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.     

Clinical Manifestations of Cutaneous Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune disease with a broad spectrum of clinical manifestations and a variable course. In numerous investigations, it has been shown that exogenous factors, such as UV‐light and drugs, can induce this disease. However, not all clinical aspects can be explained and therefore, the pathogenesis of CLE is currently under extensive research. The various cutaneous manifestations of LE are divided into LE‐nonspecific and LE‐specific skin disease based on histologic criteria. LE‐nonspecific manifestations are mostly associated with systemic LE but can also occur in other diseases and include particularly vascular skin lesions such as pe‐riungual telangiectases. LE‐specific skin disease includes the subtypes of CLE such as acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE), and intermittent CLE (ICLE). The subdivision of these subtypes with different prognosis and course is supported by genetic, clinical, histologic, and immunoserologic findings. The subtypes of CLE require a specific morphological and clinical analysis, which is described in the first part of this review. In the second part of this review, further diagnostic procedures and therapeutic strategies in patients with CLE are discussed.     

Systemische Therapie des kutanen Lupus erythematodes

The treatment of cutaneous lupus erythematosus (CLE) remains a therapeutic challenge. In many cases, systemic treatment of the disease is necessary, especially in cases resistant to topical treatment or with internal organ involvement. Even though many different agents can be employed in this situation, most are not approved in Germany for the treatment of CLE. We give an overview of the agents used in the systemic treatment of CLE and review their mechanisms of action, indications and their practical use in cutaneous LE based on literature results and our own experience. We discuss corticosteroids, antimalarials, dapsone, azathioprine, cyclophosphamide, methotrexate, retinoids, cyclosporine A, mycophenolate mofetil, sulfasalazine, thalidomide, clofazimine, tacrolimus, immunoglobulins, monoclonal antibodies, plasmapheresis, etanercept, infliximab, feflunomid, gold and interferon‐α.     

Chronic cutaneous lupus erythematosus. Thalidomide treatment of 11 patients

Eleven patients with severe, chloroquine-resistant chronic cutaneous lupus erythematosus were treated with oral thalidomide. Seven patients responded with a complete remission, and two patients' conditions improved significantly. One patient did not respond well to therapy and another patient had to be withdrawn from the treatment trial because of side effects. Six patients, who relapsed after discontinuing thalidomide treatment, were re-treated with maintenance drug dosages and achieved good results with no further relapses or exacerbations. In all subjects the side effects from the thalidomide were minor and reversible.     

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.     

Clinical and immunologic parameters during thalidomide treatment of lupus erythematosus

BACKGROUND: Thalidomide is used as an experimental drug for the treatment of chronic inflammatory diseases with an autoimmune or infectious background. The pharmacologic action involves the downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis; however, not much is known about thalidomide's effect on immunologic parameters in lupus erythematosus (LE). Method This is an open study of a group of five consecutive systemic lupus erythematosus (SLE) patients treated with thalidomide (100 mg/day) and five consecutive cutaneous LE patients not responsive to conventional therapy. The clinical and immunologic parameters (C-reactive protein, immunoglobulin, and complement serum levels, lymphocyte counts) were investigated during thalidomide treatment for up to 2 years in both patient groups. RESULTS: An increase in the absolute peripheral lymphocyte count was observed beginning after 2 weeks of systemic thalidomide treatment in nine out of 10 LE patients, and remained stable throughout thalidomide treatment. Elevated serum levels of C-reactive protein and titers of autoantibodies to double-stranded (ds) DNA decreased in SLE patients. No significant changes were detected in the serum levels of the complement components C3 and C4 and immunoglobulins in all LE patients. Regression of inflammatory skin lesions and regrowth of hair were recorded. As a side-effect, polyneuropathy was observed in four out of 10 patients, with the earliest onset at 3 weeks of thalidomide treatment. CONCLUSIONS: Thalidomide is a potent anti-inflammatory drug in patients with SLE and cutaneous LE, possibly interacting with the recruitment of lymphocytes. It leads to the regrowth of hair in LE-related alopecia and effluvium. Early symptoms of polyneuropathy should be registered and the drug should be withdrawn. Thalidomide should be restricted to patients who show no response to standard therapeutic regimens and should only be used under strict precautions with regard to its known teratogenic risk.     

