interleukin ( il)-6 is a cytokine featuring redundancy and pleiotropic activity . it was successfully cloned in 1996 as a b - cell differentiation factor , which promotes b - cell differentiation into antibody - producing cells . subsequent in vitro studies and analysis of il-6 transgenic mice have shown that il-6 acts not only on b cells but also on t cells , hepatocytes , hematopoietic progenitor cells , and various other cells [ 24 ] . one of the important functions of il-6 is the differentiation of cd4 nave t cells into effector cells . il-6 in the presence of tgf- promotes nave t - cell differentiation into th17 cells , while il-6 inhibits tgf--induced regulatory t - cell ( treg ) differentiation , causing imbalance between th17 and treg , which is a primary pathogenic factor in several autoimmune diseases . il-6 transmits its signal through its binding to transmembrane receptors or the soluble il-6 receptor ( il-6r ) [ 7 , 8 ] . after binding of il-6 to il-6r , the resultant il-6/il-6r complex associates with gp130 and induces homodimerization of gp130 , which triggers signal transduction system . the pathological significance of il-6 for diseases was first demonstrated in a case of cardiac myxoma . the culture fluid obtained from the myxoma tissues of a patient who presented with fever , arthritis with positivity for antinuclear factor , increased c - reactive protein ( crp ) levels and hypergammaglobulinemia and was diagnosed with undifferentiated connective tissue disease , contained a large quantity of il-6 , which suggested that il-6 might contribute pathologically to chronic inflammation and autoimmunity . subsequent studies have shown that dysregulation of il-6 production is implicated in the pathogenesis of castleman 's disease , rheumatoid arthritis ( ra ) , and various other autoimmune , inflammatory , and malignant diseases [ 24 ] . because of the biological activities of il-6 and its pathological role in diseases , it was anticipated that il-6 blockage would constitute a novel treatment strategy for autoimmune and inflammatory diseases [ 4 , 1315 ] . to this end , tocilizumab was developed , which is a humanized anti - il-6r monoclonal antibody ( ab ) of the igg1 class that was generated by grafting the complementarity determining regions of a mouse anti - human il-6r ab onto human igg1 . ra is a chronic , progressive inflammatory disease of the joints and surrounding tissues accompanied by intense pain , irreversible joint destruction , and systemic complications such as fatigue , anemia , and fever . at the local level , inflammatory cells invade the otherwise relatively acellular synovium leading to neovascularization , synoviocyte hyperplasia , and formation of pannus tissue , which in turn causes destruction of cartilage , erosion of the adjacent bone , and , ultimately , loss of function of the affected joint . the biological activities of il-6 such as proinflammatory activity , augmentation of synovial fibroblast proliferation , osteoclast differentiation , matrix metalloproteinase ( mmp ) , and vascular endothelial growth factor ( vegf ) production , as well as lymphocyte differentiation and its elevation in both serum and synovial fluids of patients with ra [ 1722 ] indicate that il-6 is one of the key cytokines involved in the development of ra . it has been demonstrated in animal model of ra , that are type ii collagen - induced arthritis ( cia ) , and antigen - induced arthritis , il-6 performs a major role in the development and progression of joint destruction , while il-6 deficiency generated by gene knockout or il-6 blockade by means of anti - il-6r ab reduces the incidence and severity of arthritis in these models [ 2328 ] . in the cia model , immunization with type ii collagen predominantly increased the frequency of th17 cells and treatment of mice with anti - il-6r ab during priming markedly suppressed the induction of th17 cells and arthritis development , while treatment with anti - il-6r ab on day 14 failed to suppress both th17 differentiation and arthritis . similarly , in a glucose-6-phosphate - isomerase- ( gpi-)induced arthritis model , administration of anti - il-6r ab on day 0 or 3 suppressed th17 differentiation and protected against arthritis induction , while injection of anti - il-6r ab on day 14 , at the peak of arthritis , did not bring about any improvement in arthritis . arthritis of anti - type ii collagen antibody - induced arthritis ( caia ) is another arthritis model , but , in this model , the priming phase of t cell dependent antibody generation is skipped . although il-6 is also elevated in this model , caia was profoundly suppressed in tnf mice but not in il-6 mice , indicating that tnf may play a more significant role in the development of caia than il-6 . these observations suggest that in the priming phase il-6 is a required factor for the activation of t cell response and production of antibodies specific for joint components and