bullous systemic lupus erythematosus ( bsle ) is a subepidermal blistering disease that occurs in a subset of patients with systemic lupus erythematosus ( sle ) [ 1 , 2 ] .
cutaneous lesions are reported during the course of sle in 76% of patients ; however , it has been reported that bsle is very rare and occurs in less than 1% of patients with sle [ 35 ] .
clinically , in addition to the features of sle , the bsle patients especially present with a rapid , widespread development of tense fluid - filled vesicles and bullae .
moreover , this blistering disease may vary from a small group of vesicles to large tense blisters with urticarial eruptions , erosions , itching , and crustations .
histologically , bsle is characterized by a subepidermal blister , with a predominantly neutrophilic dermal infiltrate and only occasional eosinophils .
furthermore , immunofluorescence examination showed linear deposition of lgg , lga , c3 , and c1q along the basement membrane zone [ 5 , 6 ] .
because of the particularly clinical and histological presentation of bsle , camisa and sharma proposed diagnostic criteria for bsle ; these include a diagnosis of sle based on the following criteria of the acr ; vesicles and bullae mainly located on sun - exposed areas ; the histopathology is characterised by subepidermal bullae with microabscesses of neutrophils in the dermal papillae , similar to those found in dermatitis herpetiformis and deposition of igg , igm , or both and often iga in the basement membrane zone .
although blse may exhibit any of the symptoms associated with sle , the onset and course of blistering eruption do not necessarily parallel the activity of the systemic involvement .
furthermore , the therapeutic options for sle are not usually fit for bsle [ 9 , 10 ] . in some cases
, the eruption flared after systemic corticosteroid administration for sle [ 11 , 12 ] .
however , most of the patients have a striking therapeutic response to dapsone [ 1316 ] . a response may be seen with very small doses of dapsone . in the case of the present paper ,
other drugs such as cyclophosphamide , azathioprine , and mycophenolate mofetil and biologic drugs may also be effective for bsle treatment . in the part of literature review , we provide a review of all the available treatment options for bsle .
steroids and antimalarials are the standard treatments for the cutaneous manifestations of sle . in unresponsive patients , azathioprine and high dose or pulse steroids , cyclosporin , and pulse cyclophosphamide are the most commonly used alternative therapies [ 1820 ] .
dapsone is less used in the control of the sle rash but has a dramatic improvement in the eruption of bsle patients [ 15 , 16 ] .
we also found that a 22-year - old woman with bsle had multiple tense vesiculobullous lesions on the face , trunk , and limb ( figure 1 ) .
a biopsy from the upper limb showed a subepidermal blister with a predominantly neutrophilic dermal infiltrate and only occasional eosinophils ( figure 2(a ) ) .
immunofluorescence showed a granular band of c1q , c3 , and igg at the basement membrane ; less iga and igm were observed ( figures 2(b)2(f ) ) .
the skin condition showed no response in the methylprednisolone , while a considerable improvement after dapsone administration was observed .
regarding the special clinical feature and the discriminative therapies from the sle treatments , we review all the available treatment for bsle .
dapsone is a sulfone that has played a critical role in the eradication of leprosy . besides , a number of cutaneous eruptions are effectively controlled by dapsone . due to these eruptions that are largely characterized by the presence of cutaneous neutrophilic dermal infiltrate , such as dermatitis herpetiformis and the inflammatory variant of epidermolysis bullosa acquisita
, the mechanism of its anti - inflammatory action mainly relies upon its inhibition of the functions of polymorphonuclearleukocytes and of complement activation via the alternative pathway that has been postulated [ 15 , 23 ] .
although a new or recurrent rash was considered a factor of sle disease activity index , the eruption of bsle was not constantly associated with a flare of sle .
consequently , because of being unparallel with the disease activity , the eruption of bsle patients is often unresponsive to corticosteroid therapy . due to the striking histologic resemblance to dermatitis herpetiformis
, the patients who were treated with dapsone ( 2  mg / kg / day ) usually obtained a dramatic improvement in the eruption .
patients tend to have an efficacious response with cessation of new blister formation in 1 - 2 days and healing of existing lesions within several days . a relatively low dose ( 2550  mg ) has also been shown to have a response [ 1 , 15 , 24 ] .
interestingly , improvement of the eruption did not correlate with amelioration of the systemic manifestations .
the dramatic response to dapsone therapy demonstrated that dapsone is useful in treating bullous lesions of sle [ 5 , 15 , 16 , 26 ] .
notably , the blistering eruption was not improved by dapsone in some cases , and even worsening has been noted after its administration . it has been reported that patients with bsle , who initially presented with lesions clinically resembling erythema multiform , experienced exacerbation of their disease with dapsone [ 2729 ] .
furthermore , dapsone has been assigned to pregnancy category c ; bsle patients with pregnancy might not be fit for administration of this drug .
hemolysis and hepatic and renal toxicity usually accompany administration of the drug in a dose related fashion [ 3134 ] ; therefore its clinic use was confined and a careful monitoring of its toxicity is required .
corticosteroids are usually required to improve clinical symptoms and laboratory abnormalities and are still a mainstay for inducing remission in sle patients [ 18 , 20 , 35 ] .
unexpectedly , many bullous sle patients tend to be unresponsive to systemic corticosteroid therapy that has been described .
furthermore , in some cases of sle patients , the eruption flared a few days after systemic corticosteroid administration [ 11 , 12 ] .
