Moderate cytopenias in asymptomatic individuals: Is screening for autoimmune connective tissue diseases warranted?

CA Dasanu¹, C Do²,  
¹ Medical Oncology and Blood Disorders, LLP, Hartford, CT; Hematology-Oncology, St. Francis Hospital and Medical Center, Hartford, CT, USA
² Hematology-Oncology, St. Francis Hospital and Medical Center, Hartford, CT, USA

Correspondence Address:
C A Dasanu
Medical Oncology and Blood Disorders, LLP, Hartford, CT; Hematology-Oncology, St. Francis Hospital and Medical Center, Hartford, CT
USA

Full Text

Sir,

To date no clear-cut guidelines exist for the evaluation of asymptomatic patients presenting with pancytopenia or bicytopenia. Experts suggest evaluation for any evidence of peripheral destruction / consumption (e.g., drug-induced causes, hypersplenism, disseminated intravascular coagulation, etc.), if clinical suspicion exists. Furthermore, evaluation for central causes such as vitamin B12 / folate deficiency, various bone marrow failure syndromes, and lymphoproliferative conditions is also recommended.

We retrospectively analyzed a series of 35 consecutive patients with persistent pancytopenia or bicytopenia, referred in consultation to our tertiary center. All patients consented to the analysis in accordance with the Declaration of Helsinki. They underwent a detailed medical interview and routine physical examination. Further data was obtained from the medical records. A careful medication history was performed in all the patients. Of note, none of the patients had significant musculoarticular or other complaints. Leukopenia was mild-to-moderate (mean absolute neutrophil count, 1.4 ± 0.5 × 10 6 / mm 3 ) and no increased incidence of infections was present in any of our patients. No platelet aggregation / pseudothrombocytopenia or significant mucosal / cutaneous bleeding was documented in our cohort. The platelet counts were consistent with moderate thrombocytopenia (99 ± 21 × 10 6 / mm 3 ). When present, anemia was not severe (hemoglobin > 9.5 g/dl; erythrocyte count > 3 × 10 6 / mm 3 ). To identify the etiology of the cytopenias, the following workup was initially performed: basic chemistry panel, liver function testing, hepatitis C and B serologies, PT / PTT, fibrinogen, liver-spleen ultrasound, serum vitamin B12 / folic acid, and HIV testing. It also included the hemolytic anemia workup: haptoglobin, lactate dehydrogenase, reticulocyte count, and direct Coombs testing. In all patients, we screened for the presence of collagen vascular disorders, with antinuclear antibodies (ANAs), along with C3 and C4 complement testing. The ANA values were estimated via an immunofluorescence based method.

In eight out of 35 patients, we identified significantly elevated ANA titers (in excess of 1 : 80) with or without a decreased C3 complement level [Table 1]. The C4 was within normal range in all patients. None of the patients was taking any medications associated with drug-induced lupus. Subsequently, an autoimmune connective tissue disorder was diagnosed in seven out of eight patients. The diagnoses were confirmed either via specific antibody panels or clinically, as some patients subsequently became symptomatic. Four of them were diagnosed with systemic lupus erythematosus (SLE), two with mixed connective tissue disease (MCTD), and one with rheumatoid arthritis [Table 1]. The chart analysis showed that five of these patients originally presented with pancytopenia and two with bicytopenias (one with leukopenia-thrombocytopenia and another one with leukopenia-anemia). None of the seven patients with autoimmune connective tissue disease had lymphopenia, autoimmune hemolytic anemia (AIHA) or a positive Coombs test. {Table 1}

Cytopenias affect up to 40 - 50% of SLE and MCTD patients. [1] Hematological manifestations of SLE include leukopenia, lymphopenia, thrombocytopenia, and / or anemia. Cytopenias in SLE may be drug-induced, indicative of other hematological disease (such as myelofibrosis or myelodysplasia), or most commonly, immune-mediated. This is usually due to excessive antibody-mediated peripheral cell destruction, although antibodies against bone marrow precursors may also play a role. Even if the ANA is positive, the possibility of a non-immune cause for the cytopenia must always be considered. Thrombocytopenia is moderate, but can be severe. Thrombocytopenia in SLE is most commonly immune (SLE-ITP), but may also be related to the presence of the antiphospholipid antibody syndrome. Contrary to popular belief, the most common anemia in SLE is the anemia of chronic disease / inflammation, followed by anemia of renal disease. Although specific, AIHA is rare, as is microangiopathic hemolytic anemia. Of note, immune cytopenias may pre-date the diagnosis of SLE by several years. [2]

A positive ANA result alone is not sufficient for the diagnosis of SLE, because up to 20% of healthy young women may test positive. [3] Moreover, positive ANA results are seen in many other conditions, namely infections, drug use, and some malignancies. [4] Thus, confirmatory testing with specific antibodies and / or a referral to a rheumatologist may be necessary. [5] Leukopenia in autoimmune connective tissue disorders is usually mild and does not require treatment. It is thought to occur via an autoantibody mechanism leading to either immune complex formation or antibody/complement-dependent cellular cytotoxicity (ADCC or ACDCC). As a result, the C3 and / or C4 levels may be depressed in patients with active SLE, because of their consumption in immune complex-induced inflammation, clearance in the spleen or use in ACDCC. It should also be borne in mind that C4 tends to be less helpful due to the presence of null alleles, but in practice both C3 and C4 are usually measured together. A specific antibody testing should of course be arranged if the initial ANA is positive and there is sufficient clinical concern about the underlying systemic autoimmunity. The titer, and especially the pattern of the specific antibody testing, strongly enhance the ability to discriminate between ANA-positive healthy individuals and patients with autoimmune connective tissue disease. [6]

Given the findings in our patients, we believe that screening for an autoimmune connective tissue disease with serum ANA and C3 complement levels is warranted in the initial evaluation of patients presenting with asymptomatic pancytopenia or bicytopenia (especially when leukopenia is part of the picture). We believe these simple tests may prevent further, more expensive and / or invasive tests, such as, flow cytometry and / or bone marrow aspiration and biopsy. This testing may lead to an early diagnosis of a systemic inflammatory disorder, which is minimally symptomatic or in a subclinical state. [5],[6] We believe that bone marrow examination is only indicated if there is sufficient concern about an underlying primary hematological disease or in cases of more severe cytopenias. Sensitive yet not very specific, low C3 (and possibly C4) complement levels would point to the disease activity, especially in patients with SLE. [7] Therefore, early diagnosis and treatment of autoimmune connective tissue diseases leading to the resolution of cytopenias appears effective and not cost prohibitive.

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