to date , kaposi sarcoma has not been mentioned among the adverse effects of triptolide / tripdiolide , ethyl acetate extracts or polyglycosides of the chinese herbal remedy tripterygium wilfordii hook f.
she underwent treatment with corticosteroids , methotrexate and gold sodium thiosulfate , and was chronically taking ketoprofen . at the age of 59 years
she started to take a powder ( 2 g / day ) from a chinese physician for treatment of rheumatoid arthritis .
this powder was supplied to her regularly for 10 years . at the age of 69 years
, multiple soft , violaceous to dark - red patches , plaques , nodules and blisters of varying sizes appeared on a background of severely edematous skin on her legs , and later on her arms .
triptolide ( 235 g/1 g ) and tripdiolide were found in the chinese powder by the use of liquid chromatography electrospray ionization mass spectrometry .
this case indicates a possible association between triptolide / tripdiolide chronic intake and development of human herpesvirus 8-associated kaposi sarcoma .
triptolide / tripdiolide could contribute to development of kaposi sarcoma by reactivation of latent human herpesvirus 8 , permitted by immunosuppression induced by triptolide .
our aim is to show a case of disseminated cutaneous kaposi sarcoma ( ks ) , occurring during a long - term usage of a powder containing triptolide / tripdiolide , for treatment of rheumatoid arthritis ( ra ) .
triptolide and tripdiolide , compounds originally purified from tripterygium wilfordii hook f and used for centuries in traditional chinese medicine to treat ra [ 24 ] , could contribute to development of ks by reactivation of latent human herpes virus 8 ( hhv8 ) , permitted by triptolide - induced immunosuppression . to date , ks has not been mentioned among adverse effects of triptolide , ethyl acetate extracts or polyglycosides of the chinese herbal remedy tripterygium wilfordii hook f[4,69 ] , although dermal reactions including different kinds of rush with the tendency to develop erosion and scarring were described with incidence of 55.5% during 12 weeks of treatment with polyglycosides of tripterygium wilfordii hook f.
a patient was diagnosed to have ra when she was 29 years old . since 55 year of age
the patient was regularly controlled by a nephrologist due to infections of the urinary tract resulting in chronic tubulo - interstitial nephritis , and due to possible ra influence on kidneys .
echocardiography was normal , proteinuria was not present , and glomerular filtration rate was over 60 ml / min/1.73 m body surface area .
a cyst ( diameter 20 mm ) was shown in the left kidney , not confirmed in further evaluations .
high sensitivity c - reactive protein ( hscrp ) was 4.2 mg / l ( normal value < 5 mg / l ) .
medication with chloroquine diphosphate was added to ketoprofen ( table 1 ) , but did not influence ankle edema and joint pain .
serum perinuclear antineutrophil cytoplasmic antibodies were negative . since 69 years of age , leg edema was worse and she stopped working in her profession ( a pharmacist ) .
doppler ultrasonography of leg vessels again did not reveal abnormalities , proteinuria was not present , and renal function was normal .
six months later , multiple soft , violaceous to dark - red patches , plaques , nodules and blisters of varying sizes started to appear on a background of edematous skin on her legs .
ambulatory laboratory data of the blood revealed hemoglobin level of 5.87 mmol / l ( normal range 7.449.92 g / l for women ) , total protein of 55.2
g / l ( normal range 3550 g / l ) and creatinine of 144 mol / l .
proteinuria was not present . although there was no infection of the urinary tract and renal function
was deteriorated no more then before appearance of skin changes , she was admitted to the nephrologic ward to determine her health problem . at the admission ,
severe skin lesions on the edematous background were present on the patient s legs ( figure 1 ) and incipient skin changes on her arms .
rheumatoid factor ( rf ) was 2,310 iu / ml ( normal range < 14 iu / ml ) , but decreased to 566 iu after introduction of treatment with corticosteroids . functional class iii / iv of ra was classified according to steinbrocker et al . .
g / l ) and lymphocytes constituted 22% of all leukocytes ( normal range 2044% ) .
lymphocyte subset percentage was abnormal : cd3 84.0% ( normal range 6776% ) , cd3+dr+ 43.0% ( normal range 815% ) , cd4 32% ( normal range 3846% ) , cd8 52% ( normal range 3140% ) , cd19 2% ( normal range 1116% ) , nk 6% ( normal range 1019% ) .
the histological examination of 2 biopsy specimens of the leg lesions showed a mixed proliferation of irregular slit - like vascular channels associated with pleomorphic spindle cells , a low - grade lymphocytic inflammatory infiltrate and extravasated erythrocytes consistent with a diagnosis of ks ( figure 2 ) .
immunophenotypic analysis showed cell markers f viii+ , ck ae1/ae3 , cd34 + and cd31 + ( figure 3 ) , demonstrating the endothelial nature of the proliferating tumor cells .
expression of the proliferative antigen ki-67 was shown in 20% ( specimen 1 ) and in 30% ( specimen 2 ) of cell nuclei ; p53 immunoreactivity was found in less than 5% of cell nuclei .
hh8 latent nuclear antigen protein was detected in biopsy specimens by immunohistochemistry ( figure 4 ) .
knowing the diagnosis of hh8 ks , a patient s spouse confessed that at the age of 59 years she started to take a chinese powder of unknown composition and continued it until the current hospitalization .
she evaluated this powder as a good pain reliever and was convinced that it would help her to avoid severe ra signs and symptoms .
according to the patient s spouse , she used to take 1 dose of powder a day , and sporadically took 2 doses per day . for brief intervals she would stop taking the powder .
he calculated that his wife had taken approximately 300 doses per year . during hospitalization in the nephrologic ward , administration of the powder
the patient was transferred to the oncological ward and treatments with paclitaxel ( sindaxel , sindan , romania ) were initiated according to earlier promising reports .
