lupus erythematosus is a chronic , autoimmune disease resulting from an interaction of genetic , environmental , and hormonal factors and characterized by a spectrum of clinical forms with a variable evaluation from a localized cutaneous form to life - threatening systemic form . specific skin lesions of cutaneous lupus erythematosus are classified as acute cutaneous lupus erythematosus , subacute cutaneous lupus erythematosus ( scle ) , and chronic cutaneous lupus erythematosus , according to the clinical characteristics of the lesions . subacute cutaneous lupus erythematosus ( scle ) may present with annular or papulosquamous cutaneous lesions that are symmetrically located in the sun - exposed areas of the body . scle shows typical serological findings , with anti - ro ( ss - a ) antibodies present in up to 100% of patients [ 3 , 4 ] . however , antinuclear antibodies ( anas ) , complement c3/c4 deficiency , rheumatoid factor , circulating immune complexes , lymphopenia , and thrombocytopenia can frequently be detected . severe neurological or nephrological involvement is rare in scle , whereas mild musculoskeletal involvement is commonly observed . it is well known that some patients suffering from cle develop extracutaneous manifestations during the course of their disease ; up to 30% of patients with scle show systemic involvement . most patients with scle can be sufficiently treated with photo protection , topical corticosteroids , antimalarials , or a combination of these . the complement system is a group of plasma and membrane proteins that are sequentially activated via proteolytic cleavages to defend against microbial infections [ 7 , 8 ] . complement contributes to inflammation and tissue damage in this disease , but seemingly in paradox , deficiency of some complement proteins dramatically increases the risk for sle . deficiency states within the classical pathway are associated with increased risk to develop sle and sle - like disease . genetically determined complement deficiencies are inborn errors and may have an impact on the development of the immune system . classical pathway deficiency has led to different hypothesis to explain roles for complement in sle pathogenesis . complement deficiency leads to impaired handling of immune complex and inadequate clearance apoptotic cell debris [ 11 , 12 ] . another hypothesis suggests that the complement system has an important role in the development of tolerance against self  . also , complement deficiency results in lack of normal b - cell tolerance and provides production of autoantibodies . in addition , complement components are in some ways also important for regulation of cytokine production , especially type 1 interferons have been shown to have a central role in the pathogenesis of sle [ 14 , 15 ] . while the genetic basis for a majority of sle cases is polygenic , a homozygous deficiency in one of the early complement components alone can be strong enough to cause the disease , a situation similar to a single gene defect in an autosomal recessive disease [ 16 , 17 ] . respectively , 93% and 78% of patients with complete c1q and c4 deficiencies eventually develop sle or a lupus - like disease . genetically , the complement c4 gene located in the class iii region of the major histocompatibility complex ( mhc ) on chromosome 6p21.3 . these proteins are segregated into two classes , the acidic c4a and the basic c4b . c4a is believed to be important in the clearances of immune complexes , and c4b is more powerful in propagating the complement activation cascades . the complete absence of both c4a and c4b proteins may therefore lead to decreased ability of immune defense against microbes as well as inefficient disposal of immune complexes . to date , 28 individuals with complete c4 deficiency from 19 families have been reported [ 21 , 22 ] . among them , 15 individuals developed sle , 7 developed lupus - like diseases , and four of the remaining subjects were only inflicted by kidney diseases .   in this study , we present the clinical features and determine the molecular basis responsible for the complete c4a and c4b deficiencies in a lupus patient presented with subacute cutaneous lupus erythematosus and progression systemic form and resistance to treatment . seventeen - year - old patient was a male born by parents of non consanguineous marriage . he was diagnosed with scle at the age of 15 years old and had local therapy in dermatology clinic before admitting our clinic . his temperature 38.3 , respiratory rate 38/min , pulse rate 100/min , and blood pressure was found as 90/70  mmhg . in auscultation , lungs were clear and the heart sounds were normal . his clinical presentation included severe malar rash with marked photosensitivity and bullous lesions on the tips of fingers and hands ( figure 1 ) . there was interface dermatitis with irregularity and loss of basal cells . in the papillary and upper reticular dermis was a perivascular and interstitial lymphocytic infiltrate . there was granular deposition of ig a , igm , and c3 at the dermal - epidermal junction . also he has arthritis which described swelling , tenderness , and pain on