castleman 's disease is a lymphoproliferative disorder with benign hyperplastic lymph nodes characterized histologically by ( a ) follicular hyperplasia , and ( b ) capillary proliferation with endothelial hyperplasia ( 1 ) .
this disease has been classified histopathologically as hyalinevascular , plasma cell , or a mixed type variant of the two ( 2 , 3 ) .
the plasma cell and mixed types are often associated with ' multicentric castleman 's disease ' ( mcd ) , which shows various systemic manifestations , such as fever , anemia , hypergammaglobulinemia , hypoalbuminemia , and an increase in acute phase proteins ( 2 ) .
mcd is often refractory to conventional therapeutic strategies , such as corticosteroid , cytotoxic agents , and/or radiation ( 4 , 5 ) .
the frequency of mcd associated with a lung lesion among the japanese population is high ( ~70% ) ( 6 ) and such progressive lung lesions often lead to death ( 2 , 7 ) .
interleukin-6 ( il-6 ) is a pleiotropic cytokine with a wide range of biologic activities , such as hematopoiesis , regulation of immune responses , and inflammatory responses ( 4 ) .
patients with the plasma cell type castleman 's disease often generate large quantities of il-6 in the germinal centers of hyperplastic lymph nodes ( 8) . '
tocilizumab ' is a humanized anti - interleukin-6 receptor antibody that neutralizes the pleiotropic actions of il-6 .
it was approved for use in japan for the treatment of castleman 's disease in 2005 .
this report describes a case of mcd with an associated lung lesion , which responded dramatically to tocilizumab in combination with corticosteroid and tacrolimus .
a 43-yr - old female visited a nearby hospital because of abnormal shadows including multiple nodules and reticular shadows on chest radiography found at an annual medical checkup in 2005 .
they were unable to obtain a biopsy specimen from one of the nodules in s10 of the left lung because the patient had a strong bleeding tendency .
she was referred to this hospital for further examination on june 30 , 2005 . on admission ,
the laboratory data were : erythrocyte sedimentation rate , 119 mm/1 hr ; white cell count , 8,900/l ; hemoglobin , 8.4 g / dl ; platelet count , 39.410/l ; serum aspartate aminotransferase , 22 iu / l ; alanine aminotransferase , 22 ; total protein , 9.7 g / dl ; albumin 2.6 ; creatinine , 0.48 ; pt , 13.1 sec ( inr 1.45 ) ; aptt , 39.6 ( control , 10.4 ) ; fibrinogen , 750 mg / dl ; kl-6 , 277 u / ml ( reference range < 500 ) ; c - reactive protein , 11.7 mg / dl ( < 0.3 ) ; serum immunoglobulin ( ig)g , 4,570 ( 870 - 1740 ) ; iga , 491(110 - 400 ) , igm , 706 ( 35 - 220 ) , ch50 , 52.3 u / ml ( 30 - 50 ) , soluble il-2 receptor , 1,400 ; serum il-6 , 6.8 pg / ml ( < 4 ) ; rheumatoid factor ( rf ) , 1,330 iu / ml ( < 20 ) .
autoantibodies , including antinuclear antibody , anti - ds - dna , anti - sm , anti - rnp , cytoplasmic antineutrophil cytoplasmic antibody ( anca ) , and myeloperoxidase - anca were all negative .
chest ct scan disclosed a slight enlargement of the mediastinal lymph nodes , centrilobular nodules , thin - walled cysts , the thickening of the bronchovascular bundles , and ground - grass opacities , all of these findings were compatible with those of lymphocytic interstitial pneumonia ( lip ; fig .
gallium citrate scintigraphy did not reveal any evident accumulation . a lung surgeon and a thoracic physician declined to perform a lung biopsy because of her bleeding tendency ( bleeding time : 6 min 30 sec ) and poor general condition .
a biopsy of an inguinal lymph node was obtained for making a definite diagnosis ( fig .
she was diagnosed with mcd and undifferentiated arthritis based on the characteristic pathology of the specimen of the inguinal lymph node , ct findings of the bilateral lung lesions and laboratory data .
she was initially administered intravenous corticosteroid ( methylprednisolone , 500 mg / day , 3 consecutive days ) followed by oral corticosteroid ( methylprednisolone , 16 mg / day ) , and , 375 mg / m rituximab every week for 4 weeks .
the polyarthralgia instantly disappeared ; however , none of the other clinical and laboratory parameters were fully resolved .
therefore the therapeutic regimen was changed to tocilizumab ( 8 mg / kg , every 2 weeks ) , oral corticosteroid ( methylprednisolone , 16 mg / day ) on october 25 , 2005 .
the patient requested that the interval between tocilizumab to be increased to more than every two weeks .
the dose of corticosteroid in combination with tocilizumab should be kept as low as possible to avoid various side effects , such as osteoporosis , hyperglycemia , and hypertension .
both the possible merits and demerits of the drug were explained to the patient and her oral consent was obtained .
