thyroid eye disease ( ted ) is an autoimmune disease involving the retroocular tissues associated with graves ' disease [ 1 , 2 ] .
typical signs and symptoms include proptosis , retroorbital pain , tearing , conjunctival redness and edema , corneal lesions , impaired extraocular motility with or without diplopia , periorbital edema , visual impairment , and , rarely , blindness .
treatment options for ted include immunosuppressive agents , radiotherapy , and various surgical procedures such as orbital decompression , squint surgery , and correction of eyelid retraction [ 35 ] .
glucocorticoids are still the most widely used immunosuppressive agents for the treatment of ted and appear to be the most effective for associated soft tissue inflammation , optic neuropathy , and extraocular muscle impairment [ 6 , 7 ] .
the main disadvantages of glucocorticoid therapy are the potential recurrence of the disease after discontinuation and the side effects in long - term treatment .
several alternative therapies have been proposed to manage resistant ted such as orbital radiation therapy , several other immunosuppressive agents , and biological drugs .
however , the effectiveness of these treatments is still widely debated in the literature [ 815 ] .
the aim of this study is to evaluate the efficacy of methotrexate used as single therapy in a group of patients with recurrence of the active ted after withdrawal of corticosteroids due to the onset of side - effects .
this is a retrospective comparative case series of 36 patients , from 2001 to 2010 , who experienced reactivation of ted after withdrawal of corticosteroid therapy because of side - effects .
patients with sight threatening for compressive optic neuropathy were excluded from this study as they needed urgent treatment such as high - dose steroids or surgical decompression to prevent optic atrophy . before methotrexate therapy , all patients received as initial treatment intravenous pulse - methylprednisolone therapy at a dose of 10  mg / kg twice a week for 6 weeks ( on tuesdays and thursdays ) , followed by oral prednisone at a dose of 30  mg / day , tapered to discontinuation over approximately 2 months .
patients with recurrence of inflammatory signs ( 7-point clinical activity score ( 7-cas )  3 and in patients with asymmetric presentation the eye with the worse score was considered ) received as maintenance oral prednisone at a dose of 10  mg / day . from this group ,
36 patients who stopped corticosteroids due to the occurrence of side - effects or intolerance to maintenance steroid therapy were commenced on methotrexate therapy . during a time period of 9 years
reasons for cessation of steroid therapy included mood swings ( 25% of patients ) , hyperglycemia ( 21% of patients ) , hypertension ( 19% of patients ) , fecal blood ( 7% of patients ) , and complaining of puffiness , sleeplessness , facial flushing , slight tremor , and agitation ( 28% of patients ) .
length of previous corticosteroid therapy ranged from 2 months to 1 year ( median 5.12 months , table 1 ) .
time between pulse therapy and second - line treatment ranged from 2 months to 1 year ( median 8 months , table 1 ) .
patients were aged from 35 to 70 years with a mean age of 52 years ( table 1 ) . at the onset of ted ,
hyperthyroidism was treated in 20 patients with thiamazole , 8 with a combination of thiamazole and thyroidectomy , 3 with radioiodine therapy , and 5 with thiamazole and radioiodine ( table 1 ) .
thyroid function at time of treatment with methotrexate was as follows : 22 patients ( 61% ) were euthyroid ( 12 still using thiamazole and 10 without treatment ) , 3 patients ( 8% ) were still hyperthyroid ( using thiamazole ) , and 11 patients ( 30% ) were hypothyroid ( using levothyroxine ) .
pretreatment laboratory investigations included complete blood count ; assessment of liver , kidney , and lung functions ; serum immunoglobulin levels ; and hepatitis b and c serology .
methotrexate was administered at two different weekly doses depending on the weight of the patient : 7.5  mg for patients weighing less than 60  kg and 10  mg for those weighing more than 60  kg .
the weekly dose of 7.5  mg was orally administered and fractionated as follows : two tablets of 2.5  mg on thursday and one on friday , while the dose of 10  mg was administered and fractionated as three tablets of 2.5  mg on thursday and one on friday . to minimize the potential toxicity ,
a dose of 15  mg of folic acid was prescribed for each patient on sundays .