all small joints . laboratory tests showed an erythrocyte sedimentation rate ( esr ) of 100  mm / h , c - reactive protein of < 0.3  mg / dl ( normal ) , hemoglobin of 11.1  g / dl , hematocrit of 31% , white blood cell count ( wbc ) of 4900/mm with normal differential count , platelet count of 197000/mm , serum urea of 25  mg / dl , serum creatinine of 0.8  mg / dl , albumine of 3.5  g / dl , total cholesterol of 106  mg / dl , triglycerides of 57  mg / dl , calcium of 8.7  mg / dl , sodium of 140  meq / l , potasium of 4.7  meq / l , chloride of 107  meq / l , alanine aminotransferase of 23 he had positivity for antinuclear antibody ( 1/1280 ) , positivity for anti - ro / ssa antibodies and negative ds dna . prior laboratory measurements showed no detectable c4 proteins , serum c3 levels were lower ( 77  mg / dl ) and c1q inhibitor levels were normal . immunofluorescence experiments showed mesangial deposits of igg , c3 ( + + + ) , iga ( + + + ) and c1q ( + ) .   after he was diagnosed as sle according to american college of rheumatology ( acr ) criteria , high - ose  pulse  therapy was performed with methylprednisolone ( 30  mg / kg / day for 3 days ) , followed by prednisone ( 2  mg / kg / day ) , hydroxychloroquine ( 5  mg / kg / day ) , and topical therapy . he started cyclophosphamide pulse therapy ( 500  mg / m ) because his complains were not resolved . after from second dose of cyclophosphamide ( 750  mg / m ) , he had urticarial lesions and stopped this therapy . he started mycophenolate sodium ( 720  mg / day ) . in spite of these medications , his skin lesions , he received rituximab infusions at a dose of 1 gram at days 1 and 15 . in addition , a 100-mg dose of intravenous methylprednisolone was given immediately prior to the rituximab infusion . after rituximab therapy was administered , oral low dose prednisolone ( 0,5  mg / kg7day ) and mycophenolate sodium were continued . his complaints and laboratory values and sledai scores were improved significantly after rituximab treatment , as shown in figure 1(b ) . repeated laboratory measurements showed no detectable c4 proteins , but serum c3 levels were normal . after pcr amplification with intron - exon binding primers , mutation was detected by direct dna sequencing method . we report a child with sle and c4 deficiency and with severe skin involvement that proved to be subacute cutaneous lupus erythematosus ( scle ) . in our patient , the diagnosis of sle was based on the presence of constitutional symptoms , malar rash , photosensitivity , oral ulceration , arthritis , anemia , a high titer of ana , and low c3 , c4 . the patient resistant to initial therapies including hqk , prednisolon and cyc . rituximab is a chimeric monoclonal igg1antibody that binds specifically to the cd20 antigen and mediates b- cell lysis . prior studies have shown that rituximab therapy can be a safe and efficacious addition to therapy with standard immunosuppressive agents in patients with refractory childhood sle [ 2429 ] . in our case , rituximab led to a remarkable improvement of skin lesions , resulting in a significant decrease of the sledai from 20 at the beginning to 5 at the end of therapy . in addition , he exhibited a low c4 level during the extended period of observation . finally , the genetic phenotyping of complement revealed that he was homozygous for c4b deficiency . sle is a systemic autoimmune disease characterized by the breakdown of immunotolerance and the production of a wide range of autoantibodies that target multiple tissues and organs . these are estimated to be found in less than 1% of sle patients [ 31 , 32 ] . respectively , 93% and 78% of patients with complete c1q and c4 deficiencies eventually develop sle or a lupus - like disease [ 22 , 33 ] . in addition , the concordance rates for siblings with homozygous deficiency of c1q or c4 to develop sle are 90% and 80% , respectively , which are even higher than the rate in monozygotic twins ( 2660% ) with other genetic defects . indeed , approximately 15% of caucasian sle patients exhibit homozygous c4a deficiency , whilst more than 50% of caucasian patients with sle have heterozygous c4a deficiency . c4b deficiency caused autoimmune - associated diseases , such as systemic lupus erythematosus , or diseases with an autoimmune component , such as autism [ 36 , 37 ] . heterozygous and homozygous deficiencies of c4a were present in 4060% of sle patients from almost all ethnic groups such as northern and central europeans , anglo - saxons , caucasians in the us , african americans , asian chinese , koreans , and japanese . the major causes for c4aq0 in caucasian and african sle patients are the presence of a mono - s rccx module with a single , short c4b gene and the 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant c4a gene . we found heterozygous genetic deficiency of c4a gene , also heterozygous and homozygous deficiencies of c4b in our patient .   in conclusion , we report a case of c4b deficiency accompanied with sle with therapy - resistant skin involvement . further studies are needed to clarify the relationship of c4b deficiency and sle which presented severe skin involvement .