systemic and topical corticosteroids are popularly used treatment methods in cutaneous sarcoidosis but are a poor long - term management strategy given the range of side effects . treatment with biologic agents has recently been proposed as another treatment option for cutaneous sarcoidosis [ 25 ] . in the past decade , a number of case series has shown that infliximab is an effective and well - tolerated management strategy for this condition [ 326 ] . the authors report three cases of cutaneous sarcoidosis that were refractory to standard therapy but responded to infliximab treatment . a 43-year - old african american man with a history of pulmonary sarcoidosis was seen in the authors clinic in december 2007 because of a 4-month history of lesions on the patient s cheeks and legs . the patient was treated with increasing doses of prednisone , hydroxychloroquine , and intralesional corticosteroids without improvement . as a result of a combination of lack of efficacy and intolerable side effects of these medications , the patient was switched to infliximab 5  mg / kg intravenously on weeks 0 , 2 , and 6 , and then every 8  weeks in november 2008 . after three infusions , the patient showed significant improvement of skin lesions , and prednisone was tapered back to 2.5  mg every other day . however , after 6  months of infusions , the patient began to experience some flaring of cutaneous lesions . methotrexate 7.5  mg weekly was added in may 2009 in addition to infliximab in an effort to improve further the patient s cutaneous lesions . in addition , infliximab was increased to 5  mg / kg every 7  weeks , and shortly thereafter was increased again to 7.5  mg / kg every 7  weeks in november 2009 for flares near the time of infusion . the patient s cutaneous sarcoidosis was stable on this dose of methotrexate and infliximab for 9  months . in june 2011 , the dosage again had to be increased to 10  mg / kg every 5  weeks due to flaring of lesions before infusions , which was able to control the disease better ( table  1).table  1patient demographic datacase 1case 2case 3demographics43-year - old african american man53-year - old african american woman48-year - old african american womanother organ involvementpulmonarypulmonary and eyepulmonary and eyecutaneous features at diagnosisnodular lesions on face , eyelids , and earlobesmultiple erythematous to violaceous papules on eyelids , right cheek , tip of nose , and corner of mouthmultiple erythematous annular plaques around eyes , nose , perioral area , neck , arm , back and kneeshistopathologyfrom right cheek : granulomatous inflammatory infiltrate ( lymphocytes , histiocytes , and giant cells)from right cheek : non - necrotizing granulomas ( epithelioid cells and multinucleated giant cells)n / aprevious treatment before initiating infliximabprednisonehydroxychloroquineintralesional corticosteroidsprednisonehydroxychloroquinemethotrexateminocyclinetopical tacrolimustopical imiquimodmycophenolate mofetilprednisonehydroxychloroquinemethotrexatepulse methyl prednisonethalidomidetopical corticosteroidstherapeutic side effects or complicationsa significant amount of weight gainhypertensionnew onset diabetesa spontaneous hairline left 5th metatarsal fracturehypertensiondiabetesright hip avascular necrosiscorticosteroids - induced gastrointestinal upset , fatiguehydroxychloroquine - induced diarrhea and abdominal painmethotrexate - induced leucopenia and abnormal liver function teststhalidomide - induced peripheral neuropathyduration of disease before infliximab therapy2  years18  years8  yearstreatments used at the time of infliximab initiationhydroxychloroquine ( 200  mg twice a day)intralesional corticosteroidsmycophenolate mofetil ( 4  g / day)prednisone ( 15  mg / day)prednisone ( 40  mg / day)thalidomide ( 100  mg / day)infliximab dose , duration5  mg / kg on weeks 0 , 2 , and 6 , then every 8  weeks 6  months later : add methotrexate 7.5  mg weekly after tapering prednisone 6  months later increased infliximab to 5  mg / kg and 7.5  mg / kg every 7  weeks 9  months later increased infliximab to 10  mg / kg every 5  weeks7.5  mg / kg on weeks 0 , 2 , and 6 , then every 8  weeks7.5  mg / kg on weeks 0 , 2 , and 6 , then every 8  weeks4  years later tapered to 5  mg / kg every 16  weeks3  years later taken off infliximabtime to achieve clinical response3  years5  months4  yearstreatments at the time of last follow - upinfliximab ( 10  mg / kg every 5  weeks)methotrexate ( 7.5  mg weekly)prednisone ( 2.5  mg / day every other day)infliximab ( 7.5  mg / kg every 8  weeks)discontinued infliximabfollow - upstill gradually increase new lesionsimprovement after mycophenolate mofetil and prednisone discontinuationno new lesions patient demographic data a 53-year - old african american woman with a history of pulmonary sarcoidosis for 15  years was referred to the authors clinic on april 2002 for management of 5  years of cutaneous sarcoidosis lesions . the patient s cutaneous lesions were primarily involving the nasal ala and bilateral cheeks in a distribution consistent with lupus pernio . the patient was treated with oral prednisone , hydroxychloroquine , methotrexate , minocycline , topical tacrolimus , and topical imiquimod at various points and only showed moderate improvement with systemic steroids . the patient was started on mycophenolate mofetil 500  mg twice a day in december 2003 , increasing to as high as 4  g / day . however , the patient continued to experience refractory lesions at this dose ( fig . 1 ) , with multiple erythematous to violaceous papules and plaques on the patient s right cheek , tip of the nose , and corner of the mouth . infliximab 7.5  mg / kg was started in may 2004 at weeks 0 , 2 , and 6 , and then every 8  weeks , and the dosage of mycophenolate mofetil was decreased to 1  g twice a day and prednisone 10  mg / day . five months after initiating infliximab , the patient s skin lesions showed moderate flattening without any adverse side effects . prednisone was tapered over the course of 6  weeks and ended in november 2011 . the patient s lesions have since maintained improvement with infliximab 7.5  mg / kg every 8  weeks ( fig .  2 ; table  1).fig . 2case 2 after missing two doses of infliximab and experienced a flare of the cutaneous disease the clinical manifestations of case 2 before initiating infliximab case 2 after missing two doses of infliximab and experienced a flare of the cutaneous disease a 48-year - old african american woman was first seen in the authors clinic in 2001 for management of cutaneous sarcoidosis lesions . the patient was diagnosed with cutaneous sarcoidosis by biopsy of the preauricular area in 1996 . the patient was originally treated with hydroxychloroquine and prednisone , but these medications were discontinued due to side effects . the patient was subsequently started on methotrexate 15  mg / week and minocycline 100  mg twice a day . methotrexate was increased to 22.5  mg / week , prednisone was increased to 40  mg / day , and hydroxychloroquine 250  mg / day was initiated . because of side effects from prednisone and methotrexate , these medications were discontinued . the patient was then lost to follow - up for approximately 2  years . in may 2004 , the patient s lesions flared , and thalidomide 100  mg / day was initiated with prednisone 20  mg / day and topical corticosteroids . as a result of peripheral neuropathy , thalidomide was discontinued after 2  months of treatment . infliximab 7.5  mg / kg at weeks 0 , 2 , and 6 , and every 8  weeks thereafter was started in august 2004 . figure  3 shows the lesions on the patient s upper extremities were significantly flattened compared with initial presentation.fig . 3the clinical manifestation of case 3 , 2  years after initiating infliximab the clinical manifestation of case 3 , 2  years after initiating infliximab the patient s lesions slowly improved with no new lesions manifesting ; fig . 4 shows the lesions on the patient s upper extremities are dramatically flattened compared with initial presentation . infliximab was tapered in october 2008 to 5  mg / kg every 12  weeks and was discontinued in november 2011 . 4the clinical manifestations of case 3 , 6  years after initiating infliximab the clinical manifestations of case 3 , 6  years after initiating infliximab a 43-year - old african american man with a history of pulmonary sarcoidosis was seen in the authors clinic in december 2007 because of a 4-month history of lesions on the patient s cheeks and legs . the patient was treated with increasing doses of prednisone , hydroxychloroquine , and intralesional corticosteroids without improvement . as a result of a combination of lack of efficacy and intolerable side effects of these medications , the patient was switched to infliximab 5  mg / kg intravenously on weeks 0 , 2 , and 6 , and then every 8  weeks in november 2008 . after three infusions , the patient showed significant improvement of skin lesions , and prednisone was tapered back to 2.5  mg every other day . however , after 6  months of infusions , the patient began to experience some flaring of cutaneous lesions . methotrexate 7.5  mg weekly was added in may 2009 