that in the effector phase tnf is the main generator of arthritis . we found that tocilizumab was not effective for clinical improvement in the condition of two patients with psoriatic arthritis , for whose development immune activation does not appear to be required . the clinical antiarthritic effect of tocilizumab is slower than that of tnf inhibitors , which may be due to the different pathological roles of il-6 and tnf in the development of ra ( figure 1 ) . as shown in table 1 , seven phase iii clinical trials of tocilizumab subsequent to phase i and ii studies demonstrated its efficacy either as monotherapy or in combination with disease - modifying antirheumatic drugs ( dmards ) for adult patients with moderate to severe ra [ 3440 ] . a cochrane database systematic review concluded that tocilizumab - treated patients taking concomitant methotrexate were four times more likely to achieve american college of rheumatology ( acr ) 50 improvement ( absolute % , 38.8% versus 9.6% ) and 11 times more likely to achieve disease activity score ( das ) remission ( 30.5% versus 2.7% ) than patients taking a placebo . furthermore , the samurai   and lithe studies   proved that radiological damage of joints was significantly inhibited by the treatment . the findings of the radiate trial showed that , among ra patients who had previously discontinued tnf inhibitors 50% achieved acr20 , 28.8% acr50 , and 12.4% acr70 responses . the acr improvement and das remission criteria include an acute - phase reactant component , so that there was concern that the effect of tocilizumab evaluated with these criteria might be overestimated . however , it was found that , even when criteria such as the simplified disease activity index ( sdai ) and clinical disease activity index ( cdai ) were used , remission rates for patients treated with tocilizumab were in the same range as those for patients treated with tnf inhibitors [ 42 , 43 ] . on the basis of the excellent results obtained for the efficacy of tocilizumab , it was approved in april 2008 for the treatment of ra in japan . the recommended posology of tocilizumab ( proprietary name , actemra ) is 8  mg / kg , every 4 weeks . subsequently , the european medicines agency approved tocilizumab ( proprietary name , roactemra ) for ra in january 2009 at a recommended dose of 8  mg / kg . in the united states , it was approved for ra in january 2010 , but the recommended starting dose is 4  mg / kg administered once every 4 weeks followed by an increase to 8  mg / kg depending on clinical response . while the dosage differs among countries , tocilizumab has now been approved for the treatment of ra in more than 90 countries worldwide . in addition to clinical trials , the efficacy of tocilizumab was reconfirmed in actual medical practice . the finding by the three recent studies , the german phase iiib real - life study ( tamara study ) [ 44 , 45 ] , the danish nationwide cohorts of ra patients ( danbio registry ) study , and the multicenter retrospective real - life study ( reaction study ) [ 47 , 48 ] are shown in table 2 . in the tamara study , 286 patients were registered for an analysis of the effectiveness and safety [ 44 , 45 ] , 41.6% of whom had previously been treated with tnf inhibitors . acr50 and acr70 response rates at week 24 were 50.7% and 33.9% , respectively , while 47.6% of the patients achieved das remission and 54.9% the european league against rheumatism ( eular ) good response . remission rates with the new acr / eular boolean - based criteria for clinical studies were 15.0% after 12 weeks and 20.3% after 24 weeks , and cdai and sdai remission rates were 24.1% and 25.2% , respectively . for the danbio registry in denmark , the disease activity decreased at all - time points , with remission rates for tocilizumab treatment of 39% after 24 weeks and 58% after 48 weeks . these response rates were comparable to those found for patients switching to their second tnf inhibitors and to the response rates previously observed in phase iii clinical trials . in japan , 229 patients were registered in the reaction study for an analysis of the effectiveness of tocilizumab [ 47 , 48 ] . clinical remission at week 52 was observed in 43.7% of the patients , radiographic non - progression in 62.8% , and functional remission in 26.4% . the retention rates at 24 and 52 weeks were 79.5% and 71.1% , respectively , and were the same for those with or without previous anti - tnf treatment . these results indeed show the efficacy of tocilizumab for the treatment of ra in actual medical practice . the safety and tolerability profiles of tocilizumab monotherapy for japanese ra patients obtained from six initial trials and five long - term extensions have been published . for these studies , 601 patients with a total exposure to tocilizumab of 2,188 patient - years ( pt - yr ) were enrolled . the incidence of adverse events ( aes ) , including abnormal laboratory test