Therapy of cutaneous lupus erythematosus

ABSTRACT: Patients with cutaneous lesions of lupus erythematosus (LE) can generally be managed with standard therapies. The patient should have a firmly established diagnosis. Evaluation will allow the treating physician to assign a prognosis. Patients with discoid LE and subacute cutaneous LE are generally photosensitive and therefore sunscreens, protective clothing, and behavioral alteration should be discussed with all patients. Topical corticosteroids are a standard form of therapy, but "newer" agents such as retinoids, calcipotriene, and tacrolimus might be effective. Antimalarial agents are generally effective. Attempts to reduce or stop smoking may aid in the control of cutaneous LE (CLE). The choice of alternative therapy is personal and discussions of the risks and benefits should be carefully documented. Successful therapy for CLE is possible in almost all well-motivated, cooperative patients.     

Efficacy of topical tacrolimus 0.3% in clobetasol propionate 0.05% ointment in therapy-resistant cutaneous lupus erythematosus: a cohort study

Background.  Despite a range of available topical and systemic therapies, treatment of cutaneous lupus erythematosus (CLE) can be challenging.
Objectives.  To evaluate the efficacy of a specially formulated preparation of tacrolimus 0.3% in clobetasol propionate 0.05% ointment (TCPO) in the treatment of CLE.
Methods.  Case notes of 13 patients with treatment-resistant CLE (11 discoid LE, 1 systemic LE and 1 subacute cutaneous LE) who had used twice-daily TCPO (TCPO group) were reviewed. These were compared with five similar patients with resistant CLE who had been given 0.1% tacrolimus ointment alone (TO group).
Results.  In the TCPO group (mean treatment duration 20 months, range 1–72), a good or excellent response was seen in five and six patients, respectively; one patient showed slight improvement. Telangiectasia and acne were observed in two patients. No systemic side-effects were noted. In the TO group (mean treatment duration 6 months, range 1–24), one patient showed good improvement and two showed slight improvement.
Conclusion.  The results of our small retrospective study suggest that TCPO may be more effective than either 0.1% tacrolimus or clobetasol propionate 0.05% ointment monotherapy in the treatment of recalcitrant CLE. Randomized controlled trials are needed to confirm these preliminary findings.     

Cutaneous lupus erythematosus: diagnosis and management

Cutaneous lupus erythematosus (CLE) includes a variety of lupus erythematosus (LE)-specific skin lesions that are subdivided into three categories - chronic CLE (CCLE), subacute CLE (SCLE) and acute CLE (ACLE) - based on clinical morphology, average duration of skin lesions and routine histopathologic examination. This paper describes our personal experience in the management of CLE over the last 30 years, with details on preferential therapeutic options related to clinical, histologic and immunopathologic aspects of each clinical subset of the disease. Effective sunscreening and sun protection are considered the first rule in the management of CLE because of the high degree of photosensitivity of the disease. Antimalarial agents are crucial in the treatment of CLE and are the first-line systemic agents, particularly in discoid LE (DLE) and SCLE. Dapsone is the drug of choice for bullous systemic LE (BSLE) as well as for LE in small dermal vessels (e.g. leukocytoclastic vasculitis). Retinoids, known as second-line drugs for systemic therapy, are sometimes used to treat chronic forms of CLE and are particularly successful in treating hypertrophic LE. Systemic immunosuppressive agents are required to manage the underlying systemic LE disease activity in patients with ACLE. These drugs, especially azathioprine, methotrexate, cyclophosphamide and cyclosporine, together with corticosteroids, constitute third-line systemic therapy of CLE. In our experience, oral prednisone or parenteral 'pulsed' methylprednisolone are useful in exacerbations of disease activity. Thalidomide provides one of the most useful therapeutic alternatives for chronic refractory DLE, although its distribution is limited to a few countries because of the risk of teratogenicity and polyneuropathy. However, medical treatment with local corticosteroids remains the mainstay of CLE treatment, especially for DLE. Patient education regarding the disease is also important in the management of CLE, because it helps relieve undue anxiety and to recruit the patient as an active participant in the treatment regimen.     

Clinical aspects and differential diagnosis of cutaneous lupus erythematosus

On the basis of LE cases treated at the Department of Dermatology, Düsseldorf University, during the last few years, we present the various forms of cutaneous lupus erythematosus (CLE). 72% of the patients showed discoid lupus erythematosus (DLE), whereas disseminated discoid LE (DDLE) and lupus panniculitis were found in 3% each. Lupus erythematosus tumidus (LET), as well, must be regarded as exceptional. Subacute cutaneous LE (SCLE) and systemic LE (SLE) showed nearly similar frequency (10 and 12%, resp.). Bullous LE is also very rare and must be considered a variant of SLE. The various forms of cutaneous LE can be differentiated according to clinical presentation and histopathology. Direct immunofluorescence, in contrast, has but limited diagnostic value, except with lesions on the scalp. Exact classification of cutaneous LE is the more essential, as it implies considerable therapeutic and prognostic consequences for the patient.     

