Immunoablative high-dose cyclophosphamide without stem cell rescue in a patient with pemphigus vulgaris

The use of ablative intravenous cyclophosphamide (50 mg/kg per day for 4 days) without stem cell rescue has been described in patients with refractory autoimmune diseases such as paraneoplastic pemphigus, systemic lupus erythematosus, and aplastic anemia. We describe a 33-year-old patient with pemphigus vulgaris recalcitrant to multiple therapies. The patient presented with numerous oral ulcerations, erosions, and hyperpigmented crusted plaques on his face, trunk, and arms. Findings of a skin biopsy and direct immunofluorescence were consistent with pemphigus vulgaris. The circulating pemphigus vulgaris autoantibodies were present at a titer of 1:640. The patient received immunoablative therapy (50 mg/kg of cyclophosphamide for a total of 4 days) and tolerated the regimen well. Complications such as thrombocytopenia and Pseudomonas septicemia were quickly treated. Four months after the 4-day therapy, his oral and skin lesions completely healed, and his pemphigus titers have decreased to zero. He is no longer receiving prednisone and no new lesions have developed. This provides further evidence that this regimen is relatively safe and provides a potential "cure" for refractory autoimmune diseases such as pemphigus vulgaris.     

Immunoablative high-dose cyclophosphamide without stem cell rescue in pemphigus foliaceus

BACKGROUND: There is growing evidence that immunoablative high-dose cyclophosphamide without stem cell rescue is effective and safe in patients with refractory autoimmune diseases such as paraneoplastic pemphigus, systemic lupus erythematosus, aplastic anemia, and more recently pemphigus vulgaris. METHODS: We report a 51-year-old patient with severe pemphigus foliaceus, which was recalcitrant to multiple medical regimes. The patient presented with multiple thick hyperpigmented and scaly, ill-defined plaques on the face. In addition, she had multiple superficial erosions and crusts on her scalp, thorax, upper and lower extremities. The patient also had a few discrete intact flaccid bullae. A skin biopsy and direct immunofluorescence was consistent with pemphigus foliaceus. The patient's circulating pemphigus autoantibodies were present at a titer of 1 : 2560. The patient received immunoablative high-dose cyclophosphamide (50 mg/kg/day) for 4 consecutive days, and tolerated the regime well. RESULTS: Approximately 3 months after therapy, the skin lesions had healed and her prednisone, which had been as high as 80 mg daily, was tapered to 30 mg daily. In addition, her circulating autoantibodies decreased after treatment. Nearly 10 months after treatment, the patient did relapse. However, her disease was less severe and more easily managed with lower doses of immunosuppressive therapy. CONCLUSION: This case contributes to the growing evidence of high-dose cyclophosphamide's efficacy without stem cell rescue in recalcitrant autoimmune diseases, including pemphigus foliaceus.     

Long-term efficacy of dexamethasone-cyclophosphamide pulse therapy in pemphigus

Background: Corticosteroids are used as a daily oral therapy or in a pulse form with or without various adjuvant drugs for the treatment of pemphigus. Our long-term experience with the use of dexamethasone-cyclophosphamide pulse therapy as a first-line treatment modality for pemphigus is presented. Methods: A retrospective analysis of records of pemphigus patients treated by dexamethasone-cyclophosphamide therapy was carried out. The treatment regimen consisted of the monthly administration of intravenous dexamethasone (136 mg) for 3 consecutive days with addition of intravenous cyclophosphamide (500 mg) on the second day. Oral cyclophosphamide (50 mg) daily and oral corticosteroids (low tapering doses) were given in the intervals between the pulses, till partial remission was achieved. Pulse therapy was then continued for another 6 months followed by daily oral cyclophosphamide (50 mg) for 1 year, which produced a complete remission. Results: A total of 36 patients, 32 with pemphigus vulgaris and 4 with pemphigus foliaceus, were treated with this regimen. Two to 8 pulses were required to achieve a partial remission, while the total number of pulses given for complete remission ranged from 8 to 32. The duration of pulse therapy correlated with both the disease severity and the time to achieve remission. All patients are now in complete remission with a follow-up of 0.5-12 years. Four patterns of remission were observed, related to the severity of disease. The response to pulse therapy was faster in the milder form of disease. The severe form of disease required more pulses as well as higher doses of intervening oral corticosteroids. Conclusions: Dexamethasone-cyclophosphamide pulse therapy is an effective form of treatment in pemphigus and results in long-lasting remissions.     

Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption

BACKGROUND: Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered. AIMS: The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus. METHODS: Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent. RESULTS: In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued. CONCLUSION: The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.     

CURATIVE EFFECT OF DEXAMETHASONE-CYCLOPHOSPHAMIDE PULSE THERAPY FOR THE TREATMENT OF PEMPHIGUS VULGARIS

In 1982, five patients having pemphigus vulgaris, four men and one woman, ranging in age between 16 and 48 years, were treated with an arbitrary regimen designed by us. The regimen consisted of giving 100 mg dexamethasone in 500 mL of 5% glucose by a slow intravenous infusion on three consecutive days, along with 500 mg cyclophosphamide on one day only. Such dexamethasone-cyclophosphamide pulses (DCP) were meant to be given once a month, but most patients were not regular in this treatment. In between these pulses the patients received only 50 mg cyclophosphamide orally per day. Oral corticosteroids were given only when necessary. After having received a total of 14 to 48 DCPS, further treatment for pemphigus was withdrawn. All the patients are in continuous clinical remission for the last 4 to 9 years and without any treatment for 2 to 7 years. Further studies on more pemphigus patients have yielded similar results suggesting that it may be possible to cure pemphigus.     

A body-weight-independent dosing regimen of cyclosporine microemulsion is effective in severe atopic dermatitis and improves the quality of life

BACKGROUND: Cyclosporine has shown to be effective in severe atopic dermatitis. Little has been reported on the new microemulsion form (Sandimmune, Neoral) in the treatment of this disease. Also, it has not been investigated whether a body-weight-independent dosing regimen of cyclosporine is appropriate for the treatment of atopic dermatitis. OBJECTIVE: The goal of this study was to investigate a body-weight-independent dosing regimen of cyclosporine microemulsion in severe atopic dermatitis by comparing high and low starting doses of treatment. METHODS: A total of 106 adults with severe atopic dermatitis were enrolled in this double-blind study and randomized to receive a starting dose of either 150 mg (low) or 300 mg (high) of cyclosporine microemulsion daily. After 2 weeks the dose could be reduced by 50% if the clinical symptom score was reduced by 50% or more. After 8 weeks the responders entered a 4-week follow-up phase and were randomized to either stop treatment or to continue on their last effective dose every second day. RESULTS: After 2 weeks of treatment the total symptom score decreased from 59.0 to 39.3 with 150 mg and from 60.7 to 33.2 with 300 mg cyclosporine (P <.05). Until week 8 there was a further decrease in the clinical symptom score to 30.8 with low-dose therapy and 25.5 with high-dose therapy. Similar positive effects could be observed in assessments of affected body surface area, itching, sleep loss, and quality of life. At week 2, there was an increase of 0.6% in serum creatinine in patients receiving 150 mg, and 5.8% in the 300 mg group (P <.01). At week 8, the effect on serum creatinine was similar, with a 1.1% rise in the low dose group and a 6.0% increase in the high dose group. Body weight had no influence on efficacy or tolerability in this study. CONCLUSION: Body-weight-independent dosing with cyclosporine seems to be feasible in the short-term treatment of severe atopic dermatitis. Although the starting dose of 300 mg/day is more effective than 150 mg/day, the 150 mg dose would be preferable for the initiation of therapy because of its excellent renal tolerability.     

