Example Research Article Submission Columbia Undergraduate Science Journal Gabriel Morris To the Founding Editor: Please find attached our original manuscript, "Do PAF-acetylhydrolase al elic variants affect plasma PAF-acetylhydrolase activity?", for your consideration for publication as a Research Article in the Columbia Undergraduate Science Journal. This work was complete
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Pii: s0738-081x(00)00189-9Treatment of Subepidermal
FENELLA WOJNAROWSKA, DMGUDULA KIRTSCHIG, MDNONHLANHLA KHUMALO, MD Thesubepidermalautoimmunebullousdiseases ispossibletoensurethatthepatientisnotbeingover
are, with the exception of dermatitis herpetifor- mis, characterized by autoantibodies directed against components of the hemidesmosomal adhesion Bullous Pemphigoid
complex whose function is adhesion of stratified squa-mous epithelium to dermis or mesenchyme. The mech- Bullous pemphigoid (BP) is the most common autoim- anisms by which the antibody-antigen interaction re- mune blistering disease in the West with an estimated sults in blistering is still being elucidated: however, the incidence of six to seven cases per million population evidence is accumulating that the autoantibodies are The natural history of both treated and untreated BP The treatments used have different mechanisms.
is for persistent disease with eventual remission occur- Some are aimed at suppression of the inflammatory ring within five years in the majority of cases, within process, by the use of drugs such as corticosteroids which time relapses and exacerbations may occur. The (local and topical), dapsone, and sulfonamides, anti- aim of treatment is to suppress disease activity with the inflammatory antibiotics, and other anti-inflammatory minimum treatment. The majority of BP patients are drugs. Other treatments are aimed at suppression of over 70 years old, commonly on many drugs, and sus- production of the pathogenic antibodies by the use of immunosuppressive drugs e.g., corticosteroids, aza- A systematic review of treatments for BP has so far thioprine, ciclosporin, cyclophosphamide, methotrex- identified only six randomized controlled trials with atotal of 293 patients. Two trials, one comparing pred- ate, and other drugs. Plasmapheresis/plasma exchange nisolone 0.75 with 1.25 mg/kg and another of methyl is used for removal of the pathogenic antibodies and prednisolone versus prednisolone, did not find any inflammatory mediators. Immune modifying treat- statistical difference in the groups compared for effec- ments include intravenous immunoglobulins and extra- tiveness.3,4 Two trials (one of prednisolone versus pred- corporeal photochemotherapy. Many of these treat- nisolone and azathioprine, and another of prednisolone ments are common to several diseases. Dermatitis versus prednisolone and plasma exchange) suggested herpetiformis is the only disease with a specific treat- that the combination treatments maybe better than ment, namely a gluten free diet that by removing gluten prednisolone alone.5,6 A fifth trial, however included all reverses the underlying gluten sensitive enteropathy three treatment groups, and no difference was found and in time results in remission of the skin disease.
between combination treatment and prednisolone The aim of treatment is to suppress disease activity alone.7 The sixth trial comparing prednisolone with with the minimum dose of drugs necessary. Bullous tetracycline and nicotinamide suggested that there was disease patients are often elderly, commonly on many no statistically significant difference in response param- drugs, and very susceptible to adverse drug reactions eters in the two groups, but that the prednisolone group and side effects, some of which are life threatening.
During prolonged treatment, it is advisable to aim for Therefore, in spite of the fact that BP is the common- the presence of a blister once every few weeks. The est of the immunobullous diseases of the skin, the evi- treatment should be reduced whenever the disease has dence for the effectiveness of treatment is limited been well controlled for a month or more. In this way it largely to case reports and the clinical experience ofexperts in the field.
From the Department of Dermatology, Oxford Radcliffe Hospital, Ox- Topical and systemic steroids are the mainstay of treatment. Localized or mild disease may respond sat- Address correspondence to Fenella Wojnarowska, DM, Department of isfactorily to potent topical steroids alone.9,10 Oral cor- Dermatology, Oxford Radcliffe Hospital, Old Road Headington, Oxford,England, OX3 7LJ, UK. ticosteroids are indicated for more severe or unrespon- 2001 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010 Clinics in Dermatology Y 2001;19:768 –777 sive disease, although steroid-induced problems are Table 1. Monitoring Dapsone/Sulfonamide Therapy common. Those patients with more disseminated dis- ease need oral prednisolone in a dose of 20 – 40 mg daily. Higher doses of prednisolone (up to 100 mg daily) or pulse steroid therapy are occasionally required in patients with very severe and active disease. Steroid dosage can often be reduced quite quickly over the course of a few weeks to a dose of 15–20 mg daily. The majority of patients can be maintained on doses of less than 10 mg prednisolone daily, which can be slowly withdrawn; we use a reducing regime of 1 mg per jaundicefever/septicemia/systemic illness month reduction once the dose is below 10 mg daily.
There may be occasional flares that will require tempo- rary increases in therapy. Corticosteroid therapy has lowered the morbidity from the disease considerably.
Most patients achieve remission off all therapy, and the side effects can be limited by the use of lower doses.
The role of azathioprine is controversial. Originally azathioprine was shown to reduce steroid requirements significantly.5 Recently, however, this has been refut- ed,7 and it does seem to increase mortality as well as having significant morbidity in the elderly.7,11 Even though this evidence is based on small and often un- controlled studies, the addition of azathioprine to ste-roids should no longer be routine.
