American experience with low-dose thalidomide therapy for severe cutaneous lupus erythematosus.

BACKGROUND: There is a renewed interest in thalidomide therapy after its surprising effectiveness in treating erythema nodosum leprosum was first published. Thalidomide has subsequently been reported to be effective in treating a number of dermatoses, including cutaneous lupus erythematosus. We examined the efficacy and adverse effects of low-dose, long-term thalidomide monotherapy in 7 patients with various forms of cutaneous lupus erythematosus that were unresponsive to traditional systemic treatments. OBSERVATIONS: Six of the 7 patients treated with thalidomide after discontinuation of other oral agents had complete or marked resolution of their previously treatment-resistant cutaneous lesions, with an average response time of 2.2+/-0.8 months. Our cohort of 7 patients with cutaneous lupus erythematosus was treated with thalidomide therapy for an average of 2.4+/-3.1 years (range, 1 month to 9 years). The most common adverse effects were sedation, constipation, and weight gain. Two patients reported experiencing intermittent shaking episodes, an adverse effect not previously reported in the literature. Four patients reported symptoms of paresthesia, but none was found to be caused by thalidomide-induced peripheral neuropathy. CONCLUSIONS: A low starting dose of thalidomide as a monotherapy with continued sun avoidance is a safe and effective treatment for the various cutaneous manifestations of lupus erythematosus after traditional therapeutic options have failed to control disease. Our experience with low-dose, long-term thalidomide therapy suggests that peripheral neuropathy is not as common as suggested by other studies (up to 50% of patients treated with thalidomide in some series).     

The use of tetracyclines for the treatment of sarcoidosis

BACKGROUND: To evaluate the safety and efficacy of minocycline in the treatment of sarcoidosis, a nonrandomized, open study was performed in patients with cutaneous sarcoidosis. OBSERVATIONS: Twelve patients with cutaneous sarcoidosis were treated with minocycline, 200 mg/d, for a median duration of 12 months. Three patients had extracutaneous lesions at the time of the study. The median follow-up was 26 months. A clinical response was observed in 10 patients, consisting of complete responses in 8 patients and partial responses in 2 patients. A progression of skin lesions was observed in 1 patient, and lesions remained stable in another patient. Adverse effects were minimal, except in 1 patient, who developed hypersensitivity syndrome. A slight hyperpigmentation occurred in 2 patients at the site of previous lesions, which completely disappeared after minocycline use was discontinued. A relapse of skin symptoms occurred after minocycline withdrawal in 3 patients, who further received doxycycline, 200 mg/d, allowing a complete remission of lesions. CONCLUSIONS: These results support that minocycline and doxycycline may be beneficial for the treatment of cutaneous sarcoidosis. Randomized controlled studies are warranted for the evaluation of the true efficacy of tetracyclines in these patients.     

Treatment of cutaneous sarcoidosis with chloroquine. Review of the literature

Systemic corticosteroids may be either contraindicated or not efficacious in treating the cutaneous manifestations occurring in 20% to 35% of patients with systemic sarcoidosis. Chloroquine phosphate has been reported to be a valuable alternative therapy for cutaneous lesions of sarcoidosis. With a judiciously determined daily dosage and regular 6-month ophthalmologic follow-up examinations, the risk of developing retinopathy can be avoided, because the daily dosage rate rather than total dose accumulation determines the development of chloroquine-induced retinopathy. We reviewed the efficacy and safety of chloroquine and its role in the treatment of cutaneous sarcoidosis.     

Thalidomid in der Behandlung der kutanen und systemischen Sarkoidose

The clinical courses of two patients suffering from generalized or disseminated cutaneous sarcoidosis are described. Both were treated with thalidomide 2×100 mg/day, later 100 mg/day. After 8 to 12 months of treatment the skin and systemic lesions had resolved almost completely.     

