Skin ulceration after leflunomide treatment in two patients with rheumatoid arthritis

Leflunomide is a disease‐modifying antirheumatic drug for the treatment of active rheumatoid arthritis and psoriatic arthritis. Skin ulcerations are not listed as a side effect for this drug, and there has been only one case report on leflunomide associated skin ulcerations. We report on two females, 59 and 63 years old respectively, who were treated with leflunomide for rheumatoid arthritis and subsequently developed severe skin ulcerations. After discontinuation of the drug the skin ulcerations healed complete even if very slowly.     

Erythema multiforme-like drug eruption with oral involvement after intake of leflunomide

Leflunomide is an antirheumatic agent of the type of a 'disease-modifying antirheumatic drug'. In rare cases, severe skin reactions up to the extreme expression of toxic epidermal necrolysis have been observed. A female patient with rheumatoid arthritis had been treated with systemic steroids and methotrexate for 2 years. Five weeks prior to admission to our hospital methotrexate was replaced by leflunomide. Three weeks after initiation of leflunomide therapy a progressive generalized erythema with blistering formation occurred accompanied by increase of body temperature, chills and erosive lesions on the lips and oral mucosa. The palmar and plantar surfaces revealed edema, erythema and pulpitis with epidermolysis. On histologic examination necrotic keratinocytes and epidermal spongiosis were observed. After administration of high-dose prednisolone and topical treatment the patient recovered within 14 days. This is one of the few cases of severe drug reaction after intake of leflunomide. Therefore, the indication of this relatively new drug should be considered carefully.     

Severe cutaneous adverse drug reaction to leflunomide: a report of five cases

Medications used to treat human ailments are known to cause cutaneous reactions which may vary in their severity. Leflunomide, an immunomodulating agent recently introduced to treat rheumatoid arthritis, is reported to cause severe cutaneous reactions. We are reporting five such cases. All our patients were started on leflunomide for rheumatoid arthritis, 4-6 weeks before the onset of cutaneous reaction and were admitted to the hospital with the common complaints of fever, skin rash and generalized weakness. All of them had characteristic pattern of events such as delayed onset of reaction, widespread and long lasting skin rash and internal organ involvement. These features suggest a possibility of drug hypersensitivity syndrome to leflunomide. Careful dosing and periodic monitoring of patients treated with leflunomide for possible adverse drug reaction is recommended.     

Successful treatment of a leg ulcer occurring in a rheumatoid arthritis patient under leflunomide therapy

Objective We report the case of a leg ulcer in a rheumatoid arthritis (RA) patient under treatment with leflunomide, discuss the influence of the drug on the aetiopathogenesis of the ulcer and describe its successful treatment. Case summary A 68‐year‐old woman with a 12‐year history of RA developed a leg ulcer after 4 months of leflunomide treatment. Other ulcerogenic factors were ruled out. There were some clinical hints for rheumatoid vasculitis. The ulcer was resistant to ambulant conservative phase adapted wound bed preparation and a split skin transplantation failed. After omission of leflunomide and washout procedure with cholestyramine a second split skin transplantation resulted in complete healing. Discussion Leflunomide inhibits the division of activated T cells and thus inhibits among others the production of proinflammatory cytokines and the adhesion of cells to the endothelium. These mechanisms may partly explain the possible influence of leflunomide on the perpetuation of the ulcer. Until now, occurrence of vasculitis and leg ulcers has been described in one case each for the novel immunomodulator leflunomide. No successful treatment of a leg ulcer under leflunomide has been described yet. Omission of leflunomide and a washout treatment in our case led to a complete healing. This may indicate a critical role of leflunomide in the maintenance of this slow healing ulcer. Conclusions An association between leflunomide intake, occurrence of leg ulcers in RA patients and delayed wound healing should be considered.     