There is currently much interest in the combination related to treatment especially in the elderly and debil- of tetracycline and nicotinamide for bullous pemphi- itated.11 It is therefore essential to use the least toxic goid, and it has been used successfully as first line treatment at the lowest possible dose that will control treatment by a number of authors.12,13 The doses of tetracycline up to 2000 mg (or minocycline/doxycycline200 mg) and nicotinamide 2500 mg daily are used. The Pemphigoid Gestationis (Herpes Gestationis)
already mentioned small, double-blind study found thecombination to be effective and to have significantly Treatment of pemphigoid gestationis is based on clini- cal experience; there have been no randomized con- A minority of patients with BP appears to be respon- trolled trials of treatment.27,28 There are additional as- sive to dapsone, sulfamethoxypyridazine, or sulfapyri- pects to the treatment: the drugs used must be suitable dine,14,15 but such significant adverse effects as hemo- for use in pregnancy and breastfeeding, and, in rare lysis and methemoglobinemia limit their usefulness cases, the neonate may also require treatment. The dis- (see linear IgA disease and Table 1).
ease is almost always self-limiting, but there may be a Plasmapheresis/plasma exchange, usually with cor- post-partum flare. In some cases delivery has been in- ticosteroids and immunosuppression, has been used in duced because of severe disease.27,29–31 a number of patients with bullous pemphigoid with In mild cases of pemphigoid gestationis (about 20% benefit,6,16,17 although this was not confirmed in a sub- of cases) potent topical steroids (e.g., betamethasone sequent published double blind study.7 Intravenous esters or equivalent) or very potent steroids (e.g., clo- immunoglobulins have not been demonstrated to be of betasol propionate) often combined with a systemic major benefit,18 and ciclosporin has had anecdotal suc- antihistamine suitable for use in pregnancy, (for exam- cess in some patients.19,20 Methotrexate is sometimes ple, chlorpheniramine, which is, however, sedating) are useful in the elderly and in patients with BP and pso- usually adequate treatment.27,28 The sedating antihista- riasis.21,22 There have been small uncontrolled studies mine chlorpheniramine seems to be helpful in alleviat- demonstrating the efficacy of cyclophosphamide and ing the pruritus in many patients.28 Topical steroids can chlorambucil; however, these treatments are not recom- be used in combination with systemic treatments to lower the doses of systemic treatments required.
The mortality rate in the initial 30 cases reported by Once blisters appear it is usually necessary to use Lever in 1953 was 24%; this was prior to the use of oral systemic corticosteroids, and these are used in the ma- steroids. In spite of medical advances the mortality rate jority of patients. The range used is prednisolone 5–180 is still about 15–20% in treated patients and is usually mg daily.27,28 All but the most severe cases respond to Clinics in Dermatology Y 2001;19:768 –777 20 – 40 mg daily of prednisolone, and this can usually be dren. The treatment of the children can be more diffi- reduced fairly rapidly to a much lower maintenance cult, because side effects limit the dosage of drugs dose. Plasmapheresis/plasma exchange can be consid- used.39 In young women the possibility of pregnancy ered in the most severe cases, as it helps temporarily must be borne in mind and appropriate precautions with pruritus and the eruption, but may need repeating taken; however, pregnancy is not contraindicated, and often there is a remission of the disease in the last two Other drugs that have been used with variable suc- trimesters with a postpartum flare often at around 3 cess include dapsone and sulfonamides, which are con- tra-indicated peripartum and postpartum if breastfeed- A few patients have mild disease and can be con- ing.28,33 Pyridoxine is unhelpful in most cases.28,34 There trolled with topical steroids alone. This has been our is a report of ritodrine, used to suppress uterine con- experience particularly with some children.
tractions in premature labor, being helpful; however, Dapsone is used in doses starting at less than 0.5 this drug has many potentially serious side effects and mg/kg daily, which often means giving it as 25 mg is not recommended for use for more than 48 hours; it alternate daily or less in young children, and 25–50 mg is thus unsuitable for treatment of pemphigold gesta- daily in an adult. The dose may be slowly increased over weeks and months if required to a dose of 1 A postpartum exacerbation is frequent, and postpar- mg/kg daily or a little more in a child, and 100 –150 mg tum treatment can be a problem if the mother wishes to daily in an adult to keep the patient comfortable with- breastfeed, as the drugs pass into the breast milk. An- out significant side effects. Too rapid an increase in the tihistamines can cause drowsiness in the baby. It is dose often results in a severe hemolytic anemia, which worth increasing the corticosteroid dose temporarily at does not reach its maximum for a month. A fall in the first sign of a flare; however, corticosteroids (topical hemoglobin with a low MCV indicates iron deficiency and systemic) may cause adrenal suppression. The rec- (because of intravascular hemolysis) rather than pure ommendation in the UK is that breastfeeding should be hemolytic anemia. Patients (males Ͼ females) from the avoided if the mother is taking more than 40 mg of Mediterranean, Africa, Middle East, Southeast Asia, prednisolone daily; the pediatricians should therefore and Oceania are at risk of glucose 6-phosphate dehy- be consulted in this situation. Dapsone and sulfon- drogenase (G6PD) deficiency. Such patients should be amides cause hemolysis in the neonate. Although most screened prior to treatment, and dapsone and sulfon- cases remit within 6 months of delivery,28 some are amides avoided if they are G6PD deficient. Dapsone persistent. Some cases may be severe or continue for has been used successfully in African and Asian chil- years postpartum, and treatments used in these cases dren.43–46 Methemoglobinemia is common, reaching a include azathioprine, goserelin, ciclosporin, intrave- steady state after about 2 weeks, and may cause cyano- nous immunoglobulins, and pulsed dose cyclophosph- sis, breathlessness, and angina. There is potentiation of amide.27,28,36–38 We have successfully used minocycline this with local anaesthetic. Headache is a common side postpartum for persistent disease in a single case.
effect. Hepatitis, the dapsone syndrome (lymphadenop- The oral contraceptive can produce an exacerbation athy, eosinophilia, hepatitis, and rash), and agranulo- or recurrence of the disease in perhaps 50% of pa- cytosis are serious, usually early, complications. Motor tients.30,34 The oral contraceptive, although causing neuropathy may occur. Severe drug eruptions, includ- flares, may be used in some cases when the pemphigoid ing Stevens-Johnson syndrome and toxic epidermal gestationis is in remission without a problem.