Lichenoid nail changes as sole external manifestation of graft vs. host disease

A 56-year-old-man who had refractory anemia with an excess of blasts underwent an allogeneic peripheral blood stem cell transplantation (PBSCT) from his brother after preparation with melphalan and fludarabin. He received GvHD (graft-vs.-host disease) prophylaxis with cyclosporine from day -1 at a daily dose of 5 mg/kg of body weight. The daily dosage was tapered gradually from day +20. On post-PBSCT day 68 he developed acute cutaneous GvHD grade 3 and acute gastrointestinal GvHD grade 2-3, which was resolved with a daily dose of 1 mg/kg of body weight of prednisone. The patient was discharged in good clinical condition and without signs of GvHD, and he started tapering his immunosuppressive treatment. By day 160 he developed oral lichen planus-like changes, with several reticulate white lesions on the oral mucosa. A biopsy specimen was microscopically consistent with lichenoid GvHD (Fig. 1). By day 150 after PBSCT, when he was being treated with CsA 100 mg once daily and prednisone 10 mg once daily, his fingernails started to grow abnormally and gradually became dystrophic and painful. Two months later his toenails became similarly affected. Although affecting all finger and toe nails, the lesions were especially important in both thumbs. Physical examination revealed multiple findings on his nails (Fig. 2): thickening, fragility, onycholysis, longitudinal striations, and even pterygium. The micological cultures were negative. A biopsy specimen showed an sparse papillary dermis lymphoid infiltrate with focal exocytosis and presence of isolated multiple necrotic keratinocytes (Fig. 3). These findings were interpreted as a lichenoid GvHD with oral and nail involvement. The patient did not have other associated cutaneous lesions. He did not develop signs or symptoms consistent with hepatic GvHD. In May 2000 thalidomide was added to the immunosuppressive therapy, at a daily dose from 100 to 300 mg according to tolerance (constipation, sedation, ...). The lesions on the oral mucous showed a substantial improvement, but the nail changes remained more or less stable. Thalidomide was discontinued after 7 months because the patient displayed numbness and tingling in the hands and feet consistent with a peripheral neuropathy. Twenty days later he stopped taking thalidomide and the oral lichenoid lesions worsened, resulting in difficulty in eating. He also developed periungueal erythema, swelling and intense pain after minimal trauma. The daily dose of prednisone increased to 20-30 mg with moderate improvement. However, the dose could not be increased because of the secondary immunosuppressive effects. Twenty-three months post-PBSCT the patient remains with intense oral and nail lichenoid lesions.     

Successful long-term management of refractory cutaneous and upper airway sarcoidosis with periodic infliximab infusion

A clinically refractory case of cutaneous sarcoidosis was successfully treated with infliximab infusion therapy at a dose of 5mg/kg. Skin lesions cleared dramatically and remain resolved during a 3(1/2) year follow-up, the longest follow-up reported to date. Ongoing biological drug therapy has been administered at a frequency of every 8-10 weeks. Despite cost and safety concerns, infliximab should be considered in cases of cutaneous sarcoidosis refractory to standard treatment protocols.     

Newer Therapies for Cutaneous Sarcoidosis

Skin involvement occurs in a third of patients with sarcoidosis. The type of lesions can range from the transient erythema nodosum to the chronic facial lesion lupus pernio. For some patients with sarcoidosis, lesions on the face or elsewhere on the body may be the major or only indication for therapy. These lesions are often chronic and the use of corticosteroids may lead to more long-term complications. Conventional alternatives to corticosteroids include antimalarial agents, methotrexate, and azathioprine. Recently, several drugs have been studied for chronic cutaneous sarcoidosis; thalidomide has been the most widely used. Thalidomide has been demonstrated to suppress tumor necrosis factor (TNF) release, which may be important at both the initial and chronic phases of the inflammation of sarcoidosis and appears to be crucial as part of the initial granulomatous response. Thalidomide has a different toxicity profile than corticosteroids or immunosuppressives. The usual dosage has recently been investigated in a dose-escalation trial, with the majority of patients responding to 100 mg/day. Drug toxicity has been reported in the sarcoidosis trials. The most serious adverse effect has been peripheral neuropathy, which often resolves by reducing the dose or discontinuing the medication. Other drugs that have been studied for sarcoidosis include infliximab and tetracyclines. Infliximab is a chimeric monoclonal antibody against TNF, and several published reports have shown it to be effective for the treatment of cutaneous sarcoidosis. The efficacy of tetracyclines for cutaneous sarcoidosis could be on the basis of their immunologic properties. In addition, these drugs have potent antimicrobial activity against Propionibacterium acnes; there is increasing evidence to suggest this may be one of the causes of sarcoidosis. However, most of the newer agents for cutaneous sarcoidosis have only been studied in small series. Over the next few years, it is hoped that there will be clinical trials to determine the role of each new therapy in the treatment of cutaneous sarcoidosis.     

Cutaneous sarcoidosis with cardiac involvement.

Despite the clinical importance of cardiac involvement in the prognosis of sarcoidosis, it is often overlooked because of the subclinical disease progression and difficulty in diagnosis. We report here five patients with cutaneous sarcoidosis lesions where cardiac involvement was detected with the appearance of mild cardiac symptoms on a careful examination of the heart after cutaneous sarcoidosis was diagnosed. In four of the five cases, the patients had annular lesions while the fifth case showed a nodular eruption on the face. Three of the five patients showed complete AV block while one showed complete right bundle block and left bundle anterior branch block. All four patients with conduction disturbances underwent a permanent pacemaker implantation with prednisolone tapering therapy. The remaining patient had congestive heart failure and was treated with prednisolone alone. The present findings support the belief that sarcoidosis patients with cutaneous lesions, especially facial annular lesions, should be carefully examined and monitored for cardiac involvement, even in cases without apparent cardiac symptoms.     

Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: A randomized study

The present study was undertaken to compare the efficacy and safety of thalidomide to that of oral prednisolone in the treatment of moderate to severe type 2 lepra reaction. Sixty patients with a histologically confirmed diagnosis of erythema nodosum leprosum with a clinical score of 4 or more (i.e. moderate to severe type 2 reaction) were randomly allocated to two groups comprising 30 patients each. Group 1 patients were given thalidomide at a dose of 300 mg/day for 1 week and the dose was gradually reduced, and Group 2 received prednisolone 40 mg daily for 2 weeks, which was tapered by 10 mg every 2 weeks. Thalidomide induced a faster clinical response (cutaneous as well as systemic) compared with prednisolone. Patients taking thalidomide had fewer relapses and a longer period of remission than those receiving prednisolone.     

Long-term cefuroxime axetil in subacute cutaneous lupus erythematosus. A report of three cases

BACKGROUND: Subacute cutaneous lupus erythematosus (SCLE) is a subset of lupus erythematosus characterized mainly by prominent photoaggravated cutaneous manifestations. Standard therapies for SCLE include topical or systemic steroids and antimalarial drugs. Both methods show limited efficacy in clearing cutaneous lesions and occasionally produce serious side effects. AIM: To assess the efficacy of cefuroxime axetil, an oral cephalosporin with antibacterial and immunosuppressive activity, in patients with SCLE. METHODS: Three patients with SCLE were treated with cefuroxime axetil at a daily dose of 500 mg for 30-60 days. RESULTS: In all patients complete clearing of skin lesions was achieved and no side effects were observed. CONCLUSION: We suggest that long-term cefuroxime axetil administration might be an alternative treatment for patients with SCLE skin lesions.     

Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients

Thalidomide is effective in several cutaneous diseases. Peripheral neuropathy is the most important adverse event limiting its use. Its incidence rate and its relation to thalidomide doses remain unclear. We prospectively monitored 135 patients treated with thalidomide for various dermatologic diseases for 2 y in order to estimate the annual incidence rate and risk factors for neuropathy. Patients underwent standardized neurologic examination and nerve conduction studies prior to, and regularly during treatment. Risk factors for neuropathy were assessed using a Cox proportional-hazards model. Clinical and electrophysiologic evidence of a thalidomide-induced neuropathy were present in 25.2% of the patients; however, when considering all potential cases, this rate reached 55.6%. The incidence rate was maximal during the first year of treatment (20%). The risk of neuropathy was related to the daily dose whatever the duration of treatment (p<10-3). Considering a daily dose < or =50 mg per day as reference, the relative risk for thalidomide neuropathy was 8.2 for a daily dose comprised between 50 and 75 mg per day and 20.2 for a daily dose >75 mg per day (p<10-3). No neuropathy occurred for daily doses < or =25 mg per day. The neuropathy was subclinical in nearly a quarter of patients with such an adverse event. These data confirm the high rate of thalidomide neuropathy and identify the daily dose as the main risk factor. The risk of neuropathy seems to be negligible for doses less than 25 mg per day, whatever the duration of therapy.     

Relevant diagnostic implications of the therapeutic challenge with antitubercular therapy in an unusual case of sarcoidosis mimicking lupus vulgaris

Cutaneous manifestations in sarcoidosis are seen in 25–35% of patients with systemic disease and may be the sole manifestation in few patients. It is known that isolated cutaneous sarcoidosis is a great mimicker and can be easily misdiagnosed as other granulomatous conditions especially lupus vulgaris in regions with high burden of tuberculosis (TB). Here we present a case with cutaneous sarcoidosis who was initially misdiagnosed and treated as bifocal lupus vulgaris with antitubercular therapy (ATT) for 6 months. This nonresponsiveness to therapy prompted us to investigate the patient further for other differentials, failing which a diagnosis of cutaneous sarcoidosis was made and the patient was treated with oral steroids and methotrexate with complete clearance of lesions after 14 weeks of therapy. Our case reemphasizes the value of therapeutic trial of ATT in diagnosis of cutaneous TB and highlights the remarkable clinical mimic of sarcoidosis with lupus vulgaris.     

Cutaneous sarcoidosis during interferon alfa and ribavirin treatment of hepatitis C virus infection: two cases

Interferon-induced sarcoidosis is well documented. We report two new cases of sarcoidosis in two patients with hepatitis C virus infection treated with interferon alfa and ribavirin. These patients developed cutaneous sarcoidosis about 3 months after the beginning of the combination therapy. Spontaneous regression of the lesions was noted after discontinuation of the treatment. There have been more than 20 observations of the appearance or aggravation of this granulomatosis with interferon alfa and more recently with the combination of interferon alfa plus ribavirin. Dermatological signs are found in 50% of cases, and are often diagnostic. Other clinical symptoms of sarcoidosis resemble side-effects of interferon. The evolution is fairly stereotypical and is marked by a regression of the lesions following a dose reduction or curtailment of interferon. Interferon alfa acts by stimulating the T-helper (Th) 1 immune response. In addition to its antiviral action, ribavirin also enhances the Th1 response. Indeed, the superiority of the combination of interferon alfa and ribavirin in terms of antiviral action is corroborated by the enhancement of a Th1-type immune reaction by this combination. At the same time, this immune cell reaction triggers a greater granulomatous reaction.     

Sarcoidosis associated with pegylated interferon alfa and ribavirin treatment for chronic hepatitis C: a case report and review of the literature

BACKGROUND: At least 2.7 million Americans are infected with chronic hepatitis C. An increasing number are treated with interferon alfa plus ribavirin regimens. Not surprisingly, this immune stimulation is associated with the development of autoimmune and cutaneous diseases. Several cases of sarcoidosis have been reported with hepatitis C treatment, most recently in association with pegylated interferon alfa plus ribavirin. Systemic manifestations of sarcoidosis are usually treated with oral steroids, which unfortunately often increase the hepatitis C viral load. Thus, it is important to ascertain whether systemic corticosteroids are required to treat interferon alfa-associated sarcoidosis. OBSERVATIONS: We report the third case of cutaneous sarcoidosis in association with pegylated interferon alfa plus ribavirin treatment. Our patient had both cutaneous and pulmonary involvement, which has been spontaneously resolving since his treatment regimen was completed. In addition, we review the 12 previously reported cases of cutaneous sarcoidosis that occurred in patients undergoing hepatitis C treatment with interferon alfa. CONCLUSIONS: As the number of patients being treated with interferon alfa and ribavirin for hepatitis C increases, it is essential that dermatologists recognize the association of this treatment with sarcoidosis, because skin lesions may provide the first clue to diagnosis. Development of sarcoidosis may relate to hepatitis C as a possible antigenic trigger in the presence of an enhanced helper T cells type 1 response from treatment. Sarcoidosis with skin lesions in patients undergoing hepatitis C treatment often follows a benign course, and interferon alfa therapy may sometimes be continued with resolution of sarcoidosis occurring spontaneously or within a few months of completing treatment. Cautious use of systemic corticosteroids is warranted given their adverse effects on hepatitis C viral loads.     

