grave 's ophthalmopathy , also called thyroid associated orbitopathy ( tao ) , has existed for over centuries with mention found in the 12 century persian medical writings . its association with hyperthyroidism is well known , but 10% subjects have tao associated with euthyroid or hypothyroid autoimmune thyroiditis . it is a complex autoimmune process related to the orbital autoantigens like thyroid stimulating hormone receptor ( tshr ) , calsequestrin , collagen xiii , flavoprotein , and insulin like growth factor-1 ( igf-1 ) . high dose corticosteroids alone or in combination with orbital radiation remain imperfect option due to recurrences . rituximab ( rtx ) , a monoclonal b cell antibody targeting cd20 , which depletes the b cells , has been used in hyperthyroid grave 's ophthalmopathy . here , we report a case of bilaterally symmetrical severe corticosteroid resistant hypothyroid grave 's ophthalmopathy ( hypogo ) treated with rtx . a 45-year - old reformed smoker was diagnosed as a case of primary hypothyroidism in 2001 . patient was started on thyroxine replacement therapy . presently , he reported in may 2011 with swelling and redness of right eye followed by left eye for 2 months , associated with diplopia . his clinical activity score ( cas ) was 6/7 with presence of eyelid edema and erythema , spontaneous retrobulbar pain , conjunctival chemosis , and caruncle injection with edema , with moderate to severe euorpean groups of graves orbitopathy ( eugogo ) severity [ figure 1 ] . his vision was 6/9 in both eyes with defective green color vision , with normal intraocular pressure ( iop ) and normal fundoscopy . his thyroid function tests were normal ( t3 , 2.97 pg / ml ; t4 , 1.44 ng / dl ; tsh , 0.492 iu / ml ) on replacement therapy . his anti - tpo ( 2226.80 u / ml ; normal < 9 u / ml ) and tshr ( 42.3 magnetic resonance imaging ( mri ) orbit revealed symmetrically diffuse increased bulk of bilateral extraocular muscles involving the muscle bellies with evidence of bilateral axial proptosis with sparing of tendons and with increased signal intensity . in view of severe active eye disease ( 1 6 weeks 500 mg weekly followed by 250 mg weekly for 6 weeks ) . after 12 weeks of steroid therapy , the patient reported with worsening of visual acuity ( right eye  6/18 , left eye  6/12 ) and cas of 5/7 [ figure 1 ] and nospecs score of 6 . t2 relaxometry measurements in the muscles were on average 175 ms on the right and 145 ms on the left . ratio with the temporalis muscle was 4.26 on the right side and 4.02 on the left side [ figure 2 ] . in view of his worsening clinical status after 12 weeks of steroid therapy , the options left were orbital radiotherapy or orbital decompressive surgery . since there were reports of utility of rtx in hyperthyroid grave 's ophthalmopathy , we decided to give the patient a trial of rtx therapy with oral prednisolone after informed consent was obtained from the patient . patient was screened for hepatitis b , c , and human immunodeficiency virus ( hiv ) , and any underlying active infection and tuberculosis before rtx therapy . patient was given two infusions of 1 g infusion of rtx 2 weeks apart with prednisolone ( 60 mg / day ) . two weeks after the rtx therapy , the cas improved to 1/7 in both eyes ( only mild caruncle edema was present ) with subjective improvement in visual acuity [ figure 1 ] . during the follow - up , 2 months post - rtx therapy , the patient had a cas score of 1/7 . the patient developed community - acquired pneumonia 2 months after therapy when he was due for re - evaluation . he died on the seventh day of admission due to multi - organ system failure . ( c ) regression of eye signs following rituximab therapy ( a and b ) mri orbit showing symmetrically diffuse increased bulk of extraocular muscles with increased signal intensity in pre - steroid stage . ( c and d ) minimal change post - steroid with compression at the orbital apex due to crowding about 10% of tao is seen in euthyroid and hypothyroid patients . however , tjiang , et al . reported high prevalence of eye signs ( 34% ) in patients with hashimoto 's thyroiditis . involvement of eye has also been reported in subjects with hypothyroidism on various drugs , namely thiazolidinedione , lithium , ipilimumab alone or combined with bevacizumab therapy . most patients of hypothyroid and euthyroid grave 's ophthalmopathy present as asymmetrical ophthalmopathy with little soft tissue involvement with low titers of tshr antibodies and anti - tpo antibodies . but our patient presented with bilaterally symmetrical eye disease with prominent soft tissue involvement , high titers of tshr and anti - tpo antibodies in euthyroid state , and no history of drug intake except thyroxine . however , a recent study reported no difference in demographic , clinical characteristics and severity among tao patients with hyperthyroidism or hypothyroidism . tao is thought to be due to the immunological cross - reactivity between thyroid and orbital tissue antigens like tshr , calsequestrin , collagen xiii , and flavoprotein , igf-1 . circulating tshr antibodies have been found to be correlated with the clinical activity of tao . this probably explains the clinically severe eye disease in our patient who had high circulating levels of tshr antibodies . hypogo rarely requires therapy except thyroxine replacement therapy . after extensive review of literature ; we could find few case reports of hypogo requiring therapy . described a case who developed ophthalmopathy with slight proptosis , moderate palpebral edema , conjunctival injection and