Evidence based Dermatology - part 10 ppt

with methotrexate, 10 mg/week, for 30 months. Of the four patients with skin lesions, three had at least 60% regression, and one had complete regression of lesions with methotrexate. Gedalia et al . 44 presented the results of methotrexate, 10–15 mg/week, in seven paediatric patients with sarcoidosis. Of the three patients with cutaneous lesions, two had resolution of their skin findings with methotrexate. Mean dose of prednisone for all study participants was tapered from an average of 49 mg/day to 7·3 mg/day at 6 months. 44 Lacher 45 published the first case report of methotrexate for cutaneous sarcoidosis, describing a patient in whom prednisone failed, but who responded to a combination of prednisone, 75 mg three times weekly, and methotrexate, 40 mg twice weekly. The dose of prednisone was eventually tapered and the patient maintained on methotrexate, 7·5 mg twice weekly. Webster et al. 46 presented case reports on three patients who had improvement of their severe steroid-resistant cutaneous sarcoidosis with methotrexate, 15–22·5 mg/week. Henderson et al . 47 presented a case report of a man with steroid- resistant laryngeal and cutaneous sarcoidosis who responded to methotrexate, 10 mg/week. Harms Complications of methotrexate therapy include bone marrow suppression, nausea and vomiting, hepatotoxicity, and hypersensitivity pneumonitis. 28 Albertini et al . 48 described a patient with severe systemic and ulcerative sarcoidosis who was started on methotrexate, 25 mg per week. Although her ulcerative lesions initially regressed, she soon developed anaemia, leucopenia and elevated aspartate transaminase level, necessitating the withdrawal of methotrexate. The patient subsequently died of her disease. Major toxic effects noted by Lower et al . were hepatotoxicity, leucopenia and cough. 42 Comment/implications for clinical practice Articles written to date describe experience with a total of 46 patients with cutaneous sarcoidosis treated with methotrexate, of whom 39 had positive results. While none of these articles represents a large RCT, and there is very little consistency across trials in terms of patient population, dosage or clinical endpoints, these studies suggest that methotrexate might be useful as a steroid-sparing agent in people requiring or not responding to other therapies. Thalidomide Thalidomide is an inhibitor of tumour necrosis factor (TNF)-alpha. It was originally marketed as a sedative, but was withdrawn in 1962 because of its teratogenic effects. 49 It has recently been found to be effective at low doses in the treatment of inflammatory diseases such as lupus erythematous and erythema nodosum leprosum. 50 Benefits No systematic reviews or RCTs of the role of thalidomide in the treatment of cutaneous sarcoidosis were found. One retrospective study was identified by Estines et al . 51 on data collected on 10 patients with severe disfiguring lesions treated with thalidomide, 1·84 mg/kg, who were resistant to conventional therapy. Outcomes measured were: complete regression (total disappearance); incomplete regression (remaining signs) and treatment failure (no change, or worsening). Three of the study participants had complete regression, four had incomplete regression, and treatment failed in three. The thalidomide dose was gradually reduced for five of the seven patients for whom thalidomide was effective; three of the five patients relapsed, but the drug was efficacious at re-introduction at the same dose. Three case reports of patients successfully treated with thalidomide for lesions resistant to other forms of therapy were found. 49,50,52 Carlisimo et al . 49 report on a 56-year-old woman 664 Evidence-based Dermatology with cutaneous sarcoid unresponsive to steroids who had clinical improvement after taking thalidomide, 200 mg/day for 2 weeks followed by 100 mg/day for 11 weeks. Rousseau et al . 50 report on a 30-year-old woman resistant to intralesional steroids, hydroxychloroquine, isotretinoin and isoniazid; she improved with thalidomide, 100 mg/day for 2 months, gradually tapered to a maintenance dose of 50 mg/day. Lee et al . 52 report on a 59-year-old patient who had clinical improvement of all lesions after taking thalidomide 200mg/day for 2 months and 300 mg/day for 4 months. Harms Thalidomide therapy can be complicated by neurosensory, gastrointestinal and teratogenic effects. 49,52 Neuropathy is a common and dangerous side-effect of thalidomide use, and was noted in two out of 10 patients in the study by Estines et al . 