in addition to infliximab in an effort to improve further the patient s cutaneous lesions . in addition , infliximab was increased to 5  mg / kg every 7  weeks , and shortly thereafter was increased again to 7.5  mg / kg every 7  weeks in november 2009 for flares near the time of infusion . the patient s cutaneous sarcoidosis was stable on this dose of methotrexate and infliximab for 9  months . in june 2011 , the dosage again had to be increased to 10  mg / kg every 5  weeks due to flaring of lesions before infusions , which was able to control the disease better ( table  1).table  1patient demographic datacase 1case 2case 3demographics43-year - old african american man53-year - old african american woman48-year - old african american womanother organ involvementpulmonarypulmonary and eyepulmonary and eyecutaneous features at diagnosisnodular lesions on face , eyelids , and earlobesmultiple erythematous to violaceous papules on eyelids , right cheek , tip of nose , and corner of mouthmultiple erythematous annular plaques around eyes , nose , perioral area , neck , arm , back and kneeshistopathologyfrom right cheek : granulomatous inflammatory infiltrate ( lymphocytes , histiocytes , and giant cells)from right cheek : non - necrotizing granulomas ( epithelioid cells and multinucleated giant cells)n / aprevious treatment before initiating infliximabprednisonehydroxychloroquineintralesional corticosteroidsprednisonehydroxychloroquinemethotrexateminocyclinetopical tacrolimustopical imiquimodmycophenolate mofetilprednisonehydroxychloroquinemethotrexatepulse methyl prednisonethalidomidetopical corticosteroidstherapeutic side effects or complicationsa significant amount of weight gainhypertensionnew onset diabetesa spontaneous hairline left 5th metatarsal fracturehypertensiondiabetesright hip avascular necrosiscorticosteroids - induced gastrointestinal upset , fatiguehydroxychloroquine - induced diarrhea and abdominal painmethotrexate - induced leucopenia and abnormal liver function teststhalidomide - induced peripheral neuropathyduration of disease before infliximab therapy2  years18  years8  yearstreatments used at the time of infliximab initiationhydroxychloroquine ( 200  mg twice a day)intralesional corticosteroidsmycophenolate mofetil ( 4  g / day)prednisone ( 15  mg / day)prednisone ( 40  mg / day)thalidomide ( 100  mg / day)infliximab dose , duration5  mg / kg on weeks 0 , 2 , and 6 , then every 8  weeks 6  months later : add methotrexate 7.5  mg weekly after tapering prednisone 6  months later increased infliximab to 5  mg / kg and 7.5  mg / kg every 7  weeks 9  months later increased infliximab to 10  mg / kg every 5  weeks7.5  mg / kg on weeks 0 , 2 , and 6 , then every 8  weeks7.5  mg / kg on weeks 0 , 2 , and 6 , then every 8  weeks4  years later tapered to 5  mg / kg every 16  weeks3  years later taken off infliximabtime to achieve clinical response3  years5  months4  yearstreatments at the time of last follow - upinfliximab ( 10  mg / kg every 5  weeks)methotrexate ( 7.5  mg weekly)prednisone ( 2.5  mg / day every other day)infliximab ( 7.5  mg / kg every 8  weeks)discontinued infliximabfollow - upstill gradually increase new lesionsimprovement after mycophenolate mofetil and prednisone discontinuationno new lesions patient demographic data a 53-year - old african american woman with a history of pulmonary sarcoidosis for 15  years was referred to the authors clinic on april 2002 for management of 5  years of cutaneous sarcoidosis lesions . the patient s cutaneous lesions were primarily involving the nasal ala and bilateral cheeks in a distribution consistent with lupus pernio . the patient was treated with oral prednisone , hydroxychloroquine , methotrexate , minocycline , topical tacrolimus , and topical imiquimod at various points and only showed moderate improvement with systemic steroids . the patient was started on mycophenolate mofetil 500  mg twice a day in december 2003 , increasing to as high as 4  g / day . however , the patient continued to experience refractory lesions at this dose ( fig .  1 ) , with multiple erythematous to violaceous papules and plaques on the patient s right cheek , tip of the nose , and corner of the mouth . infliximab 7.5  mg / kg was started in may 2004 at weeks 0 , 2 , and 6 , and then every 8  weeks , and the dosage of mycophenolate mofetil was decreased to 1  g twice a day and prednisone 10  mg / day . five months after initiating infliximab , the patient s skin lesions showed moderate flattening without any adverse side effects . prednisone was tapered over the course of 6  weeks and ended in november 2011 . the patient s lesions have since maintained improvement with infliximab 7.5  mg / kg every 8  weeks ( fig .  