Sarcoidosis

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Sarcoidosis

Preston W. Chadwick and Warren R. Heymann

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Sarcoidosis is a multisystem disease of unknown etiology characterized histologically by non-caseating granulomas. It is considered to be immune mediated, with a Th1-predominant cytokine profile. Skin manifestations are observed in approximately 25% of cases. Sarcoidosis has been reported to develop following exposure to inorganic particles in the environment. The use of polymerase chain reaction (PCR) techniques has also led to the identification of mycobacterial and propionibacterial DNA and RNA in sarcoidal tissue. Sarcoidosis may be the end result of immune responses to those or other specific triggers. Therapy for erythema nodosum associated with sarcoidosis is addressed in the chapter on erythema nodosum.

Management strategy

The treatment of cutaneous sarcoidosis depends on the type and extent of lesions present and is directed at suppressing the formation of granulomas. Guidelines for treating extracutaneous involvement can be found elsewhere, but it should be recognized that therapy for internal involvement may take precedence over skin disease and that response to treatment may be variable, depending on the type of tissue involved.

In small papular or extremely localized sarcoidosis, treatment with potent topical corticosteroids or intralesional triamcinolone acetonide (3.3–10 mg/mL) is reasonable. If this is ineffective or involvement is more diffuse, oral chloroquine (up to 3.5 mg/kg/day) or hydroxychloroquine (up to 6.5 mg/kg/day) may be effective in addition to methotrexate or tetracyclines. If no response is seen, or disfiguring lesions are present, oral prednisone can be used at a dose of 1 mg/kg daily (maximum 60 mg) for up to 3 months, and then tapered if improvement or a stable level is reached, to a maintenance dose of 5–10 mg on alternate days for several months. Periodic escalations in dose are necessary with flares of the disease.

Methotrexate may be used as a corticosteroid-sparing agent or as monotherapy in those patients with lupus pernio, ulcerative sarcoidosis, or severe disease that has not responded to prednisone. Initial doses of 15–20 mg weekly are favored. Mycophenolate mofetil has also shown promise as a steroid-sparing agent. Thalidomide, azathioprine, chlorambucil, isotretinoin, or allopurinol could be considered if methotrexate or mycophenolate mofetil fail in this subset of patients. Azathioprine and chlorambucil are better studied in patients with pulmonary sarcoidosis. Thalidomide seems to be more effective than isotretinoin and allopurinol in cutaneous disease. Reported failures are described with etretinate and allopurinol.

Biologic agents that inhibit tumor necrosis factor (TNF)-α are therapeutic modalities that should be considered in patients with lupus pernio, cutaneous sarcoidosis recalcitrant to systemic steroids or steroid sparing agents. Infliximab may be more effective than adalimumab, but may be associated with a higher rate of infection and autoimmune disease. Etanercept does not appear to be useful for the treatment of sarcoidosis; indeed some studies have reported on its potential role in patients developing sarcoidosis, or in relapse of pre-existing sarcoidosis.

Leflunomide and apremilast have shown promise in the treatment of cutaneous sarcoidosis unresponsive to other therapies, but further studies are needed to establish long-term usefulness.

Localized disease that does not respond to topical or intralesional corticosteroids, or in those cases in which the use of systemic antimalarial drugs or corticosteroids is undesirable, may represent a niche for other modalities, such as excision, laser, photodynamic therapy, PUVA, surgery (lupus pernio) or intralesional chloroquine.

Specific investigations

First-line therapies

image Topical corticosteroids C
image Intralesional corticosteroids C
image Oral corticosteroids C
image Chloroquine B
image Hydroxychloroquine C
image Methotrexate B

Evidence-based therapy for cutaneous sarcoidosis.

Baughman RP, Lower EE. Clin Dermatol 2007; 25: 334–40.

Whereas the recommended starting dose of prednisone for pulmonary sarcoidosis is suggested to be 20–40 mg daily, the dose and duration of treatment for cutaneous sarcoidosis has not been established. The authors suggest using this as a benchmark and tapering the steroid dose after 1 or 2 months to one that controls the disease while avoiding toxicity. The authors report that the need for long-term systemic corticosteroids for treatment of chronic sarcoidosis occurs in about a quarter of patients.

Another suggested regimen for prednisone in cutaneous sarcoidosis is 30 mg orally on alternate days until the granulomas fade. The dose is then tapered over several months to 15 mg orally on alternate days. Other protocols report a good response with prednisone 30–40 mg orally daily, with a gradual taper to 10–20 mg orally on alternate days for 1 year, or prednisone 1 mg/kg orally daily (maximum 60 mg) for 8 to 12 weeks, with a taper to 0.25 mg/kg daily continued for 6 months.