findings , was calculated as 465/100 pt - yr , with infections being the most common serious aes ( 6.2/100 pt - yr ) . of the patients treated more than 5 years , 59.7% met the das28 remission criteria at 5 years , which demonstrates the excellent tolerability and high efficacy of tocilizumab . in addition , a systemic literature review to assess the risk of aes for ra patients treated with tocilizumab reported that pooled odds ratios ( ors ) indicated statistical significance for an increased risk of aes for patients treated with 8  mg / kg of tocilizumab plus methotrexate compared with controls ( or = 1.53 ; 95%ci = 1.261.86 ) , as well as a heightened risk of infection ( or = 1.30 ; 95%ci = 1.071.58 ) . the results of an interim analysis of a postmarketing surveillance of all patients treated with tocilizumab in japan were recently reported . this analysis comprised 3,881 patients who received 8  mg / kg of tocilizumab every 4 weeks , and was observed for 28 weeks . occurrence of a total of 3,004 aes in 1,641 patients ( 167/100  pt - yr ) and 490 serious aes in 361 patients ( 27/100  pt - yr ) was reported . the most frequent ae and serious ae were infection at 31/100  pt - yr and 9/100  pt - yr , respectively , with the majority of infections being pneumonia and cellulitis . . abnormalities in laboratory test findings , such as increases in lipid and liver function parameters were common , and total and serious aes associated with laboratory test abnormalities were 35/100  pt - yr and 2/100  pt - yr , respectively . the increased lipid level resulting from tocilizumab administration is perhaps mediated by its effecting on lipoprotein receptor expression , since it was recently shown that overproduction of il-6 reduces blood lipid levels via upregulation of very - low - density lipoprotein receptors . in contrast , we and others observed that hba1c levels and insulin sensitivity improved as a result of tocilizumab treatment [ 53 , 54 ] . while white blood cell and neutrophil counts usually decreased just after tocilizumab injection , this was not related to the incidence of infection . twenty - five patients died for a standardized mortality ratio of 1.66 , which was similar to the results reported for a japanese cohort study of ra . the results of this analysis thus demonstrated that tocilizumab is acceptable in the actual clinical setting . seven cases of gastrointestinal ( gi ) perforation in six patients were reported in this postmarketing surveillance . in the worldwide roche clinical trials , 26 ( 0.65% ) cases of gi perforation were found among patients with ra treated with tocilizumab for a rate of 1.9/1,000  pt - yr and most cases appeared to be complications of diverticulitis . this rate is intermediate between the rates of gi perforations of 3.9/1,000  pt - yr for corticosteroids and 1.3/1,000  pt - yr for anti - tnf agents reported in the united health care database . the reactivation of tuberculosis is a major concern during anti - tnf treatment , but there is no medical consensus regarding the effect of il-6 blockade on tuberculosis . examined the effects of il-6 and tnf blockade on the development of tuberculosis infection in mice and observed that there was less tuberculosis infection for anti - il-6r ab than for anti - tnf ab . in addition , we showed that tuberculosis antigens - induced interferon ( ifn)- production was suppressed by the addition of tnf inhibitors ( infliximab and etanercept ) but not of tocilizumab . although it seems likely that the incidence of reactivation of tuberculosis is lower during tocilizumab treatment than that during anti - tnf treatment , further detailed studies will be needed to clarify this point . these include anti - tnf blockers ( infliximab , etanercept , adalimumab , golimumab , and certolizumab ) , an il-1 antagonist ( anakinra ) , a b - cell depletor ( rituximab ) , an il-6 receptor inhibitor ( tocilizumab ) , and a t - cell activation blocker ( abatacept ) . these biological modifiers target different molecules and b cells , leading to different clinical effects and causing different adverse effects . since no head - to - head comparative studies have been made of the efficacy of these various agents , it has not yet been determined which of these biologics should be selected for a given patient . currently , one of the anti - tnf drugs is chosen as a first - line biologic , but between 14 and 38% of patients show no or little response to anti - tnf treatment , with as many as 40% of patients discontinuing these drugs within a year and 50% within 2 years . the findings of the radiate trial showed that ra patients who had previously discontinued tnf inhibitors , mainly due to their inefficacy , achieved acr20/50/70 responses of 50% , 28.8% , and 12.4% , respectively , when tocilizumab was administered at 8  mg / kg every four weeks . at present , tocilizumab is likely to be prescribed as a second - line biologic therapy but will have to overcome significant competition from established anti - tnf therapies . it is anticipated that tocilizumab will be selected as a first - line biologic for moderately to severely active ra patients with certain complications . aa amyloidosis is a serious complication of ra , and amyloid fibril deposition causes progressive deterioration in various organs [ 59 , 60 ] . since the gene activation of serum amyloid a , a precursor protein of amyloid a fibril , depends primarily on il-6 [ 61 , 62 ] , tocilizumab administration was found to promptly reduce serum concentrations of saa , just as in the case of crp . three case reports showed the clinical ameliorative effect of tocilizumab on gastrointestinal symptoms due to intestinal amyloidosis [ 6365 ] , and amyloid a fibril deposits were found to have disappeared in two cases after three injections of tocilizumab [ 63 , 65 ] . this suggests that tocilizumab may be suitable as a first - line drug for ra patients who are complicated with or are at high risk of developing aa amyloidosis . remission induction is the current goal for ra , and with the development of biological modifiers , a growing number of ra patients has been able to achieve this goal . the long - term efficacy after cessation of tocilizumab followed by das28 remission was demonstrated in the dream ( drug - free remission after cessation of actemra monotherapy ) study . the continuous rate of tocilizumab - free efficacy was 35.1% at 24 weeks and 13.4% at 52 weeks . serum levels of il-6 and mmp-3 are useful markers for identifying patients who may be able to discontinue tocilizumab without risk of recurrence . in addition , the restore study ( retreatment efficacy and safety to tocilizumab in patients with rheumatoid arthritis at recurrence ) demonstrated that retreatment of all relapsed patients with tocilizumab resulted in re - remission . systemic lupus erythematosus ( sle ) is a multisystem autoimmune disorder with a broad spectrum of clinical presentations of unknown etiology that mainly affects young women . the pathogenesis of sle remains unclear , but the concept of apoptosis goes some way towards explaining how the immune system may recognize mainly intracellular antigens . defects in the clearance of apoptotic cells have been recognized in sle patients , leading to aberrant uptake by macrophages , which then present intracellular antigens to t and b cells , thus driving the autoimmune process . cytokine dysregulation is pervasive , and its expression profiles may serve as a marker of disease activity and severity . recent findings have highlighted type i interferon pathway   or th17 cell activation   in the pathogenesis of sle . levels of crp have been shown to rise in acute illness but not in sle flares , indicating that il-6 , a major regulator of crp production , has a minor role in sle development . however , recent findings suggest that crp dysregulation also plays a part in the pathogenesis of sle   and sle may well be a potential target for il-6 blockade . urinary excretion and renal expression of il-6 was elevated in sle patients with active proliferating lupus nephritis [ 76 , 7881 ] , as were il-6 levels in the cerebrospinal fluid of sle patients with central nervous system involvement . compared to healthy controls , sle patients had significantly more il-6 secreting peripheral blood mononuclear cells [ 83 , 84 ] . lymphoblastoid cells isolated from sle patients produced higher levels of il-6 and blocking of il-6 inhibited anti - double - stranded dna ( dsdna ) ab production in vitro [ 85 , 86 ] , indicating that il-6 is involved in autoantibody production . in murine sle models , age - associated increases in serum il-6 , soluble il-6r , and abnormal expression of il-6r have been detected in mrl / lpr mice [ 8789 ] . in old nzb / w mice , anti - il-6 ab reduced and exogenous il-6 increased production of igg dsdna ab by b cells [ 90 , 91 ] . furthermore , il-6 administration exacerbated glomerulonephritis [ 92 , 93 ] , while il-6 blockade by means of anti - il-6r or anti - il-6 ab prevented the onset and progression of the disease [ 94 , 95 ] . mice with epidermal loss of junb reportedly developed an sle phenotype linked to increased epidermal il-6 secretion , and facial skin biopsies of sle patients displayed low levels of junb protein expression , high il-6 , and activated stat3 levels within lupus lesions . these findings led to an open - label phase i dosage - escalation study of tocilizumab ( 2  mg / kg , 4  mg / kg or 8  mg / kg , every 2 weeks for 12 weeks ) with an enrollment of 16 sle patients with mild - to - moderate disease activity . significant improvement in the modified safety of estrogens in lupus erythematosus national assessment version of the systemic lupus erythematosus disease activity index score was observed in 8 of the 15 evaluable patients , accompanied by a median reduction in anti - dsdna ab levels of 47% . the percentage of cd38cd19igd