for comprehensive statistical, visual and
meta-analysis of microbiome data.
Statistical Analysis
Graphpad 8.0 (IBM, USA) and R (version 3.4.3) were used to
analyze the data. Longitudinal comparisons were used to analyze
changes in patients after treatment, and cross-sectional
comparisons were made between patients and healthy controls.
Gut microbiome composition was represented by a- and b-
diversity. To assess a-diversity (20), the Shannon and Simpson
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Chen et al. Adalimumab Therapy Restores Gut Microbiota

indices were calculated for each sample in the dataset. Wilcoxon TABLE 1 | Clinical characteristic of AS patients.
rank sum tests were performed for pairwise comparisons within M0 M6
patients with AS, and Mann-Whitney tests were performed for
comparisons between patients and healthy controls. To measure b- Age (years) 31.23 ± 7.48
Males (n, %) 27 (90)
diversity, the UniFrac distance between samples was calculated (21),
Duration (years)§ 10 (5)
and permutational multivariate analysis of variance using distance NSAIDs (n, %) 20 (66.7)
matrices (PERMANOVA) was used to assess the overlap of SASP (n, %) 5 (16.7)
taxonomy between patients with AS and healthy controls. CRP (mg/L)§ 11.25 (21.70) 0.95 (4.25)***
Comparisons of the relative abundance of taxa were made using ESR (mm/h)§ 14.00 (25.50) 4.50 (6.25)***
BASDAI§ 5.23 (1.51) 2.23 (2.72)***
Wilcoxon rank sum or Mann-Whitney tests. A P value of less than
BASFI§ 3.72 (2.64) 1.60 (2.35)***
0.05, after correcting for false discovery rate (FDR) for multiple BASMI§ 2.50 (3.00) 1.00 (3.00)**
comparisons, was considered statistically significant. ASDAS§ 3.43 (1.29) 1.33 (1.16)***
Inactive† 0 14
Low activity† 2 10
High activity† 15 5
Very high activity† 13 1
RESULTS BASDAI > 4† 30 4

Clinical Characteristic of AS Patients §

A total of 30 patients (mean age, 31.23 ± 7.48 years) and 24 healthy
controls (mean age, 38.54 ± 10.79 years) were obtained in this study.
All included patients were HLA-B27 positive, 12 of them (40%) had
peripheral arthritis and 5 (17%) had a positive family history. None
of these 30 AS patients had established IBD, psoriasis, or uveitis
history. Before treatment, 15 patients had a high level of disease
activity and 13 patients had very high level of disease activity.
NSAIDs and sulfasalazine (SASP) were prescribed for 20 and 5
patients respectively. During adalimumab therapy, NSAIDs and
SASP were remained for those patients.
Overall, clinical symptoms and signs of AS patients were
greatly relieved after 6 months of adalimumab therapy, along
with improvements in C-reactive protein (CRP), erythrocyte
sedimentation rate (ESR), BASDAI, ASDAS, Bath Ankylosing
Spondylitis Functional Index (BASFI), and Bath Ankylosing
Spondylitis Metrology Index (BASMI), comparing with
baseline values (all P values < 0.01, Table 1). Six patients still
had high or very high levels of disease activity even after
treatment. As for treatment response, 22 patients responded to
adalimumab therapy (△ASDAS > 1.1, R) while 8 patients did
not (△ASDAS ≤ 1.1, NR). Patients exhibiting different clinical
responses were similar in terms of sex, age, and disease activity
before treatment (Table S1).
Association Between Gut Microbiome and
Adalimumab Therapy
In the present study, an average of 65 194 (range, 45 295–78 205)
high-quality effective reads were obtained from 84 samples. After
taxonomic identification and filtering out taxa with a very low
abundance (reads had to be present in at least 20% of the
samples, with a count of more than 2), 602 OTUs remained
for further analysis. After species annotation, a total of 9 phyla,
16 classes, 24 orders, 47 families, and 117 genera were obtained.
For a-diversity, the Shannon and Simpson indices of AS
patients before treatment (AS_M0) were obviously lower than
healthy controls (P<0.01, Figure 1A), and there were no
statistical differences of the above indices between two groups
after treatment (P>0.05, Figure 1A). Similarly, noteworthy
difference in b-diversity between the two groups was found
Data expressed as median (IQR); †data expressed as frequency. Comparisons of CRP,
ESR, BASDAI, BASFI, BASMI, and ASDAS between M0 and M6 were calculated using
Wilcoxon rank-sum tests. **P ＜ 0.01, ***P ＜ 0.001. AS, ankylosing spondylitis; IQR,
interquartile range; NSAIDs, non-steroidal anti-inflammatory drugs; SASP, sulfasalazine;
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; BASDAI, Bath Ankylosing
Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index;
BASMI, Bath Ankylosing Spondylitis Metrology Index; ASDAS, ankylosing spondylitis
disease activity score; M0, baseline; M6, after 6 months of treatment.
before treatment (P < 0.001), while no statistical difference was
found after treatment, according to the results of PERMANOVA
based on weighted and unweighted UniFrac distance
(Figures 1B, C). These results revealed an alteration of gut
microbial community structure in AS patients and an impact
of adalimumab treatment on the gut microbiota.
The three most dominant phyla were Firmicutes,
Bacteroidetes, and Actinobacteria, which accounted for over
95% of total abundance both in AS patients and healthy
controls. The top fifteen relative abundances of taxa at
different taxonomic levels in patients with AS and in healthy
controls are listed in Table S2.
At the phylum level, gut microbiota from AS patients before
treatment exhibited a significantly higher abundance of
Actinobacteria, Firmicutes, Oxyphotobacteria, Preteobacteria, and
Tenericutes (all P <0.01, Figure 2), as well as a lower abundance of
Bacteroidetes and Fusobacteria than the microbiota from healthy
controls (P <0.001 and P <0.05, respectively, Figure 2).
Interestingly, the relative abundance of these seven phyla shifted
during adalimumab therapy, eventually resulting in no statistical
difference between the two groups (all P >0.05, Figure 2). At the
genus level, 73 genera with distinguishing abundance (such as
Bacteroides, Megamonas, and Collinsella) were identified in AS
patients before treatment compared with healthy controls (all
P<0.05, Table S3). Relative abundance of these genera altered
during adalimumab therapy, and in particular four genera namely
Lachnoclostridium, Lachnospira, Solobacterium, and Rothia shifted
greatly during this time (all P<0.05, Figure 3 and Table S3). The
relative abundance of Lachnoclostridium, Lachnospira, and
Solobacterium in AS patients was restored to levels similar with
healthy controls after therapy (P>0.05, Figure 3 and Table S3).
Only 28 out of the 73 genera (such as Rothia, Streptococcus, Blautia,

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Chen et al. Adalimumab Therapy Restores Gut Microbiota

B C

FIGURE 1 | Community structure of gut microbiota in AS patients and HCs. (A) a-diversity of gut microbiota (Shannon and Simpson index) among AS patients at
baseline and after treatment and among HCs. The horizontal bar within each box represents the median. The bottom and top of each box represent the 25th and
75th percentiles, respectively. The upper and lower whiskers extend to data no more than 1.5 × the IQR from the upper and lower edges of the box, respectively.
*P < 0.05, **P < 0.01, ns, P > 0.05. PCoA plot based on the unweighted UniFrac distance (B) and weighted UniFrac distance (C) of gut microbiota from AS patients
at baseline and after treatment and from HCs. AS, ankylosing spondylitis; AS_M0, AS patients at baseline; AS_M6, AS patients after treatment; HC, healthy control;
IQR, interquartile range; PCoA, principal coordinates analysis.

FIGURE 2 | Relative abundance of phyla in different groups. Bars represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ns, P > 0.05.

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Chen et al. Adalimumab Therapy Restores Gut Microbiota

and Dorea) remained statistically different (all P<0.05, Table S3)

between the two groups after therapy.