With long-term treatment, prevention of corticosteroid-induced osteoporosis with bisphosphonates and Pneumocystis pneumonia prophylaxis with trimethoprim–sulfamethoxazole should be considered.

Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial.

Baughman RP, Winget DB, Lower EE. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17: 60–6.

Twenty-four patients with new-onset symptomatic pulmonary disease were randomized to receive either methotrexate or placebo, in addition to their prednisone. Although only 15 patients received at least 6 months of therapy, the methotrexate group required less prednisone than the placebo group. There was no difference in toxicity between the methotrexate and the placebo groups.

A favorable response is usually expected after several months of therapy, and the dose can be tapered weekly after 4 to 6 months. Some studies indicate that methotrexate may be particularly useful for those with ulcerative sarcoidosis.

Second-line therapies

image Mycophenolate mofetil D
image Infliximab B
image Minocycline, doxycycline D

Treatment of lupus pernio: The results of 116 treatment courses in 54 patients.

Stagaki E, Mountford WK, Lackland DT, Judson, MA. Chest 2009; 135: 468–76.

This retrospective study of 54 patients with cutaneous sarcoid undergoing 116 treatment regimens showed infliximab-containing regimens to have a high likelihood of complete or near complete resolution compared to those containing corticosteroids, methotrexate, and hydroxychloroquine. Additionally, when systemic steroids were combined with a second agent there was a significant reduction in prednisone dose requirement.

Infliximab has become a second-line agent, particularly in cases of lupus pernio and neurocutaneous lupus. Studies suggest that infliximab can be used as an induction agent with long-term methotrexate. Superiority to etanercept has been demonstrated.

Recently, a double-blind randomized trial for treatment of ocular sarcoidosis with etanercept showed no comparative improvement in the sarcoidal lesions. Also, sarcoidosis was reported to develop in a patient with ankylosing spondylitis after being treated with etanercept. Therefore, etanercept does not appear to be useful for the treatment of sarcoidosis.

Treatment of sarcoidosis with infliximab.

Doty JD, Mazur JE, Judson MA. Chest 2005; 127: 1064–71.

Ten patients with sarcoidosis recalcitrant to previous therapies were treated with infliximab. Infliximab is administered via intravenous infusion in doses ranging from 3 to 10 mg/kg/dose at 0, 2, 6, and every 8 to 19 weeks subsequently. Nine of 10 patients reported subjective improvement of their lesions, and all 10 were found to have objective measures of improvement. All five patients with lupus pernio experienced significant improvement or clearance of the lesions.

Infliximab, although effective, has been shown to increase the risk of tuberculosis reactivation, of other granulomatous infections, lymphomas, and autoimmune disease. Therapy is expensive, costing up to thousands of dollars per infusion. One must be aware of the side effects and cost.

Third-line therapies

image Thalidomide D
image Allopurinol D
image Isotretinoin E
image Azathioprine E
image Chlorambucil B
image Quinacrine D
image Topical tacrolimus E
image Intralesional chloroquine E
image Excision D
image Laser E
image Melatonin D
image Pentoxifylline E
image Apremilast C
image Leflunomide D
image Adalimumab E
image Medium-dose UVA1 E
image PUVA D
image Photodynamic therapy D
image Dapsone E

Treatment of cutaneous sarcoidosis with thalidomide.

Nguyen YT, Dupuy A, Cordoliani F, Vignon-Pennamen MD, Lebbé C, Morel P, et al. J Am Acad Dermatol 2004; 50: 235–41.

A retrospective evaluation of 12 patients with cutaneous sarcoidosis, two with systemic involvement, 10 of whom were treated successfully with a treatment duration of 2 to more than 16 months, with a daily dose of thalidomide ranging from 50 to 200 mg orally daily. Two patients received combined therapy with oral corticosteroids (dose ranging from 7.5 to 30 mg daily), one patient used potent topical corticosteroids, and one received combined therapy with methotrexate (dose 25 mg weekly). The average response time was 2 to 3 months. The main adverse effect noted in this series was deep venous thrombosis in one patient.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Sarcoidosis

Preston W. Chadwick and Warren R. Heymann

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Sarcoidosis is a multisystem disease of unknown etiology characterized histologically by non-caseating granulomas. It is considered to be immune mediated, with a Th1-predominant cytokine profile. Skin manifestations are observed in approximately 25% of cases. Sarcoidosis has been reported to develop following exposure to inorganic particles in the environment. The use of polymerase chain reaction (PCR) techniques has also led to the identification of mycobacterial and propionibacterial DNA and RNA in sarcoidal tissue. Sarcoidosis may be the end result of immune responses to those or other specific triggers. Therapy for erythema nodosum associated with sarcoidosis is addressed in the chapter on erythema nodosum.