51 and in the patient discussed in the case report by Lee et al . 52 Comment/implications for clinical practice Articles written to date describe experience with a total of 13 patients treated with thalidomide, 10 of whom had positive results. This is insufficient evidence to conclude that thalidomide is beneficial for treatment of cutaneous sarcoidosis, particularly because sarcoidosis often resolves spontaneously. Large randomised placebo-controlled trials will therefore be necessary for definitive proof. Tetracyclines Tetracyclines are antibiotics that have been found to inhibit T-cell proliferation and granuloma formation in vitro , which is the rationale for their use in cutaneous sarcoidosis. 53 Benefits No systematic reviews or RCTs were found. One non-randomised non-controlled open prospective study of 12 patients treated with minocycline, 200 mg/day, for 12 months was found. 53 Notably, antimalarial therapy had failed in most patients prior to entering the study. Eight of the study participants had complete regression of their lesions, two had partial regression and treatment failed in two (one progressed and one remained stable). After withdrawal of therapy, three out of the 10 responders relapsed. Harms Side-effects of minocycline include nausea and vomiting, hypersensitivity reactions, blue skin pigmentation and vertigo. 53 Hypersensitivity was noted in one patient in this study. 53 Comment/implications for clinical practice Articles written to date describe experience with a total of 12 patients treated with tetracyclines, 10 of whom had positive results. This is insufficient evidence to conclude that tetracyclines are beneficial for treatment of cutaneous sarcoidosis, particularly because cutaneous sarcoidosis often resolves spontaneously. Therefore large randomised placebo-controlled trials will be necessary for definitive proof. Allopurinol Allopurinol is a xanthine oxidase inhibitor used in the treatment of gout and some inflammatory diseases. Its anti-inflammatory capabilities are the basis for its use in cutaneous sarcoidosis. Benefits No systematic reviews or RCTs describing the use of allopurinol for treatment of cutaneous sarcoidosis were found. One non-randomised non-controlled open prospective study of six patients with cutaneous sarcoidosis reported treatment with allopurinol, 100 mg/day, 665 Cutaneous manifestations of sarcoidosis increased by 100 mg every 2–4 weeks to 600 mg/day. Four of the six patients in the initial report had improvement of their lesions. 54 Additional information was found in several case reports. Pfau et al . 55 treated two patients with scar sarcoidosis and two patients with nodular sarcoidosis with allopurinol 300 mg/day over a 3–7-month period. Lesions completely resolved in the patients with scar sarcoidosis and partially resolved in the patients with nodular sarcoidosis. Rosof et al . 56 observed remission of cutaneous sarcoidosis in two patients treated with allopurinol. Pollock 57 reported on two patients with cutaneous sarcoidosis; one treated with allopurinol, 100 mg/day, and the other with 300 mg/day; both patients experienced marked improvement in their lesions. Brechtel et al . 58 reported on a patient who had disseminated cutaneous sarcoidosis refractory to chloroquine treatment that responded to allopurinol, 300 mg/day. Voelter-Mahlknect et al . 59 observed a patient with subcutaneous sarcoidosis who was treated with allopurinol, 200 mg/day (later increased to 600 mg/day). Allopurinol failed, and the patient’s lesions actually progressed. Antony et al . 60 reported on a case of cutaneous acral sarcoidosis unresponsive to other therapies that responded to allopurinol, 300 mg/day. Harms Allopurinol therapy can be associated with drug rash (severe as toxic epidermal necrosis) as well as nausea and vomiting, hepatotoxicity and bone marrow suppression. 57 No significant side- effects were noted in the patients reported. Comment/implications for clinical practice Articles written to date describe experience with a total of 18 patients treated with allopurinol, 15 of whom had positive results. This is insufficient evidence to conclude that allopurinol is beneficial for treatment of cutaneous sarcoidosis, particularly because cutaneous sarcoidosis often resolves spontaneously. Large randomised placebo-controlled therapeutic trials will be necessary for definitive proof. Isotretinoin Isotretinoin, a retinoid that inhibits sebaceous gland function and keratinisation, is useful for treatment of many dermatological conditions, and is proposed as a treatment for cutaneous sarcoidosis because of its immunomodulatory effects. 