patients with ankylosing spondylitis ( as ) present a higher proportion of pleuropulmonary and lung functional abnormalities when compared to healthy controls . mainly , a prevalence of 1857% in restrictive respiratory pattern on pulmonary function tests ( pft ) has been related to spinal and chest wall mobility limitation and in some extent to disease activity indices [ 25 ] , suggesting that disease activity could play a role . other research groups have suggested the existence of a subjacent inflammatory process in the lung parenchyma of some patients with as that leads to a reduction of ventilatory function with repercussion in the forced vital capacity . enocak et al . , for example , observed abnormalities in 85% of their patients with as in the high resolution computed tomography . our research group has recently described that around 57% of as patients had abnormalities in the lung function tests suggesting a restrictive pattern . a systematic review has identified that , in patients with as , abnormalities in the hrct can be found in up to 61% . different findings include radiographic features of nonspecific interstitial abnormalities in 33% , interlobular septal thickening in 30% , ground glass attenuation in 11.2% , and upper lobe fibrosis in 6.9% . despite these findings , so far , only one prospective clinical trial related to pft has been published , where a significant improvement on pft was shown after 12 weeks of treatment with etanercept when compared to placebo . with respect to clinical trials , in 2011 , braun et al . demonstrated superiority in clinical efficacy achieved with anti - tnf agents versus synthetic disease modifying antirheumatic drugs ( dmards ) in as . until now , the long - term effect of synthetic dmard and anti - tnf agents on pft has not been systematically compared in as patients . therefore , the objective of the present study was to evaluate , in a two - year observational study , modifications on pulmonary fvc% as well as other cardiopulmonary indices in patients with as who had reduced fvc% receiving dmards or anti - tnf agents + dmards . the study is designed as observational prospective cohort with two - year follow - up . we enrolled patients attending an outpatient rheumatology clinic , in a secondary - care center ( hospital general regional no . the study patients met the following criteria : ( a ) to be 18 years old , ( b ) to meet the modified new york criteria , and ( c ) to have pulmonary function tests with a reduced fvc% < 80% [ 12 , 13 ] . one - hundred and twenty consecutive as patients were screened with pft , seeking abnormalities in the fvc% . spirometry was performed according to the ats / ers task force considerations [ 14 , 15 ] . other parameters evaluated besides the fvc% were forced expiratory volume in one second ( fev1 ) and the fev1/fvc ratio . observed values were expressed as a percentage of the predicted value compared with individuals of similar sex , age , weight , and height . restrictive abnormalities were defined with fvc < 80% , fev1/fvc  70% , and decreased or normal fev1% . a normal pft was considered when patients had fvc% > 80% , fev1 > 80% , and fev1/fvc > furthermore , we arbitrarily classified the reduced fvc% as follows : mild decrement ( 7079% of predicted value ) , moderate decrement ( 5169% of predicted value ) , and severe decrement ( 50% or less of predicted value ) . we excluded patients with overlapping syndrome ( defined as those patients with a suspected or confirmed connective tissue disease associated to as such as rheumatoid arthritis , systemic lupus erythematosus , or scleroderma ) , pregnant patients , and pateints with presence of active infections , cardiac failure grade iii or iv , chronic obstructive pulmonary disease , asthma , or pulmonary tuberculosis . the decision to prescribe dmards or the addition of anti - tnf agent + dmards was left to attending rheumatologist discretion , which was independent of the study . in our hospital except in well - defined cases where synthetic dmard may have intolerable side effects , all the patients with a diagnosis of as initiate with nsaids combined with a dmard ( usually sulfasalazine or methotrexate ) and anti - tnf agents are prescribed only after failure to this combination . nevertheless , the rheumatologist can be free to prescribe a second combined synthetic dmard before the initiation of anti - tnf agents in those patients with reasonable suspicion that they may achieve a satisfactory response . patients with as and the presence of uveitis received azathioprine . according to the therapeutic schema for treatment , patients that were escalated to receive anti - tnf therapy continued taking the synthetic dmard , which was originally prescribed . all the patients that received an anti - tnf agent were tested with a ppd and chest x - rays in order to discard latent tuberculosis . if a patient presented a positive ppd test ( > 5  mm ) , or suggestive images on x - rays , they were excluded from initiation of anti - tnf therapy and referred to the specialist in infectious diseases . two groups were assembled : ( a ) dmards ( n = 20 ) : patients receiving a dmard , including one or more of the following drugs : oral methotrexate : 7.515  mg / week and oral sulfasalazine 11.5  g / day during the entire study period , and ( b ) patients who escalated to anti - tnf agent + their previous dmard ( anti - tnf + dmards ) ( n = 16 ) . briefly , as described above , this cohort of escalation to anti - tnf agent was constituted by these patients with as dmard treatment who fail to achieve improvement with dmards alone ; therefore , an anti - tnf treatment was added by the rheumatologist , either etanercept administered as a subcutaneous injection 25  mg twice a week ; infliximab 35  mg / kg given intravenously at zero , two , and