Efficacy of Adalimumab in Chronically Active and ... - ATS Journals

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from Covidien, General Electric, Air Liquide Medical Systems; he has received lecture fees from Covidien, and travel support from Air Liquide Medical Systems.
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Figure 1.

crural portions of the diaphragm, it may not be representative of diaphragmatic activity as a whole (6). In summary, we report that a patient who developed evidence of decreased diaphragmatic function in reintubation was delayed for a longer than usual time while esophageal Eadi was continuously monitored. Retrospective analysis of the recording showed a pre-terminal fall in EAdi and VTE, while the respiratory rate remained high but increasingly irregular. This pattern may reflect a decrease of EAdi as the consequence of a lowfrequency fatigue of the diaphragm and/or a reduced activity of the respiratory centers. Care should be taken, as with other modes, when using NAVA in patients with likely or suspected neuromuscular weakness. Author Disclosure: H.R.’s institution has received travel support from Maquet. J.C. M.R.’s institution has received travel support from Maquet, and research grants from Covidien, General Electric, Air Liquide Medical Systems; he has received lecture fees from Covidien, and travel support from Air Liquide Medical Systems. A.M.’s institution has received travel fees from Maquet and research grants from Covidien, General Electric, Air Liquide Medical Systems; he has received lecture fees from Covidien, and travel support from Air Liquide Medical Systems. L.B.’s institution has received research grants from Maquet.

Hadrien Rozé, M.D. Hoˆpital Haut Leveque Bordeaux University Hospital Bordeaux, France Jean Christophe Marie Richard, M.D. Rouen University Hospital Rouen, France Alain Mercat, M.D. Angers University Hopital Angers, France Laurent Brochard, M.D. Hopital Cantonal Universitaire University of Geneva Geneva, Switzerland and INSERM U955 Universite´ Paris-Est Cre´teil, France

References 1. Roze´ H, Lafrikh A, Perrier V, Germain A, Dewitte A, Gomez F, Janvier G, Ouattara A. Daily titration of NAVA using the diaphragm electrical activity. Intensive Care Med 2011;37:1087–1094.

2. Esteban A, Frutos-Vivar F, Ferguson ND, Arabi Y, Apezteguı´a C, Gonza´lez M, Epstein SK, Hill NS, Nava S, Soares MA, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 2004;350:2452–2460. 3. Nava S, Rubini F, Zanotti E, Caldiroli D, Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 1997;155:906–915. 4. Laghi F, Cattapan SE, Jubran A, Parthasarathy S, Warshawsky P, Choi YS, Tobin MJ. Is weaning failure caused by low-frequency fatigue of the diaphragm? Am J Respir Crit Care Med 2003;167:120–127. 5. Sinderby C, Beck J, Lindstro¨m L, Grassino A. Enhancement of signal quality in esophageal recordings of diaphragm EMG. J Appl Physiol 1997;82:1370–1377. 6. Sinderby C, Beck J, Weinberg J, Spahija J, Grassino A. Voluntary activation of the human diaphragm in health and disease. J Appl Physiol 1998;85:2146–2158.

Copyright ª2011 by the American Thoracic Society

Efficacy of Adalimumab in Chronically Active and Symptomatic Patients with Sarcoidosis To the Editor: Tumor necrosis factor (TNF)-a is the key cytokine associated with inflammatory symptoms of patients with sarcoidosis (1, 2). Progressive significant disease, pulmonary function deterioration, and critical organ involvement determine the necessity and choice of immunosuppressive therapy. TNF-a might become an important alternative therapeutic target (2). Two randomized trials with the TNF-a blocker infliximab demonstrated pulmonary improvement in patients with sarcoidosis (3, 4). However, a trial with the TNF-a receptor blocker etanercept showed aggravation in 65% of the patients (5). We present a case series of five patients with symptomatic, chronic (mean 10 yr [2–31 yr]), both pulmonary and extrapulmonary sarcoidosis. Adalimumab (160, 80, and 40 mg at Weeks 0, 2, and 4, hereafter biweekly 40 mg for at least 1 year) was administered subcutaneously. In an observational period of 12 weeks, several clinical parameters were studied. All patients had a durable response. In the observational period, radiological improvement occurred in four patients. One patient had a mixed response. Enlarged thoracic and axillary lymph nodes decreased on computed tomography (CT) scan (17.6% 6 14.3, P , 0.001). More clearly than on CT, the grade of intensity on somatostatin receptor scintigraphy

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described paradoxically low serum sIL-2R levels in patients with sarcoidosis with persistent pulmonary lesions as compared with patients with chest X-ray normalization (9). In line with these observations, and lack of relevant sIL-2R levels accompanying persistent pulmonary lesions in our study, we assume that sIL-2R levels do not reflect disease activity, at least not in patients with chronically active pulmonary sarcoidosis. In our and other sarcoidosis studies, IFN-g and IL-8 levels tended to correlate with radiologic and clinical findings (10). In addition to this, our observations suggest that SRS can be of value to observe the magnitude of inflammation and could be useful to monitor therapeutic efficacy in sarcoidosis. SRS enables visualization of granulomas by binding to somatostatin receptors that are frequently involved in immune and inflammation responses, but is not yet an established method in sarcoidosis (11, 12). This study suggests therapeutic efficacy of adalimumab in a small cohort of patients with systemic sarcoidosis.

