corticosteroids remain the mainstay of treatment for the vast majority of patients with immune - mediated uveitis .
however , those patients with active inflammation who are intolerant of or unresponsive to steroids require therapy with other immunosuppressive agents trying to prevent the potential sequelae associated with this vision - threatening condition . the off - label use of biologic agents and particularly those blocking tumor necrosis factor - alpha ( tnf- ) has demonstrated encouraging results when employed for management of patients with immune - mediated uveitis refractory to conventional treatment since their first reported use in 2001 .
potential advantages of these agents when compared with traditional immunosuppressors include a substantial efficacy in recalcitrant cases , as well as a lower total immunosuppressive load , a rapid clinical effect , good safety profile , and significant improvement in quality of life .
the present evidence shows that infliximab and adalimumab have the highest level of evidence and grade of recommendation , and thus both may be considered as first - line or second - line immunomodulatory agents for treatment of immune - mediated uveitis depending on which systemic immunologic disorder is associated with the intraocular inflammation [ 6 , 8 ] .
golimumab ( glm ) ( trade name simponi ) , a fully human anti - tnf- monoclonal antibody , was approved by the us food and drug administration in 2009 for the use with methotrexate ( mtx ) in adults with moderate - to - severe active rheumatoid arthritis ( ra ) and with or without mtx or other biologic disease - modifying antirheumatic drugs in adults with active psoriatic arthritis ( psa ) or active ankylosing spondylitis ( as ) .
some other studies have addressed the potential use of glm for treatment of uveitis , mainly associated with rheumatologic conditions [ 11 , 12 ] .
we would like to present the results from three uveitis units in spain when using glm for treatment of patients with immune - mediated uveitis of various etiologies that had been resistant to several immunosuppressive agents .
patients with different types of active immune - mediated uveitis that had been resistant to local and systemic corticosteroids and at least one additional immunosuppressive agent and who were treated with glm during at least 6 months were included in this study .
table 1 lists demographic and diagnostic information for the 13 patients who form the basis of this report . in 12/13 patients ( 92.3% )
glm was at least the second biologic agent used for treatment of uveitis , whereas glm was used as first - line biologic therapy in one patient ( patient 6 ) .  
table 2 shows previous treatment regimens employed for management of uveitis in all included patients .  
we defined primary failure as an absence of a two - step decrease in level of inflammation ( e.g. , anterior chamber and/or vitreous cells ) or a decrease to grade 0 .
we classified  control of inflammation  as grade 0 cells in both anterior and posterior segments in addition to absence of other signs of intraocular inflammation ( cystoid macular edema ( cme ) and vasculitis ) .
all included patients received 50  mg of subcutaneous glm every four weeks during at least 6 months without modifications during the follow - up .
chest x - ray , tuberculin skin test , and quantiferon - tb gold were performed in all patients before treatment .
glm was the only immunomodulatory agent used in six of them . in seven patients ,
topical steroids were used by three patients ( patients 6 , 8 , and 9 ) at the beginning of the follow - up and were slowly tapered and discontinued after one month in all of them .
uveitis clinical evaluation was performed at least four times ( before treatment and 1 , 3 , and 6 months after initiation of therapy with glm ) in all included patients .
clinical evaluation included visual acuity ( bcva ; best - corrected snellen va ) and ophthalmic examination .
anterior chamber was graded according to the classification established by the standardisation of uveitis nomenclature ; whereas the national eye institute system was adopted for grading vitreous inflammation [ 13 , 14 ] . optical coherence tomography ( cirrus hd - oct , carl zeiss meditec , dublin , ca , usa ) was used before and after treatment in both groups of patients to determine the presence of cme .
the 1  mm central retinal thickness was evaluated using the macular cube strategy 512  128 in all patients at each study visit .
macular edema was defined as central macular thickness > 300   and/or presence of intraretinal cysts in oct .
fluorescein angiogram ( fa ) was performed routinely before and after starting treatment ( between 1 and 3 months after initiation of therapy ) to determine the presence or absence of retinal angiographic leakage .
treatment - related side effects were assessed on each visit with a thorough review of systems and complete blood - cell counts , blood urea nitrogen ( bun ) level , creatinine level , and liver function test parameters obtained on an every study visit basis .
results were expressed as mean  sd for variables with a normal distribution or as median ( 25th75th interquartile range ( iqr ) ) when they were not normally distributed .
eight men and 5 women ( 22 affected eyes ) with a median age of 30 years ( range 2038 ) and active immune - mediated uveitides were studied .
uveitis was anterior in 8 patients ( 61.5% ) , intermediate in 1 patient ( 7.6% ) , and panuveitis in 4 patients ( 30.7% ) .
all included patients ( 13/13 ) received previous treatment with systemic steroids ( using intravenous pulses of methyl - prednisolone ) in two of them .
in addition , four patients ( 30.7% ) received coadjuvant intraocular steroids ( 2 intravitreal triamcinolone injections and 2 dexamethasone intravitreal implants ) .
about traditional immunosuppressors , all included patients had been treated with methotrexate at any time prior to glm therapy , whereas cyclosporine a was used in 2 ( 15.38% ) , azathioprine in 1 ( 7.6% ) , tacrolimus in 1 ( 7.6% ) , mycophenolate mofetil in 1 ( 7.6% ) , cyclophosphamide in 1 ( 7.6% ) , and leflunomide in 1 ( 7.6% ) . only one patient received glm as first - line biologic therapy , whereas 12 patients received previous treatment with at least one other biologic agent . from the latter , 12 patients received treatment with at least one biologic drug prior to glm , 7 patients ( 53.8% ) received treatment with at least 2 biologics , 3 patients ( 23% ) received treatment with at least 3 biologics , and 1 patient ( 7.6% ) received treatment with at least 4 biologics .
infliximab ( ifx ) was used as first biologic agent in 8 patients ( 61.5% ) , adalimumab ( ada ) in 3 patients , ( 23% ) , and etanercept ( etn ) in 1 patient ( 7.6% ) .
ada was used as second biologic agent in 6 patients ( 46.1% ) and etn in 1 patient ( 7.6% ) . mean time on second biologic agent was 25.5 months ( range 1557 ) .
abatacept was used as third biologic agent in 2 patients ( 15.3% ) and certolizumab in 1 patient ( 7.6% ) .
etn was used as fourth biologic agent in 1 patient ( 7.6% ) during 7 months .
coadjuvant immunosuppressive therapy was used in 7 of the studied patients including methotrexate ( 4 patients ) , azathioprine ( 1 patient ) , mycophenolate mofetil ( 1 patient ) , and leflunomide ( 1 patient ) .
glm therapy achieved complete control of inflammation in 12/13 patients ( 92.3% ) after six months of treatment .
the mean bcva increased from a basal value ( before initiation of glm ) of 0.60 to 0.68 at the six - month endpoint ( p = 0.009 ) .
only one patient , patient number 12 , showed a score of anterior chamber and/or vitreous inflammation different than zero at the six - month endpoint .
the mean 1  mm central retinal thickness decreased from a basal value of 317 to 261,2 at the six - month endpoint ( p = 0.05 ) .  
figure 1 shows changes in mean values of macular thickness ( 1  mm central thickness ) of all included patients over the study period .
there was no evidence of active retinal vasculitis before initiation of therapy in any of the included patients .
fluorescein angiogram results did not differ from those observed with oct regarding the presence of cme .
only a mild and local cutaneous reaction was recorded in two patients ( patients 5 and 9 ) among all included patients over the entire study period .
these results suggest that glm is well tolerated and is associated with control of inflammation in 92,3% of a heterogeneous group of immune - mediated uveitis patients resistant to traditional therapy and other biologic agents .
the use of glm is also associated with short - term improvement in mean values of bcva and decrease of mean values of central retinal thickness . despite the evident limitations of this study , including its retrospective design , lack of a control group , short follow - up , and limited number of patients , the results suggest that further evaluation of this modality is appropriate .
tnf- is recognized as one of the main inflammatory cytokines involved in the pathogenesis of immune - mediated uveitis [ 1416 ] .
this ubiquitous cytokine plays a key role in initiating and maintaining the inflammatory processes by orchestrating leukocyte infiltration , dendritic cell maturation , and macrophage activation and driving t - helper lymphocytes ' response .
therapy with two tnf- inhibitors , infliximab and adalimumab , has been proven to be effective for treatment of immune - mediated uveitis with considerable levels of recommendation and evidence [ 6 , 8 ] .
the clinical efficacy of other tnf- blockers such as glm needs to be demonstrated and thus this drug is considered only as an alternative to those patients who have failed to respond to first - line tnf- inhibitors .
however , it is necessary to emphasize that not all patients respond to their first anti - tnf agent , and so it is clearly useful to have a range of effective therapeutic options to treat those patients with severe and refractory immune - mediated uveitis . in this setting ,
. a potential limitation of these results could be related to the inclusion of less severe uveitis considering that we include 8 patients with anterior uveitis .
however , anterior uveitis in these patients was associated with juvenile idiopathic arthritis ( patients 5 , 9 , 10 , and 11 ) and hla - b27 + haplotype ( patients 1 , 4 , 6 , and 8) . despite recent therapeutic progress
, jia - associated uveitis has a severe course and the potential for long - term complications , including blindness .
hla - b27 positive - associated anterior uveitis is associated with a substantially higher incidence of ocular complications and has a much worse prognosis when compared with hla - b27 negative - associated anterior uveitis . moreover , some of the patients with anterior uveitis ( patients 2 , 9 , and 11 ) had concomitant macular edema , the most vision - threatening complication associated with uveitis [ 20 , 21 ] . in this
the seven cases that were included in our paper were severe and vision - threatening cases refractive to conventional and nonconventional treatment for such conditions . of note , patients included in the present study had a severe inflammatory condition which was resistant to several treatment - regimens inflammatory conditions .
the positive response observed in almost all included patients needs to be analysed in this mentioned difficult clinical setting .
this inclusion bias in addition to the short follow - up may have influenced the limited improvement in visual acuity observed in our study considering the long and severe course of intraocular inflammation in our patients .
tnf- is one of the inflammatory cytokines that upregulates intraocular production of vegf [ 22 , 23 ] , which plays a crucial role in the pathogenesis of cme .
we have previously reported how another tnf- blocker , adalimumab , induces a reduction in plasma vegf levels when employed for treatment of immune - mediated uveitis , which may correlate with clinical improvement . in our study glm also demonstrated a beneficial effect on cme thus strengthening the idea of a comparable efficacy with first - line tnf- blockers .
previous reports on the use of glm for treatment of uveitis have focused on those patients with uveitis secondary to behet disease , juvenile idiopathic arthritis , and/or hla - b27 + haplotype . to the best of our knowledge ,
this is the first report of glm employed in the treatment of uveitis associated with sarcoidosis , vogt - koyanagi - harada disease , and/or psoriatic arthritis .
the increasing potential treatment indications for glm may be of high interest in the therapeutical decision making of chronic uveitis patients .
the main aim of this study is to show these encouraging results on the use of glm for treatment of immune - mediated uveitis .
although these results are preliminary , further studies including a higher and more homogeneous group of patients are warranted .
 
 objective . to evaluate , in three spanish tertiary referral centres , the short - term safety and efficacy of golimumab ( glm ) for treatment of immune - mediated uveitis resistant to previous immunosuppressive therapy . methods . 
 nonrandomized retrospective interventional case series . 
 thirteen patients with different types of uveitis that were resistant to treatment with at least 2 previous immunosuppressors were included in this study . 
 all included patients were treated with glm ( 50  mg every four weeks ) during at least 6 months . clinical evaluation and treatment - related side effects 
 were assessed at least four times in all included patients .   
 results . 
 eight men and 5 women ( 22 affected eyes ) with a median age of 30 years ( range 2038 ) and active immune - mediated uveitides were studied . 
 glm was used in combination with conventional immunosuppressors in 7 patients ( 53.8% ) . 
 glm therapy achieved complete control of inflammation in 12/13 patients ( 92.3% ) after six months of treatment . 
 there was a statistically significant improvement in mean bcva ( 0.60 versus 0.68 , p = 0.009 ) and mean 1  mm central retinal thickness ( 317 versus 261.2   , p = 0.05 ) at the six - month endpoint when compared to basal values . 
 no major systemic adverse effects associated with glm therapy were observed .   
 conclusions . 
 glm is a new and promising therapeutic option for patients with severe and refractory uveitis . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion