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(Chest. 2003;124:2028-2031.)
© 2003 American College of Chest Physicians

Refractory Sarcoidosis Responding to Infliximab*

Scott D. Roberts, MD; David S. Wilkes, MD, FCCP; Richard A. Burgett, MD and Kenneth S. Knox, MD

* From the Department of Medicine (Drs. Roberts, Wilkes, and Knox), Pulmonary Division, and the Department of Ophthalmology (Dr. Burgett), Indiana University School of Medicine, Indianapolis, IN.

Correspondence to: Kenneth S. Knox, MD, Center for Sarcoidosis and Immunologic Lung Disease, Indiana University School of Medicine, 1001 West Tenth St, WD/OPW 425, Indianapolis, IN 46202; e-mail: iusarctr{at}iupui.edu


   Abstract
TOP
 Abstract
Introduction
 Case Report
 Discussion
 References
 
Despite aggressive treatment with conventional therapy, sarcoidosis may be progressive and debilitating. Tumor necrosis factor (TNF)-{alpha} is critical in the genesis and maintenance of granulomatous inflammation. Agents developed to inhibit TNF-{alpha} have been approved to treat rheumatoid arthritis and inflammatory bowel disease with unprecedented success. As such, physicians are increasingly using these agents to treat patients with other inflammatory diseases, including sarcoidosis. We report a case of refractory sarcoidosis, involving the lung, eyes, skin, and heart, which flared despite aggressive therapy. Oculocutaneous sarcoid dramatically improved after treatment with the anti-TNF antibody infliximab.

Key Words: cutaneous • infliximab • ocular • sarcoidosis • tumor necrosis factor-{alpha} • uveitis


   Introduction
TOP
 Abstract
 Introduction
Case Report
 Discussion
 References
 
Pulmonologists often are called on to take care of patients with sarcoidosis even when the primary manifestation of the disease is outside the lung. Although much has been learned about the pathophysiology of sarcoidosis, the cause of this disease is still unknown. Recent interests in therapies that target cytokines have been sparked by insights into their role in the pathogenesis of inflammatory diseases, including sarcoidosis. Infliximab, a chimeric, monoclonal antibody directed against tumor necrosis factor (TNF)-{alpha}, has been approved for use in patients with rheumatoid arthritis and Crohn disease. There have been case reports1 2 3 4 describing the success of infliximab in patients with sarcoidosis who are refractory to conventional therapy. We present a case of multisystem sarcoidosis that was refractory to treatment with multiple immunosuppressive agents. Treatment with infliximab, as part of combination therapy, ultimately resulted in control of the disease.


   Case Report
TOP
 Abstract
 Introduction
 Case Report
Discussion
 References
 
A 50-year-old white woman was referred to our institution in 1997 for management of refractory pulmonary sarcoidosis and uveitis. The diagnosis had been confirmed 8 months prior by transbronchial biopsy. She had been receiving maintenance therapy since that time with 60 mg prednisone daily. At the time of her initial visit in 1997, she had experienced a 60-lb weight gain, worsening hypertension, and glucose intolerance as complications of systemic steroid therapy. Her initial examination revealed an obese, white woman in no distress. She was afebrile and breathing comfortably on room air. Her chest had diffuse expiratory wheezes bilaterally. Heart sounds were regular without murmur or gallop. Her abdomen was soft and nontender, with striae and no organomegaly. The findings of a lymph node survey and skin examination were unremarkable. She was neurologically intact. Initial laboratory test results revealed a white count of 6,200 cells/µL with 80% neutrophils, 11% lymphocytes, 7% monocytes, and 2% eosinophils. Her serum chemistry levels were normal, including a serum angiotensin-converting enzyme level of 13 U/L. A chest CT scan showed numerous small pulmonary nodules, faint patchy infiltrates, and mediastinal lymphadenopathy. ECG showed a normal sinus rhythm. Pulmonary function tests revealed an FEV1 of 1.44 L (63% of predicted) prior to diagnosis. Uveitis was graded as 3+. This uveitis score is based on a combination of an ophthalmologist scoring system and objective flare meter readings (scale: 0, none; 4+, severe). The patient’s extensive clinical course is summarized in Figure 1 .



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  		Figure 1.. Timeline of therapeutic intervention and clinical course. Arrows above the line indicate the therapeutic regimen over a several-year period. Arrows below the line highlight key clinical events as outlined in the text. Pred = prednisone orally (mg per day); MTX = methotrexate orally (mg per week); io = intraocular injections (per month); AZA = azathioprine (mg per day); inflix = infliximab; DLCO = diffusing capacity of the lung for carbon monoxide; QD = every day; AICD = automatic implantable cardioverter/defibrillator.

 
In an attempt to minimize systemic steroid use, methotrexate, 15 mg weekly, was added to the regimen. Three months after the patient’s initial visit, this medication was switched to azathioprine due to GI intolerance and profound fatigue associated with methotrexate. Azathioprine was titrated, and therapy with prednisone was slowly tapered, as symptoms allowed. Her pulmonary functions slowly improved using this regimen, but she required monthly intraocular steroid injections for uveitis. Her course was highlighted by frequent exacerbations and an escalation of azathioprine dosing. However, therapy was limited by leukopenia on doses approaching 100 mg daily. Three years after her initial visit, in December 2000, she experienced a witnessed cardiac arrest (monomorphic ventricular tachycardia) and was successfully resuscitated. She was treated immediately with high-dose IV steroids and was loaded with amiodarone. After recovery, a thallium radionucleotide scan showed fixed perfusion defects at rest with subsequent normal coronary angiogram. The left ventricular hemodynamics were consistent with a restrictive cardiomyopathy. An electrophysiologic study revealed that the morphology of the ventricular arrhythmia was likely nonischemic, most compatible with an infiltrative process, and consistent with myocardial sarcoid. A myocardial biopsy was not performed, as the yield for this invasive test is low and likely not necessary in the setting of high clinical suspicion.5 An implantable defibrillator/pacemaker was placed in the patient prior to discharge to home. As her cardiac status stabilized and prednisone dose was tapered, she experienced a worsening of her uveitis, requiring a maximally tolerated dose of azathioprine and the addition of thalidomide (50 mg daily) to her regimen.

Despite this escalation of therapy, a right eyelid skin lesion developed. Therapy with thalidomide was discontinued for concern that the eyelid lesion was temporally associated with its use. This lesion was initially believed to be an abscess, and an incision and drainage was attempted. At surgery, the drainage of the mass lesion was unsuccessful. The mass was surgically excised, and reconstructive lid surgery was needed to correct the resultant ptosis, with good result and no residual disease. The pathology report on the lesion confirmed a conglomerate mass of noncaseating granulomas that was consistent with sarcoidosis.

Her cardiac and pulmonary function remained stable while receiving therapy with prednisone and azathioprine. However, panuveitis waxed and waned despite intraocular therapy. Two years after undergoing reconstructive surgery, the inflammatory eyelid lesion recurred, resulting in worsening visual problems and cosmetic concerns (Fig 2 , top, A). In addition, malignant arrhythmias that required overdrive pacing persisted despite therapy with immunosuppressive medications. Therapy with infliximab was initiated at 5 mg/kg IV, and was redosed on weeks 2, 4, and 8. A remarkable improvement, with resolution of the periocular cutaneous lesion was noted after the first month of therapy (Fig 2 , bottom, B). The uveitis cleared up completely, and the patient no longer requires intraocular injections. Pacemaker interrogation showed no ventricular ectopy. Her pulmonary symptoms, results of pulmonary function tests, and chest radiograph findings remained stable as well. She continues to do well receiving maintenance infusions of infliximab at 2-month intervals. Her doses of azathioprine and prednisone are currently being tapered.



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  		Figure 2.. Improvement of periocular cutaneous sarcoid with the addition of infliximab therapy. This inflammatory mass blossomed (top, A) while taking prednisone, azathioprine, and thalidomide, and resolved (bottom, B) between the third and fourth dose of infliximab therapy (at 4 to 6 weeks). Of note, these photographs are of the recurrence of the granulomatous eyelid lesion that had been surgically removed with eyelid reconstruction 2 years before.

 

   Discussion
TOP
 Abstract
 Introduction
 Case Report
 Discussion
References
 
We have described a patient with multisystem sarcoidosis, including pulmonary, cutaneous, ocular, and cardiac involvement, that progressed despite aggressive therapy. Her clinical course included multiple exacerbations of the disease and numerous therapeutic side effects. Only after the institution of infliximab therapy, as part of a multidrug regimen, did the oculocutaneous sarcoid resolve. This case illustrates the impact that targeted anticytokine therapy may have on selected patients with sarcoidosis.

There is increasing evidence that TNF-{alpha} plays a critical role in the pathophysiology of granulomatous inflammation. In experimental models,6 7 TNF is critical in the recruitment of T cells and granuloma formation in response to mycobacterial antigens. The sarcoid granuloma may be exquisitely responsive to TNF reduction. Polymorphisms of TNF genes have been suggested as markers of prognosis in patients with sarcoidosis.8 In addition to infliximab therapy, there have been anecdotal reports9 10 of sarcoidosis patients being treated with thalidomide and pentoxifylline, medications that reportedly have anti-TNF effects. We decided to use infliximab because published reports4 have documented successful treatment of cutaneous sarcoidosis with this therapy. Our patient experienced a sarcoid flare with a granulomatous eyelid lesion while receiving thalidomide. Thus, failure with one anti-TNF therapy should not preclude the use of another.

Ocular involvement in patients with sarcoidosis is common and can be particularly difficult to manage, with potentially devastating long-term effects.11 The treatment is often unpleasant. Our patient dreaded the monthly intraocular injections. We did not necessarily expect such a rapid improvement in her longstanding uveitis as few reports are available12 and it is unknown whether infliximab crosses the blood-eye barrier.

Although cardiac involvement is clinically not as common, it is one of the potentially life-threatening manifestations of this systemic disease.13 The presentation of myocardial sarcoid with ventricular arrhythmia and sudden cardiac death has been well-described.14 After initiating treatment with infliximab, there was evidence of improvement in our patient’s cardiac conduction abnormalities on interrogation of her pacemaker/implantable defibrillator. We cannot make definitive statements regarding the use of infliximab in treating this subset of patients. This case provides only a preliminary observation that anti-TNF therapy may be adjunctive.

At the time that infliximab therapy was started, our patient’s lung function was stable on a regimen of systemic steroids and azathioprine. Zabel et al9 first suggested the benefit of anti-TNF therapy in pulmonary sarcoidosis. In that study, pentoxifylline was the anti-TNF agent used, and the subgroup of patients who benefited from its use were those with active lung disease. Our patient’s lung disease was stable when infliximab therapy was initiated, and the addition of this therapy provided no further benefit. This observation has implications for future studies, given the heterogeneity of the sarcoid population. The addition of anti-TNF therapy in stable patients who have lung disease may afford no benefit over standard therapy. Alternatively, in patients whose lung function declines despite therapy, treatment with infliximab and other TNF inhibitors may be useful. A double-blinded, placebo-controlled trial studying the use of pentoxifylline in pulmonary sarcoidosis sponsored by the National Institutes of Health is currently enrolling patients. More information regarding this trial can be found on the National Institutes of Health Web site (www.cc.nih.gov).

Infliximab is considered to be an immunosuppressive agent, and patients receiving this drug may be at an increased risk of malignancy and infection.15 16 17 18 Specifically, pulmonologists must be aware of the high incidence of reactivation of latent tuberculosis17 and the increased risk of pulmonary mycoses.18 Distinguishing these infectious complications of treatment from the manifestations of underlying pulmonary sarcoid can be difficult. Because the experience with infliximab in patients with sarcoidosis is still limited, it is too early to say how these risks will compare with those of conventional therapy. Meanwhile, close monitoring of these patients is essential.

