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Table of Contents
Vol. 83, No. 3, 2012
Issue release date: February 2012
Section title: Clinical Investigations
Editor's Choice -- Free Access
Respiration 2012;83:218-224
(DOI:10.1159/000328738)

Long-Term Treatment with Infliximab in Patients with Sarcoidosis

Hostettler K.E.a · Studler U.b · Tamm M.a · Brutsche M.H.a
aClinic of Respiratory Medicine, and bDepartment of Radiology, University Hospital Basel, Basel, Switzerland
email Corresponding Author

Katrin E. Hostettler, MD, PhD

Clinic of Respiratory Medicine, University Hospital Basel

Petersgraben 4

CH-4031 Basel (Switzerland)

Tel. +41 61 328 69 16, E-Mail hostettlerk@uhbs.ch


Abstract

Background: Long-term benefit and safety of infliximab treatment in patients with chronic sarcoidosis remain unclear. Objectives: It was the aim of this study to assess the clinical benefit and safety of long-term infliximab treatment in patients with chronic steroid-resistant sarcoidosis. Methods: We conducted a retrospective chart review of all patients with chronic steroid-resistant sarcoidosis who received infliximab between January 2003 and November 2010. Pulmonary function tests and index lesions before and after infliximab therapy were assessed. Results: Between January 2003 and November 2010, 28 patients received in-fliximab, 16 of them for more than 12 months. Five (31%) of these 16 patients with long-term infliximab treatment had a predominantly pulmonary disease, whereas 11 (69%) had a predominantly extrapulmonary involvement. Mean duration of treatment for the 16 patients was 29 months (range 12-62). Six of 11 (55%) patients with mainly extrapulmonary sarcoidosis showed a complete remission of their index lesion, 4/11 (36%) had a partial remission and 1/11 (9%) showed no response. One out of 5 patients with predominantly pulmonary sarcoidosis showed a >10% improvement in percentage predicted forced vital capacity, 3/5 showed a 0-10% improvement, and in 1/5 patients, percentage predicted forced vital capacity declined during infliximab treatment. Thus, overall, 14/16 (88%) patients profited from long-term infliximab treatment. Suspected adverse effects which lead to a temporary withdrawal of infliximab therapy were noticed in 1/16 (6%) patients. Conclusions: This retrospective study indicates that long-term infliximab is very efficient and safe in patients with chronic steroid-resistant sarcoidosis when assessed with individualized treatment targets. Patients with predominantly extrapulmonary sarcoidosis seem to profit more than patients with a predominantly pulmonary disease.

© 2011 S. Karger AG, Basel


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Introduction

Sarcoidosis is a systemic granulomatous disease that may involve any organ [1,2,3,4,5,6], but the lungs and lymphatic system are most commonly affected. Although the -aetiology of this disease remains unclear, there is evidence for a genetic involvement [3,7,8,9,10], as well as interaction of environmental and genetic factors [3,8,11].

Curative treatment approaches are currently not available, but in the case of chronic and/or progressive sarcoidosis, the administration of corticosteroids is considered standard therapy [6,12]. Non-steroidal anti-inflammatory agents, cytotoxic or immunomodulatory drugs are appropriate alternatives for patients with intolerable corticosteroid-induced side effects or corticosteroid resistance [12]. However, therapy with these agents is unspecific, the clinical response is variable, and long-term treatment is frequently associated with significant toxicity [13,14].

Infliximab (Remicade; Centocor, Inc., Malvern, Pa., USA) is a monoclonal antibody that binds to tumour necrosis factor-α (TNF-α), thereby inhibiting TNF-α-induced specific effects. TNF-α plays a pivotal role in the development of non-caseating granulomas which are typically seen in sarcoidosis [2]. Importantly, in patients with active sarcoidosis, the release of TNF-α by activated alveolar macrophages has been documented [11,15,16,17], and there is evidence of a correlation between TNF-α release and the progression of sarcoidosis [16,18]. The efficacy and safety of infliximab treatment in patients with sarcoidosis has been demonstrated previously [12,19,20,21,22,23,24,25,26,27], but only recently the first randomized, double-blind, placebo-controlled trials were performed to assess the efficacy of infliximab treatment in patients with chronic sarcoidosis [1,28,29]. However, clinical benefit and safety of a long-term targeted therapy with infliximab in patients with chronic sarcoidosis still remain unclear. Here, we present results of a retrospective chart review of patients with chronic progressive, steroid-resistant sarcoidosis treated with infliximab for up to 62 months.

