Effectiveness of Infliximab in Treating Selected Cases of Sarcoidosis

Transcription

1 Specil Articles Efficcy of Inflixim in the Mngement of Srcoidosis Effectiveness of Inflixim in Treting Selected Cses of Srcoidosis Om P. Shrm, MD, FRCP, Professor of Medicine, Keck School of Medicine of USC, Los Angeles, CA USA keywords ; Inflixim, Srcoidosis, Tumor necrosis fctor (TNF) INTRODUCTION There is no cure for srcoidosis. Corticosteroids re universlly used for suppressing the progressive nd hrmful grnulomtous inflmmtion. Unfortuntely, mny ptients develop intolerle side effects tht ecome more of prolem thn the disese. In such sitution, numer of lterntive drugs, including immunosuppressives (zthioprine, cyclophosphmide, methotrexte), immune modultors (pentoxyphylline, thlidomide), non-cytotoxic nti-inflmmtory gents (chloroquine, hydroxy-chloroquine), nd rdition hve een used. These gents re not consistently effective nd cn hve serious side effects. Thus, the serch for n idel drug to control nd cure srcoidosis continues. Recent studies hve shown tht tumor necrosis fctor-lph plys n importnt role in perpetuting the grnulomtous inflmmtion. Inflixim, tumor necrosis fctor ntgonist, locks the effect of tumor necrosis fctor nd exerts eneficil effect. The following descries my experience in treting ptients with multisystem srcoidosis with Inflixim. CASE REPORTS CASE 1 In 1986, this 29-yer-old Cucsin womn developed skin plques on her forehed, sclp, nd uttocks. A chest x-ry film showed ilterl hilr denopthy. A medistinl denopthy showed non-cseting grnuloms. She ws given prednisone nd hydroxychloroquine. The ptient gined weight, ecme insomnic, nd developed severe psychologicl symptoms. Prednisone ws discontinued. Over the next ten yer the ptient ws treted with methotrexte, intrmusculr trimcinolone injections, thlidomide, nd cyclophosphmide. In 2002 her skin lesions ecme more prominent nd disfiguring, preventing the ptient from prticipting in socil nd usiness ctivities. In June 2003 she ws given her first intrvenous infusion of Inflixim of 3-mg/kg ody weight. The second injection of sme mount ws given fter four weeks. She tolerted oth injections well. The ptient received her third injection [JJSOG 2005;25:81-86] fter period of six weeks she received nother intrvenous infusion of 3 mg/kg. She developed mild urticri nd itching tht responded to Bendryl. Her skin lesions clered y 85% fter the fourth infusion nd lmost completely disppered fter the sixth injection (Figure 1,, c, d, e, f). The hilr denopthy nd lung function remin unchnged. CASE 2 In 1999, this 58-yer-old Cucsin womn developed fever, weight loss, erythem nodosum, nd su-cutneous nodules (Derrier-Roussey syndrome). A iopsy of one of the nodules showed non-cseting grnuloms. No tretment ws given. In Mrch 2001, the ptient ws found to hve norml liver function tests nd elevted ngiotensin converting enzyme level (ACE). A chest x-ry film nd gllium 72-hour totl ody scn were norml. Aout one month lter she ws found to hve splenic enlrgement, nemi, nd thromocytopeni. Splenectomy ws performed to rule out lymphom. Histology of resected spleen showed non-cseting grnuloms. In Septemer of 2002 the ptient developed dizziness, txi, memory loss nd tingling in her hnds nd feet. A CT of the rin showed diffuse meningel enhncement consistent with the dignosis of neurosrcoidosis. Prednisone 60mg per dy nd methotrexte 20 mg per week ws strted. In Jnury 2003, her skin lesions returned nd she developed hyperclcemi. Methotrexte ws discontinued nd zthioprine 100 mg/ dy ws dded. Between Mrch nd Octoer 2003, she received six infusions of Inflixim. Skin lesions susided, serum clcium nd lkline phosphtse levels ecme norml, neurologicl symptoms improved, serum ngiotensin converting enzyme level cme down from 185 to 167 U/L, nd CT of the rin improved (Figure 2, ). She responded to Inflixim therpy nd remined well for out three months efore developing ftl dominl hemorrhge due to superior mesenteric rtery dissection. Autopsy reveled the existence of n unsuspected plsm cell dyscrsi. Correspondence: Om P. Shrm, MD, FRCP Room ; LAC+USC Medicl Center 1200 North Stte Street Los Angeles, CA USA Tel: Fx: Emil: oshrm@usc.edu 81

2 日サ会誌 2005, 25(1) c d e Figure 1. Cutneous lesions: Chest () efore nd () fter Inflixim Bck (c) efore nd (d) fter Inflixim Legs (e) efore nd (f) fter Inflixim f 82