Lichenoid drug reaction to leflunomide

INTRODUCTION: Leflunomide (Arava) is an immunomodulator, recently introduced for systemic treatment of rheumatoid arthritis. We report the first case of lichenoid drug reaction due to this drug. CASE REPORT: A sixty-four year-old woman received leflunomide for rheumatoid arthritis. Two months after initiation of treatment, pruritus and lichenoid papules appeared on her hands and subsequently on her arms and her trunk, with a few bullous lesions. A skin biopsy was evocative for the diagnosis of drug induced lichenoid eruption. The treatment was stopped, and a wash out with colestyramine and topical corticotherapy resulted in dramatic improvement. No relapse was observed. Two months later, patch-tests with leflunomide diluted to 30 p. 100 in white petrolatum were negative. DISCUSSION: Side effects of leflunomide are frequent, generally benign for the cutaneous features. In our case, the delay, clinical and histological aspect and improvement on withdrawal of the drug emphasize the imputability of leflunomide. Few cases have been reported with others immunomodulators.     

Leflunomide in subacute cutaneous lupus erythematosus - two sides of a coin

Background Subacute cutaneous lupus erythematosus (SCLE), a distinct clinical subset of lupus erythematosus, remains a therapeutic challenge, especially in cases resistant to topical and standard systemic therapy. Leflunomide, a novel antirheumatic drug, has shown efficacy in the treatment of systemic lupus erythematosus in pilot studies. Methods We report two patients with SCLE who demonstrated the spectrum of possible clinical responses to leflunomide therapy. Results One patient experienced a complete clinical remission of symptoms, whereas the other developed a massive skin reaction which was distinctly related to the commencement of leflunomide therapy. Conclusion To our knowledge, this is the first time that remission and deterioration of SCLE by leflunomide therapy have been described.     

Leflunomide improves psoriasis in patients with psoriatic arthritis: an in-depth analysis of data from the TOPAS study

BACKGROUND: Leflunomide has shown promise in the treatment of psoriasis. OBJECTIVE: To provide an in-depth analysis of the effect of leflunomide on psoriasis in patients with psoriatic arthritis (PsA). METHODS: 190 patients with plaque psoriasis (at least 3% skin involvement) and active PsA were randomized to double-blind treatment with leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks. RESULTS: As previously reported, leflunomide resulted in a significantly higher Psoriatic Arthritis Response Criteria response rate than placebo (58.9 vs. 29.7%; p < 0.0001). Significant differences in favor of leflunomide were also observed in the Psoriasis Area and Severity Index (PASI 50 in 30.4% of patients vs. 18.9% for placebo; p = 0.05), target lesion response (46.4 vs. 25.3%; p = 0.0048), combined skin and joint response (27.2 vs. 8.9%; p < 0.0001), Dermatology Life Quality Index (improvement of 1.9 points vs. 0.2; p = 0.0173) and certain SF-36 subdomains. Dermatological responses were observed at the earliest examination (4 weeks) and increased throughout the 24-week study. CONCLUSION: Once-daily oral leflunomide is an effective and convenient treatment for PsA and plaque psoriasis.     

来氟米特治疗BXSB狼疮鼠的实验研究

目的 探讨来氟米特是否可改善BXSB小鼠的免疫状况和肾脏损害,为临床治疗系统性红斑狼疮(SLE)提供实验依据。方法 3月龄雄性BXSB小鼠分为4组,治疗前后测定尿蛋白;治疗后检测血清尿素氮、肌酐、抗dsDNA抗体以及肾脏免疫复合物。结果 ①各组小鼠治疗前的尿蛋白差异无显著性(P>0.05);②治疗后,来氟米特组的尿蛋白、抗dsDNA抗体明显低于地塞米松组和生理盐水组(P<0.01),而且低于环磷酰胺组,但其组间差异无统计学意义(P>0.05);③来氟米特组的血清尿素氮、肌酐及肾脏免疫复合物均低于其他治疗组(P<0.05或P<0.01)。④与生理盐水组相比,来氟米特组小鼠的生存期明显延长(x²=4.56,P<0.05)。结论 来氟米特可显著改善BXSB小鼠的免疫状况和肾脏功能,能延缓BXSB狼疮鼠的疾病进程。     

