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Extra-articular Manifestations of Rheumatoid Arthritis
MASAKAZU MATSUSHITA*, KEN YAMAJI*, NAOTO TAMURA*
*Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Tokyo, Japan
Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes persistent inflammation, primarily in
the synovial membrane of the joints. It may cause joint pain, swelling, and even deformation. Due to the strong
involvement of abnormal immune function in its pathogenesis, RA is classified as a connective tissue disease. Most
RA patients initially develop articular symptoms such as finger stiffness, pain, and swelling. They often visit
medical institutions primarily complaining of these symptoms. However, it is known that manifestations of RA are
found not only in the joints but also in a variety of organs in the entire body, including the lungs, skin, eyes, and
blood vessels. These manifestations are called extra-articular manifestations, and they pose a problem as they
significantly affect the patientʼs activities of daily living (ADL), quality of life (QOL), and life expectancy. The
pathology of RA has been elucidated in detail thanks to recent advances in molecular biology, and treatment
strategies have undergone marked changes with the advent of biological drugs. Previously, the primary treatment
goal was pain relief. Now, complete remission is becoming a reality with the prevention of bone destruction by
completely inhibiting disease activity. However, extra-articular symptoms such as those involving the lungs pose
major obstacles in drug selection for RA in many cases. When diagnosing and treating RA, it is important to not
only evaluate articular manifestations but also accurately identify extra-articular manifestations and act
appropriately.
Key words: rheumatoid arthritis (RA), extra-articular manifestations, methotrexate, biological drugs
Introduction
Rheumatoid arthritis (RA) is a chronic inflamma-
tory disease that causes persistent inflammation,
mainly in the synovial membrane of the joints,
causing joint pain, swelling, and even deformation.
Autoimmune mechanisms play a major role in the
onset and progression of RA. Prolonged inflamma-
tion causes bone and cartilage breakdown of the
affected joints and leads not only to continuous pain
but also to markedly decreased joint function.
Previously, nonsteroidal anti-inflammatory drugs
(NSAIDs) as well as disease-modifying antirheu-
matic drugs (DMARDs) including aurothiomalate,
bucillamine, and sulfasalazine were primarily used
for medical treatment of RA. However, these drugs
were not exactly effective in suppressing joint
breakdown, and there were numerous patients with
high disease activity despite undergoing treatment.
As a result, methotrexate (MTX) was approved as
a drug for RA in 1999 in Japan. Furthermore, with
the advent of infliximab, which was approved in
2003 and targets tumor necrosis factor α (TNFα),
biological drugs involved with interleukin-6 (IL-6)
and cytotoxic T-lymphocyte associated antigen 4
(CTLA-4), and Janus kinase (JAK) inhibitors,
which are small molecular compounds, were
approved in succession. These drugs are highly
effective against RA and they made it possible to
raise the treatment goals for RA, which previously
21
Health Topics forTokyoites
Juntendo Medical Journal2020. 66(1), 21-26
Corresponding author: Masakazu Matsushita
Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine
2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
TEL: +81-3-5802-1067 FAX: +81-3-5800-4893 E-mail: [email protected]
43rd Health Topics for Tokyoites: Latest Rheumatoid Arthritis Medical Care and Its Important Points〔Held on Jan. 19, 2019〕
〔Received Jan. 4, 2019〕〔Accepted Oct. 7, 2019〕
Copyright © 2020 The JuntendoMedical Society. This is an open access article distributed under the terms of Creative Commons Attribution Li-
cense (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited.
doi: 10.14789/jmj.2020.66.JMJ19-R01
focused on“relieving pain”and“slowing down
progression”, to not only“clinical remission”but
also to“structural remission”, and“functional
remission”. In the European League against Rheu-
matism (EULAR) RA guidelines, revised in 2016, it
is recommended that MTX be proactively used
provided that there are no contraindications and
that biological drugs and JAK inhibitors be
administered at an early stage for patients with a
poor response 1)-3).
However, manifestations of RA are not limited to
the joints and they involve multiple organs includ-
ing the eyes, skin, lungs, heart, kidneys, intestinal
tract, and blood vessels. They may also be
accompanied by“amyloidosis”in which amyloid
proteins are deposited in various organs. These
manifestations are called“extra-articular manifes-
tations”. They not only limit the choice of drugs but
are also major factors that affect the patientʼs ADL,
QOL, and life expectancy. In particular, MTX,
biological drugs, and JAK inhibitors, which are
highly recommended for extra-articular manifesta-
tions, may exacerbate or induce susceptibility to
infection, interstitial pneumonia (IP), hepatic dys-
function, renal dysfunction, and blood cell disorders.
