Relationship between 5,10-methylenetetrahydrofolate reductase C677T gene polymorphism and methotrexate related toxicity in patients with autoimmune diseases receiving folic acid supplementation
Authors: M Speletas, N Papadopoulos, C Daiou, E Katodritou, A Pavlitou-Tsiontsi, V Galanopoulou
Journal: Annals of the Rheumatic Diseases (2005)

A 14 year old girl presented with a year's history of joint pain, restriction, and swelling, initially diagnosed as juvenile idiopathic arthritis.She had no past medical problems but had given up her leisure pursuits owing to disability.Examination disclosed non-pitting oedema to midcalf; a woody texture of the soft tissues of the forearms and calves with fixed flexion deformities of her fingers, wrists, knees, and ankles due to the soft tissue changes, and normal overlying skin.Investigations showed the following results: normal muscle enzymes, eosinophilia of 1.7610 9 /l, erythrocyte sedimentation rate 41 mm/1st h, haemoglobin 112 g/l, negative autoantibodies, and normal complement levels.The differential diagnosis included eosinophilic fasciitis (EF) and scleroderma.At this time, the patient requested counselling as she had difficulty accepting an initial misdiagnosis, delayed correct diagnosis, and the uncertainty of the prognosis.Magnetic resonance imaging (MRI) of the forearm was performed (fig 1).A biopsy showed chronic inflammatory changes in the deep subcutaneous fat and fascia with infiltration by lymphocytes, plasma cells, histiocytes, and eosinophils.The fascia was markedly thickened and fibrosed with focal fibrinoid necrosis, consistent with EF.In view of her disability, she was treated with intravenous methylprednisolone (1 g/day for 3 days), then oral prednisolone 20 mg daily (0.3 mg/kg/day) with normalisation of her erythrocyte sedimentation rate and eosinophilia.Methotrexate 15 mg orally weekly was added 2 months later as there had been no further significant clinical response to steroids.Five months later she improved functionally with reduced contractures despite prednisolone reduction to 12.5 mg daily.A repeat MRI scan showed a reduction in the subcutaneous and fascial oedema, prompting a further reduction in steroids.At this time, she self harmed by cutting the skin of her forearms because of low mood, difficulties adjusting to her diagnosis, and the cosmetic side effects of steroids.She required treatment with antidepressants and counselling.One year after diagnosis, an MRI scan showed persistent fascial oedema, leading to an increase in methotrexate (17.5 mg orally weekly) while maintaining her prednisolone at 3 mg daily.Over the following 6 months finger movement improved despite stopping prednisolone in the interim.However, she attempted suicide by taking an overdose of methotrexate as she felt a burden to others, and required further psychological treatment.Three years after diagnosis, she remains well and continues to receive methotrexate, with minimal inflammation on MRI, mild finger and wrist contractures, and return of full function.At no time has there been evidence of internal organ involvement.EF is characterised by painful swelling and stiffness of the extremities, typically with thickened skin (peau d'orange), a peripheral eosinophilia, and characteristic histology. [1]2][3][4] In contrast with adult EF, paediatric EF predominantly affects girls and has not been reported to cause haematological complications.In contrast with scleroderma, the epidermis and dermis are spared, whereas in comparison with polymyositis there is minimal muscle inflammation, distinctions illustrated by MRI. [1]][3][4] Teenage self harm is well recognised, particularly in girls, although may be underdiagnosed in those with a chronic illness. 5 The impact of the disease itself, its impact upon body image and lifestyle, and the side effects of treatment, lack of predictability, and uncertainty of prognosis are all likely to contribute to mental health status during adolescence. 6 Prognosis in paediatric EF remains uncertain, although a previous study has reported more favourable outcomes in older children. 4 We expect to withdraw methotrexate from this girl within the next 12-18 months if her signs and MRI appearance remains stable.This case highlights the use of MRI in assessment of soft tissue disease and in guiding drug management.Furthermore, the psychological impact during adolescence of a chronic disease, its management, and correct diagnosis should not be underestimated.