Severe atopic dermatitis and leflunomide: first clinical experience and highlights of pertinent experimental data

Atopic dermatitis is a common chronically relapsing disease affecting about 10 percent of children and 3 percent of adults. Currently, no standard management exists for long-term treatment. Topical corticosteroids and recently calcineurin-inhibitors are effective in most patients. In severe cases, however, systemic agents have to be employed. Their use may be limited by unwanted effects or insufficient long-term efficiency. Leflunomide is an immunomodulating and disease-modifying antirheumatic drug with anti-inflammatory and immunosuppressive activity, exhibiting an extremely long in vivo half life. Because T cells and eosinophils play an important role in the pathophysiology of atopic dermatitis, and long-term treatment is often required, leflunomide seems to be ideally suited for treatment of severe atopic eczema. We present a case highlighting the application regimen of leflunomide, and discuss the pathophysiological mechanism of action in atopic dermatitis. Because treatment benefit differs between patients, we propose the design of a proof-of-principle study for leflunomide in atopic dermatitis encompassing an evaluation of predictive markers for successful application.     

Leflunomide as a novel treatment option in severe atopic dermatitis

BACKGROUND: Based on the increasing knowledge of T-cell-mediated pathogenesis in atopic dermatitis (AD), systemic immunosuppressive drugs are increasingly applied. The chronic, relapsing course of severe AD necessitates a drug, both efficacious and safe in long-term application. Leflunomide is a pyrimidine de novo synthesis-inhibiting immunosuppressant exhibiting an extremely long in vivo half life of its active metabolite. OBJECTIVES: To evaluate the efficacy of leflunomide in long-term treatment of AD. METHODS: As a proof of principle, we treated two patients with severe AD, recalcitrant to different systemic treatment modalities, for 20 months with leflunomide (loading dose 100 mg daily during 3 days; maintenance dose 20 mg daily). At regular visits physical examination, eczema area and severity index (EASI), visual analogue scale (VAS) for itching, and laboratory findings were assessed with according adjustment of the leflunomide dose. RESULTS: At the initiation of leflunomide therapy, both patients presented with almost erythrodermic AD (patient 1, EASI 40.0, VAS 10; patient 2, EASI 43.0, VAS 8). Partial remission was observed within 4 and 7 weeks, respectively, and maintained over 20 months (patient 1, median EASI 4.2, median VAS 2; patient 2, median EASI 8.4, median VAS 2) except for one episode of exacerbation in each case. In one patient, remission was stable even after cessation of drug dosing. Severe adverse events were not observed. CONCLUSIONS: Leflunomide was efficient in the long-term treatment of recalcitrant AD. Controlled studies will be necessary to evaluate the subset of severe AD patients benefiting most from this drug.     

Squamous syringometaplasia in lobular panniculitis and pyoderma gangrenosum

Squamous metaplasia of eccrine sweat glands has been most frequently described in chronic cutaneous ulcerations with associated epidermal hyperplasia. We found examples of the process in skin biopsy specimens from five patients: three had associated lobular panniculitis and two had lesions of pyoderma gangrenosum. The metaplasia was located in the mid-to-deep reticular dermis in all five patients and extended into the superficial subcutis in one. Immunohistochemical stains for CEA and S-100 protein were used to accentuate the relationship of the metaplastic islands with eccrine ducts. It is postulated that necrosis of a portion of the eccrine duct is the stimulus for this process.     

Scurvy presenting with ecchymotic purpura and hemorrhagic ulcers of the lower limbs

INTRODUCTION: The risk of vitamin C deficiency is underestimated in industrialized countries and is only disclosed in rare cases of severe scurvy. CASE REPORT: We report three cases of scurvy presenting with ecchymotic purpura and hemorrhagic ulcerations of the lower limbs. Vitamin C supplementation led to rapid improvement of the skin lesions. DISCUSSION: Clinical diagnosis of low-grade deficiency can be difficult. Biological diagnosis requires special care in sample taking and transport.     