The expression of human leukocyte antigen-DR and CD25 on circulating T cells in cutaneous lupus erythematosus and correlation with disease activity

BACKGROUND: Lupus erythematosus (LE) is a chronic autoimmune disease with a broad clinical spectrum reaching from primarily cutaneous manifestations [cutaneous LE (CLE)] up to systemic disease [systemic LE (SLE)]. In patients with SLE, the expression of activation markers on circulating T cells reflects disease activity. Here, we investigated whether this also holds true for patients with CLE. PATIENTS AND METHODS: The expression of the activation markers human leukocyte antigen (HLA)-DR and CD25 on circulating T lymphocytes was measured by flow cytometry in 24 patients suffering from different types of active CLE. Simultaneously, the disease activity was assessed clinically using a CLE activity index. Eighteen healthy donors were analyzed for control purposes. RESULTS: HLA-DR was expressed on a significantly elevated percentage of both CD4+ and CD8+ circulating T cells in active CLE patients when compared with healthy controls. The percentage of HLA-DR-expressing T lymphocytes closely correlated with the disease activity. Interestingly, in disseminated scarring chronic discoid LE, a significantly increased percentage of CD25+ cells was observed only in the subset of skin-homing cutaneous lymphocyte antigen (CLA)+CD4+ and CD8+ T cells. CONCLUSION: Our results provide evidence that activation markers on peripheral blood T cells might help to objectively assess the disease activity in CLE. Furthermore, a significant population of CD25+CLA+CD8+ T cells can only be detected in a subgroup of patients with disseminated scarring CLE and might reflect the systemic expansion of activated cytotoxic T lymphocytes involved in destruction of epidermal tissue.     

The value of lymphocytopenia as a marker of systemic involvement in cutaneous lupus erythematosus

BACKGROUND: Some patients suffering from cutaneous lupus erythematosus (CLE) develop extracutaneous manifestations during the course of the disease: up to 5% of patients with discoid LE (DLE) and up to 30% of subacute cutaneous LE (SCLE) patients show systemic involvement. Recent studies revealed some markers indicating systemic manifestations of CLE patients. However, the significance of diminished peripheral lymphocyte numbers as a marker of systemic involvement in CLE has not been investigated before. OBJECTIVES: To determine the value of lymphocytopenia (< 1500 cells microL(-1)) as a marker of extracutaneous manifestations in CLE patients. : Methods The records of 72 CLE patients (44 DLE; 28 SCLE) were investigated. Systemic involvement was defined in accordance with the criteria of the European Academy of Dermatology and Venereology. Analyses of peripheral lymphocyte numbers were done by fluorescence-activated cell sorter analysis. RESULTS: Five CLE patients developed extracutaneous manifestations during the course of disease. All these patients were lymphocytopenic. Differences between peripheral lymphocyte numbers of CLE patients with and without additional systemic involvement were highly significant (P < 0.01). CONCLUSIONS: Our results suggest that lymphocytopenia in patients with CLE is a high sensitive but low specific marker of systemic involvement.     

Immunology of cutaneous lupus erythematosus

The cause and effect between ultraviolet light and cutaneous lupus erythematosus (CLE) is clear. In LE patients indeed, photosensitivity is one of the major diagnostic criteria of the systemic form of lupus erythematosus. This strong clinical association has led to the postulate that abnormal photosensitivity participates in the pathogenesis of cutaneous lesions in LE. What is not clear is how the ultraviolet radiation (UVR) induces cutaneous lesions in susceptible individuals despite the fact that profound effects of UVR on the cellular components of the skin have been extensively studied. The whole scenario is complicated by the relationship between sunlight and the cutaneous immune system. Pronounced effects of UVR on the cutaneous immune response further complicate the understanding of photosensitivity in LE. In addition, the network of cutaneous cytokines, chemokines, and adhesion molecules has become increasingly intricate, thus contributing to the genetic substrate of each individual, and to the tremendous complexity of the pathogenesis of CLE.     