Thalidomide in the treatment of refractory cutaneous lupus erythematosus: prognostic factors of clinical outcome

Background Although thalidomide has been shown to be effective in patients with refractory cutaneous lupus erythematosus (CLE), its use is still hampered by its potential severe side‐effects and the current restricted availability. Objectives To evaluate prospectively the clinical efficacy and safety of low‐dose thalidomide in an observational study and to establish prognostic factors of clinical outcome. Methods Sixty consecutive patients with refractory CLE were treated with thalidomide (100 mg daily). Clinical response was assessed by the CLE Disease Area and Severity Index (CLASI). Clinical and immunological parameters were evaluated during treatment. Results Patients were followed for up to 8 years (range 2–18). One patient discontinued treatment because of side‐effects. Of the 59 remaining patients, 58 (98%) achieved clinical response, already noticeable at 2 weeks following treatment. Complete response occurred in 50 patients (85%). Clinical relapse was frequent (70%) and usually occurred 5 months after withdrawal or reduction of thalidomide. Subacute CLE (SCLE) was the predicting factor of long‐term remission after therapy discontinuation [odds ratio (OR) 30, 95% confidence interval (CI) 5·82–154·63], whereas discoid lupus erythematosus (DLE) was predictive of relapse (OR 5·71, 95% CI 1·36–24·06). Eleven patients (18%) reported paraesthesia; in five of the 11, nerve conduction studies confirmed a sensory polyneuropathy. Neurological symptoms resolved in 12 months (range 6–18) after thalidomide withdrawal. Two patients, heavy smokers and without antiphospholipid antibodies, had a cerebral ischaemic event. Conclusions Low‐dose thalidomide is an effective treatment for refractory CLE, but its benefits need to be balanced against the potential adverse effects. Whereas DLE forms tended to relapse and required a long‐term maintenance dose of thalidomide, SCLE forms showed a sustained remission after withdrawal.     

Medium-dose UV-A1 phototherapy. Successful treatment of cutaneous sarcoidosis

A 82-year-old female had a 2-year history of cutaneous sarcoidosis without systemic involvement. Various treatments including local glucocorticosteroids and tacrolimus ointment had failed. Therefore, we treated our patient with medium-dose UVA1 phototherapy. After 50 sessions with a total dose of 2.640 J/cm(2) all lesions had disappeared. Clinical follow up showed no recurrence of skin lesions after 5 months.     

Photoprotection by thalidomide in patients with chronic cutaneous and systemic lupus erythematosus: discordant effects on minimal erythema dose and sunburn cell formation

BACKGROUND: Thalidomide is an anti-inflammatory and immunomodulatory agent with proven efficacy in several refractory inflammatory skin conditions including photoexacerbated skin diseases. The effects of thalidomide on ultraviolet (UV)-induced cutaneous damage in humans have not been extensively studied. We describe the results of minimal erythema dose (MED) testing in nonlesional skin of three patients with chronic cutaneous lupus erythematosus (CCLE) before and after treatment with thalidomide. OBJECTIVES: To determine whether thalidomide treatment provides clinical and histological evidence of photoprotection from acute UV injury. METHODS: MED testing was performed in nonlesional skin of three patients with CCLE before and after treatment with thalidomide. Skin biopsy specimens were taken from MED sites for in situ immunochemistry. RESULTS: In each patient, the MED to UVB irradiation was significantly higher while the patient was receiving thalidomide treatment than in the absence of thalidomide, suggesting a systemic photoprotective effect. Thalidomide treatment had no significant effect on markers of apoptosis including sunburn cell formation and terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labelling, which identifies single-strand breaks in DNA. CONCLUSIONS: Thalidomide inhibits acute UVB erythema at 24 h after exposure, as a 100-mg daily dose of this drug for 4 weeks conveyed a sun protection factor of 1.56 to > 4.0. We conclude that inhibition of UVB-induced inflammation may, in part, explain the therapeutic benefits of this agent on photosensitive diseases.     

Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus

BACKGROUND: Thalidomide is an anti-inflammatory agent and an immunomodulator that inhibits the production of tumor necrosis factor alpha. It has shown promise as a treatment option for the cutaneous manifestations of lupus erythematosus (LE). OBJECTIVE: To assess the degree of clinical response per subtype of cutaneous lupus, the duration of therapy before documented clinical improvement, and the incidence of adverse effects, including peripheral neuropathy, with low-dose thalidomide therapy at 100 mg daily in the treatment of refractory cutaneous lesions of LE. METHODS: This retrospective medical record review of patients with refractory cutaneous manifestations of LE is one of the largest modern series in the literature. There were 29 patients seen at the Department of Dermatology, Wake Forest University School of Medicine (Winston-Salem, NC), who were unresponsive to conventional agents including antimalarial agents, and who started treatment between 1998 and 2000. Twenty-three patients who took the drug for 1 month or more were included in the analysis. Clinical responses were assessed by the investigators based on statements of improvement listed in the clinic notes and were categorized as "no response," "partial response," and "complete response." Partial response was classified as either 75% or greater or less than 75% improvement. The incidence of adverse effects including peripheral neuropathy was determined. RESULTS: Of the 23 patients, 17 (74%) demonstrated complete resolution of the cutaneous manifestations of LE, whereas 3 patients (13%) demonstrated 75% or greater partial improvement; 3 patients (13%) had less than 75% partial clinical improvement; and 21 patients (91%) who demonstrated a complete or partial response did so within 8 weeks of initiating thalidomide therapy. CONCLUSIONS: Based on the results of this case series, we believe that thalidomide should be given prime consideration as a treatment for antimalarial drug-resistant interface lesions of LE. The design of prospective, randomized, double-blind, placebo-controlled trials for this indication is warranted.     

Oral zinc sulphate in the treatment of recalcitrant viral warts: randomized placebo-controlled clinical trial

BACKGROUND: Viral warts are common dermatological diseases; although the rate of spontaneous recovery is high, it usually takes a long time, and some patients might not show this spontaneous healing. Zinc has an important effect on the immune system and it has been used as an immunomodulator to treat a variety of skin disorders. OBJECTIVE: To assess whether oral zinc was effective in treating viral warts of patients evaluated between May 1999 and April 2000. PATIENTS AND METHODS: This was a placebo-controlled clinical trial. Eighty patients with viral warts (common, plantar and plane) were all resistant to all forms of treatment. Each patient had > 15 warts. Forty patients were treated by oral zinc sulphate at a dose of 10 mg kg(-1) daily up to 600 mg day(-1) and followed-up for resolution of their warts and for any evidence of recurrence for 2-6 months. Another 40 patients were given a placebo oral treatment in the form of glucose, and followed-up for the same period. RESULTS: Only 23 patients of the first group (zinc treated) and 20 patients of the second group (placebo treated) completed the study. In all patients the serum level of zinc was low. In the zinc-treated group, the overall response was complete clearance of warts observed in 20 patients (86.9%) after 2 months of treatment. Fourteen patients (60.9%) showed complete disappearance of their warts after 1 month. Three patients (13.3%) failed to respond to the treatment after 2 months of therapy. The response to treatment was directly related to the increment in serum zinc level. No patient of the placebo-treated group showed any response. CONCLUSIONS: We conclude that zinc sulphate at a dose of 10 mg kg(-1) daily seems to be a highly efficacious therapeutic option for recalcitrant viral warts and proved to be safe with few adverse effects.     

Cutaneous sarcoidosis treated with levamisole.

16 patients with cutaneous sarcoidosis were treated intermittently over a period of 6 months with levamisole in an open study. The skin lesions cleared in 2 of 13 patients completing the course of treatment. Aggravation of the sarcoidosis was noted in 2 other patients after a few weeks of treatment. Tuberculin sensitivity did not increase during the treatment period. Dinitrochlorobenzene sensitivity increased in 5 patients but the lesions did not clear in any of these patients. It is concluded that levamisole is not useful in the treatment of cutaneous sarcoidosis.