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Rheumatology 2001; 40: 341-342
© 2001 British Society for Rheumatology
Letters to the Editor |
Late reactivation of spinal tuberculosis by low-dose methotrexate therapy in a patient with rheumatoid arthritis
Department of Rheumatology, University of Manchester, Rheumatic Diseases Centre, Hope Hospital, Stott Lane, Salford M6 8HD, UK
SIR, It is generally accepted that the use of chronic corticosteroid treatment predisposes to primary tuberculosis (TB) and reactivation of TB infection [1], and most of the TB cases reported in rheumatoid arthritis (RA) and other rheumatic diseases are associated with the use of long-term corticosteroid therapy [2]. A handful of cases of primary TB associated with the use of low-dose methotrexate (MTX) have been reported in patients with psoriasis [3]. We believe, however, that ours is the first case of TB reactivation associated with low-dose MTX therapy alone in a patient with RA.
NB, a 58-yr-old white female with a 9 yr history of well-controlled RA, was admitted with a 4-week history of generalized aches and pains, nausea and loss of appetite, episodic sweating and early morning stiffness of 20 min. She denied any history of chronic diarrhoea or dysphagia, but she had lost 5 kg in the 2 months before her hospital admission. Her RA had responded well to low-dose oral MTX (7.5 mg/week), which she had taken continuously since 1997. She had never taken oral corticosteroids. Her medical history included TB of the thoracic spine when aged 7 yr, and this had left her with gross and angulated kyphoscoliosis. There was no history of diabetes mellitus, thyroid disease, excessive alcohol intake or psychiatric disorders. She is a non-smoker who lives with her husband. There was no family history of note.
Examination revealed a thin lady weighing 42 kg, her weight during the previous 3 yr being stable at 47–49 kg. Temperature was 37.9°C. There was chronic, symmetrical, but inactive peripheral polyarthritis and there were no extra-articular features. She had angular kyphoscoliosis in the mid-thoracic region. There was no tenderness on spinal palpation and no evidence of radiculopathy/myelopathy on careful neurological assessment of the limbs. The initial differential diagnosis included malignancy (stomach or other site), MTX-induced gastritis, a systemic-only flare-up of RA, and reactivation of TB.
Laboratory examinations revealed the full blood count and renal and liver function tests to be normal. Urinalysis was normal. The erythrocyte sedimentation rate (ESR) was 110 mm/h and C-reactive protein (CRP) concentration was 140 mg/l (normal value <10), whereas during the previous 18 months the ESR had ranged from 16 to 23 mm/h and the CRP had always been <10 mg/l. Creatine kinase was 75 U/l (normal range 25–190); glucose and thyroxine were within normal limits. The test for rheumatoid factor was positive (SCAT 1/256), and tests for antinuclear antibodies, anti-DNA, p-antineutrophil cytoplasmic antibodies (ANCA) and c-ANCA were all negative. CA-125 was within normal values. Repeated blood and urine cultures were sterile. Skin tests for purified protein derivative (PPD) (1/10 000 and 1/1000) were negative. Ultrasonography of the abdomen and gastroduodenoscopy showed no abnormality. Plain (PA) radiographs of the chest showed clear lung fields, and the lateral chest radiograph showed features in keeping with her previous mid-dorsal TB, with angular kyphosis of 30°. Magnetic resonance imaging showed a large paraspinal TB abscess at the L3 vertebral level. A presumptive diagnosis of TB reactivation was made and MTX was therefore discontinued. Treatment for TB commenced. Mycobacterium tuberculosis was confirmed histologically and by positive culture. The patient made a good recovery and continues to improve 6 months later. Treatment for TB is planned to continue for 12 months.
Low-dose MTX has become a standard treatment for RA, and most rheumatologists now use it at an early stage of the disease. MTX inhibits the production of intracellular polyamines, which are essential for lymphocyte growth and replication. Friedman et al. [4] and many others have confirmed that MTX depresses established delayed hypersensitivity. Additionally, a recent study suggested that MTX promotes the apoptosis of activated T cells, which in turn limits T-cell proliferation [5].
The two peculiar features in this case, the absence of back pain and the negative PPD skin tests, can probably be explained by depression of cellular immunity due to low-dose MTX (the cumulative dose was 630 mg); this also reactivated the spinal TB, which had been dormant for more than 50 yr. We identified no other factor predisposing the patient to TB reactivation [6]. Tuberculosis is a potentially fatal complication of immunosuppressive therapy, and low-dose MTX may be more immunosuppressive than has been thought [7]. The possibility of reactivating a quiescent tuberculous focus with chronic MTX therapy must therefore be borne in mind. Although low-dose MTX in combination with corticosteroid therapy may be regarded as a risk factor for TB infection in RA patients, this risk has been recognized only recently [8]. The increasing use of low-dose MTX in RA, including its use in combination with corticosteroids, clearly predisposes to increased susceptibility to infection, including TB. We suggest that physicians caring for (iatrogenically) immunosuppressed patients should be aware of the potential hazards of TB, since early chemotherapy and chemoprophylaxis would reduce TB-associated morbidity and mortality in patients with rheumatic diseases.
Notes
Correspondence to: K. Binymin. 
References
- Kim HA, Yoo CD, Back HJ et al. Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic disease patient. Clin Exp Rheumatol1998;16:9–13.[ISI][Medline]
- Hernandez Cruz B, Sifuentes-Osorinio J. Mycobacterium tuberculosis infection in patients with systemic rheumatic disease. Clin Exp Rheumatol1999;17:289–96.[ISI][Medline]
- Smith JD, Knox JM. Psoriasis, methotrexate and tuberculosis. Br J Dermatol1971;84:590–3.[Medline]
- Friedman RM, Buckler CE. Mechanism of methotrexate action on tuberculin hypersensitivity in guinea-pigs. Fend Proc1963; 22:501–5.
- Genestier L, Paillot R, Fournel S, Ferrero C, Miossec P, Revillard J. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest1998;102:322–8.[ISI][Medline]
- Parmer M, Appleton PJ. Pott's disease of the spine. Br J Hosp Med1996;56:52.[Medline]
- Agnes M, Boerbooms T, Pit JSM, Kersten. Infections during low-dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum1995;24:411–21.[ISI][Medline]
- di Girolamo C, Pappone N, Melilo E. Cavitary lung tuberculosis in a rheumatoid arthritis patient treated with low-dose methotrexate and steroid pulse therapy. Br J Rheumol1997;37:1136–8.
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