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Rheumatology 2001; 40: 592-593
© 2001 British Society for Rheumatology
Letters to the Editor |
Elevated serum cytokine levels in a rheumatoid arthritis patient with large granular lymphocyte syndrome
Nagasaki University, Nagasaki and
1 National Uresino Hospital Fujitu-gun, Saga, Japan
SIR, Large granular lymphocyte (LGL) syndrome [1, 2] is characterized by the proliferation of LGL in the peripheral blood, and is often complicated by neutropenia and rheumatoid arthritis (RA). We experienced a case of RA with LGL clonal expansion. RA activity in this patient was low; neither joint tenderness nor swelling was observed. However, strikingly increased levels of serum cytokines [tumour necrosis factor 
(TNF-), interleukin 1ß (IL-1ß), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF)] were detected, while interleukin 4 (IL-4) and interleukin 10 (IL-10) were not detected (Table 1
).
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A 76-yr-old woman had first experienced bilateral finger and wrist joint pain and swelling in 1982, and was diagnosed as having definite RA according to the American Rheumatism Association criteria proposed in 1958 [3]. She was treated thereafter with non-steroid anti-inflammatory drugs for several years. In 1987, recurrent swelling in both knees with massive fluid accumulation occurred, and 5 mg/day of prednisolone was started. Joint pain decreased, although deformities of the affected joints gradually progressed. In 1991, she experienced localized peritonitis after treatment with parenteral antibiotics following surgery for appendicitis. In 1995 she visited a physician for protracted thirst, and upon examination was found to have increased serum calcium and parathyroid hormone (PTH) levels. She was referred to our hospital and admitted for further examination for suspected hyperparathyroidism. Before admission, neither circulating neutropenia nor an increased number of LGL had been observed.
On physical examination she was found to have the ‘duck neck’ or ‘swan neck’ deformity, along with ulnar deviation of the fingers from the metacarpophalangeal joint, although without tenderness or swelling. An X-ray of her hands demonstrated typical RA changes with destruction and bony ankylosis of the wrist joints. On laboratory examination, the white blood cell count was 4600/mm3, although severe neutropenia with only 4% (184/mm3) and relative lymphocytosis of 76% (3496/mm3) of white blood cells were found. The serum calcium and serum phosphate levels were 11.3 and 2.7 mg/dl respectively. The erythrocyte sedimentation rate was 106 mm/h and serum C-reactive protein was 1.54 mg/dl. The serum level of rheumatoid factor was increased to 1580 IU/ml (normal range <18 IU/ml). Serum anti-leucocyte antibodies were also positive. The PTH level was confirmed to be increased, and the patient was diagnosed with primary hyperparathyroidism.
A large portion of her peripheral lymphocytes were morphologically LGL with three or more azurophilic granules in the cytoplasm. She was diagnosed as having RA with LGL syndrome. Surface phenotypes of peripheral blood lymphocytes were 97.2% CD2+, 99% CD3+, 14.8% CD4+, 5.2% CD8+ and 0.8% CD16+; B-cell phenotype marker (CD21+) cells were only 1.1% of total lymphocytes. Two-colour analysis of the peripheral lymphocytes demonstrated that the LGL were CD3+, TCR-ß-, TCR-
+, CD4-CD8- and CD16- cells; T-cell type LGL. Southern blot analysis of the TCR- gene revealed that the expanded LGL population was monoclonal. Functional analysis of the lymphocytes showed slightly decreased natural killer cell activity, along with lowered responses to phytohaemaglutinin (PHA) and concanavalin A (con A). Serum levels of TNF-, IL-1ß, IL-2, IL-6, IL-8, G-CSF and GM-CSF were remarkably increased (Table 1
), although IL-4 and IL-10, which are considered to be anti-inflammatory cytokines, were not detected. Subtotal parathyroidectomy was performed for the treatment of hyperparathyroidism. Serum calcium and PTH levels were promptly normalized and no complication was observed after surgical treatment, although severe circulating neutropenia and relative lymphocytosis were still observed. The patient is currently being followed up as an out-patient and is in good health.
This report represents, to our knowledge, the first case exhibiting elevated serum levels of such a broad spectrum of cytokines in a patient with RA complicated with LGL syndrome. Serum cytokine levels were measured under fairly ordinary conditions during the admission, and the increase in serum cytokines is considered to have been caused by RA with LGL leukaemia rather than by conditions such as infections that occurred incidentally during the admission. One candidate for the origin of such increased circulating cytokines is inflamed synovial tissue of the affected joints by RA. In spite of increased concentrations of cytokines such as IL-1ß and TNF-, both of which are reported to increase in the serum parallel to the activity of RA [4, 5], this patient did not show any tenderness or swelling of the joints, indicating that her RA activity was quite low [6, 7]. Relatively low disease activity has been reported in Felty's syndrome, which is very similar to RA with LGL syndrome [8]. One hypothesis to explain the decreased activity is the switch that can occur from Th1 cells to Th2 cells in Felty's syndrome. The present patient did not show an increase in serum IL-4, which is a Th2-type cytokine, but did show increased levels of serum IL-2, which is a Th1-type cytokine [9].
To our knowledge, this is the only case report of increased cytokine levels in a patient with RA complicated with LGL syndrome. The findings of this case present interesting suggestions regarding the role of cytokines in RA with LGL syndrome, and in RA disease activity.
Notes
Correspondence to: Y. Kawabe, National Uresino Hospital, Ooaza Shimojuku hei 2436, Uresino-cho, Fujitu-gun, Saga-ken, Japan. 
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- Ropes MW, Bennett GA, Cobb S, Jacon R, Jessor RA. Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis1958;9:175–7.[Medline]
- Eastgate JA, Symons JA, Wood NC, Grinlinton FM, Di Glovine FS, Duff GW. Correlation of plasma interleukin-1 levels with disease activity in rheumatoid arthritis. Lancet1988;ii:706–9.
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Tetta C, Camussi G, Modena V, Di Vittorio C, Baglioni C. Tumor necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis. Ann Rheum Dis1990;49:665–7.
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- Bowman SJ, Sivakumaran M, Snowden N, Bhavnani M, Hall MA, Panayi GS et al. The large granular lymphocyte syndrome with rheumatoid arthritis. Immunogenetic evidence for a broader definition of Felty's syndrome. Arthritis Rheum1994;37:1326–30.[Medline]
- Bowman SJ, Corrigall V, Penayi GS, Lanchbury JS. Hematologic and cytofluorographic analysis of patients with Felty's syndrome. A hypothesis that a discrete event leads to large granular lymphocyte expansions in this condition. Arthritis Rheum1995;38:1252–9.
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