Antinuclear antibody (ANA)–positive thrombocytopenia: primary, but with a difference

To the editor:

In the recent Vicenza Consensus Conference,¹  2 clinical-immunologic entities have been considered when defining the criteria for differentiating “primary” from “secondary” forms of immune thrombocytopenias. However, although the thrombocytopenia associated with the presence of antiphospholipid antibodies is discussed at some length (obviously within the limits of a standardization conference), this is not so for ITP with antinuclear antibodies (ANA), which is even more complex and challenging.

There are 2 eras in the study and in the gradual elucidation of this intriguing clinical and immunologic entity. The first clinical era included the description of distinct histologic patterns in spleens resected from apparently idiopathic ITP patients who then went on to develop systemic lupus erythematosus (SLE).^2,3  At the same time there was a hot debate as to whether splenectomy for ITP could precipitate SLE,⁴  a hypothesis that was ultimately disproved.⁵  The second era is founded mainly on longitudinal studies of patients with ITP in which low-titered ANAs did not predict for the late development of SLE,⁶  but high-titer ANA, irrespective of subtype, did.^7,8  In a recent study Abbadi et al⁹  have found that a positive ANA test (no pattern specified) predicted for a poor response to initial steroid therapy in adults with ITP.⁹ 

There is no doubt that an isolated positive ANA test in low titers does not contradict the diagnosis of primary chronic ITP, even it there already appears to be a different response to corticotherapy. However, the condition may progress, step by step, along with the increasing amount of ANA and, of course, of other antibodies such as anti-ds DNA, anti-Sm and antinuclear ribonucleoprotein antibodies. In a landmark study, Arbuckle et al¹⁰  have found that in 115 of 130 patients with SLE (88%), at least one SLE autoantibody tested was present before the diagnosis (≤ 9.4 years earlier; mean, 3.3 years). In this clinical material ANAs appeared significantly earlier than the other, more “ominous” antibodies. Similarly, in an imprecise number of ANA-positive ITP patients, a progressive spreading of autoimmunity (“a crescendo of autoimmunity”¹⁰ ) may take place, from organ-specific to non–organ-specific antibodies.

In conclusion, the potential evolution from ITP to SLE depends on a galaxy of genetic and epigenetic factors that dictate the fate of any single case. However, the demonstration of varying degrees of steroid-refractoriness in the ANA-positive subgroup, together with long clinical and immunologic histories such as those that have been discussed warrant, in my opinion, a special consideration for this entity, which even at the stage of conventional “primariness” carries some degree of difference.