Good article for different drug trts

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Novel Therapies for Sarcoidosis

P. Baughman, M.D.; Elyse E. Lower, M.D. Semin Respir Crit Care Med. 2007;28(1):128-133. ©2007 Thieme Medical Publishers

Posted 06/29/2007

Abstract and Introduction

Abstract

The treatment of sarcoidosis remains controversial. Corticosteroids remain the cornerstone of therapy, but immunosuppressive, cytotoxic, and immunomodulatory agents have emerged as viable therapeutic options for patients failing or experiencing adverse effects from corticosteroids. Published data are most extensive with methotrexate, but favorable responses have been noted with leflunomide, azathioprine, antimalarial and antimicrobial agents, and tumor necrosis factor-á inhibitors. This review focuses on these novel therapies for sarcoidosis, including indications for use, efficacy, toxicity, and monitoring.

Introduction

The treatment of sarcoidosis has evolved over the past 20 years. Past treatment schedules had focused on the use of corticosteroids and their possible effectiveness in pulmonary disease. However, despite extensive clinical experience, indications for and clinical efficacy of corticosteroids remain controversial.[1] Although it is clear that corticosteroids could be life saving,[2] many randomized trials failed to demonstrate a clear-cut benefit for corticosteroid therapy.[3] A meta-analysis of the studies of corticosteroid therapy supported the use of corticosteroids for pulmonary sarcoidosis.[4]

Over the past 20 years, the use of newer agents has been investigated for sarcoidosis. Many of these drugs were originally evaluated as steroid-sparing agents in rheumatoid arthritis. However, some agents have been useful specifically in sarcoidosis. Table 1 summarizes these drugs. They are placed in three general classes: cytotoxic agents, antimicrobial agents, and cytokine modulators. Examples of drugs in these three classes are listed and will be discussed in detail. There are several other drugs in these categories that either have been used or have been considered for treatment of sarcoidosis.[5]

Cytotoxic Agents

The use of methotrexate was first described by Lacher in 1968.[6] The choice of the drug was based on the positive experience using methotrexate for rheumatoid arthritis and psoriasis. Dr. Harold Israel also explored the use of various cytotoxic agents for sarcoidosis.[7] He also studied chlorambucil,[8] a drug also reported by Dr. Kataria.[9] However, these early studies were limited by toxicity of the agents. Problems with these agents included leucopenia and risk for malignancy. For methotrexate, there was a specific concern about hepatic toxicity.

At our institution, we began a multidisciplinary approach evaluating the hematologic status of patients. Patients were followed by a hematologist, hepatologist, and pulmonologist. The dose of the drug was lower than that used for other conditions to minimize the initial risk. We had found that the effect of methotrexate was not apparent for several months. Although patients could have subjective improvement within 2 to 4 months of starting the drug, objective improvement was often not seen until 6 months of therapy.[10,11]

Methotrexate has proven to be steroid sparing in a double-blind, randomized trial of acute pulmonary sarcoidosis.[12] In our hands, it has proved effective in over 60% of patients treated with the drug for pulmonary,[13] skin,[13] ocular,[14] and neurological[15] manifestations. Others have reported a similar response rate for methotrexate in treating sarcoidosis.[7,16,17] Of the cytotoxic agents, it is the best supported drug for treatment of sarcoidosis.[18]

A major concern was bone marrow toxicity of the cytotoxic drugs. In an initial study at our institution, we found leucopenia, lymphopenia, and/or anemia in the majority of patients.[19] Bone marrow involvement in sarcoidosis has been noted by other groups.[20,21] In a prospective study of newly diagnosed patients with sarcoidosis in the United States, bone marrow involvement was more common in blacks and women.[22]

Monitoring white counts has allowed for adjustment of the dose of methotrexate. Most centers now give between 10 to 15 mg once a week of methotrexate, but lower the dose for those who are leukopenic. At our institution, complete blood counts are performed every 2 months and the dose is adjusted accordingly. Table 2 shows the white blood counts and range of weekly doses of methotrexate used for 450 sarcoidosis patients we treated over a 2 year period. The number of patients and number of encounters for each dose are shown. The white blood counts were lower for those receiving 2.5 mg weekly versus those treated with 10 mg.

