diseases that belong to spondyloarthritides ( spa ) are frequently manifested as asymmetric peripheral arthritis of the large joints with knee involvement . tumour necrosis factor ( tnf ) inhibitors are highly effective for the treatment of peripheral arthritis in patients with ankylosing spondylitis ( as ) [ 1 , 2 ] , psoriatic arthritis ( psa ) , undifferentiated spa ( unspa ) , or spa as a whole independently of the phenotypic disease , even in the case of arthritis resistant to disease - modifying antirheumatic drugs ( dmards ) . however , data on the effect of anti - tnf therapy specifically on knee synovitis are limited in peripheral spa . the aim of this retrospective study was to evaluate the effectiveness of anti - tnf agents as adjunctive therapy for knee synovitis that did not respond to dmards and other standard treatments in patients with peripheral spa . we retrospectively studied patients with spa according to the european spa study group criteria   and peripheral arthritis involving the knee joint , who were monitored every 24 months at the rheumatology outpatient clinic of the 424 general military hospital ( thessaloniki , greece ) between january 2005 and january 2012 . inclusion criterion was the addition of an anti - tnf agent for active peripheral arthritis with knee synovitis unresponsive to dmards and standard treatment with low - dose oral corticosteroids ( prednisone 7.5  mg / day ) and/or nonsteroidal anti - inflammatory drugs ( nsaids ) and intra - articular ( ia ) corticosteroids . exclusion criteria were ( i ) the use of ia corticosteroids and ( ii ) the increase of the dmards ' dose or the addition of a new dmard during anti - tnf therapy . knee synovitis was defined as the presence of at least 2 of the following 3 clinical criteria : swelling , tenderness , or decreased range of movement . as response of knee synovitis the absence of the aforementioned three clinical joint signs after 4 months of anti - tnf therapy were considered . the association of knee synovitis response with gender , age , disease subtype , and pattern of arthritis at anti - tnf initiation excluding interphalangeal joint involvement was also investigated . knee synovitis responders and nonresponders were compared using the mann - whitney u test for continuous variables and the  test or fischer 's exact test for categorical variables . statistical analysis was performed by using spss software for windows , version 13 ( spss inc . , twenty - one patients were on dmard monotherapy ( 9 on methotrexate ( mtx ) , eight on leflunomide ( lef ) , and four on sulfasalazine ( ssz ) ) while the remaining 6 patients were on dmards combination treatment ( 2 patients on mtx + lef , two on mtx + ssz , one on mtx + cyclosporine a ( cysa ) , and one on mtx + cysa + lef ) . thirteen patients received adalimumab , 8 infliximab , 4 etanercept , and 2 golimumab . in all but three of the patients there was response of knee synovitis to anti - tnf therapy , which sustained for an average observation period of 31.9 months . furthermore , all knee synovitis responders achieved at least low disease activity ( lda ) according to the disease activity score in 28 joints ( das28 ) . among the 3 patients with unresponsive knee synovitis , tenderness and decreased range of movement were the remaining signs in the two of them , who had psoriatic arthritis ( psa ) with knee monoarthritis and achieved lda . knee joints of these two patients presented osteoarthritis grade 2 according to the kellgren - lawrence radiologic scoring system on x - ray , leading us not to consider treatment modification as appropriate approach , because the residual clinical signs of their knees were attributed to osteoarthritis secondary to joint destruction . in the third patient , who had oligoarticular psa with remaining knee monoarthritis and achieved moderate disease activity ( das28 = 3.29 ) , both tenderness and swelling of the knee joint persisted . in this patient , whose knee x - ray was normal , a switch of adalimumab to infliximab was ineffective ; finally , radiation synovectomy led to the resolution of knee synovitis . there were no differences in gender ( p = 0.53 ) , age ( p = 0.88 ) , disease subtype ( p = 0.22 ) , and pattern of arthritis ( p = 0.20 ) between knee synovitis responders and nonresponders . fourteen patients ( 51.9% ) managed to stop dmard therapy , while the rest 13 patients ( 48.1% ) remained on combination of anti - tnf agent and dmard in order to maintain both knee synovitis response and disease activity on remission or lda ; however , in 6 of these patients , all initially on dmards combination , the number of dmards was decreased to one . there is only one study in the literature evaluating the efficacy of anti - tnf agents focusing on knee synovitis . in this prospective study , including 20 patients with peripheral spa and knee synovitis who received etanercept as monotherapy , a statistically significant decrease in the physician 's assessment of the knee joint ( median visual analog score from 53.5 at baseline to < 10 at week 12 and thereafter ) was observed . accordingly , clinical synovitis of the knee joint was present in all patients at baseline and decreased to a frequency of 12 ( 60% ) of the 20 knee joints with synovitis at week 12 and 6 ( 30% ) at week 52 . in comparison , knee synovitis persisted in approximately 11% of our spa patients at month 4 following anti - tnf addition . the combination of anti - tnf agent with dmards could explain the more favorable results of our study . indeed , at least in regard to psa , the superiority of anti - tnf agent plus mtx to mtx alone is well documented in mtx - nave patients   and , according to the danish registry , concomitant use of dmard ( mtx ) is a predictor of clinical response in patients treated with an anti - tnf agent . furthermore , it has been reported that in psa patients , early treatment before joint damage resulted in better outcome and polyarticular disease had poorer prognosis than oligoarticular disease [ 10 , 11 ] . thus , the addition of an anti - tnf agent shortly after dmard failure ( mean time interval between initiation of dmards and anti - tnf agent was 11.4 months , table 1 ) and the fact that none of our patients with psa had polyarticular disease could be additional reasons for the better response of knee synovitis in our study . notably , the two psa patients with radiographic damage of the affected knee joint at baseline were nonresponders to anti - tnf therapy . in conclusion , the high percentage of our spa patients with knee synovitis responsive to anti - tnf agent may be explained by the combination of anti - tnf therapy with dmards and the presence of good response predictors in most of them , although in the literature this could be supported only for the psa patients , who were the majority of the studied patients . it is a retrospective study with limited number of patients , who had heterogeneity on pattern of dmard therapy and were treated with different anti - tnf agents and dmards . furthermore , we did not include a control group . however , this is the first study to attempt to evaluate the efficacy of anti - tnf agents as adjunctive therapy for knee synovitis refractory to dmards in patients with peripheral spa . in all patients , knee synovitis had already failed to respond to dmards and other standard treatments before the addition of an anti - tnf agent . thus , it is reasonable to attribute knee synovitis response to anti - tnf therapy itself . the absence of swelling , tenderness , and decreased range of movement on clinical examination , which has been used as outcome in randomized controlled studies [ 12 , 13 ] , was considered as response of knee synovitis in our study . we used the term  response  over  remission  in order to exclude the possibility of mild knee joint inflammation not detectable with clinical examination . our results imply a sustained beneficial effect of adjunctive anti - tnf therapy on knee synovitis unresponsive to dmards and other standard treatments in patients with peripheral spa . because of both knee synovitis response and remission or lda , approximately half of the patients stopped dmards and all patients on dmards combination decreased the number of them to one