Patients and Methods

Patients

Twenty-eight patients with chronic progressive sarcoidosis received infliximab between November 2003 and November 2010 at the Clinic of Respiratory Medicine, University Hospital Basel, Basel, Switzerland. All 28 patients had histologically confirmed pulmonary and/or extrapulmonary sarcoidosis. Subjects had either steroid-resistant disease, were refractory to steroid-sparing agents, or had developed severe side effects under these treatments. Sixteen of these patients had been treated with infliximab for ≥12 months.

All patients had a negative tuberculin skin test and/or a negative blood test (interferon-γ release assay) and showed no signs of chronic and/or serious infections, malignancies and congestive heart failure, respectively.

Approval from the local ethics committee was obtained (Ethics Committee, Faculty of Medicine, University Hospital Basel), and patients provided written informed consent.

Infliximab Treatment

All patients received intravenous infusions of infliximab, typically 3 mg/kg, in 4-/6-/8-weekly intervals. However, during the infliximab treatment period, patients remained on their concomitant medication with oral corticosteroids and/or other immunomodulatory drugs, at a minimum dose of typically 5 mg prednisone and 50 mg of azathioprine per day.

During the whole treatment period, all patients were seen on a regular basis by a senior physician in the out-patient clinic of the University Hospital Basel, Basel, Switzerland. Treatment response and adverse events were monitored and documented continually. Patients who continued the infliximab treatment beyond the end of the observation period (November 2010) were regularly monitored to date.

Outcome Measures

The organ in which sarcoidosis lead to the greatest negative impact on clinical function and quality of life was identified for each patient as index organ, and outcome measures were individualized accordingly: (1) in patients with predominantly lung involvement, forced vital capacity (FVC) and percentage predicted FVC (FVC,%P) were assessed before and after infliximab treatment; (2) in patients with predominantly extrapulmonary sarcoidosis, response to infliximab treatment was assessed as complete remission, partial remission or no response of the index organ; decision on treatment response was reached interdisciplinary. Assessments of neurological deficit, involvement of the skin and heart were performed by sarcoidosis experienced neurologists, dermatologists and cardiologists, respectively.

Results

Baseline Characteristics and Patient Disposition

A total of 28 patients with chronic progressive, steroid-resistant sarcoidosis were treated with infliximab between November 2003 and November 2010. Among these 28 patients, 16 had been treated for ≥12 months and were thought eligible for this study (fig. 1). According to their index organ, there were 5 (31%) patients with predominantly pulmonary involvement and 11 (69%) patients with predominantly extrapulmonary disease (fig. 1). Two of the 5 patients with predominantly pulmonary disease suffered from sarcoidosis stage II according to Silzbach and 3 patients from Silzbach stage IV. A disposition according to the index organ of patients with predominantly extrapulmonary disease is shown in figure 1 (upper part). The baseline characteristics of all patients treated for ≥12 months are listed in table 1. The mean duration of treatment was 29 months (range 12-62). The disposition according to the index organ of those 12 patients with <12 months of treatment and reasons for withdrawal of infliximab therapy are shown in figure 1 (lower part).