Therefore, RA patients with“extra-articular mani-
festations”should be fully screened for organ involve-
ment and drugs should be selected carefully when
starting them on treatment 1) 3). Extra-articular
manifestations of RA and precautions involved in
them are described below.
1. Respiratory tract and pulmonary manifesta-
tions
Respiratory tract and pulmonary manifestations
are highly frequent complications of RA, and they
considerably affect the patientʼs ADL, QOL, and the
selection of drugs. Pathologically speaking, respira-
tory tract manifestations associated with RA are
found in the bronchiolar area with high frequency,
and they usually manifest as bronchiectasis, bron-
chiolitis, organizing pneumonia, respiratory bron-
chiolitis, etc. Bronchiectasis is especially frequent
and manifests in 10-30% of RA patients. It is
characterized by enlargement and destruction of
the bronchi triggered by chronic inflammation
occurring in the central bronchi, and it poses
problems of infection by Pseudomonas aeruginosa,
etc. 4)(Figure-1A, B). In particular, because drugs
including immunosuppressants, steroids, and bio-
logical drugs are used in RA patients, there are
numerous refractory cases. Smokers with the
HLA-DRBI shared epitope among RA patients are
associated with bronchiectasis. Patients affected by
it show high levels of anti-citrullinated protein
antibody (ACPA) and rheumatoid factor (RF). It
usually manifests in patients with a long duration of
RA; however, RA patients that present with
airway manifestations prior to articular symptoms
are also known to exist 5).
On the other hand, when we focus on pulmonary
manifestations, IP is a manifestation with a high
frequency. In studies where high resolution com-
puter tomography (HRCT) was used, it was
Matsushita M, et al: Extra-articular manifestations of rheumatoid arthritis
22
A BB
Figure-1A. Intercurrent bronchiectasis associated with rheumatoid arthritis.
B. Pneumonia at the site of bronchiectasis.
reported that IP was found in approximately 30% of
early RA patients and in over 50% of the entire RA
patient population when asymptomatic cases were
included 6) 7). According to a classification based on
idiopathic IP, IP that manifests as a complication of
RA, in most cases, is usual IP (UIP) and nonspecific
IP (NSIP) (Figure-2), while, although their inci-
dence is low, desquamative IP (DIP), lymphoid
(LIP) and diffuse alveolar damage (DAD) also
manifest. In particular, DAD progresses rapidly and
has a poor prognosis. Organizing pneumonia (OP)
is also a relatively common complication of RA. In
terms of image findings, it appears as an infiltrating
shadow distributed around the periphery and it
must be differentiated from bacterial pneumonia.
Pleurisy is also a common complication of RA and it
presents as pleural thickening and pleural effusion
on plain chest X-ray and CT. This complication
frequently occurs in male patients and differential
diagnosis from tuberculous pleurisy, etc. is impor-
tant as elevated adenosine deaminase (ADA) levels
in pulmonary pleurisy are noted. Additionally,
although not a pulmonary disease, cardiac tampo-
nade and heart failure may develop as a complica-
tion due to pericarditis and pericardial effusion.
In addition to the above, respiratory manifesta-
tions associated with RA such as pulmonary
rheumatoid nodules and, although not directly
associated with RA, drug-induced pulmonary
manifestations triggered by MTX, leflunomide, and
bucillamine also require attention 8).
2. Vasculitis
Vasculitis may occur in 0.5-1.0% of all RA
patients. Vasculitis associated with RA is called
rheumatoid vasculitis outside Japan but the term
malignant RA (MRA) tends to be used in Japan.
Although the 2 do not necessarily refer to the same
pathological condition, they often develop in
patients with high ACPA, RF levels, and IgG-RF
antibody titers. C-reactive protein (CRP) and
erythrocyte sedimentation rate (ESR) also tend to
be elevated. They are often characterized by
hyperglobulinemia and hypocomplementemia.
Depending on the size of the blood vessel affected
by inflammation, it manifests diverse pathological
conditions including multiple mononeurotherapy,
skin ulcers, infarction, gangrene, episcleritis, and IP,
and in some cases the patient may suffer from fever
and fatigue for a prolonged period of time.
Treatment varies depending on the complication,
but it often requires immunosuppressants such as
steroids and cyclophosphamide at high doses in
addition to MTX and biological drugs for RA9).
Some of the complications in which vasculitis is
involved are described below.
