close

Вход

Забыли?

вход по аккаунту

?

Development of sarcoidosis during etanercept therapy.

код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 55, No. 5, October 15, 2006, pp 817– 820
DOI 10.1002/art.22238
© 2006, American College of Rheumatology
CASE REPORT
Development of Sarcoidosis During Etanercept
Therapy
MARCOS A. GONZÁLEZ-LÓPEZ, RICARDO BLANCO, M. CARMEN GONZÁLEZ-VELA,
HÉCTOR FERNÁNDEZ-LLACA, AND VICENTE RODRÍGUEZ-VALVERDE
Introduction
The 3 currently available tumor necrosis factor ␣ (TNF␣)
blocking agents are a soluble receptor fusion protein (etanercept), a humanized mouse monoclonal antibody (infliximab), and a fully human monoclonal antibody (adalimumab). All of these agents are highly effective in the
treatment of rheumatoid arthritis and other inflammatory
diseases, including ankylosing spondylitis (AS), psoriatic
arthritis, and psoriasis vulgaris (1). They have been used in
refractory sarcoidosis, with different results. Whereas infliximab, the more widely used agent in this entity, has
demonstrated clear efficacy in this disease (2,3), the results
with etanercept were generally disappointing (2,4), although in isolated cases etanercept was shown to be effective (5,6). Reported experiences with adalimumab in sarcoidosis, although encouraging, are very scarce.
Recently, the development of several syndromes characterized by granuloma formation has been reported in
patients receiving TNF␣ blocking therapy for a variety of
diseases. Except for one patient treated with adalimumab
(7), the remaining patients were treated with etanercept
(8 –14). We describe a patient diagnosed with AS who
developed a granulomatous syndrome consistent with sarcoidosis while being treated with etanercept.
Case Report
A 70-year-old man was diagnosed with AS in our rheumatology clinic in 1995. He reported having inflammatory
low spinal pain for several years as well as arthritis of
Marcos A. González-López, MD, Ricardo Blanco, MD,
M. Carmen González-Vela, MD, Héctor Fernández-Llaca,
MD, Vicente Rodrı́guez-Valverde, MD: Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain.
Address correspondence to Vicente Rodrı́guez-Valverde,
MD, Professor of Medicine and Chief, Rheumatology Service, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Avda, Valdecilla s/n, 39008, Santander, Spain. E-mail: rodriguv@
unican.es.
Submitted for publication October 24, 2005; accepted in
revised form February 14, 2006.
the wrists, knees, ankles, and several metacarpophalangeal, interphalangeal, and metatarsophalangeal joints. In
addition, he had grade III bilateral sacroiliitis and was
HLA–B27 positive; rheumatoid factor and antinuclear
antibodies were negative. He was treated with various
nonsteroidal antiinflammatory drugs (NSAIDs) and lowdose prednisone (10 mg/day) in addition to sulfasalazine
(up to 3 gm/day) followed by methotrexate (up to 20 mg/
week). After initial improvement, the patient repeatedly
had a relapse of AS symptoms with increased low back
pain, peripheral arthritis, and raised acute-phase reactant
levels.
In August 2002, due to persistent clinical activity with
increased acute-phase reactant levels (erythrocyte sedimentation rate [ESR] of 62 mm/hour [Westergren] and
C-reactive protein level of 2.8 mg/dl [normal value ⬍0.5
mg/dl]), treatment with etanercept (25 mg twice weekly)
was started. Following our national guidelines to exclude latent tuberculous infection (15), a purified protein
derivative (PPD) skin test and a chest radiograph performed prior to etanercept therapy were negative and normal, respectively. Two months later the patient was clinically asymptomatic and acute-phase reactant levels were
normal.
In June 2004, after 21 months of etanercept therapy and
while asymptomatic, the patient reported a 6-week history
of skin lesions on his face. Physical examination disclosed
3 firm, nontender, red-brown nodular lesions ranging in
size from 1 cm to 1.5 cm, located on the forehead, right
eyebrow, and the nasolabial area (Figure 1). Diascopy of
the nodules showed the appearance of an apple-jelly color.
No other lesions were present on the skin or mucosa.
There were no superficial lymphadenopathies or hepatosplenomegaly.