This report describes a patient with recalcitrant, multisystem sarcoidosis who responded to infliximab therapy. Since pulmonologists are often called on to care for sarcoid patients with both lung involvement and other severe manifestations, we will undoubtedly be faced with difficult patients who may benefit from nontraditional therapies. We believe that this case report supports the use of anti-TNF therapies in select sarcoid patients and emphasizes the importance of TNF-{alpha} in the pathophysiology of sarcoidosis. Further study is warranted.


   Footnotes
 
Abbreviation: TNF = tumor necrosis factor

Received for publication March 5, 2003. Accepted for publication May 8, 2003.


   References
TOP
 Abstract
 Introduction
 Case Report
 Discussion
 References
 

  1. Baughman, RP, Lower, EE (2001) Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 18,70-74[ISI][Medline]
  2. Pettersen, JA, Zochodne, DW, Bell, RB, et al Refractory neurosarcoidosis responding to infliximab. Neurology 2002;59,1660-1661[Free Full Text]
  3. Yee, AM, Pochapin, MB Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001;135,27-31[Abstract/Free Full Text]
  4. Mallbris, L, Ljungberg, A, Hedblad, MA, et al Progressive cutaneous sarcoidosis responding to anti-tumor necrosis factor-alpha therapy. J Am Acad Dermatol 2003;48,290-293[CrossRef][ISI][Medline]
  5. Sharma, OP, Maheshwari, A, Thaker, K Myocardial sarcoidosis. Chest 1993;103,253-258[Free Full Text]
  6. Prior, C, Knight, RA, Herold, M, et al Pulmonary sarcoidosis: patterns of cytokine release in vitro. Eur Respir J 1996;9,47-53[Abstract]
  7. Roach, DR, Bean, AG, Demangel, C, et al TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168,4620-4627[Abstract/Free Full Text]
  8. Yamaguchi, E, Itoh, A, Hizawa, N, et al The gene polymorphism of tumor necrosis factor-beta, but not that of tumor necrosis factor-alpha, is associated with the prognosis of sarcoidosis. Chest 2001;119,753-761[Abstract/Free Full Text]
  9. Zabel, P, Entzian, P, Dalhoff, K, et al Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997;155,1665-1669[Abstract]
  10. Baughman, RP, Judson, MA, Teirstein, AS, et al Thalidomide for chronic sarcoidosis. Chest 2002;122,227-232[Abstract/Free Full Text]
  11. Usui, Y, Kaiser, ED, See, RF, et al Update of ocular manifestations in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19,167-175[ISI][Medline]
  12. Baughman, RP, Raymond, LO, Lower, EE, et al Double blind randomized trial of a tumor necrosis factor antagonist (etanercept) for treatment of chronic ocular sarcoidosis [abstract]. Am J Respir Crit Care Med 2002;165(suppl),A495
  13. Veinot, JP, Johnston, B Cardiac sarcoidosis: an occult cause of sudden death; a case report and literature review. J Forensic Sci 1998;43,715-717[ISI][Medline]
  14. Shabetai, R Sarcoidosis and the heart. Curr Treat Options Cardiovasc Med 2000;2,385-398
  15. Brown, SL, Greene, MH, Gershon, SK, et al Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002;46,3151-3158[CrossRef][ISI][Medline]
  16. Helbling, D, Breitbach, TH, Krause, M Disseminated cytomegalovirus infection in Crohn’s disease following anti-tumour necrosis factor therapy. Eur J Gastroenterol Hepatol 2002;14,1393-1395[CrossRef][ISI][Medline]
  17. Keane, J, Gershon, S, Wise, RP, et al Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345,1098-1104[Abstract/Free Full Text]
  18. Wood, KL, Knox, KS, Kleiman, MB, et al Histoplasmosis after treatment with anti-TNF-{alpha} therapy. Am J Respir Crit Care Med 2003;167,1279-1282[Abstract/Free Full Text]



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