laboratory evaluation including a complete blood count and liver enzyme testing was performed every 2 weeks .
the following parameters were measured at baseline ( premethotrexate treatment ) and at 3 , 6 , and 12 months after commencement of methotrexate treatment : 7-cas [ 17 , 18 ] , ocular motility , exophthalmos , eyelid aperture , and visual acuity ( va ) .
ocular motility was measured using the light reflex method , recently validated for ted motility evaluation : a score of 45 was given when the light 's reflex was at the limbus , 30 at half way between the limbus and pupil edge and 15 at the pupil edge .
improvement in ocular motility was considered if variation was at least of 15 , as previously reported .
exophthalmos was measured with hertel exophthalmometry : a decrease of 2  mm was considered significant .
where different scores or measures of severity existed for the two separate eyes of one individual , scores of the worse eye were considered for analysis .
mean 7-cas , exophthalmometry , and mrd measurements were compared before and after methotrexate treatment using student 's t - test .
the chi squared test (  ) was used to compare the results of va and ocular motility data .
there was a significant improvement in 7-cas score at 3 , 6 , and 12 months ( p < 0.0001 ) ( table 2 ) . at 3 months , 24 patients ( 67% ) had a reduction of 7-cas in both eyes ; at 6 months , 29 patients ( 80% ) had a reduction of 7-cas in both eyes ; at 12 months , 34 patients ( 94% ) had a reduction of 7-cas in both eyes . before methotrexate therapy ,
18 patients ( 50% ) had a va of 20/20 , 8 patients ( 22% ) had 20/25 , 8 patients ( 22% ) had 20/30 , and 2 patients ( 6% ) had 20/50 .
after 6 months , 2 patients had an improvement of one line on the snellen chart .
after 12 months of followup only 1 patient had an improvement of three lines on the snellen chart .
15 patients ( 42% ) had some degree of gaze restriction at baseline . at 3 months ,
4 patients improved ( 27% of patients with ocular motility disturbances ) , and at 6 and 12 months a total of 10 patients improved ( 67% of patients with ocular motility disturbances ) .
the reduction of ocular motility restriction after 6 and 12 months of treatment was significant ( p < 0.001 ) ( table 3 ) . mean hertel exophthalmometry measurement was 24  mm ( range from 17 to 27 , sd 3 ) .
there was no significant change at 3 , 6 , and 12 months after treatment ( table 3 ) .
mean mrd was 6  mm ( range from 4 to 7 , sd 1.5 ) .
there was no significant change at 3 , 6 , and 12 months after treatment ( table 3 ) .
the orbital disease usually starts with a dynamic period of active inflammation characterized by pain , redness , and swelling of the eyelids . during the active phase , disease severity increases and then plateaus .
after this , disease severity slowly decreases until stable end stage , called inactive phase .
although the shape of the curve is representative of disease course for majority of patients , the time axis of rundle 's curve shows high individual variability : it can take from a few months to more than 5 years to reach the static phase .
prompt restoration of stable euthyroidism and immunosuppression may decrease the duration of the dynamic phase and reverse the tendency to progression .
management of active inflammation in ted in the present study was based on the 7-cas .
when the inflammatory grade was 3 or greater , or if there was evidence of progression in the inflammation , immunosuppressive treatment was necessary .
systemic steroids are generally considered first - line treatment for ted as they can be given with systemic ( oral or intravenous ) or local ( subconjunctival or retrobulbar ) administration .
the efficacy of high - dose intravenous corticosteroid pulse therapy has been widely reported . in our study
all patients initially received corticosteroid pulse therapy , which is routinely used in our unit for patients with 7-cas higher than 3 .
for those patients with persistent ted or reactivation after pulse therapy , long - term corticosteroid therapy is commonly used .
however long - term use of corticosteroid can lead to complications such as high blood pressure , cushing syndrome , diabetes , osteoporosis , fragility fractures , and in rare cases acute hepatitis .
patients included in this study developed such side - effects over the treatment course , and when therapy was withdrawn , they experienced an increase in the inflammation score .
many alternative therapies have been reported for such patients , although their efficacy is still under debate [ 12 , 14 , 15 ] .
the efficacy of methotrexate has been reported for many autoimmune diseases requiring a long - term maintenance therapy such as rheumatoid arthritis , inflammatory bowel disease , and wegener 's granulomatosis .
methotrexate is an immunosuppressive drug that inhibits dihydrofolate reductase enzyme , leading to the inhibition of the dna , rna , and protein synthesis [ 15 , 22 ] .
cytotoxic and antiproliferative effects can be seen at high doses , while anti - inflammatory and immunomodulatory effects can be observed with chronic low - dose treatment [ 23 , 24 ] .
the use of methotrexate is proposed on the basis of the autoimmune nature of ted [ 11 , 15 , 25 , 26 ] .
patients who received methotrexate showed an early significant improvement of 7-cas at 3 , 6 , and 12 months ( p < 0.0001 ) .
although none of patients included in this study had an optic neuropathy , va improvement was reported but it was not significant .
the improvement in ocular motility restriction was statistically significant after 6 and 12 months of methotrexate treatment ( p < 0.001 ) .
however , side effects such as gastrointestinal disturbances , increased risk of opportunistic infections , bone marrow depression , interstitial pneumonitis , liver toxicity , asthenia , and fecal occult blood should always be considered since they have been reported in the literature [ 27 , 28 ] .
the addition of folate may reduce methotrexate toxicity , without affecting its effectiveness [ 14 , 23 ] .
the glucocorticoid - sparing effect of methotrexate is confirmed in our study , but this drug should not be used for more than 2 years in order to avoid the risk of megaloblastic anemia and lymphomas .
all the participants into this study had experienced recurrence of inflammatory signs of ted after withdrawal of corticosteroid treatment such as ocular pain and discomfort due to chemosis , hyperemia , and eyelid edema .
these patients , as reported in previous studies , seem to have a phase of activity longer than usual .
early surgical decompression could be considered for these patients even though its effectiveness needs to be confirmed .
in addition , patients with this condition may refuse surgery and methotrexate may be offered to them as a second - line therapy in order to contain the inflammatory process and prevent further complications due to fibrosis process .
hence , the indication for treatment with methotrexate should be a recurrent ted with 7-cas  3 after withdrawal of steroids because of onset of steroid side - effects or intolerance .
our study suggests that methotrexate therapy is useful for reducing the signs and symptoms of inflammation in ted , shortening the active phase , and reducing eye discomfort since all patients had a statistically significant reduction in inflammatory score .
methotrexate appears to be a suitable second - line treatment for patients with recalcitrant ted to control the clinical profile and delay surgery until the disease stability .
 
 background / aim . to evaluate the efficacy of methotrexate for the treatment of thyroid eye disease ( ted ) 
 . 
 methods . 36 consecutive patients with active ted , previously treated with corticosteroids but stopped due to the occurrence of side effects , were commenced on methotrexate therapy . 
 two different weekly doses were administered depending on the weight of the patient ( 7.5  mg or 10  mg ) . clinical activity score ( 7-cas ) , visual acuity 
 ( va ) , ocular motility , exophthalmos , and eyelid position were retrospectively evaluated at 3 , 6 , and 12 months and compared with baseline data . 
 
 results . 
 there was a statistically significant improvement in 7-cas at 3 , 6 , and 12 months after treatment ( p < 0.0001 ) . 
 there was no significant change in visual acuity . 
 ocular motility disturbances improved at 6 and 12 months ( p < 0.001 ) . 
 there was no significant change in exophthalmos ( mean 24  mm , sd 3  mm ) or eyelid position ( marginal reflex distance mean 6  mm , sd 1.5  mm ) during the follow - up period . 
 no side effects were registered . 
 
 conclusions . 
 methotrexate therapy is effective in reducing cas and ocular motility disturbances . 
 no significant improvement in proptosis or eyelid retraction should be expected from this treatment . 
 eventually , it might be considered a suitable alternative treatment in ted for patients who can not tolerate steroids . 
 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion