patient 1 , a 55-year - old man who had received a diagnosis of ankylosing spondylitis 7 
                 years previously , was admitted to laikon hosptal , athens , greece , in may 2005 for 
                 evaluation of encrusted vesicular lesions on the face .
the patient had been receiving nonsteroidal antiinflammatory agents 
                 until 12 months before admission , when his medications were changed to infliximab ( 3 
                 mg / kg ) plus methotrexate ( 10 mg weekly ) because of his deteriorating clinical 
                 condition .
he was living in a leishmaniasis - endemic area in athens , had no pets in 
                 his house , and had no history of recent travel abroad .
the central scale was removed 
                 from one of the lesions , and scrapings from the base of the lesion were stained with 
                 giemsa stain , which showed intracellular amastigotes with peripheral nuclei and 
                 rod - shaped kinetoplasts .
results of indirect immunoflorescent antibody ( ifa ) testing 
                 were positive for leishmania parasites ( titer 6,400 ) .
infliximab 
                 and methotrexate therapy was discontinued , and treatment with liposomal amphotericin 
                 b was started at a dose of 3 mg / kg , for days 1 to 5 , and 2 additional doses ( 3 
                 mg / kg ) on days 14 and 21 .
eighteen months later , treatment with etanercept was begun 
                 due to the patient s severe spondyloarthritis ; 2 years after the new 
                 anti - tnf treatment , he is well , with no signs or symptoms of leishmaniasis .
patient 2 , a 71-year - old woman who had giant cell arteritis , was admitted to the 
                 euroclinic hospital , athens , in may 2005 with a high fever and fatigue .
the patient 
                 had been treated with infliximab ( 0.25 mg / kg ) and variable doses of 
                 methylprednisolone for the previous 2 years .
she was also living in an athens suburb , which is 
                 leishmaniasis - endemic , and had 4 dogs .
laboratory tests showed a high level of 
                 c - reactive protein ( 163 mg /
06 mg / l ) , high erythrocyte 
                 sedimentation rate ( 77 mm / h ) , pancytopenia ( hemoglobin level 12.5 g / dl , leukocyte 
                 count 3,300/mm , platelet count 122,000/ mm ) , and diffuse 
                 hyperglobulinemia .
the examination of giemsa - stained smears from bone marrow 
                 aspirate demonstrated abundant leishmania parasites , and ifa was 
                 marginally positive for leishmania antibodies ( titer 400 ) .
pcr was 
                 positive for the detection of the leishmania genome in peripheral 
                 blood .
infliximab and methotrexate treatment was discontinued , and treatment with 
                 intravenous liposomal amphotericin b was started at a dose of 3 mg / kg for 5 days . 
                
two days later , the fever subsided , and within the next few days , the patient 
                 recovered from pancytopenia , while the inflammatory markers showed a gradual 
                 decrease .
she received 2 additional doses of liposomal amphotericin b ( 3 mg / kg ) on 
                 days 7 and 14 , and by that time , she exhibited no signs or symptoms of visceral 
                 leishmaniasis .
we then searched medline , embase , and current contents databases for all reports on 
                 leishmaniasis in europe and the mediterranean area among patients with autoimmune 
                 rheumatic diseases , which are often treated with anti - tnf agents . in our search 
                 strategy , we used medical subject heading terms and text words , including rheumatoid 
                 arthritis , juvenile rheumatoid arthritis , still s disease , seronegative 
                 arthritis , psoriatic arthritis , behet s disease , ankylosing 
                 spondylitis , reactive arthritis , vasculitis , giant cell arteritis , 
                 wegener s granulomatosis ( anca [ anti - neutrophil cytoplasmic 
                 antibody]associated vasculitis ) , panarteritis nodosa , leishmaniasis , 
                     leishmania , and anti - tnf .
we found 13 additional cases of 
                 leishmaniasis in patients with autoimmune rheumatic diseases ( 214 ) , all published after the introduction of anti - tnf agents in 1998 ( table ) .
all 15 patients ( including our 2 
                 patients ) were treated in the past or at the time of the diagnosis of leishmaniasis 
                 with > 1 standard immunosuppressive agents , including 
                 corticosteroids ( 11/14 [ 78.5% ] ) patients for whom treatment details were reported ) , 
                 methotrexate ( 9/14 [ 64.3% ] ) , cyclosporine ( 3/14 [ 21.4% ] ) , cyclophosphamide ( 3/14 
                 [ 21.4% ] ) , azathioprine ( 2/14 [ 14.3 ] ) , and chlorambucil ( 1/14 [ 7.1% ] ) . seven ( 46.6% ) 
                 patients received an anti - tnf agent along with standard immunosuppressive agents . 
                
two of the 15 reported patients had been treated with a recombinant 
                 interleukin1 receptor antagonist ( anakinra ; amgen inc . ,
thousand oaks , 
                 ca , usa ) ( 5,13 ) . in most of the patients ,
visceral leishmaniasis developed ( 13 patients , 
                 86.6% ) , while cutaneous leishmaniasis developed in 2 patients ( 1 was receiving an 
                 anti - tnf agent ) .
all patients were living in leishmaniasis - endemic areas of europe 
                     ( figure ) . *
reference ; anca , anti - neutrophil 
                         cytoplasmic antibody ; na , not applicable . 
all 
                         biologic treatments had been terminated 6 mo before leishmaniasis 
                     occurred . reported cases of leishmaniasis in patients with autoimmune rheumatic 
                         diseases in europe , indicated by stars ( 1 case from israel not shown ) .
dark 
                         gray shading , distribution of leishmaniasis ; light gray shading , 
                         distribution of leishmaniasis vector sandfly .
the anti - tnf agents were introduced into clinical practice in 1998 , and the first 
                 case of leishmaniasis associated with anti - tnf blockade occurred in 2001 ( 4 ) . during the 6-year period ( 19982003 ) ,
a total of 6 reports were 
                 made of leishmaniasis in patients with rheumatic diseases ; 1 ( 16.6% ) occurred in a 
                 patient treated with an anti - tnf agent . during the ensuing 5 years 
                 ( 20042008 )
, 9 cases of leishmaniasis were reported , 6 ( 66.6% ) in 
                 patients receiving anti - tnf agents .
the median duration of previous immunosuppressive therapy , before the diagnosis of 
                 leishmaniasis , was 60 months ( range 2360 months ) for all 15 patients 
                 ( able ) .
for the 7 patients who received anti - tnf agents , the median 
                 duration of anti - tnf treatment was 18 months ( range 960 months ) .
six of 
                 these 7 patients were receiving anti - tnf agents when symptoms and signs of 
                 leishmaniasis occurred . in 1 patient ( 5 ) , biologic treatments had been discontinued 6 months before the diagnosis of 
                 leishmaniasis ( table ) . only 1 patient had 
                 been tested for antibodies against leishmania spp . before 
                 immunosuppressive therapy was begun , and the results were negative ( 6 ) . therefore , this is the only case with compelling evidence that 
                 leishmaniasis was a primary infection and not reactivation of a latent 
             infection .
our data suggest that the introduction of tnf blockade into the clinical practice is 
                 associated with increasing reports of leishmaniasis in patients with autoimmune 
                 rheumatic diseases who live in leishmaniasis - endemic areas of europe .
notably , in 
                 most reported cases , patients had not received anti - tnf agents but other 
                 immunosuppressants .
however , all cases of leishmaniasis in patients with autoimmune 
                 rheumatic diseases were reported after 1998 , the year of introduction of anti - tnf 
                 agents , and most ( 9/15 ) of the reported leishmaniasis cases occurred during the past 
                 5 years ( 20042008 ) , mainly among patients receiving anti - tnf agents ( 6 
                 of the 9 patients with leishmaniasis ; 66.6% ) .
this increase coincides with the 
                 increasing use of anti - tnf agents during the same period , as prescription practice 
                 started changing toward treating patients with lower disease activity ( 15 ) .
another indirect piece of evidence that tnf blockade may increase the risk 
                 for leishmaniasis is that the median duration of previous anti - tnf treatment before 
                 the diagnosis of leishmaniasis was significantly shorter than the median duration of 
                 immunosuppressive therapy for all 15 patients ( 18 vs. 60 months ) .
it is unclear for all cases ( with 1 exception ) presented 
                 in this article whether leishmaniasis was primary infection or reactivation of 
                 latent disease .
we can not also exclude the possibility that the concomitant , 
                 long - term use of other immunosuppressants , and not the anti - tnf agents per se , 
                 played a crucial role in the development of leishmaniasis .
different prescribing 
                 patterns of anti - tnf agents might influence the number of cases reported from each 
                 disease - endemic european country .
however , the small number of reported cases and 
                 the lack of data on differences in the anti - tnf prescribing policies do not allow 
                 any conclusions to be reached .
finally , due to underreporting , the reported cases 
                 may underestimate the real incidence of leishmaniasis among patients with autoimmune 
                 rheumatic diseases .
prospective studies to estimate the incidence of the disease , the impact of risk 
                 factors and the need for serologic screening for leishmaniasis before initiation of 
                 anti - tnf agents or any other immunosuppressive treatment are clearly needed .
this is 
                 particularly important since currently only a few patients with autoimmune rheumatic 
                 diseases receive anti - tnf agents ( 15 ) .
therefore , the use of anti - tnf treatment is likely going to increase , 
                 possibly causing a parallel increase in opportunistic infections such as 
                 leishmaniasis .
 we report 2 cases of leishmaniasis in patients with autoimmune rheumatic diseases 
                     in greece . to assess trends in leishmaniasis reporting in this patient 
                     population , we searched the literature for similar reports from europe . 
 reports 
                     increased during 20042008 , especially for patients treated with 
                     anti  tumor necrosis factor agents . 