Refractory aphthous ulceration treated with thalidomide: a report of 10 years' clinical experience

Thalidomide has reported efficacy in treating refractory idiopathic aphthous ulceration and aphthous ulceration in Behçet disease (BD). However, because of its potential teratogenicity and neurotoxicity, thalidomide must be used and monitored carefully. We report our experience of using thalidomide over the past 10 years in patients referred within our region with severe refractory aphthous ulceration, and their response to treatment and side‐effects. In our experience, thalidomide works well for severe refractory aphthous ulceration, with a typical patient response reported within 4 weeks, but its use is limited by neurotoxicity. The aphthous ulceration occurring in the context of BD was more difficult to control than idiopathic aphthous ulceration.     

结节性痒疹的研究进展

结节性痒疹为一病因未明的慢性瘙痒性发疹性皮肤病.其特点为突出于皮面的角化过度的丘疹、结节,剧烈瘙痒,呈对称性分布.此病顽固,影响患者心身健康,其发病机制不明确.目前关于病因与发病机制的研究显示,结节性痒疹和精神因素密切相关,降钙素基因相关肽、P物质、神经生长因子受体超家族成员、IL-31等在结节性痒疹中起到介导瘙痒的作用.局部糖皮质激索封包疗法、维生素D3、辣椒素等药物以及紫外线等是有效的治疗方法.口服沙利度胺、环孢素也可以改善皮肤状况和瘙痒.     

An observational analysis of low-dose thalidomide in recalcitrant prurigo nodularis

Thalidomide has been used as an effective treatment for prurigo nodularis (PN) with a median dose of 200 mg, but the risk of peripheral neuropathy precludes long-term use. We analysed the efficacy of low-dose thalidomide (< 100 mg) in 17 patients with recalcitrant PN. Patients were initiated on thalidomide 50 mg on alternate days, and the dose was increased (doubled) in a stepwise manner, if needed, until a ≥ 50% reduction in score (partial response; PR) on a visual analogue scale (VAS) was achieved. Thalidomide then was continued at the same dose for 4 weeks to achieve ≥ 90% decrease in VAS score; if this was not achieved, the dose was increased to a maximum of 100 mg and continued until complete resolution of lesions (complete response; CR). Four patients discontinued thalidomide due to adverse effects. Four patients achieved PR, while 9 patients (n = 2 with 50 mg, n = 7 with 100 mg) achieved CR. No patient developed neuropathy. In addition, complete responders achieved an earlier ≥ 50% reduction in VAS score. Two patients relapsed after 12 months but responded to thalidomide 50 mg.     

Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus

The therapeutic effect of thalidomide in chronic discoid lupus erythematosus (CDLE) was studied in sixty patients who were followed up for 2 years. In fifty-four patients (90%) a complete or marked regression of the disease was observed, but when the thalidomide was stopped, thirty out of forty-one (71%) patients relapsed. Patients undergoing a second course of thalidomide treatment again responded well. Nine of the patients in whom the disease recurred after successful treatment with thalidomide and who had been unresponsive to intermittent treatment with antimalarials, showed a good response to a second or third course with thalidomide. Mild side-effects were common and 25% of patients complained of slight to moderate polyneuritic symptoms. Since electroneurological examinations had not been performed before the thalidomide therapy, the frequency of neurological side-effects cannot be accurately calculated but we recommend neurological examinations before and periodically during thalidomide treatment. Thalidomide is a very effective drug in CDLE, but in most cases it exerts its effect only whilst treatment is continued. Its use should be restricted to patients resistant to topical steroids and systemic antimalarials.     

