A Case Series of Refractory Cutaneous Sarcoidosis Successfully Treated with Infliximab
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- Tuchinda, P., Bremmer, M. & Gaspari, A.A. Dermatol Ther (Heidelb) (2012) 2: 11. doi:10.1007/s13555-012-0011-9
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Sarcoidosis 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.
The 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.
Infliximab 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.
KeywordsBiologic Cutaneous Infliximab Sarcoidosis Therapy Treatment Tumor necrosis factor inhibitor
Sarcoidosis is a multisystemic granulomatous disease of unknown origin. Cutaneous manifestations occur in approximately one quarter of sarcoid patients, and these lesions may present at the onset of the disease or following other systemic involvement . The management of sarcoidosis remains a significant therapeutic challenge. 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 [2, 3, 4, 5]. In the past decade, a number of case series has shown that infliximab is an effective and well-tolerated management strategy for this condition [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26]. The authors report three cases of cutaneous sarcoidosis that were refractory to standard therapy but responded to infliximab treatment. The authors also review the literature concerning the treatment of sarcoidosis with infliximab.
Patient demographic data
43-year-old African American man
53-year-old African American woman
48-year-old African American woman
Other organ involvement
Pulmonary and eye
Pulmonary and eye
Cutaneous features at diagnosis
Nodular lesions on face, eyelids, and earlobes
Multiple erythematous to violaceous papules on eyelids, right cheek, tip of nose, and corner of mouth
Multiple erythematous annular plaques around eyes, nose, perioral area, neck, arm, back and knees
From right cheek: granulomatous inflammatory infiltrate (lymphocytes, histiocytes, and giant cells)
From right cheek: non-necrotizing granulomas (epithelioid cells and multinucleated giant cells)
Previous treatment before initiating infliximab
Pulse methyl prednisone
Therapeutic side effects or complications
A significant amount of weight gain
New onset diabetes
A spontaneous hairline left 5th metatarsal fracture
Right hip avascular necrosis
Corticosteroids-induced gastrointestinal upset, fatigue
Hydroxychloroquine-induced diarrhea and abdominal pain
Methotrexate-induced leucopenia and abnormal liver function tests
Thalidomide-induced peripheral neuropathy
Duration of disease before infliximab therapy
Treatments used at the time of infliximab initiation
Hydroxychloroquine (200 mg twice a day)
Mycophenolate mofetil (4 g/day)
Prednisone (15 mg/day)
Prednisone (40 mg/day)
Thalidomide (100 mg/day)
Infliximab dose, duration
5 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 weeks
7.5 mg/kg on weeks 0, 2, and 6, then every 8 weeks
7.5 mg/kg on weeks 0, 2, and 6, then every 8 weeks
4 years later tapered to 5 mg/kg every 16 weeks
3 years later taken off infliximab
Time to achieve clinical response
Treatments at the time of last follow-up
Infliximab (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)
Still gradually increase new lesions
Improvement after mycophenolate mofetil and prednisone discontinuation
No new lesions
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 25–35% of cases and may present at the onset of the disease process [28, 29, 30, 31]. Diagnosis is usually made by clinical suspicion in conjunction with biopsy and the exclusion of other conditions . The clinical history and prognosis of sarcoidosis is variable. In cutaneous sarcoidosis, 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 [36, 37, 38]. 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 [6, 7, 8, 9, 10, 11], 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 [3, 4, 5, 22], neurosarcoidosis , and cardiac sarcoidosis  have also been reported.
For sarcoidosis patients reported in the literature, the usual dose of infliximab has been 3–10 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 14–51 months after the initiation of treatment. All three patients improved within 6 months of discontinuation . 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.
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.
Dr. Gaspari is the guarantor for this article, and takes responsibility for the integrity of the work as a whole.
Conflict of interest
The authors report no conflicts of interest.
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