necrolysis, are reported. Most complications occur in The rare cases of neonatal blistering because of pem- the first 3 months. There are reviews summarizing the phigoid gestationis usually resolve within a few days use and problems of dapsone and sulfonamides, and a Sulfonamides are alternatives if dapsone is not toler- ated. Sulfapyridine 250 mg–3 g daily usually controls Linear IgA disease (Chronic Bullous Disease of
the eruption rapidly, but the dose may need frequent Childhood, Linear IgA Bullous Dermatosis)
adjustment, and the drug is often poorly tolerated. Sul- The treatment of linear IgA disease evolved because of famethoxypyridazine (adult dose 250 mg–1.5 g daily) is the initial failure to distinguish it from dermatitis her- an alternative, which is often better tolerated. Sulfon- petiformis, and its response to dapsone contributed to amides have a similar side effect profile to dapsone, but cutaneous allergic reactions (e.g., Stevens-Johnson syn- DDS) and sulfonamides are the mainstay of treatment drome and toxic epidermal necrolysis) hepatitis, or but have never been the subject of randomized con- agranulocytosis are more common. An obliterative bronchiolitis may occur with sulfonamides, and breath- The treatment of children and adults is essentially lessness must always be investigated.49,50 Dapsone and the same with the necessary extra precautions for chil- sulfonamides can be combined to lessen the dose of Clinics in Dermatology Y 2001;19:768 –777 Table 2. Approved/Non-proprietary/Generic Drug Names and A few patients are very difficult to control and may U.S. Proprietary/Trade Names of Drugs need additional azathioprine, ciclosporin, or methotrex- ate.60 There is a single case report of the successful use of intravenous immunoglobulins; however, the infu-sions were required at regular intervals to suppress the The cutaneous lesions are always much more re- sponsive than the mucosal lesions, which can be treated with topical steroids (see Mucous Membrane/Cicatri- In view of the ultimate spontaneous recovery, in the majority of patients attempts should be made to avoid overtreatment and the production of side effects with systemic corticosteroids and other drugs. Regular at- tempts should be made to reduce and withdraw treat- Mucous Membrane Pemphigoid/Cicatricial
Treatment of mucous membrane pemphigoid/cicatri-cial pemphigoid (MMP) is difficult. The disease often both drugs and improve patient tolerance. The patients cannot be completely suppressed and unfortunately must be intensively monitored both as regards clinical patients may develop severe scarring despite immuno- and laboratory parameters, initially weekly and, after 3 months, monthly and, later, every 3 months (see Table It is important to examine the patient’s skin and all 1). Patients wishing to conceive should be given folic mucous membranes carefully because this will influ- acid in combination with dapsone, and sulfonamides ence the decision about which treatment may be suit- should be avoided. Often the drugs can be reduced or able for an individual patient. MMP may only involve stopped in the second trimester.42 Dapsone and sulfon- the oral mucosa, for example, presenting as a desqua- amides cause neonatal hemolysis and should be mative gingivitis without major morbidity. Involve- stopped prior to delivery and not restarted whilst the ment of the ocular, nasopharyngeal, oesophageal, and laryngeal mucosa, however, lead to blindness or life Some patients do not respond completely to dapsone threatening complications in severe cases. Therefore at or sulfonamides, and corticosteroids may need to be each patient visit, assess which mucous membranes are added. They are rarely effective on their own at doses involved, how severely the site is involved, and how less than 30 mg daily. Dapsone has been used in this way with corticosteroids in African children.43,44 There are only two randomized controlled trials in Success has been reported in 3 adult cases with tet- ocular MMP comparing cyclophosphamide, pred- racyclines (2 g daily) and nicotinamide (1.5–2 g daily) nisolone, and dapsone.64 There are no randomized con- and a single report of other antibiotics.51–53 In children trolled trials for all other patients with MMP therefore the penicillins dicloxacillin (40 mg/kg 3 times daily) treatment recommendations can only relay on case se- and oxacillin (50 mg/kg daily) have been reported to ries, case reports and personal experience.
Patients with Mild Disease (Mainly Oral Mucosa Colchicine has been used in children and adults.
There is a single adult case report of a good response to0.5 mg three times daily.56 Colchicine suppressed the As mentioned above, there are no controlled trials to disease in G6PD deficient children in Israel and Oman.
support the superior effectiveness of any treatment.
The dose was 0.5 mg twice daily as higher doses caused Therefore, it is advisable to choose the treatment that diarrhea. Initially, it was introduced with corticoste- puts an individual at least risk of side effects.
roids, but in most children it was effective as a sole Potent (betamethasone valerate 0.1% ointment, 5mg agent and could be reduced from 0.5 mg twice daily to betamethasone soluble tablets, triamcinolone acetonide once daily.57–59 It does have potentially very severe side 0.1– 0.5%) to very potent (clobetasol propionate 0.05% effects, including blood dyscrasias, hepatic, and renal ointment) topical corticosteroids are applied twice per damage, but is often well tolerated.
day. Mouthwashes may initially be necessary more fre- Clinics in Dermatology Y 2001;19:768 –777 quently. Topical treatment with corticosteroids is help- There seems to be an additional effect.70 We start with ful in some patients with localised oral and skin disease, 500 mg daily and increase the dose by 500 mg to 2000 mg daily at 2-week intervals. Side effects include gas- High dose oral prednisone (over 1 mg/kg daily) is trointestinal up-set and hepatotoxicity in very high effective in controlling MMP, but long term treatment is doses. Tetracyclines and nicotinamide should be intro- associated with too many side effects. Therefore sys- temic steroids are only used in high doses short term or Always start with the lowest dose possible and in- in very low doses (Ͻ0.5 mg/kg daily) for longer peri- crease according to clinical measures. Antibiotics and nicotinamide may be combined; this may be more ef- Sulfones or sulfonamides are indicated if topical fective. Low dose systemic corticosteroids (Ͻ0.5 mg/kg treatment fails in localised oral and skin MMP and in body weight prednisolone equivalent) may be added if ocular MMP with marked to moderate inflammation.
needed to all above mentioned regimes.
The current drug of choice is dapsone. Dapsone (25– Patients with Severe Disease (Progressive Ocular, 200mg daily) is contraindicated in patients with G6PD Nasopharyngeal, Esophageal, Laryngeal) deficiency and must be used with caution in the elderly(for side effects, see Linear IgA disease and Table 1).