four weeks and thereafter every eight weeks ; or subcutaneous adalimumab 40  mg every 2 weeks , during the entire study period . during the study period all patients received oral nonsteroidal anti - inflammatory drugs ( nsaids ) and in case of being required one or more shot of intramuscular diclofenac additionally , they could receive oral acetaminophen 500  mg to 2  gr daily for pain . a structured questionnaire was used to evaluate demographic and clinical variables including disease duration , smoking , and comorbidities . patients were assessed by the same trained researcher at baseline ( time of the initial prescription by attending rheumatologist ) and at 6 , 12 , 18 , and 24 months for the following variables : ( a ) disease activity according to bath ankylosing spondylitis activity index ( basdai )   and ( b ) functioning according to bath ankylosing spondylitis functional index ( basfi ) . in order to evaluate repercussions secondary to lung affection ( deteriorated fvc% ) , we used the following indices : ( a ) saint george respiratory questionnaire ( sgrq ) , a specific health - related quality of life index ( hrqol ) for patients with pulmonary disease that consists of a 50-item questionnaire , evaluating 3 domains : symptoms , activity , and disease impact with 10 multiple choice questions and 40 true or false answers , ( b ) 6-minute walk test ( 6mwt ) , used to evaluate one - time cardiopulmonary functional status , and ( c ) modified borg scale that provides an individual measurement of dyspnea intensity before and after the 6mwt ; this test was used to assess the severity of dyspnea . follow - up took place at 6-month intervals during a period of 2 years . throughout each visit , the same researchers completed a questionnaire detailing any change in antirheumatic therapy , adverse events associated with the therapy , and evaluated fvc% , fev1 , fev1/fvc , basdai , basfi , sgrq , 6mwt and the modified borg scale . response was defined as increment in fvc% based on the statistical difference between the evaluations during the follow - up compared with baseline and with the immediate previous measurement . additionally , improvement in disease activity , functioning indices , and cardiopulmonary scales were also evaluated as secondary outcome measures . reasons for discontinuation were identified . due to the nonparametric distribution of the data and/or small sample size , we used medians and ranges in order to describe quantitative variables and for qualitative variables , frequencies , and percentages . mann - whitney u test was used to compare quantitative variables including medians of fvc% and clinical characteristics between the two groups : ( a ) dmards and ( b ) anti - tnf + dmards . chi - square ( or fisher exact test when appropriated ) were used to compare proportions of qualitative variables between groups of treatment and mcnemar test was used to compare differences in intragroup proportions at 2 different time points . for comparison between fvc% at follow - up regarding the baseline values and at 2 different time points , we used wilcoxon test , and when the comparisons included 3 or more time points we used friedman test . statistical significance was considered as p  0.05 . the study was approved by the institutional review board of the mexican institute for social security ( imss ) of the participating hospital ( approval number imss r-2009 - 1301 - 63 ) ; all patients were informed about the study objectives and signed a voluntary consent prior to inclusion . sixty - five patients ( 54.17% ) were excluded because they had normal pft , 11 ( 9.17% ) with restrictive ventilatory pattern were excluded because they had coexisting asthma , and 8 patients ( 6.67% ) were excluded because they had active infection . therefore , 36 patients with as and fvc < 80% were included ; from them , 20 were receiving dmards and 16 received anti - tnf agents + dmards . there were no significant differences between age , gender , disease activity parameters , lung function test results , cardiopulmonary scales , and sgrq at baseline ( table 1 ) . a small difference , yet not significant , was observed between dmards and anti - tnf + dmards groups in disease duration ( 11 years versus 15 years , resp . , 8 patients ( 40% ) were taking methotrexate + sulfasalazine , 5 ( 25% ) sulfasalazine alone , 4 ( 20% ) methotrexate alone , and 2 ( 10% ) methotrexate + azathioprine and 1 patient ( 5% ) received azathioprine alone . in anti - tnf + dmards group , 10 patients ( 62.4% ) received etanercept , 5 ( 31.3% ) infliximab , and 1 ( 6.3% ) adalimumab ; dmards prescribed in combination with anti - tnf were methotrexate alone in 4 patients , azathioprine alone in 2 , sulfasalazine in 3 , and methotrexate + sulfasalazine in 4 patients , methotrexate + azathioprine in 1 , sulfasalazine + azathioprine in 1 and methotrexate + sulfasalazine + azathioprine in 1 patient . table 2 shows the secondary outcomes observed in both groups . in the intragroup comparisons at 12 months or 24 months versus baseline there was a significant improvement in all secondary variables in the dmards group including basdai , basfi , post-6mwt borg scale , 6mwt , and total stgrq% . similarly in the intragroup comparison between 12 and 24 months versus baseline in the anti - tnf + dmards group a significant improvement was observed in all these variables . figure 2 shows the increment observed in fvc% from baseline to the end of the follow - up in the group with anti - tnf + dmards versus the group with dmards alone . a persistent increment in fvc% was observed in both groups , with this improvement in fvc% being higher in the anti - tnf + dmards group and statistical significance being observed for the difference (  ) of this increment in favor of the anti - tnf + dmards since the 6 months ( p < 