interestingly , some patients responded effectively to corticosteroids , although they required relatively high doses .
a patient with sle who presented with vesiculobullous lesions during the third trimester of pregnancy has been presented .
a skin biopsy of this patient was performed , and it showed significant necrosis of keratinocytes in the epidermis and granular , dense , and continuous deposits of moderate igg positivity in the basement membrane zone .
dapsone has been assigned to pregnancy category c. the pregnant woman treated with high - dose corticosteroids obtained a satisfactory response .
as the dapsone administration often causes hepatic and renal toxicity [ 32 , 33 , 3840 ] , prednisone alone or in combination with low doses dapsone might be the treatment of choice for these bsle patients .
these observations demonstrated that corticosteroids may act as an alternative treatment for bsle when patients are unresponsive or unfit for other drugs .
biologic agents , such as infliximab , rituximab , and anakinra , have emerged as effective therapies for treating a wide spectrum of diseases which includes various rheumatic , gastrointestinal , and cutaneous diseases [ 4144 ] .
the involvement of all of the key components ( especially cytokines and immune cells ) of the immune system in the pathogenesis of sle offers many potential targets for therapeutic management of this disease .
b cells , a critical immune cell , which can act as antigen - presenting cells , differentiate into plasma cell to produce pathogenic autoantibodies and secrete various cytokines and chemokines in the immune response [ 45 , 46 ] .
these functions of the b cell support the fact that it plays an important role in the development of pathogenesis of sle . therefore , use of b cell depletion therapy in sle has emerged as a novel and promising therapeutic alternative for sle patients [ 4749 ] .
rituximab which is a chimeric monoclonal antibody that reacts with cd20 , an antigen that is present on immature , naive , and memory b cells but not on mature plasma cells , has been approved in the treatment of sle . up to now
the patient was treated with hydroxychloroquine ( hcq ) twice daily , mycophenolate mofetil 1000  mg / d , and varying doses of corticosteroids , while the eruption was not improved .
dapsone and azathioprine were added but had to be stopped because of elevated liver enzymes and leukopenia .
mycophenolate mofetil was increased to 2000  mg / d , but her skin disease remained active .
the skin lesions improved within 10 days after the first dose and cleared by day 15 after the second dose . furthermore , prednisone was successfully tapered , and the patient has remained free of recurrence of cutaneous and oral blistering lesions .
the results of this case suggest a potential role for treatment of refractory bsle with rituximab .
methotrexate ( mtx ) has been widely proved to be an effective agent in control of the rheumatoid arthritis .
it has proved that mtx was beneficial in sporadic cases of scle refractory to therapy with conventional therapy [ 5254 ] , such as antimalarials and corticosteroids .
furthermore , in a randomized and double - blind trial in 41 patients with sle , mtx reveals a role for controlling the skin lesions in 75% of cases , with a mean reduction of prednisone dose of 44% .
these reports demonstrated that mtx could represent a valid therapeutic option in controlling the cutaneous sle and in sparing the steroid dose .
however , bsle is a subepidermal blistering disease that occurs in a subset of patients with systemic lupus erythematosus ( sle ) .
cutaneous lesions of bsle are reported during the course of sle in less than 1% of patients , while lesions are not in line with the disease activity .
, a rapid and full resolution of cutaneous lesions was obtained with methotrexate alone . a case of 40-year - old female with systemic lupus erythematosus ( sle ) developed a severe bullous eruption on sun - exposed areas , while the previous manifestations of the disease were quiescent . in consideration of prior intolerance to many drugs ,
hcq is a commonly used drug for controlling the cutaneous lesions and the disease activity of the sle [ 58 , 59 ] , while it does not act effectively in the eruption of bsle .
the conventional treatment for sle only revealed modest improvement in steroids and antimalarials . although cyclophosphamide has been shown to produce moderate improvement of skin lesions of sle , the beneficial role in bsle has not been demonstrated .
mycophenolate mofetil ( mmf ) has been widely used for suppressing the lupus activity , while it also was not valid for bsle , even at a high dose [ 10 , 37 ] . in cases nonresponsive to dapsone
, the eruption has been controlled by prednisone or with combination therapy of prednisone and azathioprine .
in the treatment of bullous sle , dapsone is the effective basic therapy , and it often induces a dramatic response . in some cases , where an adequate response is not achieved with dapsone or the sle disease activity index is high , other immunosuppressants , such as prednisolone , methotrexate , and azathioprine , can be used for controlling the eruption and suppressing the systemic symptoms . moreover , in some special case , where dapsone administration or other chemical drugs ( mtx , azathioprine , etc . )
 bullous systemic lupus erythematosus ( bsle ) is an autoantibody - mediated vesiculobullous disease in patients with sle . 
 autoimmunity in bsle is characterized by the presence of circulating anti - type vii collagen antibodies . 
 bsle patients often present with multiple , tense , clear fluid - filled vesicles and bullae overlying erythematous edematous plaques . 
 skin biopsy from bsle patients shows subepidermal bullae with numerous neutrophils and only occasional eosinophils . 
 furthermore , immunofluorescence examination showed linear deposition of lgg , lga , c3 , and c1q along the basement membrane zone . 
 bsle patients with corticosteroids treatment constantly do not receive a marked improvement , while dapsone generally dramatically improved the skin condition . 
 recently , it has been reported that quite a few cases of bsle were successfully treated with other immune suppressive drugs . 
 therefore , a comprehensive review of the treatment of bsle would be beneficial to cure the disease . 