A skin biopsy was performed. The histopathologic study
demonstrated numerous noncaseating granuloma of the
sarcoidal type extending through the entire thickness of
the dermis (Figure 2). Polarizing microscopy for foreign
body evaluation; tissue stains; and bacteria, fungus, and
mycobacterium cultures, as well as polymerase chain reaction for Mycobacterium tuberculosis were all negative. A
chest radiograph and a computed tomography of the thorax revealed bilateral hilar and paratracheal adenopathies.
817
818
González-López et al
of the patient’s AS with an increase in low back pain and
peripheral arthritis was then observed, which was treated
with intravenous pamidronate (60 mg monthly during 6
months) with a good clinical response. A new chest radiograph in November 2004 showed the disappearance of the
intrathoracic lymph nodes, and the ACE levels reverted to
normal; a whole-body scintigraphy with 67Ga performed
in March 2005 was normal. When the patient was last seen
in December 2005, his AS remained controlled with
NSAIDs and he did not have any signs or symptoms of
sarcoidosis.
Figure 1. Nodular lesion in the nasolabial region.
67
A scintigraphy with Ga showed increased uptake in the
paratracheal and hilar lymph nodes, in both parotid
glands, and in the right lachrymal gland. Pulmonary function tests were normal and a new PPD skin test was again
negative; the angiotensin-converting enzyme (ACE) level
was mildly elevated at 76 units/ml (reference range 8 –52
units/ml) and the ESR was 30 mm/hour. These findings
were consistent with the diagnosis of sarcoidosis with skin
involvement.
A possible relationship between the development of sarcoidosis and treatment with etanercept was suspected, and
etanercept was stopped in August 2004. A rapid improvement of the cutaneous lesions was evident 2 weeks after
discontinuation of etanercept, and the lesions spontaneously and completely resolved in 2 months. A reactivation
Figure 2. Noncaseating sarcoid granuloma in the dermis (hematoxylin and eosin stained; original magnification ⫻ 200).
Discussion
Sarcoidosis is a multisystemic disease characterized by
noncaseating granulomatous infiltration primarily of the
lungs and lymphatic system, although it may affect multiple organ systems. Sarcoidosis often presents as bilateral
hilar lymphadenopathy and pulmonary infiltrates, and
less frequently with skin, ocular, or joint manifestations.
Skin involvement usually manifests either acutely with
erythema nodosum or chronically as lupus pernio, nodular lesions, or plaque lesions (5).
The etiology of sarcoidosis remains unknown, although
current evidence supports the concept that inflammation
and granuloma formation are the result of an antigendriven immune response mediated by the T cell CD4⫹
phenotype 1 (Th1) and activated alveolar macrophages,
with increased secretion of several cytokines such as interleukin-2, interferon-␥ (IFN␥), and TNF␣ (16). To this
respect, the cytokine most extensively studied is TNF␣,
and there is wide evidence of its pivotal role in the induction and maintenance of both inflammation and granuloma (16). Based on these data, TNF␣ blocking therapy has
been used in the treatment of refractory sarcoidosis with
mixed results. Even though a good response has been
reported with etanercept in isolated cases (5,6), the results
of an open-label study in stages II and III of progressive
pulmonary sarcoidosis were generally disappointing, with
worsening of the disease observed in 11 of 16 patients (4).
In contrast, more than 30 cases of successful results with
infliximab have been reported (2,3).
Here, we report the development of a granulomatous
process consistent with sarcoidosis in a patient with AS
after 21 months of etanercept therapy. Although we cannot
rule out the rare association between sarcoidosis and AS
(17), the rapid improvement of the skin lesions and other
manifestations of sarcoidosis after suspension of etanercept support the inducing or triggering role of etanercept.
In our review of the literature (7–14), we found 10 patients
who developed different syndromes characterized by granuloma formation while receiving TNF␣ blocking therapy.
The most frequent clinical presentations were lung involvement with nodular or reticulonodular infiltrates (6
patients) and rheumatoid nodulosis (2 patients). The outcomes after withdrawal of the TNF␣ blocking agent were
variable (Table 1). Except for 1 patient, all were being
treated with etanercept.