0.001 ) and persisting with significant differences during all the length of follow - up . table 3 shows the comparison between groups on the primary outcomes : there was a clear difference in the increase of fvc% in the group receiving anti - tnf + dmards at 24 months with respect to dmards alone group and there was also a higher increase in fev1/fvc in patients receiving anti - tnf + dmards at 24 months with respect to dmards alone group ( p = 0.03 ) . only 2 patients ( 12.5% ) remained as a restrictive pattern in lft in the anti - tnf + dmards at 24 months compared with 9 ( 45% ) of the patients in the dmards alone group . finally a 87.5% of patients in the anti - tnf + dmards group achieved normal fvc% at 24 months ( 80% ) compared with only 55% achieving normal fvc% in the dmards alone group ( p = 0.04 ) . most frequent adverse events in dmards alone group were gastritis and other gastrointestinal side effects ( 30% ) , anorexia ( 25% ) , and upper airways infections ( 25% ) , while in anti - tnf + dmards group they were local reactions ( 44% ) , upper airways infections ( 38% ) , and gastritis and vomiting ( 13% each ) . there were no differences in total adverse events between groups of treatment . in this study we observed that as patients receiving anti - tnf + dmards had a greater significant improvement in fvc% and other pulmonary test parameters at 24 months compared with patients who were taking only dmards . to date , the information about the effect of dmards in pft associated to as is scarce . in our study , the quality of life associated with pulmonary affection ( sgrq ) and cardiopulmonary tests including borg and 6mwt improved significantly in both groups during the 2 years of follow - up . our findings are in accordance with the study by dougados et al .   in their 12-week controlled trial , since they found a significant improvement in fvc% and other parameters of lung function tests with etanercept in comparison to placebo . this remarkable study has some differences in comparison with our study : first the study performed by dougados et al , was a randomised controlled double - blind trial providing high quality information ; nevertheless our study has 3 main interesting differences with the previous study . first we had a comparison group with dmards and this provides a comparison with drugs that may modify the response in our outcomes ; even when compared with dmards the addition of anti - tnf agents + dmards shows a higher significant improvement in the pulmonary parameters . second we had a 2 years of follow - up ; during the entire study we observed a persistent increment in the fvc% corresponding to the clinical improvement not only in traditional disease activity indices but also in cardiopulmonary variables such as borg or 6mwt , and finally this cohort represents patients with a wide spectrum of treatments and severity of the disease that is more related to the usual clinical scenario . nevertheless it is relevant the recognition of the limitations of our exploratory study : the small sample size could reduce the representativeness of the total as population with a restrictive ventilatory pattern and the accuracy of the observed effects in treatments ; likewise , a lack of blindness might induce an expectancy bias . only patients refractory to dmards were included in the anti - tnf + dmards group , which could affect the results observed . the use of different combinations of anti - tnf and dmard therapies diminishes the representativeness of a specific therapy and the results could differ if each specific treatment combination were evaluated separately . another limitation in this study is the lack of other pulmonary studies such as high resolution computed tomography ( hcrt ) to evaluate parenchymal damage . future studies should address whether our observations of a sustained improvement with anti - tnf + dmards in fvc% and other cardiopulmonary parameters is correlated with the findings observed in hrct in these patients . in conclusion , we found that anti - tnf + dmards treatment is superior to dmards alone in improving pft and functional capacity parameters in as in long - term treatment . further long - term double - blind , randomized , controlled trials or multicenter cohorts are required in order to corroborate the long - term effects on lung function tests of anti - tnf + dmards observed in the present cohort .
objective . to evaluate the effect of anti - tnf agents plus synthetic disease modifying antirheumatic drugs ( dmards ) versus dmards alone for ankylosing spondylitis ( as ) with reduced pulmonary function vital capacity ( fvc% ) 
 . methods . in an observational study 
 , we included as who had fvc% < 80% at baseline . 
 twenty patients were taking dmards and 16 received anti - tnf + dmards . 
 outcome measures : changes in fvc% , basdai , basfi , 6-minute walk test ( 6mwt ) , borg scale after 6mwt , and st . 
 george 's respiratory questionnaire at 24 months . 
 results . 
 both dmards and anti - tnf + dmards groups had similar baseline values in fvc% . 
 significant improvement was achieved with anti - tnf + dmards in fvc% , at 24 months , when compared to dmards alone ( p = 0.04 ) . 
 similarly , patients in anti - tnf + dmards group had greater improvement in basdai , basfi , borg scale , and 6mwt when compared to dmards alone . 
 after 2 years of follow - up , 14/16 ( 87.5% ) in the anti - tnf + dmards group achieved the primary outcome : fvc% 80% , compared with 11/20 ( 55% ) in the dmards group ( p = 0.04 ) . 
 conclusions . 
 patients with anti - tnf + dmards had a greater improvement in fvc% and cardiopulmonary scales at 24 months compared with dmards . 
 this preliminary study supports the fact that anti - tnf agents may offer additional benefits compared to dmards in patients with as who have reduced fvc% .