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Primary Sjögren’s syndrome (SS) is an autoimmune disease characterised by the presence of xerostomia and xerophthalmia without evidence of another systemic autoimmune disease. It has a wide clinical spectrum, extending from exocrinopathy to systemic autoimmune disease and to B cell lymphoma. The association of SS with aplastic anaemia (AA) has rarely been reported1 2 and only in patients with lymphoma. We report here an exceptional case of primary SS and severe AA without lymphoma who had cytogenetic and immunological abnormalities, which might give clues to the pathogenesis of ‘idiopathic’ AA.
A 28 year old white man was referred in February 1990 for lymphadenopathies and pancytopenia. He complained of xerostomia and ocular burning. Xerophthalmia was confirmed by an abnormal Schirmer’s test (right eye 2 mm, left eye 1 mm after 10 mn) and a punctate keratitis on slit lamp examination after Rose-Bengal staining was observed. Labial salivary gland biopsy examination showed features of SS (grade 4 according to Chisholm’s focus score 3).
A polyclonal hypergammaglobulinaemia with a low level of IgA was present and fluorescent antinuclear antibodies were positive in a titre of 1: 640 with a speckled pattern. Rheumatoid factor and anti-DNA antibody test were negative. HLA typing was A3,B8,B27,DR3,DR28.
A blood cell count showed pancytopenia with 3.3 × 109/l leucocytes composed of 14% neutrophils, 76% lymphocytes, and 9% monocytes; haemoglobin: 7.4 g/dl with a mean corpuscular volume of 92 μ3; reticulocytes, 2 ×109/l; and platelets: 84 × 109/l. Ninety four per cent of the patient’s peripheral blood lymphocytes were CD3 +, and 76% were γ-δ TCR (δ TCS1) + with a non-clonal pattern observed when Vd1-Jd1 amplification was performed.
Direct Coombs antiglobulin test was positive for IgG and C3d without signs of haemolysis. Antineutrophil antibodies were detected in the serum with an autologous immunological assay.4 A bone marrow aspirate and trephine biopsy examination showed a hypoplastic marrow (cellularity of 15%) composed of 60% mature lymphocytes and 8% erythroblasts. No abnormal cell or myelofibrosis was seen. Cytogenetic analysis of blood, bone marrow, and skin cells of the patient showed a reciprocal translocation involving the chromosomes 14 and 20, t(14;20) (q24;p13) within all analysed cells. Ham test, sucrose lysis test, serological tests for HIV, HTLV1, EBV, CMV, and type B and type C hepatitis were negative, serum β2 globulin was normal. Lymph node biopsy examination showed a follicular lymphoid hyperplasia without light chain restriction. Thorax and abdominal computed tomography showed no adenopathies, or feature of lymphomatous involvement. Pancytopenia gradually worsened over three months, the patient required red cells transfusion every 10 days, platelet count was 6 × 109/l, absolute neutrophil count was 0.3 × 109/l. A five day course of high dose (400 mg/kg/d) intravenous polyvalent gammaglobulins (Biotransfusion, Lille,France) was unsuccessful. Then, the patient received a seven day course of antilymphocyte globulin (Merieux, Lyon, France; 20 mg/kg/d) with objective improvement. Neutrophil and platelet counts reached respectively 1.2 × 109/l and 107 × 109/l, three weeks after the onset of the treatment while the transfusion requirement decreased.
Two months later the AA relapsed. A haematopoietic progenitor cell analysis was performed and a pronounced decrease of bone marrow mononuclear cells (50% of normal range) and colony forming unit for granulocyte-monocyte (CFU-GM) cells (4% of normal range) was observed. CFU-GM colony and cluster counts at day 8 were increased by 10-fold when bone marrow mononuclear cells were pre-incubated with antilymphocyte globulin. Preincubations with the patient’s serum or peripheral blood mononuclear cells did not influence the colony formation. A familial allogeneic bone marrow transplantation was performed. The conditioning regimen associated cyclophosphamide (200 mg/kg) and busulphan (12 mg/kg). A graft rejection occurred and the patient died two months after the transplantation of pulmonary aspergillosis.
Pancytopenia complicating primary SS is rare and AA was first described in primary SS associated with lymphoma.1 ,2 Our patient fulfilled criteria for primary SS and had no evidence of associated lymphoma.
We did not find an inhibition of mononuclear cells to the haemopoietic progenitors as reported by Seki in a case of pancytopenia and primary SS.5 However, antilymphocyte globulin, which may act in AA through a cytotoxic effect on immunocompetent cells, yielded a transient and partial improvement.
The concentration of γ-δ TCR+ cells in our patient was higher than those previously reported in SS.6 The cultured γ-δ TCR+ lymphocytes demonstrated cytotoxic function in vitro.7This suggests a possible involvement of γ-δ TCR+ cells in the pathogenesis of AA.
The strong correlation between SS and HLA B8 DR3 suggests that genetic factors may play a part in the development of some subgroups of SS.8 The translocation t(14;20) (q24,p13), present in our patient has not been described before in SS. Interestingly,14q24 and 20p12-13 are two methotrexate and aphidicolin induced common fragile sites observed in at least 40% of humans, but also in patients with Fanconi anaemia.9 The gene for transforming growth factor β has also been located in 14q2410 11 and this gene is a haematopoietic-suppressor lymphokine. So, the presence of a genetic abnormality in 14q24 in our patient as in patients with Fanconi anaemia might lead to an abnormal expression of transforming growth factor β and hence to the suppression of haematopoiesis.
In conclusion, this uncommon finding suggests that an underlying primary SS can be found in the setting of ‘idiopathic’ AA. Morever, a high concentration of γ-δ TCR+ cells as well as genetic abnormalities in 14 q24 might have contributed to the occurrence of AA.
This study has been supported in part by a grant from Schering AG (Lys les Lannoy, France)
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