Table 1

Baseline demographics, disease characteristics and concomitant medication of patients with long-term infliximab treatment

http://www.karger.com/WebMaterial/ShowPic/195310

Fig. 1

Disposition of patients with chronic steroid-resistant sarcoidosis and long-term infliximab treatment according to their predominantly involved organ (upper part), and course of patients with <12 months of in-fliximab treatment (n = 12; lower part). CNS = Central nervous system.

http://www.karger.com/WebMaterial/ShowPic/195307

Change from Baseline in Lung Function Parameters

Compared to baseline, 1/5 patients with predominantly pulmonary sarcoidosis showed a >10% improvement in FVC,%P (fig. 2a, continuous line), and 3/5 patients showed a 0-10% improvement after infliximab therapy (dashed lines). In 1/5 patients with predominantly pulmonary sarcoidosis, FVC,%P declined during inflixi mab treatment (dotted line). The mean improvement in FVC,%P was 6% (range -6 to 23). At baseline, absolute FVC values ranged from 0.94 to 3.63 litres (mean 2.26 ± 1.25; fig. 2b). After infliximab treatment, absolute FVC values ranged from 0.77 to 4.28 litres, with the mean FVC slightly increasing to 2.57 ± 1.58 liters.

Fig. 2

a FVC,%P at baseline and after infliximab treatment for each patient with predominantly pulmonary sarcoidosis (n = 5). b FVC at baseline and after infliximab treatment for each patient with predominantly pulmonary sarcoidosis (n = 5).

http://www.karger.com/WebMaterial/ShowPic/195306

Response in Patients with Predominantly Extrapulmonary Sarcoidosis

Of the 11 patients with predominantly extrapulmonary sarcoidosis, 10 (91%) responded to infliximab treatment. Six out of 11 (55%) patients showed a complete remission of their index lesion, and 4/11 (36%) had a partial remission (table 2). In 1/11 (9%) patients, no response could be observed (table 2).

Table 2

Treatment responses for patients with predominantly extrapulmonary sarcoidosis (n = 11)

http://www.karger.com/WebMaterial/ShowPic/195309

Table 3 shows the response of the index organ of each patient with predominantly extrapulmonary sarcoidosis and the respective duration of infliximab treatment. Based on clinical assessments, patient No. 15 had a partial remission of her neurologic impairment 3 months after the start of infliximab treatment, and a follow-up magnetic resonance imaging (MRI) examination of the brain was performed. Figure 3 shows improvement in gadolinium-enhancing white matter lesions after 3 months of infliximab treatment.

Table 3

Index organ and treatment response achieved during the respective duration of infliximab treatment for each patient with predominantly extrapulmonary sarcoidosis (n = 11)

http://www.karger.com/WebMaterial/ShowPic/195308

Fig. 3

Gadolinium-enhanced MRI of patient No. 15. Axial T1-weighted images (TR/TE, 663/17 ms) after intravenous administration of contrast agent (Magnevist at a dose of 0.1 mmol/kg; Bayer Schering Pharma, Berlin, Germany). Multiple gadolinium-enhancing white matter lesions consistent with an active inflammatory process are predominantly present in the left hemisphere at baseline examination (a, arrowheads). Most lesions - except for one (b, arrowhead) - completely resolved at follow-up MRI examination obtained 3 months after the start of infliximab treatment (b).

http://www.karger.com/WebMaterial/ShowPic/195305

Adverse Events

Fifteen out of 16 (94%) patients tolerated long-term infliximab treatment without any clinically relevant side effects. A possible adverse event occurred in 1/16 (6%) patients: after more than 4 years of well-tolerated infliximab treatment, the patient suffered from a symptomatic bradyarrhythmia 6 h after infliximab infusion. A cardiac involvement of sarcoidosis had not been suspected by then, and an MRI of the heart showed no evidence of myocardial granulomas - a myocardial biopsy was not performed. Due to persistent symptomatic bradyarrhythmia, a pacemaker had to be implanted. Whether the observed arrhythmia was due to infliximab treatment or whether it was a symptom of cardiac involvement of the systemic disease was not clearly evident, and infliximab therapy was continued thereafter without recurrence of cardiac symptoms.

None of the 16 patients developed severe infections or malignancies during infliximab therapy.