(1) Ocular manifestations
Scleritis is an important ocular manifestation
involving vasculitis. Scleritis is divided into episcler-
itis, in which inflammation occurs in the outermost
layer of the sclera, and scleritis, in which inflamma-
tion reaches the deep layer of the sclera. Subjective
symptoms include hyperemia of the ocular conjunc-
tiva, eye discomfort, pain, and lacrimation. Scleritis
is often associated with RA activity and, although
spontaneous remission occurs in some cases, it
requires extreme caution as it may result in
necrotizing scleritis and perforation of the sclera in
recurring cases. Systemic administration of steroids
may be required if local steroid administration
proves ineffective 10).
(2) Dermal and nervous manifestations
When inflammation spreads to the relatively thin
peripheral arteries, it may result in livedo reticula-
ris, purpura, punctate infarcts around the nails,
refractory skin ulcers (Figure-3), and necrosis of
the fingers and toes. Skin ulcers are common in the
periphery of the lower extremities, especially
around the ankle joints. They are accompanied by
Juntendo Medical Journal 66(1), 2020
23
Figure-2 Intercurrent interstitial pneumonia associatedwith rheumatoid arthritis (RA)
Interstitial pneumonia (IP) associated with RA is often usual
interstitial pneumonia (UIP) or nonspecific interstitial pneumonia
(NSIP).
pyoderma gangrenosum in many cases and their
treatment involves the use of high-dose steroids,
immunosuppressants, and vasodilators in addition
to topical therapy including external drugs. In
recent years, while it has been reported that TNFα
inhibitors, which are biological drugs, are effective
for pyoderma gangrenosum11), the possibility that
these drugs themselves may induce vasculitis has
also been suggested 12).
(3) Other
When vasculitis occurs in neurotrophic vessels, it
causes multiple mononeuropathy and it results in
numbness, pain, and movement disorder. Systemic
vasculitis leads to fever, fatigue, weight loss, and
obstructive symptoms of various organs including
pleurisy, pericarditis, and gastrointestinal bleeding,
but vasculitis rarely develops in thick blood vessels
such as the aorta 13).
3. Amyloidosis
Amyloidosis is a pathological condition in which
amyloid proteins are produced in excess and
accumulate in various organs causing disorder as a
result of chronically severe inflammation. In recent
years, its incidence has dramatically dropped
thanks to the advent of MTX and biological drugs.
However, patients in whom amyloidosis poses
problems remain. Of the many types of amyloid
proteins that exist, serum amyloid A (SAA)
accumulates in various organs and creates prob-
lems in RA. SAA belongs to the same gene family as
CRP and serum levels of SAA become elevated
when there is acute inflammation. Continuously
elevated SAA levels in the blood are a major cause
of amyloidosis. Clinically, renal, gastrointestinal, and
cardiac amyloidosis are frequently observed. Renal
amyloidosis often presents with hematuria, protei-
nuria, and even nephrotic syndrome. A renal biopsy
is required for a definitive diagnosis, and Congo red
staining and Dylon staining are primarily used to
confirm amyloid deposition. Amyloid deposition in
the digestive tract results in abdominal bloating,
abdominal pain and nausea, and refractory diarrhea,
paralytic ileus, ischemic enteritis, etc. manifest as it
progresses. Meanwhile, cardiac amyloidosis results
in impaired dilation and contraction of the heart
causing heart failure and arrhythmias. It is charac-
terized by an increased granular brightness in the
myocardium during cardiac ultrasound examina-
tion. Although the efficacy of rituximab on renal
amyloidosis has been reported 14), maintaining blood
SAA at low levels is the only way to prevent this
disease as accumulation of amyloids in the organs is
generally irreversible. Therefore, proactive initia-
tion of effective treatment including the use of MTX
and biological drugs at an early stage is recom-
mended for RA patients with high disease
activity 15).
4. Osteoporosis
Osteoporosis is a complication that poses serious
problems to RA patients because, in addition to the
fact that osteoporosis in itself is a risk factor for RA,
RA occurs more commonly in women, absolute
exercise volume decreases due to articular symp-
toms and drugs (e.g., steroids) that are risk factors
for osteoporosis are used for the treatment of RA.
