Failure of G-CSF therapy in neutropenia associated with Sjögren's syndrome

J. Vivancos, M. Vila, A. Serra1, J. Loscos2 and A. Anguita

Department of Internal Medicine,
1 Laboratory of Haematology and
2 Department of Ophthalmology, Clínica de Nuestra Señora del Pilar, Barcelona, Spain

SIR, Neutropenia is found in about 10% of patients who have Sjögren's syndrome (SS) [1]. An autoimmune mechanism has been invoked in its pathogenesis [2, 3]. It is usually mild, not requiring any therapy. Severe cases, complicated with opportunistic infections, are uncommon [2] and there is no established treatment. On the basis of the known effectiveness of granulocyte colony-stimulating factor (G-CSF) in autoimmune neutropenias [4], we attempted treatment with the recombinant G-CSF filgrastim in a patient with primary SS who developed life-threatening neutropenia. Progressive anaemia and thrombocytopenia led us to discontinue this treatment. Contrarily, the patient responded dramatically to steroid therapy.

A 58-yr-old woman was admitted to our hospital complaining of severe bilateral blepharitis and high-grade fever. Ten years ago, she had been diagnosed with primary Sjögren's syndrome because of a picture of keratoconjuctivitis sicca, a pathological Schirmer's test, xerostomia, mild non-erosive symmetrical polyarthralgias and positivity for rheumatoid factor. Simultaneously, neutropenia was detected. Bone marrow examination by sternal aspiration was normal, and no other possible causes of leucopenia were present. Since then, her neutrophil count had remained between 0.6 and 1.2x109/l and she had not developed any opportunistic infection. Her only treatment was with artificial teardrops and oral paracetamol for arthralgias. On admission, blood tests showed haemoglobin 11.5 g/dl, haematocrit 35% and platelets 225x109/l. The white blood cell count (WBC) was 1.75x109/l, 79% of the cells being lymphocytes, 6% monocytes and 5% neutrophils, giving a neutrophil count of 0.087x109/l. A culture of conjunctival exudate was positive for Pseudomonas aeruginosa. Smears of aspirated bone marrow disclosed an increased myeloid/erythroid ratio with abundant immature myeloid cells. Treatment with intravenous meropenem and amikacin and subcutaneous filgrastim (300 µg/day) was started. Fever disappeared 24 h later and ocular signs improved rapidly. On the sixth day, the neutrophil count had risen to 0.25x109/l but haemoglobin had fallen to 8.8 g/dl, haematocrit to 28% and platelets to 106x109/l. On the eighth day, the neutrophil count was 0.31x109/l, haemoglobin 8.4 g/dl, haematocrit 27% and platelets 62x109/l; reticulocytes were 0.7% of total red blood cells (RBC). Filgrastim was then discontinued. During the next few days, RBC and platelets increased progressively. On the 15th day, haemoglobin was 10.6 g/dl, haematocrit 31% and platelets 232x109/l. Neutrophils were 0.26x109/l. The patient was then discharged.

Fifteen days later the patient was readmitted because of the reappearence of fever and blepharitis. P. aeruginosa again grew in cultured conjunctival exudate. Blood tests showed haemoglobin 11.2 g/dl, haematocrit 33%, platelets 233x109/l and WBC 0.94x109/l with neutrophils 0.066x109/l. Treatment with meropenem and amikacin was restarted and oral prednisone (80 mg/day) was added. Clinical signs again responded quickly. The neutrophil count rose progressively: on the seventh day it was 0.376x109/l and on the 15th day it was 2.63x109/l. No significant changes in RBC or platelets were noted. The patient was discharged symptom-free and steroid therapy at a progressively reducing dose was prescribed. Three months later, the patient is taking 10 mg/day of prednisone. She has had no new infectious complications. The neutrophil count has been fluctuating between 1 and 1.8x109/l and RBC and platelets continue in normal ranges.

Neutropenia, which is occasionally seen complicating SS, seems to be an autoimmune extraglandular manifestation of the disease and is probably mediated by anti-neutrophil autoantibodies [2, 3]. Mature neutrophils are thought to be the target cells of the immune agression. The accelerated destruction of peripheral neutrophils would induce hyperplasia of their precursors, thus explaining the richness of myeloid cellularity, predominantly of immature forms, that is usually seen in bone marrow specimens [2, 3]. This model of autoimmune neutropenia is very similar to those described in other rheumatic diseases, such as Felty's syndrome and systemic lupus erythematosus (SLE) [1], and in idiopathic autoimmune neutropenia [5], which probably includes most of the so-called chronic idiopathic neutropenias [4]. Interestingly, some authors recommend investigation for subclinical SS in apparently idiopathic cytopenias, including neutropenia [6].

Recent studies indicate that G-CSF is very effective in idiopathic autoimmune neutropenia and seems to be preferable to other therapies, such as steroids and intravenous immunoglobulins [4]. Moreover, severe neutropenia associated with Felty's syndrome or SLE has also responded to G-CSF in most of the cases reported, with low incidences of side-effects, and this treatment has therefore become a major advance in the management of neutropenia due to rheumatic diseases [7]. The benefits of G-CSF are evident not only in emergency cases, but also when it is administered as a long-term prophylactic therapy.

To the best of our knowledge, G-CSF has not been employed previously in SS-associated neutropenia, but it is reasonable to expect similar results. However, our case has failed to demonstrate its clinical usefulness. Although a moderate increase in the neutrophil count was obtained, the progressive declines in red cells and platelets led us to discontinue G-CSF after a few days.

Anaemia and thrombocytopenia have been reported only rarely in chronic neutropenia in children [8] and Felty's syndrome [7] complicating G-CSF therapy. Bearing in mind that G-CSF produces a striking proliferation of myeloid precursors in bone marrow [9], cells that are increased in number in autoimmune neutropenia [5], one could hypothesize that these cytopenias are due to the displacement of erythroid precursors and megakaryocytes by proliferating myeloid cells. These cytopenias disappear when G-CSF is discontinued [8].

Severe SS-associated neutropenia requiring treatment is a rare condition. Steroids have been shown to be effective and safe in previous reports [3, 6, 10], as in our own case. Nevertheless, in view of the poor tolerance of long-term steroid therapy, further studies will be necessary to determine whether G-CSF may be a better alternative, not only for emergency cases but also as a maintenance treatment. It is likely that our case is representative of a minority of patients with immune-mediated neutropenias who do not tolerate G-CSF therapy. However, this case illustrates the necessity for strict haematological follow-up when G-CSF is used in SS-associated neutropenia or any other kind of autoimmune neutropenia.

Notes

Correspondence to: J. Vivancos, Servei de Medicina Interna, Clínica de Nuestra Señora del Pilar, C/Balmes 271, 08006 Barcelona, Spain. Back

References

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Accepted 10 October 2001





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