Crossover study of thalidomide vs placebo in severe recurrent aphthous stomatitis

A multicentric crossover randomized trial of 100 mg of thalidomide vs placebo each for 2 months was conducted in patients with severe aphthous stomatitis of more than 6 months' duration. Seventy-three patients were included. Complete remission was obtained in 32 patients who received thalidomide and in 6 patients who received placebo. The confidence interval of the difference between the two treatments ranged from 25% to 53%. Most of the patients who did not achieve a complete remission had a dramatic improvement with regard to the number of aphthae when they were receiving thalidomide. Thirteen of 17 patients who had a complete remission while they were receiving thalidomide had a recurrence with placebo, 19 +/- 9 (mean +/- SD) days after stopping this drug. Side effects were significantly more frequent with thalidomide, especially drowsiness and constipation. We concluded that thalidomide in a dosage of 100 mg/d is an effective treatment of severe aphthous stomatitis but is not without some risk.     

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).     

Dermatologic side effects of thalidomide in patients with multiple myeloma

BACKGROUND: Thalidomide, an antiangiogenic agent, was approved by the Food and Drug Administration in 1998 for the treatment of erythema nodosum leprosum. Although its teratogenic and neurologic side effects are well known, its dermatologic side effects continue to be defined. OBJECTIVE: We report the dermatologic side effects in 87 patients with multiple myeloma enrolled in a comparative, open-label, clinical trial treated with thalidomide alone (50 patients) or thalidomide and dexamethasone (37 patients). METHOD: We reviewed the records of all patients enrolled in the clinical trial. The frequency, type, severity, and time of onset of all skin eruptions that were temporally related to thalidomide treatment were recorded. RESULTS: Minor to moderate skin eruptions were noted in 46% of patients taking thalidomide alone and in 43% of those taking thalidomide and dexamethasone. These included morbilliform, seborrheic, maculopapular, or nonspecific dermatitis. Severe skin reactions (exfoliative erythroderma, erythema multiforme, and toxic epidermal necrolysis) that required hospitalization and withdrawal of thalidomide developed in 3 patients receiving thalidomide and dexamethasone. CONCLUSION: The prevalence of dermatologic side effects of thalidomide appear to be higher than previously reported. Although in most patients they were minor, in a few patients they were quite severe, particularly when given in conjunction with dexamethasone for newly diagnosed myeloma. Further studies are needed to verify the extent of the interaction between thalidomide and dexamethasone in this group of patients.     

Thalidomide therapy for cutaneous lupus erythematosus: historical and practical considerations

ABSTRACT: Connective tissue diseases are notoriously difficult to treat and the cutaneous manifestations of lupus erythematosus (LE) can be severe, leading to significant and progressive disfigurement. Fortunately several modalities exist for the treatment of this condition. However, oftentimes patients manifest severe disease and are refractory to conventional treatment. Second- and third-line agents used to treat cutaneous LE (CLE) can also exhibit many intolerable side effects. Thalidomide, a drug with a notorious past, has been found to be efficacious in the treatment of most of these patients. Response can be dramatic and patients are often maintained on thalidomide as a monotherapy. We review thalidomide's past, with a focus on its use in the treatment of CLE. We also discuss the practical issues involved in safely administering this drug, using three case histories. In conclusion, thalidomide is very effective in the treatment of CLE, however, prolonged use is often needed to maintain long-term remission. Properly used, thalidomide is very safe, with minimal and mild side effects. However, proper implementation and monitoring is imperative to guard against known serious side effects of teratogenicity and neuropathy.     

Thalidomide in dermatology

Thalidomide is an effective agent to treat over 25 seemingly unrelated dermatological conditions that have an inflammatory or autoimmune basis. The main side-effects of teratogenesis and peripheral neuropathy limit its use. Currently, in Australia no assurance is given as to the quality, safety and efficacy of thalidomide. The use of thalidomide for toxic epidermal necrolysis can lead to an increase in mortality, and its use as a prophylactic agent for the prevention of chronic graft-versus-host disease following bone marrow transplantation has raised more speculations as to the safety of this notorious drug. A review of the therapeutic indications for thalidomide in dermatology as well as the mechanisms of action and side-effects of this drug are presented. The current suggested guidelines for its use in clinical practice in Australia are discussed.     

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.     

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.     