A combination of medications and additional topical Dapsone is beneficial in 30 to 70% of MMP patients, and corticosteroids may be required to suppress severe dis- a response can be expected within 2 to 12 weeks. Low ease and to minimize drug side effects. Antibiotics plus dose treatment should be started and the blood moni- nicotinamide or dapsone may be tried in severe cases of tored weekly for 3 months and after any dose increase MMP; however, one controlled trial favors cyclophos- and then monthly (full blood count, methemoglobin, phamide in combination with prednisolone over dap- and liver function). The daily dose may be increased by sone for the treatment of severe ocular MMP.64 Systemic 25–50 mg after 4 weeks, hemolysis is observed mainly immunosuppressive therapy should be offered to pa- during the first weeks of treatment and is dose depen- tients with severe progressive disease, but not to pa- dent. Dapsone may be combined with topical and sys- tients with quiescent or end stage disease.
temic corticosteroids, sulfonamides, and immunosup- Cyclophosphamide (1–2 mg/kg daily) intravenously or orally is used in addition to prednisone (0.5–1.5 Sulfamethoxypyridazine used at a dose of 500 to mg/kg daily). In a randomized trial cyclophosphamide 1500 mg daily causes less hemolysis and seems as ef- (2 mg/kg daily) was given in conjunction with pred- fective as dapsone. Side effects include a toxic reaction nisone (1 mg/kg daily) and prednisone tapered by 0.25 with pyrexia, arthralgia, and albuminuria, an erythem- mg/kg daily after week 1, week 3, and week 7, and then atous maculopapular rash, hemolytic anemia, fixed monthly until completely discontinued. All 12 patients drug reaction, photosensitivity, alveolitis, and oblitera- responded to that regime within 8 weeks, active con- junctival inflammation subsided completely. Initially, Sulfapyridine (500 –3000 mg daily) is an alternative weekly, then monthly, full blood count with differential to dapsone. It is reported to be effective in 50% of white count and urine analysis is required. Side effects patients with mild to moderate ocular MMP. Side ef- include alopecia, leukopenia, anaemia, hemorrhagic fects include nausea, headache, arthralgia, drug fever, cystitis, infections (candida), bladder cancer, and infer- allergic skin rash, and mild leukopenia; rarely, neuro- toxicity, hepatotoxicity, polyarteritis, agranulocytosis, Azathioprine (1–2 mg/kg daily) may substitute for blood eosinophilia with pneumonitis, lupus-like syn- cyclophosphamide; its action may be slower than that of cyclophosphamide. Regular full blood count is re- The beneficial effect of tetracyclines in MMP is sup- quired, and in renal and hepatic impairment a reduced ported by a few case series (minocycline 100 –200 mg, dose should be administered. Measuring the serum doxycycline 100 –200 mg, or oxytetracycline 500 –2000 level of thiopurine methyltransferase activity is impor- mg daily). Although they have never been compared to tant because a low level is associated with increased other treatment regimes in controlled trials, tetracy- risk of leukopenia, and these patients also may have a clines seem effective, may be as effective as dapsone, poor clinical response to azathioprine because of inad- and are associated with fewer side effects. If long-term equate empiric dosing. Side effects include bone mar- minocycline/tetracycline is required, liver function row suppression, hypersensitivity reactions, infec- tests should be performed every 6 months. Minocycline tions, hepatotoxicity, and development of malignan- is known to cause a pneumonitis accompanied by blood eosinophilia, this requires immediate withdrawal of the drug and treatment with systemic corticosteroids.70–72 Nicotinamide at doses of 500 to 2500 mg daily is Oral ciclosporin seems ineffective in MMP,64,67,78; usually used in combination with tetracylcines in MMP.
however, topical ciclosporin is reported to be beneficial Clinics in Dermatology Y 2001;19:768 –777 in oral MMP, but the medication is not widely avail- (up to 15 mg daily) were tried in single cases, but it is difficult to judge their efficacy.84,91,92 Local interferon alfa-2b has been reported to be ben- Methotrexate (10 –25 mg/week) is described as ben- eficial in single cases of inflammatory EBA in conjunc- Subconjunctival 5-fluoruracil and mitomycin C 0.1 tion with high dose systemic steroids.87,90,93 mg are currently being tested for reduction of mucosal Ciclosporin (4 –10 mg/kg daily) usually combined with steroids gave a satisfactory response in some pa- Intravenous immunoglobulins seem effective in se- tients who failed to respond to other immunosuppres- vere ocular MMP. They have been used as a last resort sants. Improvement was sometimes seen within one in some patients in whom conventional immunosup- month, and in some patients ciclosporin was stopped pressive treatment has failed to control the disease; however, they are costly. There are different prepara- Dapsone (50 –200 mg daily) in conjunction with sys- tions available and their efficacy seems to vary; later temic corticosteroids is only helpful in single cases; it reports are more optimistic than earlier ones. Side ef- seems more beneficial in children with EBA (see be- fects are minimal (alopecia, urticaria); however, there Mesalazine (3 ϫ 800 mg daily) is reported to have may be a risk of other side effects including the trans- dramatically improved inflammatory EBA when ad- ministered because of inflammatory bowel disease.96 Surgery may be necessary in organ failure because of Colchicine (0.5–2 mg daily) has been used in a few scarring (e.g., airway obstruction, blindness), and pa- patients, and some responded within weeks. It has to be tients then have to be referred to the relevant specialist.
introduced at a low dose and may then be increased by0.5 mg daily each week to a maximum dose until diar- Epidermolysis Bullosa Acquisita
rhea develops. It is sometimes combined with systemic Treatment of epidermolysis bullosa acquisita (EBA) is steroids or dapsone and seems to reduce blister forma- difficult. Clinical features in EBA are heterogeneous; tion in patients who did not respond well to other classical EBA resembles the inherited forms of dystro- immunosuppressants. It is usually avoided in patients phic epidermolysis bullosa with major skin fragility who have inflammatory bowel disease. Side effects in- and a distribution of lesions over trauma-exposed sites.
clude diarrhea, and renal and hepatic damage.91,97 A second group of EBA patients shows clinical features Plasmapheresis/plasma exchange in addition to resembling bullous pemphigoid, including widespread prednisolone and cyclophosphamide has been used in blisters often on an inflammatory base; then there are one patient who did not respond to several other im- patients with major mucous membrane involvement resembling MMP.84–86 It seems that patients with the Extracorporeal photochemotherapy is reported to be classical form are the ones most resistant to treatment; helpful in patients resistant to conventional treat-ment.99–101 the others may better respond to the usual immunosup- Intravenous immunoglobulins (2 g/kg daily once a pressive/antiinflammatory regimes as described for the week at 2-week intervals or 400 mg/kg daily 4 –5 days other subepidermal bullous diseases. We could not per week at 2– 6 week intervals) are controversial. There identify any randomized controlled treatment trials for are encouraging and disappointing reports. In most EBA; most publications are case reports. Topical treat- patients it was combined with immunosuppressants, ment with corticosteroids, antibiotics, and emollients and these patients responded better to the intravenous are effective in reducing friction and controlling sec- immunoglobulins. The response may also depend on ondary infections but do not influence the general the preparation used and on the type of EBA. It is an course of the disease. Any measure that decreases fric- expensive treatment and therefore not used in routine tion and trauma to the skin is helpful.
Systemic corticosteroids (1–2.5 mg prednisone equiv- Surgery may be necessary in organ failure because of alent/kg daily) seem helpful in patients with inflamma- scarring (e.g., airway obstruction, blindness), and pa- tory disease and disease localized to face, genitalia, and tients then have to be referred to the relevant specialist.
mucous membranes; however, patients will develop EBA in childhood is very rare, and the disease in children may be self-limiting. Many are in remission In addition to systemic steroids, azathioprine (1–2 after 2 to 3 years disease duration; however, the course mg/kg daily) is helpful in some patients with inflam- may be protracted and lead to blindness.86,105,106 Emol- matory EBA; other investigators do not see a steroid lients and topical corticosteroids are helpful in some cases. In more severe disease, dapsone (1–2 mg/kg Cyclophosphamide (pulse therapy 1500 mg single daily; 50 –200 mg daily) and/or systemic corticosteroids dose once per month for 6 months) and chlorambucil (1–2 mg/kg daily) should be used.105,106 Chloroquine Clinics in Dermatology Y 2001;19:768 –777 (25 mg daily) in addition to prednisolone was success- abolished after 5 to 10 years of a gluten free diet.109 For fully used in one 3.5-year-old girl; the child suffered all these reasons, whenever possible patients should be from gastrointestinal upset after dapsone.107 encouraged to follow a gluten free diet. To obtain strictadherence to the diet the patient needs to be highlymotivated, intelligent, and leading a regular life; some- Dermatitis Herpetiformis
times it may be wise to postpone starting the diet until Treatment of dermatitis herpetiformis has two compo- a more settled period. Unlike patients with celiac dis- nents. Initially, there is a need for suppressive treatment ease, ingestion of small quantities of gluten does not with dapsone or alternative to rapidly eliminate the always precipitate symptoms. Wheat must be avoided, skin lesions; in the longer term the treatment of choice but oats are not damaging.110,111 The help of a dietician is the removal of gluten from the diet and healing of and the Celiac Society are essential. The patients put on both the gluten sensitive enteropathy and skin.48 weight, lose their abdominal symptoms, and often feel There have been no randomized controlled trials of generally much better. It is usually many months and treatment in dermatitis herpetiformis; however, the ef- sometimes years before patients are able to reduce their fect of dapsone in switching off the disease is so dra- dapsone requirements. Often dapsone can be discontin- matic that it has been used by some clinicians as a ued altogether after 2 to 3 years on a strict gluten-free diagnostic test. There is considerable evidence support- diet, but some patients take much longer.112 Re-intro- ing the beneficial effects of a gluten-free diet. Dapsone duction of gluten in selected patients produced a re- is the most widely used treatment for dermatitis herpe- lapse in skin lesions.113 Although systemic corticoste- tiformis, and usually has a rapid and dramatic effect in roids are in the main ineffective and not indicated, suppressing the disease within a few days. The prob- topical steroids may be helpful in lessening symp- lems and precautions required are outlined above (see Linear IgA Disease and Table 1). It is wise to start at 25to 50 mg daily in an adult and slowly increase to a dose References
that keeps the patient comfortable without significantside effects; too rapid an increase in the dose often 1. Bernard P, Vaillant L, Labeille B, et al. Incidence and results in symptomatic hemolytic anemia and methe- distribution of subepidermal autoimmune bullous skin moglobinemia with cyanosis, breathlessness, and an- diseases in three French regions. Arch Dermatol 1995;131:48 –52.
gina. The dose needed for the average case is 100 to 200 2. Zillikens D, Wever S, Roth A, et al. Incidence of autoim- mg daily, but a few may require and tolerate higher mune subepidermal blistering dermatoses in a region of Central Germany. Arch Dermatol 1995;131:957– 8.
Sulfonamides are alternatives for patients who can- 3. Dreno B, Sassolas B, Lacour P, et al. Methylprednisolone not tolerate dapsone, and their main side effects and versus prednisolone methylsulfobenzoate in pemphi- problems are outlined above (see Linear IgA Disease goid: a comparative multicenter study. Ann Dermatol and Table 1). Sulfapyridine (1.5 g daily) can be substi- tuted; however, a few patients may need higher doses.
4. Morel P, Guillaume JC. [Treatment of bullous pemphi- The long-acting sulfonamide sulfamethoxypyridazine goid with prednisolone only: 0.75 mg/kg/day versus is an alternative treatment and usually 0.5 to 1.5 g daily 1.25 mg/kg/day. A multicenter randomized study]. Ann is sufficient to control dermatitis herpetiformis; the in- Dermatol Venereol 1984;111:925– 8.
5. Burton JL, Harman RR, Peachey RD, Warin RP. Azathio- cidence of side-effects increases with doses above 1 g prine plus prednisone in treatment of pemphigoid. Br Heparin has been used successfully in the past, and 6. Roujeau JC, Guillaume JC, Morel P, et al. Plasma ex- recently, tetracycline and nicotinamide have been used change in bullous pemphigoid. Lancet 1984;286 – 8.