Discussion

In a prior randomized, double-blind, placebo-controlled trial, infliximab therapy has been demonstrated to cause a significant improvement in FVC,%P, as well as an improvement in extrapulmonary symptoms in patients with chronic sarcoidosis [1,29]. However, the study is limited by therapy duration of only 24 weeks, and further data about efficacy and safety of long-term infliximab treatment are scant. Therefore, our study with a mean duration of 29 months might give additional information for the use of infliximab in the clinical practice.

Sarcoidosis is a heterogeneous disease, and thus, responses to treatment are heterogeneous too. In this study, an index organ was identified for each patient, and outcome measures were individualized accordingly. In patients with predominantly extrapulmonary involvement, the outcome measure was defined as the extent of benefit with regard to the specific organ impairment at baseline. We acknowledge that this assessment of treatment response was not standardized and/or validated. However, medical examinations before, during and after infliximab treatment were performed by (at least) two specialists from different subspecialties who were experienced in the clinical presentation and management of sarcoidosis patients, and thus, the decision on treatment response was reached interdisciplinary. Previously designed tools to assess extrapulmonary organ involvement [29,30,31] have not been validated and/or standardized for the European population either, and thus, a validated and standardized tool to assess whether and to what extent an extrapulmonary organ is involved is still elusive. Our observation that 91% of patients with predominantly extrapulmonary sarcoidosis responded to infliximab treatment is in line with previously published data from case reports, retrospective chart analysis and non-randomized studies that demonstrated a high efficacy of infliximab for patients with refractory extrapulmonary sarcoidosis [5,12,19,20,21,23,25,26,27,29,32,33,34,35]. Importantly, our findings are supported by recently published data from a double-blind, randomized study demonstrating that infliximab therapy improved extrapulmonary sarcoidosis compared with placebo [29].

The observed mean improvement in FVC,%P of 6% in patients with predominantly pulmonary involvement was considerably greater than the improvement in FVC,%P observed in the randomized, placebo-controlled trial by Baughman et al. [1] (2.5% improvement in FVC,%P). A possible explanation for this discrepancy might be the fact that only patients with stable pulmonary disease were included in the study of Baughman et al. [1], whereas our study group was comprised of patients with unstable and progressive disease. A comparison of baseline FVC values between the two study groups supports this assumption. It has been suggested by Baughman et al. [1] that by studying only patients with stable disease, background therapy may have diminished the response to infliximab therapy, and exploratory analyses revealed that patients with more severe disease were more likely to benefit from infliximab therapy [1]. We acknowledge that the clinical importance of a 6% FVC,%P improvement is unclear, and additional assessment of quality of life or exercise testing would be mandatory in future studies.

In this study, infliximab had to be withdrawn temporarily in only 1/16 (4%) patients due to suspected adverse effect, and thus, the incidence is comparable with the one observed in the study by Baughman et al. [1] (5.5%). Symptomatic disorders of cardiac rhythm associated with the use of infliximab have been reported previously [36,37], but in our patient, cardiac involvement of the systemic disease was not excluded. In summary, infliximab treatment was well tolerated, and - even after long-term treatment - no cases of malignancies or severe infections such as tuberculosis or pneumonia occurred.

In conclusion, an analysis of this follow-up study indicates that long-term infliximab is very efficient in patients with steroid-resistant sarcoidosis when assessed with individualized treatment targets. Patients with predominantly extrapulmonary sarcoidosis seem to profit more than patients with predominantly pulmonary disease. Importantly, this observation is supported by results from a post hoc analysis within the randomized placebo-controlled trial of Baughman et al. [1] which suggested that infliximab therapy might be more beneficial in patients with multi-organ extrapulmonary involvement. Furthermore, our data suggest that in patients with chronic steroid-resistant pulmonary and/or extrapulmonary sarcoidosis, infliximab treatment is well tolerated and safe, even after long-term application. We believe that this retrospective analysis provides further evidence for a substantial clinical benefit of infliximab treatment in these patients, i.e. infliximab seems to be a valid op tion as second-/third-line therapy for patients with refractory - specifically extrapulmonary - sarcoidosis -already receiving corticosteroids and/or other immunomodulatory agents. Further large, randomized and con trolled studies with standardized assessment criteria and long-term drug administration are needed to evaluate the efficacy and safety of infliximab in patients with chronic sarcoidosis.