Experience with low-dose thalidomide therapy in chronic discoid lupus erythematosus

BACKGROUND: Low-dose thalidomide therapy (median dose 100 mg/day, 50-200 mg/day) in chronic discoid lupus erythematosus was studied with regard to efficacy, tolerance, and toxicity in 22 patients. Intense contraceptive precautions were taken in women patients of childbearing age. METHODS: An open uncontrolled trial was conducted. Age, the total drug intake, disease duration, extent/severity, and adverse reactions were studied with regard to the final clinical outcome. The follow-up duration was 1.8 years (range 1 month to 3 years). RESULTS: With the exception of age (inverse correlation, P < 0.01), the parameters studied did not influence the final clinical amelioration: complete responders numbered 54.5%, partial responders 22.7%, and 13.6% were withdrawn from the trial with complaints of intolerance. The initial (first month) clinical response correlated significantly with the final one (P < 0.01). Drowsiness (40.9%) and somnolence (18.2%) were the most common side-effects, without affecting seriously the daily life of the participants. No case of real neurotoxicity was confirmed. Relapses occurred within 39.4 +/- 21.4 days after drug withdrawal, presenting a milder clinical picture. CONCLUSIONS: In the context of a predictable final outcome, low-dose thalidomide therapy is effective as an alternative choice in cases resistant to the usual treatment.     

Partner management for gonococcal and chlamydial infection: expansion of public health services to the private sector and expedited sex partner treatment through a partnership with commercial pharmacies.

BACKGROUND: Public health partner notification (PN) services currently affect only a small minority of patients with gonorrhea or chlamydial infection and new approaches to PN are needed. OBJECTIVES: To expand PN for gonorrhea and chlamydial infection to private sector patients and to assess the feasibility of treating sex partners through commercial pharmacies. METHODS: Selected patients were offered PN assistance and were randomly offered medication to deliver to their partners. RESULTS: Providers permitted the health department to contact 3613 (91%) of 3972 potentially eligible patients, and 1693 (67%) of 2531 successfully contacted patients consented to interview. Of these, 1095 (65%) reported at least one untreated partner. Most patients (90%) wished to notify partners themselves. Patients were more likely to have partners who had not yet been treated and to request PN assistance if they had more than one sex partner in the preceding 60 days or a partner they did not anticipate having sex with in the future. These two factors characterized 49% of all patients interviewed, 70% of those with a partner that was untreated 7 or more days after index patient treatment, and 83% of those accepting PN assistance. Among 458 randomly selected patients with untreated partners at time of study interview, 346 (76%) agreed to deliver treatment to a partner. Of these, most (266) chose to obtain medication for a partner at a pharmacy, of whom 223 (84%) successfully did so. CONCLUSION: A substantial minority of private sector patients have untreated partners more than 7 days after their own treatment; some need help with PN, but most will agree to deliver medication to partners themselves.     

Thalidomide increases human keratinocyte migration and proliferation

Thalidomide is reported to have therapeutic utility in the treatment of pyoderma gangrenosum, Beh?et's disease, aphthous ulcers, and skin wounds. We investigated the effect of thalidomide on human keratinocyte proliferation and migration, two early and critical events in the re-epithelialization of skin wounds. Thalidomide at concentrations less than 1 microM did not affect keratinocyte viability. Using a thymidine incorporation assay, we found that thalidomide, at therapeutic concentrations, induced more than a 2. 5-fold increase in the proliferative potential of the cells. Keratinocyte migration was assessed by two independent motility assays: a colloidal gold assay and an in vitro scratch assay. At optimal concentrations, thalidomide increased keratinocyte migration on a collagen matrix more than 2-fold in the colloidal gold assay and more than 3-fold in the scratch assay over control. Although pro-migratory, thalidomide did not alter the level of metalloproteinase-9 secreted into culture medium. Thalidomide did, however, induce a 2-4-fold increase in keratinocyte-derived interleukin-8, a pro-migratory cellular autocrine factor. Human keratinocyte migration and proliferation are essential for re-epithelialization of skin wounds. Interleukin-8 increases human keratinocyte migration and proliferation and is chemotactic for keratinocytes. Therefore, thalidomide may modulate keratinocyte proliferation and motility by a chemokine-dependent pathway.     

Thalidomide inhibits tumor necrosis factor-alpha production and antigen presentation by Langerhans cells

Thalidomide is an effective treatment for several inflammatory and autoimmune disorders including erythema nodosum leprosum, Behcet's syndrome, discoid lupus erythematosus, and Crohn's disease. Thalidomide is believed to exert its anti-inflammatory effects, at least in part, by inhibiting tumor necrosis factor-alpha (TNF-alpha) production by monocytes. We studied the effects of thalidomide on epidermal Langerhans cells (LC). LCs are epidermal antigen-presenting dendritic cells that play important roles in skin immune responses. Using the murine epidermis-derived dendritic cell lines, XS106A from A/J mice and XS52 from BALB/c mice as surrogates for LC, we found that thalidomide inhibited TNF-alpha production in a concentration-dependent manner. Northern blot analysis revealed that thalidomide significantly decreased the peak-induced mRNA level of TNF-alpha in XS106A cells and XS52 cells. We then examined the effect of thalidomide on fresh LC enriched to approximately 98% using positive selection of Ia+ cells with antibodies conjugated to magnetic microspheres. TNF-alpha production was reduced by 67.7% at a thalidomide concentration of 200 microg per mL. Thalidomide also had a profound inhibitory effect on the ability of LC to present antigen to a responsive TH1 clone. Thalidomide inhibits TNF-alpha production and the antigen-presenting ability of epidermal LCs. These mechanisms may contribute to the therapeutic effects observed with this agent.     

A case of severe actinic prurigo successfully treated with thalidomide

Actinic prurigo is an uncommon and usually persistent idiopathic photodermatosis with typical human leukocyte antigen (HLA) associations (HLA-DR4, particularly subtypes DRB1*0407 and DRB1*0401). Although its mechanism of action is not clearly understood, thalidomide has been shown to be particularly efficacious in treating actinic prurigo, among other conditions. A 31-year-old Australian woman who had suffered actinic prurigo for most of her life was treated with two courses of thalidomide (50-100 mg nocte) over consecutive summers. Remission was observed after cessation of the second course of thalidomide and had continued 4 years later. Abnormalities in the cutaneous response to ultraviolet radiation at the time of diagnosis, detected by monochromator phototesting, reverted to normal following treatment.     

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.     

The role of thalidomide in the management of erythema nodosum leprosum

Erythema nodosum leprosum (ENL, Type 2 reactions) complicates lepromatous and borderline lepromatous leprosy and can affect many organ systems, often with irreversible damage. The reactions commonly occur in the 2 years after starting treatment and often run a recurrent or chronic course, sometimes for many years. Even with WHO multi-drug therapy about 30% of LL patients experience ENL. We review drug management of ENL focussing on data from controlled trials and other studies. The treatment of ENL is difficult because high doses of steroids may be required for prolonged periods and do not always control the inflammation. The paradox of ENL is that it can be a life-threatening disorder and requires control with immunosuppression which may itself pose life-threatening risks for patients. Treatment with thalidomide provides an effective alternative to steroid therapy, gives better long-term control and avoids the adverse effects of prolonged steroid therapy. Controlled clinical trials have demonstrated that thalidomide rapidly controls ENL and is superior to aspirin and pentoxifylline. However, thalidomide is teratogenic when taken in early pregnancy and is unavailable in many leprosy endemic countries. We discuss the role of thalidomide in treating ENL, the complications encountered and risk reduction strategies that can be used. These include good patient selection and counselling, close supervision and adequate access to appropriate contraception. Further research is needed to improve the understanding and treatment of this severe and debilitating complication of leprosy. Topics for research include: i. The development of validated tools to measure the severity and/or activity of ENL. ii. A detailed assessment of the neurotoxic effects of thalidomide when used to treat ENL. iii. A well designed trial comparing thalidomide with prednisolone. iv. The development of a safe and effective alternative to both steroids and thalidomide.