61 Benefits No systematic reviews or RCTs describing use of isotretinoin for treatment of cutaneous sarcoidosis were found. However, four cases of isotretinoin use in cutaneous sarcoidosis were identified. Georgiou et al . 61 described a 31-year-old woman with a 3-year history of cutaneous sarcoid unresponsive to intralesional steroids, oral steroids and hydroxychloroquine. She experienced complete resolution of her skin lesions after 8 months’ treatment with oral isotretinoin, 1 mg/kg/day. Waldinger et al . 62 described a woman with severe disfiguring lesions of 4 years duration in whom treatment with oral prednisone and allopurinol had failed. She was treated with isotretinoin for 30 weeks (initially 40 mg/day for 6 weeks, increased to 80 mg/day for 16 weeks, decreased back to 40 mg/day for the last 8 weeks because of side-effects), and had resolution or improvement of many of her lesions. Spiteri et al . 63 reported a case of a woman with chronic sarcoidosis treated with isotretinoin, 75 mg/day (decreased to 50 mg/day because of cheilitis) who had little resolution of her sarcoid nodules, and was withdrawn from the drug after 7 weeks because of the development of a severe exfoliative dermatitis. Vaillant et al . 64 report on a woman with cutaneous sarcoid unresponsive to steroids, allopurinol, and antimalarials. She had improvement of her lesions after 6 months’ 666 Evidence-based Dermatology treatment with oral isotretinoin, 0·4–1·0 mg/kg/ day. Harms Isotretinoin is a teratogenic drug and must not be used by woman who are pregnant or who become pregnant while undergoing treatment. Other side-effects include depression, vision impairment, hepatic dysfunction and pancreatitis. Side-effects noted by study participants included myalgia, xerosis, dryness of nasal mucosa, cheilitis and exfoliative dermatitis. 61,62,64 Comment/implications for clinical practice Articles written to date describe experience with four patients treated with isotretinoin, three of whom had a positive result. This is insufficient evidence to conclude that isotretinoin is beneficial for treatment of cutaneous sarcoidosis, particularly because cutaneous sarcoidosis often spontaneously resolves and because isotretinoin is associated with severe side-effects. Large randomised placebo- controlled trials will be necessary for definitive proof. Conclusions After reviewing the available data on the oral therapy of cutaneous sarcoidosis, there is sparse evidence-based medicine. There is a desperate need for RCTs in this cutaneous disorder. Although oral steroids have been “grandfathered in” as the first-line treatment on the basis of many clinicians’ personal experience on sarcoidosis, it has not been proven in clinical trials for cutaneous sarcoidosis. The available reported evidence-based data suggest that chloroquine or hydroxychloroquine are the most effective agents available for the treatment of cutaneous sarcoidosis. Additional agents, in order of available evidence and side- effects, would include: methotrexate, allopurinol, minocycline, isotretinoin and thalidomide. Several other drugs have been reported in isolated case reports (1–3 patients) as successful; these include tranilast, 65 melatonin, 66 clofazimine, 67 mepacrine 68 and infliximab. 69 Levamisole was studied in 16 patients with cutaneous sarcoid and was found to be effective in only two of the 13 patients completing the course of treatment. It was concluded not to be useful in the treatment of cutaneous sarcoidosis. 70 What are the effects of non-oral therapeutic interventions in patients with cutaneous sarcoidosis? Flashlamp pulsed dye laser therapy Flashlamp pulsed dye laser therapy has been successful in the treatment of portwine stains and telangiectasias, where it works by selective ablation of the affected dilated and inflamed vessels. 71 It is postulated to work by a similar mechanism in lupus pernio, a disfiguring cutaneous manifestation of sarcoidodis. Benefits There are no systematic reviews or RCTs of the role of flashlamp pulsed dye laser therapy in the treatment of cutaneous sarcoidosis. Four case reports were found. Goodman 71 reported a woman with a 5-year history of lupus pernio of the nose who responded to laser therapy at an energy level of 7–8 J/cm 2 . The improvement induced by the laser was temporary: the erythema and papules returned 7 months after the first treatment, and 6–15 months after the second treatment, but both times responded again to laser therapy. She received three sessions altogether, and no side-effects of therapy (such as atrophy, scarring or hypopigmentation) were noted in any session. 