Subacute cutaneous lupus erythematosus associated with leflunomide

A skin eruption consistent with subacute cutaneous lupus erythematosus (SCLE) occurred in a patient taking leflunomide for rheumatoid arthritis. The eruption resolved after discontinuation of the medication. Suppression of tumor necrosis factor (TNF)-effector mechanisms by leflunomide may have played a role in the pathogenesis of this disorder.     

Two sporadic cases of idiopathic multiple minute digitate hyperkeratosis

Multiple minute digitate hyperkeratosis (MMDH) is a skin disease of unknown aetiology characterized clinically by multiple minute asymptomatic keratotic lesions with spiky horny projections. The disorder has been classified into early (congenital) and late (acquired) onset forms, the latter occurring as a presenting sign of concomitant inflammatory, metabolic or malignant disease. Here we report two cases of late onset MMDH without any associated pathology. These cases emphasize that some cases of late-onset MMDH may be idiopathic.     

Idiopathic facial aseptic granuloma: a multicentre prospective study of 30 cases

BACKGROUND: Idiopathic facial aseptic granuloma (IFAG) was recently described in a single-centre retrospective study as a skin condition that occurs specifically in childhood. OBJECTIVES: To improve our epidemiological, clinical and pathological knowledge on IFAG, to search for an infectious aetiology, and to assess therapeutic recommendations. METHODS: Children presenting with one or several acquired nodules on the face, lasting for at least 1 month, with no evidence of any other recognizable clinical entity such as infantile acne, pilomatrixoma, furuncle, tumour or vascular malformation, were enrolled in a prospective multicentre study from June 2001 to June 2004, involving the main French paediatric dermatology outpatient units. We recorded clinical details about the nodule and its duration, ultrasound study pattern, cultures for bacteria and mycobacteria, and Bartonella henselae and Afipia felis antibody testing. RESULTS: Thirty children (17 boys and 13 girls, mean age 3.8 years) were enrolled. Ultrasound studies revealed a solid well-demarcated hypoechoic lesion without calcium deposit. Cultures for bacteria were negative in 70% of cases. Cultures for mycobacteria and cat scratch disease serologies were negative. Antibiotic therapy was ineffective; the lesion healed spontaneously with a mean duration of 11 months. Histological examination, performed in five cases, showed a chronic dermal lymphohistiocytic granuloma with numerous foreign body-type giant cells. CONCLUSIONS: IFAG is characterized by a painless facial nodule, presenting as a single lesion localized on the cheek, with a prolonged course but spontaneous healing. Oral or local antibiotics are usually ineffective. Regarding the pathophysiology, our study rules out a primary infectious disease, and allows considering IFAG either as a granulomatous process appearing around an embryological residue or as a manifestation to include in the spectrum of granulomatous rosacea in childhood.     

TWEAK/Fn14信号在皮肤病诊断与治疗中的作用

肿瘤坏死因子样细胞弱凋亡因子(TWEAK)属于肿瘤坏死因子配体超家族成员,通过激活其受体成纤维细胞生长诱导因子14(Fn14)而发挥多种生物学功能。TWEAK/Fn14信号的激活可以调控细胞增殖、分化过程,促进纤维增生反应、血管形成和炎症反应,参与红斑狼疮、银屑病、皮肤肿瘤等疾病的发病过程。TWEAK在某些皮肤病患者的血清及尿液中表达上调,有潜力成为早期诊断及活动度评估的生物学标志物。适度激活TWEAK/Fn14信号可促进皮肤创伤愈合,但过强或延长激活该信号则会导致各种病理性组织损害,故激活或阻断该信号的特定环节有望成为治疗皮肤病的新策略。本文综述了TWEAK/Fn14信号在皮肤病发病机制中的作用,探讨该信号在相关诊断与治疗中的潜在价值。     

Ano-recto-vaginal ulcerations caused by suppositories containing dextropropoxyphene

A patient developed ulcerations of anus, rectum and vagina after prolonged use of suppositories containing dextropropoxyphene. Twelve identical cases have been reported in French literature. The mechanism of these ulcerations and the skin and mucosal disorders due to the principal morphinomimetic drugs opiates are briefly discussed.     