Figure 1. The computed tomography (CT) scan and somatostatin receptor scintigraphy (SRS) of a patient with chronically active sarcoidosis before (left) and 12 weeks after (right) TNF-a blocking therapy with adalimumab. Increased uptake in nose, salivary glands, and right axillary lymph node and mild uptake in hilar lymph nodes is demonstrated with SRS before treatment (left). The SRS 12 weeks after treatment (right) displays mild uptake in the salivary glands. Note that although the size of cervical lymph nodes as displayed on CT scan remain almost equal, the uptake of these lesions on the SRS disappear.

(SRS, Figure 1) declined 58.3%. Pulmonary function and angiotensin-converting enzyme levels remained unremarkable. Increased lysozyme levels in three patients (14–21 mg/L) normalized. Elevated soluble interleukin-2 receptor (sIL-2R) levels occurred in only two patients, and were subsequently disregarded for further evaluation. Elevated serum interferon (IFN)-g and IL-8 levels in 80% (14.1–37.5 pg/ml) and all (14.4–31.8 pg/ml) patients, respectively, tended to decrease in three patients. Improvement of fatigue (fatigue assessment scale score, 31.0 6 6.0 to 22.6 6 3.6; P , 0.05) and dyspnea (four patients) was experienced. After this observational period, we intensified treatment of the patient with mixed response to a weekly schedule. Soon thereafter his symptoms decreased, accompanied by improved radiological images, stressing the importance to adjust dosing and await responses for a longer period. These positive results with adalimumab add to earlier observations that TNF-a blocking in patients with sarcoidosis is effective (3, 4). Patients may require higher or more frequent doses, similar to Crohn’s disease, at least at initiation, but possibly also for maintenance (6, 7). Evaluation of disease activity and therapeutic monitoring is not standardized. SIL-2R, associated with T cell activation, is often applied, but this aspecific cytokine might also reflect other inflammatory processes (1, 8). Moreover, Grutters and coworkers

Author Disclosure: L.S.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.-K.L.-T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.A.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.L.v.D. received lecture fees from Abbot. J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.v.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.J.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.W.K. has received travel support from Abbot, consultancy fees from Synthon, and is employed by ErasmusMC; he has received payment for the development of educational presentations from Elsevier; he has received travel support from Abbot. G.S.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.M.v.H.’s institution has been provided complimentary medication, grants, and travel support from Abbot; he has received consultancy fees and lecture fees from Abbot; his institution holds a patent related to TSH as immunostimulator. J.A.v.L. has received travel support from Abbot; his institution has received lecture fees and travel fees from Abbot.

Lieke S. Kamphuis, M.Sc. Wai-Kwan Lam-Tse, M.D., Ph.D. Willem A. Dik, M.D. Paul L. van Daele, M.D., Ph.D. Paula van Biezen, M.D. Dik J. Kwekkeboom, M.D., Ph.D. Robert W. Kuijpers, M.D. Herbert Hooijkaas, M.D., Ph.D. Jan A. van Laar, M.D., Ph.D. Erasmus MC, University Medical Center Rotterdam, The Netherlands Jeroen Bastiaans, B.Sc. G. Seerp Baarsma, M.D. The Rotterdam Eye Hospital Rotterdam, The Netherlands P. Martin van Hagen, M.D., Ph.D. Erasmus MC, University Medical Center and The Rotterdam Eye Hospital Rotterdam, The Netherlands References 1. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153–2165. 2. Baughman RP, Iannuzzi M. Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs 2003;17:425–431. 3. Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R, Albera C, Brutsche M, Davis G, Donohue JF, et al. Sarcoidosis Investigators. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795–802.

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4. Rossman MD, Newman LS, Baughman RP, Teirstein A, Weinberger SE, Miller W Jr, Sands BE. A double-blinded, randomized, placebocontrolled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:201–208. 5. Utz JP, Limper AH, Kalra S, Specks U, Scott JP, Vuk-Pavlovic Z, Schroeder DR. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124:177–185. 6. Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, Panaccione R, Wolf D, Kent JD, Bittle B, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56:1232–1239. 7. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, D’Haens G, Li J, Rosenfeld MR, Kent JD, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146:829–838. 8. Bargagli E, Bianchi N, Margollicci M, Olivieri C, Luddi A, Coviello G, Grosso S, Rottolli P. Chitotriosidase and soluble IL-2 receptor:

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comparison of two markers of sarcoidosis severity. Scand J Clin Lab Invest 2008;68:479–483. Grutters JC, Fellrath JM, Mulder L, Janssen R, van den Bosch JM, van Velzen-Blad H. Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation. Chest 2003;124:186–195. Shigehara K, Shijubo N, Ohmichi M, Yamada G, Takahashi R, Okamura H, Kurimoto M, Hiraga Y, Tatsuno T, Abe S, et al. Increased levels of interleukin-18 in patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 2000;162:1979–1982. Kwekkeboom DJ, Krenning EP, Kho GS, Breeman WA, van Hagen PM. Somatostatin receptor imaging in patients with sarcoidosis. Eur J Nucl Med 1998;25:1284–1292. Duet M, Liote´ F. Somatostatin and somatostatin analog scintigraphy: any benefits for rheumatology patients? Joint Bone Spine 2004;71: 530–535.

Copyright ª2011 by the American Thoracic Society