667 Cutaneous manifestations of sarcoidosis Cliff et al . 72 described a patient with lupus pernio of the nose, who improved following six treatment sessions at 6-week intervals with flashlamp pulsed dye laser at a setting of 5·6–7·3 J/cm 2 . A biopsy of her nose after treatment noted the continued presence of non- caseating sarcoid granulomas, leading the authors to conclude that laser therapy was effective in improving the appearance of the lesions, but not the underlying disease process. Dosik et al . 73 report on a woman with a 3-year history of topical and intralesional steroid- resistant lupus pernio who responded successfully to flashlamp pulsed dye laser at an energy of 7·25 J/cm 2 . The therapy was given for nine sessions at 1–2-month intervals. Harms Goodman, Cliff et al . and Dosik et al . did not report any side-effects of laser therapy in their patients. In contrast, Green et al . 74 report on a 62-year-old black woman who was treated for lupus pernio with flashlamp-pumped pulsed dye laser (6·0–7·1 J/cm 2 ) and developed worsening of her cutaneous sarcoidosis. Ulcerative lesions appeared in both the treated and untreated plaques within 3 weeks of receiving laser treatment. Because of the inherent risk of eye damage from laser therapy, protective eyewear should be employed. Comment/implications for clinical practice Articles written to date describe experience with four patients with treatment-resistant chronic lupus pernio treated with flashlamp pulsed dye laser therapy, three of whom had a positive result). This is insufficient evidence to conclude that this therapy is beneficial for treatment of cutaneous sarcoidosis. Randomised placebo- controlled therapeutic trials will be necessary for definitive proof. Plastic surgery Benefits There are no systematic reviews or RCTs of the role of plastic surgery in the treatment of cutaneous sarcoidosis; however, several case reports were found. In 1970, O’Brien described two patients successfully treated with plastic surgery for lupus pernio. 75 In 1984, Shaw et al . 76 described a man with a 6-year history of treatment-resistant lupus pernio successfully treated with surgical excision and split skin grafting; the result remained good 2·5 years after surgery. Collison et al . 77 described a man with extensive ulcerative nodules of the lower extremities, which were resistant to topical/intralesional steroids, oral steroids, hydroxychloroquine and methotrexate. He was treated with vigorous operative debridement and partial-thickness skin grafting. While the grafts were well accepted (80%), the patient developed new ulcerating nodules in previously uninvolved skin 2 months after surgery. Stack et al . 78 report on a black male with extensive facial lesions who was treated with CO 2 laser excision, followed by steroid injection. The wounds healed well, and the patient had no recurrence of lesions 2 years after surgery. Streit et al . 79 report the case of a woman with widespread ulcerative cutaneous sarcoidosis treated with Apligraf (graftskin), a bilayered human skin equivalent, with good results. Harms No complications were noted in the above studies. However, inherent risks of general anaesthesia and the operation (bleeding, scarring, postoperative infection) should be considered. Comment/implications for clinical practice Articles written to date describe experience with six patients with treatment-resistant chronic lupus pernio treated with plastic surgery, all of 668 Evidence-based Dermatology whom had a positive result. This is insufficient evidence to conclude that this therapy is beneficial for treatment of cutaneous sarcoidosis. Topical corticosteroids and intralesional injections While topical corticosteroids and intralesional injections are often recommended as first-line treatment for the cutaneous manifestations of sarcoidosis, 12,14,15,30 little evidence is presented regarding their efficacy for this indication. Khatri et al. 80 describe a case of lupus pernio which improved with topical 0·05% halobetasol propionate twice daily for 10 weeks. Volden et al . 81 describe three cases of cutaneous sarcoidosis that went into remission within 3–5 weeks of treatment with once-weekly clobetasol propionate covered with hydrocolloid dressing. The use of intralesional hydrocortisone and cortisone were reported in 1953 by Sullivan et al . .82 Eighteen skin lesions in five patients with cutaneous sarcoidosis were injected with 2·5 mg doses of hydrocortisone. All lesions developed evidence of regression by 14 days after the injection, with no evidence of recurrence 14 weeks later. Seven skin lesions in four patients were injected with 2·5 mg cortisone. All lesions improved but not to the same extent as was noted with intralesional hydrocortisone. Liedtka reported on a sarcoid patient who had cutaneous lesions affecting the face, back and upper extremities that responded to multiple injections of chloroquine hydrochloride, 50 mg/ml. 83 Harms No major side-effects were reported in any of the study participants. Post-inflammatory hypopigmentation and hyperpigmentation were noted after the intralesional hydrocortisone injections in the review of Sullivan et al . 82 Minimal bleeding from the needle puncture, and cutaneous atrophy from the steroids are inherent risks to intralesional steroid injections. 84 Comment/implications for clinical practice Articles written to date describe a limited number of patients (n = 15) with cutaneous sarcoidosis treated with intralesional injections or topical steroids. This is insufficient evidence to conclude that this therapy is beneficial for treatment of cutaneous sarcoidosis. Conclusions The evidence-based data on non-oral therapies for cutaneous sarcoidosis are extremely sparse. There are no RCTs published proving that intralesional or topical steroids are effective in the treatment of cutaneous sarcoidosis. Intralesional and topical steroids, as with oral steroids, have been accepted as first-line therapies on the basis of clinicians’ experience, with no definitive dosage or duration of therapy identified. The physical modalities of laser and plastic surgery have been reported as successful in isolated treatment-resistant cases, but larger studies are lacking. Phototherapy (PUVA and UVA1) 85,86 and phonophoresis 87 are other modalities reported in isolated case reports to be beneficial. Key points • There are no randomised, controlled trials of any therapy for the treatment of cutaneous sarcoidosis. • Having reviewed the literature on oral therapies for cutaneous sarcoidosis, only antimalarials and methotrexate have been shown to be of benefit. • Having reviewed the literature on non-oral therapies for cutaneous sarcoidosis, no therapy can be recommended at this time. 669 Cutaneous manifestations of sarcoidosis References 1. English JC, Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol 2001; 44 :725–43. 2. Mana J, Salazar A, Manresa F. Clinical factors predicting persistence of activity in sarcoidosis: a multivariate analysis of 193 cases. Respiration 1994; 61 :219–25. 3. Mana J, Marcoval J, Graells J, Salazaar A, Pyri J, Pujol R. Cutaneous involvement in sarcoidosis: relationship to systemic disease. Arch Dermatol 1997; 133 :882–8. 4. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336 :1224–34. 5. Edmonstone WM, Wilson AG. 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J Am Acad Dermatol 1999; 40 :797–9. 672 Evidence-based Dermatology Background Definition Erythema multiforme (EM) is an acute, self- limited, feverish eruption characterised by target cutaneous lesions, with a symmetric and mainly acral distribution. Lesions are rounded, with three zones: a central area of dusky erythema or purpura, sometimes bullous, a middle paler zone of oedema and an outer ring of erythema with a well-defined edge. Hands and feet are habitually the most affected areas and are sometimes selectively involved. Mucous membrane erosions are frequent and distinguish EM major from EM minor. Histopathological examination shows a predominantly inflammatory pattern characterised by a lichenoid infiltrate and limited epidermal necrosis that affects mainly the basal layer. Incidence/prevalence Unknown. Aetiology/risk factors The principal cause is infection with herpes simplex virus (HSV), which probably explains 40–70% of all cases. Many other infections can induce occasional cases. According to recent classification, EM-like drug eruptions are related to Stevens–Johnson syndrome (SJS), the clinical signs being quite similar. Prognosis EM has low morbidity and no mortality. A spontaneous resolution occurs in 1–6 weeks. 50 Erythema multiforme Pierre Dominique Ghislain and J Claude Roujeau 673 Figure 50.1 Acral lesions (palm) Figure 50.2 Typical targets with central blisters [...]