Association Between Gut Microbiome and

Response to Adalimumab Therapy
We further investigated whether the gut microbial community
structure in patients with AS before adalimumab therapy was
related to the treatment response. No significant differences of
clinical status as well as a- and b-diversity were found between the
responders and non-responders (Table S1 and Figures 4A–C).
The abundance of microbiota at different taxonomic levels were
then analyzed and no differences were found at the phylum, class,
order, or family levels, either. At the genus level, a higher
abundance of Comamonas was observed in the non-responder
group (Figure 4D). Unfortunately, after adjusting for FDR, no
statistical difference was found.

DISCUSSION

FIGURE 3 | Differential relative abundance of genera in AS patients before

and after treatment. AS, ankylosing spondylitis. The horizontal bar within each
box represents the median. The bottom and top of each box represent the
25th and 75th percentiles, respectively. The upper and lower whiskers extend
to data no more than 1.5 × the IQR from the upper and lower edges of the
box, respectively. *P < 0.05, **P < 0.01, ***P < 0.001, ns, P > 0.05.
Ankylosing spondylitis is a chronic inflammatory disease that is
thought to be associated with the gut microbiota. Previous
studies have suggested that TNFi therapy improves the gut
microbial community. In the current study, we illustrated the
effect of adalimumab on the gut microbiota composition in AS
patients during 6 months of treatment. We observed that the

A B

C D

FIGURE 4 | Gut microbial community structure of AS patients before treatment with different responses to Adalimumab. (A, B) a-diversity; (C) PCoA based on
unweighted UniFrac distance. (D) Relative abundance of Comamonas in response and no_response subgroups. AS, ankylosing spondylitis; PCoA, principal
coordinates analysis.