2 ; table  1).fig . 2case 2 after missing two doses of infliximab and experienced a flare of the cutaneous disease the clinical manifestations of case 2 before initiating infliximab case 2 after missing two doses of infliximab and experienced a flare of the cutaneous disease a 48-year - old african american woman was first seen in the authors clinic in 2001 for management of cutaneous sarcoidosis lesions . the patient was diagnosed with cutaneous sarcoidosis by biopsy of the preauricular area in 1996 . the patient was originally treated with hydroxychloroquine and prednisone , but these medications were discontinued due to side effects . the patient was subsequently started on methotrexate 15  mg / week and minocycline 100  mg twice a day . methotrexate was increased to 22.5  mg / week , prednisone was increased to 40  mg / day , and hydroxychloroquine 250  mg / day was initiated . the patient was then lost to follow - up for approximately 2  years . in may 2004 , the patient s lesions flared , and thalidomide 100  mg / day was initiated with prednisone 20  mg / day and topical corticosteroids . as a result of peripheral neuropathy , thalidomide was discontinued after 2  months of treatment . infliximab 7.5  mg / kg at weeks 0 , 2 , and 6 , and every 8  weeks thereafter was started in august 2004 . figure  3 shows the lesions on the patient s upper extremities were significantly flattened compared with initial presentation.fig . 3the clinical manifestation of case 3 , 2  years after initiating infliximab the clinical manifestation of case 3 , 2  years after initiating infliximab the patient s lesions slowly improved with no new lesions manifesting ; fig . 4 shows the lesions on the patient s upper extremities are dramatically flattened compared with initial presentation . infliximab was tapered in october 2008 to 5  mg / kg every 12  weeks and was discontinued in november 2011 . 4the clinical manifestations of case 3 , 6  years after initiating infliximab the clinical manifestations of case 3 , 6  years after initiating infliximab sarcoidosis is a multisystemic non - caseating granulomatous disease of unknown origin that is driven by t - helper type 1 immune responses . cutaneous manifestations occur in 2535% of cases and may present at the onset of the disease process [ 2831 ] . diagnosis is usually made by clinical suspicion in conjunction with biopsy and the exclusion of other conditions . , there are no definite guidelines for systemic therapy , but progressive , widespread , and disfiguring lesions should certainly be treated . systemic and topical corticosteroids remain the mainstay of treatment for various manifestations of sarcoidosis , including cutaneous sarcoidosis . unfortunately , the long - term side effects make corticosteroids a less than ideal long - term treatment option , and some patients remain refractory to this management strategy . tumor necrotic factor ( tnf)-alpha is an important proinflammatory cytokine involved in the pathogenesis of sarcoidosis . macrophages of sarcoidosis patients have been implicated as major releasers of tnf - alpha in sarcoidosis [ 34 , 35 ] . higher serum tnf - alpha levels have been shown not only in patients with slow onset sarcoidosis compared with acute onset , but levels have been shown to fluctuate in correlation with disease activity [ 3638 ] . in addition , increased levels of tnf - alpha have been correlated with a greater risk of disease progression , relapse , and difficulty with treatment . as a result of evidence of tnf - alpha involvement in the pathogenesis of sarcoidosis [ 39 , 40 ] , alternative therapies for cutaneous sarcoidosis such as the tnf - alpha antagonists have been proposed [ 2 , 3 ] . reports on the efficacy of tnf antagonists used for cutaneous sarcoidosis are increasing , although at this time this treatment modality remains off label by the standards of the us food and drug administration . although there have been no comparative trials between the biologic agents for sarcoidosis , infliximab is the most heavily reported medication in the literature [ 611 ] , and overall has shown great promise in the treatment of sarcoidosis patients refractory to more conventional therapies [ 6 , 7 , 12 , 26 ] . favorable outcomes of infliximab therapy in patients who have renal sarcoidosis , vertebral sarcoidosis , joint sarcoidosis , optic neuropathy , pulmonary sarcoidosis [ 6 , 17 ] , retinal vasculitis , cutaneous sarcoidosis [ 35 , 22 ] , neurosarcoidosis , and cardiac sarcoidosis   have also been reported . for sarcoidosis patients reported in the literature , the usual dose of infliximab has been 310  mg / kg per dose at 0 , 2 , and 6  weeks , followed by every 8  weeks for maintenance [ 25 , 34 ] . if patients respond insufficiently to 5  mg / kg , reducing the treatment interval has been shown to lead to higher trough levels than increasing the dose . a randomized , double - blind , placebo controlled study on the efficacy of infliximab in 36 sarcoidosis patients with cutaneous and pulmonary involvement used a 6-week maintenance regimen . after 24  weeks of treatment , patients overall showed improvement in cutaneous findings compared with placebo , although this was not statistically significant ( p  =  0.09 ) . in addition , a retrospective review of lupus pernio ( 13 courses of treatment with infliximab in nine patients ) reported the success of a 6-week maintenance regimen , which was statistically more efficacious than corticosteroids used with and without other non - steroid immunosuppressive agents ( p  =  0.0015 ) . all three patients in the current case study were able to control their cutaneous sarcoidosis , although doses had to be tailored to the severity and variably refractory nature of their diseases . however , it should be noted by the prescribing physician that increased doses of immunosuppression can of course lead to an increased tendency toward infection , and can also be associated with demyelination and worsening of multiple sclerosis lesions . increasing doses of infliximab should not be given lightly . while tnf inhibitors have been shown to be of benefit in treating sarcoidosis , it is of some interest that a few cases have been reported wherein patients developed sarcoidosis while undergoing treatment with anti - tnf therapy . in the largest reported series of sarcoid - like granulomas developing during tnf inhibitor therapy , three of 10 patients treated with infliximab for ankylosing spondylitis developed pulmonary sarcoidosis 1451  months after the initiation of treatment . other case reports of infliximab - treated patients include one patient with ankylosing spondylitis who developed pulmonary sarcoidosis after 5  years of therapy , and patients with psoriatic arthritis who developed pulmonary sarcoidosis   and cutaneous sarcoidosis . the mechanisms of sarcoidosis development during anti - tnf - alpha therapy are unclear . in an article by saleh et al . , the following were offered as indications to initiate treatment with infliximab for refractory sarcoidosis : unsuccessful treatment with systemic corticosteroids;intolerant to systemic steroids side effects;unsuccessful treatment or intolerance to other systemic therapies;requirement for additional systemic therapy but intolerant to alternative agents . unsuccessful treatment with systemic corticosteroids ; intolerant to systemic steroids side effects ; unsuccessful treatment or intolerance to other systemic therapies ; requirement for additional systemic therapy but intolerant to alternative agents . in summary , the authors report three cases of patients with refractory sarcoidosis successfully treated with infliximab . their clinical outcomes were good , sustained , and there was no associated morbidity from the medication . definite indications , dosage , interval , and duration of treatment for cutaneous sarcoidosis are not firmly established , although altering the dose and schedule of infusions can be useful in bringing the disease under optimal control . larger randomized controlled trials are warranted to validate the efficacy of infliximab in patients with cutaneous sarcoidosis . this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and the source are credited .
introductionsarcoidosis is a systemic granulomatous disease of unknown cause . 
 the management of sarcoidosis remains problematic . 
 systemic and topical corticosteroids are the mainstay of therapy but may cause unacceptable side effects . 
 biologic therapies , such as infliximab , have recently been proposed as another treatment option for cutaneous sarcoidosis.case reportthe authors describe three patients who were diagnosed with cutaneous sarcoidosis with systemic involvement . 
 all of the patients were refractory to conventional therapies but responded to infliximab therapy.conclusioninfliximab is an alternative medication for refractory sarcoidosis that has a relatively benign side - effect profile . 
 however , definite indications , dosage , interval , and duration of treatment for cutaneous sarcoidosis are not firmly established .