3 Specil Articles Efficcy of Inflixim in the Mngement of Srcoidosis Figure 2. Computerized tomogrphy of the rin: () Before Inflixim therpy () After Inflixim therpy Tle 1. ANA response to Inflixim CASE 3 In 1965, this 18-yer-old Cucsin mn ws found to hve ilterl hilr denopthy on chest x-ry film. A cervicl lymph node iopsy showed non-cseting grnuloms. No tretment ws given. In 1970, he developed lupus pernio. At first, the rsh ws treted with topicl corticosteroids. The ptient declined to tke prednisone. A tril of methotrexte filed to hlt the progression of the rsh. Hydroxychloroquine, zthioprine, doxycycline, nd thlidomide were tried. None of the drugs succeeded; either the ptient developed side effects or the drug ws ineffective. In August 2001, Inflixim 3 mg/kg ody weight ws strted. His lupus pernio strted to suside fter the third injection nd clered y 90% fter the eighth injection. The skin lesions recurred fter three months of the discontinution of the tretment. Inflixim ws resumed. Lupus pernio responded gin. The ptient developed high ANA titers tht fluctuted spontneously (Tle 1). The ANA pttern remined homogenous nd there were no chnges in liver or kidney function. Sedimenttion rte, CRP, nd rheumtoid fctor remined norml (Figure 3, ). 83

4 日サ会誌 2005, 25(1) Figure 3. Lupus pernio: () Before Inflixim tretment () After Inflixim tretment CASE 4 In 2001, this 61-yer-old Cucsin womn developed dry cough. A chest-x-ry film showed ilterl hilr denopthy. Medistinl node iopsy reveled non-cseting grnuloms. Her serum ngiotensin converting enzyme level ws elevted. Since the ptient hd no symptoms, no tretment ws given. In 2002, the ptient ecme txic. She hd no leg pins or tingling of feet. An MRI reveled intr-medullry lesions in the cervicl nd thorcic portions of the spinl cord. Spinl fluid showed no mlignnt cells, cid-fst orgnisms or fungi. The clinicl course ws consistent with neurosrcoidosis. Becuse of her oesity, glucom, depression, nd strong history of dietes mellitus, prednisone ws not given. Insted, she ws given methotrexte 20 mg once week. Despite six-month course of tretment with methotrexte, her neurologicl symptoms worsened. In ddition to txi she developed muscle wekness. In Novemer 2003, she ws strted on Inflixim 3 mg/kg ody weight. After six infusions her neurologicl symptoms improved. The MRI films showed significnt improvement (Figure 4, ). Figure 4. MRI lesion of the spinl cord: () Before tretment () After Inflixim tretment 84

5 Specil Articles Efficcy of Inflixim in the Mngement of Srcoidosis CASE 5 In 1995, this 42-yer-old Cucsin womn developed shortness of reth. In 1996, skin iopsy estlished the dignosis of srcoidosis. In 1997, her dyspne worsened dryness of the mouth nd joint pins ppered. A chest x- ry film ws consistent with stge disese. She ws treted with prednisone for pproximtely two yers. In 2000, her symptoms progressed. She now complined of ftigue, nd low-grde fever. Prednisone ws reduced nd methotrexte 20 mg/week ws dded. A one scn nd whole-ody gllium scn showed lesions in the femorl shft, right ischium, left ilic wing, nd right frontl skull. A two-yer tril of methotrexte filed to improve her symptoms. In Ferury 2002, she ws strted on Inflixim. After the third injection the one strted to te nd low-grde fever nd ftigue susided. A one scn showed mrked improvement. After 8 injections Inflixim ws discontinued ut methotrexte ws continued. In Mrch 2003, three months fter the discontinution of Inflixim, her symptoms returned. Her one mrrow ecme hypermetolic nd res of inflmmtion ppered in the left scrl nd right oritl res. She ws given nother course of Inflixim. CASE 6 In Octoer 1997, this 55-yer-old Africn-Americn womn with chronic skin lesions involving the sclp, fce, nd extremities ws dignosed to hve srcoidosis y skin iopsy. Her other symptoms included photophoi, wekness, weight loss, nd persistent right upper qudrnt dominl pin. A chest x-ry film of the chest showed hilr denopthy nd interstitil infiltrte. A CT of the domen showed lymph-node enlrgement nd heptosplenomegly. Over the course of the next two yers the ptient received prednisone, hydroxychloroquine, methotrexte, zthioprine, nd pentoxyphylline. In August 1999, she underwent lproscopic splenectomy tht showed multiple non-cseting grnuloms. In July 2002, ecuse of the progressive deteriortion nd poor response to conventionl therpy, the ptient ws given Inflixim. After the second infusion the ptient experienced mrked decrese in dominl pin. After the third injection her lymph nodes decresed in size nd lung functions improved (Tle 2). Two months fter the finl infusion of the drug, her symptoms recurred. Dyspne nd skin lesions ppered. These symptoms did not respond to methotrexte. She ws given second course of Inflixim. Tle 2. Lung function improvement fter Inflixim therpy (After six infusions) DISCUSSION Inflixim is chimeric IgG l nti-tnf-lph monoclonl ntiody tht inds to the solule trns-memrne TNF-lph with high ffinity nd forms stle complex tht locks the union of this cytokine with its receptor 1). Inhiition of TNF-lph is chieved in vitro with Inflixim concentrtions of microns/ml. Infusions of 3 or 10 mg/kg Inflixim t weeks 0, 2, nd 6 produce predictle, effective serum drug concentrtions nd re superior to plceo. The frequent development of nti-inflixim ntiodies requires the use of methotrexte in comintion, rther then using Inflixim only 2). Inflixim lso kills the cells tht express TNF-lph through nti-ody dependent nd complement-dependent cytotoxicity 3). Clinicl studies hve estlished stndrd regimen for treting Crohn's disese nd rheumtoid rthritis. If ptients do not respond to stndrd dose or hve n initil fvorle response followed y relpse then either the dose is incresed or the intervl etween infusions is decresed 4). In srcoidosis, there re no guidelines regrding the indictions, dose, nd durtion of therpy with Inflixim. Only limited memer of srcoidosis ptients hve received 85