Bone manifestations associated with RA include
bone erosion and joint destruction. It is assumed
that there are different mechanisms involved in the
onset of these manifestations and systemic osteopo-
rosis. Local bone atrophy observed around the
joints is called periarticular osteoporosis and it is
triggered by enhanced expression of the receptor
activator of NFκB ligand (RANKL) in osteoblasts,
activated T cells, and synovial fibroblasts caused by
inflammatory cytokines such as TNFα, IL-1 and
IL-6, which are primarily involved in the
Matsushita M, et al: Extra-articular manifestations of rheumatoid arthritis
24
Figure-3 Skin ulcer in an RA patientThe patient is undergoing treatment with topical drugs and
vasodilators, but the ulcer is refractory.
pathological development of RA. Highly expressed
RANKL differentiates synovial macrophages, which
are osteoclast precursor cells, into osteoclasts and
plays a major role in the progression of local bone
destruction. Furthermore, it has been reported that
TNFα is directly involved in the production of
osteoclasts and the progression of periarticular
osteoporosis 16).
On the other hand, in systemic osteoporosis, areas
where a marked decrease in bone mass occurs
include the calcaneus and femoral neck, while the
lumbar vertebra, which is primarily composed of
cancellous bone, rarely shows a marked decrease.
These facts suggest that, in addition to the
induction of RANKL by inflammatory cytokines
such as TNFα and IL-6, there are factors that
decrease bone mass such as suppressed expression
of runt-related transcription factor 2 (Runx2),
which is required for mesenchymal stem cells to
differentiate into osteoblasts in RA, and increased
dikkopf-1 (DKK-1), which has an inhibitory effect
on the Wnt signaling pathway required for bone
formation 17). Furthermore, reduced exercise vol-
ume due to articular symptoms associated with RA
also plays a major role in the progression of
osteoporosis. Additionally, desultory administration
of steroids should be avoided as they promote bone
absorption through various mechanisms such as
suppression of the differentiation and proliferation
of osteoblast via Runx2 and even inhibition of
osteoclast apoptosis.
While a range of methods for measuring bone
density such as digital image processing (DIP) and
computed X-ray densitometry (CXD) exist, meas-
urement of the lumbar spine and the proximal
femur using dual-energy X-ray absorptiometry
(DXA or DEXA) is recommended. Osteoporosis is
defined as a bone density of less than 70% of the
young adult mean (YAM) of those aged between 20
to 44 years as measured by these methods 18). There
are a number of drugs for osteoporosis including
active vitamin D3, vitamin K, selective estrogen
receptor modulator (SERM), bisphosphonate, para-
thyroid hormone, and denosumab, an anti-RANKL
antibody. It is important that these drugs be used
after proper selection with consideration for patient
features 19).
5. Blood and lymphoma
Continued chronic inflammation may be accom-
panied by microcytic hypochromic anemia or
normocytic normochromic anemia due to impaired
iron use, etc. Blood tests show a characteristic
decrease in serum iron and total iron binding with a
mild increase in ferritin. While administration of
iron is ineffective in most cases, patients usually
improve as the inflammation subsides. In addition,
although rare, leukopenia is observed in Feltyʼs
syndrome 20). Although it is not caused by RA itself,
pancytopenia may occur as a result of bone-marrow
suppression due to immunosuppressants such as
MTX. Furthermore, it is known that the incidence
of malignant lymphoma is high, although its
frequency varies depending on the study. Lym-
phoma that develops during MTX therapy is called
MTX-lymphoproliferative disorders (LPD), and it
is known to spontaneously remiss with the discon-
tinuation of MTX. In Japan, investigation led by the
Japan College of Rheumatology (JCR) is currently
underway 21) 22).
Conclusions
We described extra-articular manifestations of
RA. With recent advances in molecular biology, the
pathology of RA has been elucidated in detail. In
particular the discovery of ACPA, which is highly
specific to RA, has greatly contributed not only to
the diagnosis of RA but also to research in genetic
backgrounds and environmental factors. In terms of
treatment, the prognosis of RA has significantly
improved thanks to the practical use of biological
drugs that target TNFα, IL-6, and CTLA4. In the
past, the goal of treatment was to alleviate joint pain
or to slow down the decline of joint function, but it
has become possible to achieve complete remission
in some RA patients with treatments that address
the pathological manifestations at a more funda-
mental level and with prevention of bone destruc-
tion in patients. However, due to extra-articular
manifestations, many cases remain where drugs
required for articular symptoms cannot be used.
Furthermore, these drugs may not necessarily be
effective for all patients, and we must pay adequate
attention to infectious diseases such as tuberculosis
and hepatitis B. With further elucidation of the
pathology of RA in the future, we expect that a
Juntendo Medical Journal 66(1), 2020
25
reliable and effective treatment will be established
for all RA patients regardless of the presence of
extra-articular symptoms.
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