Type I leucocyte adhesion deficiency in Yemenian family managed with appropriate treatment: A case series

Primary immunodeficiencies are rare, inherited diseases, characterized by altered function or absence of immune cells. Among them is leukocyte adhesion deficiency Type I (LAD‐I), an autosomal recessive disorder characterized by primary immunodeficiency, caused by mutations in the ITGB2 gene which produces inability of leucocytes to migrate toward the area of inflammation and is associated with recurrent life‐threatening bacterial and fungal infections. Pyoderma gangrenosum (PG) is an uncommon noninfectious neutrophilic dermatosis, characterized by recurrent, necrotic ulcers. It is a diagnosis of exclusion and can be challenging and its management is empirical, with local (topical tacrolimus or intralesional triamcinolone) or systemic immunosuppressive therapy (oral or intravenous glucocorticoids, sulfasalazine, especially in cases associated with Crohn's disease, cyclosporine and, recently, anti‐tumor necrosis factor drugs such as Infliximab, Etanercept, and Adalimumab). Though skin ulcerations are common, predominant clinical presentation as PG can often mimic other diseases. It is unusual in children even more in LAD‐I. Here, we present a Yemenian family with LAD‐I from consanguineous relatives. All patients had history of chronic recurrent skin ulcerations without any bleeding tendency, associated with persistent neutrophilia and requiring steroids and antibiotics. There was no history of delayed cord separation and the condition was initially diagnosed as epidermolysis bullosa, but successively as PG. LAD‐I should be kept in mind while evaluating patients with PG especially in children with persistent neutrophilia in the absence of other rheumatological disorders. Its diagnosis is extremely important from the management perspective, as treating these patients without adequate antibiotic cover may be fatal, as happened to one of our patient, and these patients often require hematopoietic stem cell transplantation for permanent cure. Therefore, genetic counseling especially in population with high consanguinity is mandatory.     

Basal cell carcinoma of the scrotum. Report of three cases and review of the literature.

BACKGROUND: Although basal cell carcinoma (BCC) is the most common human malignancy, only 21 cases involving the scrotum have been previously reported. OBJECTIVE: Our purpose is to describe three additional cases of scrotal BCC and review the literature summarizing the clinical features and identifying any predisposing factors. METHODS: We retrospectively reviewed 21 cases of scrotal BCC and described three new cases. Polymerase chain reaction (PCR) was used to detect human papillomavirus (HPV) DNA in our biopsy specimens. RESULTS: Scrotal BCCs present as persistent ulcerations or plaques without identifiable predisposing factors. Lymphatic, pulmonary, or skin metastases were present in 3 of 24 cases (13%) resulting in death in one case. PCR did not detect HPV DNA in our three cases. CONCLUSION: Scrotal BCC rarely occurs and should be considered in the diagnosis of a persistent scrotal ulcer or plaque. Metastatic disease may be more common than with other BCCs and wide local excision or Mohs micrographic surgery may be the most appropriate initial therapeutic approach.     

The vascular lesions associated with skin necrosis in renal disease

Three renal allograft recipients and one uraemic patient presented with skin necrosis. In all cases, the subcutaneous arteries and arterioles were narrowed or occluded by mural calcification with or without intimal fibrosis. A review of the literature shows that uraemic patients or allograft recipients with skin necrosis involving the trunk or thighs have a poor prognosis while recovery is common in patients with more peripheral lesions. The aetiology of the arterial lesions is unknown. Their relationship to renal disorders and/or hyperparathyroidism is uncertain and therapy remains unsatisfactory.