igg4-related diseases are systemic syndromes characterized by elevated serum levels of igg4 and igg4-positive lymphoplasmacytic infiltrative lesions in the body .
it was first observed that mikulicz 's disease correlated with igg4-related disease   and later determined that igg4-related disease can occur in any ocular adnexal tissues [ 25 ] .
here , we review the clinicopathological features , differential diagnosis , and treatments of orbital igg4-related disease on the basis of a meta - analysis of 42 patients including 3 case series studies .
the median age of patients with orbital igg4-related disease is 59 years ( range : 30 to 86 years ) with a 1  :  1 male - to - female ratio [ 35 ] .
notably , there is a 1  :  3 for bilateral lacrimal lesions similar to finding in mikulicz 's disease .
although orbital igg4-related disease can occur in men and women of any age , many patients have a history of allergic diseases such as asthma and allergic rhinitis .  
the signs and symptoms of orbital igg4-related disease are chronic lid swelling ( figure 1 ) and proptosis ( figure 2 ) , but otherwise there are only mild signs , or no signs of inflammation or periocular pain .
ocular motility is restricted mildly if at all , despite the presence of one or more enlargements of the large extraocular muscles ( figure 1 ) .
there are generally no visual disturbances , although they may occur due to apical orbital lesions ( figure 2 ) .
imaging studies show infiltrative lesions in ocular adnexal tissues such as the lacrimal glands ( figure 1 ) [ 25 ] , extraocular muscles ( figure 1 ) [ 3 , 4 ] , infraorbital nerves ( figure 2 ) , optic nerve sheath , lacrimal sac , and even cavernous sinus ( figure 2 ) or the intracranial extension . in cases of orbital igg4-related disease
, 62% have bilateral lesions , 69% have lacrimal gland involvement , and 48% have bilateral lacrimal gland involvement [ 35 ] .
patients with orbital igg4-related disease sometimes have systemic igg4-related lesions in their submandibular glands ( 29% ) , lymph nodes ( 14% ) , pancreas ( 5% ) , or bile ducts ( 5% ) [ 35 ] .
igg4-related lesions in the thyroid and pituitary may also be present [ 7 , 8 ] .
chronic rhinosinusitis with orbital igg4-related lesions has similar histology ( figure 3 ) , although nonspecific chronic rhinosinusitis can be also associated with igg4-positive plasma cells in the lesions .
laboratory data of patients with orbital igg4-related disease show elevated serum levels of igg4 and ige , as well as hypergammaglobulinemia [ 25 ] .
high igg4 levels are associated with elevated levels of the soluble interleukin ( il-2 ) receptor .
sclerosing pancreatitis and cholangitis , considered as igg4-related diseases , have lymphocytes that signal for il-4 and il-10 in situ .
although an etiology for the igg4-related group of disease has been not determined yet , one plausible hypothesis for these serological and immunological abnormalities is that they result from in vivo activation of the immune system by activated th2 cells [ 3 , 10 ] .
the histology of orbital igg4-related disease includes different degrees of lymphoplasmacytic infiltration with dominant sclerosing lesions or reactive lymphoid follicle ( reactive lymphoid hyperplasia , figure 3 ) [ 25 ] .
rarely , orbital igg4-related disease may have an infiltration by lymphoplasmacytic cells and macrophages containing eosinophilic material .
igg4-related diseases in the body are characterized histologically by obliterative phlebitis ; however , it is rare in orbital igg4-related disease .
immunohistochemical analysis shows igg4-positive plasma cells ( figure 3 ) , which differentiate igg4-related disease from other inflammatory conditions arising from the ocular adnexa [ 3 , 4 ] .
for optimal treatment and resolution , orbital igg4-related disease must be differentiated from the following : idiopathic orbital inflammation , idiopathic orbital myositis , marginal zone b - cell lymphoma , antineutrophil cytoplasmic antibody- ( anca- ) mediated systemic vasculitis ( such as churg - strauss syndrome and wegener granulomatosis ) , and reactive lymphoid hyperplasia without igg4-positive plasma cells ( figure 4 ) .
they are characterized by sudden onset of orbital inflammation , periocular pain , swelling and redness of the eyelids , proptosis , ptosis , and ocular motility restrictions .
however , some cases of idiopathic orbital inflammation have atypical signs and symptoms , that is , they have lacked acute onset and inflammatory signs . in such cases ,
ocular adnexal marginal zone b - cell lymphomas make up the majority of lymphomas arising from the ocular adnexa .
they are characterized histologically by the presence of reactive follicles in up to 64% of cases , sclerosis in up to 20% of cases , and plasma cells in up to 35% of cases .
in addition , 9% of patients with ocular adnexal marginal zone b - cell lymphomas have infiltration of igg4-positive plasma cells and elevated serum level of igg4 .
evidence of light chain restrictions by in situ hybridization and immunoglobulin heavy chain gene rearrangements by southern blot analysis can differentiate between marginal zone b - cell lymphomas with igg4-positive plasma cells and igg4-related inflammatory disorder .
ocular adnexal lymphomas are reported to arise in igg4-related sclerosing dacryoadenitis , indicating a possible link between the two conditions .
the symptoms of patients with orbital lesions include periocular pain , which can differentiate these patients from those with orbital igg4-related disease
thus , anca - related vasculitis may not only include nonspecific inflammatory lesions , but also have abundant igg4-positive plasma cells .
finally , mikulicz 's disease includes symmetrical bilateral lacrimal gland enlargements and frequently correlates with igg4-related disease .
however , symmetrical bilateral lacrimal gland enlargements do not always indicate igg4-related lesions ( figure 4 ) .
treatments for patients with orbital igg4-related diseases may include systemic steroids , radiotherapy , or rituximab [ 35 ] .
studies of each of these treatments involved relatively few patients , making it difficult to evaluate the treatment outcomes via meta - analysis .
orbital igg4-related diseases resolve after systemic steroid therapy , but relapse is often observed following therapy discontinuation . in mikulicz 's disease , relapses of lesions are observed when steroids were discontinued .
therefore , it may be best to continue prednisolone at 5 to 10  mg / day or to combine prednisolone with an immunosuppressant such as azathioprine .
rituximab treatment leads to prompt clinical and serologic improvement in patients with refractory igg4-related diseases , although recurrence is also observed after rituximab treatment ends in some patients with orbital igg4-related disease .
orbital igg4-related disease has several unique characteristics that distinguish it from other orbital inflammatory conditions .
orbital igg4-related disease differs from other igg4-related diseases in the body in that it arises from nonglandular lesions and is not associated histologically with obliterative phlebitis .
 orbital igg4-related disease , which can occur in adults of any age , is characterized by igg4-positive lymphoplasmacytic infiltrations in ocular adnexal tissues . 
 the signs and symptoms include chronic noninflammatory lid swelling and proptosis . 
 patients often have a history of allergic disease and elevated serum levels of igg4 and ige as well as hypergammaglobulinemia . 
 orbital igg4-related disease must be differentiated from idiopathic orbital inflammation and ocular adnexal marginal zone b - cell lymphoma to ensure appropriate and effective treatment . 
 systemic steroid therapy decreases the size of the lesions , but relapse often occurs when systemic steroid therapy is discontinued . 