Haseki Son Hali 2012-1: Layout 1

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Case Report / Olgu Sunumu

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Ad dress for Cor res pon den ce/Ya z›fl ma Ad re si: Songül Çildağ

Adnan Menderes University School of Medicine, Department of Immunology-Rheumatology, Aydın, Turkey

Phone: [phone]  E-mail: [e-mail]

Received/Gelifl Tarihi: 25 March 2011 Ac cep ted/Ka bul Ta ri hi: 20 June 2011

Özet

Tümör nekrozis faktör alfa, romatoid artrit patogenezinde ve

progresyonunda yer alan önemli bir sitokindir. Romatoid artritli

hastaların tedavisinde anti tümör nekrozis faktör alfa oldukça

önemli bir tedavi seçneğidir. İyi tolere edilmesi ve etkinliğinin iyi

olmasına rağmen ilacın tetiklediği otoimmün hastalıklar endişe

yaratmaktadır. Anti tümör nekrozis faktör alfa kullanımına bağlı

otoimmün hastalık gelişim insidansı bilinmemektedir. Bu çalışmada

adalimumab kullanımı sonrasında lupus gelişen romatoid artritli bir

olgu sunulmuştur (Ha se ki T›p Bül te ni 2012; 50: 27-9)

Anah tar Ke li me ler: Anti-TNF tedavisi, romatoid artrit, sistemik

lupus eritematozus, yan etki

Abs tract

Tumour necrosis factor alpha is a pivotal cytokine involved in the

pathogenesis and progression of rheumatoid arthritis. Anti-tumor

necrosis factor-alpha therapy has become a very important modality

in the treatment of patients with rheumatoid arthritis. Despite good

clinical efficacy and tolerance, the possible occurrence of drug-

induced autoimmune disorders remains a matter of concern.The

incidence of anti-tumor necrosis factor-alpha therapy induced

autoimmune disorders is unknown.We report a new case of

adalimumab-induced lupus syndrome with rheumatoid arthritis.

(The Me di cal Bul le tin of Ha se ki 2012; 50: 27-9)

Key Words: Adverse effect, anti-TNF therapy, rheumatoid arthritis,

systemic lupus erythematosus

Adalimumab Induced Systemic Lupus Erythematosus

Adalimumab Kullanımının Tetiklediği Sistemik Lupus Eritematozus

Songül Çildağ, Taşkın Şentürk

Adnan Menderes University School of Medicine, Department of Immunology-Rheumatology, Aydın, Turkey

Introduction

Rheumatoid arthritis (RA) is a chronic disease

characterized by an immune mediated inflammatory synovitis

leading to joint cartilage and bone destruction (1). Although

the causes of RA are not fully understood, laboratory and

clinical evidence suggests that proinflammatory cytokines,

particularly tumor necrosis factor (TNF) alpha, have an

important role in its pathogenesis (2). 

TNF-alpha, an inflammatory cytokine that is released by

activated monocytes, macrophages, and T lymphocytes,

promotes inflammatory responses that are important in the

pathogenesis of rheumatoid arthritis (3). TNF alpha

concentrations are increased in the synovial fluid of persons

with active RA and increased plasma levels of TNF alpha are

associated with joint pain (4). 

Therapy with anti-TNF-alpha is effective in the

management of RA (5,6). The frequent side effects are

injection/infusion reactions, infections, autoimmunity,

malignancy, congestive heart failure, demyelinating disease,

and hematologic disorders. All three anti-TNF agents,

infliximab, adalimumab and etanercept, have been

associated with the induction of a variety of autoantibodies

(7). The mechanism responsible for the production of these

autoantibodies during anti-TNF-alpha therapy has not been

clearly defined (8). Of concern is the possible induction of

lupus-like (or drug-induced lupus) syndromes, but few cases

have been reported, most commonly associated with

infliximab and etanercept, and rarely related to

adalimumab. In all reported cases, the signs disappeared

after treatment was stopped (9,10). 

We report a new case of adalimumab-induced lupus

syndrome with RA, who had clinical response to early

methylprednisolone and after anti-TNF therapy was stopped. 

Case Report

A 57-year-old woman presented with increasing

dyspnea, cough and fever which persisted for 10 days. She

was diagnosed as having seropositive RA seven years ago

and had been treated with prednisolone, salozopyrine and

methotrexate. Since she had continued with active joint

inflammation, anti-TNF alpha treatment (40 mg of

subcutaneous adalimumab administered in bi-weekly

The Medical Bulletin of Haseki Training and Research Hospital, 

published by Galenos Publishing. All rights reserved.

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Galenos Yay›nevi taraf›ndan bas›lm›flt›r. Her hakk› sakl›d›r.  

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Çildağ et al. Systemic Lupus Erythematosus

injection) was added to the treatment three months ago.

Her symptoms started about two months after initiation of

adalimumab for RA. 

On admission, she was febrile (38,4°C), with

tachycardia (102/min) and tachypnea (28/min), blood

pressure was  110/90 mmHg. The palpebral conjunctiva

was anemic. On auscultation, loud crackles were audible

lower the both lungs. Her hands demonstrated typical

changes of RA with deformity of her fingers.

Laboratory data revealed the following values:

hemoglobin: 8.6 g/dL, hematocrit: 25.9%, reticulocyte index:

1, white blood cell count: 7800/mm³, platelet count:

576000/mm³, direct Coombs IgG: (+++): indirect Coombs -

negative, blood urea nitrogen: 45 mg/dl, serum creatinine: 0.9

mg/dL, urinalysis - normal, C3: 68.6 mg/dl (normal: 85-200

mg/dl), C4: 7.3 mg/dl (normal: 15-50 mg/dl), erythrocyte

sedimentation rate: 94 mm/h.  Antinuclear antibody (ANA)

was positive with a titer of 1:320 homogenous pattern, SS-A,

SS-B, Ro52, nucleosemes, anti-histone were positive, anti-

double- stranded DNA (dsDNA) was negative, rheumatoid

factor was positive at 137 U/mL (normal: <18 U/mL), anti-CCP

was positive at 50 U/ml (normal: <5 U/ml). Electrocardiogram

showed a normal sinus rhythm. Echocardiogram showed

pericardial effusion. Her chest radiography revealed bilateral

pleural effusion. Chest computerized tomography (CT)

demonstrated pneumonia and pleural, pericardial effusion.

Her PPD was negative. It had negative stains and cultures for

bacteria, M. tuberculosis and fungi. ANA was negative before

initiation of adalimumab treatment.

A diagnosis of drug-induced lupus erythematosus was

made. Adalimumab treatment was discontinued and high-

dose corticosteroid was started. She was maintained on

prednisolone 12 mg/day, hydroxychloroquine 400 mg/day

with no symptoms at 6-month follow-up. However, she still

had high titers of ANA.

Discussion

TNF-alpha plays a central role in the pathogenesis of

rheumatic diseases and has become a target molecular

structure for antibody or TNF-receptor (TNF-R) based

treatment in the past few years (11). TNF inhibitors, such as

infliximab, etanercept and adalimumab were shown to be

very effective in reducing synovial inflammation and

retarding structural damage in RA patients (12). Adalimumab

is a recombinant, fully human IgG1 antibody that binds

specifically to human TNF-alpha and neutralizes the activity

of this citokine. It is administered by subcutaneous injection.

It has been approved alone or in combination with

methotrexate for the treatment of RA in Europe and the

United States. Its side effect profile is favorable when

compared with traditional systemic treatments for these

diseases (11,13). The most common side effects are injection

site reactions. One of the most common side effects is the

development of autoantibodies (14).

There are no specific diagnostic criteria for drug-induced

lupus, but certain immunologic features of drug-induced

lupus help distinguish it from other autoimmune diseases.

Patients with drug-induced lupus typically display anti-histone

antibodies, which are present in >95% of cases. When

associated with TNF antagonists, anti-dsDNA antibodies are

usually elevated as well (15).  In our patient, ANA was

positive after adalimumab therapy. SS-A, SS-B, Ro-52,

nucleosemes, anti-histone were positive but anti-double-

stranded DNA (dsDNA) was negative. 

A French national survey was performed in 2003 to

investigate the prevalence and clinical presentation of TNF

antagonist-induced autoimmune disease. Of the 866 patients

surveyed, only 10 patients had anti-DNA antibodies and skin

manifestations classified as limited skin lupus, whereas 12

patients had systemic manifestations and met the American

College of Rheumatology lupus criteria. None of the patients

had pleural effusions or nephritis, although one patient had

a pericardial effusion (16). Our patient had haemolitic

anemia, pericardial and pleural effusion, arthritis but there

was no renal involvement. 

The immunopathological mechanism of the development

of SLE upon anti-TNF alpha therapy is unclear. It has been

suggested that the drug affects the Th1/Th2 balance.

Adalimumab treatment strongly increases cytokines

stimulating Th1 activity in contrast to ’anti-inflammatory’ and

Th2-associated cytokines, which are not significantly

changed (14).

There is an increase in the incidence of various antibodies

with anti-TNF therapy, but this very rarely results in clinical

disease. The British Society for Rheumatology recommends

stopping anti-TNF therapy and appropriate treatment if

symptoms of an SLE-like syndrome develop on anti-TNF

treatment (17). 

In summary, here, we report a new case of adalimumab-

induced lupus syndrome with RA. We stopped adalimumab

therapy and then started prednisolone 12 mg/day,

hydroxychloroquine 400 mg/day with no symptoms at 6-

month  follow-up.

References

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arthritis. Arthritis Rheum 1995;38:151-60.

3. Choy EH, Panayi GS. Cytokine pathways and joint inflammation

in rheumatoid arthritis. N Engl J Med 2001;344:907-16.

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Çildağ et al. Systemic Lupus Erythematosus

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