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: collagen@juntendo.ac.jp

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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