laboratory findings , including anemia , hypergammaglobulinemia , and an increase in acute phase proteins responded to this regimen ( fig .
the enlargement of mediastinal lymph nodes and abnormal shadows were also partially alleviated ( fig .
the intervals of the tocilizumab - administration sessions were extended from every 2 weeks to every 3 weeks from january 2006 .
oral corticosteroid was gradually tapered from 16 mg / day finally to 4 mg / day .
the treatment of mcd includes various therapeutic strategies such as corticosteroid , chemotherapy , rituximab , or tocilizumab .
rituximab , an immunoglobulin g1 ( igg1 )  monoclonal antibody to cd20 , has the potential for b - lymphocyte depletion via antibody - dependent cell mediated - cytotoxicity ( adcc ) , complement dependent cytotoxicity ( cdc ) , and apoptosis .
kaposi 's sarcoma - associated herpes virus ( kshv / hhv8 ) was thought to be associated with the development of castleman 's disease , especially in patients infected with human immunodeficiency virus ( hiv ) and rituximab was reported to be effective in hiv - related castleman 's disease ( 11 ) .
the effectiveness of rituximab was limited in the present case because the patient was not infected with hiv . a humanized anti - interleukin-6 receptor antibody , tocilizumab ,
was shown to be effective for the treatment of mcd in an open label trial , and has been widely used in japan ( 5 ) .
the frequency of mcd associated with a lung lesion is relatively low ( 10 - 20% ) in the united states .
in contrast , nishimoto et al . reported that 18 of 28 japanese cases ( = 64.3% ) had a lung lesion ( 6 ) .
the ct findings of intrathoracic involvement in mcd include bilateral hilar and mediastinal lymphadenopathy , centrilobular nodular opacities , thin - walled cysts , interlobular septal thickening , and ground - glass attenuation ( 9 ) .
some reports have noted that the lung lesion in mcd is compatible with lymphocytic interstitial pneumonia ( lip ) ( 5 , 9 ) .
( 12 ) reported a case of mcd with a lung lesion that responded to tocilizumab .
( 7 ) described that the administration of tocilizumab for 2 yr had no effect on the lung lesion in an mcd patient .
il-6 production by the germinal center b cells in the swollen lymph nodes of patients with mcd is remarkable ( 8) , but the roles of t cells are unknown .
if t cells do participate in the pathogenesis , immunosuppressive drugs for t cells should be useful .
in fact , mcd , which is classified as a lymphoproliferative disorder , has characteristics of an autoimmune disease , demonstrated by the production of autoantibodies .
several studies have shown that these drugs are active not only against t cells but also against other cells .
they suppress the promotion of il-6 in the rheumatoid synovium where t cells are relatively scarce ( 13 ) .
they also suppress il-6 production in monocytes , and tnf- production in b cells ( 14 , 15 ) .
pham et al . ( 16 ) reported that inhibition of nf-b and nfat activation in aggressive b - cell lymphomas by calcineurin inhibitors suppressed the cd40 ligand expression in b cells and lymphoma cell survival in an in vitro experiment .
some of these actions of tacrolimus , if not all , may be associated with the efficacy of the drug for the treatment of mcd .
( 17 ) reported that non - cytostatic immunomodulatory therapy including corticosteroid , cyclosporine a and thalidomide treatment was effective for castleman 's disease .
the long - time use of tocilizumab and corticosteroid is necessary for the treatment of mcd .
corticosteroid has various dose - related side effects , and acquisition of drug resistance possible .
p - glycoprotein ( p - gp ) plays a pivotal role in the latter .
peripheral lymphocytes in patients with autoimmune diseases could express p - gp on their cell surface .
calcineurin inhibitors have an antagonistic activity to p - gp : they may inhibit corticosteroid - resistance in peripheral lymphocytes in vivo ( 18 , 19 ) .
the dose of corticosteroid could be tapered in the current case , at least in part , due to the antagonistic activity to p - gp of tacrolimus . in conclusion , this is the first report to describe that tocilizumab , in combination with corticosteroid and tacrolimus , shows a dramatic effectiveness in the treatment of a lung lesion in an mcd patient .
 this report presents the case of a patient demonstrating multicentric castleman 's disease ( mcd ) with a lung lesion that was successfully treated with an anti - interleukin-6 receptor antibody , tocilizumab in combination with corticosteroid and tacrolimus . 
 a 43-yr - old female with abnormal shadows on a chest x - ray was referred to the hospital for further examination . 
 she was diagnosed as having mcd based on the characteristic pathology of inguinal lymph node , lung lesions , laboratory data , and undifferentiated arthritis . 
 corticosteroid and rituximab therapy did not fully ameliorate the symptoms ; thus , the therapeutic regimen was changed to include tocilizumab , oral corticosteroid and tacrolimus . 
 this regimen resulted in clinical remission and the dose of tocilizumab and corticosteroid could be tapered . 
 tocilizumab in combination with corticosteroid and tacrolimus may therefore be a beneficial treatment regimen for lung lesions associated with mcd . 