7. Guillaume J-C, Vaillant L, Bernard P, et al. Controlled A gluten free diet is the treatment of choice in the trial of azathioprine and plasma exchange in addition to long term. There are several reasons for this. A gluten- prednisolone in the treatment of bullous pemphigoid.
free diet reverses the gut changes of gluten-sensitive enteropathy, resulting in the disappearance of gastro- 8. Fivenson D, Breneman D, Rosen G, et al.D. Nicotinamide intestinal symptoms, which may have been severe or and tetracycline therapy of bullous pemphigoid. Arch have been considered by the patient to be normal. The 9. Zimmermann R, Faure M, Claudy A. Prospective study malabsorption is cured and there is an increase in of treatment of bullous pemphigoid by a class I topical weight, energy, and wellbeing in most patients. The corticosteroid (see comments). Ann Dermatol Venereol diet in the long term permits discontinuation of drug therapy for the rash and avoidance of all the potential 10. Westerhof W. Treatment of bullous pemphigoid with problems of drug therapy. The risk of lymphoma asso- topical clobetasol propionate. J Am Acad Dermatol 1989; ciated with dermatitis herpetiformis is decreased or Clinics in Dermatology Y 2001;19:768 –777 11. Venning V, Wojnarowska F. Lack of predictive factors nis: Clinical and histologic features of twenty-eight cases.
for the course of bullous pemphigoid. J Am Acad Der- J Am Acad Dermatol 1983;8:214 –24.
31. Shornick J, Black M. Fetal risks in herpes gestationes.
12. Berk MA, Lorinez AL. The treatment of bullous pemphi- J Amer Acad Dermatol 1992;26:63– 8.
goid with tetracycline and niacimamide. A preliminary 32. Van de Wiel A, Har H, Flinterman J, et al. Plasma ex- report. Arch Dermatol 1986;122:670 – 4.
change in herpes gestationis. Br Med J 1980;281:1041–2.
13. Kolbach DN, Remme JJ, Bos WH, et al. Bullous pemphi- 33. Hocking D. Neonatal haemolytic disease due to dapsone.
goid successfully controlled by tetracycline and nicotin- 34. Holmes R, Black M. Herpes gestationis. Dermatol Clinics 14. Venning V, Millard P, Wojnarowka F. Dapsone as first line therapy for bullous pemphigoid. Br J Dermatol 1989; 35. McDonald K, Raffle E. Ritodrine therapy associated with remission of pemphigoid gestationis. Br J Dermatol 1984: 15. Rogers RSD Dapsone and sulfapyridine therapy of pem- phigoid diseases. Australas J Dermatol 1986;27:58 – 63.
36. Jenkins R, Vaughan S, Black M. Conversion of pemphi- 16. Guillot B, Donadio D, Guilhou JJ, et al. Bullous pemphi- goid gestationis to bullous pemphigoid— Two refractory goid treated by plasma exchange. Open study in 10 cases highlighting this association. Br J Dermatol 1996; patients. Presse Med 1983;12:1855– 8.
17. Guillot B, Donadio D, Guilhou JJ, et al. Long term plasma 37. Castle S, Mather-Mondrey M, Bennion S, et al. Chronic exchange therapy in bullous pemphigoid. Acta Derm herpes gestationis sucessfully treated with cyclophosph- amide. J Am Acad Dermatol 1996;34:333– 6.
18. Beckers R, Brand A, Vermeer B, et al. Adjuvant high- 38. Hern S, Harman K, Bhogal B, et al. A severe persistent dose intravenous gammaglobulin in the treatment of case of pemphigoid gestationis treated with intravenous pemphigus and bullous pemphigoid: Experience in six immunoglobulins and cylcsporin. Clin Exp Dermatol patients. Br J Dermatol 1995;133:289 –93.
19. Eisen D, Ellis CN, Voorhees JJ. Topical cyclosporine for 39. Marsden R. The treatment of benign chronic bullous oral bullous disorders. J Am Acad Dermatol 1990;23: dermatosis of childhood and bullous pemphigoid begin- ning in childhood. Clin Exp Dermatol 1982;7:653– 63.
20. Barthelemy H, Thivolet J, Cambazard F, et al. Cyclo- 40. Leonard JN, Haffenden GP, Ring NP, et al. Linear IgA sporin in the treatment of bullous pemphigoid: Prelimi- disease in adults. Br J Dermatol 1982;107:301–16.
nary study. Ann Dermatol Venereol 1986;113:309 –13.
41. Wojnarowska F, Delacroix D, Gengoux P. Cutaneous IgA 21. Paul M, Jorizzo J, Fleischer A, et al. Low dose metho- subclasses in dermatitis herpetiformis and linear IgA trexate treatment in elderly patients with bullous pem- disease. J Cutan Pathol 1988;15:272–5.
phigoid: J Am Acad Dermatol 1994;31:620 –5.
42. Collier P, Kelly S, Wojnarowska F. Linear IgA disease 22. Kirtschig G, Chow E, Venning V, et al. Acquired subepi- and pregnancy. J Am Acad Dermatol 1994;30:407–12.
dermal bullous diseases associated with psoriasis: a clin- 43. Aboobaker J, Wojnarowska F, Bhogal B, et al. Chronic ical, immunopathological and immunogenetic study.
bullous dermatosis of childhood— clinical and immuno- 23. Taieb A, Klene C, Maleville J. Immediate treatment of logical features seen in African patients. Clin Exp Der- bullous pemphigus with a corticosteroid-cyclophospha- mide combination. Ann Dermatol Venereol 1986;113: 44. Denguezuli M. Ben Nejma B, Nouira R. et al. La derma- tose bulleuse aIgA lineaire de L enfant: une serie de 12 24. Itoh T, Hosokawa H, Shirai Y, et al. Successful treatment malades tunisiens. Ann Dermatol Venereol 1994;121: of bullous pemphigoid with pulsed intravenous cyclo- phosphamide. Br J Dermatol 1996;134:931–3.
45. Mahe A, Flageul B, Bobin P. La dermatose bulleuse a IgA 25. Dawe RS, Naidoo DK, Ferguson J. Severe bullous pem- lineaire de L’enfant au Mali. Ann Dermatol Venereol phigoid responsive to pulsed intravenous dexametha- sone and oral cyclophosphamide [letter]. Br J Dermatol 46. Ajithkumar K, Kurian S, Jacob M, et al. linear IgA der- matosis in South India. Int J Deramtol 1997;36:191–3.
26. Milligan A, Hutchinson P. The use of chlorambucil in the 47. Lang P. Sulfones and sulfonamides in dermatology to- treatment of bullous pemphigoid. Am Ac Dermatol 1990; day. J Am Acad Dermatol 1979;1:479 –92.