chemosis , reduction of visual acuity , diplopia , and secondary glaucoma in euthyroid stage following thyroxine replacement therapy for primary hypothyroidism . they treated him with two doses of 0.5 g intravenous methylprednisolone for 3 days , followed by oral prednisone 40 mg / day tapered to 10 mg / day in 4 weeks . one of the earliest reports of treatment of hypogo was by hiromatsu , et al . in which they reported improvement of eye signs after pulse methylprednisolone therapy and decrease in anti - tsh receptor antibodies . grzesiuk , et al . observed remission of ophthalmic symptoms with methylprednisolone pulse therapy and levothyroxine in a case of hypogo with extremely high titers of tshr antibodies . rajput , et al . reported two cases of infiltrative ophthalmopathy with primary hypothyroidism treated with levothyroxine alone or in combination with steroids . tambe , et al . described two hypothyroid patients with grave 's ophthalmopathy in a series of 38 patients treated with oral prednisolone over 1 month following intravenous methylprednisolone . recently , razenberg , et al . reported four cases of hypogo ; among them , two required steroid therapy . our patient had a high cas , hence was given intravenous methylprednisolone pulse therapy according to the current eugogo guidelines . despite this , the patient , rather than showing improvement in cas , had deteriorated with decrease in the visual acuity and increase in iop . the established methods of treatment with oral or intravenous glucocorticoids , orbital radiation , and surgical decompression do not halt the natural progression of this disease and improvement of quality of life after therapy remains modest . considering adverse impact of orbital radiation and surgery , we decided to offer him rtx therapy . rtx , a mouse human chimeric monoclonal antibody against cd20 protein on pre - b cells and mature b lymphocytes , blocks the b cell activation and differentiation without affecting b cell regeneration from stem cells or immunoglobulin production by plasma cells . initially used in the treatment of b cell lymphomas , it subsequently proved useful in a variety of autoimmune diseases . the rationale behind the use of rtx in these diseases was the putative role of autoantibodies in the pathogenesis of these diseases . the possible mechanisms in the mostly t cell mediated tao is probably that rtx abolishes the antigen presenting function of b cells . natural history of tao consists of an active phase lasting a relatively limited duration ( 6 - 18 months ) and followed by clinical stabilization . rtx causes a transient b cell depletion for 4 - 6 months , which may affect the clinically active phase of tao and the further clinical course . chong , et al . in a retrospective case series reported the beneficial effects of rtx in six patients of glucocorticoid - resistant hyperthyroid tao with improvement in orbital inflammation and dysthyroid optic neuropathy without effect on proptosis and strabismus , suggesting the potential use of rtx as salvage therapy . rtx with systemic steroid therapy has been shown to reduce tao activity and severity over 30 weeks in an open label study . the side effects of rtx reported in studies examining rtx therapy in tao are of varying prevalence and severity . few of the patients developed hypotension , febrile illness , sinus tachycardia , and serum sickness . some of the late side effects reported were polyarthritis , ulcerative colitis , and urinary tract infection . a series of six cases of pneumocystis jirovecii pneumonia ( pcp ) in 46 lymphoma patients treated with rtx and chemotherapy was reported by kolstad , et al . however , fatal results due to pcp have been reported after rtx therapy in a patient with rheumatoid arthritis who was also on steroid and methotrexate therapy and a patient with posterior scleritis . another study reported no increase in the incidence of pcp in patients of lymphoma receiving rtx on adequate pcp prophylaxis . armed with these reports , we had given rtx with oral prednisolone dose in the present case with remarkable improvement in cas ; however , even though the patient reported improvement in cas , he succumbed to p. jirovecii infection prior to repeat investigations , 2 months post - rtx therapy . a repeat mri , which could not be done , may have indicated improvement in the form of decrease in the signal intensity ratio , t2 relaxometry , and extraocular muscle edema . recently , one phase i / ii clinical trial assessed the efficacy and safety of rtx - mediated b - lymphocyte depletion as treatment for thyroid eye disease . to the best of our knowledge , this is the first case where rtx has been used in steroid - resistant hypogo . however , sudden demise due to community - acquired infection with underlying immune compromised status has dampened our enthusiasm and indicated caution against its use . the improvement in the quality of life after the established therapy remains less than satisfactory . hence , we suggest that rtx therapy can be used in treatment of thyroid associated ophthalmopathy in severe corticosteroid resistant eye disease as a second line of therapy , though one should be aware of the side effects and risk associated with the therapy .
association of grave 's ophthalmopathy with hyperthyroidism is well known , and it has also been reported in euthyroid or hypothyroid autoimmune thyroiditis , which rarely requires treatment . here , we report a case of bilaterally symmetrical severe corticosteroid - resistant hypothyroid grave 's ophthalmopathy successfully treated with rituximab .