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Chen et al.
overall gut microbial composition of AS patients exhibited
obvious differences comparing with healthy controls, as did
most bacterial taxa. After 6 months of adalimumab treatment,
the gut microbial composition was restored to a state similar with
healthy controls. In addition, no difference was observed in the
overall gut composition between the responders and non-
responders in AS patients. A higher abundance of Comamonas
was observed in the non-responders, but this result was not
statistically significant after adjustment.
Decreased gut microbiota diversity occurs in many diseases,
including IBD and AS. In the current study, we confirmed that
gut microbiota diversity was reduced in AS. In addition, we
identified bacterial species which were differentiated between AS
patients and controls. Depletion of Bacteroides and Megamonas
and enrichment of Collinsella in AS patients were noted in our
study, which was consistent with findings of previous studies (22,
23). All of these three species restored to indistinguishable from
healthy controls after treatment. Carriage of Dialister species has
been previously reported be associated with disease activity in
SpA patients (6). However, we found depletion of Dialister in AS
patients before treatment and it was restored to similar with
healthy controls after treatment. Neither Yin et al. (16) revealed
remarkable difference of Dialister in AS patients. So, the
pathogenic significance of Dialister is therefore uncertain.
Restoration of the gut microbiota after treatment has been
reported in several other autoimmune diseases, such as IBD and
RA (24). One previous study analyzed patients with SpA before
and after TNFi therapy and revealed modest differences in
microbial composition, but no specific taxon was found to be
modulated, which is likely due to the small sample size (8). In
another previous study comparing AS patient with and without
TNFi treatment, restoration of the overall microbial composition
and the abundance of specific taxa were both revealed (16). These
indicated TNFi therapy was correlated with a restoration of the
perturbed gut microbiota. However, the previous studies did not
assess the change in the gut microbiota dynamics of each
individual patient. In our study, we compared the baseline
state of the gut microbiome of each patient to that 6 months
after treatment. Adalimumab therapy was associated with
restoration of the microbial composition, and several notable
bacterial species modulated by the treatment were identified. We
observed that adalimumab therapy restored the normal
abundances of Bacteroidetes and Firmicutes. A decrease in the
Bacteroidetes/Firmicutes ratio has been associated with
autoimmune diseases. Moreover, at the genus level, the
abundance of four genera were found to shifted greatly during
treatment. Specifically, Lachnoclostridium was reduced in AS
patients and increased to a level similar with healthy controls
after treatment. Lachnoclostridium was also found to be less
abundant in children with autism spectrum disorders in a
previous study (25). As known, AS patients are prone to
mental disorders such as depression (26), the effect of
perturbations in the gut microbiome on mental disorders in
AS patients is worth investigation.
Although great improvement has been reported in some AS
patients treated with TNFi, nearly 30% of patients show no
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Adalimumab Therapy Restores Gut Microbiota
response. In the current study, we observed a comparable
proportion that 8 out of 30 enrolled patients showed no
response to TNFi therapy Thus it is important to identify non-
responsive patients, as TNFi therapy is costly. An increasing
number of studies have indicated that the gut microbiome was a
potential indicator of the response to TNFi treatment, and gut
microbiome plays an important role in drug efficacy (27–29). To
our knowledge, only one previous study has utilized gut
microbiome features to predict the TNFi response in SpA
patients in which only 8 non-responders and 5 responders
were included (8). A higher abundance of Burkholderiales
orders was observed in responders prior to treatment. In our
study, we included a larger cohort and longer treatment
durations and a higher abundance of the Comamonas genus in
non-responders to adalimumab prior to treatment were revealed.
Comamonas species are infrequently reported as an infectious
agent in routine clinical practice due to rare isolates in
microbiology laboratories. In recent years, Comamonas
kerstersii and Comamonas testosteroni were identified to cause
appendicitis and bacteremia by microbiome sequencing (30, 31).
Subclinical gut inflammation is common in AS patients, but its
relationship with Comamonas needs further study. The
discrepancy between our results and those of the prior study
may be due to differences in racial composition, dietary habits,
and treatment duration. These two studies together suggest a
possible association between gut microbial features and clinical
response, without presuming causality. If the results are further
confirmed, it could be clinically helpful to use gut microbiome
features as a reliable indicator of treatment response before the
initiation of TNFi therapy to avoid a delay in symptom relief and
ease the economic burden on health services, paving the way for
precision therapy for AS.
Our study had several limitations. Firstly, patients treated
with other TNFis or other treatments such as NSAIDs were not
recruited, so we cannot conclude that the restoration of the
microbiota was specifically related to adalimumab treatment.
Secondly, as information of dietary patterns was not collected,
the influence of diet was not taken into account. However, since
we compared the same patients before and after treatment, any
effects of diet should have been somewhat reduced. Finally, due
to the small size of our cohort, the power of the statistical analysis
may be limited. Nevertheless, in our study, nearly 30% of the
patients showed no response to adalimumab therapy, which was
consistent with previous larger-scale studies, thereby enhancing
the external validity of our study. Further prospective, large-scale
studies are required to confirm our results.
CONCLUSION
In summary, our study revealed the gut microbiota features in
patients with AS and provided insights into the dynamic
alterations during adalimumab treatment. Our investigation
suggests that the gut microbiota may be a potential tool for
predicting the treatment response to adalimumab in AS patients.
Additional studies are needed to further investigate the exact
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Chen et al.
bacterial species that play key roles in the response to
adalimumab treatment, which will be helpful to achieve precise
medical interventions.
DATA AVAILABILITY STATEMENT
The data presented in the study are deposited in the SRA
repository, accession number is PRJNA755445.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Ethics committee of the Third Affiliated Hospital of
Sun Yat-sen University. The patients/participants provided their
written informed consent to participate in this study.
AUTHOR CONTRIBUTIONS
(I) Conception and design: JG and ZC. (II) Administrative
support: JG. (III) Provision of study materials or patients: All
authors. (IV) Collection and assembly of data: ZC. (V) Data
analysis and interpretation: All authors. (VI) Manuscript writing
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and revision: All authors. (VII) Final approval of the manuscript:
All authors. (VIII) Funding acquisition: JG. All authors
contributed to the article and approved the submitted version.
FUNDING
This study was supported by the General Program of the
National Natural Science Foundation of China (81871294) and
the Science and Technology Planning Project of Guangdong
Province (2019B030316004).
ACKNOWLEDGMENTS
All authors of this paper fulfilled the criteria of authorship. The
authors thank the participants for this study.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.
700570/full#supplementary-material
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
The reviewer WS declared a shared affiliation with the authors to the handling
editor at the time of review.
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Copyright © 2021 Chen, Zheng, Wu, Wu, Li, Wei, Zhang, Fang, Jin and Gu. This is
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