... treatment was safe and was associated with a more rapid re-epithelialisation N-acetylcysteine (NAC) NAC increases the clearance of several drugs and their metabolites and in vitro inhibits production of tumour necrosis factor (TNF )- and interleukin-1β We found no evidence of clinical effectiveness in TEN 681 Evidence- based Dermatology Benefits We found no evidence concerning SJS or TEN Harms High doses of... epidermal sheets reduced healing time of partial-thickness burns by 44%.35 A living skin equivalent, Apligraf, was applied over meshed split-thickness autografts in 38 patients while a control site in each patient was treated with split-thickness autograft alone 683 Evidence- based Dermatology There was no difference in the per cent and delay of graft take, but Apligraf-treated sites were rated superior to... solution in 10 patients Sweat production was reduced from 201 mg /10 minutes to 44 mg /10 minutes (22% of baseline value) Brandrup et al.8 reported on 23 women with axillary hyperhidrosis treated with 25% aluminium chloride hexahydrate, with (n = 11) and without occlusion (n = 12) The treatment was considered to be effective, the amount of sweat produced in 10 minutes (measured by 689 Evidence- based Dermatology. .. risk for life was so high that rechallenge with a highly suspect drug is not ethically acceptable toxic epidermal necrolysis A population -based study with particular reference to reactions caused by drugs among outpatients Arch Dermatol 1990;126:43–7 685 Evidence- based Dermatology 4 Roujeau JC, Kelly JP, Naldi L et al Medication use and 16 Kelemen JJ, Cioffi WG, McManus WF, Mason ADJ, Pruitt the risk... of severely acid trimethoprim-sulfamethoxazole as primary prophylaxis administration: a randomized, prospective study Arch for Pneumocystis carinii pneumonia: AIDS Clinical Surg 2000;135:326–31 Trials Group 268 J Acquir Immune Defic Syndr burned patients using ascorbic 35 Alvarez-Diaz C, Cuenca-Pardo J, Sosa-Serrano A, 2000;24:337–43 Juarez-Aguilar E, Marsch-Moreno M, Kuri-Harcuch W 44 Bonfanti P, Pusterla... studies will probably remain the only available clinical evidence for this question Corticosteroids We found no good evidence about the use of corticosteroids in TEN/SJS Beneficial effects are doubtful and are accompanied by many sideeffects 679 Evidence- based Dermatology Benefits We found only uncontrolled series in which fourteen patients with 45 100 % skin detachment were treated with high doses of corticosteroids... patient of 10 in the case series of Castells Rodellas et al had to discontinue 693 Evidence- based Dermatology bornaprin because of dizziness, and dryness of the mucosa limited as only patients with moderate palmar hyperhidrosis were included Comment/implications for clinical practice Harms So far there is no good evidence on the efficacy of oral anticholinergics There certainly is a trade-off between... • There is some evidence for the efficacy of sympathectomy, although there is a lack of objective criteria to measure efficacy Sympathectomy for axillar and palmar sweating is associated with long-term sideeffects such as compensatory and gustatory sweating Because of the unknown longterm side-effects, sympathectomy should be only considered in very severe cases 695 Evidence- based Dermatology References... RCT, 10 30% aluminium-chloride hexahydrate seems likely to be effective There is a trade-off between efficacy and side-effects (i.e local irritation of the skin) Occlusive dressings seem to increase irritation RCTs have demonstrated the efficacy of this treatment in axillary hyperhidrosis Heckmann et al.6 investigated the efficacy of botulinum toxin A 200 units (two-fifths of a vial Dysport) in 145 participants... chest surgically, but a general anaesthetic is still 691 Evidence- based Dermatology required The lungs are collapsed by pumping in carbon dioxide, and the sympathetic nerve nodes that transmit the nervous signals to the sweat glands in the upper limb and the face (T1–T4) are destroyed Benefits In a retrospective study of the long-term efficacy and side-effects in 270 patients with a total of 480 T1–T4 sympathectomies, . a 56-year-old woman 664 Evidence- based Dermatology with cutaneous sarcoid unresponsive to steroids who had clinical improvement after taking thalidomide, 200 mg/day for 2 weeks followed by 100 . patients with treatment-resistant chronic lupus pernio treated with plastic surgery, all of 668 Evidence- based Dermatology whom had a positive result. This is insufficient evidence to conclude. and side-effects are frequent. However, the 674 Evidence- based Dermatology methodology of most studies is poor: patient numbers are small and there is often a mix of idiopathic or viral-associated