sixteen weeks after withdrawal of the chinese powder and after 12 weeks of paclitaxel administration ( 6 doses of paclitaxel were given ) the patient s condition improved and the skin lesions diminished significantly , presenting postinflammatory hyperpigmentation and crust ( figure 5 ) . at the 10 month of treatment with paclitaxel , she died at the age of 71.3 years due to sepsis complicating perforation of the sigmoid diverticulum .
we obtained a sample of the powder from the patient s spouse and performed an analysis .
qualitative examination was done using liquid chromatography electrospray ionization mass spectrometry ( lc / esi - ms ) system .
the presence of triptolide m / z=359 ( m - h ) and tripdiolide m / z=375 ( m - h ) , 2 major active components of trypterigium wilfordii hook f , was confirmed .
the content of triptolide in 1 g of the analyzed sample , determined by hplc quantitative analysis , was 235 g .
we obtained a sample of the powder from the patient s spouse and performed an analysis .
qualitative examination was done using liquid chromatography electrospray ionization mass spectrometry ( lc / esi - ms ) system .
the presence of triptolide m / z=359 ( m - h ) and tripdiolide m / z=375 ( m - h ) , 2 major active components of trypterigium wilfordii hook f , was confirmed .
the content of triptolide in 1 g of the analyzed sample , determined by hplc quantitative analysis , was 235 g .
a question arises how triptolide / tripdiolide , taken in the high daily dose   for years , could influence the patient s health status .
triptolide is a small molecule known to act as an anti - inflammatory   and anti - cancer   compound .
aa amyloidosis , present in 4.44% of early ra patients , was shown to be inhibited in mice by experimental treatment with triptolide .
thus , progression of ra seemed to be slower than usually observed , independently of triptolide / tripdiolide administration .
however , only while receiving triptolide / tripdiolide was she almost free from joint pain .
the most important point to determine is the possible association of ks with triptolide / tripdiolide medication .
ks is a multifocal angioproliferative neoplasm of the skin ( mainly affecting the skin of the limbs ) and mucosa , frequently seen in immunosuppressed patients , also due to ra .
regardless of their source or clinical subtype , have been found to be infected with hhv8 .
hhv8 latent transcripts , such as latency - associated nuclear antigen , viral cyclin , viral flip and viral - encoded micrornas , drive cell proliferation and prevent apoptosis , whereas hhv8 lytic proteins such as viral g protein - coupled receptor , k1 and virally encoded cytokines ( viral interleukin-6 and viral chemokines ) contribute to the angioproliferative and inflammatory ks lesions through a mechanism called paracrine neoplasia . in patients infected with hiv ,
expression of the proliferative antigen ki-67 , shown in our patient in 2030% of cell nuclei , does not correlate with skin and organ lesions   or early- and late - stage ks lesions , but is valuable in ks diagnosis .
decreasing cd4 cells , triptolide could contribute to development of ks by reactivation of latent hhv8 , permitted by triptolide - induced immunosuppression .
on the other hand , triptolide is an anti - cancer compound   and ks is not mentioned among the adverse effects of triptolide , ethyl acetate extracts or polyglycosides of the chinese herbal remedy tripterygium wilfordii hook f[4,69 ] .
moreover , ks lesions are attributed to the release of angiogenic molecules , most notably vascular endothelial growth factor ( vegf )   and angiopoietin - like 4 .
it was recently found that the antitumor action of triptolide is partly via inhibition of tumor angiogenesis by blocking 2 endothelial receptor - mediated signalling pathways , and triptolide can be a promising antiangiogenic agent .
thus , triptolide as an immunosuppressant could contribute to development of ks , but also could potentially be helpful by vegf inhibition
although we can not definitively answer the question of whether triptolide/ tripdiolide contributed to development of ks in our patient , we also can not exclude such a possibility .
the case of our patient indicates an association between triptolide / tripdiolide chronic intake and development of hhv8 ks .
triptolide/ tripdiolide could contribute to development of ks by reactivation of latent hhv8 , permitted by immunosuppression induced by triptolide .
we believe that this case will help other physicians to be vigilant for a possible association between ks and medication with chinese remedies containing triptolide .
 summarybackgroundto date , kaposi sarcoma has not been mentioned among the adverse effects of triptolide / tripdiolide , ethyl acetate extracts or polyglycosides of the chinese herbal remedy tripterygium wilfordii hook f.case reporta patient was diagnosed with rheumatoid arthritis at the age of 29 years . 
 she underwent treatment with corticosteroids , methotrexate and gold sodium thiosulfate , and was chronically taking ketoprofen . at the age of 59 years 
 she started to take a powder ( 2 g / day ) from a chinese physician for treatment of rheumatoid arthritis . 
 this powder was supplied to her regularly for 10 years . at the age of 69 years 
 , multiple soft , violaceous to dark - red patches , plaques , nodules and blisters of varying sizes appeared on a background of severely edematous skin on her legs , and later on her arms . 
 biopsy specimens of the leg lesions were diagnostic for human herpesvirus 8-associated kaposi sarcoma . 
 triptolide ( 235 g/1 g ) and tripdiolide were found in the chinese powder by the use of liquid chromatography electrospray ionization mass spectrometry . 
 administration of the powder was stopped and medication with paclitaxel was introduced . 
 general condition of the patient improved and skin lesions diminished significantly.conclusionsthis case indicates a possible association between triptolide / tripdiolide chronic intake and development of human herpesvirus 8-associated kaposi sarcoma . 
 triptolide / tripdiolide could contribute to development of kaposi sarcoma by reactivation of latent human herpesvirus 8 , permitted by immunosuppression induced by triptolide . 