plasma cells in the peripheral blood , which was higher for sle patients than for normal controls ( mean 5.3% versus 1.2% ) , was significantly reduced to 3.1% at 6 weeks . systemic sclerosis ( ssc ) is a connective tissue disease , characterized by fibrosis of the skin and internal organs , vasculopathy , and immune abnormalities . il-6 in the serum of ssc patients was reportedly elevated and the level correlated with the skin severity score [ 100104 ] . moreover , the culture supernatants of peripheral blood mononuclear cells and skin tissues from ssc patients contained higher concentrations of il-6 than those from controls [ 105109 ] . in vitro studies demonstrated that il-6 may contribute to fibrosis by inducing collagen production   and induce -smooth muscle actin ( -sma ) expression by dermal fibroblasts , leading to their differentiation into myofibroblasts . on the other hand , anti - il-6 ab suppressed procollagen type 1 production in fibroblasts derived from ssc patients in vitro . ssc serum mediated largely by il-6 was found to induce endothelial cell activation and apoptosis in endothelial cell - neutrophil cocultures . il-6 is also associated with humoral and cellular immunological abnormalities in ssc [ 98 , 99 ] . il-6 is thus thought to play a significant role in producing the characteristics of ssc . moreover , in a ssc model mouse , induced by immunization with topoisomerase i and complete freund 's adjuvant , loss of il-6 expression could ameliorate skin and lung fibrosis . we also examined the clinical effect of tocilizumab on two diffuse ssc patients who had been resistant to conventional treatment regimens . six months after the treatment , both patients showed softening of the skin with reductions of 50.7% and 55.7% for the total z - score determined with the vesmeter , a novel device for measuring the physical properties of the skin , and of 51.9% and 23% for the modified rodnan total skin score . histological examination showed thinning of the collagen fiber bundles and reduction of the number of -sma positive cells in the dermis . since there are few therapeutic drugs for ssc at the present time , these improvements suggest that tocilizumab appears to be a promising biologic for the treatment of ssc . the inflammatory myopathies encompass a group of heterogenous muscle diseases which share the common clinical features of slowly progressive symmetrical muscle weakness , decreased muscle endurance , and fatigue . they include polymyositis ( pm ) , dermatomyositis , and inclusion body myositis , but are generally considered to be distinct diseases with different pathophysiological mechanisms . muscles produce il-6 , and il-6 has been also shown to play a regulatory role in muscle wasting . among these inflammatory myopathies , pm appears to be another suitable target disease for tocilizumab . excessive il-6 expression has been found in the sera and infiltrating mononuclear cells in the muscles of pm patients [ 121123 ] . infiltrating cytotoxic t cells are thought to be involved in muscle fiber damage , and il-6 functions as a helper factor in the induction of cytotoxic t cells . moreover , in a model of myosin - induced experimental myositis it was shown that control mice developed clinically manifest muscle damage , whereas il-6-deficient mice showed no clinical or histological signs of muscle damage . in another model of pm , known as c - protein - induced myositis , intraperitoneal administration of anti - il-6r ab suppressed the severity of myositis preventatively as well as therapeutically . we tested the efficacy of tocilizumab in two pm patients who had been refractory to corticosteroids and immunosuppressive drugs . creatine phosphokinase levels of both patients normalized and mr images showed the disappearance of high - intensity zones in the thigh muscles . these findings suggest that tocilizumab may also be effective as a novel drug for refractory pm . dermatomyositis is a complement - mediated microangiopathy associated with destruction of capillaries , hypoperfusion , and inflammatory stress on the perifascicular regions , so that the pathology is different from that of pm . production of il-6 and type i interferon signature genes was recently proposed as a biomarker for disease activity in childhood dermatomyositis , which thus may be another disorder suitable for tocilizumab targeting . the pathological consequence of such inflammation is destruction of the vessel wall , which is histologically detected as fibrinoid necrosis . takayasu 's arteritis ( ta ) and giant cell arteritis ( gca ) belong to an entity designated vasculitis syndrome , and involve both large and medium - sized arteries [ 129 , 130 ] . the pathogenesis of ta and gca remains unclear , but it is clear that il-6 is involved in their development [ 129133 ] . tocilizumab treatment for a 20-year - old woman with refractory active ta improved the clinical manifestations and abnormal laboratory