Sarcoidosis often affects the liver.[23] Rarely, it can lead to severe liver damage, even cirrhosis.[24,25] Methotrexate can also affect the liver, even leading to severe cirrhosis.[26] Monitoring for hepatotoxicity for patients varies from just routine monitoring of liver function studies[27] to routine liver biopsies.[28] For sarcoidosis, some centers will monitor liver function tests,[16] whereas others perform routine liver biopsies.[29] In a consecutive series of 100 liver biopsies of sarcoidosis patients on chronic methotrexate therapy, 14 patients were felt to have changes consistent with methotrexate toxicity.[29] However, 47 patients had changes consistent with sarcoidosis. Routine liver function testing was not useful in distinguishing between these groups. No patient in this series went on to develop irreversible cirrhosis from methotrexate.

Pulmonary toxicity can also be seen with methotrexate.[30,31] However, fibrotic lung changes due to methotrexate have not been reported in sarcoidosis. In our experience, unexplained cough can be a manifestation of pulmonary toxicity.[13,32]

Leflunomide, another antimetabolite with properties similar to methotrexate, has been useful in treating rheumatoid arthritis.[33] However, leflunomide has less severe toxicity. In a randomized, double-blind study of 999 rheumatoid arthritis patients, leflunomide was associated with lower liver function test abnormalities.[34] Also, five of the 498 patients treated with methotrexate developed interstitial pneumonitis, whereas none of the 501 patients treated with leflunomide developed interstitial pneumonitis.[34] Others have successfully used leflunomide in patients with methotrexate-associated pulmonary symptoms.[35]

Leflunomide has been used to treat sarcoidosis patients.[35,36] In a series of 32 sarcoidosis patients, the drug was felt to lead to complete response in 16 cases and partial response in nine.[35] The drug was used in 17 patients who were intolerant of methotrexate due to either nausea or pulmonary symptoms.

Another aspect of therapy was the use of leflunomide with methotrexate. For 15 patients who had progressive sarcoidosis despite at least 6 months of methotrexate, the addition of leflunomide led to complete response in nine cases and partial response in three cases.[35] The combination of leflunomide with methotrexate was based on the synergism demonstrated in treating rheumatoid arthritis.[37]

The future for cytotoxic therapy in sarcoidosis appears to be combinations of treatment.[38] In addition to leflunomide, methotrexate has also been combined with azathioprine.[14,39] The advantage of this combination is the minimization of toxicity while increasing the immunosuppression by multiple mechanism of action. In addition, the combination of a cytotoxic agent with the biological agent infliximab is considered standard.[40]

Antimicrobial Agents

The antimalarial agents have long been known to be effective in treating some forms of sarcoidosis,[41,42] This has been mostly for skin disease, but others have demonstrated the usefulness of these agents for hypercalcemia,[43] chronic pulmonary disease,[44] and occasionally neurological disease.[45] These agents do not seem to act as antimicrobial agents, but as anti-inflammatory drugs.

A report demonstrated the utility of minocycline and doxycycline in treating cutaneous sarcoidosis.[46] This has led to some debate as to the mechanism of action of these drugs. The possibility of an infectious agent as a cause of sarcoidosis has been studied recently.[47,48,49] These antibiotics may have activity against these putative agents, especially Propionibacterium acnes. However, these antibiotics have immunosuppressive properties.[50,51]

Cytokine Modulators

Tumor necrosis factor-á (TNF-á) has been found to be released by alveolar macrophages from some, but not all, sarcoidosis patients.[52,53,54] In one study, Ziegenhagen et al measured TNF-á release from alveolar macrophages from four groups:[55] controls, sarcoidosis patients off therapy who were stable, sarcoidosis patients off therapy who worsened over the next 6 months, and sarcoidosis patients on corticosteroid therapy who worsened despite therapy. As shown in Figure 1, the sarcoidosis patients who worsened over the next 6 months released higher levels of TNF-á. This occurred whether the patients were receiving corticosteroids or not.