6 日サ会誌 2005, 25(1) Inflixim so fr. This study is not prospective, controlled, doule lind study. Inflixim ws used ecuse of one or more of the following indictions: 1 The ptients with srcoidosis who filed to response to corticosteroids. 2 The ptients who responded fvorly to corticosteroid ut did not wish to continue tretment ecuse of the intolerle side effects. 3 The ptients who could not tolerte prednisone nd lso developed side effects or filed tretment with chloroquine, hydroxychloroquine, methotrexte, imurn, thlidomide or pentoxyphylline. 4 The ptients who could tolerte methotrexte only in smll doses, ut whose severity of the disese required dding nother drug not tolerted y the ptient. In this series of ptients, Inflixim ws effective not only in controlling the skin lesions of srcoidosis, ut lso fvorly influencing one, pulmonry, neurl, heptic, nd lymph node involvement, nd hyperclcemi. Inflixim ws effective in controlling the grnulomtous inflmmtion in ll the ptients, the illness; however, recurred 3-6 months fter the initil course of eight infusions hd ended. The ptient #5 required the second course of Inflixim to control one pins. There were only few side effects ttriutle to Inflixim. No ptient developed side effects requiring interruption or discontinution of the drug. Repeted tretment with the drug my led to the development of humn ntichimeric ntiodies 5). In ptient #3, nti-nucler ntiody levels climed ut these elevtions were not ssocited with other hemtologicl, immunologicl or renl function chnges. None of the ptients experienced ny severe llergic or nphylctic rections, nd pulmonry or extrpulmonry infections. The ptients hve reported n incresed incidence risk of opportunistic infections with Crohn's disese treted with Inflixim. An incresed incidence of lymphom nd mlignncy hs een reported in ptients with rheumtoid rthritis nd srcoidosis who received Inflixim, ut it is uncler if the risk is relted to the primry illness or previous immunosuppressive tretment or Inflixim. The ptient #2 developed myelom fter termintion of Inflixim therpy. I elieve it ws not relted to Inflixim tretment. In conclusion, Inflixim is effective in controlling vrious mnifesttions of srcoidosis. It is prticulrly eneficil in progressive, inexorle cutneous srcoidosis tht is poorly or non-responsive to corticosteroids nd immunosuppressive gents. The drug is likely to find its niche in controlling overwhelming grnulomtous inflmmtion in the orgns ffected y srcoidosis. REFERENCES: 1) Knight DM, Trinh H, Le J. et l. Construction nd initil chrcteriztion of mouse-humn chimeric nti-tnf ntiody. Mol Immunol 1993; 30: ) St Clir EW, Wgner CL, Fsnmde AA, et l. The reltionship of serum Inflixim concentrtions to clinicl improvement in rheumtoid rthritis. Arthritis Rheum 2002; 46: ) Scllon B, Moore M, Trinh H. et l. Chimeric nti-tnf-lph monoclonl ntiody ca2 inds recominnt trnsmemrne TNF-lph nd ctivtes immune effector functions. Cytokine 1995; 7: ) Olsen N, Stein M. New Drugs for Rheumtoid Arthritis. N Engl J Med 2004; 350: ) Bughmn R, Lower E. Inflixim in refrctory srcoidosis. Srcoidosis Vsc Diffuse Lung Dis 2001; 18: