Cutaneous polyarteritis nodosa (PAN) is a rare form of polyarteritis involving the deep dermis and panniculus. It is characterized by livedo reticularis, nodules, and ulcerations in more severe disease (1, 2). The lower extremities are most commonly involved. Constitutional and musculoskeletal symptoms and polyneuropathy may be associated findings (2). Underlying systemic disorders may be seen with cutaneous PAN, although in the majority of cases, it occurs in isolation (2). Here we describe a case of cutaneous PAN occurring in a patient with natural killer (NK) cell lymphocytosis, an exceedingly unusual combination of two rare diseases.
A 61-year-old man presented with several months of progressive lacy discoloration involving both feet, which progressed to cover his entire lower extremities, buttocks, trunk, and lower arms. He also reported a long-standing burning sensation in his right foot, although otherwise, he had no additional symptoms.
His past medical history was remarkable for multiple malignancies, including 2 desmoid tumors, a malignant adenomatous polyp, a gastrointestinal stromal tumor, as well as renal cell carcinoma. These were all treated surgically; he had not received chemotherapy or radiation treatment. At the time of presentation to our clinic and up until the present, there had been no evidence of recurrent malignancy.
On examination, there was generalized livedo reticularis in the same distribution as was described in his history (Figure 1). There were no ulcerations, nodules, or ischemia of his digits. In his right foot, mild length-dependent changes and diminished pinprick sensation were detected by neurologic examination; however, weakness was not appreciated. The remainder of his physical examination was unremarkable.
Laboratory analysis showed a leukocytosis of 14,600 cells/dl with an absolute lymphocyte count of 8,900 cells/dl (normal range 900–2,900); hemoglobin level and platelet counts were normal. Inflammatory markers, renal function, liver studies, cryoglobulins, complement, antiphospholipid antibodies, antinuclear antibody, extractable nuclear antigen, and antineutrophil cytoplasmic antibodies (ANCAs) were negative. Hepatitis B and C and human immunodeficiency virus serologies were also normal. An antistreptolysin O titer was not obtained. To investigate the numbness in the right foot, an electromyogram sample was obtained, but it did not show evidence of a large fiber peripheral neuropathy. A skin biopsy of the patient's anterior thigh was performed and revealed findings consistent with cutaneous PAN (Figure 2).
In review of prior laboratory values, the presence of a leukocytosis dated back one year, which corresponded to one year after the patient's last resection of malignancy, a renal cell carcinoma. Given the presence and duration of leukocytosis, further workup was pursued. A peripheral blood smear revealed increased granular lymphocytes. Further characterization with peripheral blood flow cytometry showed a phenotypically abnormal NK cell population. Eighty-two percent of the lymphocyte population was comprised of NK cells that were phenotypically CD3−, CD16+, and CD56+. There was aberrantly uniform CD8 expression. In-depth immunophenotyping of the NK population revealed that the cells also expressed CD57, a cell surface adhesion molecule, and CD94, an activating receptor; there was loss of CD161, an activating receptor. The cells lacked expression of the killer cell immunoglobulin-like receptors (KIRs) CD158a, CD158b, and CD158e (p70). The restricted KIR expression pattern was suggestive of an NK cell clonal disorder. T cell gene rearrangement studies were negative for T cell clonal populations.
Initially, the patient was treated with oral prednisone at 40 mg daily; however, there was minimal response and his skin condition actually worsened with prednisone taper. He developed several painful and tender nodules on the lower extremities and methotrexate was added as a steroid-sparing therapy. This resulted in improvement of the tender nodules, although the livedo reticularis persisted. Repeat flow cytometry 2 months after the initiation of methotrexate showed persistence of the abnormal NK population.
Cutaneous PAN was first described in 1931 by Lindberg, who contrasted the disorder with systemic polyarteritis by its lack of visceral organ involvement (3). Infectious causes such as hepatitis B and streptococcal infections have been reported to occur with cutaneous PAN, as have other inflammatory conditions (4–6). Recently, criteria have been proposed for diagnosing minocycline-associated cutaneous PAN, which may occur with positive perinuclear ANCAs (7). Despite various associations, none have been consistent. In one retrospective review of cases, 60% of cutaneous PAN cases had no underlying medical condition (2).
NK cell lymphocytosis, also known as chronic NK cell leukemia or NK large granular lymphocyte lymphocytosis, is differentiated from aggressive, acute NK cell leukemia or lymphoma by its indolent nature (8, 9). Frequently, patients with the condition have no symptoms, although constitutional features, cytopenias, and peripheral neuropathy have been described (10). Small case series of patients with NK cell lymphocytosis have also included isolated reports of vasculitis occurring in these patients; other cutaneous findings have been peripheral T cell lymphoma and aphthous stomatitis (8, 10, 11). Cutaneous PAN in conjunction with NK cell lymphocytosis is exceedingly rare and has not been reported in the rheumatology literature. The temporal relationship of the 2 diagnoses in this patient strongly suggests a pathogenic link. Particular features of the patient's NK cell population also strengthen the case for an association with autoimmune manifestations.
Recently, there is increasing recognition that NK cells may play a role in autoimmunity. Beyond their innate functions of cytotoxicity and cytokine release, NK cells can influence downstream adaptive immune responses. NK cells may participate in autoimmune responses by modulating the function of dendritic cells and by promoting or inhibiting the activation of autoreactive T cells (12).
NK cells possess both activating and inhibitory receptors that recognize major histocompatibility complex (MHC) class I molecules. It is the balance of signals through these receptors that determines NK cell function. Normally, the triggering of KIR transduces a dominant inhibitory signal that blocks NK cell activation. On the other hand, loss of inhibition occurs and cytolytic activity is promoted when NK cells encounter non-healthy cells that have downregulated MHC class I molecules, such as tumor- or viral-infected cells. Both KIR and MHC class I genes are highly polymorphic, and it is suggested that particular combinations of these genes produce phenotypes that may be associated with a higher risk of autoimmunity as a result. Several studies have reported associations between KIR expression patterns and autoimmune diseases such as psoriatic arthritis, scleroderma, and rheumatoid arthritis (13). For example, some patients with rheumatoid vasculitis express activating KIR in the absence of opposing inhibitory KIR. This KIR pattern, in combination with particular HLA–C (the ligand for KIR) alleles, appears to predispose patients with rheumatoid arthritis to develop vascular inflammation (14). It is therefore plausible that in our patient, lack of inhibitory KIR expression (CD158a, CD158b, and CD158e) on the aberrant NK cell population led to unopposed NK cell activation and consequent vascular inflammation.
Treatment of cutaneous PAN and NK lymphocytosis is focused on control of inflammatory symptoms. Although the etiologies of both NK lymphocytosis and cutaneous PAN are poorly understood, the conditions have an indolent course with rare progression to their more aggressive counterparts: systemic polyarteritis nodosa and aggressive NK leukemia or lymphoma (2, 9). Because of their benign course, conservative therapeutic plans are often implemented, including nonsteroidal antiinflammatory drugs or prednisone for the treatment of inflammatory symptoms. Various immunosuppressive agents are also used if required (2, 10).
In conclusion, we have described a case of cutaneous PAN in a patient with NK cell lymphocytosis, an exceedingly rare combination of two uncommon diseases. The majority of cutaneous PAN cases have no underlying medical condition, and similarly, most cases of NK lymphocytosis have no or limited skin manifestations. Awareness of possible associated conditions, however, should be recalled when evaluating patients with livedo reticularis or cutaneous PAN. The diagnoses of cutaneous PAN and NK lymphocytosis as described in this case may be unrelated, but may also highlight a possible role of NK cells in the development of vascular inflammation.
Dr. Hoganson had full access to all of the data in the study and takes responsibility for the integrity of the data.
Acquisition of data. Hoganson, Weenig, Warrington.
Analysis and interpretation of data. Hoganson, Weenig, Warrington.