Acknowledgements

This study was supported by a non-conditional grant of Centocor, Inc., Malvern, Pa., USA. K.E.H. is supported by a grant from the Swiss National Research Foundation, Switzerland.

Financial Disclosure and Conflicts of Interest

The authors have no conflicts of interest to disclose.


References

  1. Baughman RP, Drent M, Kavuru M, et al: Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795-802.
  2. Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997;336:1224-1234.
  3. Iannuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med 2007;357:2153-2165.
  4. Rybicki BA, Iannuzzi MC: Epidemiology of sarcoidosis: recent advances and future prospects. Semin Respir Crit Care Med 2007;28:22-35.

    External Resources

  5. Lower EE, Weiss KL: Neurosarcoidosis. Clin Chest Med 2008;29:475-492.

    External Resources

  6. Judson MA: Sarcoidosis: clinical presentation, diagnosis, and approach to treatment. Am J Med Sci 2008;335:26-33.

    External Resources

  7. Rybicki BA, Iannuzzi MC, Frederick MM, et al: Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001;164:768-780.
  8. Müller-Quernheim J, Schürmann M, Hofmann S, et al: Genetics of sarcoidosis. Clin Chest Med 2008;29:391-414.

    External Resources

  9. Sverrild A, Backer V, Kyvik KO, et al: Heredity in sarcoidosis - a registry-based twin study. Thorax 2008;63:894-896.
  10. Steele MP, Brown KK: Genetic predisposition to respiratory diseases: infiltrative lung diseases. Respiration 2007;74:601-608.
  11. Baughman RP, Iannuzzi M: Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs 2003;17:425-431.
  12. Baughman RP, Costabel U, du Bois RM: Treatment of sarcoidosis. Clin Chest Med 2008;29:533-548.

    External Resources

  13. Martin WJ, Iannuzzi MC, Gail DB, et al: Future directions in sarcoidosis research: summary of an NHLBI working group. Am J Respir Crit Care Med 2004;170:567-571.

    External Resources

  14. Lower EE, Baughman RP: Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;155:846-851.
  15. Steffen M, Pettersen J, Oldigs M, et al: Increased secretion of tumour necrosis factor alpha, interleukin-1-beta, and interleukin-6 by alveolar macrophages from patients with sarcoidosis. J Allergy Clin Immunol 1993;91:939-949.
  16. Ziegenhagen MW, Benner UK, Zissel G, et al: Sarcoidosis: TNF-α release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med 1997;156:1586-1592.
  17. Ziegenhagen MW, Rothe ME, Zissel G, et al: Exaggerated TNF-α release of alveolar macrophages in corticosteroid-resistant sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19:185-190.
  18. Baughman RP, Strohofer SA, Buchsbaum J, et al: Release of tumour necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990;115:36-42.
  19. Baughman RP, Lower EE: Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:70-74.
  20. Yee AMF, Pochapin MB: Treatment of complicated sarcoidosis with infliximab anti-tumour necrosis factor-α therapy. Ann Intern Med 2001;135:27-31.
  21. Roberts SD, Wilkes DS, Burgett RA, et al: Refractory sarcoidosis responding to infliximab. Chest 2003;124:2028-2031.

    External Resources

  22. Baughman RP, Judson MA, Costabel U, et al: Randomized, double-blind, placebo-controlled trial of infliximab in patients with chronic pulmonary sarcoidosis. Chest 2005;128:202S.