95例住院天疱疮患者回顾性治疗分析

目的:对95例住院天疱疮患者的治疗情况进行回顾性分析。方法:95例患者分为3组,第1组采用糖皮质激素联合免疫抑制剂治疗;第2组在第1组基础上加用糖皮质激素冲击疗法;第3组在第1组基础上加用静脉滴注大剂量免疫球蛋白,分别评价近期疗效。结果:出院时第1组77例患者中68例(88.31%)皮损完全消退;第2组13例患者中10例(76.92%)皮损完全消退;第3组5例患者中4例(80.00%)皮损完全消退。结论:糖皮质激素联合免疫抑制剂是目前治疗天疱疮的主要方法,对部分常规剂量不能控制病情者加用糖皮质激素冲击疗法或静脉滴注大剂量免疫球蛋白可取得较好疗效。     

Synchronization of plasmapheresis and pulse cyclophosphamide therapy in pemphigus vulgaris

Long-lasting and complete remission was obtained in a 48-year-old patient with refractory pemphigus vulgaris by an experimental treatment protocol that tries to synchronize plasmapheresis with subsequent pulse cyclophosphamide therapy. The rationale of the approach tries to utilize the plasmapheresis-induced increased proliferation of pathogenic cell clones for partial deletion of these clones through application of maximum pulse immunosuppression treatment during the period of assumed maximum proliferation and, thus, maximum vulnerability of the antibody-producing cells. The treatment schedule consisted of initial withdrawal of immunosuppressive drug therapy, repeated large-volume plasmaphereses substituted with immunoglobulin-free albumin solutions, subsequent application of high-dose (36 mg/kg of body weight) cyclophosphamide therapy, and low-dose maintenance immunosuppression for several months. As a result, our patient remained disease free over a follow-up period of 40 months without any further immunosuppressive treatment. Stimulation of postexchange antibody production and subsequent application of high-dose cytotoxic drugs might be a valuable tool in the management of refractory pemphigus vulgaris and, possibly, in the management of other autoantibody-mediated diseases.     

塞来昔布胶囊治疗带状疱疹神经痛的临床观察

目的初步评价塞来昔布胶囊(商品名:西乐葆,生产厂家:辉瑞制药有限公司)治疗带状疱疹神经痛的有效性。方法按照随机、单盲、安慰剂平行对照的原则将96例患者分成大剂量组、小剂量组和安慰剂组,共3组。大剂量组给予西乐葆400mg;小剂量组给予西乐葆200mg;安慰剂组给予安慰剂(胶囊内装的是淀粉)治疗,分两次口服,同时所有患者给予阿昔洛韦500mg静滴,1次/d,连续两周。在治疗前、治疗后3天、1周、2周和3周时对三组患者的疼痛症状评分,分析并比较三组患者的疗效。结果三组间疗效比较,治疗前各组间疼痛无明显差异,治疗后大剂量组疼痛程度低于小剂量组,小剂量组疼痛程度低于安慰剂组(P0.05)。结论塞来昔布胶囊有助于带状疱疹神经痛治疗。     

Pemphigus in Kuwait

BACKGROUND: Although pemphigus is a well-characterized entity, detailed epidemiologic studies from the Arabian Peninsula are not available. The purpose of this study was to elucidate the clinical features, course, and prognosis of pemphigus patients followed at a national dermatology center in Kuwait. METHODS: Fifty-four patients with pemphigus in this report were treated between 1981 and 1996, and were studied for several clinical features, treatment, course and prognosis. RESULTS: Around 80% of pemphigus patients were Arabs, and Kuwaitis constituted the largest number (46.3%) with a female predominance (F: M = 2:1). Pemphigus vulgaris (PV) was the commonest clinical type. The mean age of onset was 36 years. The follow-up period ranged from 2 months to 12 years (mean, 4.5 years). The majority of the patients could be managed with low-dose steroids (30-60 mg/day). Twenty per cent of the patients were in complete clinical remission and were off systemic therapy for an average of 3 years. No death secondary to the disease or its treatment was observed. CONCLUSIONS: Kuwaiti patients with pemphigus were observed to have a relatively young age of onset and a female predominance. Low doses of steroids were enough to control the disease in the majority, and at least 20% of patients were off therapy and in complete remission on follow-up.     

Dexamethasone-Cyclophosphamide Pulse Therapy in Pemphigus

Fifty patients with pemphigus (45 pemphigus vulgaris, 5 pemphigus foliaceus) were treated with dexamethasone-cyclophosphamide pulse therapy. The pulse consisted of 136 mg dexamethasone dissolved in 5% dextrose given in a drip over a period of 1-2 hours on 3 consecutive days. In addition, 500 mg cyclophosphamide was added in the drip on the first day. Such pulses were given at monthly intervals. In between the pulses patients were given 50 mg cyclophosphamide orally each day. The results were encouraging, the chief advantage being freedom from side effects of corticosteroid therapy. The lesions healed in 3-4 days and the patients were able to resume their work within one week. Further scope of such therapy in pemphigus is discussed.     

Oral doxycycline for the treatment of chronic leg ulceration

This pilot study investigated oral doxycycline as an adjunct to compression therapy for non-healing venous leg ulcers. Ten patients received doxycycline 20 mg twice daily (low-dose doxycycline) and ten patients received doxycycline 100 mg twice daily (high-dose doxycycline). Utilising a pre-test post-test study design, ulcer area was measured and wound fluid was collected before and after 4 weeks of treatment. In the high-dose doxycycline group, the reduction in median ulcer area was 48% (p = 0.1) and there was a significant reduction in wound fluid total matrix metalloprotease-1 (p = 0.02). These effects were not observed with low-dose doxycycline. There were no significant changes in wound fluid tumour necrosis factor-α or quantitative bacteriology following treatment with low-dose or high-dose doxycycline. There was no significant relationship between change in ulcer area and matrix metalloprotease-1, -8 or -9 activities in wound fluid at the end of treatment. Median wound fluid doxycycline concentrations after 4 weeks of treatment were 0.2 mg/L(0.45 lM) and 2.3 mg/L (5.18 lM) [DOSAGE ERROR CORRECTED] in the low-dose and high-dose groups, respectively, which are lower than that previously shown to inhibit matrix metalloproteases and tumour necrosis factor-α. Our study suggests that doxycycline 100 mg twice daily may improve the healing rate of recalcitrant leg ulcers, however the mechanism remains unclear.     

Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate

The objective of this study was to compare the efficacy of a combination of allopurinol (AL) and low-dose meglumine antimoniate (MA) with standard-dose MA in cutaneous leishmaniasis caused by Leishmania major. An open, controlled study was performed. Seventy-two patients were randomly selected from volunteers with cutaneous leishmaniasis living in a hyperendemic area. Exclusion criteria included pregnancy, nursing vs. gestation, age less than 5 years, and duration of disease of more than 4 months. Each patient received MA (60 mg/kg/day) or AL (20 mg/kg/day) plus low-dose MA (30 mg/kg/day) for 20 days, and was followed up for 30 days after cessation of treatment. The study was completed as planned in 66 patients. Complete healing occurred in 74.2% of patients in the MA group and in 80.6% of patients in the MA + AL group. No difference was found between the two groups with respect to side-effects. The combination of AL and MA increases the anti-leishmanial effects of antimoniate. In this study, it was confirmed that low-dose MA plus AL is as effective as high-dose MA in the treatment of cutaneous leishmaniasis caused by L. major.     

Successful treatment of autoimmune bullous diseases with a combination therapy of ciclosporin and corticosteroid

Three patients with autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, were treated with a combination therapy of ciclosporin and corticosteroid. These patients responded to systemic low-dose prednisolone (or dexamethasone) and low-dose ciclosporin therapy; the result was prolonged complete remission. The addition of low-dose ciclosporin may produce enhanced clinical effects of steroid therapy without increasing any significant side effects.     

Severe pemphigus vulgaris: successful combination therapy of plasmapheresis followed by intravenous high-dose immunoglobulin to prevent rebound increase in pathogenic IgG

A case of severe pemphigus vulgaris (PV), which did not respond to pulse therapy with intravenous (IV) methylprednisolone (1,000 mg/day for 3 days), but was successfully treated with a combination of double-filtration plasmapheresis (DFPP), immediately followed by high-dose IVIg (20 g/day for 5 days), eventually leading to suppression of the rebound increase in pathogenic PV-IgG for 12 months, is reported. Weekly enzyme-linked immunosorbent assay for desmoglein (Dsg) 1 and Dsg3 demonstrates a distinct difference in the alteration curves of serum levels of pathogenic IgG (anti-Dsg1 and Dsg3 antibodies) after DFPP with and without high-dose IVIg. Our experience suggests that combination therapy of DFPP with high-dose IVIg is effective for pathogenic PV-IgG removal and prevention of feedback rebound increases in pathogenic PV-IgG, leading to a long-term amelioration of clinical blistering in the present case.     

Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma

OBJECTIVE: To evaluate the efficacy of pulsed high-dose corticosteroids combined with orally administered low-dose methotrexate therapy in patients with severe localized scleroderma (LS). DESIGN: A prospective, nonrandomized, open pilot study. SETTING: Dermatology department at a university hospital in Bochum, Germany.Patients Fifteen patients with histologically confirmed severe LS.Interventions Oral methotrexate (15 mg/wk) combined with pulsed intravenous methylprednisolone (1000 mg for 3 days monthly) for at least 6 months. MAIN OUTCOME MEASURES: Treatment outcome was evaluated by means of a clinical score, 20-MHz ultrasonography, and histopathologic analysis. Safety assessment included the monitoring of adverse effects and clinical laboratory parameters. RESULTS: One patient discontinued therapy. In most of the remaining 14 patients, significant elimination of all signs of active disease (inflammation) and remarkable softening of formerly affected sclerotic skin that resulted in a decrease of the mean +/- SD clinical score from 10.9 +/- 5.3 at the beginning to 5.5 +/- 2.5 at the end of therapy was observed (P < .001). Clinical improvement was confirmed by histologic and ultrasonographic assessments. No serious adverse effects were noted. CONCLUSIONS: These data suggest that pulsed high-dose corticosteroids combined with orally administered low-dose methotrexate therapy is beneficial and safe in the treatment of patients with LS. This treatment regimen should especially be considered for severe forms of LS in which conventional treatments have failed.     

The treatment of pemphigus vulgaris. Experience with 48 patients seen over an 11-year period

We present a retrospective analysis of 48 patients with pemphigus vulgaris (PV) who were seen between 1978 and 1988. They were divided into three treatment groups: 25 (group A) received 40100 mg of oral prednisone daily; eight (group B) received > 100 mg of prednisone daily; 15 (group C) received 40 mg of oral prednisone every other day and azathioprine lOOmg daily. A second immunosuppressive agent was subsequently added to the treatment regimen of three patients in group A and eight patients in group B. By 1989, 10% of the patients had been able to discontinue all therapy, and were in complete remission. Sixty-five per cent of patients were on maintenance therapy, but in clinical remission. Twenty-five per cent of the patients had died [eight in group A (31%) and four in group B (50%)] either as a consequence of the disease or its treatment. None of the patients in group C had died. Most of the deaths occurred during the first 2-3 months of therapy. Morbidity and mortality were related to the severity of the disease, to the maximum dose of prednisone required to induce remission, and to the presence of other diseases. Patients needing a total of 5 g or more of prednisone to induce a remission during the acute stage had a high mortality rate.     