findings , and subsequent studies reported that tocilizumab treatment induced a rapid remission in 2 patients with ta and 5 patients with gca . surprisingly , two of the patients with gca went into remission without concomitant use of corticosteroids . moreover , tocilizumab was also shown to be effective as rescue treatment for three gca patients for whom the prednisone dose could not be tapered to less than 30  mg / day . positron emission tomography / ct scans revealed that in two patients generalized large - vessel vasculitis was detected during the active phase , which completely resolved upon a 6-month course of tocilizumab therapy . these reports strongly imply that il-6 inhibition may serve as an innovative strategy for the treatment of both ta and gca . however , several studies have suggested that gca patients with a lesser inflammatory response without an increase in il-6 expression were at a higher risk of developing ischemic manifestations than were other patients , since the angiogenic activity of il-6 offers protection against ischemia in such gca patients . these findings indicate that further clinical studies are required to evaluate the efficacy and safety of tocilizumab for gca and ta . it is worthy of note that il-6 has been also implicated in the development of other types of vasculitis syndrome such as polyarteritis nodosa ( pan ) and antineutrophil - cytoplasmic - antibody- ( anca ) associated vasculitis [ 139142 ] . however , so far there have been no reports about off - label use of tocilizumab for pan or anca - associated vasculitis . on the basis of excellent results of the efficacy of tocilizumab for castleman 's disease [ 143 , 144 ] and systemic juvenile idiopathic arthritis [ 145147 ] , it has been approved and used as the first - line biologic in japan . pilot studies and case reports with off - label use of tocilizumab also indicate the potential indications of this biologic for various other organ - specific autoimmune and chronic inflammatory diseases . these include relapsing polychondritis , acquired hemophilia a , autoimmune hemolytic anemia , adult - onset still 's disease [ 151165 ] , crohn 's disease , bechet 's disease with posterior uveitis , polymyalgia rheumatica [ 135 , 168 ] , remitting seronegative , symmetrical synovitis with pitting edema , spondyloarthritides [ 170175 ] , graft - versus - host disease [ 176 , 177 ] , tnf - receptor - associated periodic syndrome , and pulmonary arterial hypertension complicated with castleman 's disease or mixed connective tissue disease [ 179181 ] . further clinical trials are essential , however , to evaluate the efficacy and safety of tocilizumab for these diseases . acute il-6 synthesis provides a warning signal and protects the host from environmental stress , while its prolonged production causes the onset and progression of various autoimmune diseases . several clinical trials have verified the efficacy and safety of tocilizumab for ra , systemic juvenile idiopathic arthritis and castleman 's disease , resulting in approval of this innovative biologic for the treatment of these diseases . case reports of off - label use or pilot studies have also raised the possibility that tocilizumab could become the biological drug of choice for other systemic autoimmune diseases including sle , systemic sclerosis , polymyositis and large vessel vasculitis . at present , the mechanisms through which tocilizumab exerts its clinical ameliorative effects on phenotypically different autoimmune diseases are not completely understood . il-6 blockade may suppress autoantibody production or correct the imbalance of autoantigen - specific th17 and/or th1 versus treg . thus , clarification of the mechanisms as well as further clinical trials to evaluate the efficacy and safety of tocilizumab for these diseases are important issues .
interleukin ( il)-6 is a cytokine featuring redundancy and pleiotropic activity . while il-6 , when transiently produced , contributes to host defense against acute environmental stress , continuous dysregulated il-6 production plays a significant pathological role in several systemic autoimmune diseases . in response to the expectation that il-6 blockade would constitute a novel therapeutic strategy for the treatment of these diseases , tocilizumab , a humanized anti - il-6 receptor antibody , was developed . 
 clinical trials have verified the efficacy and the safety of tocilizumab for patients with rheumatoid arthritis , resulting in approval of this innovative biologic for the treatment of rheumatoid arthritis in more than 90 countries worldwide . 
 pathological analyses of the effect of il-6 on the development of autoimmune diseases and a considerable number of case reports and pilot studies have also indicated the beneficial effects of this antibody on other systemic autoimmune diseases , including systemic lupus erythematosus , systemic sclerosis , polymyositis , and large - vessel vasculitis .