48. Fry L. The treatment of dermatitis herpetiformis. Clin 27. Lawley T, Stingl G, Katz S. Fetal and maternal risk factors in herpes gestationis. Arch Dermatol 1978;114: 49. McFadden J, Leonard J, Powles A, et al. Sulphamethoxy- pyridazine for dermatitis herpetiformis, linear IgA dis- 28. Jenkins R, Hern S, Black M. Clinical features and man- ease and cicatricial pemphigoid. Br J Dermatol 1989;121: agement of 87 patients with pemphigoid gestationis. Clin 50. Godfrey K, Wojnarowska F, Friedland J. Obliterative 29. Holmes R, Black M, Dann J, et al. A comparative study of bronchiolitis and alveolitis associated with Sulphame- toxic erythema of pregnancy and herpes gestationis. Br J thoxypyridazine (Lederkyn) therapy for linear IgA dis- ease of adults. Br J Dermatol 1990;123:125.
30. Shornick J, Bangert J, Freeman R, et al. Herpes gestatio- 51. Peoples D, Fivenson D, Linear IgA bullous dermatosis: Clinics in Dermatology Y 2001;19:768 –777 Successful treatment with Tetracycline and Nicotin- 72. Dragan L, Eng AM, Lam S, et al. Tetracycline and niaci- amide. J Am Acad Dermatol 1992;26:498 –9.
namide: Treatment alternatives in ocular cicatricial pem- 52. Chaffins M, Collinson D, Fivenson D. Treatment of pem- phigus and linear IgA dermatosis with nicotinamide and 73. Elder MJ, Lightman S, Dart JK. Role of cyclophospha- tetracycline: areview of 13 cases. J Am Acad Deramtol mide and high dose steroid in ocular cicatricial pemphi- goid. Br J Ophthalmol 1995;79:264 – 6.
53. Khan I, Bhol K, Ahmed A. Linear IgA bullous dermatosis 74. Snow JL, Gibson LE. The role of genetic variation in in a patient with chronic renal failure: Response to intra- thiopurine methyltransferase activity and the efficacy venous immunoglobulin therapy. J Am Acad Dermatol and/or side effects of azathioprine therapy in dermato- logic patients [see comments]. Arch Dermatol 1995;131: 54. Skinner R, Rotondo C, Schneider M, et al. Treatment of chronic bullous disease of childhood with oral Diclox- 75. Dave VK, Vickers CF. Azathioprine in the treatment of acillin. Ped Dermatol 1995;12:65– 6.
55. Siegfried E, Sirawan S. Chronic bullous disease of child- hood: Successful treatment with dicloxacillin. J Am Acad 76. Tauber J, Sainz de la Maza M, Foster CS. Systemic che- motherapy for ocular cicatricial pemphigoid. Cornea 56. Aram H. Linear IgA bullous dermatosis: successful treat- ment with Colchicine. Arch-Dermatol 1984;120:960 –1.
77. Foster CS, Ahmed AR. Intravenous immunoglobulin 57. Zeharia A, Hodak E, Mukamel M, et al. Successful treat- therapy for ocular cicatricial pemphigoid: A preliminary ment chronic bullus dermatosis of childhood with col- study. Ophthalmology 1999;106:2136 – 43.
chicine. J Am Acad Dermatol 1994;30:660 –1.
78. Williams DY, Oziemski M, Varigos G. Cyclosporine ther- 58. Banodkar D, Al-Suwaid A. Colchicine as a novel thera- apy of life-threatening cicatricial pemphigoid affecting peutic agent in chronis bullous dermatosis of childhood.
the respiratory tract. Int J Dermatol 1995;34:639 – 41.
79. Azana JM, de Misa RF, Boixeda JP, Ledo A. Topical 59. Ang P, Tay Y-K. Treatment of linear IgA bullous derma- cyclosporine for cicatricial pemphigoid [letter; com- tosis of childhood with colchicne. Ped Dermatol 1999;16: ment]. J Am Acad Dermatol 1993;28:134 –5.
80. Gillies M, Francis I, McCluskey P, et al. Local interferon 60. Burrows N, Russell Jones R. Methotrexate and cyclo- alfa-2b for ocular cicatricial pemphigoid [letter]. Br J sporin are of value in the treatment of adult linear IgA disease. J Dermatol Treatment 1992;3:31–3.
81. Donnenfeld ED, Perry HD, Wallerstein A, et al. Subcon- 61. Leonard J, Griffiths C, Powles A, et al. Experience with a junctival mitomycin C for the treatment of ocular cica- gluten free diet in the treatment of linear IgA disease.
tricial pemphigoid. Ophthalmology 1999;106:72– 8.
Acta Dermatol Venerol 1987;67:145– 8.
82. Urcelay ML, McQueen A, Douglas WS. Cicatricial pem- 62. Mondino BJ, Brown SI. Immunosuppressive therapy in phigoid treated with intravenous immunoglobulin [let- ocular cicatricial pemphigoid. Am J Ophthalmol 1983;96: ter]. Br J Dermatol 1997;137:477– 8.
83. Bohn J, Benfeldt E, Dabelsteen E, et al. Treatment of 63. Mondino B. Cicatricial pemphigoid and erythema mul- ocular cicatricial pemphigoid with intravទenous gamma- tiforme. Ophthamol 1990;97:939 –52.
globulin [letter]. Acta Derm Venereol 1998;78:316 –7.
64. Foster CS. Cicatricial pemphigoid. Trans Am Ophthal- 84. Gammon WR. Epidermolysis bullosa acquisita. Semin 65. Vincent SD, Lilly GE, Baker KA. Clinical, historic, and 85. Lang PJ, Tapert M. Severe ocular involvement in a pa- therapeutic features of cicatricial pemphigoid. A litera- tient with epidermolysis bullosa acquisita. J Am Acad ture review and open therapeutic trial with corticoste- roids. Oral Surg Oral Med Oral Pathol 1993;76:453–9.
86. Caux F, Kirtschig G, Lemarchand-Venencie F, et al. IgA- 66. Nayar M, Wojnarowska F. Cicatricial pemphigoid. A epidermolysis bullosa acquisita in a child resulting in re-evaluation of therapy. J Dermatol Treat 1993;4:89 –93.
blindness. Br J Dermatol 1997;137:270 –5.