Cutaneous lupus erythematosus: a review

This article will review and update information about the pathogenesis, clinical presentation, diagnosis, and treatment of cutaneous lupus erythematosus. Lupus erythematosus (LE) can present as a skin eruption, with or without systemic disease. Cutaneous LE is subdivided into chronic cutaneous LE, subacute cutaneous LE and acute LE. The prevalence of systemic lupus erythematosus (SLE) is 17-48/100,000 population worldwide. Skin disease is one of the most frequent clinical complaints of patients suffering from SLE. It has been found to occur in up to 70% of patients during the course of the disease. The most frequent mucocutaneous manifestations of SLE are malar rash (40%), alopecia (24%), and oral ulcers (19%). It has been suggested that risk factors that are more likely to signal transition of cutaneous into systemic LE are high ANA titers (> 1:320) and the presence of arthralgias. CLE patients who exhibit these symptoms should be monitored closely, since they may be at increased risk to develop SLE.     

Thalidomide in cutaneous lupus erythematosus

For nearly 50 years, thalidomide has struggled between success and controversy. After causing an epidemic of phocomelia and other birth defects during the 1960s, affecting thousands of neonates, thalidomide was used as a sedative in selective disorders including leprosy. The potent anti-inflammatory properties of thalidomide were serendipitously discovered while treating patients with erythema nodosum leprosum, and the drug is now approved by the US FDA for the treatment of this disease. Subsequently, the immunosuppressant effects of thalidomide, including the complex modulation of many cytokines, have been recognized. One promising application of thalidomide has been the treatment of cutaneous lupus erythematosus. Among the largest series reviewed, the drug has been found to ameliorate cutaneous lupus erythematosus in 90% of patients, on average. Remission is achieved in approximately 15-20% of patients with cutaneous lupus erythematosus at doses between 50-400 mg daily. Contraceptive concerns and the recognized neuropathic effects of thalidomide limit the use of the drug in patients with cutaneous lupus. Physicians who prescribe thalidomide in the US must be registered with the drug manufacturer. With appropriate control of drug access and close physician monitoring, thalidomide provides a needed therapeutic option for the treatment of refractory cases of cutaneous lupus erythematosus.     

Treatment of idiopathic prurigo nodularis in Taiwanese patients with low-dose thalidomide

Prurigo nodularis is an intensely pruritic dermatosis characterized by lichenified and excoriated papules and nodules. The course of prurigo nodularis is often chronic, and some patients respond very poorly to the standard therapeutic modalities. Because the pathogenesis of this disease remains obscure, the treatment of prurigo nodularis can be disappointing and frustrating for both the patients and physicians. Thalidomide, a tumor necrosis factor-alpha antagonist, has been suggested as an alternative treatment option for recalcitrant prurigo nodularis. In the past, the regimen for treatment of prurigo nodularis often required thalidomide at 200 mg/day. We recruited patients with intractable prurigo nodularis and treated them with low-dose thalidomide. Six patients with idiopathic prurigo nodularis were successfully treated with low-dose thalidomide (50-100 mg/day) without clinical development of peripheral neuropathy. In summary, our preliminary results suggest that low-dose thalidomide may be a safe and effective treatment option for patients with recalcitrant idiopathic prurigo nodularis.     

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.     

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.     

Histopathologic findings in lupus erythematosus tumidus: review of 80 patients

BACKGROUND: In a recent study, we demonstrated that lupus erythematosus (LE) tumidus (LET) is a distinct subset of cutaneous LE (CLE), which is clinically characterized by erythematous, urticaria-like, nonscarring plaques in sun-exposed areas. OBJECTIVE: Our purpose was to analyze skin biopsy specimens from 80 patients with this disease and to determine whether it could be differentiated from other variants of CLE on histopathologic grounds. METHODS: Skin biopsy specimens from 53 primary and 38 UVA- and/or UVB-induced lesions of 80 patients with LET were examined and compared with skin biopsy specimens from patients with discoid LE (DLE) and subacute CLE (SCLE). RESULTS: Specimens from LET lesions showed a characteristic and diagnostic pattern of perivascular and periadnexal cellular infiltrates in the papillary and reticular dermis composed almost entirely of lymphocytes. In some cases, few scattered neutrophils were present. Furthermore, interstitial mucin deposition was observed in all specimens, as confirmed by colloidal iron staining. In contrast to discoid LE and subacute CLE lesions, epidermal atrophy or alteration at the dermoepidermal junction was not detected. CONCLUSION: Skin lesions of patients with LET present with specific histopathologic features, and the differences compared with subacute CLE and discoid LE further support the concept to consider LET as a separate entity of CLE.