Management strategy

The treatment of cutaneous sarcoidosis depends on the type and extent of lesions present and is directed at suppressing the formation of granulomas. Guidelines for treating extracutaneous involvement can be found elsewhere, but it should be recognized that therapy for internal involvement may take precedence over skin disease and that response to treatment may be variable, depending on the type of tissue involved.

In small papular or extremely localized sarcoidosis, treatment with potent topical corticosteroids or intralesional triamcinolone acetonide (3.3–10 mg/mL) is reasonable. If this is ineffective or involvement is more diffuse, oral chloroquine (up to 3.5 mg/kg/day) or hydroxychloroquine (up to 6.5 mg/kg/day) may be effective in addition to methotrexate or tetracyclines. If no response is seen, or disfiguring lesions are present, oral prednisone can be used at a dose of 1 mg/kg daily (maximum 60 mg) for up to 3 months, and then tapered if improvement or a stable level is reached, to a maintenance dose of 5–10 mg on alternate days for several months. Periodic escalations in dose are necessary with flares of the disease.

Methotrexate may be used as a corticosteroid-sparing agent or as monotherapy in those patients with lupus pernio, ulcerative sarcoidosis, or severe disease that has not responded to prednisone. Initial doses of 15–20 mg weekly are favored. Mycophenolate mofetil has also shown promise as a steroid-sparing agent. Thalidomide, azathioprine, chlorambucil, isotretinoin, or allopurinol could be considered if methotrexate or mycophenolate mofetil fail in this subset of patients. Azathioprine and chlorambucil are better studied in patients with pulmonary sarcoidosis. Thalidomide seems to be more effective than isotretinoin and allopurinol in cutaneous disease. Reported failures are described with etretinate and allopurinol.

Biologic agents that inhibit tumor necrosis factor (TNF)-α are therapeutic modalities that should be considered in patients with lupus pernio, cutaneous sarcoidosis recalcitrant to systemic steroids or steroid sparing agents. Infliximab may be more effective than adalimumab, but may be associated with a higher rate of infection and autoimmune disease. Etanercept does not appear to be useful for the treatment of sarcoidosis; indeed some studies have reported on its potential role in patients developing sarcoidosis, or in relapse of pre-existing sarcoidosis.

Leflunomide and apremilast have shown promise in the treatment of cutaneous sarcoidosis unresponsive to other therapies, but further studies are needed to establish long-term usefulness.

Localized disease that does not respond to topical or intralesional corticosteroids, or in those cases in which the use of systemic antimalarial drugs or corticosteroids is undesirable, may represent a niche for other modalities, such as excision, laser, photodynamic therapy, PUVA, surgery (lupus pernio) or intralesional chloroquine.

Specific investigations

First-line therapies

image Topical corticosteroids C
image Intralesional corticosteroids C
image Oral corticosteroids C
image Chloroquine B
image Hydroxychloroquine C
image Methotrexate B

Evidence-based therapy for cutaneous sarcoidosis.

Baughman RP, Lower EE. Clin Dermatol 2007; 25: 334–40.

Whereas the recommended starting dose of prednisone for pulmonary sarcoidosis is suggested to be 20–40 mg daily, the dose and duration of treatment for cutaneous sarcoidosis has not been established. The authors suggest using this as a benchmark and tapering the steroid dose after 1 or 2 months to one that controls the disease while avoiding toxicity. The authors report that the need for long-term systemic corticosteroids for treatment of chronic sarcoidosis occurs in about a quarter of patients.

Another suggested regimen for prednisone in cutaneous sarcoidosis is 30 mg orally on alternate days until the granulomas fade. The dose is then tapered over several months to 15 mg orally on alternate days. Other protocols report a good response with prednisone 30–40 mg orally daily, with a gradual taper to 10–20 mg orally on alternate days for 1 year, or prednisone 1 mg/kg orally daily (maximum 60 mg) for 8 to 12 weeks, with a taper to 0.25 mg/kg daily continued for 6 months.

With long-term treatment, prevention of corticosteroid-induced osteoporosis with bisphosphonates and Pneumocystis pneumonia prophylaxis with trimethoprim–sulfamethoxazole should be considered.

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