Taking into account the pivotal role of TNF␣ in the
pathogenesis of sarcoidosis and granuloma formation, the
development of these granulomatous reactions while re-
73/M/RA
50/F/RA
37/M/PsA
41/F/RA
53/F/RA
67/M/RA
52/M/RA
50/M/RA
79/F/RA
21/M/PsA
70/M/AS
(7)
(8)
(9)
(10)
(11)
(12)
(12)
(12)
(13)
(14)
Current report
Etanercept/21
Etanercept/35
Etanercept/24
Etanercept/3
Etanercept/2
Etanercept/2
Etanercept/4
Etanercept/19
Etanercept/19
Etanercept/2
Adalimumab/6
Rheumatoid nodules in lungs,
fingers, and elbows
Cough, dyspnea, pleural
effusions, and cavitating lung
lesions
Rheumatoid nodulosis in fingers
and elbows
Rheumatoid nodulosis in
fingers; nailfold infarcts
Giant cell arteritis, with
temporal headache and jaw
pain
Crohn’s-like disease with
abdominal pain, diarrhea, and
bloody stools
Cutaneous nodules, bilateral
hilar and paratracheal
adenopathies
Cough, weight loss, bilateral
nodular lung infiltrates
Cough, dyspnea, reticulonodular
lung infiltrates, and skin
lesions
Fever, cough, dyspnea, and
bilateral reticulonodular lung
infiltrates
Subpleural nodule and cavitated
lung lesion
Clinical manifestations
* TNF␣ ⫽ tumor necrosis factor ␣; RA ⫽ rheumatoid arthritis; PsA ⫽ psoriatic arthritis; AS ⫽ ankylosing spondylitis.
Age/sex/disease
Reference
TNF␣ blocking agent/time
to reaction, months
Acute and chronic
inflammation with
crypt destruction
Noncaseating sarcoid
granulomas
Giant cell arteritis
Not performed
Not performed
Necrotizing pulmonary
nodules and vasculitis
Necrotizing area
surrounded by a
palisade of histiocytes
and chronic
inflammatory cells
Rheumatoid nodules
Noncaseating granulomas
Noncaseating granulomas
in lungs and skin
Necrotizing granulomas
Biopsy results
Granulomatous reaction
Table 1. Granulomatous reactions associated with TNF␣ blocking therapy*
Resolution 2 months after
etanercept withdrawal
Etanercept continued/controlled
with mesalamine
Slight improvement after adding
leflunomide to etanercept
No data
Improvement after etanercept
withdrawal
Resolution after etanercept
withdrawal and treatment with
azathioprine and steroids
Stable despite continuing etanercept
Etanercept withdrawn/outcome not
specified
Adalimumab withdrawn/persistence
despite antituberculous therapy
Stabilization after etanercept
withdrawal/resolution with
prednisone
Resolution 9 months after
etanercept withdrawal
Treatment/outcome
Etanercept Therapy and Sarcoidosis
819
820
ceiving TNF␣ blocking therapy, mainly with etanercept,
seems paradoxical. This might indicate that other cytokines could play a crucial role in granuloma formation. In
this respect, it is known that IFN␥ is able to activate
macrophages and to transform them into giant cells, which
are important building blocks of the granuloma (18). In
contrast, the mechanisms of action of etanercept differ in
several respects from those of the monoclonal anti-TNF␣
antibodies (reviewed in references 19 and 20). These differences could account for the limited efficacy of etanercept in sarcoidosis and Crohn’s disease, and for allowing
the development of the reported granulomatous reactions.
To this respect, it is known that etanercept does not lyse
CD4⫹ T cells expressing TNF␣ on their membranes and
preferentially neutralizes soluble TNF␣, leaving TNF receptor p75 (TNFR p75) signaling largely intact. In addition, the binding of etanercept to TNF␣ has both high-on
and high-off kinetics, shedding ⬃50% of soluble and 90%
of transmembrane TNF␣ only 10 minutes after binding,
thus allowing redistribution of bioactive TNF␣ from sites
of production, such as the inflamed joints, into other tissues where overall TNF␣ concentrations are low. Moreover, in patients with AS treated with etanercept, a significant increase in the percentage of T cells expressing TNF␣
and INF␥ has been reported, suggesting that neutralization
of peripheral TNF␣ is able to up-regulate the ability of
T cells to produce these cytokines. Therefore, treatment
with etanercept would preserve, at least to some degree,
the mechanisms leading to granuloma formation and integrity by increasing the proportion of T cells expressing
TNF␣ and INF␥, by preserving the TNFR p75–mediated
immunoregulatory functions, and by its incomplete blockade of TNF␣ bioactivity.
In summary, we report a patient with AS who developed
a granulomatous syndrome consistent with sarcoidosis
while receiving etanercept therapy. This observation,
along with the reported cases of other granulomatous reactions in relation almost exclusively to etanercept therapy and the rather poor results obtained with this agent in
Crohn’s disease and refractory sarcoidosis would suggest
that by its mechanism of action, this TNF␣ blocking agent
leaves, at least in some patients, sufficient cytokine activity to support granuloma formation.
REFERENCES
1. Haraoui B. Differentiating the efficacy of the tumor necrosis
factor inhibitors. Semin Arthritis Rheum 2005;34 Suppl 1:7–
11.
González-López et al
2. Keystone EC. The utility of tumour necrosis factor blockade
in orphan diseases. Ann Rheum Dis 2004;63 Suppl 2:ii79 –
83.
3. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with
infliximab. Chest 2005;127:1064 –71.
4. Utz JP, Limper AH, Kalra S, Specks U, Scott JP, VukPavlovic Z, et al. Etanercept for the treatment of stage II
and III progressive pulmonary sarcoidosis. Chest 2003;124:
177– 85.
5. Khanna D, Liebling MR, Louie JS. Etanercept ameliorates
sarcoidosis arthritis and skin disease. J Rheumatol 2003;30:
1864 –7.
6. Hobbs K. Chronic sarcoid arthritis treated with intraarticular
etanercept [letter]. Arthritis Rheum 2005;52:987– 8.
7. Vavricka SR, Wettstein T, Speich R, Gaspert A, Bachli EB.
Pulmonary granulomas after tumour necrosis factor ␣ antagonist therapy. Thorax 2003;58:278 –9.
8. Peno-Green L, Lluberas G, Kingsley T, Brantley S. Lung injury
linked to etanercept therapy. Chest 2002;122:1858 – 60.
9. Phillips K, Weinblatt M. Granulomatous lung disease occurring during etanercept treatment. Arthritis Rheum 2005;53:
618 –20.
10. Hubscher O, Re R, Iotti R. Pulmonary rheumatoid nodules in
an etanercept-treated patient [letter]. Arthritis Rheum 2003;
48:2077– 8.
11. Kekow J, Welte T, Kellner U, Pap T. Development of rheumatoid nodules during anti–tumor necrosis factor ␣ therapy with
etanercept [letter]. Arthritis Rheum 2002;46:843– 4.
12. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum 2002;47:445–9.
13. Seton M. Giant cell arteritis in a patient taking etanercept and
methotrexate [letter]. J Rheumatol 2004;31:1467.
14. Oh J, Arkfeld DG, Horwitz DA. Development of Crohn’s disease in a patient taking etanercept. J Rheumatol 2005;32:
752–3.
15. Comité de Expertos de la SER. Actualización de la Conferencia de Consenso de la Sociedad Española de Reumatologı́a
sobre terapia anti-TNF en Artritis Reumatoide. Rev Esp
Reumatol 2002;29:51–5.
16. Ziegenhagen MW, Muller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance. J Intern Med
2003;253:18 –30.
17. Stucki G, von Felten A, Speich R, Michel BA. Ankylosing
spondylitis and sarcoidosis: coincidence or association? Case
report and review of the literature. Clin Rheumatol 1992;11:
436 –9.
18. Judson MA. The etiologic agent of sarcoidosis: what if there
isn’t one? Chest 2003;124:6 – 8.
19. Ehlers S. Why does tumor necrosis factor targeted therapy reactivate tuberculosis? J Rheumatol Suppl 2005;74:
35–9.
20. Dinarello CA. Differences between anti-tumor necrosis
factor-␣ monoclonal antibodies and soluble TNF receptors
in host defense impairment. J Rheumatol Suppl 2005;74:
40 –7.
Документ
Категория
Без категории
Просмотров
0
Размер файла
275 Кб
Теги
development, sarcoidosis, etanercept, therapy
1/--страниц
Пожаловаться на содержимое документа