67. Neumann R, Tauber J, Foster CS. Remission and recur- 87. Woodley DT, Briggaman RA, Gammon WT. Review and rence after withdrawal of therapy for ocular cicatricial update of epidermolysis bullosa acquisita. Semin Der- pemphigoid. Ophthalmology 1991;98:858 – 62.
68. Rogers RSd, Mehregan DA. Dapsone therapy of cicatri- 88. Lee CW, Jun KM. Epidermolvsis bullosa acquisita pre- cial pemphigoid. Semin Dermatol 1988;7:201–5.
senting with localized facial blisters. Clin Exp Dermatol 69. Elder M, Leonard J, Dart J. Sulphapyridine—A new agent for the treatment of ocular cicatricial pemphigoid.
89. Richter BJ, McNutt NS. The spectrum of epidermolysis bullosa acquisita. Arch Dermatol 1979;115:1325– 8.
70. Reiche L, Wojnarowska F, Mallon E. Combination ther- 90. Gammon W, Briggaman R, Woodley D, et al. Epidermol- apy with nicotinamide and tetracyclines for cicatrical ysis bullosa acquisita — A pemphigoid-like disease.
pemphigoid: further support for efficacy. Clin Exp De- J Am Acad Dermatol 1984;11:820 –38.
91. Kofler H, Wambacher-Gasser B, Topar G, et al. Intrave- 71. Poskitt L, Wojnarowska F. Minimising cicatricial pem- nous immunoglobulin treatment in therapy-resistant phigoid orodynia with minocycline. Br J Dermatol 1995; epidermolysis bullosa acquisita. J Am Acad Dermatol Clinics in Dermatology Y 2001;19:768 –777 92. Murakami S, Shiraishi S, Miki Y. Epidermolysis bullosa dermolysis bullosa acquisita: efficacy of high-dose intra- acquisita in identical twins. J Dermatol 1991;18:230 – 4.
venous immunoglobulins. J Am Acad Dermatol 1993;29: 93. Gammon WR, Briggaman RA, Wheeler CE Jr. Epider- molysis bullosa acquisita presenting as an inflammatory 104. Harman KE, Black MM. High-dose intravenous immune bullous disease. J Am Acad Dermatol 1982;7:382–7.
globulin for the treatment of autoimmune blistering dis- 94. Clement M, Ratnesar P, Thirumoorthy T, Epidermolysis eases: an evaluation of its use in 14 cases. Br J Dermatol bullosa acquisita–A case with upper airways obstruction requiring tracheostomy and responding to cyclosporin.
105. Kirtschig G, Wojnarowska F, Marsden R, et al. Acquired Clin Exp Dermatol 1993;18:548 –51.
bullous diseases of childhood: Re-evaluation of diagno- 95. Zillikens D, Erhard H, Prost C, et al. Inflammatory type sis by indirect immunofluorescence examination on IM of epidermolysis bullosa acquisita. Hautarzt 1994;45: NaCl split skin and immunoblotting. Br J Dermatol 1994; 96. Robinowitz BN, Towery DS, Meyers SW, et al. Successful 106. Callot-Mellot C, Bodemer C, Caux F, et al. Epidermolysis treatment of epidermolysis bullosa acquisita with me- bullosa acquisita in childhood. Arch Dermatol 1997;133: salazine [letter]. Br J Dermatol 1997;137:154 –5.
97. Cunningham BB, Kirchmann TT, Woodley D. Colchicine 107. Roger H, Machado P, Nicolas JF, et al. Epidermolysis for epidermolysis bullosa acquisita. J Am Acad Dermatol bullosa acquisita in a 3 1/2-year-old girl. J Am Acad 98. Furue M, Ando I, Inoue Y, et al. Pretibial epidermolysis 108. Alexander JD. Treatment of dermatitis herpetiformis.
bullosa. Successful therapy with a skin graft. Arch Der- 99. Gordon K, Chan L, Woodley D. Treatment of refractory 109. Lewis H, Renula T, Garioch J, et al. Protective effect of a epidermolysis bullosa acquisita with extracorporeal pho- gluten-free diet against development of lymphoma in tochemotherapy. Br J Dermatol 1997;136:415–20.
dermatitis herpetiformis. Br J Dermatol 1996;135:363–7.
100. Miller JL, Stricklin GP, Fine JD, et al. Remission of severe 110. Janatuinen E, Pikkarainen K, Kosma V, et al. A compar- epidermolysis bullosa acquisita induced by extracorpo- ison of diets with and without oats in adults with celiac real photochemotherapy. Br J Dermatol 1995;133:467–71.
disease. New Engl J Med 1995;333:1033–7.
101. Camara A, Becherel PA, Bussel A, et al. Resistant ac- 111. Hardman CM, Garioch JJ, Leonard JN, et al. Absence of quired bullous epidermolysis with severe ocular in- toxicity of oats in patients with dermatitis herpetiformis.
volvement: the success of extracorporeal photochemo- therapy. Ann Dermatol Venereol 1999;126:612–5.
112. Garioch J, Lewis H, Sargeant S, et al. Twenty five years 102. Caldwell JB, Yancey KB, Engler RJ, et al. Epidermolysis experience of a gluten free diet in the treatment of der- bullosa acquisita: efficacy of high-dose intravenous im- matitis herpetiformis. Br J Dermatol 1994;131:541–5.
munoglobulins [letter] J Am Acad Dermatol 1994;31: 113. Leonard J, Haffenden G, Tucker W, et al. Gluten chal- lenge in dermatitis herpetiformis. New Engl J Med 1983; 103. Meier F, Sonnichsen K, Schaumburg-Lever G, et al. Epi-
CURRICULUM VITAE PERSONAL DATA: Name : MOHAMED BADAWY HASSAN TAWFIK ABDEL-NASER Address for Correspondence: Dept. of Dermatology and Venereology, Faculty of Medicine Ain Shams University, Abbassia Square 11566, Cairo, Egypt Private : 28 Abou Hayan El Tawhidi, Madina Nasr, 7 th District Tel: (++202) 24031131/25084034/22575252/26830767 Mobile: (++2012) 2342288 Fax: (++20