Intravenous dexamethasone‐cyclophosphamide pulse therapy in comparison with oral methylprednisolone‐azathioprine therapy in patients with pemphigus: Results of a multicenter prospectively randomized study

Background: Pemphigus is a potentially life‐threatening autoimmune blistering skin disease usually treated with high‐dose corticosteroids in combination with immunosuppressive drugs. In a multicenter, prospectively randomized study we compared efficacy and side effects of a dexamethasone‐cyclophosphamide (D/C) pulse therapy with a methylprednisolone‐azathioprine (M/A) therapy in 22 patients with newly diagnosed pemphigus vulgaris and pemphigus foliaceus. Patients and methods: The 11 patients of the M/A group were treated with daily doses of methylprednisolone (initially 2 mg/kg body weight) and azathioprine (2 – 2,5 mg/kg body weight) which were subsequently tapered. D/C pulse therapy in 11 patients consisted of intravenous administration of 100 mg dexamethasone/d on 3 consecutive days along with cyclophosphamide (500 mg) on day one. Pulses were initially repeated every 2 – 4 weeks and then at increasing intervals. In between the pulses, oral cyclophosphamide (50 mg) was given daily for 6 months. Results: Within 24 months after treatment initiation, 5/11 patients of the D/C group had a remission (complete remissions after discontinuation of therapy in 3 patients) and 6/11 patients had a progression. In the M/A group, there were remissions in 9/11 patients (complete remissions after discontinuation of therapy in 3 patients) and progression in 1/11 patients. There were more relapses in M/A therapy after remission than in D/C therapy. Side effects were more common in the M/A group. These differences were not significant (p > 0,05). Conclusion: Because of the high number of progressions in patients treated with D/C therapy, we can not confirm the encouraging results of earlier reports about pulse D/C therapy. Nevertheless D/C therapy seemed to be better tolerated and, in case of primary efficacy, was associated with fewer recurrences than M/A therapy.     

大剂量氨溴索联合气管镜治疗高位截瘫患者肺部感染临床研究

目的观察大剂量氨溴索联合纤支镜在治疗高位截瘫患者合并肺部感染的临床效果。方法合并严重肺部感染的高位截瘫患者30例,随机分成3组：小剂量氨溴索组（氨溴索30mg,壶入3次／d）;大剂量氨溴索组（氨溴索300mg,壶入3次／d）;联合治疗组（氨溴索300mg,壶入3次,d）,联合纤支镜下吸痰治疗。比较各组患者治疗前以及治疗第3d,第7d的临床效果、体征、X线表现、血气分析及呼吸机使用时间等。结果大剂量组患者在临床效果、体征及X线表现好转程度明显优与小剂量组（均P〈0．05）,且感染控制及脱机时间均显示缩短。联合治疗组较大剂量组治疗效果更加明显。结论对高位截瘫合并肺部感染患者,应用大剂量氨溴索可以有效化痰,控制感染,减少控制感染时间,减少呼吸机辅助呼吸时间,联合纤支镜治疗效果更好。     

Therapy of pemphigus. Critical remarks based on 44 clinical cases

The results are evaluated of therapy administered between 1957 and 1983 to 44 patients with pemphigus (28 pemphigus vulgaris, 5 pemphigus vegetans, 11 pemphigus seborrhoicus). The mean initial steroid dosage was 87 mg prednisone equivalent per day. The 5-year survival rate was 83%. Fifteen patients who were additionally treated with azathioprine during the initial phases of the disease had a 5-year survival rate of 100%. However, after having the disease for 5 years 41% of all pemphigus patients have to be rehospitalized. This percentage is only 21% in the group requiring less than 100 mg prednisone per day initially. Mortality related to pemphigus or infection occurs significantly earlier than cardiovascular deaths. The prognosis for survival is relatively good, but the prognosis for recovery remains uncertain. Combined therapy with corticosteroids and azathioprine in the early stages of the disease resulted in a 5-year survival rate of 100%, and is therefore recommended. However, even this therapeutic modality does not change the uncertain prognosis regarding recovery.