    External Resources

  23. Doty JD, Mazur JE, Judson MA: Treatment of sarcoidosis with infliximab. Chest 2005;127:1064-1071.
  24. Pettersen JA, Zochodne DW, Bell RB, et al: Refractory neurosarcoidosis responding to infliximab. Neurology 2002;59:1660-1661.
  25. Pritchard C, Nadarajah K: Tumour necrosis factor α inhibitor treatment for sarcoidosis refractory to conventional treatments: a report of five patients. Ann Rheum Dis 2004;63:318-320.
  26. Saleh S, Ghodsian S, Yakimova V, Henderson J, Sharma OP: Effectiveness of infliximab in treating selected patients with sarcoidosis. Respir Med 2006;100:2053-2059.

    External Resources

  27. Elfferich MD, Nelemans P, Ponds R, et al: Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-α treatment. Respiration 2010;80:212-219.
  28. Rossman MD, Newman LS, Baughman RP, et al: A double-blind, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:201-208.
  29. Judson MA, Baughman RP, Costabel U, et al: Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomized trial. Eur Respir J 2008;31:1189-1196.
  30. Judson MA, Baughman RP, Teirstein AS, et al: Defining organ involvement in sarcoidosis: the ACCES proposed instrument. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:75-86.
  31. Wasfi YS, Rose CS, Murphy JR, et al: A new tool to assess sarcoidosis severity. Chest 2006;129:1234-1245.

    External Resources

  32. Santos E, Shaunak S, Renowden S, et al: Treatment of refractory neurosarcoidosis with infliximab. J Neurol Neurosurg Psychiatry 2010;81:241-246.

    External Resources

  33. Stagaki E, Mountford W, Lackland D, et al: The treatment of lupus pernio - results of 116 treatment courses in 54 patients. Chest 2009;135:468-476.
  34. Sollberger M, Fluri F, Baumann T, et al: Successful treatment of steroid-refractory neurosarcoidosis with infliximab. J Neurol 2004;251:760-761.
  35. Sweiss N, Welsch M, Curran J, et al: Tumor necrosis factor inhibition as a novel treatment for refractory sarcoidosis. Arthritis Rheum 2005;53:788-791.
  36. Sood A, Midha V: Symptomatic sinus bradycardia with infliximab. Indian J Gastroenterol 2004;23:118-119.
  37. Sote Y, Green S, Maddison P: Complete heart block after infliximab therapy. Rheumatology 2008;47:227-228.

Author Contacts

Katrin E. Hostettler, MD, PhD

Clinic of Respiratory Medicine, University Hospital Basel

Petersgraben 4

CH-4031 Basel (Switzerland)

Tel. +41 61 328 69 16, E-Mail hostettlerk@uhbs.ch


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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References

  1. Baughman RP, Drent M, Kavuru M, et al: Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795-802.
  2. Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997;336:1224-1234.
  3. Iannuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med 2007;357:2153-2165.
  4. Rybicki BA, Iannuzzi MC: Epidemiology of sarcoidosis: recent advances and future prospects. Semin Respir Crit Care Med 2007;28:22-35.

    External Resources

  5. Lower EE, Weiss KL: Neurosarcoidosis. Clin Chest Med 2008;29:475-492.

    External Resources

  6. Judson MA: Sarcoidosis: clinical presentation, diagnosis, and approach to treatment. Am J Med Sci 2008;335:26-33.

    External Resources

  7. Rybicki BA, Iannuzzi MC, Frederick MM, et al: Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001;164:768-780.
  8. Müller-Quernheim J, Schürmann M, Hofmann S, et al: Genetics of sarcoidosis. Clin Chest Med 2008;29:391-414.

    External Resources

  9. Sverrild A, Backer V, Kyvik KO, et al: Heredity in sarcoidosis - a registry-based twin study. Thorax 2008;63:894-896.
  10. Steele MP, Brown KK: Genetic predisposition to respiratory diseases: infiltrative lung diseases. Respiration 2007;74:601-608.
  11. Baughman RP, Iannuzzi M: Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs 2003;17:425-431.
  12. Baughman RP, Costabel U, du Bois RM: Treatment of sarcoidosis. Clin Chest Med 2008;29:533-548.

    External Resources

  13. Martin WJ, Iannuzzi MC, Gail DB, et al: Future directions in sarcoidosis research: summary of an NHLBI working group. Am J Respir Crit Care Med 2004;170:567-571.

    External Resources

  14. Lower EE, Baughman RP: Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;155:846-851.
  15. Steffen M, Pettersen J, Oldigs M, et al: Increased secretion of tumour necrosis factor alpha, interleukin-1-beta, and interleukin-6 by alveolar macrophages from patients with sarcoidosis. J Allergy Clin Immunol 1993;91:939-949.
  16. Ziegenhagen MW, Benner UK, Zissel G, et al: Sarcoidosis: TNF-α release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med 1997;156:1586-1592.
  17. Ziegenhagen MW, Rothe ME, Zissel G, et al: Exaggerated TNF-α release of alveolar macrophages in corticosteroid-resistant sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19:185-190.
  18. Baughman RP, Strohofer SA, Buchsbaum J, et al: Release of tumour necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990;115:36-42.
  19. Baughman RP, Lower EE: Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:70-74.
  20. Yee AMF, Pochapin MB: Treatment of complicated sarcoidosis with infliximab anti-tumour necrosis factor-α therapy. Ann Intern Med 2001;135:27-31.
  21. Roberts SD, Wilkes DS, Burgett RA, et al: Refractory sarcoidosis responding to infliximab. Chest 2003;124:2028-2031.

    External Resources

  22. Baughman RP, Judson MA, Costabel U, et al: Randomized, double-blind, placebo-controlled trial of infliximab in patients with chronic pulmonary sarcoidosis. Chest 2005;128:202S.

    External Resources

  23. Doty JD, Mazur JE, Judson MA: Treatment of sarcoidosis with infliximab. Chest 2005;127:1064-1071.
  24. Pettersen JA, Zochodne DW, Bell RB, et al: Refractory neurosarcoidosis responding to infliximab. Neurology 2002;59:1660-1661.
  25. Pritchard C, Nadarajah K: Tumour necrosis factor α inhibitor treatment for sarcoidosis refractory to conventional treatments: a report of five patients. Ann Rheum Dis 2004;63:318-320.
  26. Saleh S, Ghodsian S, Yakimova V, Henderson J, Sharma OP: Effectiveness of infliximab in treating selected patients with sarcoidosis. Respir Med 2006;100:2053-2059.

    External Resources

  27. Elfferich MD, Nelemans P, Ponds R, et al: Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-α treatment. Respiration 2010;80:212-219.
  28. Rossman MD, Newman LS, Baughman RP, et al: A double-blind, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:201-208.
  29. Judson MA, Baughman RP, Costabel U, et al: Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomized trial. Eur Respir J 2008;31:1189-1196.
  30. Judson MA, Baughman RP, Teirstein AS, et al: Defining organ involvement in sarcoidosis: the ACCES proposed instrument. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:75-86.
  31. Wasfi YS, Rose CS, Murphy JR, et al: A new tool to assess sarcoidosis severity. Chest 2006;129:1234-1245.

    External Resources

  32. Santos E, Shaunak S, Renowden S, et al: Treatment of refractory neurosarcoidosis with infliximab. J Neurol Neurosurg Psychiatry 2010;81:241-246.

    External Resources

  33. Stagaki E, Mountford W, Lackland D, et al: The treatment of lupus pernio - results of 116 treatment courses in 54 patients. Chest 2009;135:468-476.
  34. Sollberger M, Fluri F, Baumann T, et al: Successful treatment of steroid-refractory neurosarcoidosis with infliximab. J Neurol 2004;251:760-761.
  35. Sweiss N, Welsch M, Curran J, et al: Tumor necrosis factor inhibition as a novel treatment for refractory sarcoidosis. Arthritis Rheum 2005;53:788-791.
  36. Sood A, Midha V: Symptomatic sinus bradycardia with infliximab. Indian J Gastroenterol 2004;23:118-119.
  37. Sote Y, Green S, Maddison P: Complete heart block after infliximab therapy. Rheumatology 2008;47:227-228.