Department of Internal Medicine, Hopital Huriez, Regional University Hospital, Lille and 1 Department of Immunology, Hotel Dieu, Nantes University Hospital, Nantes, France.
Correspondence to: H. Charlanne, Service de Médecine Interne, Hôpital Claude Huriez, CHRU Lille, 59037 Lille Cedex, France. E-mail: hilaire.charlanne{at}wanadoo.fr
SIR, Large granular lymphocytes (LGL) are a morphologically distinct lymphoid subset constituting 1015% of normal peripheral blood mononuclear cells. LGL leukaemia (LGLL) is a rare disorder characterized by the clonal proliferation of LGL [1] of either T cell (CD3+) or NK (CD3) lineage. CD3+ LGLL represents 85% of cases of LGLL and is often associated with neutropenia, various autoimmune disorders and biological immune abnormalities [2].
We report a patient with clonal proliferation of LGL who developed several autoimmune disorders, including systemic sclerosis (SSc), rheumatoid arthritis, secondary Sjögren's syndrome, uveitis and autoimmune neutropenia associated with an anti NB-1 antibody.
A 72-yr-old Caucasian woman was diagnosed in 1990 with rheumatoid arthritis according to ACR criteria: bilateral and symmetrical polyarthritis with hand erosions on X-ray and positivity for rheumatoid factor. After she had been diagnosed, antifilaggrin antibody was 2537.5 UA (normal <100 UA). She was treated with low-dose corticosteroids. She had a medical history of recurrent episodes of anterior uveitis, especially in the left eye, stabilized by topical therapy and prednisone introduced for arthritis.
She had a sicca syndrome which fulfilled the criteria for Sjögren's syndrome according to the revised version of the European criteria proposed by the AmericanEuropean Consensus Group: subjective xerostomia, subjective xerophthalmia, positive Schirmer's test, positivity for antinuclear antibody with a titre of 1:80 and a speckled pattern, and positive western blot for 52 kDa specificity evocative of anti-Ro/SSA antibody; biopsy of the minor salivary glands revealed an inflammatory infiltration of CD8+ T cells (Chisholm grade 3).
In 2002, SSc was suspected. CREST syndrome was diagnosed because of Raynaud's phenomenon, sclerodactyly, telangiectasia, microangiopathy on nailfold microscopy, pyrosis, and antinuclear antibody positivity with a titre of 1:5120, with an anticentromere pattern. She had no pulmonary hypertension.
A few months later, blood counts showed neutropenia without infectious complications. Neutrophil count was 500/mm3 and lymphocytosis was 5800/mm3. Haemoglobin, platelet count and lymphocyte size and cytology were normal but lymphocyte immunophenotyping showed LGL proliferation (CD3 93%, CD8 68%, CD57 31%, ß 92%). Spleen size was normal. Bone marrow examination and biopsy showed mild infiltration by normal lymphoid cells and a reduced granulocyte population. There was no evidence of lymphadenopathy on the chest and abdomen CT scan. Neither treatment nor infectious agents were found to explain this neutropenia. LGLL was confirmed by the clonal nature of the proliferation in the TCR gene rearrangement study.
Anti HNA-2a (anti NB-1) antibody was found in the patient's serum. Since her neutrophils reacted positively with a CD177 monoclonal antibody (anti NB-1), we concluded that it was an autoantibody.
Methotrexate was given orally at the single low dose of 7.5 mg per week. The lymphocyte count decreased to normal, SSc and rheumatism stabilized, and there was a durable improvement in the neutrophil count to >1000/mm3 from 6 months of treatment, with a follow-up of more than 1 yr.
The diagnosis of LGLL was established by demonstrating clonal proliferation of lymphocytes with the LGL phenotype, which allowed differentiation from reactive LGL proliferation. A normal lymphocyte size is not uncommon in LGLL [3].
LGLL with rheumatoid arthritis may often be difficult to distinguish from Felty's syndrome or may be misdiagnosed during the course of Felty's syndrome, which is defined as rheumatoid arthritis, splenomegaly and neutropenia. Thus, these two entities are considered to be part of the spectrum of the same disorder since no differences with regard to age, sex, response to methotrexate and frequency of infections are observed. Moreover, a DR4 haplotype, which our patient had, is extremely frequent in both entities and TCR clonality may be established in either of them [2].
Immune abnormalities, including positivity for rheumatoid factor and antinuclear antibody, frequently occur in LGLL. Clinical autoimmune manifestations are also reported, mainly rheumatoid arthritis but also Sjögren's syndrome [4], recurrent uveitis [5] or other autoimmune disorders.
Anti-FcRIII B antibody has already been reported in neutropenia associated with Sjögren's syndrome [6] but never anti NB-1, which has rarely been associated with autoimmune neutropenia. The significance of this antibody, which targets a glycosyl-phosphatidylinositol (GPI)-linked glycoprotein [7], and the mechanism of neutropenia remains unclear. This glycoprotein is expressed from the myelocyte to the adult stage in most cells of the neutrophil lineage. Central destruction by anti-NB1 antibodies in association with direct cytotoxicity of CD8+ T cells could explain both the neutropenia and the decreased granulocyte population [8, 9].
To our knowledge, SSc has never been described associated with LGLL. SSc usually begins during the fourth decade. Our patient was 72 yr old, suggesting a link between haematological and immunological disorders. Moreover, the salivary infiltration is predominantly CD4+ in Sjögren's syndrome, whereas it was CD8+ in our case, indicating the potential role of LGLL in sicca syndrome.
The association of multiple autoimmune disorders, including rheumatoid arthritis, with relative lymphocytosis is evocative of LGLL. Immunophenotyping of the peripheral lymphocytes in association with a study of the TCR clonality confirms a diagnosis of LGLL. Methotrexate treatment may occasionally lead to a complete haematological response with disappearance of the TCR clonality [10].
The authors have declared no conflicts of interest.
References