Figure 1. The spontaneous release of tumor necrosis factor-á (TNF-á) by alveolar macrophages (AM) retrieved by bronchoalveolar lavage from four groups of patients: controls, sarcoidosis patients off therapy who were stable, sarcoidosis patients off therapy who worsened over the next 6 months, and sarcoidosis patients on corticosteroid therapy who worsened despite therapy. There was significantly higher release of TNF-á by those patients who progressed. (Adapted from Ziegenhagen et al.[55])

These observations have led to the concept of TNF-á as a potential target for therapy in sarcoidosis.[56] Table 3 [4,13,57-63] lists various agents that have been studied for both their ability to suppress TNF-á release by alveolar macrophages and their treatment of sarcoidosis. These studies support that these drugs, which include corticosteroids and methotrexate, may be successful in treating sarcoidosis by suppressing TNF-á. Not all these agents are equally effective at treating sarcoidosis. Although thalidomide has been found effective in treating chronic cutaneous sarcoidosis,[57,58] it is not as effective in treating pulmonary disease.[64] In the latter study, the use of thalidomide may have been limited by the toxicity of the drug. Somnolence and peripheral neuropathy have been significant problems

with higher doses of thalidomide.[58,64]

Biological agents have been developed that have specific activity against TNF-á. Three of these drugs are available in the United States and are summarized in Table 4 .[40,65-82] These agents all seem to be effective for rheumatoid and psoriatic arthritis. The drugs appear to be quite similar in level of effectiveness. However, there is a marked difference between the effectiveness in the clinical trials of Crohn's disease. In that situation, etanercept is not effective, whereas the two monoclonal antibody agents are both effective.

For sarcoidosis, the majority of the studies have been with etanercept and infliximab. For etanercept, there is limited evidence of effectiveness of the drug for sarcoidosis. In an open-label study of pulmonary sarcoidosis, Utz et al discontinued the study at an early time point because some patients developed progression of their disease.[65] We studied chronic ocular sarcoidosis who failed methotrexate alone. In a double-blind, randomized trial, etanercept was no better than placebo.[66] Infliximab was effective in some of these patients who failed etanercept therapy.[83]

The use of infliximab for sarcoidosis was first reported over 5 years ago.[67,84] To date, a large number of case reports and case series have been reported.[68,85,86] These observations led to a recently completed double-blind, placebo-controlled trial of infliximab for sarcoidosis.[69] This study was the largest randomized trial of any agent for chronic sarcoidosis. All patients were stable but still symptomatic on systemic therapy. The study demonstrated a significant improvement in the forced vital capacity for those treated with infliximab versus those treated with placebo. The overall improvement was 2.5%, but the response to treatment was twice as high for those patients with evidence of more severe disease, such as lower vital capacity, more systemic therapy, or longer duration of disease.

Table 1. New Treatments for Sarcoidosis

Table 2. Weekly Dose of Methotrexate for 450 Patients Treated with Methotrexate Alone

Table 3. The Effect of Drugs on Tumor Necrosis Factor-á Release from Alveolar Macrophages and Treatment of Sarcoidosis

Table 4. Biological Anti-tumor Necrosis Factor-á Agents

References

DeRemee RA. The present status of therapy of pulmonary sarcoidosis: a house divided. Chest 1977;71:388-393 Siltzbach LE. Effects of cortisone in sarcoidosis: a study of thirteen patients. Am J Med 1952;12:139-160 Baughman RP, Lower EE, Lynch JP. Treatment modalities for sarcoidosis. Clin Pulm Med 1994;1:223-231 Paramothayan S, PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA 2002;287: 1301-1307 Baughman RP, Peddi R, Lower EE. Therapy: general issues. In: Baughman RP, du Bois RM, Lynch JP III, Wells AU, eds. Diffuse Lung Disease: A Practical Approach. London: Arnold; 2004:78-90 Lacher MJ. Spontaneous remission response to methotrexate in sarcoidosis. Ann Intern Med 1968;69:1247-1248 Israel HL. The treatment of sarcoidosis. Postgrad Med J 1970;46:537-540 Israel HL, McComb BL. Chlorambucil treatment of sarcoidosis. Sarcoidosis 1991;8:35-41 Kataria YP. Chlorambucil in sarcoidosis. Chest 1980;78:36-42 Lower EE, Baughman RP. The use of low dose methotrexate in refractory sarcoidosis. Am J Med Sci 1990;299:153-157 Baughman RP, Winget DB, Lower EE. Prospective, randomized, double blind trial of methotrexate as a steroid sparing agent for sarcoidosis: analysis of first 25 patients [abstract]. Am J Respir Crit Care Med 1997;155:A944 Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 2000;17: 60-66 Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;155:846-851 Baughman RP, Lower EE, Bradley DA, Kaufman AH. Use of cytotoxic therapy for chronic ophthalmic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:S17 Lower EE, Broderick JP, Brott TG, Baughman RP. Diagnosis and management of neurologic sarcoidosis. Arch Intern Med 1997;157:1864-1868 Vucinic VM. What is the future of methotrexate in sarcoidosis? A study and review. Curr Opin Pulm Med 2002; 8:470-476 Gedalia A, Molina JF, Ellis GS, Galen W, C, Espinoza LR. Low-dose methotrexate therapy for childhood sarcoidosis. J Pediatr 1997;130:25-29 Paramothayan S, Lasserson T, Walters EH. Immunosuppressive and cytotoxic therapy for pulmonary sarcoidosis. Cochrane Database Syst Rev 2003;3:CD003536 Lower EE, JT, Martelo OJ, Baughman RP. The anemia of sarcoidosis. Sarcoidosis 1988;5:51-55 Browne PM, Sharma OP, Salkin D. Bone marrow sarcoidosis. JAMA 1978;240:43-50 Longcope WT, Frieman DG. A study of sarcoidosis based on a combined investigation of 160 cases including 30 autopsies. Medicine 1952;31:1-132 Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164:1885-1889 Judson MA. Hepatic, splenic, and gastrointestinal involvement with sarcoidosis. Semin Respir Crit Care Med. 2002;23:529- 543 Maddrey WC, s CJ, Boitnott JK, Iber FL. Sarcoidosis and chronic hepatic disease: a clinical and pathologic study of 20 patients. Medicine 1970;49:375-395 Kennedy PT, Zakaria N, Modawi SB, et al. Natural history of hepatic sarcoidosis and its response to treatment. Eur J Gastroenterol Hepatol 2006;18:721-726 AM, Funch D, Dreyer NA, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum 1993;36:329-335 Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis: suggested guidelines 28. Roenigk HH, Auerbach R, Mailbach HI, Weinstein GD. Methotrexate guidelines revised. J Am Acad Dermatol 1982; 6:145-155 Baughman RP, Koehler A, Bejarano PA, Lower EE, Weber FL Jr. Role of liver function tests in detecting methotrexateinduced liver damage in sarcoidosis. Arch Intern Med 2003;163:615-620 Zisman DA, McCune WJ, Tino G, Lynch JP III. Druginduced pneumonitis: the role of methotrexate. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:243-252 Kremer JM, Alarcon GS, Weinblatt ME, et al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum 1997;40:1829-1837 G, Mierins E, Karsh J. Methotrexate-induced asthma. Am Rev Respir Dis 1991;143:179-181 Osiri M, Shea B, V, et al. Leflunomide for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 2003;30:1182-1190 Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000;39:655-665 Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004;21:43- 48 Majithia V, S, Harisdangkul V, JG. Successful treatment of sarcoidosis with leflunomide. Rheumatology (Oxford) 2003;42:700-702 Kremer JM, Caldwell JR, Cannon GW, et al. The combination of leflunomide and methotrexate in patients with active rheumatoid arthritis who are failing on methotrexate treatment alone: a double-blind placebo controlled study. Arthritis Rheum 2000;43:S224 Baughman RP, Ohmichi M, Lower EE. Combination therapy for sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:133-137 Bradley DA, Lower EE, Baughman RP. Diagnosis and management of spinal cord sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:58-65 Kavanaugh A, Clair EW, McCune WJ, Braakman T, Lipsky P. Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol 2000;27:841-850 British Tuberculosis Association (BTA). Chloroquine in the treatment of sarcoidosis: a report from the Research Committee of the British Tuberculosis Association. Tubercle 1967;48:257-272 Siltzbach LE, Teirstein AS. Chloroquine therapy in 43 patients with intrathoracic and cutaneous sarcoidosis. Acta Med Scand 1964;425:302S-308S JS, Diz MM, Sharma OP. Effective reduction in the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia with shortcourse chloroquine therapy. Ann Intern Med 1989;111: 437-438 Baltzan M, Mehta S, Kirkham TH, Cosio MG. Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med 1999;160:192- 197 Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurologic involvement. Arch Neurol 1998;55:1248-1254 Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol 2001;137:69-73 Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 2002;40:198-204 Song Z, Marzilli L, Greenlee BM, et al. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005;201:755-767 Drake WP, Pei Z, Pride DT, RD, Cover TL, Blaser MJ. Molecular analysis of sarcoidosis tissues for Mycobacterium species DNA. Emerg Infect Dis 2002;8:1334-1341 Kalish RS, Koujak S. Minocycline inhibits antigen processing for presentation to human T cells: additive inhibition with chloroquine at therapeutic concentrations. Clin Immunol 2004;113:270-277 Kloppenburg M, Verweij CL, Miltenburg AM, et al. The influence of tetracyclines on T cell activation. Clin Exp Immunol 1995;102:635-641 Bachwich PR, Lynch JP III, Larrick J, Spengler M, Kunkel SL. Tumor necrosis factor production by human sarcoid alveolar macrophages. Am J Pathol 1986;125:421-425 Baughman RP, Strohofer SA, Buchsbaum J, Lower EE. Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990;115:36-42 Bost TW, Riches DW, Schumacher B, et al. Alveolar macrophages from patients with beryllium disease and sarcoidosis express increased levels of mRNA for tumor necrosis factor-alpha and interleukin-6 but not interleukin-1 beta. Am J Respir Cell Mol Biol 1994;10:506-513 Ziegenhagen MW, Rothe E, Zissel G, Muller-Quernheim J. Exaggerated TNFalpha release of alveolar macrophages in corticosteroid resistant sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19:185-190 Baughman RP, Iannuzzi M. Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs 2003;17:425-431 Carlesimo M, Giustini S, Rossi A, Bonaccorsi P, Calvieri S. Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol 1995;32:866-869 Baughman RP, Judson MA, Teirstein AS, Moller DR, Lower EE. Thalidomide for chronic sarcoidosis. Chest 2002; 122:227-232 Baughman RP, Lower EE. The effect of corticosteroid or methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis. Am Rev Respir Dis 1990;142:1268-1271 Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U. Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. Am J Respir Crit Care Med 1999;159: 508-511 Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997; 155:1665-1669 Muller-Quernheim J, Kienast K, Held M, Pfeifer S, Costabel U. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J 1999;14:1117-1122 Tavares JL, Wangoo A, Dilworth P, Marshall B, Kotecha S, Shaw RJ. Thalidomide reduces tumour necrosis factor-alpha production by human alveolar macrophages. Respir Med 1997;91:31-39 Judson MA, Silvestri J, Hartung C, Byars T, CE. The effect of thalidomide on corticosteroid-dependent pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:51- 57 Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124:177-185 Baughman RP, Lower EE, Bradley DA, LA, Kaufman A. Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial. Chest 2005;128: 1062-1067 Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:70-74 Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest 2005;127:1064-1071 Baughman RP, Drent M, Kavuru MS, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795-802 Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000;342:763-769 Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264-2272 Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebocontrolled trial. Gastroenterology 2001;121:1088-1094 Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 2005;52:1227-1236 Akobeng AK, Zachos M. Tumor necrosis factor-alpha antibody for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2004;1:CD003574 Sands BE, FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004;350:876-885 Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis 2006;65:753-759 Furst DE, Schiff MH, Fleischmann RM, et al. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003;30:2563-2571 Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:3279- 3289 Sandborn WJ, Hanauer S, Loftus EV Jr, et al. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn's disease. Am J Gastroenterol 2004;99:1984-1989 Heffernan MP, DI. Adalimumab for treatment of cutaneous sarcoidosis. Arch Dermatol 2006;142:17-19 Philips MA, Lynch J, Azmi FH. Ulcerative cutaneous sarcoidosis responding to adalimumab. J Am Acad Dermatol 2005;53:917 Callejas-Rubio JL, Ortego-Centeno N, - L, Benticuaga MN. Treatment of therapy-resistant sarcoidosis with adalimumab. Clin Rheumatol 2006;25:596-597 Baughman RP, Bradley DA, Lower EE. Infliximab for chronic ocular inflammation. Int J Clin Pharmacol Ther 2005;43:7-11 Yee AMF, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis-alpha therapy. Ann Intern Med 2001;135:27-31 Sweiss NJ, Welsch MJ, Curran JJ, Ellman MH. Tumor necrosis factor inhibition as a novel treatment for refractory sarcoidosis. Arthritis Rheum 2005;53:788-791 Saleh S, Ghodsian S, Yakimova V, J, Sharma OP. Effectiveness of infliximab in treating selected patients with sarcoidosis. Respir Med 2006

Reprint Address

PBaughman, M.D., Division of Pulmonary and Critical Care Medicine, University of Cincinnati Medical Center 231 Bethesda Ave., Cincinnati, OH 45267 Bob.Baughman@...

P. Baughman, M.D.1 and Elyse E. Lower, M.D.11Division of Pulmonary and Critical Care Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio